Interconsulta

de Nefrologia

Programa (não-oficial) do R1 de Clinica Médica

Teoria Básica

1) Lesão Renal Aguda (texto + artigo)

2) Emergências Dialíticas (texto + artigo)

3) Síndromes Glomerulares (artigo)

4) Acesso Vascular Guiado por Ultrassom (artigo)

5) Diagnósticos Diferenciais e Manejo das Hipercalemias (artigo)

6) Diagnósticos Diferenciais e Manejo das Hipercalcemias (artigo)

7) Síndromes Cardiorrenais (artigo)

8) Teste de Estresse com Furosemida (artigo)

9) Gasometria Arterial (artigo)

10) Tipos de Acesso Vascular (artigo)

11) Princípios de Hemodiálise (artigo)

Lucas Theotonio
 2

Teoria Básica
A idéia desse caderno não é de esgotar o assunto de forma alguma, mas sim dar um
norte para as discussões diárias.

1. Lesão Renal Aguda

a. Definição
Lesão renal aguda é definida pela KDIGO como:
• Aumento da Creatinina ≥ 0,3 mg/dL dentro de 48h; ou
• Aumento da Creatinina para ≥ 1,5 vezes a de base dentro de 7 dias; ou
• Débito urinário < 0,5 mL/kg/hora em um período de 6 horas.

Podemos ainda classificar a lesão renal aguda em 3 estágios diferentes,

progressivos em gravidade, conforme creatinina e débito urinário;

Estadio Creatinina Débito Urinário

1,5 a 1,9 x Creatinina de Base < 0,5 mL/kg/hora

1
Ou em 6 a 12 horas
Aumento ≥ 0,3 mg/dL
2,0 a 2,9 x Creatinina de Base < 0,5 mL/kg/hora
2
por mais de 12 horas
≥ 3 x Creatinina de Base < 0,3 mL/kg/hora
3
Ou por mais de 24 horas
Aumento da Creatinina para níveis ≥ 4,0 OU
mg/dL Anúria
Ou por mais de 12 horas
Necessidade de Terapia Renal Substitutiva

 Atualmente não utilizamos mais as antigas escalas AKIN e RIFLE para

classificar o quadro de lesão renal aguda.
 3

b. Creatinina
A creatinina é um bom marcador de função renal pela sua simplicidade e
ampla disponibilidade, porém está longe de ser o método ideal de
avaliação, podendo sofrer interferência em qualquer fase da sua síntese,
como exposto abaixo:

Deste esquema podemos inferior que:

• Pacientes sarcopênicos (pouca musculatura), como idosos e
desnutridos, podem apresentar níveis falsamente baixos de creatinina;
• Pacientes cirróticos também podem apresentar níveis falsamente baixos
de creatinina pois há menor síntese da Creatina, sua precursora.

c. Classificação cronológica
A alteração aguda da função renal ainda pode ser classificada quanto a
sua evolução em:
• Lesão Renal Aguda – se durar até 7 dias entre o início do quadro e
sua completa resolução
• Doença Renal aguda – se o quadro durar de 7 a 89 dias até sua
resolução.
 4

d. Investigação etiológica
Para fins didáticos, podemos dividir as causas de LRA em três
categorias, a saber:
• LRA pré-renal (desidratação/hipoperfusão)
• LRA pós-renal (obstrução de trato urinário, por exemplo HPB)
• LRA renal (glomerulopatias, nefrotóxicos, nefrite intersticial, etc)

Algumas dicas práticas para avaliação de cada uma das três

possibilidades:
• LRA pré-renal
o Avaliar grau de hidratação pelo exame de mucosas é válido,
porém pouco sensível para a real detecção de hipovolemia –
principalmente em idosos.
o Procure dados na história que possam te fazer pensar nesta
hipótese, como: diarréia, vômitos, exposição solar
prolongada, baixa ingesta alimentar/hídrica e uso de
diuréticos.
• LRA pós-renal
o Tanto homens quanto mulheres podem apresentar obstrução
do trato urinário, de diversas causas, as quais devem ser
devidamente excluídas com cateterismo vesical e exame de
imagem (a palpação de bexigoma é pouco sensível):
§ Obstrução baixa (uretra/bexiga): bexiga neurogênica,
hiperplasia prostática benigna, câncer de próstata,
câncer de reto, câncer de bexiga, câncer de colo
uterino, nefrolitíase bilateral, disfunção de assoalho
pélvico.
 5

• LRA renal
o Glomerulopatias
Síndrome Achados Clínicos Patologias
Alterações 1. GESF, Membranosa
1. Proteinúria Isolada
Urinárias 2. IgA, Alport,
2. Hematúria Isolada
Assintomáticas GNMP,DMBF
*Proteinúria > 3,0-3,5g
Em 24 horas
*Hipoalbuminemia
*Edema GESF, Membranosa,
Nefrótica
Pode ter: Doença de Lesão Mínina
Hipercoagulabilidade
Infecções de repetição
Desnutrição
* Hematúria dismórfica
*Hipertensão
GNDA (pós-
*Disfunção Renal
estreptocócica), GNMP
Nefrítica *Edema
(Lupus, nefropatia por
*Proteinúria
IgA, vasculite por IgA)
usualmente não
nefrótica
Síndrome Nefrítica com
Três grandes grupos:
perda rápida de função
1. por Imunocomplexos
GNRP renal (dias a semanas),
2. Relacionadas ao ANCA
caracterizada por
3. Anti-MBG
crescentes glomerulares
Doença renal crônica Qualquer glomerulopatia
GNC secundária a que evolua para doença
glomerulopatias renal crônica
GESF: Glomeruloesclerose Segmentar e Focal
GNMP: Glomerulonefrite Membranoproliferativa
DMBF: Doença da Membrana Basal Fina
GNDA: Glomerulonefrite Difusa Aguda
GNRP: Glomerulonefrite Rapidamente Progressiva
GNC: Glomerulonefrite Crônica
 Síndromes Relacionadas a LRA: Nefrótica, Nefrítica e GNRP.
 Exames complementares: Urina I, Frações do Complement0 (C3,
C4, C2, CH50), ANCA, FAN, Biópsia Renal.
 Suspeitar de glomerulopatias em pacientes com suposta infecção
urinária de repetição com urocultura sempre negativa.
 6

• LRA renal
o Nefrotóxicos
§ Diversos são os agentes nefrotóxicos. Em pacientes
internados, lembrar sempre dos principais
antimicrobianos com potencial nefrotóxico, a saber:
• Bactrim
• Polimixina
• Vancomicina
• Amicacina/Gentamicina
• Anfotericina B
• Aciclovir/Ganciclovir
• Piperacilina-Tazobactam (controverso)

o Nefrite Intersticial Aguda

§ Várias causas, dentre elas medicações e infecções;
§ Não há um período típicos de apresentação após a
exposição ao fator causal, podendo se apresentar de 3
a 5 dias após, ou até mesmo semanas a meses após;
§ A NIA relacionada a Rimfapicina, por exemplo, pode
se instalar em 24 horas;
§ Drogas: Beta-lactâmicos, Bactrim, Rimfampicina,
Furosemida, Ciprofloxacina, Alopurinol, IBPs
(Omeprazol por exemplo) e Claritromicina
§ Patógenos: Legionella spp., Leptospira spp., CMV e
Streptococcus spp.
§ Tríade clássica: rash cutâneo, febre e eosinofilia
§ Outros sintomas possíveis: dor lombar bilateral,
hematuria microscópica (podendo ser confundida com
nefrolitíase no pronto-socorro).
 7

2. Emergências Dialíticas

a. Princípios Gerais
• A hemodiálise de urgência é sempre do tipo intermitente (duração usual de
4 a 6 horas).
• Usualmente, não utilizamos a diálise peritoneal para tratamento de
emergências dialíticas.
• Sempre que pensar em caracterizar uma situação como emergência
dialítica, sempre tenha em mente a refratariedade a outros tratamentos
menos invasivos (por exemplo, hipercalemia refratária a furosemida, ou
hipercalemia em paciente anúrico)

b. As Emergências (AEIOU)

A (Acidose Metabólica): usualmente acidose metabólica não relacionada a cetonemia ou

hiperlactatemia.

• Usualmente consideramos emergência se Bic < 15 ou pH < 7,15, após outras medidas)
E (Eletrólitos): K+ > 5,0-5,5 mEq/L com repercussão no ECG ou K+ ≥ 6,5 refratário a medidas
clínicas que reduzam o pool (diuréticos) ou redistribuam definitivamente (corrigir acidose) o K+.

• Glico-insulina, B2 agonista e Gluconato de Cálcio são medidas temporárias.

I (Intoxicações exógenas): alguns drogas são dialisáveis, como por exemplo Lítio, Atenolol,
Metanol, Metformina, Acido Valpróico, Carbamazepina e Paracetamol.

• Os critérios para indicar TRS para cada uma das intoxicações fogem ao escopo desse guia.
As drogas em negrito são as que tem maior indicação.
O (Overload): sobrecarga de volume, principalmente edema agudo de pulmão ou IC
descompensada refratários a diuréticoterapia, ou com boa resposta porém com efeitos colaterais
importantes dos diuréticos (citados abaixo).

• Hiper/Hiponatremia, Hipocalemia, Alcalose Metabólica com BIC > 35 mEq/L

U (Uremia): coma urêmico, sangramento urêmico (TGI), pericardite/pleurite urêmica,
convulsão secundária a uremia

• Crise usualmente do tipo mioclônica – excluir outras causas como sangramento de SNC
 ARTIGO 1

LESÃO RENAL AGUDA

 Annals of Internal Medicine!

In the Clinic®

Acute Kidney Injury

A
cute kidney injury is a heterogeneous group
Screening and Prevention
of conditions characterized by a sudden de-
crease in glomerular filtration rate, mani-
fested by an increase in serum creatinine concentra-
tion or oliguria, and classified by stage and cause. Diagnosis
This type of injury occurs in approximately 20% of
hospitalized patients, with major complications in-
cluding volume overload, electrolyte disorders, ure- Treatment
mic complications, and drug toxicity. Management
includes specific treatments according to the under-
lying cause and supportive treatment to prevent and
manage complications. Kidney replacement therapy
is used when complications cannot be managed
with medical therapy alone. Despite advances in
care, the mortality rate in patients requiring kidney
replacement therapy remains approximately 50%.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC201711070

Andrew S. Levey, MD
Matthew T. James, MD
From Tufts Medical Center,
Boston, Massachusetts; and
the University of Calgary,
Calgary, Alberta.
CME Objective: To review current evidence for screening, prevention, diagnosis, and
treatment of acute kidney injury.
Funding Source: American College of Physicians.
Disclosures: Dr. Levey, ACP Contributing Author, reports that he was a member of the KDIGO
Workgroup for the Clinical Practice Guideline on Acute Kidney Injury (published 2012). Dr.
James, ACP Contributing Author, reports grants from Amgen Canada outside the submitted
work. Disclosures can also be viewed at www.acponline.org/authors/icmje
/ConflictOfInterestForms.do?msNum=M17-2010.
Acknowledgment: The authors thank Sara Couture, BS, and Bryan Ma for assistance with
manuscript preparation.
With the assistance of additional physician writers, the editors of Annals of Internal Medi-
cine develop In the Clinic using MKSAP and other resources of the American College of
Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical
guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.

© 2017 American College of Physicians

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1. Kellum JA, Lameire N,
Aspelin P. Kidney Disease:
Improving Global Out-
comes (KDIGO) Acute
Kidney Injury Work Group.
KDIGO clinical practice
guideline for acute kidney
injury. Kidney Interna-
tional Supplement 1s.
2012;2:1-138.
2. Mehta R, Bagga A, Pati-
bandla R, Chakravarthi R.
Detection and manage-
ment of AKI in the devel-
oping world: The 18th
Acute Disease Quality
Initiative (ADQI) Interna-
tional Consensus Confer-
ence. Kidney International
Reports. 2017;2:515-8.
3. Susantitaphong P, Cruz
DN, Cerda J, et al; Acute
Kidney Injury Advisory
Group of the American
Society of Nephrology.
World incidence of AKI: a
meta-analysis. Clin J Am
Soc Nephrol. 2013;8:
1482-93. [PMID:
23744003]
4. Wonnacott A, Meran S,
Amphlett B, Talabani B,
Phillips A. Epidemiology
and outcomes in
community-acquired ver-
sus hospital-acquired AKI.
Clin J Am Soc Nephrol.
2014;9:1007-14. [PMID:
24677557]
5. Wang Y, Wang J, Su T,
et al; ISN AKF 0by25
China Consortium.
Community-acquired
acute kidney injury: a
nationwide survey in
China. Am J Kidney Dis.
2017;69:647-657. [PMID:
28117208]
6. James MT, Hemmelgarn
BR, Wiebe N, et al; Alberta
Kidney Disease Network.
Glomerular filtration rate,
proteinuria, and the inci-
dence and consequences
of acute kidney injury: a
cohort study. Lancet.
2010;376:2096-103.
[PMID: 21094997]
7. Tsai TT, Patel UD, Chang
TI, et al. Validated contem-
porary risk model of acute
kidney injury in patients
undergoing percutaneous
coronary interventions:
insights from the National
Cardiovascular Data Regis-
try Cath-PCI Registry. J Am
Heart Assoc. 2014;3:
e001380. [PMID:
25516439]
8. Allen DW, Ma B, Leung
KC, et al. Risk prediction
models for contrast-
induced acute kidney
injury accompanying
cardiac catheterization:
systematic review and
meta-analysis. Can J Car-
diol. 2017;33:724-736.
[PMID: 28545621]
" 2017 American College of Physicians
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Acute kidney inj ry (AKI) is not a
single disease entity. It is a hetero-
geneous group of conditions char-
acterized by a sudden decrease in
glomerular filtration rate (GFR) fol-
lowed by an increase in serum cre-
atinine concentration (SCC) or oli-
guria. AKI generally occurs in the
setting of acute or chronic illness. It
affects approximately 20% of hos-
pitalized patients, of whom 10%
require kidney replacement ther-
apy (KRT). Recent clinical guide-
lines from Kidney Disease Improv-
ing Global Outcomes (KDIGO)
define AKI as a subgroup of acute
kidney diseases and disorders
(AKD), and classify AKI according
to severity (stages) and cause,
which influence prognosis and
management (1). Major complica-
tions include volume overload,
electrolyte disorders, uremic com-
plications, and drug toxicity. De-
spite advances in prevention and
treatment, the mortality in patients
requiring KRT remains approxi-
Screening and Prevention
Which patients are at increased
risk for AKI, and how should
clinicians identify them?
AKI generally occurs in the set-
ting of acute and chronic illness,
and is common among hospital-
ized patients.
A systematic review of large cohort studies, pri-
marily among hospitalized patients, con-
ducted between 2004 and 2012, showed sig-
nificant heterogeneity in estimates among
studies, countries, and clinical settings, and
between adults and children (3). In studies of
adults that identified AKI according to the
KDIGO criteria and staging system, the pooled
incidence rate of AKI was 21.6% (95% CI,
19.3%–24.1%). Approximately 10% required
dialysis. The highest pooled AKI rate was ob-
served in critical care settings (32%). In other
studies, among hospitalized patients approxi-
mately two thirds of AKI episodes were com-
munity-acquired—the remaining one third
were hospital-acquired (4, 5).
In 1 population-based study (6), the rate of adults
with AKI but not CKD who required hospital ad-
mission was 0.1% per year. Approximately 10%
ITC66 In the Clinic Annals of Internal Medicine
mately 50%. AKI may occur in pa-
tients with or without underlying
chronic kidney disease (CKD). In-
complete recovery may lead to
new onset or worsening of CKD.
Evaluation and management of
AKI proceed in parallel rather than
sequentially. The goals are to ap-
ply specific treatments according
to the underlying cause and pro-
vide supportive care to prevent
and treat complications. KRT is
used when complications of kid-
ney failure cannot be managed
with medical therapy alone. The
need for nephrologist consultation
or comanagement depends on
the stage, cause, and severity of
complications. This review focuses
on general features of AKI in adults
in developed countries, not includ-
ing pregnant women or kidney
transplant recipients. AKI is a more
serious problem in developing
countries due to risk factors re-
lated to underdevelopment and
lack of availability of KRT (2).
required dialysis. Rates were substantially higher
for patients with CKD. Decreased GFR and pro-
teinuria were independent risk factors. Adjusted
rate ratios were 2.5– 4.4 for patients with GFR
>60 mL/min/1.73 m2 (CKD stages 1–2); 2.3– 8.2
for GFR 45–59 mL/min/1.73 m2 (CKD stage 3a);
5.6 –13 for GFR 30-44 mL/min/1.73 m2 (CKD
stage 3b); and 13–19 for GFR 15–29 mL/min/
1.73 m2 (CKD stage 4).
The Box shows risk factors for AKI.
Acute illness, complications of medi-
cations, and medical procedures are
the most common. Older age and
preexisting CKD are the main sus-
ceptibility factors. Risk prediction
instruments are available for some
high-risk settings, such as percuta-
neous coronary intervention, cardiac
surgery, liver surgery, and vascular
surgery (7–11).
AKI is generally asymptomatic, so
screening is usually required for
detection. The U.S. Preventive Ser-
vices Task Force does not have
recommendations regarding
7 November 2017
 screening for AKI. KDIGO recom-
mends screening based on stratifi-
cation by risk according to expo-
sures and susceptibility. Because
there are few risk prediction instru-
ments, we suggest the following
approach guided by the clinical
setting. For outpatients with acute
illness, measure SCC and calculate
estimated GFR (eGFR) and com-
pare to previous (“baseline”) val-
ues (12). Remeasure if SCC or
eGFR are abnormal or worse than
previous values. The urgency of
repeated measurement depends
on the severity of illness and the
level of SCC and eGFR; hospital-
ization should be considered. For
hospitalized patients, SCC and
eGFR are generally measured on
admission and should be mea-
sured daily or every other day. For
patients with critical illness, SCC
and eGFR, as well as urine output,
should be measured at least daily.
In our experience, accurate mea-
surement of urine output is diffi-
cult, unless the patient is in an
intensive care unit (ICU). In all set-
tings, urinalysis should be done for
detection of AKD and CKD.
Increased SCC and oliguria may
not occur for several hours after
the onset of an acute decline in
GFR. Novel biomarkers are under
investigation to determine
whether they may enable earlier
detection of decreased GFR and
complications of AKI (13, 14).
Which measures are useful for
preventing AKI, and when
should they be used?
We recommend general measures
to reduce exposures and suscepti-
bility when possible—for example,
correcting volume depletion by
increasing oral salt and fluid intake
or intravenous (IV) isotonic saline.
Other examples are avoiding di-
uretics and angiotensin-converting
enzyme inhibitors (ACEIs) and
angiotensin-receptor blockers
(ARBs) during acute illness to pre-
vent volume depletion and hypo-
tension, and avoiding nephrotoxic
7 November 2017 Annals of Internal Medicine
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drugs in patients with CKD, such
as nonsteroidal anti-inflammatory
drugs (NSAIDs) and iodinated ra-
diocontrast media (contrast-
induced AKI) (15–17).
Risk for contrast-induced AKI
seems to be greater after arterial
than venous administration of
contrast media. For patients at
increased risk for this disorder,
KDIGO recommends using either
an iso-osmolal or a low-osmolal
medium (osmolality 2–3 times
that of plasma) rather than a
high-osmolal contrast medium
(osmolality >4 times that of
plasma). IV volume expansion
with either an isotonic sodium chlo-
ride or a sodium bicarbonate solu-
tion should be done rather than no
IV volume expansion. Several proto-
cols are available for intra-arterial
contrast administration, and these
can be used for high-risk patients
receiving IV contrast administration
(18–22). Tailoring administration to
left ventricular filling pressure can
safely facilitate more volume expan-
sion and reduce the incidence of
contrast-induced AKI during cardiac
catheterization (23, 24). A recent
comparative effectiveness review
compares other strategies for pre-
venting this complication (25, 26).
We also recommend volume ex-
pansion with isotonic sodium chlo-
ride for other high-risk conditions,
such as cardiac surgery; hemolysis;
rhabdomyolysis; tumor lysis; and
administration of cisplatinum, car-
boplatin, ifosphamide, and am-
photericin B. Caution is warranted
in patients with volume overload,
and IV fluids should be discontin-
ued if symptoms of volume over-
load develop (see below).
Monitoring therapeutic levels of
nephrotoxic drugs, such as van-
comycin, aminoglycosides, and
calcineurin inhibitors, can reduce
risk for AKI. KDIGO suggests ad-
ditional measures to reduce the
risk for nephrotoxicity of amino-
glycosides and amphotericin B.
In the Clinic ITC67
Risk Factors for Acute Kidney
Injury
Exposures
Critical illness
Sepsis
Circulatory shock
Burns
Trauma
Cardiac surgery (especially
with cardiopulmonary bypass)
Major noncardiac surgery
Nephrotoxic drugs
Iodinated radiocontrast
agents
Poisonous plants and animals
Susceptibility factors
Volume depletion
Older age
Female sex
Black race
Chronic kidney disease
Other chronic diseases
(heart, lung, liver)
Diabetes mellitus
Cancer
Anemia
From reference 1.
9. Wijeysundera DN, Kark-
outi K, Dupuis JY, et al.
Derivation and validation
of a simplified predictive
index for renal replace-
ment therapy after cardiac
surgery. JAMA. 2007;297:
1801-9. [PMID:
17456822]
10. Wilson T, Quan S,
Cheema K, et al. Risk
prediction models for
acute kidney injury fol-
lowing major noncardiac
surgery: systematic re-
view. Nephrol Dial Trans-
plant. 2016;31:231-40.
[PMID: 26705194]
11. Borthwick E, Ferguson A.
Perioperative acute kid-
ney injury: risk factors,
recognition, manage-
ment, and outcomes.
BMJ. 2010;341:c3365.
[PMID: 20603317]
" 2017 American College of Physicians
 Screening and Prevention... AKI generally occurs in the setting of
acute and chronic illness and is common among hospitalized patients.
Older age and CKD are the main susceptibility factors. Measurement of
SCC and eGFR and monitoring during hospitalization are essential to
detect AKI. Urine output should be monitored in patients with critical
illness. Urinalysis is helpful to detect AKD and CKD. General measures
to reduce risk include prevention and treatment of volume depletion
and avoidance of nephrotoxic drugs. IV isotonic fluids before, during,
and after intra-arterial administration of iodinated radiocontrast media
can reduce risk for contrast-induced AKI.

CLINICAL BOTTOM LINE

Diagnosis
What criteria should clinicians tion based on severity (stages)
use to define and classify AKI? and cause (Figure 2 ). KDIGO
AKI is a heterogeneous group of definition and staging are
conditions, with a common defi- based on the Risk, Injury, Fail-
nition (Figure 1 ) and classifica- ure, Loss, End-Stage Renal Dis-
ease (RIFLE) and AKI Network
(AKIN) criteria and studies on
Figure 1. Relationships and definitions of kidney diseases and disorders. risk relationships. The rationale
for defining AKI separately from
other acute kidney diseases and
disorders was to provide a
more rigorous basis for re-
search studies, clinical practice
guidelines, and public health
efforts.
AKD AKI CKD
The KDIGO definition of AKI in-
cludes a change in SCC within
2–7 days and oliguria for 6 or
more hours. The stage is defined
by the peak rise in SCC com-
pared with previous values and
nadir in urine output and is re-
Variable AKI AKD CKD NKD*
Duration Within 7 d ≤3 mo >3 mo lated to risk for complications
Functional Increase in serum AKI GFR <60 GFR ≥60 and prognosis (Figure 2 ). eGFR
criteria creatinine clearance OR mL/min/1.73 m2 mL/min/1.73 m2 is preferred to SCC for assessing
by ≥50% within 7 d GFR <60
OR mL/min/1.73 m 2 GFR in the steady state (i.e.,
Increase in serum OR when GFR is stable) because the
creatinine clearance Decrease in GFR by
by ≥0.3 mg/dL ≥35% times baseline
coefficients for age, sex, and race
within 2 d OR in the estimating equation take
OR Increase in serum into account variation in creati-
Oliguria for ≥6 h creatinine clearance by
≥50% times baseline nine generation by muscle, inde-
Structural Not defined Marker of kidney Marker of kidney No marker of pendent of GFR (12). A 1.5-, 2.0-,
criteria damage damage for >3 mo kidney damage and 3.0-fold increase in SCC dur-
(albuminuria, (albuminuria is most
hematuria, or pyuria common)
ing steady-state conditions re-
is most common) flect a 39%, 57%, and 74% de-
crease in eGFR, respectively.
AKI = acute kidney injury; AKD = acute kidney diseases and disorders; CKD = chronic kidney However, during AKI, SCC may
disease; GFR = glomerular filtration rate; NKD = no kidney disease. be in the nonsteady state, so
* Implies no functional or structural criteria according to the definitions for AKI, AKD, or CKD.
Clinical judgment required for individual patient decision making. changes in SCC and eGFR lag

" 2017 American College of Physicians ITC68 In the Clinic Annals of Internal Medicine 7 November 2017

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 Figure 2. Overview of acute kidney injury.

At Risk Complications
Older age, comorbid conditions, CKD (decreased GFR, albuminuria) Volume overload
Electrolyte disorders
Stage 1 (hyperkalemia, metabolic acidosis,
Serum creatinine: 1.5–1.9 times baseline, or ≥0.3 mg/dL increase, or hyponatremia and hypernatremia,
KDIGO Staging and

urine output: <0.5 mL/kg/h for 6–12 h hypocalcemia and hypercalcemia,

Complications

hyperphosphatemia, hypermagnesemia)
Stage 2
Uremic complications
Serum creatinine: 2.0–2.9 times baseline, or urine output: <0.5 mL/kg/h for ≥12 h
(encephalopathy, pericarditis, pruritus, bleeding)
Stage 3 Drug toxicity
Initiation or renal replacement therapy, or serum creatinine: 3.0 times baseline, or
≥4.0 mg/dL, or urine output: <0.3 mL/kg/h for ≥24 h, or anuria for ≥12 h

Decreased Kidney Obstruction of the Urinary Parenchymal Kidney ATN

Perfusion Tract Diseases Other Than ATN
Causes
Causes Causes Causes Toxic ATN; ischemic ATN
Volume depletion; heart, Obstructive nephropathy Acute glomerulonephritis;
Causes, Clinical Setting and

lung, or liver disease; acute interstitial nephritis; Clinical Setting

Urinary Tract Findings

sepsis; increased intra-
abdominal pressure; renal
artery stenosis; NSAID
toxicity
Clinical Setting
Signs of volume depletion
or overload; SIRS; severe
hypertension
Urinary Tract Findings
Concentrated urine; no
RTE cells or casts
Clinical Setting
Urinary tract symptoms;
history of urolithiasis,
genitourinary tract neoplasia,
or retroperitoneal disease
Urinary Tract Findings
Hydronephrosis; relief with
urinary catheter
pyelonephritis; thrombotic
microangiopathy; cast neph-
ropathy; infarction;
atheroembolism
Clinical Setting
Systemic diseases;
microangiopathic hemolysis
Urinary Tract Findings
Hematuria with RBC casts;
pyuria with WBC casts; RTE
cells
Circulatory shock; sepsis;
drug exposure; transient
hypotension; hemolysis;
rhabdomyolysis; tumor lysis
Urinary Tract Findings
Urine not concentrated
urine; RTE cells; granular
casts

Prevention Strategies Nephrologist

Intravenous fluid volume expansion, nephrotoxic medication avoidance, minimization Consultation and Comanagement
of radiocontrast media, hemodynamic monitoring and management Uncertainty about diagnosis
Management

Uncertainty about cause

Early-Stage Management Treatment of parenchymal diseases
Specific therapies and interventions that are dependent on the cause of acute kidney injury. Need for kidney replacement therapy
Intravenous fluid volume resuscitation, vasopressors, therapeutic drug level monitoring,
and adjustment of medication dosing Kidney Replacement Therapy
Volume overload, electrolyte disorders, uremic
Late-Stage Management complications (refractory to medical management)
Supportive care (maintenance of nutrition, electrolyte, and volume balance) and
assessment for complications requiring kidney replacement therapy

ATN = acute tubular necrosis; CKD = chronic kidney disease; GFR = glomerular filtration rate; NSAID = nonsteroidal anti-inflammatory drug;
RBC = red blood cell; RTE = renal tubular epithelial; SIRS = systemic inflammatory response syndrome; WBC = white blood cell.

12. Levey AS, Becker C, Inker

LA. Glomerular filtration
behind changes in GFR, and than 1 cause. Identifying causes rate and albuminuria for
detection and staging of
eGFR may be a less accurate esti- other than ATN is important be- acute and chronic kidney
mate of measured GFR. None- cause specific treatment of other disease in adults: a sys-
tematic review. JAMA.
theless, reporting eGFR in AKI causes can reverse the decline in 2015;313:837-46.
may be useful because changes GFR, whereas treatment for ATN [PMID: 25710660]
13. Kimmel M, Shi J, Latus J,
in eGFR show the direction and is supportive. The Box discusses et al. Association of renal
stress/damage and filtra-
estimate the magnitude of features that distinguish de- tion biomarkers with
changes in GFR. creased kidney perfusion from subsequent AKI during
hospitalization among
ATN. patients presenting to
The causes of AKI, which are cat- the emergency depart-
egorized according to underlying Complications of AKI result from ment. Clin J Am Soc
Nephrol. 2016;11:938-
pathophysiology, are decreased impaired excretory, endocrine, 46. [PMID: 27026519]
14. Perazella MA, Coca SG.
kidney perfusion, obstruction of and metabolic kidney functions. Traditional urinary bio-
the urinary tract, parenchymal Decreased GFR and tubular func- markers in the assess-
ment of hospital-
kidney diseases other than acute tion lead to retained water and acquired AKI. Clin J Am
tubular necrosis (ATN), and ATN solutes, manifested by volume Soc Nephrol. 2012;7:
167-74. [PMID:
(Figure 2 ). AKI often has more overload, hyperkalemia, high an- 22096038]

7 November 2017 Annals of Internal Medicine In the Clinic ITC69 " 2017 American College of Physicians

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Features Distinguishing
Decreased Kidney Perfusion
From ATN
Extracellular fluid volume depletion
or circulatory disorders
associated with volume
expansion are common in
decreased kidney perfusion,
whereas recent exposure to
radiographic contrast or
nephrotoxic drugs or
hypotension is more prominent
in ATN.
Decreased kidney perfusion
improves rapidly after
measures to increase kidney
perfusion (e.g., intravenous
fluid in volume depletion), but
no such response is observed
in ATN.
Decreased kidney perfusion usually
has concentrated urine and no
RTE cells or granular casts in
urine; ATN usually has
nonconcentrated urine, RTE
cells, and granular casts.
ATN = acute tubular necrosis;
RTE = renal tubular epithelial.
15. Huerta C, Castellsague J,
Varas-Lorenzo C, Garcı́a
Rodrı́guez LA. Nonsteroi-
dal anti-inflammatory
drugs and risk of ARF in
the general population.
Am J Kidney Dis. 2005;
45:531-9. [PMID:
15754275]
16. Lapi F, Azoulay L, Yin H,
Nessim SJ, Suissa S.
Concurrent use of diuret-
ics, angiotensin convert-
ing enzyme inhibitors,
and angiotensin receptor
blockers with non-
steroidal anti-
inflammatory drugs and
risk of acute kidney in-
jury: nested case-control
study. BMJ. 2013;346:
e8525. [PMID:
23299844]
17. Dreischulte T, Morales
DR, Bell S, Guthrie B.
Combined use of non-
steroidal anti-
inflammatory drugs with
diuretics and/or renin-
angiotensin system in-
hibitors in the commu-
nity increases the risk of
acute kidney injury.
Kidney Int. 2015;88:
396-403. [PMID:
25874600]
18. Trivedi HS, Moore H,
Nasr S, et al. A random-
ized prospective trial to
assess the role of saline
hydration on the devel-
opment of contrast neph-
rotoxicity. Nephron Clin
Pract. 2003;93:C29-34.
[PMID: 12411756]
" 2017 American College of Physicians
Downloaded From: https://annals.org/ by a Scott Memorial Library User on 12/03/2017
ion gap metabolic acidosis, hy-
ponatremia, hyperphosphatemia,
hypermagnesemia, encephalop-
athy, pericarditis, pruritus, and
bleeding due to platelet dysfunc-
tion. Deficiencies of erythropoie-
tin and decreased synthesis of
active vitamin D lead to anemia
and hypocalcemia. During recov-
ery from AKI, persistent impair-
ment in tubular function despite
increasing GFR may give rise to
excessive water and solute loss,
leading to volume depletion, hy-
pernatremia, hypokalemia, non–
anion gap metabolic acidosis,
hypophosphatemia, hypomag-
nesemia, and hypercalcemia in
some cases. Drug toxicity is com-
mon because of altered pharma-
cokinetics and pharmacodynam-
ics. Complications may occur in
other organ systems throughout
the course of disease; multiple
organ failure is associated with
the highest mortality.
What clinical manifestations
should clinicians look for?
AKI is generally asymptomatic
until the onset of kidney failure,
emphasizing the importance of
monitoring SCC and eGFR and
urine output in patients at in-
creased risk. However, clinical
manifestations are useful to de-
termine the cause of AKI and de-
tect its complications. After de-
tection, whether rapid evaluation
is necessary depends on the clin-
ical setting and severity of AKI.
We recommend a combined di-
agnostic and therapeutic ap-
proach (see the Box). If AKI is
severe, treatment must begin
concurrently with evaluation.
Evaluating Causes
Decreased kidney perfusion is
the most common cause of
community-acquired AKI, whereas
ATN is the most common cause of
hospital-acquired AKI.
Causes of community-acquired AKI were de-
scribed in a large survey of hospital discharges
in China. Of 4136 patients, 49% of AKI cases
ITC70 In the Clinic
were due to decreased kidney perfusion, 12%
were due to obstruction, 27% had “intrinsic
kidney diseases” (parenchymal diseases, in-
cluding ATN), and 12% were not classified (5).
Causes of hospital-acquired AKI in patients
were described in patients admitted to general
medical or surgical services of an urban teach-
ing hospital. Of 380 episodes, 39% were due
to decreased kidney perfusion, 2% to obstruc-
tion, 3% to parenchymal kidney diseases other
than ATN, and 55% to causes associated with
ATN; 3% were not classified (27).
Decreased kidney perfusion de-
creases GFR and increases tubu-
lar reabsorption of sodium, chlo-
ride, urea, and water, leading to
urine concentration. Volume de-
pletion as the cause of decreased
kidney perfusion should be con-
sidered in patients with a history
of decreased oral intake, vomit-
ing, diarrhea, increased ostomy
output, excessive sweating, per-
cutaneous fluid drainage, bleed-
ing, dizziness, light-headedness,
fainting, or recent weight loss,
especially in the setting of dietary
Combined Diagnostic and
Therapeutic Approach to AKI
Assess volume status; administer
intravenous fluid if volume
depleted or volume status is
uncertain
Assess for indications for urgent
kidney replacement therapy
(volume overload, uremic
complications, electrolyte
disorders, drug toxicity)
Conduct urine studies
Consider additional laboratory
tests and imaging
In all cases, thoroughly review the
history of present illness,
medical history, medications
and exposure to radiocontrast
media, recent surgery and
other procedures, recent travel
or exposure to infectious
diseases, fluid intake and
output, and laboratory tests and
imaging and conduct a careful
physical examination. In
particular, assessment for
complications should be done
promptly to determine the
need for urgent therapy.
AKI = acute kidney injury.
Annals of Internal Medicine 7 November 2017
 salt restriction or diuretic therapy.
Increased GFR within hours of
volume repletion with oral or IV
fluids confirms the diagnosis. De-
creased kidney perfusion due to
exacerbations of chronic heart,
lung, or liver disease manifests as
weight gain and edema (car-
diorenal and hepatorenal syn-
dromes), often with low blood
pressure. Sepsis may also be as-
sociated with low blood pressure
and other features of the sys-
temic inflammatory response
syndrome. Intra-abdominal pres-
sure may increase in critically ill
patients with abdominal or pelvic
disorders (trauma, hemoperito-
neum, pancreatitis, surgery, ra-
diologic procedures) or in condi-
tions that do not originate in that
region (fluid resuscitation, sepsis,
burns). Bilateral renal artery ste-
nosis may occur in patients with
aortic aneurysm or diffuse ath-
erosclerotic cardiovascular dis-
ease and causes severe hyper-
tension. Use of NSAIDs can
decrease kidney perfusion, even
without volume or blood pres-
sure abnormalities. ACEIs and
ARBs reduce GFR in patients with
acute and chronic kidney disease
and may cause severe AKI in the
setting of decreased kidney
perfusion.
Obstruction of both kidneys or
obstruction of a solitary kidney
may cause AKI. Obstruction may
be acute or chronic, complete or
partial, due to upper or lower
urinary tract disease, and due to
lesions within or outside the uri-
nary tract. Flank pain or a history
of urolithiasis, genitourinary tract
neoplasia, or retroperitoneal dis-
ease should raise suspicion for
obstruction (28). Symptoms of
lower urinary tract disease in-
clude dysuria, suprapubic pain,
slow urine stream, and increased
frequency of urination. Bladder
distention may be detectable by
physical examination. Gross he-
maturia (with blood clots) sug-
7 November 2017 Annals of Internal Medicine
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gests lesions in the urinary tract.
Complete obstruction causes
anuria, but partial obstruction may
cause polyuria due to impairment
of tubular function. Immediate im-
provement in GFR is expected af-
ter relief of acute obstruction, but
improvement after relief of chronic
obstruction may be slow or
incomplete.
Parenchymal kidney diseases
other than ATN are frequent
causes of AKI. Many of these
diseases occur in the setting of
systemic disorders (infections;
vasculitis; inflammatory, my-
eloproliferative, or lymphoprolif-
erative diseases; or drug toxicity)
and may be associated with fe-
ver, night sweats, arthralgias,
mononeuropathy, or skin rash.
Glomerulonephritis may cause
gross hematuria (without clots).
Acute interstitial nephritis is gen-
erally due to an allergic or toxic
drug reaction (see the Box). Bac-
terial pyelonephritis must be se-
vere and bilateral to cause AKI
and often causes flank pain with
high fever. Urinary symptoms are
prominent when pyelonephritis is
caused by ascending infection
from the lower urinary tract but
may be absent in the presence of
hematogeneous dissemination of
bacteremia. Thrombotic microan-
giopathy is accompanied by mir-
coangiopathic hemolysis and
thrombocytopenia with schisto-
cytes. Cast nephropathy in my-
eloma is typically associated with
a high tumor burden and large
amounts of paraprotein in the
urine and frequently with hyper-
calcemia. Renal infarction is asso-
ciated with flank pain and abrupt
onset of severe hypertension.
Atheroembolism may occur af-
ter percutaneous intra-arterial
procedures or surgery involving
the aorta or initiation of
anticoagulation.
The pathology of ATN is charac-
terized by necrosis of tubular
epithelial cells diffusely or local-
In the Clinic
Drugs That Contribute to
Acute Kidney Injury and the
Pathophysiologic Mechanism
of Injury*
Iodinated radiocontrast media
(acute tubular necrosis)
Nonsteroidal anti-inflammatory
drugs (decreased kidney
perfusion and tubular
toxicity)
Aminoglycosides (acute tubular
necrosis)
Amphotericin B (acute tubular
necrosis)
!-Lactam antibiotics (interstitial
nephritis)
Sulfonamides (interstitial
nephrtitis)
Vancomycin (acute tubular
necrosis)
Acyclovir (crystal nephropathy)
Tenofovir (tubular toxicity)
Methotrexate (crystal
nephropathy)
Cisplatinum and carboplatin
(acute tubular necrosis)
Ifosphamide (acute tubular
necrosis)
Vascular endothelial growth factor
inhibitors (thrombotic
microangiopathy)
Calcineurin inhibitors (e.g.,
cyclosporine, tacrolimus)
(decreased kidney perfusion
and tubular toxicity)
Herbal and dietary supplements
(e.g., aristolochic acid;
creatine; vitamins A, C, and
D; germanium; star fruit)
(interstitial nephritis)
Proton-pump inhibitors (interstitial
nephritis)
Angiotensin-converting enzyme
inhibitors, angiotensin-receptor
blockers, direct renin inhibitors
(decreased kidney perfusion)
* Many drugs have several
pathyphysiologic
mechanisms.
19. Taylor AJ, Hotchkiss D,
Morse RW, McCabe J.
PREPARED: Preparation
for Angiography in Renal
Dysfunction: a random-
ized trial of inpatient vs
outpatient hydration
protocols for cardiac
catheterization in mild-
to-moderate renal dys-
function. Chest. 1998;
114:1570-4. [PMID:
9872190]
ITC71 " 2017 American College of Physicians

20. Mueller C, Buerkle G,
Buettner HJ, et al. Pre-
vention of contrast
media-associated ne-
phropathy: randomized
comparison of 2 hydra-
tion regimens in 1620
patients undergoing
coronary angioplasty.
Arch Intern Med. 2002;
162:329-36. [PMID:
11822926]
21. Krasuski RA, Beard BM,
Geoghagan JD, Thomp-
son CM, Guidera SA.
Optimal timing of hydra-
tion to erase contrast-
associated nephropathy:
the OTHER CAN study. J
Invasive Cardiol. 2003;
15:699-702. [PMID:
14660821]
22. Bader BD, Berger ED,
Heede MB, et al. What is
the best hydration regi-
men to prevent contrast
media-induced nephro-
toxicity? Clin Nephrol.
2004;62:1-7. [PMID:
15267006]
23. Brar SS, Aharonian V,
Mansukhani P, et al.
Haemodynamic-guided
fluid administration for
the prevention of
contrast-induced acute
kidney injury: the POSEI-
DON randomised con-
trolled trial. Lancet.
2014;383:1814-23.
[PMID: 24856027]
24. Qian G, Fu Z, Guo J, Cao
F, Chen Y. Prevention of
contrast-induced ne-
phropathy by central
venous pressure-guided
fluid administration in
chronic kidney disease
and congestive heart
failure patients. JACC
Cardiovasc Interv. 2016;
9:89-96. [PMID:
26685074]
25. Subramaniam RM,
Suarez-Cuervo C, Wilson
RF, et al. Effectiveness of
prevention strategies for
contrast-induced ne-
phropathy: a systematic
review and meta-
analysis. Ann Intern
Med. 2016;164:406-16.
[PMID: 26830221]
26. Eng J, Wilson RF, Subra-
maniam RM, et al. Com-
parative effect of contrast
media type on the inci-
dence of contrast-
induced nephropathy: a
systematic review and
meta-analysis. Ann Intern
Med. 2016;164:417-24.
[PMID: 26830055]
27. Nash K, Hafeez A, Hou S.
Hospital-acquired renal
insufficiency. Am J Kid-
ney Dis. 2002;39:930-6.
[PMID: 11979336]
28. Licurse A, Kim MC, Dz-
iura J, et al. Renal ultra-
sonography in the evalu-
ation of acute kidney
injury: developing a risk
stratification framework.
Arch Intern Med. 2010;
170:1900-7. [PMID:
21098348]
" 2017 American College of Physicians
Downloaded From: https://annals.org/ by a Scott Memorial Library User on 12/03/2017
ized to nephron segments, with-
out involvement of the glomeruli,
accompanied by variable intersti-
tial inflammation. However, clini-
cal pathologic correlations are
imprecise, and renal biopsy is
rarely done in AKI. As a result,
the diagnosis of ATN in AKI is
generally presumed in patients
with a typical clinical history and
urinary tract findings (as de-
scribed below) after exclusion of
other causes of AKI. Despite this
uncertainty, we will retain use of
the term ATN as a cause of AKI
because it remains a useful clini-
cal concept in diagnosis and
treatment. Circulatory shock and
sepsis are the most common
causes of ATN. Other common
causes include recent exposure to
nephrotoxic drugs (see the Box) or
radiocontrast media, transient hy-
potension after surgery or a proce-
dure, and rapid cell necrosis (he-
molysis, rhabdomyolysis, and
tumor lysis). Pigment-associated
ATN may cause urine discolor-
ation. Tumor lysis can occur before
or after chemotherapy.
It is essential to review the history
and medical record to determine
whether the patient has had CKD
or past episodes of AKD. Com-
parison of current values of SCC
and eGFR to previous levels is
helpful for early detection of AKI.
Past urinalyses, measures of albu-
minuria (albumin-to-creatinine
ratio, protein-to-creatinine ratio),
and imaging studies of the kid-
neys (abdominal ultrasonogra-
phy, computed tomography,
magnetic resonance imaging,
and angiography) may also be
used. AKI superimposed on CKD
may be due to an exacerbation
of the underlying disease, which
is common in chronic diseases
causing decreased kidney perfu-
sion, or onset of a new condition.
A history of AKD may provide a
clue to the cause of a current epi-
sode, such as a flare of autoim-
mune disease or nephrotoxicity
ITC72 In the Clinic
of intermittently administered
medication.
Evaluating Complications
Irrespective of cause, the stage
(severity) of AKI is related to the
risk for complications.
The frequency of AKI-related complications was
studied in 18 410 patients in ICUs in 4 hospitals
(29). The risk for volume overload increased
from 41% in patients without AKI to 58% for
stage 1, 77% for stage 2, and 83% for stage
3 AKI. Other comparisons found respective
increases in hyperkalemia from 3% to 9%,
17%, and 32%; in metabolic acidosis from
59% to 74%, 86%, and 91%; in hyponatre-
mia from 19% to 30%, 46%, and 60%; and
azotemia (blood urea nitrogen >60 mg/dL)
from 1% to 10%, 20%, and 49%.
Physical examination can detect
volume overload (dyspnea, jugu-
lar venous distention, rales, as-
cites, lower extremity edema),
uremic encephalopathy (leth-
argy, asterixis, hyperreflexia, and
myoclonus), and pericarditis
(pericardial friction rub), which
require urgent therapy. Detec-
tion of other complications re-
quires laboratory testing.
What laboratory tests and
imaging should clinicians use?
The need for laboratory tests and
imaging depends on the clinical
setting. No further evaluation
may be necessary for outpatients
with AKI and decreased kidney
perfusion due to volume deple-
tion and rapid resolution of AKI
after oral or IV volume repletion.
If volume status is not clear, we rec-
ommend an early therapeutic trial of
withholding diuretics and adminis-
tering an IV fluid bolus of 500 mL
isotonic saline over 4–6 hours with
assessment of volume status, urine
output, and SCC and eGFR within
8–12 hours. Improved urine output,
SCC, and eGFR suggests AKI due to
volume depletion, whereas no im-
provement suggests some other
cause.
In patients with AKI from some
other cause, urine appearance,
dipstick, sediment, and chemis-
Annals of Internal Medicine 7 November 2017
 tries (osmolality, sodium, urea
nitrogen, creatinine, albumin,
and total protein) must be as-
sessed to ascertain concentra-
tion; albuminuria and total pro-
teinuria; and the presence or
absence of hematuria, pyuria,
renal tubular epithelial cells, and
granular and cellular casts (Ap-
pendix Table 1 , available at
Annals.org). If obstruction is sus-
pected, ultrasonography of the
kidneys is warranted, with a
postvoiding image of the blad-
der if symptoms occur during
urination (Appendix Table 1 )
(28). We generally obtain a urine
culture, since urinary tract infec-
tion can be a cause of AKI (pye-
lonephritis or ATN associated
with sepsis) or may complicate
other causes. Additional tests
are required to assess complica-
tions, systemic diseases or dis-
eases in other organ systems,
and hemodynamic status in criti-
cally ill patients.
Tests of urine concentration were
initially proposed for the evalua-
tion of oliguric AKI to distinguish
decreased kidney perfusion from
ATN (14, 30). They are also useful
in nonoliguric AKI due to these
and other causes. The glomerular
filtrate is isotonic with plasma; con-
centration of the urine requires in-
tact tubular function. Concentration
of the urine in the setting of AKI indi-
cates decreased kidney perfusion
and preserved tubular function. Ab-
sence of urine concentration indi-
cates impaired tubular function. The
fractional excretion of sodium and
urea (FENa and FEurea) can be
computed easily from simultaneous
serum and spot urine samples (Ap-
pendix Table 1 ). Diuretic therapy
impairs sodium reabsorption more
than urea reabsorption, so a low
FEurea may be a more reliable test
for distinguishing decreased kidney
perfusion from ATN than a low
FENa in patients with recent diuretic
therapy. Exacerbations of heart,
lung, or liver disease may be associ-
7 November 2017 Annals of Internal Medicine
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ated with preserved urine concen-
tration, despite the presence of
urine sediment findings suggestive
of ATN.
Tests for albumin rather than to-
tal protein are preferred for eval-
uation of kidney disease in adults
(12), but both may be helpful in
the evaluation of AKI. Loss of al-
bumin in the urine is a marker of
glomerular damage and occurs
in most parenchymal kidney dis-
eases other than ATN. Total pro-
teinuria in the absence of albu-
minuria is a marker of increased
production or impaired tubular
reabsorption of low-molecular-
weight serum proteins (light-
chain proteinuria or tubular pro-
teinuria, respectively). The urine
dipstick is more sensitive to albu-
min than other serum proteins;
the albumin-to-creatinine ratio
and protein-to-creatinine ratio
provide a quantitative assess-
ment, but urine creatinine excre-
tion decreases when SCC in-
creases, which may cause a
falsely elevated albumin-to-
creatinine or protein-to-
creatinine ratio.
Red blood cells and white blood
cells may be detected in unspun
urine with a dipstick (heme or
leukocyte esterase reagent pads,
respectively) and quantified with
a manual or automated cell coun-
ter. We do not recommend rou-
tine testing for urine eosinophils
(31). Detection of renal tubular
epithelial cells and granular and
cellular casts requires micro-
scopic examination of urine sedi-
ment. Increased red or white
blood cells in the urine indicates
a urinary tract lesion, but the
presence of renal tubular epithe-
lial cells or granular or cellular
casts in the sediment localizes
the lesion to the kidney. The di-
agnostic accuracy of these find-
ings has not been well-studied
(32, 33). Our interpretation is that
the presence of renal tubular epi-
thelial cells and granular and cel-
In the Clinic
29. Libório AB, Leite TT,
Neves FM, Teles F, Be-
zerra CT. AKI complica-
tions in critically ill pa-
tients: association with
mortality rates and RRT.
Clin J Am Soc Nephrol.
2015;10:21-8. [PMID:
25376761]
30. Miller TR, Anderson RJ,
Linas SL, et al. Urinary
diagnostic indices in
acute renal failure: a
prospective study. Ann
Intern Med. 1978;89:47-
50. [PMID: 666184]
31. Muriithi AK, Nasr SH,
Leung N. Utility of urine
eosinophils in the diag-
nosis of acute interstitial
nephritis. Clin J Am Soc
Nephrol. 2013;8:1857-
62. [PMID: 24052222]
32. Wald R, Bell CM, Nisen-
baum R, et al. Interob-
server reliability of urine
sediment interpretation.
Clin J Am Soc Nephrol.
2009;4:567-71. [PMID:
19261816]
33. Perazella MA, Coca SG,
Kanbay M, Brewster UC,
Parikh CR. Diagnostic
value of urine micros-
copy for differential diag-
nosis of acute kidney
injury in hospitalized
patients. Clin J Am Soc
Nephrol. 2008;3:1615-9.
[PMID: 18784207]
34. Chawla LS, Bellomo R,
Bihorac A, et al; Acute
Disease Quality Initiative
Workgroup 16. Acute
kidney disease and renal
recovery: consensus
report of the Acute Dis-
ease Quality Initiative
(ADQI) 16 Workgroup.
Nat Rev Nephrol. 2017;
13:241-257. [PMID:
28239173]
35. Bellomo R, Vaara ST,
Kellum JA. How to im-
prove the care of patients
with acute kidney injury
[Editorial]. Intensive Care
Med. 2017;43:727-729.
[PMID: 28600756]
36. Davenport A, Anker SD,
Mebazaa A, et al; Acute
Dialysis Quality Initiative
(ADQI) consensus group.
ADQI 7: the clinical man-
agement of the Cardio-
Renal syndromes: work
group statements from
the 7th ADQI consensus
conference. Nephrol Dial
Transplant. 2010;25:
2077-89. [PMID:
20494894]
37. Facciorusso A, Chandar
AK, Murad MH, et al.
Comparative efficacy of
pharmacological strate-
gies for management of
type 1 hepatorenal syn-
drome: a systematic
review and network
meta-analysis. Lancet
Gastroenterol Hepatol.
2017;2:94-102. [PMID:
28403995]
ITC73 " 2017 American College of Physicians
 lular casts for the conditions in bodies, complement compo-
Appendix Table 2 (available at nents, and inflammatory markers
38. Dellinger RP, Levy MM,
Rhodes A, et al; Surviv-
Annals.org) is more specific than may be indicated.
ing Sepsis Campaign sensitive—in other words, paren-
Guidelines Committee
chymal kidney disease is more Hemodynamic monitoring (jugular
including the Pediatric
Subgroup. Surviving likely when these findings are venous pressure or pulmonary capil-
sepsis campaign: inter-
present but is not ruled out lary wedge pressure) may be re-
national guidelines for
management of severe
when they are absent. Kidney quired to assess cardiac filling and
sepsis and septic shock:
2012. Crit Care Med. biopsy may be performed when guide volume management in pa-
2013;41:580-637.
suspicion for a parenchymal dis- tients with hypotension. Dynamic
[PMID: 23353941]
39. Cattran DC, Feehally J, ease other than ATN is high. variables, such as pulse–pressure
Cook TH, et al. Kidney variation, inferior vena cava filling on
disease: Improving
global outcomes (KDIGO) Imaging studies are usually done ultrasonography, and echocardiog-
glomerulonephritis work
group. KDIGO clinical
to assess hydronephrosis, de- raphy may be useful. Intra-
practice guideline for fined as dilatation of the renal abdominal pressure can be as-
glomerulonephritis.
Kidney International collecting system due to obstruc- sessed by measuring bladder
Supplement 1s. 2012;2): tion. However, they may also be pressure. Subclavian vein catheters
135.
40. González E, Gutiérrez E, performed to assess kidney should be avoided in patients with
Galeano C, et al; Grupo
Madrileño De Nefritis
shape and size in patients with CKD stages 4–5 (GFR <30 mL/min/
Intersticiales. Early ste- AKI superimposed on CKD or in 1.73 m2) to avoid venous stenosis
roid treatment improves
the recovery of renal patients who have not had previ- that may preclude later vascular ac-
function in patients with ous imaging studies. Renal ultra- cess for hemodialysis.
drug-induced acute inter-
stitial nephritis. Kidney sonography is preferred because
Int. 2008;73:940-6. What other diagnoses should
it has >90% sensitivity for detect-
[PMID: 18185501]
clinicians consider in patients
41. Koyner JL, Davison DL, ing hydronephrosis and is not
Brasha-Mitchell E, et al.
associated with radiation expo- with possible AKI?
Furosemide Stress Test
and Biomarkers for the sure or contrast administration. Decreased GFR is classified as
Prediction of AKI Sever-
ity. J Am Soc Nephrol. Causes of obstruction of the urinary CKD, AKD, or AKI, depending on
2015;26:2023-31.
tract without hydronephrosis in- severity and duration; AKD and
[PMID: 25655065]
42. Chawla LS, Davison DL, clude massive bleeding into the AKI can be superimposed on
Brasha-Mitchell E, et al.
Development and stan- urinary tract or extensive retroperito- CKD (Figure 1 ). Distinguishing
dardization of a furo- neal fibrosis. Dilatation of the urinary among these conditions is impor-
semide stress test to
predict the severity of tract in the absence of obstruction tant for determining the cause of
acute kidney injury. Crit
may be observed after relief of ob- kidney disease and for determin-
Care. 2013;17:R207.
[PMID: 24053972] struction in vesicoureteral reflux, ing the urgency of evaluation and
43. Ho KM, Sheridan DJ.
Meta-analysis of during massive diuresis, and in treatment. Many causes of kidney
frusemide to prevent or
pregnancy. A combination of clinical disease may have an acute or
treat acute renal failure.
BMJ. 2006;333:420. characteristics can identify patients chronic presentation, although
[PMID: 16861256]
in which ultrasonography could be the most common causes of CKD
44. Cantarovich F, Rangoon-
wala B, Lorenz H, et al; omitted (28). (diabetic glomerulosclerosis and
High-Dose Flurosemide
in Acute Renal Failure
hypertension nephrosclerosis) do
Study Group. High-dose Other tests are required to assess not have an acute presentation,
furosemide for estab-
lished ARF: a prospec-
causes and complications of AKI. and ATN does not have a chronic
tive, randomized, Serum urea nitrogen and electro- presentation. Due to the non-
double-blind, placebo-
controlled, multicenter lyte (sodium, potassium, chlo- steady state, changes in SCC and
trial. Am J Kidney Dis.
2004;44:402-9. [PMID:
ride, bicarbonate, calcium, phos- eGFR lag behind those in GFR,
15332212] phorus, magnesium) levels causing delayed recognition of
45. Finfer S, Bellomo R,
Boyce N, et al; SAFE
should be measured. Venous or AKI. The rise in SCC (and de-
Study Investigators. A arterial blood gasses may be re- crease in eGFR) may be slower in
comparison of albumin
and saline for fluid resus- quired for interpretation of acid– patients with low muscle mass or
citation in the intensive
care unit. N Engl J Med.
base disorders. Complete blood volume overload and faster in
2004;350:2247-56. count; liver function tests; muscle patients with high muscle mass
[PMID: 15163774]
46. Perel P, Roberts I. Col- enzymes; and imaging for heart, or volume depletion. When base-
loids versus crystalloids lung, and liver diseases should line GFR is low, minor fluctua-
for fluid resuscitation in
critically ill patients. be obtained. Blood and body tions in GFR can cause a rise in
Cochrane Database Syst
Rev. 2007:CD000567.
fluid cultures and serologic tests SCC by 0.3 mg/dL in the absence
[PMID: 17943746] for infectious diseases, autoanti- of acute kidney disease. Adher-

" 2017 American College of Physicians ITC74 In the Clinic Annals of Internal Medicine 7 November 2017

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 ence to the time requirement for
diagnosis of AKI (48 hours) can
minimize overdiagnosis. An in-
crease in SCC (and decrease in
eGFR) in the absence of decline
in GFR may occur after a medica-
less than 20 mL/min/1.73 m2, it can
be assessed as the mean of urine
clearance of urea and creatinine
during a timed urine collection.
47. Young P, Bailey M, Beas-
When should clinicians consider ley R, et al; SPLIT Investi-

tion is started that inhibits creati- consulting a specialist? gators. Effect of a buff-
ered crystalloid solution
nine secretion (trimethoprim or Consultation with a nephrologist vs saline on acute kidney
injury among patients in
cimetidine) or interferes with the is often unnecessary for detect- the intensive care unit:
assay for creatinine (flucytosine ing AKI. However, it should usu- The SPLIT randomized
clinical trial. JAMA.
for the creatinine iminohydrolase ally be requested for identifying 2015;314:1701-10.
[PMID: 26444692]
assay). Serum ketones interfere with the cause of AKI resulting from 48. Hewitt J, Uniacke M,
the widely used colorimetric assay something other than volume Hansi NK, Venkat-Raman
G, McCarthy K. Sodium
for creatinine. GFR, measured using depletion that resolves promptly bicarbonate supplements
for treating acute kidney
clearance of an exogenous filtration with volume repletion (Figure 2 ). injury. Cochrane Data-
marker, or creatinine clearance, can Consultation may also be helpful base Syst Rev. 2012:
CD009204. [PMID:
be assessed to identify misleading for identifying the cause of 22696382]
alterations in SCC or eGFR. If GFR is CKD. 49. Bellomo R, Cass A, Cole
L, et al; RENAL Study
Investigators. Calorie
intake and patient out-
comes in severe acute
Diagnosis... Decreased GFR may be due to AKI, AKD, or CKD. KDIGO kidney injury: findings
guidelines define AKI as an increase in SCC by ≥50% within 7 days or from The Randomized
Evaluation of Normal vs.
≥0.3 mg/dL (26.5 μmol/L) within 2 days, or oliguria for ≥6 hours. The Augmented Level of
stage (severity) is defined by the peak increase in SCC compared with Replacement Therapy
(RENAL) study trial. Crit
previous values and the nadir in urine output, and is related to the risk Care. 2014;18:R45.
for complications and the prognosis. The causes of AKI— decreased kid- [PMID: 24629036]
ney perfusion, obstruction of the urinary tract, parenchymal kidney dis- 50. Bellomo R, Cass A, Cole
L, et al; RENAL Study
eases other than ATN, and ATN—are grouped according to underlying Investigators. Daily pro-
pathophysiology and are the basis for specific therapy. The clinical set- tein intake and patient
outcomes in severe acute
ting, including response to IV fluid, and urinary tract findings are helpful kidney injury: findings of
in determining the cause of AKI. the randomized evalua-
tion of normal versus
augmented level of
replacement therapy
CLINICAL BOTTOM LINE (RENAL) trial. Blood Purif.
2014;37:325-34. [PMID:
25171270]
51. Cox ZL, McCoy AB, Ma-
theny ME, et al. Adverse
drug events during AKI

Treatment and its recovery. Clin J

The goals of management of AKI
include use of specific treatments
according to the underlying
cause and providing supportive
care to prevent and manage
complications. KRT is used when
complications develop that can-
not be managed with medical
therapy alone (Figure 2 ).
When should patients be
hospitalized?
For outpatients with new-onset
or worsening GFR decline, early
follow-up is required to distin-
guish AKI from AKD and CKD
(1, 34). Although evidence to sup-
port specific criteria for hospitaliza-
tion is not available, hospitalization
is generally recommended if fur-
Am Soc Nephrol. 2013;
8:1070-8. [PMID:
ther diagnostic evaluation is re- 23539228]
quired, if AKI is severe or not 52. Matzke GR, Aronoff GR,
Atkinson AJ Jr, et al.
rapidly reversible, or when Drug dosing consider-
ation in patients with
complications are present. Man- acute and chronic kidney
agement in the ICU should be disease-a clinical update
from Kidney Disease:
considered for patients with AKI Improving Global Out-
comes (KDIGO). Kidney
and serious illness (35). Int. 2011;80:1122-37.
[PMID: 21918498]
What pharmacologic therapies 53. McCoy AB, Waitman LR,
Gadd CS, et al. A com-
should be used? puterized provider order
The use of pharmacologic thera- entry intervention for
medication safety during
pies in the setting of AKI is spe- acute kidney injury: a
quality improvement
cific to the underlying cause report. Am J Kidney Dis.
(Appendix Table 2 ). IV fluids are 2010;56:832-41. [PMID:
20709437]
recommended to correct volume 54. Bagshaw SM, Wald R.
Strategies for the optimal
depletion. Afterload reducing timing to start renal
agents are appropriate in cases replacement therapy in
critically ill patients with
of acute heart failure (36), acute kidney injury.
whereas midodrine, octreotide, Kidney Int. 2017;91:
1022-1032. [PMID:
and albumin can be used in 28222898]

7 November 2017 Annals of Internal Medicine In the Clinic ITC75 " 2017 American College of Physicians

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55. Gaudry S, Hajage D,
Schortgen F, et al; AKIKI
Study Group. Initiation
strategies for renal-
replacement therapy in
the intensive care unit. N
Engl J Med. 2016;375:
122-33. [PMID:
27181456]
56. Zarbock A, Kellum JA,
Schmidt C, et al. Effect of
early vs delayed initia-
tion of renal replacement
therapy on mortality in
critically ill patients with
acute kidney injury: the
ELAIN randomized clini-
cal trial. JAMA. 2016;
315:2190-9. [PMID:
27209269]
57. Bellomo R, Cass A, Cole
L, et al; RENAL Replace-
ment Therapy Study
Investigators. Intensity of
continuous renal-
replacement therapy in
critically ill patients. N
Engl J Med. 2009;361:
1627-38. [PMID:
19846848]
58. Palevsky PM, O’Connor
TZ, Chertow GM, et al;
US Department of Veter-
ans Affairs/National Insti-
tutes of Health Acute
Renal Failure Trial Net-
work. Intensity of renal
replacement therapy in
acute kidney injury:
perspective from within
the Acute Renal Failure
Trial Network Study. Crit
Care. 2009;13:310.
[PMID: 19678919]
59. Pannu N, Klarenbach S,
Wiebe N, Manns B, To-
nelli M; Alberta Kidney
Disease Network. Renal
replacement therapy in
patients with acute renal
failure: a systematic
review. JAMA. 2008;
299:793-805. [PMID:
18285591]
60. Vinsonneau C, Camus C,
Combes A, et al; Hemo-
diafe Study Group. Con-
tinuous venovenous
haemodiafiltration versus
intermittent haemodialy-
sis for acute renal failure
in patients with multiple-
organ dysfunction syn-
drome: a multicentre
randomised trial. Lancet.
2006;368:379-85.
[PMID: 16876666]
61. Coca SG, Yusuf B, Sh-
lipak MG, Garg AX,
Parikh CR. Long-term risk
of mortality and other
adverse outcomes after
acute kidney injury: a
systematic review and
meta-analysis. Am J
Kidney Dis. 2009;53:
961-73. [PMID:
19346042]
62. James MT, Samuel SM,
Manning MA, et al.
Contrast-induced acute
kidney injury and risk of
adverse clinical out-
comes after coronary
angiography: a system-
atic review and meta-
analysis. Circ Cardiovasc
Interv. 2013;6:37-43.
[PMID: 23322741]
" 2017 American College of Physicians
Downloaded From: https://annals.org/ by a Scott Memorial Library User on 12/03/2017
cases of liver failure (37). IV fluid
and early antibiotic therapy is
important for treating infections
(38). Withdrawal of NSAIDs,
ACEIs, and ARBs is recom-
mended. Immunosuppressive
therapies are recommended for
many causes of acute glomerulo-
nephritis (39). Although high-
quality evidence is lacking, many
experts recommend corticoste-
roids to treat acute interstitial ne-
phritis when AKI is severe or in
cases of drug-induced interstitial
nephritis if AKI does not resolve
after the causative medication is
discontinued (40). Plasma ex-
change is recommended for some
causes of thrombotic microangi-
opathy. High-dose chemotherapy
is used in multiple myeloma. There
are currently no effective pharma-
cotherapies for treating ATN. The
KIDGO guidelines recommend
against diuretics to treat AKI ex-
cept for management of volume
overload. However, a furosemide
“stress test” (administration of 1
mg/kg of IV furosemide with 1:1
replacement of urine output with
saline) can be used to assess prog-
nosis: Patients with <200 mL of
urine output over the subsequent
2 hours are at greater risk for pro-
gression to a higher AKI stage or
to the need for KRT (41, 42). Al-
though high-dose loop diuretics
can increase urine output in AKI,
they do not seem to reduce mor-
tality or the need for dialysis.
A systematic review of 6 moderate- to low-
quality randomized controlled trials of furo-
semide to treat AKI reported that it did not re-
duce in-hospital mortality, requirement for
dialysis, or the number of dialysis treatments
required until recovery of kidney function. In
addition, higher doses were associated with in-
creased toxicity (43).
In a moderate-quality randomized trial of 338
patients from ICUs and nephrology wards who
had AKI requiring KRT, patients who were ran-
domly assigned to daily furosemide 25 mg/kg
IV or 35 mg/kg orally more rapidly achieved
urine output >2 L per day (5.7 days with furo-
semide vs. 7.8 days with placebo). However,
no significant differences in mortality, time re-
ITC76 In the Clinic Annals of Internal Medicine
ceiving dialysis, or time to achieve a serum cre-
atinine level < 200 umol/L was noted (44).
KDIGO guidelines recommend
using vasopressors (e.g., norepi-
nephrine or vasopressin) in con-
junction with fluids in patients
with vasomotor shock accompa-
nying AKI (1). Low-quality evi-
dence suggests using a protocol-
based approach to achieve
specific mean arterial pressure and
other physiologic targets (1). On
the basis of moderate-quality evi-
dence, KDIGO guidelines recom-
mend against dopamine, fenoldo-
pam, atrial natriuretic peptides,
insulin-like growth factor, or
N-acetylcysteine to treat AKI (1).
How should clinicians manage
volume problems?
AKI may develop in the setting of
volume depletion or overload,
and either condition may occur
during the course of AKI. Volume
overload is more likely to occur
in the setting of oliguria, is asso-
ciated with poor outcomes in
AKI, and should be avoided to
prevent life-threatening pulmo-
nary edema. Volume depletion
should also be avoided because
it can delay recovery of AKI due
to other conditions. Frequent
monitoring of fluid intake and
output, body weight, and volume
status and administering or re-
stricting fluid depending on the
results are important.
IV fluids are recommended for
correcting AKI with volume de-
pletion and for intravascular vol-
ume expansion in AKI with sepsis
(1). Isotonic crystalloids (e.g., nor-
mal saline, Ringer lactate, or
other balanced crystalloid solu-
tions) are recommended rather
than colloids (albumin or
starches) as initial management
on the basis of moderate-quality
evidence (45– 47). Colloids may
be used for patients with liver
failure or burns. Treatment of vol-
ume overload in patients with
AKI can sometimes be accom-
7 November 2017
 plished using high doses of IV
loop diuretics, given as multiple
doses throughout the day or as
an infusion and often in conjunc-
tion with IV thiazide diuretics.
How should clinicians manage
electrolyte problems?
Initial management of electrolyte
abnormalities should start with
medical management and pro-
ceed to KRT when medical man-
agement is no longer satisfac-
tory. Dietary potassium should
be restricted, and medications
that cause hyperkalemia should
be used cautiously. Treatment of
severe hyperkalemia (serum po-
tassium > 6.5 mmol/L or with
electrocardiographic changes)
includes administration of cal-
cium gluconate to reduce the risk
for arrhythmia, followed by insu-
lin plus dextrose, !-agonists, or
sodium bicarbonate to shift po-
tassium from the extracellular to
the intracellular compartment.
These treatments are temporary
and must be accompanied by
measures to remove potassium
from the body. For patients with-
out oliguria, high-dose loop di-
uretics can be used to increase
urine output and potassium ex-
cretion. For patients with oliguria,
sorbitol with sodium polystyrene
sulfonate or calcium polystyrene
sulfonate resins can be used to
induce osmotic diarrhea and fe-
cal potassium losses. Most ex-
perts suggest using supplemen-
tal sodium bicarbonate when
metabolic acidosis is severe, al-
though there is no high-quality
evidence (48). Hypernatremia
may be encountered in AKI with
dehydration, after normal saline
resuscitation, or when access to
water is restricted. It can usually
be corrected by providing water
via enteral routes or IV hypnatric
solutions. The management of
hyponatremia in the setting of
AKI depends on its cause. In
states of volume depletion, admin-
istration of isotonic IV fluids is gen-
7 November 2017 Annals of Internal Medicine
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erally appropriate. In the presence
of volume overload, water restric-
tion and loop diuretics should be
used. Hypercalcemia may be en-
countered in AKI accompanying
multiple myeloma and can be cor-
rected by volume expansion and
loop diuretics in patients who are
not oliguric or by promoting bone
uptake with administration of an IV
bisphosphate. Hyperphos-
phatemia can be managed by di-
etary phosphate restriction and
oral phosphate binders. Hyperma-
gnesemia may occur after magne-
sium infusion and can be man-
aged by discontinuing the infusion
and administering loop diuretics.
How should clinicians manage
nutrition, drug dosing, and
anticoagulation?
Nutrition should provide ade-
quate calories with restricted po-
tassium and phosphate. KDIGO
guidelines for patients with AKI
recommend a total energy intake
of 20 –30 kcal/kg per day, prefer-
ably provided via the enteral
route (49). Minimal nitrogenous
waste production is desirable in
AKI; however, protein restriction
is not suggested as a means to
avoid KRT. On the basis of low-
quality evidence, KDIGO guide-
lines recommend protein goals
of 0.8 –1.0 g/kg per day in non-
catabolic patients, 1.1–1.5 g/kg
per day in patients receiving re-
nal replacement therapy, and a
maximum 1.7 g/kg per day in
hypercatabolic patients or those
requiring continuous KRT (1, 50).
In critically ill patients, KDIGO
guidelines suggest insulin ther-
apy targeting plasma glucose
110 –149 mg/dL.
Patients with AKI require special
drug dosing due to buildup from
decreased excretion and metab-
olism by the kidney as well as the
effects of kidney failure on other
routes of drug excretion and me-
tabolism (51, 52). Estimated GFR
is less accurate to guide dosing
in the nonsteady state than in the
ITC77
63. Coca SG, Singanamala S,
Parikh CR. Chronic kid-
ney disease after acute
kidney injury: a system-
atic review and meta-
analysis. Kidney Int.
2012;81:442-8. [PMID:
22113526]
64. Hsu CY, Hsu RK, Yang J,
et al. Elevated BP after
AKI. J Am Soc Nephrol.
2016;27:914-23. [PMID:
26134154]
65. Sawhney S, Marks A,
Fluck N, et al. Post-
discharge kidney func-
tion is associated with
subsequent ten-year
renal progression risk
among survivors of acute
kidney injury. Kidney Int.
2017;92:440-452.
[PMID: 28416224]
66. Schmitt R, Coca S, Kan-
bay M, et al. Recovery of
kidney function after
acute kidney injury in
the elderly: a systematic
review and meta-
analysis. Am J Kidney
Dis. 2008;52:262-71.
[PMID: 18511164]
67. Heung M, Steffick DE,
Zivin K, et al; Centers for
Disease Control and
Prevention CKD Surveil-
lance Team. Acute kidney
injury recovery pattern
and subsequent risk of
CKD: an analysis of Vet-
erans Health Administra-
tion data. Am J Kidney
Dis. 2016;67:742-52.
[PMID: 26690912]
68. Wu VC, Wu CH, Huang
TM, et al; NSARF Group.
Long-term risk of coro-
nary events after AKI. J
Am Soc Nephrol. 2014;
25:595-605. [PMID:
24503241]
69. Ftouh S, Thomas M;
Acute Kidney Injury
Guideline Development
Group. Acute kidney
injury: summary of NICE
guidance. BMJ. 2013;
347:f4930. [PMID:
23985310]
70. Soares DM, Pessanha JF,
Sharma A, Brocca A,
Ronco C. Delayed ne-
phrology consultation
and high mortality on
acute kidney injury: a
meta-analysis. Blood
Purif. 2017;43:57-67.
[PMID: 27915348] doi:
10.1159/000452316
" 2017 American College of Physicians
 steady state. Expert consensus
recommends closely monitoring
drug response in patients with
known nephrotoxicity or other
toxicities, using therapeutic drug
monitoring when clinically useful
assays are available, and being
cognizant of residual effects of
medicines that are excreted by
the kidney even after they have
been discontinued (e.g., oral
hypoglycemic agents and opi-
oids) (52, 53). The assistance of a
pharmacist may be helpful, par-
ticularly in determining dosing
and dosing intervals in patients
receiving dialysis and those re-
quiring antibiotics for AKI ac-
companying sepsis.
Certain anticoagulants should be
used with caution in patients with
AKI due to the increased bleeding
risk attributed to uremic platelet
dysfunction and to decreased
excretion of low-molecular-weight
heparins and direct oral anticoag-
ulants. Although some manufac-
turers provide altered dosing
schedules based on creatinine
clearance for some low-
molecular-weight heparins (e.g.,
enoxaparin) and direct oral anti-
coagulants (e.g., dabigatran), de-
termining safe dosing schedules
when GFR is changing, especially
during dialysis, is difficult. Al-
though low-molecular-weight
heparins are used intermittently in
patients receiving long-term dialy-
sis and some organizations have
suggested monitoring anti-factor
X activity with continuous use,
many experts prefer to use unfrac-
tionated heparin in severe AKI.
For patients with active bleeding
in the presence of uremia, desmo-
pressin (0.3 mcg/kg IV, subcuta-
neous, or intranasal) and cryopre-
cipitate can be used to rapidly
diminish bleeding time, whereas
conjugated estrogens and dialysis
(without systemic anticoagulation)
can be used for more prolonged
bleeding control.
" 2017 American College of Physicians
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What is the role of KRT?
KRT is used to manage the com-
plications of severe AKI. Com-
mon indications include life-
threatening changes in fluid,
electrolyte, and acid– base bal-
ance that require emergent cor-
rection (Figure 2 ). KRT may be
started before these complications
develop, although evidence con-
flicts about whether preemptive
initiation at an earlier stage of AKI
is more beneficial than when com-
plications occur (54 –56). KRT
should be discontinued as soon as
it is no longer required, either be-
cause kidney function has recov-
ered enough to meet the patient's
needs or life-sustaining therapy is
no longer the goal of the patient's
care.
Several types of KRT can be
used, and the type varies by loca-
tion of care and available equip-
ment and expertise (Appendix
Table 3 , available at Annals.org).
Peritoneal dialysis is rarely used
for KRT in adults with AKI in
North America, although it is
more commonly used in areas
with limited resources. Continu-
ous KRT is a slow, continuous
form of therapy delivered 24
hours a day in ICUs and is usu-
ally used to treat hemodynami-
cally unstable patients (57).
Conventional intermittent hemo-
dialysis is used in AKI for hemo-
dynamically stable patients; it is
similar to the in-center long-term
hemodialysis used for end-stage
kidney disease (58). More fre-
quent sessions may be required
to manage fluid and electrolyte
abnormalities for some patients
with AKI. Prolonged intermittent
KRT uses the same equipment
as conventional dialysis but pro-
vides dialysis using lower blood
flow rates over longer sessions
(usually ≥6 hours/session). Sev-
eral randomized trials have com-
pared outcomes with continuous
KRT versus intermittent hemodi-
alysis in critically ill patients (59).
ITC78
Significant differences between
the 2 methods in terms of mor-
tality, length of hospitalization,
and long-term requirements for
dialysis have not been found
(59, 60).
What is the prognosis?
AKI is associated with high mor-
tality rates that range from 16%–
50% according to stage (Appen-
dix Figure, available at Annals.
org) and vary according to the
cause, coexisting conditions, and
availability of KRT (3). Survivors
of AKI are at increased risk for
hypertension and progressive
CKD, including end-stage kidney
disease (61– 65). KDIGO guide-
lines thus recommend evaluat-
ing patients after AKI for recov-
ery of kidney function, new
onset, or worsening of preexist-
ing CKD. Older age, lower base-
line eGFR, higher baseline albu-
minuria, and AKI severity
(KDIGO stage) are predictors of
CKD after AKI and should
prompt postdischarge follow-up
(6, 66, 67). Referral to commu-
nity nephrology services may be
appropriate for patients who do
not recover kidney function
given the associated long-term
risks of kidney failure, cardiovas-
cular events, and mortality for
several years after hospital dis-
charge (62, 68).
In a systematic review, the pooled mortality
rate was 23.0% overall and 49.4% in patients
needing dialysis (Appendix Figure) (3). The
pooled unadjusted odds of death were 3.4-
fold higher for patients with KDIGO stage 1
AKI, 7.5-fold higher for stage 2, 13.2-fold
higher for stage 3, and 24-fold higher in pa-
tients needing dialysis compared with patients
without AKI. The AKI-associated mortality rate
declined over 8 years and was inversely related
to the percentage of a country's gross domes-
tic product spent on total health
expenditure.
When should clinicians
consider consulting a specialist?
Because AKI is a common com-
plication of many medical and
surgical illnesses, most patients
Annals of Internal Medicine 7 November 2017
 with AKI are cared for by general
internists, hospitalists, surgeons,
and critical care and primary care
physicians. These clinicians
should consult a nephrologist or
critical care specialist for patients
who have AKI with any indication
for KRT (69). Nephrology referral
and comanagement is also appro-
priate if the cause of AKI is uncertain,
particularly when decreased kidney
perfusion and urinary tract obstruc-
tion have been excluded or cor-
rected. Clinicians should discuss
management with a nephrologist if
a diagnosis that may need specific
treatments is suspected (e.g., paren-
chymal kidney diseases other than
ATN), response to treatment has
been inadequate, there are associ-
ated complications, AKI is severe
(KDIGO stage 3), or it is superim-
posed on CKD stages 4–5 (baseline
GFR < 30 mL/min/1.73 m2) (70).

Treatment... The main goals of managing AKI are specific pharmaco-

logic therapy addressing underlying causes and providing supportive
care to prevent and manage complications. Supportive care includes
maintenance of hemodynamic stability and kidney perfusion using IV
crystalloids when volume expansion is needed and the use of diuretics
in states of volume overload, medical management of electrolyte disor-
ders, provision of adequate nutrition and glycemic control, and cau-
tious use of medications to avoid adverse drug events. When AKI is se-
vere, KRT may be required to manage complications. Survivors of AKI
should be assessed for recovery of kidney function and receive subse-
quent follow-up to identify and subsequently manage CKD.

CLINICAL BOTTOM LINE

In the Clinic Clinical Guidelines

Tool Kit
www.kdigo.org/clinical_practice_guidelines/pdf
/KDIGO%20AKI%20Guideline.pdf
Guidelines published by the International Society of
Nephrology.
www.clinicalguidelines.gov.au/portal/2481/clinical
IntheClinic
-practice-guideline-acute-kidney-injury
2014 guideline from the National Health and Medical

Acute Kidney Research Council of Australia.

www.nice.org.uk/guidance/cg169
Injury Guidance from the National Institute for Health and Care
Excellence.

Patient Information
www.kidney.org/atoz/content/AcuteKidneyInjury
Information presented by the National Kidney foundation
for both patients and caregivers.
www.thinkkidneys.nhs.uk/aki/wp-content/uploads
/sites/2/2015/11/BKPA-RCGP-A4-Printout-Leaflet_v4
.pdf
Printable leaflet of the British Kidney Patient Association.
www.ncbi.nlm.nih.gov/pubmedhealth/PMH0071507/
Information for patients and caregivers from PubMed
Health.
www.nhs.uk/conditions/acute-kidney-injury/Pages
/Introduction.aspx
Information from the National Health Service.

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 WHAT YOU SHOULD KNOW In the Clinic
Annals of Internal Medicine
ABOUT ACUTE KIDNEY INJURY
What Is Acute Kidney Injury?
Doctors diagnose acute kidney injury (AKI) when
your kidneys stop working properly and the
change happens over a few hours or a few days.
It can cause a buildup of waste products in your
blood and make it hard for your kidneys to bal-
ance the fluids in your body. It can lead to seri-
ous health problems, such as permanent kidney
damage and even death.
AKI usually happens to people who are sick, espe-
cially when they are in the hospital. AKI can be a
complication of the following conditions:
• Sepsis (a type of infection)
• Shock
• Accidents
• Burns • Swelling or retaining fluid
• Heart attack or other heart disease • Shortness of breath
• Blockage of the urinary tract • Feeling dizzy or lightheaded
• Infection of the urinary tract
• Surgery How Is It Diagnosed?
• Dyes for x-rays • Your doctor will ask you questions about your
• Certain over-the-counter and prescription health history and take blood and urine
medicines samples.
• Contact with a poisonous plant or animal • If there is something wrong with your kidneys,
• Severe allergic reaction you may have an imaging test. This could
include an ultrasound.
What Are the Risk Factors?
You are more susceptible to AKI if you: How Is It Treated?
• Are an older adult • Patients with AKI are usually treated in a
• Are female hospital. Your health care provider will give
• Are African American you intravenous fluids to bring your levels

Patient Information
• Have chronic kidney disease back to normal. You may also take medicines
• Have chronic heart, lung, or liver disease to help balance your fluid levels.
• Have diabetes • In more serious cases, you may need dialysis
• Have cancer while your kidneys recover. Dialysis filters the
• Are anemic waste in your body, just as healthy kidneys do.
What Are the Symptoms? Questions for My Doctor
AKI usually has no symptoms until your kidneys • What caused my AKI?
start to fail. Kidney failure means that your kid- • Will I need dialysis?
neys can no longer properly remove waste from • Will I have permanent damage?
your body. These symptoms may occur if you • If I recover, what are the chances I'll get it
have kidney failure: again in the future?
• Feeling sleepy • Should I eat a special diet?
• Feeling sick to your stomach • Should I avoid any medications?

For More Information

National Kidney Foundation
www.kidney.org/atoz/content/AcuteKidneyInjury
Medline Plus
https://medlineplus.gov/ency/article/000501.htm

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 Appendix Table 1. Findings of Urine Testing in Acute Kidney Injury
Variable Normal Decreased Obstruction of the Parenchymal Kidney ATN
Kidney Perfusion Urinary Tract Diseases Other Than ATN
Concentration* Varies, depending Concentrated, Concentrated, not if Not concentrated, may Not concentrated;
on water intake possibly not if chronic be concentrated in may be concen-
recent glomerulonephritis trated in heart
diuretic failure or liver
administration failure
Albumin/total Normal to mildly Normal to mildly Normal to mildly Increased albumin Normal to mildly
protein levels† increased increased increased (unless and total protein in increased
chronic) glomerular disease;
normal albumin and
increased total protein
in cast nephropathy
(immunoglobulin light
chains) and in tubular
diseases (!2-micro-
globulin)
Hematuria (RBCs)‡ No No Yes, with instrinsic Yes, with dysmorphic No, heme-positive
disease RBCs and RBC casts in dipstick in
glomerulonephritis; yes, hemolysis and
without RBC casts in rhabdomyolysis
thrombotic
microangiopathy
Pyuria (WBCs)‡ No No Yes, if superimposed Yes, with WBC casts in No
urinary tract interstitial nephritis
infection
Renal tubular No No (may contain No (except if Yes Yes
epithelial cells hyaline casts) chronic)
and granular
casts
Hydronephrosis, No No Hydronephrosis, No hydronephrosis, No
kidney shape hydronephrosis, hydronephrosis, enlarged, may be normal size, may be hydronephrosis,
and size§ normal size, normal size, small if chronic, large in infiltrative normal size
symmetrical symmetrical, may be diseases, symmetrical,
may be asymmetrical if may be small if chronic
asymmetrical unilateral,
if renal artery nephrolithiasis
stenosis may be present

RBC = red blood cell; HPF = high-power field; WBC = white blood cell.
* Urine concentration assessed from urine specific gravity (concentrated > 1.020); osmolality (concentrated >500 mosm/kg);
fractional excretion of sodium (FENa) (concentrated <1%); fractional excretion of urea (FEurea) (concentrated <35%); ratio of SUN
to serum creatinine clearance (Scr) >20:1. FENa is calculated from UNa x Scr/SNa x Ucr. FEurea is calculated from UUN x Scr/SUN
x Ucr.
† Albumin and total protein assessed from dipstick (more sensitive to albumin than other proteins); albumin-to-creatinine ratio
(ACR), moderately increased 30 –300 mg/g, severely increased >300 mg/g (nephrotic range >2200 mg/g); and total protein-to-
creatinine ratio (PCR), moderately increased 150 –500 mg/g, severely increased >500 mg/g (nephrotic range >3500 mg/g).
Ranges for ACR and PCR are defined for steady-state conditions; values may be higher in acute kidney injury because urine
creatinine excretion decreases with increased Scr.
‡ Normal urine contains <5 RBC/HPF and <5 WBC/HPF.
§ Renal ultrasonography is the preferred method for evaluating hydronephrosis. Hydronephrosis may be absent in cases of
massive bleeding into the urinary tract or extensive retroperitoneal fibrosis.

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 Appendix Table 2. Treatment According to Specific Causes of AKI Other Than Acute Tubular Necrosis
Cause of AKI
Decreased kidney perfusion
Volume depletion
Heart failure, left- or right-sided
(with lung disease) (cardiorenal
syndrome)
Liver failure (hepatorenal syndrome)
Sepsis
Increased intra-abdominal pressure
Renovascular disease
Nonsteroidal anti-inflammatory
drugs
ACE inhibitors and ARBs
Urinary tract obstruction
Obstructive nephropathy
Parenchymal kidney disease
Acute glomerulonephritis
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Treatment/Intervention
Intravenous fluid
Afterload reduction and
diuretics if volume
overloaded
Albumin, midodrine, and
octreotide
Intravenous fluid and
antibiotics
Intra-abdominal
decompression
Antihypertensive therapy;
revascularization
Withdrawal of medications
Temporary medication
withdrawal
Nephrostomy tube or
urinary catheter
Immunosuppressive therapy
Comment
Isotonic crystalloids (normal saline, Ringer lactate, or
balanced crystalloid solutions) are recommended
rather than colloids as initial management for
intravascular volume expansion; improvement in Scr
and eGFR and urine output after intravenous fluid
administration confirms the diagnosis of decreased
kidney perfusion due to volume depletion
Cardiac output may be improved with ACE/ARB,
hydralazine or nitrates; diuresis can improve GFR when
left ventricular filling pressure exceeds that for
optimum cardiac output or when systemic venous
pressure is elevated so as to reduce the afferent versus
efferent arteriolar pressure gradient across the
glomerulus
Volume may be expanded with albumin, especially in
setting of bacterial peritonitis or paracentesis;
midodrine and octreotide are used to raise blood
pressure and promote splanchnic vasoconstriction;
terlipressin may improve outcomes (but is not currently
available in the United States or Canada); kidney failure
can be an indication for liver transplant in eligible
patients
Intravenous volume expansion and early broad-spectrum
antibiotics, subsequently tailored to culture and
sensitivity results
Nasogastric and rectal drainage, and evacuation of
intra-abdominal space-occupying lesions (e.g., ascites,
fluid collections, hematomas); may require surgical
decompression (open abdomen) when
intra-abdominal pressure is ≥20 mm Hg
Angioplasty with or without stenting or surgical bypass of
the renal artery can be considered in select situations
of AKI (e.g., bilateral renal artery stenosis or stenosis to
a solitary kidney)
Isotonic crystalloid is a useful adjunct
Consider educating patients about tablet holidays
(withholding ACE inhibitors or ARBs, especially when
combined with diuretics); during periods of potential
volume depletion from acute illness, to avoid recurrent
AKI episodes
Percutaneous nephrostomy tubes or ureteric stenting for
relief of upper tract obstruction or Foley catheter or
definitive surgical intervention for lower tract
obstruction
Dependent on histopathologic findings on kidney biopsy
and underlying cause; crescentic glomerulonephritis
(e.g., anti-neutrophil cytoplasmic antibody and
anti-GBM disease) is usually treated with induction
therapy using steroids and cyclophosphamide;
proliferative lupus nephritis is treated with steroids and
cyclophosphamide or mycophenolate mofetil for
induction therapy; corticosteroids or other
immunosuppressive regimens may be used to treat IgA
nephropathy; when glomerulonephritis is due to an
infection or cancer, these secondary causes should be
treated
Continued on following page
" 2017 American College of Physicians
 Appendix Table 2—Continued
Cause of AKI Treatment/Intervention
Acute interstitial nephritis Withdrawal of culprit
medication and
corticosteroids
Acute pyelonephritis Antibiotics
Thrombotic microangiopathy Plasma exchange
Cast nephropathy (multiple Chemotherapy
myeloma)
Renal infarction Revascularization or
anticoagulation
Atheroembolism Avoidance of intra-arterial
procedures
Comment
Stop culprit drug when medication-related; may consider
corticosteroids if AKI is severe or patient is not
recovering
Intravenous antibiotics when accompanied by AKI;
consider investigations for anatomical urinary tract
abnormalities, obstruction or stones, or sources of
hematogenous dissemination
Used for thrombotic thromobocytopenia purpura and
some secondary (immune-mediated) causes of
thrombotic microangiopathy.
High-dose chemotherapy provided through consultation
with a hematologist, which may include steroids,
cyclophosphamide, immunomodulatory drugs (e.g.,
lenolidamide, or proteasome inhibitors (e.g.,
bortezemab) for initial treatement, followed by
autologous hematopoietic cell transplantation for
eligible patients
Consider revascularization for arterial fibromuscular
dysplasia of the renal arteries or anticoagulation for
arterial embolism or venous thrombosis to prevent
recurrence; not indicated for treatment of acute events
Avoidance of intra-arterial procedures to prevent
recurrence; consider withdrawal of anticoagulation (if
recently initiated) and atheroembolism is spontaneous
(not following intra-arterial procedures)

ACE = angiotensin-converting enzyme; AKI = acute kidney injury; ARB = angiotensin-receptor blocker; eGFR = estimated glo-
merular filration rate; GBM = glomerular basement membrane; GFR = glomerular filration rate; Scr = serum creatinine.

Appendix Table 3. Kidney Replacement Therapies for Hemodialysis and Hemofiltration in Acute Kidney Injury
Example Solute Removal Blood Flow Rate Duration Recommended Dose
Continuous kidney
replacement
therapies
Continuous Convective 150–250 mL/min Daily for 24 h/d (minus To deliver an effluent volume
venovenous interruptions) (replacement for fluid
hemofiltration removed by ultrafiltration)
of 20–25 mL/kg per h
Continuous Diffusive
venovenous
hemodialysis
Continuous Diffusive and
venovenous convective
hemodiafiltration
Intermittent kidney
replacement
therapies
Intermittent Diffusive 200–350 mL/min Typically 3–4 times/wk, To deliver a weekly Kt/V (a
hemodialysis 4 h/session measure of urea clearance)
of 3.9
Prolonged intermittent
kidney replacement
therapies
Sustained low Diffusive 100–300 mL/min Typically daily for ≥6 h To deliver a weekly Kt/V (a
efficiency dialysis measure of urea clearance)
of 3.9
Sustained low Diffusive and
efficiency convective
diafiltration
Sustained continuous Convective
ultrafiltration

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 Appendix Figure. Pooled AKI-associated mortality rate from studies based on KDIGO creatinine-based staging.

70

60 49.4
47.8

Pooled AKI-Associated
50

Mortality Rate 40
28.5
30 23.0
15.9
20

10

Overall Stage 1 Stage 2 Stage 3 Dialysis

(KDIGO- (Risk) (Injury) (Failure) Requirement
Equivalent)

Studies, n 110 26 25 25 31
Patients With AKI, n 429 535 8226 42 354 42 354 6534

Error bars represent 95% CIs. AKI = acute kidney injury; KDIGO = Kidney Disease Improving Global Outcomes.

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 ARTIGO 2

EMERGÊNCIAS DIALÍTICAS
 ACUTE KIDNEY INJURY
The management of acute
kidney injury
Carolyn E Amery
Annette Davies
Lui G Forni
Abstract
Acute kidney injury affects up to 15% of in patients in the acute hospital
setting. Although accurate history-taking, careful physical examination
and meticulous monitoring of volume balance are essential, there is,
to-date, little evidence supporting any intervention that may reverse
this process. Acute kidney injury presents a unique set of metabolic de-
rangements that, if untreated, will result in death. We outline the initial
management of acute kidney injury as well as specific treatments that
may be required. Some consideration is also given to the use of renal
replacement therapies.
Keywords Acute kidney injury; glomerular filtration rate; haemofiltra-
tion; hyperkalaemia; metabolic acidosis; uraemic encephalopathy; urae-
mic pericarditis
Introduction
In 2004, the Acute Dialysis Quality Initiative group (ADQI) pro-
posed the RIFLE classification of acute kidney injury (AKI)
encompassing two separate criteria, the calculated glomerular
filtration rate (GFR) and urine output.1 The previously adopted
acronym RIFLE provides diagnostic definitions for the three
grades of increasing severity of AKI and the two outcome vari-
ables of loss (L) and end-stage renal disease (E). The grades of
severity of injury include the stage at which injury can be pre-
vented (risk, R), when the kidney has already been damaged
(injury, I) and when renal failure has occurred (failure, F). In
2007, the Acute Kidney Injury Network (AKIN) modified the
RIFLE criteria.2 The AKIN criteria refer to the same stages (risk,
injury and failure) but the time frame for diagnosis of AKI is
reduced to 48 hours, and a lower threshold for the rise of serum
creatinine from baseline to peak value is used. Both sets of
criteria have been validated for in-hospital mortality in numerous
studies and can offer prognostic information based on the stages
of AKI.3,4 More recently, the Kidney Disease: Improving Global
Carolyn E Amery MBChB MRCP is a Specialist Registrar in Renal Medicine
at Brighton and Sussex University Hospitals Trust, Brighton, East
Sussex, UK. Competing interests: none.
Annette Davies RN BSc (Hons) MSc is Teaching Fellow at School of Health
Sciences, University of Surrey, UK. Competing interests: none.
Lui G Forni MBBS BSc PhD MRCPI is visiting Professor in Intensive Care
Medicine at the School of Health Sciences, University of Surrey and
Consultant Intensivist, Department of Intensive Care Medicine, Surrey
Peri-Operative Anaesthesia Critical Care Collaborative Research Group
(SPACeR), Royal Surrey County Hospital NHS Foundation Trust, UK.
Competing interests: none.
MEDICINE --:-
Please cite this article in press as: Amery CE, et al., The management of acute kidney injury, Medicine (2015), http://dx.doi.org/10.1016/
j.mpmed.2015.05.015
Outcomes (KDIGO) Work Group has integrated the RIFLE and
AKIN criteria, including patients under 18 with a decrease in
eGFR to less than 35 ml/min in the stage 3 category.5 (see Table 1
of Assessment and initial management of acute kidney injury on
pages 000e000 of this issue).
General management of AKI
Early recognition and treatment of AKI saves nephrons and
prevents further decline in GFR. It is important to remember that
measured serum creatinine may not rise appreciably until GFR
has fallen significantly. This is of particular relevance in in-
dividuals of small build, vegetarians and the undernourished,
such as patients with hepatic failure, in whom a serum creatinine
in the normal range can be misleading. Tubular secretion of
creatinine is increased as GFR falls, and this may also lead to an
overestimation of renal function in AKI.6 Treatment in AKI is
aimed at minimizing further damage to the kidney while
providing support until there are signs of functional recovery.
This includes restoration of the circulating volume, relief of
outflow obstruction if present, removal of tubular toxins and
specific treatment of glomerular disease. Early restoration of
renal perfusion in precipitant AKI due to presumed acute tubular
necrosis is essential. Recovery of GFR depends on the number of
remaining functional nephrons that will increase their filtration
to maintain GFR. However, continued hyperfiltration may result
in progressive glomerular sclerosis and nephron death, leading to
end-stage renal failure. (See Assessment and initial management
of acute kidney injury on pp xxexx of this issue.)
Specific problems
Volume resuscitation
In hypovolaemia, volume expansion is recommended. However,
uncontrolled volume substitution may result in clinical deterio-
ration with an increased risk of morbidity and mortality in pa-
tients with AKI and should be avoided. Isotonic crystalloids
remain the mainstay of volume replacement therapy. Crystalloids
expand plasma volume by about 25% of the infused volume,
correcting sodium depletion as well as restoring solute and water
diuresis. However, large-volume infusion of sodium chloride can
lead to so-called ‘hyperchloraemic acidosis’, which may be
associated with renal vasoconstriction and gut hypoperfusion.7
Colloids, such as albumin, gelatins and hydroxyethyl starch,
result in volume expansion approximate to the infused volume
but, if administered in isolation in AKI, can lead to osmotic
nephrosis (osmotic tubular damage). Hydroxyethyl starches are
highly polymerized sugars characterized by their molecular
weight, grade of substitution and concentration. They are
degraded through hydrolytic cleavage, the remnants of which are
excreted by the kidney, and should be avoided in AKI particularly
when this has resulted from sepsis.
Volume overload
The volume status of a patient with AKI should be assessed
carefully. Although somewhat unfashionable, careful bedside
examination including assessment of the venous pressure,
capillary refill time, pulse and postural blood pressure changes
are elementary tools for assessing volume status. Hourly urine-
output and accurate fluid-input charts need to include all fluid
1 Crown Copyright ! 2015 Published by Elsevier Ltd. All rights reserved.
 ACUTE KIDNEY INJURY
losses, including estimated insensible losses, drain/stoma output
and nasogastric losses where appropriate. If possible, patients
should be weighed daily. A central venous catheter and an
arterial cannula can be helpful where multi-organ failure (MOF)
is imminent. In established MOF, absolute measurement of
central venous pressure can be misleading, especially in the
ventilated patient in whom high intrathoracic pressures may be
present, and further invasive monitoring may be required.
Where volume overload is encountered in the setting of AKI,
symptoms can be alleviated by high-flow oxygen. Where pul-
monary oedema is refractory to pharmacological management
while preparing the patient for urgent RRT, continuous positive
airway pressure ventilation (CPAP) should be considered. Trials
using diuretics, such as furosemide and mannitol, and ‘low-dose’
dopamine have yielded inconsistent results in AKI.8,9 Although
loop diuretics may promote diuresis in oliguric renal failure, there
is little evidence that they influence outcome,10 and the large
doses of furosemide often required for diuresis in AKI can result
in ototoxicity. Similarly, the use of dopamine does not reduce
mortality or accelerate the recovery of renal function and, in the
critically ill, dopamine use can lead to peripheral vasoconstric-
tion, causing gut ischaemia, tissue necrosis and digital gangrene.
Hyperkalaemia
This life-threatening complication arises through cellular shifts of
potassium or release from lysed cells, together with decreased
renal excretion of potassium, and requires immediate treatment.
Acidosis, hyponatraemia and hypocalcaemia all potentiate the
harmful effects of hyperkalaemia on cardiac function and must
also be corrected. Muscle weakness may be present and, if se-
vere, can lead to flaccid paralysis, although symptoms are rarely
apparent until the serum potassium exceeds 7.0 mmol/litre. The
most serious effect is on cardiac conduction, which classically
presents as a shortened QT interval with a tall peaked T wave on
the electrocardiogram (ECG). Without treatment, progressive
lengthening of QRS duration and PR interval ultimately lead to a
‘sine wave’ appearance, followed by ventricular standstill or
fibrillation. A variety of other conduction disturbances may
occur, including bundle-branch block, bifascicular block and
advanced atrioventricular block. Asymptomatic patients with
serum potassium <6.5 mmol/litre, or whose ECG does not
manifest signs of hyperkalemia, should be treated with a low
potassium diet; additional sources of potassium intake should be
withheld and any potentiating drugs discontinued. (Specific
treatment of hyperkalaemia is set out in the article Assessment
and initial management of acute kidney injury (Table 3) on pages
000e000 of this issue.)
Acidosis
Metabolic acidosis in AKI results from increased acid production,
increased acid retention and decreased renal reabsorption of bi-
carbonate. Acidosis is exacerbated by sepsis, malnutrition and
some drugs, and is very common among critically ill patients and
acute admissions. Metabolic acidosis is easily detected by
measuring venous serum bicarbonate in the above patient groups
when requesting routine blood tests. (Specific treatment of
acidosis is set out is set out in the article Assessment and initial
management of acute kidney injury (Table 3) on pages 000e000
of this issue.)
MEDICINE --:-
Please cite this article in press as: Amery CE, et al., The management of acute kidney injury, Medicine (2015), http://dx.doi.org/10.1016/
j.mpmed.2015.05.015
Uraemic pericarditis
Uraemic pericarditis is observed in 6e10% of patients with
advanced renal failure, resulting from inflammation of both the
visceral and parietal membranes of the pericardial sac. Pericar-
ditis in AKI presents with fever and pleuritic chest pain, char-
acteristically worse in the recumbent position. A pericardial rub
may be heard on auscultation, although the ECG does not show
the typical diffuse ST and T wave elevations observed with other
causes of acute pericarditis. The development of pericarditis in a
patient with AKI is an indication to institute RRT, unless there are
signs of cardiac tamponade due to a pericardial effusion. Under
such conditions, heparin-free haemodialysis or haemofiltration
should be used because of the risk of increased bleeding into the
pericardial sac with anticoagulation.
Uraemic encephalopathy
Like uraemic pericarditis, uraemic encephalopathy tends to be
related to the degree of uraemia. Early clinical features include
rambling speech, disorientation, lethargy, irritability, hallucina-
tions and, more rarely, coma. Commonly encountered signs
include tremor, myoclonus and asterixis, which tend to occur with
deterioration in mental status. Transient focal signs, such as hem-
iparesis or reflex asymmetry, occur rarely but resolve with treat-
ment, although mental state may not improve for up to 48 hours. If
the signs do not resolve, other pathologies should be excluded.
Renal replacement therapy
Renal replacement therapy (RRT) does not cure acute kidney
injury but it is a safe and efficient way of replacing renal function
while the kidneys recover from disease or injury. Historically,
single-organ AKI has been treated with either peritoneal or
intermittent haemodialysis, which are the mainstay of chronic
renal replacement therapy. Hospitals with acute nephrology
services will perform haemodialysis in haemodynamically stable
patients, although RRT is most commonly performed acutely in a
level 2 or 3 facility employing haemodialysis or more commonly
continuous therapies such as haemofiltration or haemodiafiltra-
tion. However, more recently there has been a trend towards
using hybrid therapies such as prolonged intermittent renal
replacement therapy (PIRRT). Although superficially similar, the
mechanisms by which the composition of the blood is altered
differ markedly.11,12 In haemodialysis, blood flows along one
side of a semipermeable membrane as a solution of crystalloids
(the dialysis fluid) is pumped against the direction of the blood
flow along the other side of the membrane. Molecules diffuse
across the membrane from higher to lower concentrations driven
by the law of mass action. The composition of the dialysis fluid
allows as near normalization of the plasma as possible. The
dialysis-fluid compartment is under lower pressure, generating a
transmembrane pressure gradient enabling the removal of salt
and water. Haemofiltration in its simplest form involves the
passage of blood under pressure passing down one side of a
highly permeable membrane, allowing water and other mole-
cules up to a size of about 20 kDa to pass through the membrane
by convection. Thus, filtrate is discarded and replaced by an
idealized buffered replacement fluid, the crystalloid components
of which are at physiological concentration. Haemodiafiltration
as the name implies is a combination of the two therapies
2 Crown Copyright ! 2015 Published by Elsevier Ltd. All rights reserved.
 ACUTE KIDNEY INJURY
offering theoretically enhanced clearances of some middle mol-
ecules. Indications for renal replacement depend on the clinical
and biochemical derangements outlined above and, although
these are general indications, use will be guided by the clinical
situation. In the intensive care unit, for example, treatment may
begin before the absolute indications are reached, as there is
uncertainty surrounding the optimal timing of the initiation of
renal support. There is some evidence that, in the critically ill
intensively managed patient, early treatment may result in
improved outcome. However, a randomized controlled trial from
India in 2013, using intermittent therapies in a non-ITU popula-
tion, found that time to recovery of renal function was longer in
the group with early initiation of dialysis.13 A large multicentre
randomized controlled trial in critically ill patients is currently
recruiting participants.14
Practical aspects of renal replacement therapy
RRT requires access to the circulation. Various double-lumen
vascular catheters are commercially available, allowing blood
flow rates up to 200 ml/minute. Adequate venous access is critical
in preventing technical difficulties with blood flow from the pa-
tient and potential problems with clotting, leading to a loss of the
extracorporeal circuit. In most cases anticoagulation is required,
with unfractionated heparin being commonly used to prime the
circuits, and a continuous infusion is maintained through the
inflow side of the circuit. If the patient is thrombocytopenic,
alternative anticoagulants can be used, including sodium chlo-
ride, citrate or prostacyclin, but care must be taken with the latter
given its vasodilator effects. More recently, regional anti-
coagulation with citrate has increased in popularity with citrate
acting as both an anticoagulant and a buffer. Citrate is adminis-
tered as sodium citrate before the filter and chelates calcium ions.
The associated regional hypocalcemia in the filter inhibits the
generation of thrombin and thereby the clotting process. Citrate is
partially removed by filtration or dialysis and the remainder is
rapidly metabolized in the citric acid (Krebs) cycle e especially in
the liver, muscle and renal cortex. The chelated calcium is
released and the lost calcium replaced after the filter. Systemic
coagulation is therefore unaffected. For adequate anticoagulation,
the citrate dose is adjusted to blood flow to attain an ionized
calcium concentration <0.4 mmol/litre in the filter; it follows that
the lower the calcium concentration, the higher the degree of
anticoagulation, with various protocols being employed.15,16
In haemofiltration the flow rate, which reflects the rate of
ultrafiltrate produced and solute clearance, is taken as a surro-
gate for the dose. In 2000 Ronco et al.17 demonstrated survival
rates to be significantly lower in patients treated with ultrafil-
tration rates of 20 mL/kg/h compared to 35 mL/kg/h. However
more recently the Randomised Evaluation of Normal versus
Augmented Level of renal replacement therapy in ICU (RENAL)18
studied a dose of 35 mL/kg/h compared to 20 ml/kg/h and found
there to be no difference in mortality between the two groups at
90 days. The Acute Renal Failure Trial Network (ATN) demon-
strated similar findings when comparing the two doses and,
interestingly, recorded more hypotensive episodes in those
receiving the higher dose.19
High-volume haemofiltration (HVHF) defined as a treatment
dose of greater then 50 ml/kg/h has been cited as a potential
method of reducing cytokine levels and thereby reducing
MEDICINE --:-
Please cite this article in press as: Amery CE, et al., The management of acute kidney injury, Medicine (2015), http://dx.doi.org/10.1016/
j.mpmed.2015.05.015
mortality in patients with both AKI complicated by sepsis.
However, the IVOIRE (Impact of High-volume Venovenous
Continuous Haemofiltration in the Early Management of Septic
Shock Patients with Acute Renal Failure) study, which compared
patients treated with 70 ml/kg/h or 35 ml/kg/h, found no evi-
dence that HVHF leads to a reduction in mortality at 28 days or
contributes to early improvements in organ function.20 A
REFERENCES
1 Bellomo R, Ronco C, Kellum JA, Mehta R, Palevsky P. the ADQI
workgroup. Acute renal failureedefinition, outcome measures, ani-
mal models, fluid therapy and information technology needs: the
Second International Consensus Conference of the Acute Dialysis
Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204e12.
2 Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network:
report of an initiative to improve outcomes in acute kidney injury. Crit
Care 2007; 11: R31.
3 Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal
failure: from advocacy to consensus and validation of the RIFLE
criteria. Intensive Care Med 2007; 33: 409e13.
4 Haase M, Bellomo R, Matalanis G, Calzavacca P, Dragun D, Haase-
Fielitz A. A comparison of the RIFLE and acute kidney injury, network
classifications for cardiac surgery-associated acute kidney injury: a
prospective cohort study. J Thorac Cardiovasc Surg 2009; 138:
1370e6.
5 KDIGO clinical practice guideline for acute kidney injury. Kidney Int
Supplements 2012; 2.
6 Shemesh O, Golbetz H, Kriss JP, et al. Limitations of creatinine as a
filtration marker in glomerulopathic patients. Kidney Int 1985; 28:
830e8.
7 Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus
saline-based hetastarch and crystalloid solutions on acid base and
electrolyte status and gastric mucosal perfusion in elderly surgical
patients. Anesth Analg 2001; 93: 811e6.
8 Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute
renal failure. Crit Care Med 2004; 32: 1669e77.
9 Kellum JA, Decker M. Use of dopamine in acute renal failure: a met-
aanalysis. Crit Care Med 2001; 29: 1526e31.
10 Mehta RL, Chertow GM. Diuretics in critically ill patients with acute
renal failure. JAMA 2003; 289: 1379e81.
11 Forni LG, Hilton PJ. Continuous haemofiltration in the treatment of
acute renal failure. N Engl J Med 1997; 336: 1303e9.
12 D’Intini V, Ronco C, Bonello M, Bellomo R. Renal replacement therapy
in acute renal failure. Best Pract Res Clin Anaesthesiol 2004; 18:
145e57.
13 Jamale TE, Hase NK, Kulkarni M, et al. Earlier-start versus usual-start
dialysis in patients with community-acquired acute kidney injury: a
randomized controlled trial. Am J Kidney Dis 2013; 62: 1116e21.
14 Smith ON, Wald R, Adhikari N, et al. Standard versus accelerated
initiation of renal replacement therapy in acute kidney injury
(STARRT-AKI): study protocol for a randomized controlled trial. Trials
2013; 14: 320.
15 Joannidis Michael, Oudemans-van Straaten HM. Clinical review:
patency of the circuit in continuous renal replacement therapy. Crit
Care 2007; 11: 218.
16 Oudemans-van Straaten HM, Osterman M. Bench-to-bedside review:
citrate for continuous renal replacement therapy, from science to
practice. Crit Care 2012; 16: 249.
3 Crown Copyright ! 2015 Published by Elsevier Ltd. All rights reserved.
 ACUTE KIDNEY INJURY

17 Ronco C, Bellomo R, Homel P, et al. Effects of different doses in
continuous veno-venous haemofiltration on outcomes of acute
renal failure: a prospective randomised trial. Lancet 2000; 356:
26e30.
18 Bellomo R, Cass A, Cole L, et al. Intensity of continuous renal-
replacement therapy in critically ill patients (RENAL study). N Engl J
Med 2009; 361: 1627e38.
19 The VA/NIH Acute Renal Failure Trial Network. Intensity of renal
support in critically ill patients with acute kidney injury. N Engl J Med
2008; 359: 7e20.
20 The IVORE study group. High-volume versus standard-volume hae-
mofiltration for septic shock patients with acute kidney injury (IVOIRE
study): a multicentre randomized controlled trial. Intensive Care Med
2013; 39: 1535e46.

MEDICINE --:- 4 Crown Copyright ! 2015 Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Amery CE, et al., The management of acute kidney injury, Medicine (2015), http://dx.doi.org/10.1016/
j.mpmed.2015.05.015
 ARTIGO 3

SÍNDROMES GLOMERULARES
 1 Síndromes
glomerulares
Juliano Sacramento Mundim ® Viktoria Woronik

} Introdução
O acometimento glomerular pode ocorrer tanto em doenças sistêmicas,
situação na qual a glomerulopatia é dita secundária (nefrite lúpica, nefro-
esclerose diabética, etc.), como em doenças originárias do rim, situação
na qual a glomerulopatia é dita primária.
Independentemente do mecanismo da lesão envolvido, a lesão glomeru-
lar é acompanhada por alterações na função, estrutura e permeabilidade do
glomérulo, levando à passagem anormal de proteínas e de outros elementos
e à redução variável na função de filtração glomerular, além de ocasionar
distúrbios na excreção de sódio e água.
Em qualquer uma das formas, primária ou secundária, a lesão ao gloméru-
lo se manifesta por meio de alguns sintomas e sinais clínicos, listados a seguir:

} proteinúria: decorrente do aumento de permeabilidade glomerular;

} hematúria: decorrente da inflamação da parede capilar;
} elevação de ureia e creatinina: decorrente da queda no ritmo de filtração
glomerular;
} oligúria ou anúria: a depender da intensidade da inflamação glomerular
e queda do ritmo de filtração glomerular;
} hipertensão: decorrente, habitualmente, da retenção de fluido (sal e
água) pelo rim.

De forma geral, o achado de sinais e sintomas sugestivos de doença

glomerular requer, do ponto de vista diagnóstico, a realização de biópsia
renal. Há algumas poucas situações, entretanto, nas quais a biópsia renal
não é necessária. A síndrome nefrótica em crianças pode prescindir da re-
alização inicial de biópsia renal, uma vez que a doença de lesões mínimas
14 Silvia Titan

é preponderante nesta faixa etária, permitindo o início de tratamento com

corticoide mesmo sem a realização da biópsia. Na síndrome nefrítica aguda
com características clínicas e laboratoriais muito sugestivas de glomerulo-
nefrite pós-estreptocócica, particularmente se em situação de epidemia, a
biópsia pode ser indicada apenas naqueles casos de evolução desfavorável. A
biópsia renal também não costuma ser necessária em pacientes com quadro
clínico sugestivo de nefropatia diabética, ou seja, naqueles com diabetes de
longa data e com sinais de lesão em outros órgãos-alvo. A biópsia também
não está rotineiramente indicada em pacientes assintomáticos com doença
glomerular leve (p. ex., hematúria isolada), dado o prognóstico favorável
desse tipo de lesão.
Em todas as outras situações, a biópsia renal é imperativa. Vale notar
que as doenças glomerulares apresentam, muitas vezes, curso insidioso, o
que dificulta o diagnóstico precoce. Assim, o médico deve estar atento ao
achado de sinais sugestivos de glomerulopatias, indicando prontamente a
avaliação diagnóstica e a conduta terapêutica pertinentes.
As síndromes clínicas glomerulares podem ser classificadas como mos-
tra a Tabela 1.1. Cada uma das síndromes glomerulares será abordada em
capítulo específico neste livro.

} Achados clínicos
Hematúria microscópica assintomática
Caracteriza-se pelo achado de hematúria isolada ao exame de urina,
portanto sem a presença de proteinúria, alteração da função renal ou
manifestações sistêmicas de edema e hipertensão. É um achado comum,
pois ocorre em 5 a 10% da população, sendo, em sua maioria, de causa
urológica. Em pacientes acima de 40 anos de idade com micro-hematúria
persistente isolada sem evidência de origem glomerular, a cistoscopia é
obrigatória para excluir a malignidade uroepitelial.
Entre as hematúrias isoladas, apenas 10% ou menos são causadas
por glomerulopatias. Portanto, a investigação urológica é obrigatória, e
o achado de hemácias dismórficas, quando presente, sugere o diagnóstico
de glomerulopatia. O protocolo clínico de avaliação da biópsia renal em
adultos com hematúria microscópica assintomática (excluída causa uro-
lógica) mostrou rim normal em 30%; doença de membrana fina em 26%;
 Princípios Básicos de Nefrologia 15

glomerulopatia por IgA em 28%; e, no restante, glomerulonefrite membra-

noproliferativa e síndrome de Alport.

TABELA 1.1. SÍNDROMES CLÍNICAS E DOENÇAS (HISTOPATOLOGIA)

Hematúria microscópica assinto-

mática

Hematúria macroscópica recor-

rente

Síndrome nefrítica
-

GN rapidamente progressiva (GN

crescêntica)

Proteinúria assintomática

Síndrome nefrótica

Doença renal crônica estágios IV e V

Hematúria macroscópica recorrente

Nesta circunstância, o paciente relata o achado de urina de tom mar-
rom, sendo rara a presença de coágulos. A hematúria macroscópica deve
ser distinguida de outras causas de urina marrom ou vermelha, incluindo
hemoglobinúria, mioglobinúria, porfiria, consumo de comidas com coran-
tes, particularmente beterraba, e consumo de medicamentos ou outras
substâncias, em particular a rifampicina. A hematúria macroscópica requer
avaliação urológica, incluindo cistoscopia em qualquer idade, a menos que
a história seja característica de hematúria glomerular.
16 Silvia Titan

A hematúria recorrente é, em geral, episódica, relacionada a infecções

do trato respiratório e/ou exercício físico, autolimitada, ocorrendo predo-
minantemente em adolescentes e adultos jovens. As causas mais frequentes
são nefropatia por IgA, glomerulopatia da membrana basal fina, assim como
síndrome de Alport e suas variantes.
Na nefropatia por IgA, a hematúria é franca, episódica e ocorre geral-
mente um dia após infecção respiratória de vias áreas superiores. Difere,
portanto, da manifestação de glomerulonefrite difusa aguda (GNDA), na
qual a hematúria macroscópica ocorre duas a três semanas após o quadro
infeccioso, geralmente de etiologia estreptocócica.

Glomerulonefrite aguda ou síndrome nefrítica

As doenças que produzem inflamação glomerular aguda são aquelas que
se exteriorizam de forma mais exuberante com síndrome nefrítica, carac-
terizada por edema, hipertensão, hematúria e graus variáveis de insufici-
ência renal, além de proteinúria pouco intensa (< 3 g/dia). São chamadas
de difusas quando o acometimento glomerular ocorre em mais de 50% do
total de glomérulos da biópsia, e denominadas focais quando há menos de
50% de glomérulos acometidos. Neste grande grupo de doenças, as causas
imunológicas são as mais comuns, como nefrite lúpica, nefropatia por IgA
e glomerulonefrite difusa aguda pós-infecciosa. Para o diagnóstico das glo-
merulopatias mais comuns que se exteriorizam sob a forma nefrítica, alguns
aspectos clínico-sorológicos mais importantes estão listados na Tabela 1.2.

TABELA 1.2. TESTES SOROLÓGICOS E ASSOCIAÇÕES COM SÍNDROME NEFRÍTICA

Doença Associação Teste sorológico
Glomerulonefrite pós-estreptocócica ASLO
Endocardite
Shunt Hidrocefalia tratada
História
Glomerulopatia por IgA
Lúpus eritematoso sistêmico rash malar

A apresentação clássica da síndrome nefrítica é vista na glomerulone-

frite difusa aguda pós-estreptocócica em crianças. As crianças geralmente
apresentam oligúria, ganho de peso e edema generalizado de apresentação
 Princípios Básicos de Nefrologia 17

aguda (poucos dias). O exame de urina revela proteinúria, hematúria e, co-

mumente, a presença de cilindros hemáticos. A proteinúria costuma ocorrer
em valor não nefrótico e a albumina sérica é geralmente normal. O volume
circulante está aumentado, causando hipertensão e, eventualmente, edema
pulmonar sem evidência de doença cardíaca primária.

Glomerulonefrite rapidamente progressiva

Aqui as manifestações são as de síndrome nefrítica, mas associadas
à perda rápida da função renal (dias ou semanas). A lesão histológica
responsável pela natureza agressiva da lesão é a crescente glomerular.
A crescente decorre da proliferação das células epiteliais da cápsula de
Bowman, promovida pelo intenso processo inflamatório que ocorre no
glomérulo, sendo o macrófago uma célula particularmente importante em
sua gênese. Quando há mais de 50% de glomérulos acometidos por cres-
centes, o diagnóstico histopatológico é de glomerulonefrite crescêntica,
que se expressa clinicamente por perda rápida e intensa da função renal.
Portanto, existe correlação clínica entre número de crescentes e gravidade
da doença. Assim, doenças com mais de 80% de crescentes se exteriorizam,
geralmente, por insuficiência renal dialítica. A causa mais comum dessa
forma de glomerulonefrite crescêntica é a vasculite. Doenças de imuno-
complexos, como nefropatia por IgA e nefrite lúpica, expressam-se mais
comumente com número menor de crescentes e, portanto, quadro clínico
renal mais brando. A resolução (involução) dos crescentes depende, entre
outros fatores, da sua idade histológica, ou seja, sua natureza epitelial ou
fibroblástica. No entanto, outros fatores também participam desse processo,
já que crescentes da mesma “idade” histológica em nefrite lúpica revertem
mais facilmente ao tratamento do que os de nefropatia por IgA.
São três os grupos mais frequentes de doenças que se apresentam como
glomerulonefrite rapidamente progressiva: glomerulonefrite antimembrana
basal glomerular, glomerulonefrite por imunocomplexos e glomerulonefrite
relacionada a ANCA. As formas relacionadas a ANCA podem se apresentar
com manifestações sistêmicas de Wegener, poliangeíte microscópica e
Churg-Strauss, ou ter manifestação exclusivamente renal. A forma relacio-
nada ao anticorpo antimembrana basal glomerular pode se apresentar como
doença de Goodpasture ou sem sinais de comprometimento pulmonar. As
18 Silvia Titan

doenças de imunocomplexos mais comumente encontradas são a nefrite

lúpica, a crioglobulinemia (sendo a forma mais comum à secundária ao
vírus da hepatite C) e a nefropatia por IgA. Para o diagnóstico das doenças
glomerulares que se apresentam sob a forma rapidamente progressiva, os
aspectos clínico e sorológico mais importantes estão na Tabela 1.3.

TABELA 1.3. DOENÇAS GLOMERULARES QUE SE APRESENTAM COMO GLOMERULONEFRITE RAPIDAMENTE PROGRESSIVA
Doença Associação Teste sorológico
Doença de Goodpasture Hemorragia alveolar
Granulomatose de Wegener ANCA C (citoplasmático)
Poliangeíte microscópica Envolvimento multissistêmico ANCA P (perinuclear)
Vasculite pauci-imune Somente envolvimento renal ANCA P (perinuclear)
Lúpus eritematoso sistêmico Envolvimento sistêmico
Glomerulonefrite pós-estreptocócica Faringite/impetigo
Nefropatia por IgA/púrpura de
Henoch-Schönlein
Endocardite

Proteinúria assintomática
É definida quando existe proteinúria isolada em valores acima de 150 mg/dia
e abaixo de 3 g/dia na ausência de outros achados urinários, como hematúria,
e, também, sem sinais ou sintomas sistêmicos, como edema e/ou hipertensão.
É, portanto, um diagnóstico feito por exame de urina. As doenças mais
frequentes neste grupo são a glomeruloesclerose segmentar e focal (GESF)
e a glomerulonefrite membranosa (Tab. 1.1), de evolução benigna, a me-
nos que mudem suas características clínicas com o desenvolvimento de
hipertensão ou proteinúrias nefróticas.
A microalbuminúria é definida como a excreção de 30 a 300 mg de
albumina/dia (equivalente à relação albumina/creatinina urinária entre
0,03 e 0,3). Este parâmetro também é utilizado para identificar o risco de
desenvolvimento de nefropatia em pacientes diabéticos, assim como risco
cardiovascular em pacientes hipertensos.
O achado de outras proteínas urinárias, que não a albumina, tem signi-
ficado fisiopatológico próprio. Assim, a proteinúria tubular, constatada pelo
achado urinário de beta-2-microglobulina, retinol binding protein (RBP) ou
de outras proteínas de baixo peso molecular, é característica de doenças
 Princípios Básicos de Nefrologia 19

com comprometimento tubulointersticial, seja de natureza primária ou

secundária à glomerulopatias (p. ex., GESF). Além de seu papel diagnóstico
em relação ao tipo de proteinúria presente, os marcadores de proteinúria
tubular são clinicamente úteis como marcadores de mau prognóstico em
diversas doenças, como ocorre na própria GESF e no transplante renal.
A proteinúria encontrada em estados de hiperprodução de proteínas, parti-
cularmente cadeias leves de globulinas, filtradas pelo glomérulo, é característica
de paraproteinemias e deve ser pesquisada ativamente, já que as proteínas
não são detectadas por testes laboratoriais que detectam somente albumina.
O achado de pequenas quantidades de albumina também pode ocorrer
em certas situações funcionais, não patológicas, como febre ou estados hi-
peradrenérgicos, sendo denominada de proteinúria funcional, que também
pode ser desencadeada pela posição ortostática e deambulação, quando é
chamada de ortostática.
Quanto à indicação de biópsia renal em proteinúria assintomática, geral-
mente, ela não está indicada, sobretudo se a proteinúria for inferior a 1 g/dia.

Síndrome nefrótica
É uma síndrome clínico-laboratorial decorrente do aumento de per-
meabilidade às proteínas plasmáticas, caracterizando-se por proteinúria
acima de 3,5 g/1,73 m2 de superfície corpórea/dia, com consequente hi-
poalbuminemia e edema.
O achado de hiperlipidemia não é obrigatório, porém é muito comum,
assim como os distúrbios relacionados à hipercoagulabilidade por perda
de fatores inibidores de coagulação, a desnutrição proteica e a suscetibili-
dade às infecções. Dentre as glomerulopatias que mais causam síndrome
nefrótica estão, entre as primárias, a glomerulopatia de lesões mínimas,
GESF e glomerulonefrite membranosa, e, entre as secundárias, a glome-
ruloesclerose diabética (Tab. 1.1). As doenças clínicas mais comuns que
se apresentam como síndrome nefrótica estão na Tabela 1.4.

Doença renal crônica (estágios IV e V)

A maioria das glomerulopatias, com exceção da glomerulopatia de lesões
mínimas e da nefropatia da membrana basal fina, pode evoluir para lesão
glomerular crônica esclerosante, com manifestações clínicas de insuficiência
20 Silvia Titan

renal. Estatísticas brasileiras do Ministério da Saúde mostram que as glo-

merulonefrites são, no momento, a segunda causa de doença renal crônica
terminal no país, atrás apenas da hipertensão arterial.

Doença Teste sorológico

Nenhum
GESF Sorologia para HIV
-
nosa neoplasia FAN/anti-DNA
-
proliferativa ou normais
- -

Amiloidose Imunoeletroforese no soro e na urina

Nenhum

AINH = anti-inflamatório não hormonal; GESF = glomeruloesclerose segmentar e focal;

LES = lúpus eritematoso sistêmico.

} Diferenças clínico-laboratoriais entre

síndromes nefrítica e nefrótica
O diagnóstico clínico das síndromes nefrítica e nefrótica frequentemente
não é fácil, pela superposição de sintomas e sinais entre as duas síndromes.
No entanto, como orientação diagnóstica, algumas diferenças podem ser
encontradas na Tabela 1.5.

Sintoma/sinal Síndrome nefrótica Síndrome nefrítica

Instalação Insidiosa
Edema ++++ ++
Pressão arterial Normal Alta
Proteinúria ++++ + ou ++
Hematúria - ou + +++
Normal

} Glomerulopatias e síndromes nefrítica e

nefrótica
É sabido que o diagnóstico histológico de uma glomerulopatia não
permite, via de regra, inferir quanto à sua exteriorização nefrítica ou ne-
 Princípios Básicos de Nefrologia 21

frótica. Assim, apenas a glomerulopatia de lesões mínimas se exterioriza na

forma nefrótica sempre. As doenças glomerulares que mais se aproximam
de formas nefríticas puras são a GNDA e a glomerulonefrite crescêntica,
como descrito na Tabela 1.6.

TABELA 1.6. ASPECTOS NEFRÍTICOS E NEFRÓTICOS EM DOENÇAS GLOMERULARES

Doenças glomerulares Aspectos nefróticos Aspectos nefríticos

Glomerulopatia de lesão mínima ++++ -
++++ +
GESF +++ ++
+++ ++
Glomerulopatia proliferativa mesangial ++ ++
++ +++
GNDA + ++++
Glomerulonefrite crescêntica + ++++

} Glomerulopatias primárias e frequência de

distribuição
Dados provenientes do Registro Paulista de Glomerulopatias (RPG)
mostram que, no estado de São Paulo, as biópsias renais de 1.844 pacientes
foram indicadas por:

} síndrome nefrótica em 41,5% dos casos;

} hematúria associada a proteinúria em 27,2%;
} doença renal crônica em 8,9%;
} síndrome nefrítica-nefrótica em 7,9%;
} glomerulonefrite rapidamente progressiva em 7,1%;
} hematúria isolada em apenas 1,9% dos casos.

Outras casuísticas podem apresentar perfis diferentes quanto a sintomas

clínicos indicativos de biópsia, acarretando inclusive diferentes distribui-
ções de glomerulopatias. É conhecido que, no Japão, onde a indicação de
biópsia renal por hematúria isolada é mais ampla, a frequência de glome-
rulopatia por IgA é maior.
22 Silvia Titan

Ainda em relação à casuística do RPG, apenas em glomerulopatias

primárias (n = 1.131), o perfil de distribuição é o seguinte:

} GESF: 29,7%;
} glomerulonefrite membranosa: 20,7%;
} glomerulopatia por IgA: 17,8%;
} glomerulopatia de lesões mínimas: 9,1%;
} glomerulonefrite membranoproliferativa: 7%;
} glomerulonefrite crescêntica: 4,1%;
} glomerulonefrite proliferativa não IgA: 3,8%;
} GNDA: 2,5% e outras.

Os dados da Tabela 1.7 mostram uma comparação entre nossa casuística

e a de outros países.

TABELA 1.7. FREQUÊNCIA DAS VÁRIAS FORMAS DE DOENÇAS GLOMERULARES PRIMÁRIAS EM DIFERENTES PAÍSES

Brasil n: Itália n: Romênia China n:

1.131 (%) 6.990 (%) Tcheca n: 9.278 (%)
2.333 (%)
GESF 6

Nefropatia por IgA

- 7
ferativa
Glomerulonefrite crescêntica
Glomerulonefrite mesangial não IgA -- --

Outras 7

} Tópicos importantes
} O acometimento glomerular pode ocorrer tanto em doenças sistêmicas
(glomerulopatia secundária), como em doenças originárias do rim (glo-
merulopatia primária).
} Geralmente o achado de doença glomerular implica a realização de bi-
ópsia renal. Há situações, entretanto, nas quais a biópsia renal não é ne-
 Princípios Básicos de Nefrologia 23

cessária, por exemplo crianças com síndrome nefrótica isolada (doença

de lesões mínimas é o diagnóstico mais provável, permitindo o início de
tratamento com corticoide mesmo sem a realização da biópsia), em pa-
cientes com síndrome nefrítica aguda com características muito sugestivas
de glomerulonefrite pós-estreptocócica e que estejam evoluindo favoravel-
mente e em pacientes com quadro clínico muito sugestivo de nefropatia
diabética. A biópsia também não está rotineiramente indicada em pacien-
tes assintomáticos com doença glomerular leve (p. ex., hematúria isolada.

} Leituras sugeridas
Barros RT, Sens YAS. Propedêutica das glomerulopatias. In: Barros RT, Alves MAR,
Dantas M, Kirsztajn GM, Sens YAS. Glomerulopatias: patogenia, clínica e trata-
mento. 2. ed. São Paulo: Sarvier; 2005.
Carvalho MFC, Franco MF, Soares VA. Glomerulonefrites primarias. In: Riella MC.
Princípios de nefrologia e distúrbios hidroeletrolíticos. 4. ed. Rio de Janeiro: Gua-
nabara Koogan; 2003.
Covic A, Schiller A, Volovat C, Gluhovschi G, Gusbeth-Tatomir P, Petrica L, et al.
Epidemiology of renal disease in Romania: a 10 year review of two regional renal
biopsy databases. Nephrol Dial Transplant. 2006;21(2):419-24.
Feehally J, Johnson RJ. Introduction to glomerular disease: clinical presentations.
In: Feehally J, Floege J, Johnson RJ. Comprehensive clinical nephrology. 3rd ed.
Philadelphia: Mosby; 2007.
Gesualdo L, Di Palma AM, Morrone LF, Strippoli GF, Schena FP. The Italian ex-
perience of the national registry of renal biopsies. Kidney Int. 2004;66(3):890-4.
Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained
adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979
and 1995-1997. Am J Kidney Dis. 1997;30(5):621-31.
Jennette JC, Falk RJ. Glomerular clinicopathologic syndromes. In: Greenberg A. Primer
on kidney diseases. 3rd ed. San Diego: Academic; 2001. p. 129-43.
Li LS, Liu ZH. Epidemiologic data of renal diseases from a single unit in China: analysis
based on 13,519 renal biopsies. Kidney Int. 2004;66(3):920-3.
Malafronte P, Mastroianni-Kirsztajn G, Betônico GN, Romão Jr JE, Alves MA, Carvalho
MF, et al. Paulista registry of glomerulonephritis: 5-year data report. Nephrol Dial
Transplant. 2006;21(11):3098-105.
Meyer TW. Tubular injury in glomerular disease. Kidney Int. 2003;63:774-87.
Morales JV. Glomerulopatias. In: Barros E, Manfro RC, Thomé FS, Gonçalves LFS.
Nefrologia: rotinas, diagnóstico e tratamento. 3. ed. Porto Alegre: Artmed; 2006.
v. 1, p. 189-212.
24 Silvia Titan

Nachman PH, Jennette JC, Falk RJ. Primary glomerular disease. In: Brenner BM. Bren-
ner and Rector’s the kidney. 8th ed. Philadelphia: Saunders Elsevier; 2008. cap. 30.
Oliveira MB, Saldanha LB, Mota EL, Penna DO, Barros RT, Romão Junior JE. Primary
glomerular diseases in Brazil (1978-1999): is the frequency of focal and segmental
glomeruloesclerosis increasing? Clin Nephrol. 2004;61:90-7.
Rychlík I, Jancová E, Tesar V, Kolsky A, Lácha J, Stejskal J, et al. The Czech registry
of renal biopsies. Occurrence of renal diseases in the years 1994-2000. Nephrol
Dial Transplant. 2004;19(12):3040-9.
Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA. Management of
glomerular proteinuria: a commentary. J Am Soc Nephrol. 2003;14:3217-32.
 ARTIGO 4

ACESSO VASCULAR
Saugel et al. Critical Care (2017) 21:225
DOI 10.1186/s13054-017-1814-y

REVIEW Open Access

Ultrasound-guided central venous catheter

placement: a structured review and
recommendations for clinical practice
Bernd Saugel1* , Thomas W. L. Scheeren2 and Jean-Louis Teboul3

Abstract
The use of ultrasound (US) has been proposed to reduce the number of complications and to increase the safety
and quality of central venous catheter (CVC) placement. In this review, we describe the rationale for the use of US
during CVC placement, the basic principles of this technique, and the current evidence and existing guidelines for
its use. In addition, we recommend a structured approach for US-guided central venous access for clinical practice.
Static and real-time US can be used to visualize the anatomy and patency of the target vein in a short-axis and a
long-axis view. US-guided needle advancement can be performed in an "out-of-plane" and an "in-plane" technique.
There is clear evidence that US offers gains in safety and quality during CVC placement in the internal jugular vein.
For the subclavian and femoral veins, US offers small gains in safety and quality. Based on the available evidence
from clinical studies, several guidelines from medical societies strongly recommend the use of US for CVC
placement in the internal jugular vein. Data from survey studies show that there is still a gap between the existing
evidence and guidelines and the use of US in clinical practice. For clinical practice, we recommend a six-step
systematic approach for US-guided central venous access that includes assessing the target vein (anatomy
and vessel localization, vessel patency), using real-time US guidance for puncture of the vein, and confirming the
correct needle, wire, and catheter position in the vein. To achieve the best skill level for CVC placement the
knowledge from anatomic landmark techniques and the knowledge from US-guided CVC placement need to be
combined and integrated.
Keywords: Central venous access, Ultrasound, Internal jugular vein, Subclavian vein, Femoral vein, Short axis,
Long axis, Out of plane, In plane

Background technique, and the current evidence and existing guide-

Although placement of a central venous catheter (CVC) lines for its use. In addition, we recommend a structured
is a routine procedure in intensive care medicine and approach for US-guided central venous access for clinical
anesthesiology, acute severe complications (such as practice.
arterial puncture or cannulation, hematoma, hemotho-
rax, or pneumothorax) occur in a relevant proportion
Rationale for ultrasound-guided central venous
of patients [1, 2]. The use of ultrasound (US) has been
catheter placement
proposed to reduce the number of CVC complications
Traditionally, CVC placement is performed using land-
and to increase the safety and quality of CVC placement.
mark techniques based on the knowledge of anatomic
In this review, we describe the rationale for the use of
structures and palpation of arteries next to the veins.
US during CVC placement, the basic principles of this
These landmark techniques cannot account for anatomic
* Correspondence: bcs.muc@gmx.de; bernd.saugel@gmx.de variations at the CVC insertion site. Anatomic variations
1
Department of Anesthesiology, Center of Anesthesiology and Intensive Care to the "normal anatomy", however, have been described
Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, in a relevant proportion of patients for the internal jugular
20246 Hamburg, Germany
Full list of author information is available at the end of the article vein (IJV), the subclavian vein (SV), and the femoral vein
(FV) [3–11]. In addition to anatomic variations, venous
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Saugel et al. Critical Care (2017) 21:225
thrombosis that is especially common in oncologic and
critically ill patients can make CVC placement impossible
or dangerous for the patient [9].
The described anatomic variations and the presence of
venous thrombosis can hardly be identified using a land-
mark technique. In contrast, US can be used to easily
visualize anatomic structures and confirm patency of the
vein and thus help to avoid unintended arterial puncture
or unsuccessful cannulation. In addition, US can facili-
tate CVC placement in special clinical situations in
which landmark techniques based on palpation of the
arterial pulse are challenging or impossible (e.g., femoral
CVC placement during cardiopulmonary resuscitation
[12] or in patients with a nonpulsatile ventricular assist
device).
Ultrasound for central venous catheter placement:
basic principles and techniques
Ultrasound probe
US probes best suited for CVC placement are small linear
array probes with high-frequency transducers (5–15 MHz)
[13]. These probes usually have a scanning surface of
about 20–50 mm and allow high-resolution imaging of
superficial anatomic structures [13]. 2D imaging (comple-
mented by Doppler US functions) is currently the stand-
ard technique used for US-guided central venous access
[13]. All US probes have an index mark (a small physical
notch on one side of the probe) that corresponds with an
orientation marker on one side of the US scan sector
shown on the US device screen and thus helps to obtain
the correct probe orientation during US examination.
Preferably, US machines should have the ability to record
and save US images and loops for clinical documentation
(and teaching purposes) [13].
Ultrasound techniques for central venous catheter
placement
US can be used in different ways to facilitate CVC place-
ment. "Static" US (also called indirect US) describes a
technique using US only before CVC placement to iden-
tify the anatomy of the target vein and adjacent anatomic
structures (including the patency of the vein and its
dimensions and depth from the skin) [14]. This ap-
proach of preprocedural US evaluation is also referred
to as "US-assisted" CVC placement.
In contrast, "real-time" US (also called direct US)
describes a technique of needle advancement and vessel
puncture under permanent US control (i.e., the needle is
permanently visualized on the US screen). This is also
referred to as "US guidance" [14].
Short-axis/long-axis and out-of-plane/in-plane views
The US probe can be placed in a transverse position
relative to the vessel, resulting in a "short-axis" view on
Page 2 of 11
the US screen (i.e., a cross-sectional image of the vessel).
A "long-axis" view (i.e., a longitudinal image of the ves-
sel) is obtained by placing the US probe in a parallel
position relative to the course of the vessel. Short-axis
and long-axis views can be used for both US assistance
and guidance of CVC placement. Of note, the terms
"out-of-plane" and "in-plane" describe the direction of the
needle relative to the US plane, refer to US-guided needle
advancement, and should not be mixed up with the terms
"short-axis" and "long-axis".
For real-time US guidance, different US approaches
can be used. US guidance during needle advancement
can be performed using: a short-axis probe orientation
and an out-of-plane view of the needle (Fig. 1a); a long-
axis probe orientation and an in-plane view of the needle
(Fig. 1b); or a so-called oblique orientation [15]. It is im-
portant to understand that the user needs to align the
US plane and the needle plane containing the needle
that appears on the screen as a point (short-axis/out-
of-plane) or an echogenic line (long-axis/in-plane)
with ring-down artifacts [14].
Whether or not one approach is superior to the other
cannot be answered rigorously based on the existing
data. The advantage of the short-axis/out-of-plane view is
that it allows better visualization of the vein in relation to
the artery and other anatomic structures, and thus might
more sufficiently help to avoid accidental arterial puncture
[15]. The short-axis/out-of-plane approach is easier to
learn for physicians not familiar with US [16]. Among ex-
perienced US users, the short-axis/out-of-plane approach
seems to result in a higher success rate with the first at-
tempt for CVC placement in the IJV and SV [17, 18].
However, in the short-axis view, the needle is only visual-
ized as an echogenic point (that must not necessarily be
the tip of the needle). In contrast, when using the long-
axis/in-plane view, the entire needle in its complete course
and the depth of the needle tip can be visualized on the
US image, thus reducing the risk of penetration of the
posterior vessel wall [15, 19].
Combining advantages of both techniques, the oblique
axis view (a view that is halfway between the short-axis
and the long-axis view with the US probe placed at
approximately 45° with respect to the target vessel) can
be used by experienced US users [20, 21].
Can ultrasound make central venous catheter placement
safer? What is the evidence?
The use of US to reduce the number of complications
related to vascular access for CVC placement has been
evaluated in numerous previous studies in a variety of
clinical settings. Recent Cochrane systematic reviews and
meta-analyses summarize the current evidence for US
guidance versus anatomic landmark techniques for CVC
placement in the IJV [22], SV [23], and FV [23] with
Saugel et al. Critical Care (2017) 21:225
Fig. 1 Ultrasound probe orientation and view of the needle. Ultrasound guidance during needle advancement can be performed using a short-
axis probe orientation and an out-of-plane view of the needle (a) or a long-axis probe orientation and an in-plane view of the needle (b)
regard to complications of CVC placement. These meta-
analyses included adult and pediatric patients treated in
the intensive care unit or the operating room and com-
pared conventional landmark techniques with techniques
using static or real-time US or Doppler US. The primary
outcome measure was the total rate of peri-interventional
complications and adverse events.
For the IJV, 35 trials enrolling a total of 5108 patients
were included in the meta-analysis [22]. The analysis
demonstrated that the use of US for CVC placement in
the IJV reduces the total rate of complications compared
with conventional landmark techniques (US, 48 compli-
cations in 1212 patients (4.0%) vs landmark, 161/1194
(13.5%); risk ratio (95% confidence interval (CI)) 0.29
(0.17–0.52)). The overall success rate was higher when
US was used (US, 2120/2172 (97.6%) vs landmark, 1900/
2168 (87.6%); risk ratio (95% CI) 1.12 (1.08–1.17)) [22].
In addition, the use of US resulted in a decrease in the
rate of arterial puncture, hematoma formation, and
number of attempts and time until successful cannula-
tion, and in an increase in the success rate with the first
attempt of puncture [22]. The benefits of US-guided or
US-assisted CVC placement with regard to the total
complication rate, overall success rate, and number of
attempts until success were consistent across experi-
enced and inexperienced operators. Thus, this meta-
analysis clearly provides evidence that US offers gains
in safety and quality during CVC placement in the
IJV. The quality of the evidence, however, was very
Page 3 of 11
low for most outcome measures and the heterogeneity
among the studies was high.
For the SV, a meta-analysis including nine studies with
2030 patients showed that the use of US resulted in a re-
duced rate of accidental arterial puncture (US, 2/242
(0.8%) vs landmark, 15/256 (5.9%); risk ratio (95% CI)
0.21 (0.06–0.82)) and hematoma formation (US, 3/242
(1.2%) vs landmark, 17/256 (6.6%); risk ratio (95% CI) 0.26
(0.09–0.76)) [23]. However, no statistically significant
difference was found between the use of US and the
conventional landmark technique with regard to the total
complication rate, the overall success rate, the number of
attempts until success, the time to successful cannulation,
and the success rate with the first attempt [23].
For CVC placement in the FV, the use of US com-
pared with the landmark technique increased the overall
success rate (US, 134/150 (89.0%) vs landmark, 127/161
(78.9%); risk ratio (95% CI) 1.11 (1.00–1.23)) and the
success rate with the first attempt (US, 91/107 (85.0%)
vs landmark, 57/117 (48.7%); risk ratio (95% CI) 1.73
(1.34–2.22)) [23].
Although the use of US offers small gains in safety and
quality, the authors conclude that the meta-analysis does
not generally support the use of US for CVC placement
in the SV and FV [23].
On behalf of the Canadian Perioperative Anesthesia
Clinical Trials Group, Lalu et al. [24] performed a
systematic review and meta-analysis of US-guided SV
catheterization. Based on data from 10 studies (including
Saugel et al. Critical Care (2017) 21:225
2168 patients; six real-time US studies, one static US
study, three Doppler US studies), the authors revealed
that US reduced the overall complication rate compared
with the landmark technique (odds ratio (95% CI) 0.53
(0.41–0.69)). Real-time US particularly reduced acci-
dental arterial puncture, pneumothorax, and hematoma
formation.
A CVC via the SV can be placed using either an infra-
clavicular (most commonly used) or a supraclavicular
approach. To the best of our knowledge there are no
randomized controlled trials on US-guided CVC place-
ment via the SV comparing the supraclavicular and the
infraclavicular approach. The supraclavicular approach
(using different US probes) needs to be evaluated in fu-
ture studies.
When discussing the evidence for US during CVC
placement at the different anatomic sites based on the
available studies and meta-analyses, one needs to keep
in mind that—compared to the IJV—it might be more
challenging to prove the advantages of US for CVC
placement in the SV, because the ultrasound approach is
technically more challenging, and in the FV, because se-
vere complications other than arterial puncture occur
infrequently.
Guidelines for ultrasound-guided central venous
catheter placement
Various recommendations and guidelines with different
clinical scopes and for different target audiences have
been published during the last years.
In 2012, a joint guideline from the American Society
of Echocardiography and the Society of Cardiovascular
Anesthesiologists [15] strongly recommended the use of
real-time US for CVC placement in the IJV (category A,
level 1 evidence), while it was not recommended for
the SV (category A, level 3 evidence). For the FV, no
recommendation for routine use of US was made be-
cause of insufficient scientific evidence (category C,
level 2 evidence).
A practice guideline from the American Society of
Anesthesiologists task force, also in 2012 [25], recom-
mended the use of static US imaging in elective situa-
tions for prepuncture identification of the anatomy and
to evaluate the vessel localization and patency and real-
time US for venipuncture for the IJV. Further, it is recom-
mended that both static and real-time US "may" be used
for CVC placement in the SV or FV [25].
For CVC placement in critically ill patients treated in
the intensive care unit, an international expert panel rec-
ommended in 2012 the routine use of US for short-term
and long-term central venous access in adults [13]. More
specifically, the panel recommended the utilization of
2D US imaging with a long-axis/in-plane technique for
vascular access [13] and agreed on the very strong
Page 4 of 11
recommendation (based on Level A evidence) that "US-
guided vascular access has to be used because it results
in clinical benefits and reduced overall costs of care
makes it cost-effective” [13].
The guidelines for the appropriate use of bedside gen-
eral and cardiac US from the American College of Critical
Care Medicine [26] give a strong (1-A) recommendation
for the general use of US for central venous access in real-
time technique (1-B) using a short-axis approach (1-B).
Regarding the site for CVC placement, the guidelines give
a strong (1-A) recommendation for the IJV and the FV,
but a conditional recommendation (2-C) for the SV [26].
A guideline from the European Federation of Societies
for Ultrasound in Medicine and Biology (EFSUMB) [9]
also recommends pre-interventional US vessel screening
of target vessels to determine the most appropriate ana-
tomical site and the optimal patient position (5-D) and
routine real-time US guidance during CVC placement
(1-A) [9].
In 2016, the Association of Anaesthetists of Great
Britain and Ireland [27] also recommended the routine
use of US for CVC placement in the IJV. In addition,
the expert group recommends US use "for all other
central venous access sites, but recognizes evidence is,
at present, limited" [27]. Nevertheless, the recommen-
dation also underlines that the understanding of the
landmark technique is necessary for situations when
US is not available.
Use of ultrasound for central venous catheter
placement in clinical practice
Several survey studies evaluated the attitudes and beliefs
of intensivists and anesthesiologists on the use of US for
CVC placement and the frequency of its use in clinical
practice.
In 2008, McGrattan et al. [28] performed a survey
among 2000 senior anesthesiologists in the United King-
dom and revealed that only 27% of these stated using
US as the first-choice approach for CVC placement in
the IJV (50% used the surface landmark technique and
30% palpation of the carotid artery as first-choice
approaches).
Among emergency physicians in the United States,
44% stated in 2014 that they never use US to guide CVC
placement [10]. On the other hand, 20% and 9% of
respondents stated using US in at least 90% and 100% of
cases, respectively.
A survey among 784 intensivists in the United States
performed in 2016 [29] revealed a moderate to very
frequent use of US depending on the site for CVC
placement ranging from 31% for the SV to 80% for the
IJV (45% for the FV). Barriers to the use of US re-
ported by these respondents were limited availability
Saugel et al. Critical Care (2017) 21:225 Page 5 of 11

of US equipment (28%), perception of increased time

for US-guided CVC insertion (22%), and concerns about a
losing skills for the landmark technique (13%) [29].
Among 190 French intensivists, a practice survey [30]
reported high rates of US use for CVC placement in
2016, with 18% and 50% of physicians always or almost
always, respectively, using an US-guided CVC technique
(6% never, 10% almost never, 17% half of the time).
Interestingly, a higher proportion of residents compared
with senior doctors stated always or at least almost al-
ways using US.

How to perform ultrasound-guided central venous b

catheter placement? Recommendations for clinical
practice—a systematic approach
For clinical practice, we recommend a systematic ap-
proach including the following steps:

I. Identify anatomy of the insertion site and

localization of the vein.
II. Confirm patency of the vein.
III.Use real-time US guidance for puncture of the vein.
IV.Confirm needle position in the vein.
V. Confirm wire position in the vein.
VI.Confirm catheter position in the vein. Fig. 2 Ultrasound views to identify the anatomy of the target vein.
Short-axis (transverse) view (a) and long-axis (longitudinal) view (b)
of the right internal jugular vein (*) and its anatomic relation to the
Identify anatomy of the insertion site and localization of carotid artery (#)
the vein
As a first step, one should use US to identify the anatomy Confirm patency of the vein
of the insertion site (vein and artery, adjacent anatomic By applying pressure to the vein and thus testing its
structures) and the localization of the target vein. This compressibility with the US probe, one can confirm the
includes checking for anatomic variations of the vessels patency of the vein and thus exclude venous thrombosis.
(both vein and artery) and the localization of the vein in Of note, in patients with very low arterial blood pressure
relation to the artery. This step requires combining a pro- (systolic arterial pressure < 60 mmHg), the artery might
found knowledge about anatomic structures and landmarks also be compressible [14].
with the competencies required for US-guided CVC place-
ment (such as knowledge about probe orientation and
image display, converting the 2D US image into 3D real-
ity, and hand–eye coordination) [31]. Given the variability
in anatomic structures, this first step of US assessment is
best performed before prepping and draping of the punc-
ture site and the US probe.
The location of the vein and its anatomic relation to
the artery is best identified when using both a short-axis
(transverse) and a long-axis (longitudinal) view of the
vessels (Fig. 2a, b). This also allows identifying hypoplas-
tic veins or underfilling of the veins due to intravascular
hypovolemia (Fig. 3). To exactly differentiate between
venous and arterial vessels one can additionally perform Fig. 3 Ultrasound view of a small internal jugular vein. Short-axis
color Doppler imaging and apply Doppler flow measure- (transverse) view of a small right internal jugular vein (*) and
its anatomic relation to the carotid artery (#) (e.g., in a patient
ments to derive venous and arterial Doppler flow pro-
with intravascular hypovolemia)
files (Fig. 4a, b).
Saugel et al. Critical Care (2017) 21:225 Page 6 of 11

body gown; covering the US probe and cable with a sterile

cover/shield; and using a sterile conductive medium
(US gel) [13, 32].
The position of the operator performing US-guided
CVC placement should be such that he/she has the in-
sertion site, the needle, and the US screen in their line
of sight during needle insertion [13]. Usually, the oper-
ator should hold the US probe with the nondominant
hand while advancing the needle with the dominant
hand. This approach is referred to as the "single-oper-
ator technique" and allows the operator to optimally
align the US plane and the direction of the needle.
These practical aspects of US-guided CVC placement
are illustrated in Fig. 5.
While advancing the needle, its tip should be con-
stantly identified with US during the needle approach to
the vein and puncture of the vein. This can be done
using a short-axis/out-of-plane view or a long-axis/in-
plane view.

Confirm needle position in the vein

The use of real-time US then allows confirmation that
the needle tip is placed centrally in the vein before ap-
proaching the guide wire (Fig. 6a, b).

Confirm wire position in the vein

As a next step after wire advancement, the correct pos-
ition of the guide wire should be confirmed in both a
short-axis and a long-axis US view (Fig. 6c, d).

Fig. 4 Color Doppler imaging and Doppler flow measurements.

Short-axis (transverse) view of the right internal jugular vein (blue)
and the carotid artery (red) using color Doppler imaging and
Doppler flow measurements of the venous (a) and arterial (b)
blood flow profile (Color figure online)

To further confirm the patency of the vein and to

quantify venous and arterial blood flow, color Doppler
imaging and Doppler flow measurements should be
performed (Fig. 4a, b).
Use real-time ultrasound guidance for puncture of the vein
CVC placement should be performed using US guidance.
This requires an aseptic approach to avoid catheter-related
bloodstream infections. An aseptic technique includes:
prepping and covering the puncture site with a large sterile
drape; wearing a hat, a mask, sterile gloves, and a sterile
Fig. 5 Practical aspects of ultrasound-guided central venous catheter
placement in the internal jugular vein using the "single-operator
technique”. An aseptic approach including covering the puncture
site with a large sterile drape, using sterile barriers (hat, mask, sterile
gloves, sterile body gown), and covering the ultrasound probe and
cable with a sterile cover is shown. The position of the operator
(who holds the ultrasound probe with the nondominant hand while
advancing the needle with the dominant hand) allows aligning the
insertion site, the needle, and the ultrasound screen in the line of
sight during needle insertion (red lines) (Color figure online)
Saugel et al. Critical Care (2017) 21:225 Page 7 of 11

Fig. 6 Ultrasound to confirm needle, wire, and catheter position in the vein. Ultrasound images during real-time ultrasound-guided central venous
catheter placement in the right internal jugular vein. Ultrasound guidance should include confirmation of the needle position in the vein before
approaching the guide wire (short-axis/out-of-plane view (a) and long-axis/in-plane view (b)). In addition, the correct position of the guide wire in the
vein (short-axis (c) and long-axis (d)) and the correct position of the catheter in the vein (short-axis (e) and long-axis (f)) should be confirmed

Confirm catheter position in the vein
Finally, after placement of the CVC over the guide wire,
the correct position of the CVC in the vein can be
visualized with US, again in a short-axis and a long-axis
view (Fig. 6e, f ).
Figure 7 summarizes the six-step approach to US-guided
CVC insertion.
How to integrate knowledge from landmark and
ultrasound techniques?
To achieve the personal best skill level for CVC place-
ment, it is crucial that one combines and integrates the
anatomic knowledge from landmark techniques and the
knowledge gained from US-guided vascular access (know-
ledge about image display and converting the 2D image
into 3D reality, and hand–eye coordination) [31]. In
this context, previous US studies provided important
information on the effect of different interventions on
the venous puncture sites.
It has been demonstrated repeatedly that positioning of
the patient in a head-down (Trendelenburg) position in-
creases the filling and thus the cross-sectional lumen of the
IJV [33]. On the contrary, to increase the lumen of the FV,
patients can be positioned in a head-up (reverse Trende-
lenburg) position [34]. Positioning of the leg in an
abducted and externally rotated position also can help to
maximize the cross-sectional diameter of the FV [35].
For the IJV, imaging studies showed that the position
of the head plays an important role in optimizing the
conditions during CVC placement. Several studies dem-
onstrated that rotation of the head to the opposite side
increases the overlap of the IJV and the carotid artery
[36–38]. In a US study, Miki et al. [37] investigated in 30
volunteers the anatomical relationship between the IJV
and the carotid artery during head rotation. The overlap
Saugel et al. Critical Care (2017) 21:225 Page 8 of 11

I. Identify anatomy of insertion site and localization of the vein

• Identify vein, artery, anatomic structures

• Check for anatomic variations
• Use short axis (transverse; A) and long
axis (longitudinal; B) view
• Perform this step before prepping and
draping of the puncture site

II. Confirm patency of the vein

• Use compression ultrasound to exclude Compression

venous thrombosis
• Use color Doppler imaging and Doppler
flow measurements to confirm the patency of
the vein and to quantify blood flow

III. Use real-time US guidance for puncture of the vein

• Use an aseptic approach

• Use a short axis/out-of-plane (A) or a long
axis/in-plane (B) approach
• Try to constantly identify the tip of the
needle during the needle approach to the
vein and puncture of the vein

IV. Confirm needle position in vein

• Confirm that the needle tip is placed

centrally in the vein before approaching the
guide wire

V. Confirm wire position in vein

• Confirm the correct position of the guide

wire in a short axis (A) and a long axis (B)
view

VI. Confirm catheter position in vein

• Confirm the correct position of the central

venous catheter in the vein in a short axis
(A) and a long axis (B) view

Fig. 7 Six-step approach to ultrasound-guided central venous catheter placement

of the IJV and the carotid artery gradually increased with
increasing rotation of the head to the left. In parallel,
however, the flattening of the IJV decreased with head
rotation to the left. DeAngelis et al. [39] described that
the IJV becomes more vertically separated from the ca-
rotid artery at more extreme angles of contralateral head
rotation. These findings underline that US should be
used in each individual patient to assess the optimal
angle of head rotation and best approach to the IJV.
Technical developments in the field of
ultrasound-guided vascular access
Needle guides are devices placed on the US transducer
that might improve the cannulation success by facilitating
aligning the angle between the US and the needle
plane so that the two planes intersect at the depth of
the vessel selected for cannulation [40]. Especially for
inexperienced users [41], the needle guides help to
guide the needle along the path of the US beam at the
correct angle and distance depending on the depth of
the targeted structure. Needle guides facilitate faster
cannulation for IJV CVCs (only for inexperienced op-
erators) [42] and SV CVCs [40]. Nevertheless, in a
simulation model study, a needle guide used in a long-
axis vessel approach improved needle visualization but
did not improve puncture of the target vessel compared
with a free-hand technique [43]. Altogether, based on the
contradicting evidence [43, 44], no rigorous conclusion
Saugel et al. Critical Care (2017) 21:225
about the clinical value of needle guide devices can
currently be drawn.
Different real-time 3D techniques (sometimes referred
to as 4D US with time being the fourth dimension) for
US-guided CVC placement have been described [45, 46].
Lower image resolution, larger US probe dimensions, and
artifacts making needle visualization difficult, however, are
still major limitations of this innovative concept [46].
Limitations of ultrasound-guided central venous
catheter placement
Although US is noninvasive and thus does not bear a
risk to directly harm the patient, some limitations and
disadvantages of US during central venous access are
worth considering.
One might argue that the risk of catheter-related
bloodstream infections might be higher if US is used for
CVC placement without applying a strict aseptic approach
as already described [47]. In addition, an insufficient num-
ber of US machines in a certain unit (intensive care unit
or anesthesia induction area) might cause procedural
delays [47]. Moreover, it is expensive to purchase and
maintain US machines and to provide adequate training
for all operators involved in CVC placement [47].
US might give the inexperienced user a false sense of
security and mislead him/her to neglect traditionally
taught principles with regard to needle direction. It is key
to visualize the needle (or needle tip) constantly during
needle advancement to avoid accidental arterial puncture,
posterior wall penetration, or pneumothorax. In addition,
rapid movements with the needle during "searching the
needle on the US screen" must be avoided rigorously. To
overcome these problems related to insufficient US skills
and to ensure high-quality care, formal education and
training (including simulation) with a structured certifica-
tion of US skills for vascular access and the development
of a consensus standard for these training programs has
been suggested [13].
Moreover, concerns have been expressed that routine
US use will result in a "de-skilling" with regard to the
landmark techniques because these techniques will not
be taught and practiced anymore, thus resulting in higher
complication rates when CVCs need to be placed when
US is not available (e.g., in emergencies) [47].
Besides these general limitations, different problems
specific for the different anatomical sites for CVC place-
ment might occur during US-guided CVC placement. In
patients with a shorter neck anatomy, the long-axis US
view of the IJV might be difficult to obtain. Although
the FV can usually be visualized easily using US in adults,
in severely obese patients a second operator might be
necessary to provide access to the inguinal region. In
addition, a curved-array abdominal US probe can be
necessary for visualizing deeper anatomic structures. In
Page 9 of 11
comparison to the IJV and FV, the anatomic location
and course of the SV under the clavicle bone can be
more difficult to visualize using US. Smaller US probes
can facilitate US-guided access to the SV [48, 49]. Of
note, the use of US to puncture the SV results in a
puncture site that is usually more lateral compared to
the landmark puncture technique. The close proximity
of the vessels and the pleura must be kept in mind also
during US-guided puncture of the SV. Because the
angle of cannulation is usually steeper when using US, it is
especially important to align and constantly visualize the
needle to avoid pleural injury.
Conclusion
US guidance can improve patient safety and procedural
quality during CVC placement in the IJV, FV, and SV.
Based on evidence from clinical studies, several guide-
lines of medical societies strongly recommend the use of
US for CVC placement in the IJV. Data from survey
studies show that there is still a gap between the existing
evidence and guidelines and the use of US in clinical
practice. We recommend a six-step systematic approach
for US-guided central venous access. To achieve the best
skill level for CVC placement the knowledge from ana-
tomic landmark techniques and the knowledge from
US-guided CVC placement need to be combined and
integrated.
Abbreviations
CVC: Central venous catheter; FV: Femoral vein; IJV: Internal jugular vein;
SV: Subclavian vein; US: Ultrasound
Acknowledgements
The authors thank Oliver Diener, Maximilian Leistenschneider, and Elisabeth
von Heckel for their support in obtaining the US images and the photographs
illustrating the procedure for US-guided CVC placement.
Funding
None.
Availability of data and materials
Not applicable.
Authors’ contributions
BS, TWLS, and J-LT conceived the article, performed the literature search,
drafted the manuscript, and read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent for publication of their ultrasound images was
obtained from the patients and volunteers. A copy of the consent form is
available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Saugel et al. Critical Care (2017) 21:225
Author details
1
Department of Anesthesiology, Center of Anesthesiology and Intensive Care
Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52,
20246 Hamburg, Germany. 2Department of Anesthesiology, University of
Groningen, University Medical Centre Groningen, Groningen, The
Netherlands. 3Service de Réanimation Médicale Hôpital de Bicêtre, Hôpitaux
Universitaires Paris-Sud, AP-HP, Le Kremlin-Bicêtre, France.
References
1. McGee DC, Gould MK. Preventing complications of central venous
catheterization. N Engl J Med. 2003;348:1123–33.
2. Merrer J, De Jonghe B, Golliot F, Lefrant JY, Raffy B, Barre E, Rigaud JP,
Casciani D, Misset B, Bosquet C, Outin H, Brun-Buisson C, Nitenberg G.
Complications of femoral and subclavian venous catheterization in critically
ill patients: a randomized controlled trial. JAMA. 2001;286:700–7.
3. Hoffman T, Du Plessis M, Prekupec MP, Gielecki J, Zurada A, Shane Tubbs R,
Loukas M. Ultrasound-guided central venous catheterization: a review of the
relevant anatomy, technique, complications, and anatomical variations.
Clin Anat. 2017;30:237–50.
4. Gordon AC, Saliken JC, Johns D, Owen R, Gray RR. US-guided puncture of
the internal jugular vein: complications and anatomic considerations.
J Vasc Interv Radiol. 1998;9:333–8.
5. Turba UC, Uflacker R, Hannegan C, Selby JB. Anatomic relationship of
the internal jugular vein and the common carotid artery applied to
percutaneous transjugular procedures. Cardiovasc Intervent Radiol.
2005;28:303–6.
6. Denys BG, Uretsky BF. Anatomical variations of internal jugular vein location:
impact on central venous access. Crit Care Med. 1991;19:1516–9.
7. Benter T, Teichgraber UK, Kluhs L, Papadopoulos S, Kohne CH, Felix R,
Dorken B. Anatomical variations in the internal jugular veins of cancer
patients affecting central venous access. Anatomical variation of the internal
jugular vein. Ultraschall Med. 2001;22:23–6.
8. Docktor B, So CB, Saliken JC, Gray RR. Ultrasound monitoring in cannulation
of the internal jugular vein: anatomic and technical considerations.
Can Assoc Radiol J. 1996;47:195–201.
9. Jenssen C, Brkljacic B, Hocke M, Ignee A, Piscaglia F, Radzina M, Sidhu PS,
Dietrich CF. EFSUMB Guidelines on Interventional Ultrasound (INVUS). Part
VI—Ultrasound-Guided Vascular Interventions. Ultraschall Med. 2016;37:473–6.
10. Buchanan MS, Backlund B, Liao MM, Sun J, Cydulka RK, Smith-Coggins R,
Kendall J. Use of ultrasound guidance for central venous catheter placement:
survey from the American Board of Emergency Medicine Longitudinal Study of
Emergency Physicians. Acad Emerg Med. 2014;21:416–21.
11. Beaudoin FL, Merchant RC, Lincoln J, Gardiner F, Liebmann O, Cohn J.
Bedside ultrasonography detects significant femoral vessel overlap:
implications for central venous cannulation. CJEM. 2011;13:245–50.
12. Hilty WM, Hudson PA, Levitt MA, Hall JB. Real-time ultrasound-guided
femoral vein catheterization during cardiopulmonary resuscitation.
Ann Emerg Med. 1997;29:331.
13. Lamperti M, Bodenham AR, Pittiruti M, Blaivas M, Augoustides JG, Elbarbary M,
Pirotte T, Karakitsos D, Ledonne J, Doniger S, Scoppettuolo G, Feller-Kopman D,
Schummer W, Biffi R, Desruennes E, Melniker LA, Verghese ST. International
evidence-based recommendations on ultrasound-guided vascular access.
Intensive Care Med. 2012;38:1105–17.
14. Dietrich CF, Horn R, Morf S, Chiorean L, Dong Y, Cui XW, Atkinson NS,
Jenssen C. Ultrasound-guided central vascular interventions, comments on
the European Federation of Societies for Ultrasound in Medicine and Biology
guidelines on interventional ultrasound. J Thorac Dis. 2016;8:E851–68.
15. Troianos CA, Hartman GS, Glas KE, Skubas NJ, Eberhardt RT, Walker JD,
Reeves ST. Special articles: guidelines for performing ultrasound guided
vascular cannulation: recommendations of the American Society of
Echocardiography and the Society Of Cardiovascular Anesthesiologists.
Anesth Analg. 2012;114:46–72.
16. Blaivas M, Brannam L, Fernandez E. Short-axis versus long-axis approaches
for teaching ultrasound-guided vascular access on a new inanimate model.
Acad Emerg Med. 2003;10:1307–11.
17. Chittoodan S, Breen D, O'Donnell BD, Iohom G. Long versus short axis
ultrasound guided approach for internal jugular vein cannulation:
a prospective randomised controlled trial. Med Ultrason. 2011;13:21–5.
Page 10 of 11
18. Vezzani A, Manca T, Brusasco C, Santori G, Cantadori L, Ramelli A, Gonzi G,
Nicolini F, Gherli T, Corradi F. A randomized clinical trial of ultrasound-
guided infra-clavicular cannulation of the subclavian vein in cardiac surgical
patients: short-axis versus long-axis approach. Intensive Care Med. 2017.
doi: 10.1007/s00134-017-4756-6. [Epub ahead of print]
19. Stone MB, Moon C, Sutijono D, Blaivas M. Needle tip visualization during
ultrasound-guided vascular access: short-axis vs long-axis approach.
Am J Emerg Med. 2010;28:343–7.
20. Phelan M, Hagerty D. The oblique view: an alternative approach for
ultrasound-guided central line placement. J Emerg Med. 2009;37:403–8.
21. Wilson JG, Berona KM, Stein JC, Wang R. Oblique-axis vs. short-axis view in
ultrasound-guided central venous catheterization. J Emerg Med. 2014;47:45–50.
22. Brass P, Hellmich M, Kolodziej L, Schick G, Smith AF. Ultrasound guidance
versus anatomical landmarks for internal jugular vein catheterization.
Cochrane Database Syst Rev. 2015;1:Cd006962.
23. Brass P, Hellmich M, Kolodziej L, Schick G, Smith AF. Ultrasound guidance
versus anatomical landmarks for subclavian or femoral vein catheterization.
Cochrane Database Syst Rev. 2015;1:Cd011447.
24. Lalu MM, Fayad A, Ahmed O, Bryson GL, Fergusson DA, Barron CC, Sullivan P,
Thompson C. Ultrasound-guided subclavian vein catheterization: a systematic
review and meta-analysis. Crit Care Med. 2015;43:1498–507.
25. Rupp SM, Apfelbaum JL, Blitt C, Caplan RA, Connis RT, Domino KB, Fleisher LA,
Grant S, Mark JB, Morray JP, Nickinovich DG, Tung A. Practice guidelines for
central venous access: a report by the American Society of Anesthesiologists
Task Force on Central Venous Access. Anesthesiology. 2012;116:539–73.
26. Frankel HL, Kirkpatrick AW, Elbarbary M, Blaivas M, Desai H, Evans D,
Summerfield DT, Slonim A, Breitkreutz R, Price S, Marik PE, Talmor D, Levitov A.
Guidelines for the Appropriate Use of Bedside General and Cardiac
Ultrasonography in the Evaluation of Critically Ill Patients—Part I: General
Ultrasonography. Crit Care Med. 2015;43:2479–502.
27. Bodenham Chair A, Babu S, Bennett J, Binks R, Fee P, Fox B, Johnston AJ,
Klein AA, Langton JA, McLure H, Tighe SQ. Association of Anaesthetists of
Great Britain and Ireland: safe vascular access 2016. Anaesthesia. 2016;71:573–85.
28. McGrattan T, Duffty J, Green JS, O'Donnell N. A survey of the use of ultrasound
guidance in internal jugular venous cannulation. Anaesthesia. 2008;63:1222–5.
29. Soni NJ, Reyes LF, Keyt H, Arango A, Gelfond JA, Peters JI, Levine SM,
Adams SG, Restrepo MI. Use of ultrasound guidance for central venous
catheterization: a national survey of intensivists and hospitalists.
J Crit Care. 2016;36:277–83.
30. Maizel J, Bastide MA, Richecoeur J, Frenoy E, Lemaire C, Sauneuf B, Dupont H,
Tamion F, Nseir S, Du Cheyron D. Practice of ultrasound-guided central venous
catheter technique by the French intensivists: a survey from the BoReal study
group. Ann Intensive Care. 2016;6:76.
31. Weiner MM, Geldard P, Mittnacht AJ. Ultrasound-guided vascular access:
a comprehensive review. J Cardiothorac Vasc Anesth. 2013;27:345–60.
32. Marhofer P, Fritsch G. Sterile working in ultrasonography: the use of
dedicated ultrasound covers and sterile ultrasound gel. Expert Rev Med
Devices. 2015;12:667–73.
33. Mallory DL, Shawker T, Evans RG, McGee WT, Brenner M, Parker M, Morrison G,
Mohler P, Veremakis C, Parrillo JE. Effects of clinical maneuvers on
sonographically determined internal jugular vein size during venous
cannulation. Crit Care Med. 1990;18:1269–73.
34. Stone MB, Price DD, Anderson BS. Ultrasonographic investigation of the
effect of reverse Trendelenburg on the cross-sectional area of the femoral
vein. J Emerg Med. 2006;30:211–3.
35. Randall C, Schmeiser E, Fiers E, Little A, Dogbey G, Richardson G.
Ultrasound investigation of leg position to enhance femoral vein
exposure for cannulation. J Emerg Med. 2014;47:176–81.
36. Sulek CA, Gravenstein N, Blackshear RH, Weiss L. Head rotation during
internal jugular vein cannulation and the risk of carotid artery puncture.
Anesth Analg. 1996;82:125–8.
37. Miki I, Murata S, Nakazawa K, Onozawa S, Mine T, Ueda T, Yamaguchi H,
Yasui D, Takeda M, Kumita S. Anatomical relationship between the common
carotid artery and the internal jugular vein during head rotation.
Ultrasound. 2014;22:99–103.
38. Troianos CA, Kuwik RJ, Pasqual JR, Lim AJ, Odasso DP. Internal jugular vein
and carotid artery anatomic relation as determined by ultrasonography.
Anesthesiology. 1996;85:43–8.
39. DeAngelis V, Denny J, Chyu D, Jan T, Lemaire A, Chiricolo A, Solina A.
The optimal angle of head rotation for internal jugular cannulation as determined
by ultrasound evaluation. J Cardiothorac Vasc Anesth. 2015;29:1257–60.
Saugel et al. Critical Care (2017) 21:225 Page 11 of 11

40. Maecken T, Heite L, Wolf B, Zahn PK, Litz RJ. Ultrasound-guided

catheterisation of the subclavian vein: freehand vs needle-guided
technique. Anaesthesia. 2015;70:1242–9.
41. Jaffer U, Normahani P, Singh P, Aslam M, Standfield NJ. Randomized study
of teaching ultrasound-guided vascular cannulation using a phantom and
the freehand versus needle guide-assisted puncture techniques.
J Clin Ultrasound. 2015;43:469–77.
42. Augoustides JG, Horak J, Ochroch AE, Vernick WJ, Gambone AJ, Weiner J,
Pinchasik D, Kowalchuk D, Savino JS, Jobes DR. A randomized controlled
clinical trial of real-time needle-guided ultrasound for internal jugular
venous cannulation in a large university anesthesia department.
J Cardiothorac Vasc Anesth. 2005;19:310–5.
43. Ball RD, Scouras NE, Orebaugh S, Wilde J, Sakai T. Randomized, prospective,
observational simulation study comparing residents' needle-guided vs
free-hand ultrasound techniques for central venous catheter access.
Br J Anaesth. 2012;108:72–9.
44. Luyet C, Hartwich V, Urwyler N, Schumacher PM, Eichenberger U, Vogt A.
Evaluation of a novel needle guide for ultrasound-guided phantom vessel
cannulation. Anaesthesia. 2011;66:715–20.
45. Dowling M, Jlala HA, Hardman JG, Bedforth NM. Real-time three-dimensional
ultrasound-guided central venous catheter placement. Anesth Analg.
2011;112:378–81.
46. French JL, Raine-Fenning NJ, Hardman JG, Bedforth NM. Pitfalls of
ultrasound guided vascular access: the use of three/four-dimensional
ultrasound. Anaesthesia. 2008;63:806–13.
47. Hessel 2nd EA. Con: we should not enforce the use of ultrasound as a
standard of care for obtaining central venous access. J Cardiothorac Vasc Anesth.
2009;23:725–8.
48. Kim SC, Graff I, Sommer A, Hoeft A, Weber S. Ultrasound-guided
supraclavicular central venous catheter tip positioning via the right
subclavian vein using a microconvex probe. J Vasc Access. 2016;17:435–9.
49. Lanspa MJ, Fair J, Hirshberg EL, Grissom CK, Brown SM. Ultrasound-guided
subclavian vein cannulation using a micro-convex ultrasound probe.
Ann Am Thorac Soc. 2014;11:583–6.
 ARTIGO 5

HIPERCALEMIAS
review
Treatment of hyperkalemia: something old,
something new
Richard H. Sterns1,2, Marvin Grieff1,2 and Paul L. Bernstein1,2
1
Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA;
and 2Department of Medicine, Rochester General Hospital, Rochester, New York, USA
Treatment options for hyperkalemia have not changed
much since the introduction of the cation exchange resin,
sodium polystyrene sulfonate (Kayexalate, Covis
Pharmaceuticals, Cary, NC), over 50 years ago. Although
clinicians of that era did not have ready access to
hemodialysis or loop diuretics, the other tools that we use
today—calcium, insulin, and bicarbonate—were well
known to them. Currently recommended insulin regimens
provide too little insulin to achieve blood levels with a
maximal kalemic effect and too little glucose to avoid
hypoglycemia. Short-acting insulins have theoretical
advantages over regular insulin in patients with severe
kidney disease. Although bicarbonate is no longer
recommended for acute management, it may be useful in
patients with metabolic acidosis or intact kidney function.
Kayexalate is not effective as acute therapy, but a new
randomized controlled trial suggests that it is effective
when given more chronically. Gastrointestinal side effects
and safety concerns about Kayexalate remain. New
investigational potassium binders are likely to be approved
in the coming year. Although there are some concerns
about hypomagnesemia and positive calcium balance from
patiromer, and sodium overload from ZS-9 (ZS Pharma,
Coppell, TX), both agents have been shown to be effective
and well tolerated when taken chronically. ZS-9 shows
promise in the acute treatment of hyperkalemia and may
make it possible to avoid or postpone the most effective
therapy, emergency hemodialysis.
Kidney International (2016) 89, 546–554; http://dx.doi.org/10.1016/
j.kint.2015.11.018
KEYWORDS: cation exchange resins; hyperkalemia; insulin; potassium; renal
dialysis; sodium bicarbonate
ª 2016 International Society of Nephrology
Correspondence: Richard H. Sterns, Rochester General Hospital, 1425 Port-
land Avenue, Rochester, New York 14621, USA. E-mail: richard.sterns@
rochesterregional.org
Received 17 September 2015; revised 23 October 2015; accepted 11
November 2015; published online 2 February 2016
546
www.kidney-international.org
T
reatment options for hyperkalemia have not changed
much since the introduction of the cation exchange
resin, sodium polystyrene sulfonate ([SPS]; Kayexalate,
Covis Pharmaceuticals, Cary, NC), over 50 years ago.1–4
Although clinicians of that era did not have ready access to
hemodialysis or loop diuretics, the other tools that we use
today—calcium, insulin, and bicarbonate—were well known
to them.5,6 In recent years, our comfort with traditional
therapies has been shaken by warnings that Kayexalate mixed
with sorbitol may be harmful, and by a growing realization
that many of our standard treatments for hyperkalemia have
little evidence to support them.4,7–9 The coming year is likely
to see the release of 2 new pharmaceutical products, providing
clinicians with new therapeutic weapons for their arsenal.10
This review is intended to weigh the available evidence on
both new and old treatments for hyperkalemia.
Confirming the diagnosis
When any degree of hyperkalemia is discovered, the accuracy
of the measurement must be verified. A repeat serum po-
tassium concentration is often normal, without therapy,
because of distribution or excretion of recently ingested po-
tassium, diurnal variation, or laboratory error.11–14 Pseudo-
hyperkalemia (a falsely high potassium), caused by poor
phlebotomy technique, hemolysis, laboratory processing,
thrombocytosis, and leukocytosis, can lead to inappropriate
intervention.15 The serum potassium rises with exercise and
falls after.16 Because contractions of forearm muscles release
intracellular potassium, fist clenching during phlebotomy
raises both serum and plasma potassium by as much as
1 mmol/l.17–20 Potassium is released from platelets during
clotting, raising the serum but not plasma potassium in pa-
tients with thrombocytosis. To exclude pseudohyperkalemia,
plasma potassium (obtained from a heparinized sample) or
whole blood potassium should be measured, if platelet counts
exceed 500,000.15,21 Leukemic lymphocytes are fragile and
release potassium during centrifugation, when exposed to
high concentrations of heparin in the test tube, or when
shaken by pneumatic tube transport. In patients with lym-
phocytic leukemia, the potassium concentration can be higher
in plasma than in serum; this observation led to the term
“reverse pseudohyperkalemia” to contrast it with the previ-
ously reported pseudohyperkalemia caused by thrombocy-
tosis (in which the potassium concentration in serum is
higher than in plasma).15 When the potassium concentration
is falsely elevated because of mechanical fragmentation of
Kidney International (2016) 89, 546–554
RH Sterns et al.: Treatment of hyperkalemia
lymphocytes, both serum and plasma potassium are
affected.22–24 To avoid confusion, we suggest the terms
“platelet-induced serum pseudohyperkalemia,” “lymphocyte-
induced plasma pseudohyperkalemia,” and “shaken-lympho-
cyte pseudohyperkalemia.” To exclude lymphocyte-induced
plasma pseudohyperkalemia, serum potassium or whole
blood potassium from a sample drawn in a blood gas syringe
(which contains lower concentrations of heparin) should be
measured; if shaken-lymphocyte pseudohyperkalemia is sus-
pected, samples should be hand-carried to the laboratory.22–24
The electrocardiogram in hyperkalemia
Hyperkalemia decreases the transmembrane potassium
gradient leading to increased potassium conductance, and this
shortens the duration of the action potential.25 As potassium
rises to 5.5 to 6.5 mmol/l, peaked T-waves and a prolonged
PR segment may be seen, advancing with higher levels of
potassium to progressive widening of the QRS complex,
fascicular and bundle branch blocks, a “sine-wave” appear-
ance, and asystole.26–29
The electrocardiogram is insensitive in assessing the
severity of hyperkalemia.30 Profound hyperkalemia can occur
without electrocardiographic manifestations.31–34 Cardiac
conduction defects, most commonly severe bradycardia, can
be the presenting manifestation of hyperkalemia and hyper-
kalemia can cause malfunction of pacemakers and implant-
able cardioverter-defibrillators.35,36 Abnormalities include
widening of the QRS complex, increased pacing thresholds,
which can lead to failure to capture, as well as oversensing of
the paced or spontaneous T-wave by the implantable
cardioverter-defibrillator and potentially inappropriate
shocks.36
Intravenous calcium
Calcium antagonizes the effects of hyperkalemia at the
cellular level through effects on the threshold potential and
the speed of impulse propagation.25 In 1964, Chamberlain37
reported 5 patients with serum potassium concentrations
ranging from 8.6 to 10 mmol/l, illustrating “immediate”
(within 5 minutes) resolution of the most advanced electro-
cardiographic findings after intravenous calcium. Our
knowledge of when to use this intervention, or what dose and
formulation (calcium gluconate or calcium chloride) to use
has not advanced since these early observations. The most
common dose of calcium recommended today is 10 to 20 ml
of 10% calcium gluconate given intravenously as a bolus and
repeated as needed.
Because digoxin, an inhibitor of sodium-potassium
adenosine triphosphatase, increases intracellular calcium,
there are theoretical concerns about calcium treatment for
hyperkalemia caused by or associated with digitalis toxicity,
and there have been case reports of adverse effects.38 A small
case-controlled study found no mortality differences
between 23 patients with hyperkalemia and digitalis toxicity
who were treated with calcium and 136 patients who were
not.38 Nonetheless, the risk of hyperkalemia on the cardiac
Kidney International (2016) 89, 546–554
review
rhythm should be balanced against the potential adverse
effect of intravenous calcium in the presence of digoxin
toxicity.
Promoting uptake of potassium by cells
Skeletal muscle is the reservoir for more than 70% of body
potassium. Transport of extracellular potassium into muscle
cells in exchange for intracellular sodium, by the membrane-
bound sodium pump, sodium-potassium adenosine triphos-
phatase, serves as the primary extrarenal mechanism for
achieving potassium homeostasis, with a calculated maximal
transport rate of 134 mmol/min—enough to transfer one-half
of the potassium normally residing in the extracellular space
(or the potassium absorbed in a large meal) within 15 sec-
onds. Insulin, beta-2 agonists, and bicarbonate accelerate the
movement of potassium into muscle cells, and these agents
are widely used to treat “severe” hyperkalemia.
Insulin. When insulin binds to its receptor on skeletal
muscle, the abundance and activity of sodium-potassium
adenosine triphosphatase and the abundance of the glucose
transporter, GLUT4, on the cell membrane increase through
independent signaling pathways (reviewed in Ho39). Thus,
while the glycemic response is maximal at insulin levels of
approximately 100 mU/ml, the kalemic effect of the hormone
continues to increase as insulin levels rise. Studies utilizing the
euglycemic insulin clamp technique show that infusion of
regular insulin at 20 U/h after a 6.6-U priming dose in a 70-kg
healthy subject will rapidly raise insulin levels to approxi-
mately 500 mU/ml, with a near maximal kalemic effect; to
maintain euglycemia at these insulin levels, infusion of
glucose at 40 g/h is required.40,41 Although uremia and type-2
diabetes cause resistance to the glycemic effect, insulin’s
ability to enhance potassium uptake by skeletal muscle and
liver are unimpaired.42,43
The most commonly recommended regimen for emer-
gency treatment of severe hyperkalemia is a bolus intravenous
injection of 10 U of regular insulin, which, if blood glucose
is <250 mg/dl, is given with a bolus injection of 25 g of
glucose (50 ml of a 50% solution).7,44,45 This regimen and
others have been studied under standardized conditions in
several small trials of stable, mildly hyperkalemic patients
with dialysis-dependent kidney disease.43,46–57 Although in-
sulin given as a 10-U bolus or as a 1-hour 20-U infusion
without a loading dose lowers the serum potassium by about
1 mmol/l within an hour, Figure 1 illustrates why both of
these regimens are suboptimal.58 Neither regimen provides
maximal kalemic insulin levels for very long, and both lead to
persistently elevated insulin levels that can cause hypoglyce-
mia. If glucose is given as a bolus, hyperglycemia occurs in the
first few minutes, which may blunt the kalemic effect of in-
sulin; hyperglycemia leads to water movement from the
intracellular to extracellular compartment, favoring potas-
sium efflux from cells through solvent drag.59,60 Hypoglyce-
mia often develops an hour or more after the start of therapy
for 2 reasons: (i) the amount of glucose is insufficient to
replace the glucose utilized in response to exogenous insulin;
547
review
10-U insulin bolus 20-U insulin infusion
600
Plasma insulin (μU/ml)
400
200
0
0 20 40 60 80
Minutes
Figure 1 | Idealized plasma insulin levels after commonly used
regimens in a patient with ESRD. After a 10-U bolus, insulin levels
are transiently very high but quickly become suboptimal. After a
1-hour infusion of 20 U without a loading dose, insulin levels are
initially suboptimal. After both regimens, insulin levels persist at levels
high enough to cause hypoglycemia unless glucose administration is
continued for more than an hour. ESRD, end-stage renal disease.
(ii) insulin’s prolonged half-life in end-stage renal disease
leads to insulin levels high enough to promote glucose utili-
zation for more than an hour.40,61–63 Retrospective studies
confirm that hypoglycemia commonly occurs within 1 to 3
hours when hyperkalemia is treated with insulin and indicate
that its incidence depends more on the dose of glucose than
on the dose of insulin; for example, in one study, 2 of 5 pa-
tients given only 5 units of insulin with 25 g of glucose
developed a blood glucose <2.2 mmol/l.64
Short-acting insulins (lispro and aspart) have shorter half-
lives than regular insulin and, in contrast to regular insulin,
their half-lives are not prolonged by kidney failure.58,61,65 A
randomized, prospective study of infusion therapy to main-
tain normoglycemia in critical care patients showed the
postinfusional drop in blood glucose to be less profound and
of briefer duration after lispro than after regular insulin.62 A
retrospective study of outcomes after a 10-U insulin aspart
bolus for hyperkalemia found rates of hypoglycemia compa-
rable to previously reported rates after regular insulin; how-
ever, only 25 g of glucose were given, an insufficient dose to
prevent hypoglycemia.66
Based on what is known of physiology and drug
kinetics,40,58,61,67 the most logical regimen for a 70-kg subject
(with weight adjustment of dosages for others) would be an
infusion of short-acting insulin at 20 U/h after a 6-U loading
dose, given with 60 g of glucose per hour. Particularly if in-
sulin is continued for more than an hour, administration of
an adequate amount of glucose intravenously is difficult.
Infusion of 10% glucose would require 600 ml/h, causing
hyponatremia. High concentrations of glucose to reduce the
volume infused would require use of a central vein. It should
be possible to give glucose orally to avoid the need for central
venous access. Because short-acting insulin is more rapidly
absorbed than regular insulin, subcutaneous administration
would be expected to be effective, but the dose needed to
achieve maximally kalemic insulin levels is not known.
Clinical trials to assess these theoretical regimens are needed.
548
RH Sterns et al.: Treatment of hyperkalemia
Beta-2 agonists. The beta-2 agonist albuterol (also called
Maximum
salbutamol) administered by inhalation, nebulization, or
kalemic intravenously has been studied in stable hyperkalemic patients
effect with end-stage renal disease.47,68 The serum potassium falls by
0.3 to 0.6 mmol/l within 30 minutes, regardless of mode of
administration, but some patients fail to respond. The doses
used when albuterol is given by inhalation (the only formu-
Maximum
glycemic lation available in the United States) are 4 to 8 times those
effect prescribed for the treatment of acute asthma, and although no
severe adverse events have been reported in studies of stable
100 120 patients, some studies excluded patients with heart disease. At
high doses, albuterol may stimulate both beta-1 receptors,
which can precipitate arrhythmias, and alpha-receptors, which
cause potassium release from the liver and can transiently in-
crease serum potassium by >0.4 mmol/l.69 Subcutaneous
terbutaline, known to cause hypokalemia when used to treat
premature labor, also lowers the serum potassium in mildly
hyperkalemic patients with end-stage renal disease.
Several studies have documented a substantially greater fall
in potassium when beta-2 agonists are combined with insulin
than when either agent is given alone and hypoglycemia is less
likely with combination therapy than with insulin
alone.47,68,69 However, these studies employed submaximal
doses of insulin and glucose, and it is unclear whether
coadministration would offer any advantage over an adequate
dose of insulin given with sufficient glucose.8
Sodium bicarbonate. Administration of bicarbonate pro-
motes uptake of potassium by skeletal muscle by favoring
sodium-bicarbonate cotransport and sodium-hydrogen ex-
change, which, by increasing intracellular sodium, increases
the activity of sodium-potassium adenosine triphosphatase.60
In 1959, Schwarz showed that infusion of between 144 and
408 mmol of sodium bicarbonate over 2 to 4 hours lowered
the serum potassium by 2 to 3 mmol/l in 4 patients with
severe acidosis.70 For many years, bicarbonate was often
chosen as the first-line treatment for acute hyperkalemia.71
Bicarbonate ceased to be a recommended intervention for
acute hyperkalemia after the publication of studies showing
that bicarbonate has little effect on the serum potassium
concentration in stable hemodialysis patients.46,56,57,72,73
However, bicarbonate therapy may be beneficial for patients
with metabolic acidosis.74,75 A 4-hour infusion of sodium
bicarbonate in 5% dextrose in patients with chronic kidney
disease (CKD) resulted in a substantial fall in serum potas-
sium concentration that was proportional to the increase in
serum bicarbonate, with a mean decrease of approximately 2
mmol/l after a 10-mmol/l increase in serum bicarbonate
concentration.76 Bicarbonate is also rational therapy to
enhance potassium excretion in patients with intact kidney
function.
Combination “cocktails.”. In 1954, Meroney and Hern-
don77 reported on a standard battlefield intravenous solution
containing 400 ml of 25% dextrose, 50 U of regular insulin,
50 mmol of sodium bicarbonate, which, along with boluses of
intravenous calcium as needed, was effective in controlling
hyperkalemia for several days in soldiers with traumatic acute
Kidney International (2016) 89, 546–554
RH Sterns et al.: Treatment of hyperkalemia review

kidney injury. More recently, Janjua et al.78 reported that a a End dialysis 2-h postdialysis
similar standard “cocktail” (containing sodium lactate instead 4
of sodium bicarbonate to permit the inclusion of calcium in 3.5

ΔPlasma potassium (mmol/l)

the solution) controlled hyperkalemia for up to 32 hours in 3
children and adolescents.
2.5

Elimination of potassium 2

Strategies to shift potassium into cells are temporizing ma- 1.5

neuvers that should be followed by efforts to eliminate excess 1
potassium. Reducing total body potassium involves decreased
0.5
potassium intake, enhanced urinary and fecal potassium
excretion, and dialysis. It is important for ambulatory patients 0
3 3.5 4 4.5 5 5.5 6 6.5 7
with hyperkalemia to see a dietician to guide food choices. Predialysis plasma potassium (mmol/l)
Patients should be instructed to limit intake of citrus fruit,
potatoes, tomato products, and salt substitutes, which are b 3.5
made of potassium salts.79
3
Patients with hyperkalemia are commonly taking po-
ΔPlasma K per 100 mmol
tassium supplements or medications that limit potassium 2.5
excretion; discontinuation or temporary dose reduction K+ removed
may be all that is required to restore normokalemia.80 2

Drug-induced hyperkalemia occurs most often in patients 1.5

with impaired kidney function and associated hypo-
reninemic hypoaldosteronism, and it is particularly com- 1

mon in the elderly.81–86 Common medications that cause 0.5

hyperkalemia include potassium supplements, angiotensin-
converting enzyme inhibitors, angiotensin-II blockers,
trimethoprim, calcineurin inhibitors, heparin, potassium-
sparing diuretics, digoxin, beta-blockers, and nonsteroidal
anti-inflammatory agents.79 Combinations of these agents
are most likely to increase the risk of hyperkalemia and
sudden death.82,85,87–89
Patients with severe hyperkalemia require active mea-
sures to remove potassium. Studies of potassium removal by
hemodialysis show that for a given negative potassium
balance, patients with higher serum potassium concentra-
tions experience a larger fall in serum potassium (Figure 2a
and b).74,75,90 This phenomenon makes it difficult to
interpret studies purporting to show a “dose-response”
relationship to potassium binders when patients with higher
serum potassium concentrations are given higher doses of
the agent.91
Dialysis. Hemodialysis is the most effective way to
eliminate excess potassium. Although potassium is directly
removed from plasma, distribution of potassium between the
plasma and interstitial fluid is nearly instantaneous, so po-
tassium is effectively removed from extracellular fluid. The
effect of dialysis on the plasma potassium concentration
depends on the rate of potassium removal from the extra-
cellular fluid and the rate that potassium is replenished from
intracellular stores.90,92–94 In a 70-kg subject, unreplenished
removal of only 14 mmol of potassium from the extracellular
fluid will decrease plasma potassium by 1 mmol/l. At a blood
pump speed of 0.3 l/min and a plasma-to-dialysate concen-
tration gradient >5 mmol/l, such a decrease can be achieved
within minutes. This explains why hemodialysis can be
successful during cardiopulmonary resuscitation, when
0
3 4 5 6 7
Predialysis plasma potassium (mmol/l)
Figure 2 | Response of plasma potassium to potassium removal
by dialysis. (a) Change in plasma potassium levels at the end of a
3-hour dialysis against a zero potassium dialysate (blue symbols) and
2 hours after dialysis (red symbols). There is a significantly greater fall
in plasma potassium when the predialysis potassium concentration is
higher. (b) The change in plasma potassium per 100 mmol of po-
tassium removed (mmol/kg data normalized to 70-kg subject) at the
end of dialysis (blue symbols) and 2 hours after dialysis (red symbols).
For a given amount of potassium removal, there is a significantly
greater fall in plasma potassium when the predialysis potassium
concentration is higher. Based on data in Feig et al.,90 used with
permission.
perfusion of peripheral tissues is minimal.95–97 In more
stable patients, over 100 mmol of potassium can be removed
during a 4-hour dialysis session; the amount removed de-
pends on the plasma-to-dialysate concentration gradient,
blood and dialysate flow rates, and total body potassium
stores (a function of muscle mass).90,92–94 Because replen-
ishment from cellular stores continue when potassium
removal stops, there is a substantial postdialysis rebound of
plasma potassium (Figure 3).90,93
Urinary excretion. In patients with only moderately
compromised kidney function, loop diuretics, flu-
drocortisone, and sodium bicarbonate can substantially in-
crease urinary potassium losses and have been used to
manage extremely severe hyperkalemia without dial-
ysis.60,81,98–100 Although sodium retention and the potential
for adverse mineralocorticoid effects on the myocardium
make chronic fludrocortisone unattractive for chronic

Kidney International (2016) 89, 546–554 549

review
Dialysis
7 potassium (mean difference between groups 1.07 mmol/l;
Plasma potassium (mmol/l)
6
5
4 had been identified. During 289 months of Kayexalate
0 1 2 3
Hours
Figure 3 | Plasma potassium concentration during and after
dialysis. Modified, with permission, from Figure 3 in Blumberg A,
Roser HW, Zehnder C, Muller-Brand J. Plasma potassium in patients
with terminal renal failure during and after haemodialysis;
relationship with dialytic potassium removal and total body
potassium. Nephrol Dial Transplant. 1997;12:1629–1634.93
therapy, it can be useful acutely as it begins to work within
3 hours.98,101 Large doses of fludrocortisone (up to 0.4 mg
daily) may be required, as patients with kidney disease may
have aldosterone resistance as well as aldosterone deficiency.98
Unfortunately, although many clinicians use such measures
routinely, they have not been well studied.
Sodium polystyrene sulfonate (Kayexalate). Kayexalate is a
cation exchange resin, first introduced in the 1950s, before the
U.S. Food and Drug Administration was required to establish
that drugs are safe and effective before approving them.4
Kayexalate was the name given to the powdered form of
SPS, which exchanges sodium for calcium, ammonium, and
magnesium in addition to potassium.102 At an acid pH, its
sulfonate groups are occupied by hydrogen ions and are un-
able to bind potassium. For this reason, and because of higher
potassium concentrations in the distal colon, Kayexalate is
most effective in binding potassium when it reaches the
rectum, either by retention enema or by oral administration
with cathartics.103 Because the resin swells when it contacts
water, large doses of Kayexalate can cause bowel obstruction.
To avoid this complication and to speed its delivery to the
distal colon, Kayexalate has been given together with sorbitol,
an osmotic cathartic.1 A placebo-controlled trial failed to
show any difference between the amount of fecal potassium
within 12 hours of oral ingestion when sorbitol is given with
or without Kayexalate to patients with end-stage renal disease,
and there was no effect on the serum potassium concentra-
tion.104 No controlled trials in humans or animals have
demonstrated that Kayexalate increases fecal potassium losses.
However, in a double-blind, randomized, placebo-
controlled trial, conducted in 33 ambulatory patients with
CKD and mild hyperkalemia (5.0–5.9 mmol/l), LePage
550
RH Sterns et al.: Treatment of hyperkalemia
et al.105 found that 30 g/day of Kayexalate without sorbitol for
Postdialysis 7 days was superior to placebo in the reduction of serum
95% confidence interval: -1.37 to -0.71). There were trends
for patients treated with Kayexalate to have more hypomag-
nesemia (P ¼ 0.08), hypocalcemia (P ¼ 0.10), nausea, and
constipation than those in the control group. Neither urinary
nor stool potassium balance was measured.
Chernin et al.106 retrospectively analyzed the course of all
patients taking target doses of renin-angiotensin-aldosterone
system inhibitors for heart disease who were maintained on
long-term therapy with a low dose of sorbitol-free Kayexalate
(15 g/day in water) after a serum potassium $6.0 mmol/l
therapy with continued use of renin-angiotensin-aldosterone
1 2 3 4 system inhibitors, the mean serum potassium fell from
6.4 " 0.3 mmol/l (range 6.0–7.1) to 4.6 " 0.6 (range
3.0–5.8 mmol/l), P < 0.01. The study had no control group,
and there was no routine monitoring of serum magnesium.
Other than this study, data on long-term use of Kayexalate or
SPS in sorbitol are lacking.107
Serious gastrointestinal complications from SPS have been
reported, given with and without sorbitol, including fatal
colonic perforation (reviewed in Harel et al.108). Because a
small study in rats suggested that sorbitol was the cause of
colonic perforation,109 the U.S. Food and Drug Administra-
tion issued a warning to avoid administration of Kayexalate
with sorbitol.4 This advice was problematic, because most
hospital pharmacies in the United States stock a premixed
preparation of SPS suspended in 33% sorbitol rather than
powdered Kayexalate. A retrospective cohort study of 123,391
adult inpatients identified 2194 patients who had been treated
with SPS in sorbitol, of whom, 0.14% developed colonic
necrosis, a rate that did not differ significantly from the rate
in patients not receiving the drug (0.07%).110 Assuming sta-
tistical significance, the number needed to harm was esti-
mated at 1395. A much larger population would be required
for a rigorous multivariate analysis of the risk of SPS-
associated colonic necrosis after acute administration.
Patiromer. Patiromer is an investigational nonabsorbable
synthetic polymer consisting of smooth spherical beads
approximately 100 mm in diameter; unlike Kayexalate,
patiromer does not swell appreciably when exposed to water
and it does not require a laxative to reach the distal colon.
Patiromer’s active groups are comprised of alpha-fluo-
rocarboxylic acids that are paired with calcium ions rather
than sodium. As the resin travels through the gastrointestinal
tract, some of the calcium is replaced with hydrogen ions. The
pKa of Patiromer’s cation binding groups is such that at the
prevailing pH in the colon, the acid groups are dissociated,
allowing them to bind potassium, which is present in high
concentrations in this bowel segment, as well as ammonium
and magnesium.86 Controlled experiments in both experi-
mental animals and normal volunteers have demonstrated
that when taken orally, the polymer increases fecal potassium
in a dose-related fashion; doses of 15 to 30 g/day increased
Kidney International (2016) 89, 546–554
RH Sterns et al.: Treatment of hyperkalemia
daily fecal potassium by approximately 15 to 20 mmol.111 In
subjects studied while on a potassium-restricted and sodium-
restricted diet, patiromer decreased serum potassium by 0.23
mmol/l within 7 hours.112 The drug’s ability to achieve nor-
mokalemia has been proven in randomized multicenter
placebo-controlled trials involving a total of 603 hyperkalemic
patients on active treatment;113–115 its safety was demon-
strated in an open-label 52-week trial.115 In addition to minor
and infrequent gastrointestinal side effects, the most impor-
tant recognized adverse drug effect is hypomagnesemia (0.58
mmol/l), which developed in the first month of therapy in
8.6% of patients; hypomagnesemia responded readily to
magnesium supplementation and did not progress. Because
patiromer exchanges calcium for potassium it has the po-
tential of causing positive calcium balance and ectopic calci-
fications; this theoretical concern would be difficult to
disprove without very long-term studies. Patiromer was
approved by the United States Food and Drug Administration
in October 2015 and should be available in early 2016. Based
on in vitro data showing that Patiromer binds to many orally
administered medications, which could decrease their ab-
sorption and reduce their effectiveness, a black-box warning
was issued indicating that the drug should be separated by 6
hours from other orally administered medications.
Sodium zirconium cyclosilicate (ZS-9). Unlike patiromer
and SPS, the investigational drug, ZS-9 (ZS Pharma, Coppell,
TX) is not a polymer. It is a crystal that is highly selective for
potassium and ammonium ions through mechanisms that are
very similar to those of naturally occurring ion channels.116
Potassium and ammonium ions, which are nearly identical
in size, must first shed their hydration shells before they enter
the crystal structure, a process that requires energy; unhy-
drated ions are of the right size to form thermodynamically
stable and energetically favorable hydrogen bonds to sur-
rounding oxygen atoms in the crystal structure. After shed-
ding their hydration shells, sodium, calcium, and magnesium
ions are too small to form such stable bonds, making it
thermodynamically unfavorable for them to be bound by the
crystal. Controlled trials have proven that ZS-9 increases fecal
potassium losses in rats, in a dose-dependent manner.117 ZS-9
has been shown to be effective in maintaining normokalemia
in randomized placebo controlled trials involving 1101
hyperkalemic patients taking the active drug.117–119 Its safety
Table 1 | Definitions of the severity of hyperkalemia
Minimal or mild
Author Year hyperkalemia Moderate hyperkalemia
5
Levinsky 1966 <6.5 mmol/l 6.5–8 mmol/l with ECG
limited to peaked T-waves
Vanden Hoek et al., for the 2005 5.1–5.9 mmol/l
American Heart
Association45
Soar et al., for the European 2010 5.5–5.9 mmol/l
Resuscitation Council44
El-Sherif and Turitto121 2011 5.5–7.5 mmol/l
ECG, electrocardiogram.
Kidney International (2016) 89, 546–554
review
has been studied in an open-label 28-day trial,119 and it is
currently being studied in a larger 52-week trial. In addition
to minor gastrointestinal side effects, edema developed in
6% of patients taking 10 g/day and 14% of patients taking
15 g/day (as compared to 2% of control subjects).119 ZS-9
exchanges sodium and hydrogen ions for potassium and
maintenance doses of the drug (5, 10, or 15 g/day) provide
approximately 17, 34, and 50 mmol of sodium per day.
Because ZS-9 does not contain acid groups that dissociate,
it binds potassium throughout the gastrointestinal tract.116
This suggests that it will be effective in the management
of acute hyperkalemia. In a subgroup of 45 patients with
serum potassium concentrations of at least 6 mmol/l (6.1 to
7.2 mmol/l), who participated in 2 controlled trials, admin-
istration of 10 g of ZS-9 significantly reduced the serum
potassium concentration below baseline by 0.4 mmol/l at
1 hour, by 0.6 mmol/l at 2 hours, and by 0.7 mmol/l at
4 hours (P < 0.001).120
Who to treat
Our knowledge of how to decrease the serum potassium
concentration, while imperfect, has improved substantially
in the past 2 years. Our understanding of when to treat
hyperkalemia has lagged behind. Opinions vary widely as
to what level of serum potassium should be defined as
“severe” or what level constitutes a hyperkalemic emergency
(Table 1).5,44,45,121 Hospital admission is often recommended
for patients with a serum potassium >6 mmol/l and elec-
trocardiographic monitoring and acute interventions for any
patient with a serum potassium >6.5 mmol/l.73 Although that
is our practice, we recognize that it has not been established
that this is necessary; 1 small study showed favorable out-
comes among patients with serum potassium concentrations
>6 mmol/l (6.7 " 0.5 mmol/l) who were managed as out-
patients,122 and no deaths were recorded in another study of
242 consecutively admitted patients with a serum potassium
>6 mmol/l despite substantial delays in treatment.80
Recent studies have reported increased risk of mortality
among patients with hyperkalemia, findings that are likely to
be emphasized when the new potassium binders reach the
market.28,123–126 For example, a 1-year retrospective analysis
of a national cohort of 245,808 veterans with at least 1 hos-
pital admission and 1 inpatient or outpatient potassium value
Severe hyperkalemia
>8 mmol/l or any level associated with prolongation
of the QRS complex, ventricular arrhythmias, or
heart block
6.0–6.9 mmol/l >7 mmol/l
6.0–6.4 mmol/l $6.5 mmol/l
7.5–10 mmol/l >10 mmol/l
551
review
found that among patients with CKD the risk of dying within
a day of documenting potassium between 5.5 and <6 mmol/l
as an outpatient, values usually labeled as “mild or minimal
hyperkalemia” (Table 1), was 2.73 times higher than with
potassium <5.5 mmol/l; the risk was 13 times higher for
potassium >6 mmol/l.123 These alarming statistics should be
placed in perspective. The absolute mortality rates were 0.2%
for potassium between 5.5 and <6 mmol/l and 0.9% for
potassium >6 mmol/l (although much higher rates were
recorded among hospitalized patients). Curiously, both rela-
tive risks (6.17 and 27.4) and absolute risks (0.4% and 1.7%)
of dying within 24 hours for the same potassium values were
much higher among patients without CKD. One may specu-
late with the authors that this finding reflects an adaptation to
more chronic hyperkalemia, but the paradoxical finding that
CKD (a powerful predictor of mortality) was protective may
also mean that deaths in patients without CKD were not
caused by hyperkalemia per se, but rather from underlying
cardiovascular disease.
Retrospectively determined associations between hyper-
kalemia and mortality or between resolution of hyper-
kalemia and improved mortality do not prove cause and
effect, and they are a poor basis for therapeutic strategies
that are likely to be expensive127 and potentially risky.
Currently, because of hyperkalemia, many patients cannot be
treated with inhibitors of the renin-angiotensin-aldosterone
system that have been shown to prolong life. This population
is likely to be the major beneficiary of new agents to treat
hyperkalemia. However, as pointed out in a recent edito-
rial,128 it is quite possible that development of hyperkalemia
under renin-angiotensin-aldosterone system blockade is a
marker for underlying pathology that may lead to mortality
regardless of treatment; control of the plasma potassium
concentration is ultimately a surrogate marker for the hard
outcomes that should be studied: mortality rates, reduced
progression of CKD, deferral of dialysis, improved heart
failure outcomes. It is highly unlikely that we will see such
outcome trials in the foreseeable future. Without them, the
next 50 years may be as frustrating as the last for those who
must treat hyperkalemia.
DISCLOSURE
All the authors declared no competing interests.
REFERENCES
1. Flinn RB, Merrill JP, Welzant WR. Treatment of the oliguric patient with a
new sodium-exchange resin and sorbitol: a preliminary report. N Engl J
Med. 1961;264:111–115.
2. Anonymous. Treatment of potassium retention. N Engl J Med. 1961;264:
149–150.
3. Scherr L, Ogden DA, Mead AW, et al. Management of hyperkalemia
with a cation-exchange resin. N Engl J Med. 1961;264:115–119.
4. Sterns RH, Rojas M, Bernstein P, Chennupati S. Ion-exchange resins for
the treatment of hyperkalemia: are they safe and effective? J Am Soc
Nephrol. 2010;21:733–735.
5. Levinsky NG. Management of emergencies. VI. Hyperkalemia. N Engl J
Med. 1966;274:1076–1077.
6. Merrill JP, Levine HD, Somerville W, Smith S. Clinical recognition and
treatment of acute potassium intoxication. Ann Intern Med. 1950;33:
797–830.
552
RH Sterns et al.: Treatment of hyperkalemia
7. Elliott MJ, Ronksley PE, Clase CM, et al. Management of patients with
acute hyperkalemia. CMAJ. 2010;182:1631–1635.
8. Kamel KS, Wei C. Controversial issues in the treatment of
hyperkalaemia. Nephrol Dial Transplant. 2003;18:2215–2218.
9. Mahoney BA, Smith WA, Lo DS, et al. Emergency interventions for
hyperkalaemia. Cochrane Database Syst Rev. 2005;(2):CD003235.
10. Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J
Med. 2015;372:275–277.
11. Gumz ML, Rabinowitz L, Wingo CS. An integrated view of potassium
homeostasis. N Engl J Med. 2015;373:60–72.
12. Yang A, Singh B, Lavin PT, et al. Placebo effect in clinical studies in
hyperkalemia: a double-blind, randomized, placebo-controlled phase 3
study of sodium zirconium cyclosilicate (ZS-9) [Abstract]. Am J Kidney
Dis. 2015;65:A91.
13. Gumz ML, Rabinowitz L. Role of circadian rhythms in potassium
homeostasis. Semin Nephrol. 2013;33:229–236.
14. Schmidt ST, Ditting T, Deutsch B, et al. Circadian rhythm and day to day
variability of serum potassium concentration: a pilot study. J Nephrol.
2015;28:165–172.
15. Meng QH, Wagar EA. Pseudohyperkalemia: a new twist on an old
phenomenon. Crit Rev Clin Lab Sci. 2015;52:45–55.
16. Bia MJ, DeFronzo RA. Extrarenal potassium homeostasis. Am J Physiol.
1981;240:F257–268.
17. Graber M, Subramani K, Corish D, Schwab A. Thrombocytosis elevates
serum potassium. Am J Kidney Dis. 1988;12:116–120.
18. Don BR, Sebastian A, Cheitlin M, et al. Pseudohyperkalemia caused by
fist clenching during phlebotomy. N Engl J Med. 1990;322:1290–1292.
19. Seimiya M, Yoshida T, Sawabe Y, et al. Reducing the incidence of
pseudohyperkalemia by avoiding making a fist during phlebotomy: a
quality improvement report. Am J Kidney Dis. 2010;56:686–692.
20. Bailey IR, Thurlow VR. Is suboptimal phlebotomy technique impacting on
potassium results for primary care? Ann Clin Biochem. 2008;45:266–269.
21. Thurlow V, Ozevlat H, Jones SA, Bailey IR. Establishing a practical blood
platelet threshold to avoid reporting spurious potassium results due to
thrombocytosis. Ann Clin Biochem. 2005;42:196–199.
22. Chawla NR, Shapiro J, Sham RL. Pneumatic tube “pseudo tumor lysis
syndrome” in chronic lymphocytic leukemia. Am J Hematol. 2009;84:
613–614.
23. Kellerman PS, Thornbery JM. Pseudohyperkalemia due to pneumatic
tube transport in a leukemic patient. Am J Kidney Dis. 2005;46:746–748.
24. Sindhu SK, Hix JK, Fricke W. Pseudohyperkalemia in chronic
lymphocytic leukemia: phlebotomy sites and pneumatic tubes. Am J
Kidney Dis. 2011;57:354–355.
25. Parham WA, Mehdirad AA, Biermann KM, Fredman CS. Hyperkalemia
revisited. Tex Heart Inst J. 2006;33:40–47.
26. Bashour T, Hsu I, Gorfinkel HJ, et al. Atrioventricular and intraventricular
conduction in hyperkalemia. Am J Cardiol. 1975;35:199–203.
27. Ettinger PO, Regan TJ, Oldewurtel HA. Hyperkalemia, cardiac conduction,
and the electrocardiogram: a review. Am Heart J. 1974;88:360–371.
28. McCullough PA, Beaver TM, Bennett-Guerrero E, et al. Acute and chronic
cardiovascular effects of hyperkalemia: new insights into prevention and
clinical management. Rev Cardiovasc Med. 2014;15:11–23.
29. Mattu A, Brady WJ, Robinson DA. Electrocardiographic manifestations
of hyperkalemia. Am J Emerg Med. 2000;18:721–729.
30. Wrenn KD, Slovis CM, Slovis BS. The ability of physicians to predict
hyperkalemia from the ECG. Ann Emerg Med. 1991;20:1229–1232.
31. Aslam S, Friedman EA, Ifudu O. Electrocardiography is unreliable in
detecting potentially lethal hyperkalaemia in haemodialysis patients.
Nephrol Dial Transplant. 2002;17:1639–1642.
32. Khattak HK, Khalid S, Manzoor K, Stein PK. Recurrent life-threatening
hyperkalemia without typical electrocardiographic changes.
J Electrocardiol. 2014;47:95–97.
33. Martinez-Vea A, Bardaji A, Garcia C, Oliver JA. Severe hyperkalemia with
minimal electrocardiographic manifestations: a report of seven cases.
J Electrocardiol. 1999;32:45–49.
34. Szerlip HM, Weiss J, Singer I. Profound hyperkalemia without
electrocardiographic manifestations. Am J Kidney Dis. 1986;7:461–465.
35. Chon SB, Kwak YH, Hwang SS, et al. Severe hyperkalemia can be
detected immediately by quantitative electrocardiography and
clinical history in patients with symptomatic or extreme bradycardia:
a retrospective cross-sectional study. J Crit Care. 2013;28:
1112.e7–1112.e13.
36. Barold SS, Herweg B. The effect of hyperkalaemia on cardiac rhythm
devices. Europace. 2014;16:467–476.
Kidney International (2016) 89, 546–554
RH Sterns et al.: Treatment of hyperkalemia
37. Chamberlain M. Emergency treatment of hyperkalaemia. Lancet. 1964;1:
464–467.
38. Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in
patients with digoxin toxicity. J Emerg Med. 2011;40:41–46.
39. Ho K. A critically swift response: insulin-stimulated potassium and
glucose transport in skeletal muscle. Clin J Am Soc Nephrol. 2011;6:
1513–1516.
40. DeFronzo RA, Felig P, Ferrannini E, Wahren J. Effect of graded doses of
insulin on splanchnic and peripheral potassium metabolism in man. Am
J Physiol. 1980;238:E421–427.
41. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method
for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:
G214–G223.
42. Alvestrand A, Wahren J, Smith D, DeFronzo RA. Insulin-mediated
potassium uptake is normal in uremic and healthy subjects. Am J
Physiol. 1984;246:E174–E180.
43. Nguyen TQ, Maalouf NM, Sakhaee K, Moe OW. Comparison of insulin
action on glucose versus potassium uptake in humans. Clin J Am Soc
Nephrol. 2011;6:1533–1539.
44. Soar J, Perkins GD, Abbas G, et al. European Resuscitation Council
Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special
circumstances: electrolyte abnormalities, poisoning, drowning,
accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac
surgery, trauma, pregnancy, electrocution. Resuscitation. 2010;81:
1400–1433.
45. Vanden Hoek TL, Morrison LJ, Shuster M, et al. Part 12: cardiac arrest in
special situations: 2010 American Heart Association Guidelines for
Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
Circulation. 2010;122(suppl 3):S829–S861.
46. Allon M, Shanklin N. Effect of bicarbonate administration on plasma
potassium in dialysis patients: interactions with insulin and albuterol.
Am J Kidney Dis. 1996;28:508–514.
47. Allon M, Copkney C. Albuterol and insulin for treatment of
hyperkalemia in hemodialysis patients. Kidney Int. 1990;38:869–872.
48. Chothia MY, Halperin ML, Rensburg MA, et al. Bolus administration of
intravenous glucose in the treatment of hyperkalemia: a randomized
controlled trial. Nephron Physiol. 2014;126:1–8.
49. Lens XM, Montoliu J, Cases A, et al. Treatment of hyperkalaemia in renal
failure: salbutamol v. insulin. Nephrol Dial Transplant. 1989;4:228–232.
50. Ljutic D, Rumboldt Z. Should glucose be administered before, with,
or after insulin, in the management of hyperkalemia? Ren Fail. 1993;15:
73–76.
51. Mushtaq MA, Masood M. Treatment of hyperkalemia with salbutamol
and insulin. Pakistan J Med Sci. 2006;22:176.
52. Ngugi NN, McLigeyo SO, Kayima JK. Treatment of hyperkalaemia by
altering the transcellular gradient in patients with renal failure: effect of
various therapeutic approaches. East Afr Med J. 1997;74:503–509.
53. Duranay M, Ates K, Erturk S, et al. Comparison of aminophylline and
insulin infusions in treatment of hyperkalemia in patients with end-
stage renal disease. Nephron. 1996;73:105.
54. Mahajan SK, Mangla M, Kishore K. Comparison of aminophylline
and insulin-dextrose infusions in acute therapy of hyperkalemia in
end-stage renal disease patients. J Assoc Physicians India. 2001;49:
1082–1085.
55. Kim HJ. Combined effect of bicarbonate and insulin with glucose in
acute therapy of hyperkalemia in end-stage renal disease patients.
Nephron. 1996;72:476–482.
56. Blumberg A, Weidmann P, Ferrari P. Effect of prolonged bicarbonate
administration on plasma potassium in terminal renal failure. Kidney Int.
1992;41:369–374.
57. Blumberg A, Weidmann P, Shaw S, Gnädinger M. Effect of various
therapeutic approaches on plasma potassium and major regulating
factors in terminal renal failure. Am J Med. 1988;85:507–512.
58. Galloway JA, Spradlin CT, Nelson RL, et al. Factors influencing the
absorption, serum insulin concentration, and blood glucose responses
after injections of regular insulin and various insulin mixtures. Diabetes
Care. 1981;4:366–376.
59. Goldfarb S, Cox M, Singer I, Goldberg M. Acute hyperkalemia induced
by hyperglycemia: hormonal mechanisms. Ann Intern Med. 1976;84:
426–432.
60. Palmer BF. Regulation of potassium homeostasis. Clin J Am Soc Nephrol.
2015;10:1050–1060.
61. Iglesias P, Díez JJ. Insulin therapy in renal disease. Diabetes Obes Metab.
2008;10:811–823.
Kidney International (2016) 89, 546–554
review
62. Bilotta F, Badenes R, Lolli S, et al. Insulin infusion therapy in critical care
patients: regular insulin vs short-acting insulin. A prospective,
crossover, randomized, multicenter blind study. J Crit Care. 2015;30:
437.e1–437.e6.
63. DeFronzo RA, Alvestrand A, Smith D, et al. Insulin resistance in uremia.
J Clin Invest. 1981;67:563–568.
64. Schafers S, Naunheim R, Vijayan A, Tobin G. Incidence of hypoglycemia
following insulin-based acute stabilization of hyperkalemia treatment.
J Hosp Med. 2012;7:239–242.
65. Czock D, Aisenpreis U, Rasche FM, Jehle PM. Pharmacokinetics and
pharmacodynamics of lispro-insulin in hemodialysis patients with
diabetes mellitus. Int J Clin Pharmacol Ther. 2003;41:492–497.
66. Estep P, Efird L. Evaluation of hypoglycemia incidence and risk factors
in patients treated with IV insulin aspart for hyperkalemia. Endocrinol
Diabetes Res. 2015;3:1–4.
67. Silvers A, Swenson RS, Farquhar JW, Reaven GM. Derivation of a three
compartment model describing disappearance of plasma insulin-131-I
in man. J Clin Invest. 1969;48:1461–1469.
68. Allon M, Dunlay R, Copkney C. Nebulized albuterol for acute
hyperkalemia in patients on hemodialysis. Ann Intern Med. 1989;110:
426–429.
69. Mandelberg A, Krupnik Z, Houri S, et al. Salbutamol metered-dose
inhaler with spacer for hyperkalemia: how fast? How safe? Chest.
1999;115:617–622.
70. Schwarz KC, Cohen BD, Lubash GD, Rubin AL. Severe acidosis and
hyperpotassemia treated with sodium bicarbonate infusion. Circulation.
1959;19:215–220.
71. Iqbal Z, Friedman EA. Preferred therapy of hyperkalemia in renal
insufficiency: survey of nephrology training-program directors. N Engl J
Med. 1989;320:60–61.
72. Gutierrez R, Schlessinger F, Oster JR, et al. Effect of hypertonic versus
isotonic sodium bicarbonate on plasma potassium concentration in
patients with end-stage renal disease. Miner Electrolyte Metab. 1991;17:
297–302.
73. Greenberg A. Hyperkalemia: treatment options. Semin Nephrol. 1998;18:
46–57.
74. Sterns RH, Spital A. Disorders of internal potassium balance. Semin
Nephrol. 1987;7:399–415.
75. Sterns RH, Cox M, Feig PU, Singer I. Internal potassium balance and
the control of the plasma potassium concentration. Medicine. 1981;60:
339–354.
76. Fraley DS, Adler S. Correction of hyperkalemia by bicarbonate despite
constant blood pH. Kidney Int. 1977;12:354–360.
77. Meroney W, Herndon R. The management of acute renal insufficiency.
J Am Med Assoc. 1954;155:877–883.
78. Janjua HS, Mahan JD, Patel HP, et al. Continuous infusion of a standard
combination solution in the management of hyperkalemia. Nephrol Dial
Transplant. 2011;26:2503–2508.
79. Perazella MA. Drug-induced hyperkalemia: old culprits and new
offenders. Am J Med. 2000;109:307–314.
80. Acker CG, Johnson JP, Palevsky PM, Greenberg A. Hyperkalemia in
hospitalized patients: causes, adequacy of treatment, and results of an
attempt to improve physician compliance with published therapy
guidelines. Arch Intern Med. 1998;158:917–924.
81. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin–
angiotensin–aldosterone system. N Engl J Med. 2004;351:585–592.
82. Antoniou T, Gomes T, Juurlink DN, et al. Trimethoprim-
sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors
of the renin-angiotensin system: a population-based study. Arch Intern
Med. 2010;170:1045–1049.
83. Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum
creatinine elevation associated with different dosage levels of
outpatient trimethoprim-sulfamethoxazole with and without
concomitant medications. Ann Pharmacother. 2013;47:1618–1626.
84. Lam N, Weir MA, Juurlink DN, et al. Hospital admissions for
hyperkalemia with trimethoprim-sulfamethoxazole: a cohort study
using health care database codes for 393,039 older women with urinary
tract infections. Am J Kidney Dis. 2011;57:521–523.
85. Schepkens H, Vanholder R, Billiouw J, Lameire N. Life-threatening
hyperkalemia during combined therapy with angiotensin-converting
enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J
Med. 2001;110:438–441.
86. Weir MA, Juurlink DN, Gomes T, et al. Beta-blockers, trimethoprim-
sulfamethoxazole, and the risk of hyperkalemia requiring
553
review
hospitalization in the elderly: a nested case-control study. Clin J Am Soc
Nephrol. 2010;5:1544–1551.
87. Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal
insufficiency and hyperkalemia in patients with heart failure. Am Heart J.
2004;148:971–978.
88. Susantitaphong P, Sewaralthahab K, Balk EM, et al. Efficacy and safety
of combined vs. single renin-angiotensin-aldosterone system blockade
in chronic kidney disease: a meta-analysis. Am J Hypertens. 2013;26:
424–441.
89. Fralick M, Macdonald EM, Gomes T, et al, for the Canadian Drug Safety
and Effectiveness Research Network. Co-trimoxazole and sudden death
in patients receiving inhibitors of renin-angiotensin system: population
based study. BMJ. 2014;349:g6196.
90. Feig P, Shook A, Sterns R. Effect of potassium removal during hemodialysis
on the plasma potassium concentration. Nephron. 1981;27:25–30.
91. Kessler C, Ng J, Valdez K, et al. The use of sodium polystyrene sulfonate in
the inpatient management of hyperkalemia. J Hosp Med. 2011;6:136–140.
92. Agar BU, Culleton BF, Fluck R, Leypoldt JK. Potassium kinetics during
hemodialysis. Hemodial Int. 2015;19:23–32.
93. Blumberg A, Roser HW, Zehnder C, Muller-Brand J. Plasma potassium in
patients with terminal renal failure during and after haemodialysis;
relationship with dialytic potassium removal and total body potassium.
Nephrol Dial Transplant. 1997;12:1629–1634.
94. Bolasco P, Concas G, Steckiph D, et al. Simple model of intra-
extracellular potassium kinetics and removal applied to constant and
potassium-profiled dialysis. J Nephrol. 2008;21:384–393.
95. Kao KC, Huang CC, Tsai YH, et al. Hyperkalemic cardiac arrest
successfully reversed by hemodialysis during cardiopulmonary
resuscitation: case report. Chang Gung Med J. 2000;23:555–559.
96. Lin JL, Lim PS, Leu ML, Huang CC. Outcomes of severe hyperkalemia in
cardiopulmonary resuscitation with concomitant hemodialysis.
Intensive Care Med. 1994;20:287–290.
97. Lin JL, Huang CC. Successful initiation of hemodialysis during
cardiopulmonary resuscitation due to lethal hyperkalemia. Crit Care
Med. 1990;18:342–343.
98. DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism.
Kidney Int. 1980;17:118–134.
99. Carvalhana V, Burry L, Lapinsky SE. Management of severe
hyperkalemia without hemodialysis: case report and literature review.
J Crit Care. 2006;21:316–321.
100. Dick T, Raines A, Stinson J, et al. Fludrocortisone is effective in the
management of tacrolimus-induced hyperkalemia in liver transplant
recipients. Transplant Proc. 2011;43:2664–2668.
101. Kamel KS, Ethier JH, Quaggin S, et al. Studies to determine the basis for
hyperkalemia in recipients of a renal transplant who are treated with
cyclosporine. J Am Soc Nephrol. 1992;2:1279–1284.
102. Evans B, Milne M, Jones NH, Yellowlees H. Ion-exchange resins in the
treatment of anuria. Lancet. 1953;265:791–795.
103. Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium
absorption and secretion by the human intestine. Gastroenterology.
1994;107:548–571.
104. Gruy-Kapral C, Emmett M, Santa Ana CA, et al. Effect of single dose
resin-cathartic therapy on serum potassium concentration in patients
with end-stage renal disease. J Am Soc Nephrol. 1998;9:1924–1930.
105. LePage L. Sodium polystyrene sulfonate for the treatment of mild
hyperkalemia in chronic kidney disease: a randomized clinical trial. Clin
J Am Soc Nephrol. 2015;10:2136–2142.
106. Chernin G, Gal-Oz A, Ben-Assa E, et al. Secondary prevention of
hyperkalemia with sodium polystyrene sulfonate in cardiac and kidney
patients on renin-angiotensin-aldosterone system inhibition therapy.
Clin Cardiol. 2012;35:32–36.
107. Straube B, Reaven N, Funk S, Little D, Nee R, Abbott K, et al. Cost utility
analysis of sodium polystyrene sulfate vs. potential alternatives for
554
RH Sterns et al.: Treatment of hyperkalemia
chronic hyperkalemia. Clinical Nephrology, 2014;81:259–268. Clin
Nephrol. 2015;83:380–381.
108. Harel Z, Harel S, Shah PS, et al. Gastrointestinal adverse events with
sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am
J Med. 2013;126:264.e9–264.e24.
109. Lillemoe KD, Romolo JL, Hamilton SR, et al. Intestinal necrosis due
to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical
and experimental support for the hypothesis. Surgery. 1987;101:267–272.
110. Watson MA, Baker TP, Nguyen A, et al. Association of prescription of
oral sodium polystyrene sulfonate with sorbitol in an inpatient setting
with colonic necrosis: a retrospective cohort study. Am J Kidney Dis.
2012;60:409–416.
111. Huang I. RLY5016: a novel, non-absorbed, therapeutic polymer for
serum potassium control. J Am Soc Nephrol. 2010;21:482A–483A.
112. Bushinsky DA. Patiromer induces a rapid and sustain potassium lowering
in CKD patients with hyperkalemia. Kidney Int. 2015;88:1427–1433.
113. Pitt B, Anker SD, Bushinsky DA, et al. PEARL-HF Investigators. Evaluation
of the efficacy and safety of RLY5016, a polymeric potassium binder, in
a double-blind, placebo-controlled study in patients with chronic heart
failure (the PEARL-HF) trial. Eur Heart J. 2011;32:820–828.
114. Weir MR, Bakris GL, Bushinsky DA, et al, for the OPAL-HK Investigators.
Patiromer in patients with kidney disease and hyperkalemia receiving
RAAS inhibitors. N Engl J Med. 2015;372:211–221.
115. Bakris GL, Pitt B, Weir MR, et al, for the AMETHYST-DN Investigators.
Effect of patiromer on serum potassium level in patients with
hyperkalemia and diabetic kidney disease: the AMETHYST-DN
randomized clinical trial. JAMA. 2015;314:151–161.
116. Stavros F, Yang A, Leon A, et al. Characterization of structure and
function of ZS-9, a Kþ selective ion trap. PLoS One. 2014;9:e114686.
117. Ash SR, Singh B, Lavin PT, et al. A phase 2 study on the treatment of
hyperkalemia in patients with chronic kidney disease suggests that the
selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015;88:
404–411.
118. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium
cyclosilicate in hyperkalemia. N Engl J Med. 2015;372:222–231.
119. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium
cyclosilicate on potassium lowering for 28 days among outpatients
with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA.
2014;312:2223–2233.
120. Kosiborod M, Peacock WF, Packham DK. Sodium zirconium cyclosilicate
for urgent therapy of severe hyperkalemia. N Engl J Med. 2015;372:
1577–1578.
121. El-Sherif N, Turitto G. Electrolyte disorders and arrhythmogenesis.
Cardiol J. 2011;18:233–245.
122. Charytan D, Goldfarb DS. Indications for hospitalization of patients with
hyperkalemia. Arch Intern Med. 2000;160:1605–1611.
123. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and
its significance in chronic kidney disease. Arch Intern Med. 2009;169:
1156–1162.
124. Khanagavi J, Gupta T, Aronow WS, et al. Hyperkalemia among
hospitalized patients and association between duration of
hyperkalemia and outcomes. Arch Med Sci. 2014;10:251–257.
125. McMahon GM, Mendu ML, Gibbons FK, Christopher KB. Association
between hyperkalemia at critical care initiation and mortality. Intensive
Care Med. 2012;38:1834–1842.
126. Conway R, Creagh D, Byrne DG, et al. Serum potassium levels as an
outcome determinant in acute medical admissions. Clin Med (Lond).
2015;15:239–243.
127. Little DJ, Nee R, Abbott KC, et al. Cost-utility analysis of sodium
polystyrene sulfonate vs. potential alternatives for chronic
hyperkalemia. Clin Nephrol. 2014;81:259–268.
128. Winkelmayer WC. Treatment of hyperkalemia: from “Hyper Kþ”
strikeout to home run? JAMA. 2015;314:129–130.
Kidney International (2016) 89, 546–554
 ARTIGO 6

HIPERCALCEMIAS
BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015)
Clinical Review
The diagnosis and management of hypercalcaemia
Salvatore Minisola professor, Jessica Pepe consultant, Sara Piemonte consultant, Cristiana Cipriani
consultant
Department of Internal Medicine and Medical Disciplines, “Sapienza” Rome University, 00161 Rome, Italy
Hypercalcaemia is a common finding in the setting of primary
care,1 as well as in emergency departments2 and patients
admitted to hospital.3 Primary hyperparathyroidism and
malignancy are the two most common causes of increased serum
calcium levels, together accounting for about 90% of all cases.4
The remaining 10% represent an important figure, and thus the
need to consider other disorders in the evaluation of patients
with hypercalcaemia. This review aims to give an overview of
the diagnosis and clinical management of hypercalcaemia for
non-specialist clinicians and health professionals.
What is the definition of hypercalcaemia?
Hypercalcaemia is diagnosed when the concentration of serum
calcium is 2 standard deviations above the mean of values found
in people with normal calcium levels, in at least two samples
at least one week apart over a period of three months. The serum
concentration of total calcium in adults usually ranges between
2.15 and 2.60 mmol/L (8.6-10.4 mg/dL; 4.3-5.2 mEq/L). About
45% of calcium in blood is bound to plasma proteins,
particularly albumin, and approximately 10% is bound to anions
such as phosphate and citrate; free or ionised calcium (normal
values 1.17-1.33 mmol/L) represents about 45% of total calcium.
Although the ionised fraction of calcium is the one readily
available for activating cellular processes, measurement of total
serum calcium is mostly requested in clinical practice. However,
when the serum protein concentration fluctuates, the total serum
calcium level may vary accordingly, while ionised calcium
remains stable. Total serum calcium can then be derived from
the formula: total calcium
concentration(mmol/L)+0.02(40−serum albumin
concentration(g/L).
Changes in blood pH can alter the equilibrium constant of the
albumin-ionised calcium complexes, with acidosis reducing the
binding and alkalosis enhancing it. When major changes in
serum proteins or pH are suspected, measurement of ionised
calcium is recommended to determine the physiological serum
calcium level.
Correspondence to: S Minisola salvatore.minisola@uniroma1.it
For personal use only: See rights and reprints http://www.bmj.com/permissions
Page 1 of 9
CLINICAL REVIEW
What is the prevalence of
hypercalcaemia?
Primary hyperparathyroidism is a relatively common endocrine
disorder, with an estimated prevalence of 1-7 cases per 1000
adults.4 5 It is considered the most common cause of
hypercalcaemia, predominantly affecting the older population
(≥65 years) and women two or three times more frequently than
men.4 5 The incidence of primary hyperparathyroidism is poorly
defined; evidence from the United Kingdom5 and the United
States6 shows a wide range, from 0.41 to 21.6 cases per 100 000
population annually. This variety arises from heterogeneity in
screening methods, case definition, and population studied, as
well as unexplained annual fluctuations in incidence within the
same population.7
Data on the prevalence and incidence of hypercalcaemia from
other causes are poor. Malignancy associated hypercalcaemia
is estimated to affect 2.7% of people with cancer in the USA.8
Data in children with cancer indicates a lower frequency of
hypercalcaemia (about 0.5-1%).9
What causes hypercalcaemia?
The box summarises the most common causes of
hypercalcaemia. Mechanisms associated with hypercalcaemia
are classically divided into parathyroid hormone and
non-parathyroid hormone mediated.
Parathyroid hormone mediated
hypercalcaemia
Parathyroid related causes of hypercalcaemia comprise primary
(including the various genetic forms) and tertiary
hyperparathyroidism. Parathyroid hormone is the main regulator
of calcium homeostasis and its primary increased secretion alters
the regulation of serum calcium by acting on different target
organs (bone, kidney, gut).
A particular genetic form is represented by familial benign
hypocalciuric hypercalcaemia. This disorder results from altered
calcium sensing receptor function and a decreased sensitivity
to increases in extracellular calcium; the latter determines an
impaired suppression of parathyroid hormone secretion by the
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BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015) Page 2 of 9

CLINICAL REVIEW

The bottom line

• Primary hyperparathyroidism and malignancy are the two most common causes of increased serum calcium levels
• The diagnosis of hypercalcaemia is made when the corrected serum calcium concentration is 2 standard deviations above the mean
of values found in people with normal calcium levels, in at least two samples at least one week apart over a period of three months
• The presence of high or not adequately suppressed serum parathyroid hormone levels should point the diagnosis towards
hypercalcaemia of parathyroid origins
• Mild hypercalcaemia is usually caused by primary hyperparathyroidism, the treatment for which is typically surgery; those aged 50 or
more with serum calcium levels <0.25 mmol/L above the upper limit of normal and without end organ damage may be followed up
conservatively. Treatment with a calcimimetic agent, cinacalcet, is an option in selected cases
• Severe hypercalcaemia requires admission to hospital and treatment with aggressive intravenous hydration and bisphosphonates
along with treatment of the underlying disease

Sources and selection criteria

We carried out a search through Medline and PubMed of articles published from 1990 to 2015 using the terms “mild hypercalcaemia” and
“severe “hypercalcemia”, “primary hyperparathyroidism”, “hypercalcemia of malignancy”, “parathyroid hormone measurement”,
“parathyroidectomy”, and “cinacalcet” and through the National Cancer Institute using the term “hypercalcaemia”. We also retrieved personal
archived references to identify peer reviewed articles. We gave priority to randomised controlled trials, systematic reviews, meta-analyses,
and prospective epidemiological studies. As appropriate we also included observational, retrospective, and non-randomised studies and
case reports.

Box Common causes of hypercalcaemia. Adapted from Minisola et al26

Parathyroid hormone mediated
• Sporadic (adenoma, hyperplasia, or carcinoma)
• Familial (multiple endocrine neoplasia 1, 2a, or 4, hyperparathyroidism jaw tumour syndrome, familial isolated hyperparathyroidism,
familial hypocalciuria hypercalcaemia)
• Ectopic parathyroid hormone in malignancy (rare)
• “Tertiary” hyperparathyroidism

Malignancy
• Humoral hypercalcaemia of malignancy (parathyroid hormone related protein)
• Local osteolysis (cytokines, chemokines, parathyroid hormone related protein)
• Ectopic parathyroid hormone in malignancy (rare)
• Calcitriol related hypercalcaemia

Vitamin D related
• Granulomatous disease (for example, sarcoidosis, tuberculosis, berylliosis, coccidiodomycosis, histoplasmosis, leprosy, inflammatory
bowel disease, foreign body granuloma)
• Vitamin D intoxication (vitamin D supplements, metabolites, or analogues)

Endocrine disorders
• Thyrotoxicosis
• Adrenal insufficiency
• Pheochromocytoma
• VIPoma (Verner-Morrison) syndrome

Drugs
• Thiazide diuretics
• Lithium
• Milk-alkali syndrome (calcium and antacids)
• Vitamin A
• Parathyroid hormone

Other
• Coexisting malignancy and primary hyperparathyroidism
• Immobilisation
• Acute renal failure
• Chronic renal failure treated with calcium and calcitriol or vitamin D analogues
• Renal transplant

parathyroid cells and continuous reabsorption of calcium by the
kidney tubules. As a consequence, such people develop
hypocalciuria, with tubular calcium reabsorption being increased
by parathyroid hormone as well.
Lithium induced hypercalcaemia could be considered as a
reversible form of parathyroid hormone mediated
hypercalcaemia. Lithium can directly stimulate parathyroid
hormone secretion and increase renal calcium reabsorption;
these effects may be reversed by withdrawal of the drug.

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BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015)
Non-parathyroid hormone mediated
hypercalcaemia
Hypercalcaemia of non-parathyroid origin is mostly related to
production of parathyroid hormone related protein, calcitriol,
or cytokines as mediators (box).
Malignancy related hypercalcaemia—humoral hypercalcaemia
of malignancy is a paraneoplastic syndrome resulting from the
secretion of parathyroid hormone related protein by the tumour.10
Although any kind of neoplasia may cause the syndrome of
humoral hypercalcaemia of malignancy, squamous carcinomas
are most commonly implicated. Hypercalcaemia may be due to
local osteolysis, most usually observed in haematological
cancers. Overproduction of calcitriol represents the key
mechanism in the development of hypercalcaemia associated
with some forms of malignancy and with granulomatous diseases
(box). Malignant cells and granulomas can over-express
1-α-hydroxylase and increase the conversion of calcidiol to the
active form of vitamin D, calcitriol, leading to increased
intestinal absorption of calcium, hypercalciuria, and
hypercalcaemia. Finally, authentic ectopic hyperparathyroidism
is a rare cause of hypercalcaemia, with few cases described in
the literature.10
Thiazide diuretics—thiazides are commonly prescribed and can
increase renal reabsorption of calcium, resulting in hypocalciuria
and eventually high serum calcium levels. As many as 8% of
people develop hypercalcaemia while taking thiazides.11 12
Endocrine disorders—hypercalcaemia is relatively common in
people with hyperthyroidism and is probably related to increases
in RANK-ligand mediated bone resorption, stimulated by an
excess of thyroid hormones.10 Hypercalcaemia can be sustained
by primary hyperparathyroidism in patients with
pheochromocytoma in the setting of multiple endocrine
neoplasia type 2. Some pheochromocytomas have been found
to secrete parathyroid hormone related protein or to directly
stimulate bone resorption.10 Hypercalcaemia is not a common
finding in Addisonian crisis, but it could occur in association
with the underlying disorder, such as tuberculosis; reduction in
the extracellular fluid volume associated with the relative
hyperalbuminaemia may lead to factitious hypercalcaemia.10
Acute renal failure and rhabdomyolysis—patients with
rhabdomyolysis associated acute renal failure may develop
hypercalcaemia. The hypercalcaemia is probably related to
severe secondary hyperparathyroidism in the acute, oliguric
phase—the effect of parathyroid hormone on bone along with
the release of calcium phosphate into soft tissues during the
early hypocalcaemic and hyperphosphataemic phase. The use
of calcium, calcitriol, or vitamin D analogues supplementation
in patients who have end stage renal disease or receive dialysis
may cause hypercalcaemia; in this setting, hypercalcaemia may
also occur in association with tertiary hyperparathyroidism.
Finally, increased serum calcium levels may be observed after
kidney transplantation.10
Immobilisation hypercalcaemia—this arises from suppression
of bone formation and increased bone resorption, with
consequent loss of calcium from the skeleton and
hypercalcaemia. Immobilisation hypercalcaemia is generally
observed when there is a concomitant cause of high bone
turnover, such as in younger people. However, data from
observational and retrospective studies suggest that
hypercalcaemia may develop in cases of prolonged
immobilisation from different causes, such Parkinson’s disease
or prolonged intensive care for major burns.13 14
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Page 3 of 9
CLINICAL REVIEW
Malignancy related hypercalcaemia
The occurrence of hypercalcaemia together with systemic
symptoms (for example, fever, weight loss, decreased appetite,
worsening malaise) or rapid onset hypercalcaemia, typically
with very high serum calcium levels, should raise suspicion of
malignancy. In particular, suppressed or undetectable serum
parathyroid hormone levels are found in the setting of
hypercalcaemia of malignancy. Hypercalcaemia is usually a
late finding in malignancy and therefore the underlying disease
is often known when it occurs. If the primary malignancy is
unknown, the need for a rapid differential diagnosis is critical,
as hypercalcaemia represents a negative prognostic factor in
people with cancer. Physical examination (including lymph
nodes, rectal, breasts, gynaecological, mouth, and ear, nose, and
throat) should be performed, as well as laboratory assessment
including blood count, biochemistry, serum tumour markers,
chest, abdomen, and pelvis imaging. Serum and urinary
immunoelectrophoresis are recommended, whereas in selected
cases, measurement of serum parathyroid hormone related
protein (where available)19 and calcitriol might be of value. The
finding of an increased parathyroid hormone related protein
level implies the need to search for solid tumours (lung,
oesophagus, skin, cervix, breast, and kidney are the most
commons sites)19 (see box). High serum calcitriol levels are
typically associated with lymphoproliferative and granulomatous
disorders (table). In this context, diagnoses should be considered
even in the setting of normal serum calcitriol levels when
parathyroid hormone and parathyroid hormone related protein
levels are suppressed. The production of the active form of
vitamin D is no longer subject to regulation by parathyroid
hormone or parathyroid hormone related protein, but rather
primarily driven in these conditions by the underlying disease.
Parathyrotoxic crisis
Although acute and severe hypercalcaemia is mostly associated
with malignancy, the measurement of parathyroid hormone
levels has a key role in excluding parathyrotoxic crisis, the
association of which with parathyroid carcinoma has been
described in case reports.20 21 The clinical presentation is severe
and patients require admission to hospital. Parathyrotoxic crisis
comprises profound volume depletion, coma, heart failure, and
abdominal pain possibly mimicking acute abdomen.
Hyperthyroid activity can be associated with hypercalcaemia
and suppressed parathyroid hormone serum levels. Evaluation
of thyroid function is therefore needed.
Mediators of hypercalcaemia are typically suppressed in
immobilisation hypercalcaemia; serum phosphorus levels are
often high, thus helping to differentiate those cases from primary
hyperparathyroidism, where phosphorus levels are typically
low.
Hypercalcaemia associated with suppressed parathyroid
hormone, normal parathyroid hormone related protein, and high
or normal serum calcitriol levels strongly suggest the diagnosis
of calcitriol mediated diseases (box); however, other possible
diagnoses should be taken into account. Levels of calcidiol
should also be checked, particularly in those whose clinical
presentation does not suggest the presence of malignancy.
Clinical case reports suggest that the occurrence of vitamin D
toxicity, although unusual, should be excluded, particularly
when the consumption of high doses of exogenous vitamin D
is unrecognised.22 The misuse of high dose vitamin D
preparations (daily dosing rather than weekly or monthly) should
be investigated.
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BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015)
Thiazide diuretics
In patients who were hypercalcaemic while taking thiazide
diuretics, serum calcium and parathyroid hormone levels should
be re-evaluated at least three weeks after withdrawal of the
drugs. In a population based study, about two third of patients
who discontinued thiazides had persistence of hypercalcaemia,
suggesting that primary hyperparathyroidism is common in
those who develop hypercalcaemia while taking thiazides.12
How should hypercalcaemia be
investigated in primary care?
The primary goal in the differential diagnosis of hypercalcaemia
is to determine the underlying mechanism.
Medical history should focus on the use of supplements and
drugs possibly causing hypercalcaemia (box) and include an
evaluation of family history aimed at identifying underlying
genetic forms of primary hyperparathyroidism.
Clinicians need to evaluate carefully the severity of clinical
presentation, degree of hypercalcaemia, and timing of
development of the condition. It is clinically relevant to
distinguish those people with mild hypercalcaemia from those
with a more severe form, as this could help in diagnosis and
guiding further investigation. The table⇓ describes the clinical
presentation of people with hypercalcaemia. Importantly,
symptoms associated with chronic hypercalcaemia are related
to severe forms—those with chronic mild hypercalcaemia are
typically asymptomatic.
Contrary to what is observed among inpatients, hypercalcaemia
is most commonly attributable to primary hyperparathyroidism
in the outpatient setting. In this context the finding of
pre-existing mild hypercalcaemia may suggest the diagnosis of
primary hyperparathyroidism. However, the detection of mildly
increased serum calcium levels on a routine biochemical panel
in asymptomatic people is also a common finding.
The evaluation of “outpatients” with hypercalcaemia usually
follows a stepwise diagnostic approach (figure⇓). Laboratory
evaluation should first include the confirmation of
hypercalcaemia by remeasuring serum calcium levels and
correcting for albumin or by measuring serum ionised calcium
wherever available. Renal function should also be evaluated.
Second or third generation immunoradiometric parathyroid
hormone assays should be used, as they have been proved to
perform similarly and better than first generation assays15 16;
with a sensitivity in diagnosis of primary hyperparathyroidism
ranging from 88% to 97%. Hence, confirmation of
hypercalcaemia in association with an increased or
non-suppressed or normal parathyroid hormone concentration
suggests primary hyperparathyroidism as the most likely
diagnosis.
Assessment of vitamin D status is indicated, as low serum
calcidiol (25(OH)D) levels are highly prevalent in people with
primary hyperparathyroidism and have been associated with
many negative outcomes in cross sectional studies.16 Most recent
guidelines suggest a cautious replenishment with supplemental
doses of vitamin D in case of hypovitaminosis17; however, since
no data from large randomised controlled trials are currently
available, there is no specific recommendation on the dose
regimen of vitamin D. Serum levels between 50 and 75 nmol/L
are considered the goal of treatment in these patients.17 18
The diagnosis of primary hyperparathyroidism should be
confirmed by ruling out familial hypocalciuric hypercalcaemia,
another possible cause of high serum calcium associated with
high or unsuppressed serum parathyroid hormone (box). A 24
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Page 4 of 9
CLINICAL REVIEW
hour urine collection for calcium and creatinine determination
should therefore be performed to calculate the calcium to
creatinine clearance ratio. As calcium excretion could possibly
be decreased in association with vitamin D deficiency, the
accuracy of this evaluation implies the need for replenishment
in deficient patients. Calcium to creatinine clearance values less
than 0.01 are strongly indicative of familial hypocalciuric
hypercalcaemia and require an evaluation of family history of
hypercalcaemia and eventually screening of serum calcium in
family members. Serum magnesium could be helpful in pointing
towards the differential diagnosis of familial hypocalciuric
hypercalcaemia, as it is typically in the high range of normal or
modestly increased in this condition. Genetic testing is useful
for confirmation of the diagnosis.16
How is hypercalcaemia treated?
Understanding the mechanism of hypercalcaemia is crucial for
the most efficient management. Regardless of the diagnosis, all
patients with hypercalcaemia require hydration. The timing and
regimens of hydration strongly depend on the severity of the
hypercalcaemia.
Mild hypercalcaemia
Mild hypercalcaemia (values not exceeding 0.25 mmol/L above
normal range or <3 mmol/L) is usually caused by primary
hyperparathyroidism. Adults aged 50 or more with primary
hyperparathyroidism, a serum calcium level less than 0.25
mmol/L above the upper limit of normal, and without end organ
damage may be followed up conservatively—that is, without
intervention and specific drugs. People with serum calcium
levels greater than 0.25 mmol/L above the normal range, even
if asymptomatic, should be referred for surgery. In addition,
regardless of calcium levels, the most recent guidelines for
asymptomatic people with primary hyperparathyroidism suggest
a more complete evaluation of skeletal and renal complications,
including imaging studies.23 24 Skeletal (osteoporosis, as
evaluated by bone mineral density measurement, fragility
fractures) or renal involvement (nephrolithiasis or
nephrocalcinosis, creatinine clearance <60 mL/min, or
hypercalciuria >10 mmol/d associated with an increased risk of
stone disease) and age less than 50 years are considered criteria
for surgery in people with primary hyperparathyroidism, even
when calcium levels are not greater than 0.25 mmol/L above
the normal range.23 In those who decline surgery or are not
suitable candidates for surgery, serum calcium and creatinine
levels should be measured every year and bone density measured
every one or two years, together with monitoring by renal
imaging. During follow-up, if the increase in serum calcium
levels is greater than 0.25 mmol/L or there is renal or skeletal
involvement the patient should be referred for surgery.23
If surgery is not performed, or not indicated, patients should be
encouraged to have an above average intake of fluids and avoid
drugs, such as thiazide diuretics, that can increase plasma
calcium levels.24
Recently, cinacalcet, a calcimimetic agent, has been proved in
a prospective observational study to be effective in lowering
serum calcium levels in people with sporadic and familial
primary hyperparathyroidism, but it has no effects on other
features of primary hyperparathyroidism—that is, bone mineral
density and hypercalciuria.25 Cinacalcet given orally in a dosing
regimen of 30-120 mg/d is generally well tolerated, with only
nausea described as a common adverse event. The European
Medicines Agency in 2008 and the US Food and Drug
Administration in 2011 approved the use of cinacalcet in people
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BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015)
with primary hyperparathyroidism with specific indications.
The EMA panel stated that cinacalcet can be an option in those
where parathyroidectomy is indicated based on serum calcium
levels but for whom surgery is otherwise “not clinically
appropriate or contraindicated.” The FDA approves the use of
cinacalcet in primary hyperparathyroidism for people with
severe hypercalcaemia who are unable to undergo
parathyroidectomy.
Severe hypercalcaemia
If serum calcium levels are moderately increased (3.0-3.5
mmol/L), the type of treatment and timing for administering
drugs should be guided by clinical manifestations. Admission
to hospital is required for people with severe hypercalcaemia
(>3.5 mmol/L); emergency treatment includes aggressive
intravenous hydration with 3-4 litres of 0.9% saline daily, or
1-2 litre bolus of 0.9% saline, followed by 200-250 mL saline
hourly.25 The rationale underlying hydration is that people with
hypercalcaemia are often severely dehydrated, mainly because
of nephrogenic diabetes insipidus due to hypercalcaemia and
reduced water intake. The latter results from anorexia, nausea,
and vomiting induced by the hypercalcaemia itself as well as
the causative disease, such as neoplasia. Hydration alone may
be effective in slowly reducing serum calcium levels; however,
most commonly it is not the only treatment and may lead to
fluid overload. Caution is therefore needed to avoid excessive
fluid loading in patients with cardiac and renal disease. In such
patients, it is important to assess serum electrolytes and to carry
out electrocardiography during treatment.
Loop diuretics, such as furosemide (frusemide), which could
theoretically enhance calcium excretion, may worsen electrolyte
derangements and volume depletion when administered at high
doses. Thus, even in patients with volume overload, loop
diuretics should be used with caution. A recent review of
randomised controlled trials, prospective single group trials,
systematic reviews, and meta-analyses shows limited or no
evidence to support the use of loop diuretics in people with
hypercalcaemia.27
Since the major mechanism responsible for severe
hypercalcaemia is the increased bone resorption from activation
of osteoclasts, bisphosphonates are the treatment of choice as
they inhibit the osteoclast’s’ activity. Pamidronate and
zoledronic acid are approved by EMA and FDA for the treatment
of hypercalcaemia of malignancy, both having shown
effectiveness in clinical trials.28 29 Head to head comparison of
pamidronate and zoledronic acid in two randomised controlled
trials showed that zoledronic acid was superior to pamidronate
in both efficacy and duration of response.30 A single 15 minute
intravenous infusion of 4 mg of zoledronic acid in 100 mL of
isotonic saline, with adequate hydration, resulted in complete
normalisation of serum calcium levels in less than three days
in 80-100% of patients. Zoledronic acid can be readministered
as necessary to control hypercalcaemia. The most common
reported side effects have been transient fever, myalgias, and
infusion site reaction. Zoledronic acid is contraindicated in
patients with creatinine clearance values lower than 30 mL/min;
in this situation, dose reduction according to creatinine clearance
values could be an option. Ibandronate, a bisphosphonate with
lower renal toxicity, is approved by EMA for the treatment of
malignancy related hypercalcaemia.
As the administering of intravenous bisphosphonates out of
hospital can be troublesome, patients with hypercalcaemia and
end stage malignancy could benefit from subcutaneous
clodronate when discharged from hospital. Subcutaneous
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Page 5 of 9
CLINICAL REVIEW
clodronate has been reported to be effective, with no or minimal
toxicity. This form of treatment may avoid hospital stay and
overcome any possible problems related to difficult intravenous
access.31
Although bisphosphonates are proved to be effective in the
treatment of hypercalcaemia, a drug with a rapid hypocalcaemic
effect, such as calcitonin, could be used when a prompt
resolution is needed. Calcitonin inhibits bone resorption and
also decreases renal tubular reabsorption of calcium. Its onset
of action is within two hours of being administered, but the
effect is short, and drug tolerance commonly develops within
two days. Thus, calcitonin is used as an early treatment for
severe hypercalcaemia until the onset of the hypocalcaemic
effects of other drugs.32
A recent single harm intervention study in people with persistent
hypercalcaemia of malignancy despite intravenous
bisphosphonate treatment showed that denosumab (120 mg
subcutaneously on days 1, 8, 15, and 29 and then every four
weeks) lowered serum calcium levels in 64% of patients within
10 days.33 Denosumab is a fully human monoclonal antibody
that binds to RANK-ligand and inhibits the maturation,
activation, and function of osteoclasts; it could be given even
to those with a creatinine clearance of less than 30 mL/min.
Further trials with denosumab are needed before it can be
broadly recommended for use in people with hypercalcaemia.
Haemodialysis (as well as peritoneal dialysis) against a low or
zero calcium dialysate is a treatment option in cases of treatment
failure or when calcium levels are so high as to be life
threatening; patients already receiving haemodialysis or with
severe renal insufficiency may take advantage of this
procedure.34
It should be borne in mind that in hypercalcaemia of malignancy
treatment of the underlying malignancy will also reduce serum
calcium levels. Surgical removal of the lesion is currently the
only cure for severe hypercalcaemic crisis associated with
parathyroid carcinoma, an extremely rare presentation requiring
urgent admission to hospital.
Different treatments need to be considered in people with
hypercalcaemia from other causes, such as vitamin D
intoxication or granulomatous disorders. Since in these cases,
the underlying cause is an increased production of calcidiol,
drugs that enhance vitamin D metabolism, such as
glucocorticoids, are indicated. Prednisone inhibits
1-α-hydroxylase and activates 24-hydroxylase, thus reducing
hypercalcaemia; it is usually administered orally at a dose of
20-40 mg daily. The effects are observed within 24-72 hours of
starting treatment.
Contributors: SM conceived the review, helped to write the article,
coordinated with other authors’ work, dealt with the editors, reviewed
the final version of the article, and helped check the proofs. JP and SP
helped to write the article and reviewed the final version. CC helped to
write the article, designed the figure and table, helped check the proofs,
and reviewed the final article. All authors are the guarantors.
Competing interests: We have read and understood the BMJ policy on
declaration of interests and declare the following: none.
Provenance and peer review: Not commissioned; externally peer
reviewed.
1 Dalemo S, Eggertsen R, Hjerpe P, et al. Long-term follow-up of patients with elevated
serum calcium concentrations in Swedish primary care. Scand J Prim Health Care
2012;30:48-54.
2 Lindner G, Felber R, Schwarz C, et al. Hypercalcemia in the ED: prevalence, etiology,
and outcome. Am J Emerg Med 2013;31:657-60.
3 National Cancer Institute. PDQ® Hypercalcemia. 2013. www.meb.uni-bonn.de/Cancernet/
CDR0000062737.html.
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BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015) Page 6 of 9

CLINICAL REVIEW

Questions for future research

• What is the epidemiology of primary hyperparathyroidism and hypercalcaemia from non-parathyroid causes in different geographical
areas of the world?
• What is a safe vitamin D serum level to target supplementation in patients with primary hyperparathyroidism who are deficient in
vitamin D?
• Randomised controlled trials to define the role and safety of denosumab use in the treatment of severe hypercalcemia: could denosumab
be a second line after bisphosphonates use or possible first line therapy?

Tips for non-specialists

• The diagnosis of hypercalcaemia is made when the corrected concentration of serum calcium is 2 standard deviations above the
mean of values found in people with normal calcium levels, in at least two samples at least one week apart over a period of three
months
• Measurement of serum parathyroid hormone and patient’s clinical presentation should be rapidly assessed, particularly in severe
hypercalcaemic states
• People presenting with a history of mild asymptomatic hypercalcaemia typically have a diagnosis of primary hyperparathyroidism and
could be managed in the outpatient setting
• People with severe, new onset hypercalcaemia with symptoms require admission to hospital for intravenous treatment and diagnosis

Additional educational resources

Resources for healthcare professionals
Rosen CJ. Primer on the metabolic bone diseases and disorders of mineral metabolism, 8th ed. Wiley-Blackwell, 2013—discusses the
pathophysiology and clinical concepts of hypercalcaemia
Bilezikian JP, Marcus R, Levine M, et al. Parathyroids, basic and clinical concepts. 3rd ed. Academic Press, 2014—discusses the
pathophysiology, differential diagnosis, and clinical algorithm for the management of hypercalcaemia
National Cancer Institute, med News. Hypercalemia (www.meb.uni-bonn.de/Cancernet/CDR0000062737.html) (no registration required)

Resources for patients

Mayoclinic.org (www.mayoclinic.org/diseases-conditions/hypercalcemia/basics/definition/con-20031513) (no registration
required)—discusses symptoms and causes of hypercalcaemia
BMJ Best Practice (http://bestpractice.bmj.com/best-practice/monograph/159/diagnosis.html)—(no registration required) provides a step
by step diagnostic approach of hypercalcaemia; can be a useful resource for patients and clinicians to look at together for shared decision
making

4 Potts JT Jr, Jüppner H. Disorders of the parathyroid gland and calcium homeostasis. In:
Longo DL, Fauci AS, Kasper DL, Hauser S, eds. Harrison’s principles of internal medicine.
18th ed. McGraw-Hill, 2012:3096-120.
5 Yu N, Donnan PT, Murphy MJ, et al. Epidemiology of primary hyperparathyroidism in
Tayside, Scotland, UK. Clin Endocrinol 2009;71:485-93.
6 Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary hyperparathyroidism in
Rochester, Minnesota, 1993-2001: an update on the changing epidemiology of the disease.
J Bone Miner Res 2006;21:171-7.
7 Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of primary
hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab
2013;98:1122-9.
8 Gastanaga V, Jain R, Pirolli M, et al. Prevalence of hypercalcemia of malignancy in the
United States. Projection methods using oncology electronic health records. Eur J Cancer
2013;49:S302-3.
9 McKay C, Furman WL. Hypercalcemia complicating childhood malignancies. Cancer
1993;72:256-60.
10 Horwitz MJ, Hodak SP, Stewart AF. Non-parathyroid hypercalcemia. In: Rosen CJ, ed.
Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th ed.
Wiley-Blackwell, 2013:562-71.
11 Grieff M, Bushinsky DA. Diuretics and disorders of calcium homeostasis. Semin Nephrol
2011;31:535-41.
12 Wermers RA, Kearns AE, Jenkins GD, et al. Incidence and clinical spectrum of
thiazide-associated hypercalcemia. Am J Med 2007;120:911.e9-15.
13 Kohut B, Rossat J, Raffoul W, et al. Hypercalcaemia and acute renal failure after major
burns: An under-diagnosed condition. Burns 2010;36:360-6.
14 Sato Y, Honda Y, Iwamoto J, et al. Abnormal bone and calcium metabolism in immobilized
Parkinson’s disease patients. Mov Disord 2005;20:1598-603.
15 Carnevale V, Dionisi S, Nofroni I, et al. Potential clinical utility of a new IRMA for parathyroid
hormone in postmenopausal patients with primary hyperparathyroidism. Clin Chem
2004;50:626-31.
16 Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary
hyperparathyroidism: proceedings of the fourth international workshop. J Clin Endocrinol
Metab 2014;99:3570-9.
17 Marcocci C, Bollerslev J, Khan AA, et al. Medical management of primary
hyperparathyroidism: proceedings of the fourth International Workshop on the Management
of Asymptomatic Primary Hyperparathyroidism. J Clin Endocrinol Metab 2014;99:3607-18.
18 Minisola S, Romagnoli E, Scillitani A, et al. Hypovitaminosis D in primary
hyperparathyroidism: to treat or not to treat? That is the question. J Endocrinol Invest
2014;37:413-4.
19 Streeten EA, Jaimungal S. The differential diagnosis of hypercalcemia. The parathyroids.
3rd ed. Academic Press, 2014:607-16.
20 Minisola S, Romagnoli E, Scarnecchia L, et al. Parathyroid storm: immediate recognition
and pathophysiological considerations. Bone 1993;14:703-6.
21 Dionisi S, Minisola S, Pepe J, et al. Concurrent parathyroid adenomas and carcinoma in
the setting of multiple endocrine neoplasia type 1: presentation as hypercalcemic crisis.
Mayo Clin Proc 2002;77:866-9.
22 Lowe H, Cusano NE, Binkley N, et al. Vitamin D toxicity due to a commonly available
“over the counter” remedy from the Dominican Republic. J Clin Endocrinol Metab 2011
;96:291-5.
23 Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic
primary hyperparathyroidism: summary statement from the Fourth International Workshop.
J Clin Endocrinol Metab 2014;99:3561-9.
24 Silverberg SJ, Clarke BL, Peacock M, et al. Current issues in the presentation of
asymptomatic primary hyperparathyroidism: proceedings of the Fourth International
Workshop. J Clin Endocrinol Metab 2014;99:3580-94.
25 Schwarz P, Body JJ, Cap J, et al. The PRIMARA study: a prospective, descriptive,
observational study to review cinacalcet use in patients with primary hyperparathyroidism
in clinical practice. Eur J Endocrinol 2014;171:727-35.
26 Minisola S, Romagnoli E, Carnevale V, et al. Acute management of hypercalcemia. In:
Bilezikian JP, Marcus R, Levine M, Marcocci, C, Silverberg SJ, Potts J, eds. Parathyroids,
basic and clinical concepts. 3rd ed. Academic Press, 2014:617-29.
27 LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an
unproven yet common practice. Ann Intern Med 2008;149:259-63.
28 Kawada K, Minami H, Okabe K, et al. A multicenter and open label clinical trial of zoledronic
acid 4 mg in patients with hypercalcemia of malignancy. Jpn J Clin Oncol 2005;35:28-33.
29 Purohit OP, Radstone CR, Anthony C, et al. A randomised double-blind comparison of
intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer
1995;72:1289-93.
30 Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the
treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled
clinical trials. J Clin Oncol 2001;19:558-67.
31 Roemer-Bécuwe C, Vigano A, Romano F, et al. Safety of subcutaneous clodronate and
efficacy in hypercalcemia of malignancy: a novel route of administration. J Pain Symptom
Manage 2003;26:843-8.
32 Reagan P, Pani A, Rosner MH. Approach to diagnosis and treatment of hypercalcemia
in a patient with malignancy. Am J Kidney Dis 2014;63:141-7.
33 Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of
malignancy. J Clin Endocrinol Metab 2014;99:3144-52.
34 Kindgen-Milles D, Kram R, Kleinekofort W, et al. Treatment of severe hypercalcemia using
continuous renal replacement therapy with regionalcitrate anticoagulation. ASAIO J
2008;54:442-4.
Cite this as: BMJ 2015;350:h2723
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Table

Table 1| Clinical presentation of hypercalcaemia

System Acute hypercalcaemia Chronic hypercalcaemia

General Flushing, fatigue, weight loss Fatigue
Cardiovascular Prolonged PR interval, widened QRS complex, shortened QT interval, Prolonged PR interval, widened QRS complex, shortened QT interval,
bundle branch block, bradycardia, arrhythmias, syncope, cardiac arrest bundle branch block, bradycardia, arrhythmias, hypertension, valvular
heart disease, vascular calcification
Renal Thirst, polydipsia; dehydration; polyuria; nocturia; frequent urination; Nephrocalcinosis, nephrolithiasis, chronic renal failure, renal
renal failure from obstructive uropathy, nephrolithiasis, osteodystrophy
nephrocalcinosis, or pre-renal causes
Neurological Tiredness, obtundation, lethargy, confusion, delirium, somnolence, Dementia, memory loss, sleep disturbance, decreased concentration
stupor, coma, hypotonia, hyporeflexia, paresis
Psychiatric Irritability, depression, anxiety, hallucination, psychosis Irritability, depression, anxiety
Gastrointestinal Anorexia, nausea, vomiting, abdominal pain, dyspepsia, constipation, Anorexia, dyspepsia, constipation, pancreatitis, peptic ulcer
pancreatitis, peptic ulcer
Skeletal and muscle Bone pain, muscle weakness Bone pain, muscle weakness, myalgias, osteoporosis, osteopenia,
fragility fractures, osteitis fibrosa cystica, bone cysts, brown tumours
of long bones, condrocalcinosis, joint calcification
Haematological Anaemia Anaemia
Ocular — Band keratopathy (cornea)

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BMJ 2015;350:h2723 doi: 10.1136/bmj.h2723 (Published 2 June 2015) Page 9 of 9

CLINICAL REVIEW

Figure

Suggested algorithm for diagnosis of hypercalcaemia; based on available evidence, mostly derived from retrospective or
observational, non-randomised, non-blinded studies. The algorithm also underlines the need for clinical evaluation as a
key guide for diagnosis and management in any given patient. Corrected calcium (mmol/L)=total calcium concentration
(mmol/L)+0.02(40−serum albumin concentration (g/L). Serum ionised calcium (Ca2+) should be directly measured, whenever
available, through the ion specific electrode and could increase accuracy of diagnosis. GFR=glomerular filtration rate

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 ARTIGO 7

SÍNDROMES CARDIORRENAIS
Review
Cardiorenal syndrome: review of our current
understanding
Savvas Hadjiphilippou and Sui Phin Kon
King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK
Corresponding author: Sui Phin Kon. Email: suiphin.kon@nhs.net
Summary
Renal and cardiac diseases are both prevalent and carry
significant morbidity and mortality. They share common
vascular risk factors and are physiologically interlinked.
Dysfunction in one organ affects the other. Concurrent
renal and cardiac disease is associated with a poor progno-
sis. This close relationship is reflected through cardiorenal
syndrome. A classification system has been proposed; how-
ever, the underlying process is complex and multifactorial.
Management of this syndrome focuses on improving heart
function, reducing volume overload, and managing heart
failure and chronic kidney disease. This, however, is chal-
lenging, limited by paucity of evidence and may lead to
suboptimal therapy. Increased recognition of this syndrome
should raise awareness in providing early therapy and
avoiding adverse outcomes due to under-treatment. In
this article, we provide an overview of our current under-
standing of cardiorenal syndrome, as well as its pathophysi-
ology and treatment options.
Keywords
Heart failure, acute kidney injury, chronic kidney disease,
cardiorenal syndrome, pathophysiology
Introduction
Within the human body, interactions between various
organs are tightly controlled. The heart is responsible
for ensuring that blood is circulated within the body,
including to the kidneys, while the kidneys are
responsible for filtering the circulating blood and
managing electrolyte homeostasis. Both organs are
undoubtedly crucial to our survival, tightly linked
and inevitably inter-reliant. The maintenance of car-
diovascular haemostasis is therefore dependent upon
fine interactions between the heart and kidneys. It is
thus not surprising that dysfunction in one organ will
affect the other.
Indeed, cardiac disease and renal disease share
common vascular risk factors (hypertension and dia-
betes to name but a few). Both renal disease and heart
failure (HF) are independently associated with a
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Journal of the Royal Society of Medicine; 2016, Vol. 109(1) 12–17
DOI: 10.1177/0141076815616091
poor prognosis. Concurrent renal disease and HF,
given their close bi-directional relationship, are as a
consequence associated with a worse prognosis1 and
hence a greater burden on our healthcare system and
patient quality of life. The existence of this dual dys-
function has been recently termed as ‘cardiorenal
syndrome’.
Cardiorenal syndrome has been difficult to define
because it encompasses complex multifactorial facets
including physiological, biochemical and hormonal.
Following a consensus conference in 2008,2 the
report defines cardiorenal syndrome as ‘disorders of
the heart and kidneys whereby acute or chronic dys-
function in one organ may induce acute or chronic
dysfunction of the other’.
The purpose of this article is to provide an over-
view of our current understanding of cardiorenal syn-
drome as well as its pathophysiology and treatment
options.
Methods
Within this review, we aimed to summarise the results
of a MEDLINE, PubMed, Cochrane Library,
Google and Google Scholar search (from January
1931 to September 2014) on the current understand-
ing of the epidemiology, pathophysiology and treat-
ment of cardiorenal syndrome. Databases were
searched using the term ‘cardiorenal syndrome’, and
articles were selected and analysed according to their
relevance.
Epidemiology
Renal dysfunction frequently coexists with HF. The
Acute Decompensated Heart Failure National
Registry demonstrated that 30% of patients admitted
with acute decompensated HF had chronic kidney
disease (CKD) and 21% had a creatinine of >2 mg/
dL.3 In a study by Forman et al.,4 irrespective of HF,
with or without preserved ejection fraction, raised
serum creatinine on admission to hospital and wor-
sening renal impairment during admission were both
Hadjiphilippou and Kon 13

Table 1. Classification of cardiorenal syndrome based on a system proposed by Ronco and McCullough.2

Cardiorenal syndrome type Characteristics

Type 1 (acute cardiorenal) Acute cardiac impairment leading to acute kidney injury

Type 2 (chronic cardiorenal) Chronic cardiac impairment leading to renal impairment

Type 3 (acute renocardiac) Acute kidney injury leading to cardiac impairment

Type 4 (chronic renocardiac) Chronic kidney disease leading to cardiac impairment

Type 5 (secondary cardiorenal) Systemic condition leading to both cardiac and renal impairment

associated with prolonged inpatient stay and
increased mortality.
Worse baseline renal function is a powerful inde-
pendent risk factor for adverse cardiovascular out-
comes.5 However, not all studies show an adverse
association with declining glomerular filtration rate
(GFR). The Evaluation Study of Congestive Heart
Failure and Pulmonary Artery Catheterisation
Effectiveness trail did not show statistical significance
or increased mortality with a 25% decline in GFR.6
This reflects that a decline in kidney function due to
adequate diuresis or blockade of the renin–angioten-
sin–aldosterone system (RAAS) may be associated
with improved outcomes.
Classification
Recognising the bi-directional relationship between
cardiac and renal dysfunction, the classification
system from the 2008 consensus conference2 is five-
part and recognises that patients may move between
subtypes during the course of their disease (Table 1).
Acute cardiorenal syndrome (type 1)
Cardiorenal syndrome type 1 is characterised by
acute worsening of cardiac function (pulmonary
oedema, cardiogenic shock, acute HF) leading to an
acute kidney injury (AKI). Approximately 27% of
patients admitted with acute decompensated HF
develop AKI.4 The challenge in this subtype is the
early identification of an AKI as creatinine will
increase once AKI is established and early bio-
markers such as neutrophil gelatinase-associated lipo-
calin have been studied as early predictors of AKI.7
and has been reported in 63% of patients admitted
with congestive HF.2,8 The mechanism underlying
this process is likely to be due to chronic renal hypo-
perfusion although there is limited evidence as of yet
to suggest how left ventricular function correlates to
GFR levels.7
Acute renocardiac syndrome (type 3)
Cardiorenal syndrome type 3 is characterised by
acute cardiac dysfunction (uraemic cardiomyopathy,
arrhythmias due to hyperkalaemia) as a result of
acute renal impairment. Defining the epidemiology
in this subtype has proven a challenge due to different
methods for defining AKI, different baseline risks for
developing acute cardiac dysfunction and limited
reporting by studies of AKI on the incidence of
acute cardiac dysfunction as an outcome measure.2
Chronic renocardiac syndrome (type 4)
Cardiorenal syndrome type 4 describes CKD leading
to cardiac dysfunction (left ventricular failure or dia-
stolic HF). Cardiac disease in patients with CKD is
common, and adverse cardiac outcomes correlate
well with severity of CKD.2
Secondary cardiorenal syndromes (type 5)
Cardiorenal syndrome type 5 is characterised by sim-
ultaneous cardiac and renal dysfunction as a part of a
systemic condition whether that may be acute or
chronic. This most commonly includes systemic con-
ditions such as sepsis and less so others such as amyl-
oid or vasculitis.

Chronic cardiorenal syndrome (type 2) Pathophysiology

Cardiorenal syndrome type 2 is characterised by A number of mechanisms have been identified
chronic cardiac dysfunction leading to renal dysfunc- as having a role in the development of cardiorenal
tion and can be used to describe chronic HF leading syndrome. The pathogenesis is complex involving
to renal failure. This syndrome is the most common multiple pathways which have not yet been fully
14
elucidated; however, a number of mechanisms have
been proposed. Detailed descriptions of these are
beyond the scope of this article; however, chronic
over-activation of the neurohormonal systems and
increased venous pressure are thought to be import-
ant factors.
Neurohormonal system
Initial triggering of the neurohormonal systems such
as the RAAS, the sympathetic nervous system (SNS),
the arginine-vasopressin system and the endothelin
system is thought to be protective and aims to main-
tain homeostasis. The chronic activation, however, of
all these mechanisms can have deleterious effects on
both the cardiac and renal system.
Activation of the RAAS in the kidney leads to
sodium and water retention, systemic vasoconstric-
tion and further reduced glomerular filtration.
The RAAS activation increases oxidative stress and
further downstream profibrotic neurohormonal
enhancement resulting in ventricular remodelling.9
Chronic SNS over-activation results in reduced car-
diac b-adrenoceptor density and sensitivity,10 cardio-
myocyte hypertrophy11 and, through the
enhancement of neuropeptide Y, vascular neointimal
formation.12 Impaired left ventricular function fur-
ther contributes to decreased forward flow.
Increased venous pressure
HF is marked by an increase in central venous pres-
sure which leads to a reduction in the perfusion gra-
dient across the glomerular capillary bed and decline
in renal function. The result of increased back pres-
sure and its effects on urine formation was first stu-
died around a century ago. In an experiment by
Winton,13 it was noted that urine formation was
reduced with rising pressure. Right ventricular dila-
tation and dysfunction from elevated venous pressure
further impairs left ventricular filling.
Management
The management of cardiorenal syndrome can be
challenging. Treatment for HF may worsen renal
function, and thus patients may receive suboptimal
therapy impacting on their prognosis. Primary pre-
vention cannot be overemphasised for both renal and
cardiac disease as they share common risk factors.
This includes blood pressure, cholesterol and glucose
management as well as physical activity and smoking
cessation. Although established guidelines exist for
the management of HF and CKD separately, there
is as of yet no consensus on the management of each
Journal of the Royal Society of Medicine 109(1)
cardiorenal syndrome individually. Instead, treat-
ment strategies focus on managing the predominant
underlying condition, whether that is cardiac or
renal. As our understanding of the pathophysiology
improves, we can look forward to more targeted
therapies.
In this article, the management of cardiorenal syn-
drome has not been divided by subtype. This reflects
the close interrelations between the different subtypes
and in particular how therapies targeted to one sub-
type can also have a beneficial effect for other sub-
types, such as the use of RAAS blockade in type 2
and 4. In general, however, within subtypes 1 and 2,
therapy predominantly focuses on managing acute
and chronic HF. For subtype 3, management of the
underlying cause of AKI is most appropriate, while in
type 4, management is challenging due to the multi-
factorial nature of HF secondary to CKD. Therapies
for type 5 focus primarily on treating underlying
pathology such as sepsis, amyloid or vasculitis.
We have subdivided treatment options therefore
into the three following areas:
1. Improving cardiac function:
. Inotropes
The use of inotropic drugs is relevant in the treat-
ment of cardiogenic shock. However, the hypothesis
that use of intravenous milrinone in patients with HF
in order to permit more effective diuresis has been
refuted.14 Similarly, no clinical benefit has been
demonstrated with low-dose dopamine when used
for the treatment or prevention of AKI.15
. Vasodilators
Vasodilators such as nitrates form part of the
treatment for HF. The effects of nesiritide (a recom-
binant human brain natriuretic peptide) on renal
function in the treatment of acute decompensated
HF are conflicting. The Acute Study of Clinical
Effectiveness of Nesiritide in Decompensated Heart
Failure trial found no change in risk of worsening
renal function with nesiritide therapy, but it was asso-
ciated with higher rates of hypotension.16
. Cardiac resynchronisation
In a study by Van Bommel et al.,17 patients with
HF who had a GFR of <60 ml/min/1.73 m2 demon-
strated a reduced response to cardiac resynchronisa-
tion therapy (CRT), defined as a decrease in left
ventricular end-systolic volume >15% at six-month
follow-up, compared to those with normal renal
Hadjiphilippou and Kon
function. Worse renal function was also associated
with worse long-term prognosis after CRT. Despite
this, a systematic review by Garg et al.18 demon-
strated that CRT in patients with CKD led to an
improvement in left ventricular ejection as well as
GFR. More studies are required to evaluate this fur-
ther; however, this suggests a degree of reversibility in
cardiorenal syndromes 1 and 2.
. Beta-blockers
Beta-blockers are avoided in acute HF but used in
the management of chronic HF. In a systematic
review by Badve et al.,19 of patients with HF and
CKD, the use of b-blockers reduced the risk of all-
cause and cardiovascular mortality. However, it was
associated with an increase in bradycardia and hypo-
tension. Caution is to be exercised in their use in
acute decompensated HF as they may further
reduce forward flow and exacerbate renal
dysfunction.
. Adenosine-receptor antagonists
These drugs increase GFR by causing vasodilata-
tion and increased renal perfusion. However, data
from the PROTECT trial20 suggests no difference in
cardiovascular outcomes compared to placebo in the
treatment of acute HF with renal dysfunction.
2. Decreasing volume overload:
. Diuretics
First, low sodium intake needs to be reinforced.
Diuretics are the mainstay of management in fluid
overload in both HF and renal failure. Aggressive
diuresis improves survival despite worsening renal
function.21 Intravenous diuretics, high dose loop
diuretics and adding thiazides to loop diuretics are
needed to try to overcome diuretic resistance where
necessary. Diuretics are particularly useful in the
management of type 1, 2 and 4 cardiorenal syndrome.
. Vasopressin receptor antagonists
Tolvaptan is a selective vasopressin 2 receptor
antagonist whose effect on cardiovascular actions
was described in the Efficacy of Vasopressin
Antagonism in Heart Failure Outcome Study With
Tolvaptan-Outcomes trial.22 The study showed no
effect on long-term mortality or HF-related morbid-
ity. However, there was an increase in urine output
resulting in improved dyspnoea as it increased free
water clearance. Currently in the UK, tolvaptan is
15
licensed for the treatment of hyponatraemia second-
ary to the syndrome of inappropriate antidiuretic
hormone secretion.
. Ultrafiltration
In recent years, ultrafiltration has had an increas-
ing role in patients with decompensated HF and renal
dysfunction, particularly affecting cardiorenal syn-
drome subtype 2. Three randomised trials
(Ultrafiltration versus Intravenous Diuretics for
Patients Hospitalised for Acute Decompensated
Congestive Heart Failure [UNLOAD], Relief for
Acutely Fluid-Overloaded Patients With
Decompensated Congestive Heart Failure [RAPID-
CHF], Cardiorenal Rescue Study in Acute
Decompensated Heart Failure [CARESS-HF]) have
compared diuretic therapy in patients with acute
decompensated HF.23–25 In UNLOAD and RAPID-
CHF, ultrafiltration was associated with greater fluid
loss than diuretic therapy but no difference in serum
creatinine, while in CARESS-HF weight loss was
similar, but there was an increase in serum creatinine
and greater adverse events. The 2013 American
College of Cardiology Foundation/American Heart
Association guidelines for the management of HF
stated that ‘‘ultrafiltration may be considered for
patients with refractory congestion not responding
to medical therapy.’’26 Peritoneal dialysis has been
trialled for the symptomatic management of refrac-
tory dyspnoea in end-stage HF with paucity of data
from large randomised controlled trials.27 Additional
trials are ongoing to see the benefit of ultrafiltration.
3. Drugs for reduced ejection fraction and CKD:
. Renin–angiotensin–aldosterone system antagonism
RAAS antagonism is an integral part of therapy
for acute and chronic HF and renal failure. Subgroup
analyses of clinical trials of RAAS antagonism in HF
have demonstrated that the beneficial effects on mor-
bidity are not reduced by concurrent CKD.28 The
risk of hyperkalaemia and worsening renal function
is higher in patients with CKD28 and therefore
requires regular monitoring.
Similarly, aldosterone antagonists showed a bene-
fit in cardiovascular outcome despite a fall in GFR29
with the same problem of hyperkalaemia.
Angiotensin-converting enzyme inhibition and
angiotensin receptor blockers are known to worsen
renal function prompting reluctance to prescribe and
a low threshold for stopping. They should not be
discontinued as such patients had decreased mortality
despite a decline in GFR.30 Caution or specialist
16
Table 2. Key points.
Key points
1 Renal disease and heart failure frequently coexist due to their close bi-directional relationship.
2 Pathophysiology is poorly understood; however, it carries a poor prognosis.
3 Management is challenging often leading to under-treatment. Current strategies focus on the predominant failing
organ rather than on both organs.
4 Recognition of this syndrome is crucial in providing early and appropriate therapy.
advice is appropriate; however, this should not be
interpreted as withholding treatment, while renal
impairment should not be a contraindication to
RAAS blockade but instead should reinforce fre-
quent monitoring and a multidisciplinary manage-
ment approach with nephrology specialists.
Conclusion
There is a high prevalence of cardiorenal syndrome
where patients with HF have concurrent renal dys-
function. Reduced renal function is associated with
increased morbidity and mortality in this population.
It is a bi-directional relationship where dysfunction in
either the heart or kidneys worsens the function of
the other. Cardiorenal syndrome is difficult to define
because it has multiple contributing factors; however,
potential mechanisms include neurohormonal system
activation leading to reduced forward flow and renal
perfusion and increased venous pressure. Medical
treatment options are primarily focused on improv-
ing cardiac function, reducing volume overload and
managing HF and CKD. Although management of
cardiorenal syndrome remains a challenge, increased
recognition of this syndrome should raise our aware-
ness in providing early therapy to improve patient
care and avoid adverse outcomes due to under-treat-
ment (Table 2).
Declarations
Competing interests: None declared
Funding: None declared
Ethical approval: Not required
Guarantor: SPK
Contributorship: Both SH and SPK contributed equally to the
literature search, analysis, design and write-up of this manuscript.
Acknowledgements: None
Provenance: Not commissioned; peer-reviewed by Muhammad
Siddiqui.
Journal of the Royal Society of Medicine 109(1)
References
1. Schrier RQ. Cardiorenal versus renocardiac syndrome: is
there a difference? Nat Clin Pract Nephrol 2007; 3: 637.
2. Ronco C and McCullough SD. Cardio-renal syn-
dromes: reports from the consensus conference of the
acute dialysis quality initiative. Eur Heart J 2010; 31:
703–711.
3. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel
TH, Costanzo MR, Abraham WT, et al. Characteristics
and outcomes of patients hospitalized for heart failure
in the United States: rationale, design, and preliminary
observations from the first 100,000 cases in the Acute
Decompensated Heart Failure National Registry
(ADHERE). Am Heart J 2005; 149: 209–216.
4. Forman DE, Butler J, Wang Y, Abraham WT,
O’Connor CM, Gottlieb SS, et al. Incidence, predictors
at admission, and impact of worsening renal function
among patients hospitalized with heart failure. J Am
Coll Cardiol 2004; 43: 61–67.
5. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok
M, et al. Chronic kidney disease and mortality risk: a sys-
tematic review. J Am Soc Nephro 2006; 17: 2034–2047.
6. Nohria A, Hasselblad V, Stebbins A, Pauly DF,
Fonarow GC, Shah M, et al. Cardiorenal interactions:
insights from the ESCAPE trial. J Am Coll Cardiol
2008; 51: 1268–1274.
7. Ronco C, Haapio M, House AA, Anavekar N and
Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol
2008; 52: 1527.
8. Heywood JT, Fonarow GC, Costanzo MR, Mathur
VS, Wigneswaran JR, Wynne J, et al. High prevalence
of renal dysfunction and its impact on outcome in
118,465 patients hospitalized with acute decompen-
sated heart failure: a report from the ADHERE data-
base. J Card Fail 2007; 13: 422–430.
9. Bock JS and Gottlieb SS. Cardiorenal syndrome: new
perspectives. Circulation 2010; 121: 2592–2600.
10. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS,
Sageman WS, Lurie K, et al. Decreased catecholamine
sensitivity and b-adrenergic-receptor density in failing
human hearts. N Engl J Med 1982; 307: 205–211.
11. Amin JK, Xiao L, Pimental DR, Pagano PJ, Singh K,
Sawyer DB, et al. Reactive oxygen species mediate
alpha-adrenergic receptor-stimulated hypertrophy in
adult rat ventricular myocytes. J Mol Cell Cardiol
2001; 33: 131–139.
Hadjiphilippou and Kon
12. Li L, Lee EW, Ji H and Zukowska Z. Neuropeptide
Y-induced acceleration of postangioplasty occlusion of
rat carotid artery. Arterioscler Thromb Vasc Biol 2003;
23: 1204–1210.
13. Winton FR. The influence of venous pressure on the
isolated mammalian kidney. J Physiol 1931; 72: 49–61.
14. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge
R, Colucci WS, et al. Short-term intravenous milrinone
for acute exacerbation of chronic heart failure: a ran-
domized controlled trial. JAMA 2002; 287: 1541–1547.
15. Kellum JA and Decker J. Use of dopamine in acute
renal failure: a metaanalysis. Crit Care Med 2001; 29:
1526–1531.
16. O’Connor CM, Starling RC, Hernandez AF,
Armstrong PW, Dickstein K, Hasselblad V, et al.
Effect of nesiritide in patients with acute decompen-
sated heart failure. N Engl J Med 2011; 365: 32.
17. Van Bommel RJ, Mollema SA, Borleffs CJ, Bertini M,
Ypenburg C, Marsan NA, et al. Impaired renal func-
tion is associated with echocardiographic nonresponse
and poor prognosis after cardiac resynchronization
therapy. J Am Coll Cardiol 2011; 57: 549–555.
18. Garg N, Thomas G, Jackson G, Rickard J, Nally JV Jr,
Tang WH, et al. Cardiac resynchronization therapy in
CKD: a systematic review. Clin J Am Soc Nephrol
2013; 8: 1293–1303.
19. Badve SV, Roberts MA, Hawley CM, Cass A, Garg
AX, Krum H, et al. Effects of beta-adrenergic antag-
onists in patients with chronic kidney disease: a system-
atic review and meta-analysis. J Am Coll Cardiol 2011;
58: 1152–1161.
20. Massie BM, O’Connor CM, Metra M, Ponikowski P,
Teerlink JR, Cotter G, et al. Rolofylline, an adenosine
A1-receptor antagonist, in acute heart failure. N Engl J
Med 2010; 363: 1419.
21. Testani JM, Chen J, McCauley BD, Kimmel SE and
Shannon RP. Potential effects of aggressive deconges-
tion during the treatment of decompensated heart fail-
ure on renal function and survival. Circulation 2010;
122: 265.
22. Konstam MA, Gheorghiade M, Burnett JC Jr,
Grinfeld L, Maggioni AP, Swedberg K, et al. Effects
of oral tolvaptan in patients hospitalized for worsening
heart failure: the EVEREST outcome trial. JAMA
2007; 297: 1319.
17
23. Bart BA, Boyle A, Bank AJ, Anand I, Olivari MT and
Kraemer M. Ultrafiltration versus usual care for hos-
pitalized patients with heart failure: the Relief for
Acutely Fluid-Overloaded Patients With
Decompensated Congestive Heart Failure (RAPID-
CHF) trial. J Am Coll Cardiol 2005; 46: 2043.
24. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML,
Bart BA, Teerlink JR, et al. Ultrafiltration versus intra-
venous diuretics for patients hospitalized for acute
decompensated heart failure. J Am Coll Cardiol 2007;
49: 675.
25. Bart BA, Goldsmith SR, Lee KL, Givertz MM,
O’Connor CM, Bull DA, et al. Ultrafiltration in
decompensated heart failure with cardiorenal syn-
drome. N Engl J Med 2012; 367: 2296.
26. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE
Jr, Drazner MH et al. ACCF/AHA guideline for the
management of heart failure: A report of the American
College of Cardiology Foundation/American Heart
Association Task Force on practice guidelines.
Circulation 2013; 128: e240–327.
27. Khalifeh N, Vychytil A and Hörl WH. The role of
peritoneal dialysis in the management of treatment-
resistant congestive heart failure: a European perspec-
tive. Kidney Int Suppl 2006; 70: S72–S75.
28. Anand IS, Bishu K, Rector TS, Ishani A, Kuskowski
MA and Cohn JN. Proteinuria, chronic kidney disease,
and the effect of an angiotensin receptor blocker in
addition to an angiotensin-converting enzyme inhibitor
in patients with moderate to severe heart failure.
Circulation 2009; 120: 1577.
29. Rossignol P, Cleland JG, Bhandari S, Tala S,
Gustafsson F, Fay R, et al. Determinants and conse-
quences of renal function variations with aldosterone
blocker therapy in heart failure patients after myocar-
dial infarction: insights from the Eplerenone Post-
Acute Myocardial Infarction Heart Failure Efficacy
and Survival Study. Circulation 2012; 125: 271–279.
30. Testani JM, Kimmel SE, Dries DL and Coca SG.
Prognostic importance of early worsening renal func-
tion after initiation of angiotensin-converting enzyme
inhibitor therapy in patients with cardiac dysfunction.
Circ Heart Fail 2011; 4: 685–691.
 ARTIGO 8

TESTE DE ESTRESSE COM

FUROSEMIDA
 REVIEW

Renal Stress Testing in the Assessment

of Kidney Disease
Lakhmir S. Chawla1,2 and Claudio Ronco3,4
1
Department of Medicine, Veterans Affairs Medical Center, Washington, DC, USA; 2Department of Medicine, George Wash-
ington University, Washington, DC, USA; 3Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital,
Vicenza, Italy; and 4International Renal Research Institute of Vicenza, Vicenza, Italy

As part of human evolutionary development, many human organ systems have innate mechanisms to
adapt to increased “work demand” or stress. This reserve capacity can be informative and is used
commonly in cardiology to assess cardiac function (e.g., treadmill test). Similarly, the kidney possesses
reserve capacity, which can be demonstrated in at least 2 of the following renal domains: glomerular and
tubular. When appropriate stimulants are used, healthy patients with intact kidneys can significantly in-
crease their glomerular filtration rate and their tubular secretion. This approach has been used to develop
diagnostics for the assessment of renal function. This article reviews both glomerular and tubular kidney
stress tests and their respective diagnostic utility.
KI Reports (2016) 1, 57–63; http://dx.doi.org/10.1016/j.ekir.2016.04.005
KEYWORDS: acute kidney injury; chronic kidney disease; furosemide stress test; glomerular filtration; kidney stress
test; maximum GFR
ª 2016 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A s part of human evolutionary development, many

human organ systems have innate mechanisms to
adapt to increased “work demand” or stress. At rest,
organ systems operate at baseline capacity, and this
capacity can be increased to a certain maximum ca-
pacity. A familiar example of this concept is cardiac
function. In a healthy person at rest, cardiac output is
approximately 5.0 liters/min. However, when a healthy
person exercises, the cardiac output can double or even
triple. Similarly, the kidney has reserve capacity of its
multiple physiological functions (Figure 1). The ability
to test the reserve of an organ system is often an
excellent diagnostic tool to uncover subclinical disease
(e.g., treadmill test). Similarly, stress testing of the
kidney appears to generate insights into the presence
or absence of kidney disease and parenchymal loss due
to injury and potentially fibrosis. The 2 main domains
of kidney stress testing are glomerular and tubular. In a
healthy kidney, these 2 components of the nephron
work in concert. However, when the kidney is diseased
or injured, the glomerular and tubular function may be
affected equally, or their form and functional capacity
Correspondence: Lakhmir S. Chawla, Veterans Affairs Medical
Center, 50 Irving Street, Washington, DC 20310, USA. E-mail:
minkchawla@gmail.com
Received 8 March 2016; revised 25 April 2016; accepted 26 April
2016; published online 5 May 2016
Kidney International Reports (2016) 1, 57–63
may diverge. An assessment of both glomerular and
tubular function may be more informative than just 1
of these domains. Glomerular reserve testing has been
well established but is used infrequently in routine
clinical care. Tubular function diagnostic testing is
relatively new and in its clinical “infancy.” However,
tubular assessment appears to hold significant promise
for the assessment of both chronic and acute kidney
disease.
Renal Functional Reserve–Glomerular
Because of the common use of estimated glomerular
filtration rate (GFR) equations, there is a tendency for
non-nephrologists to think that the GFR is a constant.
In fact, the actual GFR changes throughout the day,
particularly after meals, based on physiological needs.1
One of the kidney’s primary roles is to effectively
remove nitrogenous waste, and as a consequence, the
consumption and metabolism of protein results in an
increase in GFR.2 GFR can also be increased through
other mechanisms that work along the protein meta-
bolic pathway. For instance, an i.v. infusion of amino
acids will result in an increase in GFR.3 This increase in
GFR over baseline GFR is known as renal functional
reserve–glomerular (RFR-G).4 Protein ingestion,
particularly red meat, is a potent stimulant for
increasing GFR, and the teleologic explanation is likely
related to an adaptive response to increased protein in
the diet.5
57
REVIEW LS Chawla and C Ronco: Renal Stress Testing in the Assessment of Kidney Disease
Figure 1. Comparison of stressors in the heart and kidney. C-R,
cardiorenal.
Bosch and colleagues first described glomerular
functional reserve (RFR-G) in 1983.4 In this seminal
paper, Bosch and colleagues demonstrated that the
consumption of protein, not carbohydrates or fat, re-
sults in a substantial increase in GFR in patients with
healthy kidneys. Multiple subsequent studies have
confirmed these findings. The clinical implications of
RFR-G will be reviewed.
Baseline (Unstressed) GFR
GFR is normally utilized as a surrogate of kidney
function in healthy subjects as well as in patients with
kidney disease. Studies in healthy subjects under the
age of 50 have identified the average baseline normal
values of GFR to be between 100 and 130 ml/min per
1.73 m2.6 Evaluation of population-wide “normal”
values is useful, but the concept of “normal” GFR in
the single individual is more nuanced. It is important to
recognize that a person’s GFR at any given point in
time will vary in relation to the physiological demands
of dietary and hemodynamic conditions. Baseline value
for GFR (bGFR) also depends on age, sex, and body
size, with considerable variation among healthy in-
dividuals. Overall, the average daily GFR is remarkably
stable over years, although there is an age-related
decline in GFR physiologically by 0.8 ml/min per
1.73 m2 per year, after the age of 30 years.6,7
In general, serum creatinine tends to remain rela-
tively normal even in the presence of kidney damage,
until approximately 50% of nephrons are lost or
simply when bGFR approaches 60 ml/min per 1.73 m2
(Figure 2).8 For this reason serum creatinine cannot be
considered an accurate marker of renal function when
GFR is above 60 ml/min per 1.73 m2. Similarly, GFR
estimation (eGFR) by creatinine-derived equations (e.g.,
MDRD9) cannot be considered a sensitive index for
early detection of renal disease during the early phases
of parenchymal damage. A good example of this can be
58
seen in patients who donate a kidney; despite a halving
of their nephron mass, their serum creatinine and
calculated eGFR are “normal.”10 Therefore, when renal
disease becomes apparent due to an elevated serum
creatinine, this occurs only after the residual nephrons
can no longer compensate for the functional loss
(Figure 3).8
Renal Functional Reserve (RFR-G)
Normal subjects display a significant increase in GFR 1
or 2 hours after an acute protein load (1–1.2 g/kg) over
their baseline GFR. The difference between peak or
“maximum” GFR (maxGFR) and baseline GFR describes
the renal functional reserve of glomerular function
(RFR-G). Fliser and colleagues11 compared the baseline
and maxGFR in young and elderly healthy subjects and
found that RFR was significantly lower in elderly than
in young healthy individuals while virtually all base-
line GFR values of elderly were within the reference
range. The renal reserve as assessed by RFR-G is a
measure of the kidney’s capacity to increase GFR by a
combination of nephron recruitment and increases in
renal blood flow coupled with hyperfiltration.12–15
The stimulus to tap into this reserve capacity can
arise from adaptive physiological needs like pregnancy
or the presence of a solitary kidney. Utilization of RFR
in non-disease states is best illustrated by pregnancy.
In pregnancy, GFR significantly increases during each
trimester, such that there is a significant rise in bGFR
from first to last trimester. Studies done on normal
pregnant women in each trimester have shown a pro-
gressive increase of baseline GFR with a parallel
reduction of RFR due to its progressive utilization.13
MaxGFR in normal pregnant women, however, does
not change. However, pathological states can also
initiate processes that increase GFR above the normal
baseline. Primary hyperfiltration in kidney disease has
been shown in patients with diabetes mellitus, poly-
cystic kidney disease, secondary focal segmental
Figure 2. Relationship between glomerular filtration rate (GFR) and
serum creatinine changes. RFR-G, renal functional reserve–glomerular.
Kidney International Reports (2016) 1, 57–63
LS Chawla and C Ronco: Renal Stress Testing in the Assessment of Kidney Disease
Figure 3. Variation in baseline glomerular filtration rate (GFR).
glomerulosclerosis, sickle cell anemia, high-altitude
renal syndrome, obesity, hypertension, nephrotic
syndromes, and glomerulonephritis.16 In physiological
states of diminished RFR, the observed hyperfiltration
is likely due to recruitment of more nephron units,
whereas in pathological states, hyperfiltration is prob-
ably due to an increase in single nephron filtration
fraction. This, in part, is the basis of angiotensin II
blockade in chronic kidney disease (CKD), and is often
demonstrable by a drop in GFR when angiotensin-
converting enzyme inhibitors are given to patients
with CKD.
A current limitation on the use of RFR-G assessment
is that these assessments have not been conducted in
large cross-sectional cohorts, thus the population
variability of the RFR response is not known. Several
investigators have estimated RFR by measuring the
difference between protein-stimulated GFR and base-
line GFR after a protein load.4 In a separate study,17
Bosch and colleagues demonstrated the estimation of
RFR by a short-term oral protein loading method. De
Nicola and colleagues18 demonstrated that the estima-
tion of RFR can be assessed by amino acid infusion.
Numerous mechanisms have been hypothesized for
the increase in GFR after protein load. In their study,
Woods and colleagues19 hypothesized that protein
loading increases GFR because digested protein raises
plasma amino acid levels, which are then filtered at the
glomerulus, thereby stimulating proximal tubular ab-
sorption. In addition, filtered amino acids change the
sensitivity of macula densa sensing mechanisms,
causing release of nitric oxide and prostaglandins
locally resulting in vasodilation, increasing renal blood
flow and GFR. In our own laboratory we analyzed the
response to acute protein loading, and we detected an
increase in GFR proportional to an increase in renal
blood flow with a constant of filtration fraction. This
observation seems to support the hypothesis that an
Kidney International Reports (2016) 1, 57–63
REVIEW
overall increase in blood flow is the main mechanism
rather than a temporary hemodynamic perturbation in
the afferent and efferent tone and equilibrium
(C. Ronco and colleagues, unpublished data).
Stress testing with a protein load is the definitive
way to assess for the loss of RFR-G, but the significance
of renal reserve is not just a diagnostic consideration. It
is important to recognize that the loss of renal reserve
may also manifest as a loss in autoregulation capacity in
the kidney. This loss of autoregulation may increase
the vulnerability of those patients with CKD to volume
depletion and certain nephrotoxins (e.g., nonsteroidal
anti-inflammatory drugs). Population studies suggest
that increased creatinine variability, which could be
due to the loss of autoregulation, predicts progression
to end-stage renal disease.20
Kidney Stress Testing of GFR in Clinical
Practice and Future Research
Assuming RFR-G represents the difference between
maximal filtration capacity of the kidney (maxGFR) and
the baseline GFR (bGFR), a protein load is the basis of a
kidney stress test forcing the kidneys to utilize the
entire filtration capacity. This technique can be used to
“reveal” subclinical kidney disease. MaxGFR and bGFR
assessment with protein loading has been extensively
studied and can be used in the clinic to assess RFR-G in
patients with kidney disease.4,8,13,14 Because dietary
protein raises GFR, establishing bGFR is important
when attempting to assess RFR-G; developing stan-
dardized protocols to accomplish this is an important
research recommendation. There is another approach
that would allow single GFR assessment instead of
having to conduct a baseline and a stimulated stress
test. In this approach, the maxGFR would be assessed
among healthy patients across a wide age range, ethnic
range, and in both genders. Once these data were
known, then normative values could be determined for
maxGFR. These data would be used for diagnostic
purposes for patients who underwent a kidney stress
test to achieve maxGFR. Those patients who could not
achieve the appropriate maxGFR adjusted for age,
gender, and race could be referred for further work-up.
As part of a future research plan, the safety of
repeated protein loading in patients with CKD should
also be assessed. Since protein is a stimulant for GFR,
the effects of repeated protein loading in patients with
CKD is unknown. The exposure of repeated high levels
of protein in patients with CKD might be deleterious,
but might also “condition” the kidney as well and
stimulate restorative or protective effects—this concept
should be studied further.
The idea of assessing renal reserve has been present
for decades, but is infrequently used in clinical
59
REVIEW LS Chawla and C Ronco: Renal Stress Testing in the Assessment of Kidney Disease
practice, whereas the cardiac stress test is used
routinely. Why is this the case? In our view, the simple
reason is that cardiologists perceive that they can
intervene on patients with diminished cardiac reserve
(e.g., heart failure treatment), whereas the nephrology
community may not feel that an intervention is avail-
able, and therefore may be unwilling to perform an
extra test. We hypothesize that patients with loss of
renal reserve are at risk for CKD. Future trials should
assess whether early identification of diminished renal
reserve can reliably predict the risk of progression to
CKD. If this can be shown, early screening of renal
reserve may prompt early intervention and forestall the
development of CKD.
Tubular Function Assessment in Kidney Disease
The renal tubule portion of the nephron is tasked with
an enormous portfolio of responsibilities. Chief among
those chores are the handling of electrolytes, water,
and amino acids, catabolism of various proteins, and
the active secretion of endogenous and exogenous
acids. Tubular function assessment may be more
informative than glomerular reserve in patients who
already have advanced kidney disease. When patients
do not have obvious kidney disease, the loss of
glomerular reserve (RFR-G) can be an indicator of loss
of nephron mass.8 However, once a patient has kidney
injury or disease, glomerular reserve is already sub-
stantially reduced and therefore is less informative.
In patients with decreased GFR, tubular function
appears to be more variable. One reason for this
observation may be due to renal fibrosis. During the
assessment of kidney disease by tissue biopsy, the
level of interstitial fibrosis is one of the strongest pre-
dictors of renal survival.21,22 Interstitial fibrosis can
represent scarred tubules that are fibrosed, or the
secretion of matrix that fills in between the nephrons,
or both of these. However, because CKD is generally
marked by a reduction of kidney size, this makes the
possibility of “extra” matrix an unlikely sole expla-
nation for fibrosis (an exception to this would be
multiple myeloma). In most forms of kidney disease,
the kidneys shrink and become more echogenic over
time. Based on this observation, we believe that it is
more likely that diseased tubules are replaced by ma-
trix and fibrosis. In order to test the notion that tubular
function may identify patients who are at increased
risk for worse outcomes, various studies in patients
with both acute and chronic kidney disease have been
conducted to determine the utility of tubular secretion
capacity to predict outcomes.23,24
Different aspects of tubular function can be inter-
rogated in various ways depending on what feature of
tubular function is being assessed. For instance, the
60
tubule’s capacity to secrete acid or sodium can be
assessed via acid or salt loading. The tubule’s concen-
trating capacity can be assessed via water deprivation
or exogenous administration of desmopressin (DDAVP).
Among these different techniques, thus far the primary
methodology to assess tubular functional capacity in
patients with kidney disease has been via tubular
secretion of either creatinine or an exogenous drug
(e.g., furosemide).
Tubular Function Assessment in CKD
The first studies of tubular functional capacity in patients
with CKD utilized the difference between creatinine
clearance and inulin clearance as an assessment of tubular
function. Herrera and colleagues24 developed an elegant
study to demonstrate the potential use of tubular secre-
tion. In this study, the investigators took the following 3
cohorts of patients: normal, renal allograft donors (uni-
nephrectomized), and CKD. In these subjects, baseline
creatinine clearance and inulin-based GFR were
measured and then reassessed after a protein meal. They
found that both healthy patients and patients with CKD
were able to increase their inulin-measured GFR in
response to a protein meal; as expected, healthy patients
could increase their GFR after stimulation much more
than CKD patients. Similarly, healthy patients were able
to increase their tubular secretion of creatinine (TScr),
but CKD patients were unable to increase their TScr.
When all 3 groups of patients were compared, uni-
nephrectomized patients were able to increase their
TScr (but to a lesser degree than normal healthy subjects),
while CKD patients were unable to increase their TScr.
These data are consistent with previous studies that show
that patients with CKD maintain some glomerular renal
reserve at all levels of baseline GFR.8 In addition, this
study demonstrated that CKD patients likely operate at
near their maximum TScr, and thus are less able to in-
crease their TScr when challenged with a protein meal.
In a second trial, this same group of investigators
assessed TScr by infusing i.v. creatinine into normal
subjects and kidney transplant recipients.25 They found
that creatinine infusion did not increase GFR, and that
an infusion of i.v. creatinine resulted in an increased
TScr in healthy patients, but not in kidney transplant
recipients. Thus, a tubular functional assessment with a
challenge of i.v. creatinine had the capacity to reveal the
subjects with decreased nephron mass who otherwise
had normal serum creatinine levels.
In aggregate, preliminary studies suggest that
tubular stress tests that measure the secretory capacity
of the renal tubule are informative and predictive of
outcomes.23–26 However, it should be noted that
tubular stress tests remain research tools and have not
yet been deployed into the clinic for CKD.
Kidney International Reports (2016) 1, 57–63
LS Chawla and C Ronco: Renal Stress Testing in the Assessment of Kidney Disease
Tubular Assessment in Acute Kidney Injury
The aforementioned studies in CKD used creatinine
secretion to assess tubular functional assessment. In
patients with acute kidney injury (AKI), many factors,
including lack of steady state, increased catabolism,
and concurrent medications that interfere with creati-
nine secretion, preclude the use of TScr as a reliable
measure of tubular secretion. One approach uses i.v.
furosemide to assess tubular function. Furosemide, a
loop diuretic, has pharmacokinetic properties that
make it an appealing functional tool. In contrast to
other drugs cleared by the kidney, furosemide is not
effectively filtered by the glomerulus. As an organic
acid, furosemide is tightly bound to albumin and gains
access to the tubular lumen by active secretion via the
human organic anion transporter system in the prox-
imal convoluted tubule.27,28 Once in the tubular lumen,
furosemide blocks luminal cation–chloride cotransport
throughout the thick ascending limb of Henle, thereby
preventing sodium reabsorption and resulting in
natriuresis and increased urine flow.29–31 Based on
these properties, furosemide-induced increases in urine
output represent a methodology to assess the integrity
of the renal tubular function in the setting of AKI. This
methodology was developed by Chawla and col-
leagues23 and is referred to as the furosemide stress test
(FST).
The FST has been prospectively assessed in a single
cohort study of critically ill patients with AKI and was
found to have good diagnostic performance. In that
study, Chawla and colleagues23 administered a stan-
dard dose of i.v. furosemide (1.0–1.5 mg/kg) to criti-
cally ill patients with Kidney Disease: Improving
Global Outcomes (KDIGO) stage I or stage II AKI and
then assessed the urine output response. This study
showed that the 2-hour urine output response to a
furosemide challenge was able to predict progression to
KDIGO stage III within 14 days with a receiver oper-
ating characteristic area under the curve of 0.87
(SE, 0.05). At a cutoff of 200 cm3 at 2 hours, the
sensitivity and specificity of the FST were 87.1% and
84.1%, respectively.23 In a follow-up study of the same
cohort, the same research group showed that FST
performed better than known AKI biomarkers.
Importantly, the follow-up study demonstrated that
the FST performance improves when utilized in pa-
tients with increased levels of AKI biomarkers.32 These
data suggest that the combination of AKI biomarkers
with tubular functional assessment is informative, and
can be used at the bedside to assist clinicians in
assessing the severity of AKI. It remains unclear
whether the FST reveals the severity of AKI, or the loss
of tubular functional capacity. An important caveat to
the FST is that the subject must be euvolemic for the
Kidney International Reports (2016) 1, 57–63
REVIEW
test to be safe and valid, and any volume losses induced
by the diuresis should be replaced.
A version of the FST has also been analyzed in patients
with advanced-stage AKI requiring renal replacement
therapy to determine whether a standardized furosemide
challenge can predict renal recovery. van der Voort and
colleagues reported that a standardized 4-hour infusion
of furosemide was also an excellent predictor of renal
recovery.26,33 This analysis was a post hocassessment of a
randomized clinical trial, which compared a 4-hour
infusion of furosemide to placebo as an intervention to
promote renal recovery in patients who are on contin-
uous renal replacement therapy. In this post hocanalysis,
the authors assessed the intervention arm of the trial (i.e.,
the patients randomized to furosemide) and found that
the mean urine output was much higher in patients
destined to recover (654 ml vs. 48 ml, P ¼ 0.007) and had
a diagnostic performance receiver operating character-
istic area under the curve of 0.84. These 2 studies
demonstrate that the urine output response to furose-
mide is informative about renal tubular function
throughout the phases of AKI (progression and recov-
ery). Another advantage of the FST is that it does not just
measure the tubule’s secretion capacity, but is actually
an assessment of integrated renal function34 (Figure 4). In
order for furosemide to increase urine output, furose-
mide must be actively secreted into the proximal lumen,
and the thick ascending limb, luminal patency, and
collecting duct function must all be intact.35 Because the
FST requires an intact nephron for full function, the FST
does not readily identify the location of the defect in
cases in which the FST response is poor.
The aforementioned studies of FST are of modest size
and are currently undergoing larger-scale validation
(NCT 01275729). However, the FST is based on the
bedside practice of many clinicians, which involves
challenging patients with a loop diuretic and assessing
the clinical response. The FST, as currently devised, is
simply a framework around this common bedside
practice. The FST is also being assessed by the 0 by 25
Figure 4. Furosemide urinary response tests tubular integrity. TAL,
thick ascending limb.
61
REVIEW LS Chawla and C Ronco: Renal Stress Testing in the Assessment of Kidney Disease
initiative spearheaded by the International Society of
Nephrology. In an austere medical environment, simple
diagnostic tools like serum urea and creatinine are not
readily available. Thus, the use of FST in euvolemic
patients with oliguria may allow a thoughtful way to
triage patients who may need more advanced care.
Because furosemide is inexpensive and available
worldwide, this physiological assessment may allow for
broader use of this diagnostic approach.
Summary
Kidney stress testing can be accomplished by assessing
glomerular and tubular domains. These assessments are
safe and relatively inexpensive and can be done at the
bedside or in the clinic. Importantly, these assessments
have been shown to be informative in both acute and
chronic kidney disease. However, neither of these
stress tests is currently used routinely at the bedside or
the clinic. Assessment of RFR-G can and, in the opinion
of these authors, should be used to reveal the loss of
RFR in patients at risk for kidney disease. Tubular
functional testing has been less developed; early
studies demonstrate good diagnostic performance, but
large validation studies are still needed. Because
tubular testing may have the capacity to assess multiple
anatomic domains of the nephron, we believe that
noninvasive kidney stress testing may allow clinicians
to phenotype, prognosticate, and better follow patients
with kidney disease. Further research into the appro-
priate use of these diagnostic techniques is warranted.
DISCLOSURE
LSC has received consulting fees from Astute Medical. The
other author declared no competing interests.
REFERENCES
1. Koopman MG, Koomen GC, Krediet RT, et al. Circadian
rhythm of glomerular filtration rate in normal individuals. Clin
Sci. 1989;77:105–111.
2. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and
the progressive nature of kidney disease: the role of
hemodynamically mediated glomerular injury in the pathogen-
esis of progressive glomerular sclerosis in aging, renal ablation,
and intrinsic renal disease. N Engl J Med. 1982;307:652–659.
3. Graf H, Stummvoll HK, Luger A, Prager R. Effect of amino acid
infusion on glomerular filtration rate. N Engl J Med. 1983;308:
159–160.
4. Bosch JP, Saccaggi A, Lauer A, et al. Renal functional reserve
in humans. Effect of protein intake on glomerular filtration
rate. Am J Med. 1983;75:943–950.
5. Hostetter TH. Human renal response to meat meal. Am J
Physiol. 1986;250:F613–F618.
6. Delanaye P, Schaeffner E, Ebert N, et al. Normal reference
values for glomerular filtration rate: what do we really know?
Nephrol Dial Transplant. 2012;27:2664–2672.
62
7. Davies DF, Shock NW. Age changes in glomerular filtration
rate, effective renal plasma flow, and tubular excretory ca-
pacity in adult males. J Clin Invest. 1950;29:496–507.
8. Barai S, Gambhir S, Prasad N, et al. Functional renal reserve
capacity in different stages of chronic kidney disease.
Nephrology. 2010;15:350–353.
9. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method
to estimate glomerular filtration rate from serum creatinine: a
new prediction equation. Modification of Diet in Renal Dis-
ease Study Group. Ann Intern Med. 1999;130:461–470.
10. Tsuda A, Ishimura E, Uedono H, et al. Comparison of the
estimated glomerular filtration rate (eGFR) in diabetic pa-
tients, non-diabetic patients and living kidney donors. Kidney
Blood Press Res. 2016;41:40–47.
11. Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in
healthy elderly subjects. J Am Soc Nephrol. 1993;3:1371–1377.
12. Bosch JP, Lew S, Glabman S, Lauer A. Renal hemodynamic
changes in humans. Response to protein loading in normal
and diseased kidneys. Am J Med. 1986;81:809–815.
13. Ronco C, Brendolan A, Bragantini L, et al. Renal functional
reserve in pregnancy. Nephrol Dial Transplant. 1988;3:157–161.
14. Pecly IM, Genelhu V, Francischetti EA. Renal functional
reserve in obesity hypertension. Int J Clin Pract. 2006;60:
1198–1203.
15. Zitta S, Stoschitzky K, Zweiker R, et al. Dynamic renal function
testing by compartmental analysis: assessment of renal
functional reserve in essential hypertension. Nephrol Dial
Transplant. 2000;15:1162–1169.
16. Cachat F, Combescure C, Cauderay M, et al. A systematic
review of glomerular hyperfiltration assessment and defini-
tion in the medical literature. Clin J Am Soc Nephrol. 2015;10:
382–389.
17. Bosch JP, Lauer A, Glabman S. Short-term protein loading in
assessment of patients with renal disease. Am J Med.
1984;77:873–879.
18. De Nicola L, Blantz RC, Gabbai FB. Renal functional reserve in
treated and untreated hypertensive rats. Kidney Int. 1991;40:
406–412.
19. Woods LL. Mechanisms of renal hemodynamic regulation in
response to protein feeding. Kidney Int. 1993;44:659–675.
20. O’Hare AM, Batten A, Burrows NR, et al. Trajectories of kid-
ney function decline in the 2 years before initiation of long-
term dialysis. Am J Kidney Dis. 2012;59:513–522.
21. Bohle A, Grund KE, Mackensen S, Tolon M. Correlations
between renal interstitium and level of serum creatinine.
Morphometric investigations of biopsies in perimembranous
glomerulonephritis. Virchows Arch A Pathol Anat Histol.
1977;373:15–22.
22. Mackensen-Haen S, Bader R, Grund KE, Bohle A. Correlations
between renal cortical interstitial fibrosis, atrophy of the
proximal tubules and impairment of the glomerular filtration
rate. Clin Nephrol. 1981;15:167–171.
23. Chawla LS, Davison DL, Brasha-Mitchell E, et al. Development
and standardization of a furosemide stress test to predict the
severity of acute kidney injury. Crit Care. 2013;17:R207.
24. Herrera J, Rodriguez-Iturbe B. Stimulation of tubular secre-
tion of creatinine in health and in conditions associated with
reduced nephron mass. Evidence for a tubular functional
reserve. Nephrol Dial Transplant. 1998;13:623–629.
Kidney International Reports (2016) 1, 57–63
LS Chawla and C Ronco: Renal Stress Testing in the Assessment of Kidney Disease
25. Rodriguez-Iturbe B, Herrera J, Marin C, Manalich R. Tubular
stress test detects subclinical reduction in renal functioning
mass. Kidney Int. 2001;59:1094–1102.
26. van der Voort PH, Boerma EC, Pickkers P. The furosemide
stress test to predict renal function after continuous renal
replacement therapy. Crit Care. 2014;18:429.
27. Hasannejad H, Takeda M, Taki K, et al. Interactions of human
organic anion transporters with diuretics. J Pharmacol Exp
Ther. 2004;308:1021–1029.
28. Bowman RH. Renal secretion of [35-S]furosemide and
depression by albumin binding. Am J Physiol. 1975;229:
93–98.
29. Burg M, Stoner L, Cardinal J, Green N. Furosemide effect on
isolated perfused tubules. Am J Physiol. 1973;225:119–124.
30. Dirks JH, Seely JF. Effect of saline infusions and furosemide
on the dog distal nephron. Am J Physiol. 1970;219:114–121.
Kidney International Reports (2016) 1, 57–63
REVIEW
31. Brater DC, Anderson SA, Strowig S. Azosemide, a “loop”
diuretic, and furosemide. Clin Pharmacol Ther. 1979;25:
435–439.
32. Koyner JL, Davison DL, Brasha-Mitchell E, et al. Furosemide
stress test and biomarkers for the prediction of AKI severity.
J Am Soc Nephrol. 2015;26:2023–2031.
33. van der Voort PH, Boerma EC, Koopmans M, et al. Furose-
mide does not improve renal recovery after hemofiltration for
acute renal failure in critically ill patients: a double blind
randomized controlled trial. Crit Care Med. 2009;37:533–538.
34. Powell TC, Warnock DG. The furosemide stress test and
predicting AKI outcomes. J Am Soc Nephrol. 2015;26:
1762–1764.
35. Berger BE, Warnock DG. Mechanisms of action and clinical
uses of diuretics. In: Brenner BM, eds. The Kidney. 3rd ed.
Philadelphia: W.B. Saunders; 1986:433–456.
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 ARTIGO 9

GASOMETRIA ARTERIAL
[Downloaded free from http://www.ijccm.org on Tuesday, May 19, 2015, IP: 78.130.192.104]

Review Article

Interpretation of arterial blood gas

Pramod Sood, Gunchan Paul, Sandeep Puri1
Abstract

Disorders of acid–base balance can lead to severe complications in many disease states, and occasionally the abnormality
may be so severe as to become a life-threatening risk factor. The process of analysis and monitoring of arterial blood
gas (ABG) is an essential part of diagnosing and managing the oxygenation status and acid–base balance of the high-risk
patients, as well as in the care of critically ill patients in the Intensive Care Unit. Since both areas manifest sudden and
life-threatening changes in all the systems concerned, a thorough understanding of acid–base balance is mandatory for
any physician, and the anesthesiologist is no exception. However, the understanding of ABGs and their interpretation can
sometimes be very confusing and also an arduous task. Many methods do exist in literature to guide the interpretation
of the ABGs. The discussion in this article does not include all those methods, such as analysis of base excess or
Stewart’s strong ion difference, but a logical and systematic approach is presented to enable us to make a much easier
interpretation through them. The proper application of the concepts of acid–base balance will help the healthcare
provider not only to follow the progress of a patient, but also to evaluate the effectiveness of care being provided.

Keywords: Arterial blood gas interpretation, ABG analysis, rules for rapid ABG analysis, Anion gap,
Approach to mixed disorders

DOI: 10.4103/0972-5229.68215

Introduction concept of SID was introduced, which is defined as the

absolute difference between completely dissociated
Arterial blood gas (ABG) analysis is an essential part of
anions and cations. According to the principle of
diagnosing and managing a patient’s oxygenation status
electrical neutrality, this difference is balanced by the
and acid–base balance. The usefulness of this diagnostic
weak acids and CO2. The SID is defined in terms of weak
tool is dependent on being able to correctly interpret
acids and CO2 subsequently has been re-designated as
the results. Disorders of acid–base balance can create
effective SID (SIDe) which is identical to “buffer base.”
complications in many disease states, and occasionally
Similarly, Stewart’s original term for total weak acid
the abnormality may be so severe so as to become a
concentration (ATOT) is now defined as the dissociated
life-threatening risk factor. A thorough understanding
(A-) plus undissociated (AH) weak acid forms. This
of acid–base balance is mandatory for any physician,
is familiarly known as anion gap (AG), when normal
and intensivist, and the anesthesiologist is no exception.
concentration is actually caused by A-. Thus all the three
methods yield virtually identical results when they
The three widely used approaches to acid–base
are used to quantify acid–base status of a given blood
physiology are the HCO3- (in the context of pCO2),
sample.[1]
standard base excess (SBE), and strong ion difference
(SID). It has been more than 20 years since the Stewart’s
Why is it Necessary to Order an ABG
Analysis?
From:
Critical Care Division,1Department of Medicine, Dayanand Medical College The utilization of an ABG analysis becomes necessary
and Hospital, Ludhiana, Punjab, India in view of the following advantages:
Correspondence: • Aids in establishing diagnosis.
Dr. Sood Pramod, • Guides treatment plan.
Dayanand Medical College and Hospital, Ludhiana, Punjab, India
E-mail: soodpramod@yahoo.com • Aids in ventilator management.

Free full text available from www.ijccm.org

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Indian J Crit Care Med April-June 2010 Vol 14 Issue 2
• Improvement in acid/base management; allows for
optimal function of medications.
• Acid/base status may alter electrolyte levels critical
to a patient's status.
Accurate results for an ABG depend on the proper
manner of collecting, handling, and analyzing the
specimen. Clinically important errors may occur at any of
the above steps, but ABG measurements are particularly
vulnerable to preanalytic errors. The most common
problems that are encountered include nonarterial
samples, air bubbles in the sample, inadequate or
excessive anticoagulant in the sample, and delayed
analysis of a noncooled sample.
Potential Preanalytical Errors
Preanalytical errors are caused at the following stages:
During preparation prior to sampling
• Missing or wrong patient/sample identification;
• Use of the incorrect type or amount of anticoagulant
• - dilution due to use of liquid heparin;
- insufficient amount of heparin;
- binding of electrolytes to heparin;
• Inadequate stabilization of the respiratory condition
of the patient; and
• Inadequate removal of flush solution in arterial lines
prior to blood collection.
During sampling/handling
• Mixture of venous and arterial blood during
puncturing;
• Air bubbles in the sample. Any air bubble in the
sample must be expelled as soon as possible after
withdrawing the sample and before mixing with
heparin or before any cooling of the sample has been
done. An air bubble whose relative volume is up to
1% of the blood in the syringe is a potential source
of significant error and may seriously affect the pO2
value.
• Insufficient mixing with heparin.
During storage/transport
• Incorrect storage
• Hemolysis of blood cells
General Storage Recommendation
• Do not cool the sample.[2]
• Analyze within 30 min. For samples with high paO2,
e.g., shunt or with high leukocyte or platelet count
also analyze within 5 min.
• When analysis is expected to be delayed for more
58
than 30 minutes, use of glass syringes and ice slurry
is recommended.
During preparation prior to sample transfer
• Visually inspect the sample for clots.
• Inadequate mixing of sample before analysis.
Insufficient mixing can cause coagulation of the sample.
It is recommended to mix the blood sample thoroughly
by inverting the syringe 10 times and rolling it between
the palms as shown in Figure 1. This prevents stacking
(such as coins or plates) of red blood cells.
During anticoagulation
Modern blood gas syringes and capillary tubes
are coated with various types of heparin to prevent
coagulation in the sampler and inside the blood gas
analyzer:
• Liquid nonbalanced heparin
• Dry nonbalanced heparin
• Dry electrolyte-balanced heparin (Na+, K+, Ca2+)
• Dry Ca2+-balanced heparin
Other anticoagulants, e.g., citrate and EDTA are both
slightly acidic which increase the risk of pH being falsely
lowered.
Liquid heparin
The use of liquid heparin as the anticoagulant causes
a dilution of the sample, i.e., dilutes the plasma, but
not the contents of the blood cells. As a consequence,
parameters such as pCO2 and electrolytes are affected.
Only 0.05 mL of heparin is required to anticoagulate 1 mL
of blood. Dead space volume of a standard 5 mL syringe
with 1 inch 22 gauge needle is 0.2 mL; filling the syringe
dead space with heparin provides sufficient volume to
Figure 1: Correct method of mixing of the arterial sample with the
anticoagulant in two dimensions to prevent stacking of red blood cells.
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Indian J Crit Care Med April-June 2010 Vol 14 Issue 2

anticoagulate a 4-mL blood sample. If smaller sample Table 1: pH value and corresponding H+ ion concentration
volumes are obtained or more liquid heparin is left in pH H+ pH H+
the syringe, then the dilution effect will be even greater. 6.70 200 7.40 40
The dilution effect also depends on the hematocrit value. 6.75 178 7.45 35
Plasma electrolytes decrease linearly with the dilution of 6.80 158 7.50 32
the plasma along with pCO2, cGlucose, and ctHb values. 6.85 141 7.55 28
pH and pO2 values are relatively unaffected by dilution. 6.90 126 7.60 25
paO2 is only as little as 2% of the O2 physically dissolved 6.95 112 7.65 22
in the plasma, and so the oximetry parameters given in 7.00 100 7.70 20
7.05 89 7.75 18
fractions (or %) will remain unaffected.[3]
7.10 79 7.80 16
7.15 71 7.85 14
Syringes for blood gas analysis can have a wide range 7.20 63 7.90 13
of heparin amounts.[4] The units are typically given as IU/ 7.25 56 7.95 11
mL (international units of heparin per milliliter) blood 7.30 50 8.00 10
drawn into the syringe. In order to obtain a sufficient final 7.35 45
concentration of heparin in the sample, blood volume
recommended on the syringe must be drawn. Example:
Obtain a relevant clinical history
a syringe stated to contain 50 IU/mL when filled with
While making an interpretation of an ABG, never
1.5 mL of blood means that the syringe contains a total
comment on the ABG without obtaining a relevant
75 IU of dry heparin. If the user draws 2 mL of blood,
clinical history of the patient, which gives a clue to the
then the resulting heparin concentration will be too low
etiology of the given acid–base disorder. For example,
and the sample may coagulate. If the user draws only
a patient with a history of hypotension, renal failure,
1 mL, then the resulting heparin concentration will be
uncontrolled diabetic status, of treatment with drugs
higher than that aimed for, which may lead to producing
such as metformin is likely to have metabolic acidosis;
falsely low electrolyte results.
a patient, with a history of diuretic use, bicarbonate
administration, high-nasogastric aspirate, and vomiting,
Heparin binds to positive ions such as Ca2+, K+, and
is likely to have metabolic alkalosis. Respiratory acidosis
Na+. Electrolytes bound to heparin cannot be measured
would occur in COPD, muscular weakness, postoperative
by ion-selective electrodes, and the final effect will be
cases, and opioid overdose, and respiratory alkalosis is
measurement of falsely low values. The binding effect
likely to occur in sepsis, hepatic coma, and pregnancy.
and the resulting inaccuracy of results are especially
significant for corrected Ca2+. The use of electrolyte-
balanced heparin significantly reduces the binding effect Look at the oxygenation status of the patient
and the resulting inaccuracy.[5] The oxygenation status of the patient is judged by the
paO2; however, never comment on the oxygenation status
The following steps for rapid interpretation of ABG without knowing the corresponding FiO2. Calculate the
are recommended: expected paO2 (generally five times the FiO2).[6]

Based on the expected paO2 classify as mild, moderate,

Check for the consistency of ABG
and severe hypoxia.
While making an interpretation of an ABG always
check for the consistency of the report by the modified
Henderson equation. Ventilatory status
Look at paCO2.
[H ][HCO ] = 24
+_
3

PaCO2 Acid–base status

The hydrogen ion is calculated by subtracting the two Identify the primary disorder by looking at the pH
digits after the decimal point of pH from 80, e.g., if the
pH is 7.23 then pH > 7.40—Alkalemia: < 7.40—Acidemia
[H+] = 80 - 23 = 57
or Then look at paCO2 which is a respiratory acid, whether
[H+] = 10(9-pH) it is increased, i.e., >40 (acidosis) or decreased <40
(alkalosis) and if this explains the change of pH, then it
The hydrogen can be calculated from Table 1. is respiratory disorder; otherwise, see the trend of change

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Indian J Crit Care Med April-June 2010 Vol 14 Issue 2
of HCO3- (whether increased in alkalosis or decreased
in acidosis)—if it explains the change of pH, then it is a
metabolic disorder.
In a normal ABG
• pH and paCO2 move in opposite directions.
• HCO3- and paCO2 move in same direction.
1. When the pH and paCO2 change in the same direction
(which normally should not), the primary problem
is metabolic; when pH and paCO2 move in opposite
directions and paCO2 is normal, then the primary
problem is respiratory.
2. Mixed Disorder—if HCO3- and paCO2 change in
opposite direction (which they normally should
not), then it is a mixed disorder: pH may be normal
with abnormal paCO2 or abnormal pH and normal
paCO2).[7]
If the trend of change in paCO2 and HCO3- is the same,
check the percent difference. The one, with greater
% difference, between the two is the one that is the
dominant disorder.
e.g.: pH = 7.25 HCO3 =16 -
paCO2 =60
Here, the pH is acidotic and both paCO2 and HCO3-
explain its acidosis: so look at the % difference
HCO3- % difference = (24 - 16)/24 = 0.33
paCO2 % difference = (60 - 40)/40 = 0.5
Therefore, respiratory acidosis as the dominant
disorder.
Respiratory disorders
After the primary disorder is established as respiratory,
then the following points will help us to approach further
with regard to the respiratory disorder).[8]
• Ratio of rate of change in H+ to change in paCO2
• Alveolar arterial oxygen gradient
• Compensation
Ratio of rate of change in H+ to change in paCO2
The above ratio of rate of change in H+ to change in
paCO2 helps in guiding us to conclude whether the
respiratory disorder is acute, chronic, or acute on chronic.
As we have seen, the hydrogen can be calculated from
Table 1 and the change in H+ is calculated by subtracting
the normal H+ from the calculated H+ ion.[9]
60
∆H +
< 0.3 − Chronic
∆PaCO 2
>0.8—acute
0.3–0.8—acute on chronic
Alveolar Arterial Oxygen Gradient
It is calculated as follows:
PAO2 = PiO2 – PaCO2
R
PiO2= FiO2 (PB-PH2O)
PAO2= FiO2 (PB-PH2O)- PaCO2
R
where PAO2, alveolar partial pressure of oxygen; PiO2,
partial pressure of inspired oxygen; FiO2, fraction of
inspired oxygen; PB, barometric pressure (760 mmHg
at sea level); PH2O, water vapor pressure (47 mm Hg),
PaCO2, partial pressure of carbon dioxide in blood; R,
respiratory quotient assumed to be 0.8.
= FiO2 (760 - 47) - PaCO2
0.8
Hypoxemic respiratory failure can be associated with
normal (10–15 mmHg) or increased alveolar arterial
oxygen gradient. Figure 2 shows the alogrithim for
approach in a patient with hypoxemic respiratory failure.
If this gradient is <20, then it indicates an extrapulmonary
cause of respiratory failure.
Differentials of extrapulmonary causes of respiratory
failure:
(a) Central nervous system—Respiratory center
depression due to causes such as drug overdose,
primary alveolar hypoventilation, and myxedema.
(b) Peripheral nervous system—Spinal cord diseases,
Guillain-Barré syndrome, Amyotrophic lateral
sclerosis.
(c) Respiratory muscles—Hypophosphatemia, muscle
fatigue, myasthenia gravis, and polymyositis.
(d) Chest wall diseases—Ankylosing spondylitis, flail
chest, thoracoplasty.
(e) Pleural diseases—Restrictive pleuritis
(f) Upper air way obstruction—Tracheal Stenosis, vocal
cord tumor
Compensation
Rules of compensation
(1) The compensatory response depends upon the
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Figure 2: Flow diagram showing approach to hypoxemic respiratory failure
proper functioning of the organ system involved in
the response (lungs or kidneys) and on the severity
of acid–base disturbance. For example, the likelihood
of complete compensation in chronic respiratory
acidosis is <15% when paCO2 exceeds 60 mmHg.
(2) Acute compensation occurs within 6–24 h and chronic
within 1–4 days. Respiratory compensation occurs
faster than metabolic compensation.
(3) In clinical practice, it is rare to see complete
compensation. The maximum compensatory
response in most cases is associated with only
50–75% return of pH to normal. However, in chronic
respiratory alkalosis, the pH may actually completely
return to normalcy in some cases.
Respiratory acidosis
Acute: [HCO3-] increase by 1 mEq/L for every 10 mmHg
increase in paCO2 above 40.
Chronic: [HCO3-] increase by 3.5 mEq/L for every 10
mmHg increase in paCO2 above 40.
Respiratory alkalosis
Acute: [HCO3-] decrease by 2 mEq/L for every 10
mmHg decrease in paCO2 below 40.
Chronic: [HCO3-] decrease by 5 mEq/L for every 10
Indian J Crit Care Med April-June 2010 Vol 14 Issue 2
mmHg decrease in paCO2 below 40.
Metabolic disorders
In patients with metabolic acidosis, an excess of acid
or loss of base is present. This causes the HCO3-:H2CO3
ratio and pH to fall while no change occurs in pCO2—
uncompensated metabolic acidosis.
As a result of compensatory mechanisms, the lungs in
the form of CO2 excrete H2CO3 and the kidneys retain
HCO3-. pCO2 falls and HCO3-: H2CO3 ratio and pH rise
toward normal even though concentrations of HCO3- and
H2CO3 are less than normal. This is called compensated
metabolic acidosis and the expected paCO2 is calculated
as paCO2 = [1.5 × HCO3 + 8] ± 2.
Anion gap
For more than 40 years, the AG theory has been used
by clinicians to exploit the concept of electroneutrality
and has evolved as a major tool for evaluating the acid–
base disorder. Anion gap is the difference between the
charges of plasma anions and cations, calculated from the
difference between the routinely measured concentration
of the serum cations (Na+ and K+) and anions (Cl- and
HCO3-). Because electroneutrality must be maintained,
the difference reflects the unmeasured ions. Normally,
this difference or the gap is filled by the weak acids (A-)
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Indian J Crit Care Med April-June 2010 Vol 14 Issue 2
principally albumin, and to a lesser extent phosphates,
sulfates, and lactates.
When the AG is greater than that produced by the
albumin and phosphate, other anions (e.g., lactates
and ketones) must be present in higher than normal
concentration.
Anion gap = (Na+ + K+) - [Cl- + HCO3-]
Because of its low and narrow extracellular
concentration, K+ is often omitted from the calculation
The normal value ranges from 12 ± 4 when K + is
considered, and 8 ± 4 when K+ is omitted. Figure 3 shows
the alogrithm for the approach to patients with normal
AG acidosis.
The primary problem with AG is its reliance on the
use of the normal range produced by the albumin and
to a lesser extent phosphate, the level of which may be
grossly abnormal in critically ill patients. Because these
anions are not strong anions, their charges will be altered
by changes in pH.[10,11]
Serum protein and phosphate
Normal AG = 2{albumin(gm/L)} + 0.5 {phosphate
(mg/dL)}
Acid–base status
In Acidemic state – Anion gap decreases by 1–3
In Alkalemic state – Anion gap increases by 2–5
Major clinical uses of the anion gap
• For signaling, the presence of a metabolic acidosis
and confirm other findings.
+ +
Urinary anion gap = (Urinary Na + Urinary K ) - Urinary Cl
Positive
renal
(type I, II, IV Renal tubular acidosis)
Urinary pH
>6 <5.5
(Type I, renal tubular acidosis)
Hypokalemia
(Type II renal tubular acidosis)
Figure 3: Approach to a patient with normal anion gap acidosis
62
• Helping to differentiate between causes of metabolic
acidosis: High AG versus normal AG metabolic
acidosis. In an inorganic metabolic acidosis (e.g., due
to HCl infusion), the infused Cl- replaces HCO3-, and
the AG remains normal. In an organic acidosis, the
lost bicarbonate is replaced by the acid anion which
is not normally measured. This means that the AG
is increased.
• Providing assistance in assessing the biochemical
severity of the acidosis and follow the response to
treatment.
Disorders that are associated with a low or negative
serum AG are listed in Table 2.
Table 3 elaborates the species of the unaccounted
anions along with their sources of origin and diagnostic
adjunts in case of high AG metabolic acidosis.
In the patients with metabolic alkalosis, there is
an excess of base or a loss of acid which causes the
HCO3-:H2CO3 ratio and pH to rise, but with no change
occurring in pCO2, which is called uncompensated
metabolic alkalosis. However, the kidney has a large
capacity to excrete excess bicarbonate and so, for
sustaining the metabolic alkalosis, the elevated HCO3-
concentration must be maintained through an abnormal
renal retention of HCO3-.
Compensatory respiratory acidosis may be so marked
that pCO2 may rise higher than 55 mmHg. Expected paCO2
is calculated as paCO2 = [0.7 × HCO3- + 21] ± 2 or 40 + [0.7
∆HCO3]. This is called compensated metabolic alkalosis.
Most of the patients with metabolic alkalosis can be
-
treated with chloride ions in the form of NaCl (saline
responsive) rather than KCl (which is preferable). When
NaCl is given, Cl- ions are supplied, and so the blood
volume increases and the secretion of aldosterone in
Negative excess decreases. Thus, excessive urinary loss of K+ and
extra renal
excessive reabsorption of HCO3- stops. When metabolic
alkalosis is due to the effects of excessive aldosterone or
other mineralocorticoids, the patient does not respond
to NaCl (saline resistant) and requires KCl.
Based on the urinary chloride, metabolic alkalosis is
divided into:
Chloride responsive or extracellular volume depletion
(urinary chloride < 20)
• Vomiting
Hyperkalemia
• Diuretic
(Type IV renal tubular A)
• Post hypercapnic
• Chronic diarrhea
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Indian J Crit Care Med April-June 2010 Vol 14 Issue 2

Table 2: Disorders associated with low serum anion gap

Cause Comments
Laboratory error Most frequent cause of low anion gap
Hypoalbuminemia Second most common cause of low serum anion gap
Multiple myeloma Level of anion gap correlates with serum concentration of paraprotein
Halide intoxication Anion gap depends on serum halide concentration
(bromide, lithium, iodide) (low anion gap with lithium ≥4 mEq/L)
Hypercalcemia more likely in hypercalcemia associated with 10 hyperparathyroidism
Hypermagnesemia Theoretical cause but not documented in literature
Polymyxin B Anion gap depends on serum level; occurs with preparation with chloride
Underestimation of serum sodium Most frequent with hypernatremia or hypertriglyceridemia
Overestimation of serum chloride Rare with ion selective electrodes
Overestimation of serum bicarbonate Spurious ↑in serum HCO3 if cells not separated from sera

Table 3: Description of the species of unmeasured anions, source of origin, and diagnostic adjuncts in case of high anion gap
metabolic acidosis
Cause High serum anion gap
Comments
Species Origin Diagnostic adjuncts
Renal failure Phosphates, sulphates Protein metabolism BUN/creatinine
Ketocidosis Ketoacids Fatty acid metabolism Serum/urine ketones
Diabetic β Hydroxybutyrate
Alcoholic
Starvation Acetoacetate
Lactic acidosis Lactate Lactate levels
Exogenous poisoning Salicylate Salicylate Concomitant
Lactate Respiratory and metabolic alkalosis
ketoacids

Chloride resistant (urinary chloride > 20)
• Severe potassium depletion
• Mineralocorticoid excess—Primary
hypealdosteronism, Cushing's Syndrome, Ectopic
ACTH
• Secondary hypereldosteronism—Renovascular
disease, malignant hypertension, CHF, cirrhosis
evaluation of blood gas and acid–base disturbances in
the body, the following scheme is suggested:
1. Look at pH – < 7.40 – Acidosis; > 7.40 – Alkalosis
2. If pH indicates acidosis, then look at paCO2 and
HCO3-

Aproach to mixed disorder 3. If paCO2 is ↑, then it is primary respiratory acidosis

Mixed metabolic disturbances (e.g., high AG from (a) To determine whether it is acute or chronic
diabetic ketoacidosis plus normal AG from diarrhea)
∆H+/∆paCO2 <0.3—chronic
can be identified using the relationship between AG
>0.8—acute
and HCO3-, which is called the gap–gap ratio. It is
0.3–0.8—acute on chronic
the ratio of change in anion gap (∆AG) to change in
(b) Calculate compensation by the respective methods
HCO3- (∆HCO3-). When hydrogen ions accumulate in
Acute: [HCO3-] ↑ by 1 mEq/L for every 10 mmHg
blood, the decrease in serum HCO3- is equivalent to the
increase in AG and the increase in AG excess/HCO3- ↑ in paCO2 above 40.
deficit ratio is unity, i.e., pure increase in AG metabolic Chronic: [HCO3-] ↑ by 3.5 mEq/L for every 10
acidosis. When a normal AG acidosis is present, the mmHg ↑ in paCO2 above 4
ratio approaches zero. When a mixed acidosis is present
(high AG + normal AG), the gap–gap ratio indicates the 4. If paCO2 ↓ and HCO3- is also ↓→ primary metabolic
relative contribution of each type to the acidosis. If it is acidosis
<1, then it suggests that there is a normal AG metabolic Calculate expected paCO2 as follows:
acidosis associated with it and if >2 it suggests that there paCO2 = [1.5 × HCO3 + 8] ± 2 metabolic acidosis only
is associated metabolic acidosis. paCO2 < expected paCO2 → concomitant respiratory
alkalosis.
Rules for rapid clinical interpretation of ABG paCO2 > expected paCO2 → concomitant respiratory
When required to make a proper approach towards the acidosis

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Indian J Crit Care Med April-June 2010 Vol 14 Issue 2
5. If HCO3- is ↓, then AG should be examined.
6. If AG is unchanged → then it is hyperchloremic
metabolic acidosis.
7. If AG is ↑ → then it is wide AG acidosis.
8. Check gap–gap ratio
∆AG/∆ HCO3- = 1, pure increased AG metabolic
acidosis
<1 normal anion gap metabolic acidosis
>2 associated metabolic acidosis.
9. If pH indicates alkalosis, then look at HCO3- and
paCO2.
10. If paCO 2 is ↓ → then it is primary respiratory
alkalosis.
(a) Whether it is acute or chronic (with the same
formula as above)
(b) Calculate compensation by the respective methods:
Acute: [HCO3-]↓ by 2 mEq/L for every 10 mmHg
↓ in paCO2 below 40.
Chronic: [HCO 3 - ] ↓ by 5 mEq/L for every
10mmHg ↓ in paCO2 below 40.
11. If paCO2 ↑ and HCO3- also ↑ → then it is primary
metabolic alkalosis.
Calculate the expected paCO2
paCO2 = [0.7 × HCO3- + 21] ± 2 Or 40 + [0.7 ∆HCO3]
→ metabolic alkalosis only
paCO2 < expected paCO2 → concomitant respiratory
alkalosis.
paCO2 > expected paCO2 → concomitant respiratory
acidosis
12. Check urinary chloride
if urinary chloride < 20 → chloride responsive or ECV
depletion
if urinary chloride > 20→ chloride resistant
64
13. If pH is normal ABG may be normal or mixed
disorder
(a) ↑paCO2 and ↓HCO3- → respiratory and metabolic
acidosis
(b) ↓paCO2 and↑ HCO3- → respiratory and metabolic
alkalosis.
Calculate % difference (∆HCO 3- /HCO 3- and
∆paCO 2 /paCO 2) to see which is dominant
disorder.
References
1. Kellum JA. Making Strong Ion Difference the "Euro" for Bedside Acid-
Base Analysis. Yearbook of Intensive Care and Emergency Medicine.
Spr Ber Heid Publ 2005;5:675.
2. Phillips B, Peretz DI. Blood Gas Pre-analytical considerations.
Specimen collection, Calibration, and Controls (proposed guidelines).
In: National Committee for Clinical Laboratory Standards. NCCLS
publication. villanova PA, NCCLS; 1985.
3. Börner U, Müller H, Höge R, Hempelmann G. The influence of
anticoagulation on acid-base status and blood-gas analysis. Acta
Anaesthesiol Scand 1984;28:277-9.
4. Hutchison AS, Ralston SH, Dryburgh FJ, Small M, Fogelman I. Too
much heparin: possible source of error in blood gas analysis. Br Med J
1983;287:1131-2.
5. Toffaletti J, Ernst P, Hunt P, Abrams B. Dry electrolyte-balanced
heparinized syringes evaluated for determining ionized calcium and
other electrolytes in whole blood. Clin Chem 1991;37:1730-3.
6. Woolf CR. Letter: Arterial blood gas levels after oxygen therapy. Chest
1976;69:808-9.
7. Narins RG, Emmett M. Simple and mixed acid-base disorders: a
practical approach. Medicine 1980;59:161-87.
8. Marino PL. Arterial Blood Gas Interpretation. In; The ICU book, 2nd
edi. Lippincott, Williams and Wilkins Publishers;1998. P. 582-605.
9. Bartter TC, Abouzgheib WB, Pratter MR, Irwin RS. Respiratory
Failure- Part 1. In: Irwin and Rippe’s Intensive Care Medicine, 6th
edi. Lippincott, Williams and Wilkins Publishers; 2008. P. 485-9.
10. Rao SM, Nagendranath V. Arterial Blood Gas Monitoring: Indian J
Anaesth 2002;46:289-97.
11. Chawla LS, Shih S, Davison D, Junker C, Seneff MG. Anion gap,
anion gap corrected for albumin, base deficit and unmeasured anions
in critically ill patients: implications on the assessment of metabolic
acidosis and the diagnosis of hyperlactatemia. BMC Emerg Med
2008;8:18.
Source of Support: Nil, Conflict of Interest: None declared.
 ARTIGO 10

TIPOS DE ACESSO VASCULAR

Vascular Access
for Hemodialysis
What is a vascular access?
A
vascular access is a hemodialysis
patient’s lifeline. A vascular access
makes life-saving hemodialysis
treatments possible. Hemodialysis is a
treatment for kidney failure that uses
a machine to send the patient’s blood
through a filter, called a dialyzer, outside
the body. The access is a surgically
created vein used to remove and return
blood during hemodialysis. The blood
goes through a needle, a few ounces at a
time. The blood then travels through a
tube that takes it to the dialyzer. Inside
the dialyzer, the blood flows through thin
fibers that filter out wastes and extra fluid.
The machine returns the filtered blood
to the body through a different tube. A
vascular access lets large amounts of blood
flow continuously during hemodialysis
treatments to filter as much blood as
possible per treatment. About a pint of
blood flows through the machine every
minute. A vascular access should be in
place weeks or months before the first
hemodialysis treatment.
Two types of vascular access designed for
long-term use include the arteriovenous
(AV) fistula and the AV graft. A third type
of vascular access—the venous catheter—is
for short-term use.
What is an arteriovenous fistula?
An AV fistula is a connection, made by a
vascular surgeon, of an artery to a vein.
Arteries carry blood from the heart to the
body, while veins carry blood from the
body back to the heart. Vascular surgeons
specialize in blood vessel surgery. The
surgeon usually places an AV fistula in
the forearm or upper arm. An AV fistula
causes extra pressure and extra blood to
flow into the vein, making it grow large
and strong. The larger vein provides easy,
reliable access to blood vessels. Without
this kind of access, regular hemodialysis
sessions would not be possible. Untreated
veins cannot withstand repeated needle
insertions. They would collapse the way
a straw collapses under strong suction.
National Kidney and Urologic Diseases
Information Clearinghouse
 Health care providers recommend an AV fistula over
the other types of access because it
■ provides good blood flow for dialysis To hemodialysis From hemodialysis
machine machine
■ lasts longer than other types of access
Arterial needle Venous needle
■ is less likely to get infected or cause blood clots
than other types of access Vein

Before AV fistula surgery, the surgeon may perform

a vessel mapping test. Vessel mapping uses Doppler
ultrasound to evaluate blood vessels that the surgeon
may use to make the AV fistula. Ultrasound uses a Fistula Artery
device, called a transducer, that bounces safe, painless
sound waves off organs to create an image of their
structure. A specially trained technician performs
AV fistula in forearm
the procedure in a health care provider’s office, an
outpatient center, or a hospital. A radiologist—a
doctor who specializes in medical imaging— At the start of a hemodialysis session, a health care
interprets the images. A patient does not need provider or the patient inserts two needles into the
anesthesia. A Doppler ultrasound shows how much vascular access. One needle carries blood from
and how quickly blood flows through arteries and the body to the dialyzer. The other carries filtered
veins so the surgeon can select the best blood vessels blood back to the body. To tell the needles apart,
to use. the needle that carries blood away from the body is
called the arterial needle. The needle that carries
A surgeon performs AV fistula surgery in an
blood back to the body is called the venous needle.
outpatient center or a hospital. The vascular access
Some patients prefer to insert their own needles into
procedure may require an overnight stay in the
the vascular access, which requires training to learn
hospital; however, many patients go home afterward.
how to prevent infection and protect the vascular
A health care provider uses local anesthesia to numb
access. No matter who inserts the needles, the
the area where the surgeon creates the AV fistula.
patient should know how to take care of the needle
An AV fistula frequently requires 2 to 3 months to insertion area to prevent infection.
develop, or mature, before the patient can use it for
If an AV fistula does not mature, an AV graft is the
hemodialysis. If an AV fistula fails to mature after
second choice for a long-lasting vascular access.
surgery, a surgeon must repeat the procedure.

2
What is an arteriovenous graft?
An AV graft is a looped, plastic tube that connects
an artery to a vein. A vascular surgeon performs
AV graft surgery, much like AV fistula surgery, in an
outpatient center or a hospital. As with AV fistula
surgery, the patient may need to stay overnight in
the hospital, although many patients can go home
after the procedure. A health care provider uses
local anesthesia to numb the area where the surgeon
creates the AV graft.
A patient can usually use an AV graft 2 to 3 weeks
after the surgery. An AV graft is more likely than
an AV fistula to have problems with infection and
clotting. Repeated blood clots can block the flow of
blood through the graft. However, a well-cared-for
graft can last several years.
Artery
Looped graft
Arterial needle
Venous needle
To
hemodialysis
machine
AV graft in forearm
Set Up the Vascular Access Well
before Starting Hemodialysis
Patients should set up a vascular access well
before starting hemodialysis, as AV fistulas
and AV grafts both need time to mature before
they are ready for use. A health care provider
can help schedule an appointment with a
vascular surgeon well before the patient starts
hemodialysis, even if the patient is feeling fine.
Giving a vascular access time to mature can help
prevent problems with narrow veins, low blood
flow, and blood clots.
Before the procedure, health care providers
should use the back of the patient’s hand for
drawing blood to preserve the blood vessels in
the arm. A health care provider can teach the
patient simple exercises that help the blood
vessels grow larger for the surgeon’s use. The
same exercises help the AV fistula grow larger
Vein
after the procedure.
What is a venous catheter?
A venous catheter is a tube inserted into a vein in
the neck, chest, or leg near the groin, usually only
for short-term hemodialysis. The tube splits in two
after the tube exits the body. The two tubes have
From
hemodialysis caps designed to connect to the line that carries
machine blood to the dialyzer and the line that carries blood
from the dialyzer back to the body. A person must
close the clamps on each line when connecting and
disconnecting the catheter from the tubes.
3
 If kidney disease has progressed quickly, a patient
may not have time for placement of an AV fistula or
AV graft before starting hemodialysis treatments.
A nephrologist—a doctor who specializes in kidney
problems—or an interventional radiologist—a doctor
who uses medical imaging equipment to perform
operations—performs the venous catheter placement
procedure in a hospital or an outpatient center. The
patient receives local anesthesia and sedation to stay
calm and relaxed during the procedure.
Venous catheters are not ideal for long-term use.
With a venous catheter, a patient may develop a
blood clot, an infection, or a scarred vein, causing
the vein to narrow. However, if a patient needs to
start hemodialysis right away, a venous catheter will
work for several weeks or months until a surgeon can
perform a long-term access surgery and the AV fistula
or AV graft has time to mature.
If fistula or graft surgery is unsuccessful, then a
patient will need a long-term venous catheter access.
When a patient needs a venous catheter for more
than 3 weeks, the surgeon will “tunnel” the catheter
under the skin, rather than insert it directly into
the vein. A tunneled catheter is more comfortable
and has fewer problems. Even tunneled catheters,
however, may become infected.
Tunneled portion
of the catheter
Arterial line to
hemodialysis
machine
Venous line from
hemodialysis
machine
Tunneled venous catheter
4
What problems could a vascular
access cause?
All three types of vascular access—AV fistula,
AV graft, and venous catheter—can cause problems
that require further treatment or surgery. The most
common problems include access infection and low
blood flow due to blood clotting in the access.
Infection and low blood flow happen less frequently
in properly formed AV fistulas than in AV grafts and
venous catheters. Still, having an AV fistula does not
guarantee the access will be problem-free.
AV grafts more often develop low blood flow, an
indication of clotting or narrowing of the access. The
AV graft may then require angioplasty, a procedure
to widen the narrow part. Another option involves
surgery on the AV graft to replace the narrow part.
Venous catheters are the most likely to cause
infection and clotting problems. If these problems
develop, medication may help. Antibiotics are
medications that fight bacteria that can cause
infection. Blood thinners such as warfarin keep
blood from clotting. If these treatments fail, a
nephrologist or an interventional radiologist will
need to replace the catheter.
Arterial line
Clamps
Venous line
Caps
How does a patient care for and protect
a vascular access?
A patient can care for and protect a vascular access by
■ ensuring that the health care provider checks the
access for signs of infection or problems with
blood flow before each hemodialysis treatment,
even if the patient is inserting the needles.
■ keeping the access clean at all times.
■ using the access site only for dialysis.
■ being careful not to bump or cut the access.
■ checking the thrill in the access every day. The
thrill is the rhythmic vibration a person can feel
over the vascular access.
■ watching for and reporting signs of infection,
including redness, tenderness, or pus.
■ not letting anyone put a blood pressure cuff on
the access arm.
■ not wearing jewelry or tight clothes over the
access site.
■ not sleeping with the access arm under the head
or body.
■ not lifting heavy objects or putting pressure on
the access arm.
Eating, Diet, and Nutrition
Researchers have not found that eating, diet, and
nutrition play a role in causing or preventing
problems with a vascular access.
Read more about eating well during hemodialysis
in Eat Right to Feel Right on Hemodialysis at
www.kidney.niddk.nih.gov.
Points to Remember
■ A vascular access is a surgically created vein used
to remove and return blood during hemodialysis.
■ An arteriovenous (AV) fistula is a connection,
made by a vascular surgeon, of an artery to a
vein.
■ Health care providers recommend an AV fistula
over the other types of access because it
– provides good blood flow for dialysis
– lasts longer than other types of access
– is less likely to get infected or cause blood
clots than other types of access
■ An AV graft is a looped, plastic tube that
connects an artery to a vein.
■ A venous catheter is a tube inserted into a vein
in the neck, chest, or leg near the groin, usually
only for short-term use.
■ Venous catheters are not ideal for long-term
hemodialysis. With a venous catheter, a patient
may develop a blood clot, an infection, or a
scarred vein, causing the vein to narrow.
■ All three types of vascular access can cause
problems that require further treatment or
surgery. The most common problems include
access infection and low blood flow due to blood
clotting in the access.
5
 Hope through Research
The National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK) has many research
programs aimed at improving the treatment of
kidney failure. One research program aimed at
better understanding fistula maturation is the
Hemodialysis Fistula Maturation Study. This
multicenter study enrolled approximately 600 study
participants with newly placed fistulas to study the
influence of vascular anatomy, vascular biology,
patient factors, and process of care on the fistulas’
usefulness for maintenance hemodialysis. The
results of this study will become available in 2015.
Clinical trials are research studies involving people.
Clinical trials look at safe and effective new ways to
prevent, detect, or treat disease. Researchers also
use clinical trials to look at other aspects of care,
such as improving the quality of life for people with
chronic illnesses. To learn more about clinical trials,
why they matter, and how to participate, visit the
NIH Clinical Research Trials and You website at
www.nih.gov/health/clinicaltrials. For information
about current studies, visit www.ClinicalTrials.gov.
6
For More Information
People on hemodialysis can learn more about how
to care for an access site from their health care
provider. For a copy of the booklet Hemodialysis
Access: What You Need to Know, contact
National Kidney Foundation
30 East 33rd Street
New York, NY 10016–5337
Phone: 1–800–622–9010 or 212–889–2210
Fax: 212–689–9261
Internet: www.kidney.org
For a copy of the booklet Understanding Your
Hemodialysis Access Options, contact
American Association of Kidney Patients
2701 North Rocky Point Drive, Suite 150
Tampa, FL 33607
Phone: 1–800–749–2257 or 813–636–8100
Fax: 813–636–8122
Email: info@aakp.org
Internet: www.aakp.org
Life Options has developed an interactive
patient education website called Kidney School.
Module 8 of this program addresses vascular access
for hemodialysis. To view this module, go to
www.kidneyschool.org or contact
Life Options
c/o Medical Education Institute, Inc.
414 D’Onofrio Drive, Suite 200
Madison, WI 53719
Phone: 1–800–468–7777 or 608–833–8033
Fax: 608–833–8366
Internet: www.lifeoptions.org
The Centers for Medicare & Medicaid Services,
the End-stage Renal Disease Networks, and the
Institute for Healthcare Improvement launched
the National Vascular Access Improvement
Initiative in 2003. Materials from the Fistula
First Change Package are available by contacting
Fistula First Breakthrough Initiative
IPRO ESRD Network Coordinating Center
1979 Marcus Avenue, Suite 105
Lake Success, NY 11042
Phone: 516–209–5306
Fax: 516–326–7805
Email: FFBI@ncc.esrd.net
Internet: www.fistulafirst.org
Acknowledgments
Publications produced by the Clearinghouse are
carefully reviewed by both NIDDK scientists and
outside experts. This publication was reviewed
by Michael Allon, M.D., University of Alabama
at Birmingham.
About the Kidney Failure Series
The NIDDK Kidney Failure Series includes booklets
and fact sheets that can help the reader learn
more about treatment methods for kidney failure,
complications of dialysis, financial help for the
treatment of kidney failure, and eating right on
hemodialysis. Free single printed copies of this series
can be obtained by contacting the National Kidney
and Urologic Diseases Information Clearinghouse.
National Kidney Disease
Education Program
3 Kidney Information Way
Bethesda, MD 20892
Phone: 1–866–4–KIDNEY (1–866–454–3639)
TTY: 1–866–569–1162
Fax: 301–402–8182
Email: nkdep@info.niddk.nih.gov
Internet: www.nkdep.nih.gov
The National Kidney Disease Education Program
(NKDEP) is an initiative of the National Institute
of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, U.S. Department of
Health and Human Services. The NKDEP aims to
raise awareness of the seriousness of kidney disease,
the importance of testing those at high risk, and the
availability of treatment to prevent or slow kidney
disease.
7
National Kidney and Urologic
Diseases Information Clearinghouse
3 Information Way
Bethesda, MD 20892–3580
Phone: 1–800–891–5390
TTY: 1–866–569–1162
Fax: 703–738–4929
Email: nkudic@info.niddk.nih.gov
Internet: www.kidney.niddk.nih.gov
The National Kidney and Urologic Diseases
Information Clearinghouse (NKUDIC) is a
service of the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK).
The NIDDK is part of the National Institutes
of Health of the U.S. Department of Health
and Human Services. Established in 1987,
the Clearinghouse provides information
about diseases of the kidneys and urologic
system to people with kidney and urologic
disorders and to their families, health care
professionals, and the public. The NKUDIC
answers inquiries, develops and distributes
publications, and works closely with
professional and patient organizations and
Government agencies to coordinate resources
about kidney and urologic diseases.

This publication is not copyrighted. The Clearinghouse

encourages users of this publication to duplicate and
distribute as many copies as desired.
This publication is available at
www.kidney.niddk.nih.gov.

You may also find additional information about this

topic by visiting MedlinePlus at www.medlineplus.gov.
This publication may contain information about
medications and, when taken as prescribed,
the conditions they treat. When prepared, this
publication included the most current information
available. For updates or for questions about
any medications, contact the U.S. Food and Drug
Administration toll-free at 1–888–INFO–FDA
(1–888–463–6332) or visit www.fda.gov. Consult
your health care provider for more information.

NIH Publication No. 14–4554

May 2014

The NIDDK prints on recycled paper with bio-based ink.

 ARTIGO 11

HEMODIÁLISE
DOI: 10.1111/sdi.12671

DIALYSIS EDUCATION:
ISSUES, INNOVATIONS AND IMPACT
Guest Editors: Bernard G. Jaar and Michael J. Choi

What the non-nephrologist needs to know about dialysis

Matt Foy1 | C. John Sperati2

1
Division of Nephrology, Department of
Medicine, Louisiana State University Health
Science Center, Baton Rouge, LA, USA
2
Division of Nephrology, Department of
Medicine, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
Correspondence
C. John Sperati, MD, MHS, Johns Hopkins
University School of Medicine, Baltimore,
MD, USA.
Email: jsperati@jhmi.edu
Abstract
The End-Stage Renal Disease (ESRD) program now serves approximately 675,000
individuals in the United States at a cost of $26.1 billion to the Medicare system.
Given the size of this population, healthcare providers from all disciplines will deliver
care to patients on dialysis. Mortality remains high among patients on chronic dialy-
sis, with 42.3% surviving 5 years. As this is a vulnerable population, it is important
in the care of ESRD patients that non-nephrologists have a working knowledge of
issues germane to dialysis. This review examines the physiology, mechanics, compli-
cations, and care delivery concerns of kidney dialysis modalities relevant to the non-
nephrologist. The majority of patients receive in-center hemodialysis thrice weekly,
with a small proportion on home-based therapies such as peritoneal dialysis or
home hemodialysis. Inpatients may undergo hemodialysis or peritoneal dialysis, and
in critically ill patients, continuous renal replacement therapies are utilized. Practical
aspects of each of these modalities are discussed.

Since the inception of the Medicare End-stage Renal Disease (ESRD)
program in 1972, the number of patients on dialysis has grown stea-
dily. The prevalence of ESRD in the United States in 2014 was approxi-
mately 675,000 patients, with close to 63% of these patients receiving
hemodialysis (HD). The annual cost for HD in the United States
approximates $87,500 per patient, with a total cost to Medicare of
$26.1 billion.1 As healthcare providers of all disciplines will encounter
ESRD patients, the purpose of this study was to orient non-nephrolo-
gists to dialysis therapies and the issues relevant to their delivery.
Though dialysis is considered a fairly commonplace procedure
today, the beginnings of the therapy started a little more than
100 years ago. In 1912, John Jacob Abel experimented with a “vividif-
fusion” apparatus in animals, with some degree of success.2 Clinical
HD in humans began in 1943 under the work of Dr. Willem Kolff.3
Though with limited success initially, the information gained from
these early HD treatments helped pave the way for future exploration
of the artificial kidney. The first repeated hemodialysis treatments for
chronic kidney failure began at the University of Washington Hospital
in Seattle in 1960.4 Remarkably, this first patient lived another
11 years on HD before dying of a myocardial infarction. Early imple-
mentation of peritoneal dialysis (PD) began in the early 1960s as well.5
Perhaps one of the greatest concerns on how to safely conduct
HD centered on the permanent dialysis access. In 1960, Belding
Scribner and Wayne Quinton devised an external device using
Teflon tubing that could reliably be used for repeated HD access,
effectively becoming the first arteriovenous graft.4,6 Hemodialysis
became more available through development of procedures to create
arteriovenous fistulae, leading to a more permanent and longer last-
ing HD access.7 As HD use continued to grow in safety and applica-
bility, its implementation faced challenges regarding who would
receive this precious resource.4,6 Access to this therapy changed
immensely with passage of the Medicare ESRD Act.8,9
Overall, survival trends on dialysis have improved over the past
15 years, although the adjusted 5-year survival for patients initiating
all forms of dialysis in 2009 was 42.3%.1 The incidence of ESRD in
black patients is 3.1 times higher than Caucasians. Discrepancy in sur-
vival on HD exists based on ethnicity with older black patients with
ESRD having a lower mortality compared to white patients, with one
study noting a higher mortality in black patients with ESRD under the
age of 50.10 In another study, an even more pronounced discrepancy
in survival in young black patients of lower socio-economic status was
demonstrated (65% higher risk of death compared to whites, 95% CI,

Seminars in Dialysis. 2018;1–10. wileyonlinelibrary.com/journal/sdi © 2018 Wiley Periodicals, Inc. | 1

2 |
1.38-1.97).11 Additionally, survival differences between men and
women exist, with men having a slightly higher adjusted mortality
compared to women across all age groups (1.09, 95% CI 1.04-1.14).12
1 | INTERMITTENT HEMODIALYSIS
1.1 | Indications
Even though dialysis technology has evolved over the years, the indi-
cations for initiating renal replacement therapy (RRT) have remained
largely constant (Table 1).13 On the most fundamental level, treatment
is meant to replicate essential functions of the kidney, including elimi-
nation of waste and clearance of small solutes from the bloodstream,
removal of excess body volume, and maintenance of blood pH.14 Addi-
tionally, HD is useful in removing certain toxic ingestions. Timing of
dialysis is patient-dependent, but data suggest that in the setting of
chronic kidney disease (CKD), there does not appear to be a benefit to
starting dialysis early as compared to waiting for an indication for dial-
ysis initiation.15,16 The IDEAL study randomized adult patients with
CKD to start dialysis at an estimated glomerular filtration rate (eGFR)
of 10-14 mL/min/1.73 m2 or an eGFR of 5-7 mL/min/1.73 m2. Fol-
lowing randomization, the delayed start group initiated dialysis
approximately 6 months later than the early start group, with no dif-
ference in mortality or adverse events between the two.15
1.2 | Physiologic principles
As noted above, HD is designed to replace some of the normal
physiology of the kidney. Blood is removed from the patient and fil-
tered through a dialyzer consisting of over 10,000 small hollow
fibers constructed of a semipermeable membrane. These fibers have
small pores to facilitate exchange of substances between the blood
and dialysis fluid compartment that bathes the fibers and allows the
necessary solute and fluid exchange to occur.
1.3 | Volume removal
Retention of excess total body volume is one of the hallmarks of
advancing CKD. Unwanted body water is removed by applying a
T A B L E 1 Indications for HD initiation
Indication Description
Acidosis Sustained severe metabolic acidosis refractory to
medical therapy. Typically pH <7.1
Electrolyte Sustained moderate to severe hyperkalemia despite
disturbance medical therapy and dietary modifications.
Ingestion Dialyzable substances. Typically acute intoxication
of salicylates, alcohols (ie, methanol and ethylene
glycol), and lithium.
Volume overload Persistent excess total body volume impacting
pulmonary or cardiac function despite optimal
diuretic use.
Uremia Protein-calorie malnutrition, persistent nausea,
confusion, uremic pericarditis, or uremic bleeding.
FOY AND SPERATI
negative pressure to the dialysis membrane, which subsequently
pulls off plasma water, or effluent, from the patient via ultrafiltra-
tion.17 It is worth noting that the fluid removed is not pure water,
but rather contains similar concentrations of solutes present within
plasma that are capable of passing through the small pores of the
dialysis membrane. The amount removed is selected through volu-
metric controls on the dialysis machine. Selecting the amount of vol-
ume for removal is patient-dependent, and typically is determined by
the patient’s estimated euvolemic weight (or “dry weight”), as well as
how much volume can be removed in a single dialysis session with-
out leading to complications such as cramping or hypotension
(Table 2). A patient’s interdialytic weight gain determines how much
volume to remove in an individual session. For example, if a patient’s
previous postdialysis session weight was 70 kg, and the current pre-
dialysis weight is 73 kg, then the ultrafiltration goal for the HD ses-
sion will be 3 L since 1 L of water is 1 kg. Hypotension should
prompt re-evaluation of UF goals, prescribed dry weight, use of pre-
dialysis antihypertensive medications, infection, cardiac dysfunction,
the presence of pericardial effusion, and adrenal insufficiency. In
select patients, the use of midodrine, an a agonist, may be benefi-
cial.18 Albumin administered shortly before HD can sometimes facili-
tate ultrafiltration in the hospitalized, hypotensive, volume-
overloaded patient, although its use is largely nonevidence-based.
1.4 | Solute clearance
Maintenance of small molecule homeostasis, such as potassium, cal-
cium, and phosphorous balance, is an essential component of normal
renal function. With the loss of renal function, the kidney’s capacity
T A B L E 2 Complications of renal replacement therapy
Hemodialysis
Hypotension
Muscle cramping
Arrhythmia
Hemolysis
Air embolus
Thrombosis of filter and/or vascular access
Infection of the bloodstream and/or vascular access
Vascular steal in patients with AVF/AVG
Aneurysm or pseudoaneurysm of AVF/AVG
Heparin-induced thrombocytopenia
Removal of water-soluble vitamins
Continuous venovenous therapies
Air embolus
Thrombosis of filter and/or vascular access
Infection of the bloodstream and/or vascular access
Thrombocytopenia
Hypophosphatemia
Peritoneal dialysis
Peritonitis
Hyperglycemia
Bowel obstruction
Abdominal wall and inguinal hernias
Pleural effusion
FOY AND SPERATI
to maintain normal levels of these substances is diminished. During
HD, exchange of these small molecules occurs through pores within
the dialysis membrane by diffusion. Given the technical differences
between dialysis and ultrafiltration, patients can undergo solute clear-
ance, volume removal, or both simultaneously. Though dialysis gener-
ally results in removal of small molecules (such as potassium and
phosphorous) from the patient, the movement is bidirectional and can
include the movement of other small molecules (such as calcium and
19
bicarbonate) from the dialysis fluid into the patient’s bloodstream.
Middle molecular weight and larger sized protein-bound mole-
cules in the bloodstream do not easily cross the dialysis membrane.
These substances are removed from the blood in a time-dependent
fashion which is augmented through the process of convection, also
known as solvent drag.20,21 In convective removal, larger molecules
are pulled across the membrane as water is removed through ultrafil-
tration. It is important to recognize that dialysis does not selectively
clear the bloodstream of uremic toxins over more beneficial sub-
stances, such as water-soluble B vitamins. The concept of convec-
tion is reviewed in Figure 1.
1.5 | The dialyzer and dialysate
Blood is driven through the dialysis circuit using rotary pumps. Along
the course of the circuit are sensors to detect dialysis access
K+
K+
K+
K+
K+
K+
K+
K+
F I G U R E 1 Principles in hemodialysis. Diffusion: small molecules
(K) move from the patient’s blood (PB) through pores in the dialysis
membrane (DM) into the dialysis fluid (DF). Ultrafiltration: water
molecules move via generation of negative pressure on the dialysate
side of the DM. As the water moves across the DM, middle-sized
molecules are pulled via convection (solvent drag)
| 3
pressures, pumps to inject heparin to prevent access clotting, and air
detectors which can clamp the circuit and stop blood flow when air
in the circuit is detected. Modern dialyzers are made of synthetic
biocompatible material such as polysulfone; older more immunogenic
filters of substituted cellulose are now rarely employed.22 Most dia-
lyzers in use today are considered high efficiency (large surface area)
and many are high flux (larger sized pores) to improve clearance dur-
ing the dialysis treatment.23 Dialyzers are available in varying sizes
with different surface areas for exchange. While patient body sur-
face area and treatment duration are considered in the dialysis pre-
scription, there tends to be little variation in the size of the dialysis
membrane selected.
The water used to make the dialysate must undergo an extensive
purification process with charcoal filtration, de-ionization, and
reverse osmosis.24 Failure of the water purification system may
result in patient exposure to aluminum, fluoride, chloramine, copper,
and lead, which can lead to acute hemolysis or long-term toxicity
such as dementia and osteomalacia (Table 2). Dialysate does not
have to be completely sterile in order to be used for a dialysis treat-
ment because the dialysis membrane acts as a barrier to bacteria. If
endotoxin is present within the dialysis fluid, pyrogenic reactions
may occur.25
Once the water meets standards for use in a dialysis treatment,
adjustments are made to the dialysis bath to achieve the desired
concentrations of sodium, bicarbonate, potassium, and calcium.26
Typically, the concentrations in the dialysate fluid approximate nor-
mal serum concentrations, although adjustments are made based on
patient needs. For example, if a patient has hyperkalemia of 6 mEq/
L, a 1 or 2 mEq/L potassium bath is selected to achieve a normal
postdialysis serum potassium concentration. It is worth noting that
when patients present with profound electrolyte derangements (ie,
severe hyponatremia or severe hyperkalemia), careful consideration
should be given to selection of dialysis fluid electrolytes to avoid
overly rapid correction.
1.6 | HD access and complications
Given the technical components of HD, functional access to the
patient’s bloodstream is essential to long-term success. Three forms
of dialysis access predominate as follows: arteriovenous fistula
(AVF), arteriovenous graft (AVG), and a dual lumen dialysis catheter.
Though the least preferred access long-term, a dual lumen dialysis
catheter is often necessary in the setting of acute kidney injury
when no other access exists, or if an existing arteriovenous access is
not ready for use. Dialysis catheters may be tunneled or nontun-
neled.
Though the nontunneled dialysis catheters may be faster and
easier to place, they are associated with greater rates of infection
compared to tunneled catheters.27 Any long-term central vein dialy-
sis catheter is associated with increased risk of acute infection,
which in turn can lead to complications such as endocarditis. Surveil-
lance data from US HD centers in 2014 demonstrated an 8.3-fold
higher rate of blood stream infection with a central vein dialysis
4 |
catheter compared to an AVF.28 Dialysis catheter infections can be
challenging to eradicate without its removal. Consideration for
prompt removal of an infected dialysis catheter should be given to
unstable patients with a suspected catheter infection.29 Additional
concerns and complications from dialysis catheters include injury to
surrounding anatomic structures during insertion (eg, arterial cannu-
lation and pneumothorax), low blood flow rates with subsequent
inadequate clearance, and clotting.
The AVF is the preferred modality for long-term HD access, as it
has the greatest longevity and lowest complication rates. It is cre-
ated surgically via ligation of a vein with anastomosis to an artery,
preferably in the distal forearm (a radial-cephalic anastomosis),
though more proximal vessels may be selected (a brachial-cephalic
30
anastomosis or brachial-basilic anastomosis). Generally, the non-
dominant arm is selected, and patients with CKD are advised to pro-
tect this arm from venipuncture and blood pressure checks to
preserve integrity of the blood vessels for future access use. It is
incumbent on all healthcare providers to preserve future HD access
sites in patients with CKD, especially in the acute care and hospital
setting. In general, peripherally inserted central catheters and subcla-
vian catheters should be avoided in patients with CKD.31
Because the AVF must undergo maturation prior to use, referral
for access placement should occur in a timely fashion, though efforts
should be made to avoid unnecessary access placement. Generally
speaking, ideal timing for referral occurs within 6-12 months of
anticipated need for HD in a patient with CKD, as the AVF typically
requires 8-12 weeks to mature.31,32 The most common complication
from an AVF is failure for the access site to adequately develop, typ-
ically due to proximal venous stenosis, insufficient arterial flow, or
30
collateral venous side branches. Additional complications associ-
ated with the AVF may include edema in the access arm, aneurysmal
dilation of the vein, arterial steal phenomenon with distal ischemia,
and bleeding from the access site. Unprovoked access bleeding (ie,
unrelated to recent cannulation or occurring after post-HD hemosta-
sis has been achieved) or breakdown of skin over the fistula war-
rants prompt medical evaluation, as it may herald a more significant
impending hemorrhage.33,34 Though not emergent, suspected clot-
ting of an AVF, demonstrated by a diminished or absent thrill and
bruit, pulsatile access, or prolonged postdecannulation bleeding, also
warrants prompt surgical evaluation to restore access flow and main-
tain patency.30
If an AVF cannot be created, AVG placement is generally the
next best choice for long-term hemodialysis access.31 The AVG typi-
cally consists of polytetrafluorethylene (PTFE) and most commonly
involves anastomosis of the brachial artery and basilic vein.30 One
benefit of an AVG over an AVF is that it can be used for HD much
sooner, typically within 2 weeks of placement.31 Because the AVG is
constructed of synthetic material, rates of stenosis, thrombosis, and
infection are higher than an AVF.30 Like AVF, prolonged or unpro-
voked bleeding from an AVG warrants prompt surgical investigation,
especially if associated with aneurysmal dilation or skin breakdown,
as there may be little separating high vascular flow from the outside
world beyond a thin layer of skin or an eschar. Also like AVF, the
FOY AND SPERATI
AVG may be associated with edema of the access arm and distal
steal phenomenon. Long-term patency rates are lower for AVGs
than AVFs, with most AVG having primary patency rates (ie, without
intervention to maintain function) of under 18 months.35
HD is a remarkably well-tolerated procedure, although the previ-
ously described hemodynamic, vascular, and dialysate complications
are of concern. In addition, equipment failures and inappropriate
dialysis prescriptions may contribute to morbidity and potentially
mortality (Table 2).36 The greatest concern with dialysis initiation is
dialysis disequilibrium syndrome (DES). DES results from rapid solute
shifts and pH changes from overly aggressive dialysis initiation,
resulting in nausea, vomiting, headache, confusion, seizure, and pos-
sibly death.37 In addition, cerebral edema is more likely to occur in
patients undergoing HD within the first 24 hours of stroke or cere-
bral hemorrhage. As such, the first 3 dialysis sessions are performed
at slower blood flows rate and for less time, and neurologically
unstable patients should be considered for continuous renal replace-
ment therapy (CRRT). Anaphylactic “Type A” dialyzer reactions have
essentially been eliminated with the use of biocompatible mem-
branes and avoidance of ethylene oxide for sterilization, although
lesser “Type B” reactions such as back pain may occur on occasion
30 or more minutes into treatment. Symptomatic management is
sufficient for Type B reactions.
Mechanical failure of the dialysis machine may result in air
embolism or injury to the AV access; filter thrombosis may require
the use of anticoagulation. The prevalence of antibodies to platelet
factor 4 is increased in HD patients, although uncertainty remains
regarding the risk for clinically relevant heparin-induced thrombocy-
topenia.38 It is important to remember that heparin is often placed
into the lumen of central venous catheters to maintain patency.
1.7 | Dialysis dose adequacy
The dialysis prescription should provide for adequate uremic solute
removal. It is typically assessed by evaluating the kinetics of urea, a
“marker” solute. It is quantified by two measurements in patients on
dialysis: Kt/V and the closely related urea reduction ratio (URR).39
Kt/V is a unit-less measurement determined by (1) K, the clearance
of urea (mL/min) during a dialysis treatment; (2) t, the time (min) of
the treatment; and (3) V, the volume of distribution of urea (mL),
which is approximately the total body water. URR is the fractional
reduction in the blood urea during a single dialysis treatment
[URR = 1 ! (postdialysis BUN/predialysis BUN)]. Kt/V is the pre-
ferred method for assessing dialysis adequacy.
Though a number of factors can affect Kt/V, such as blood flow
rate, dialysate flow rate, and the size of the dialysis membrane, the
most easily modifiable variable to achieve adequate dialysis is the
time spent on treatment.
The minimum Kt/V was established by the HEMO trial.40 In this
study, patients were randomized to the either a lower clearance
group with single treatment Kt/V 1.2 or a higher clearance group
with single treatment Kt/V 1.65. At a mean of 2.8 years of follow-
up, there was no difference in overall patient mortality or
FOY AND SPERATI | 5

hospitalization rates. Current Kidney Disease Improving Global Out-
comes (KDIGO) guidelines recommend a single treatment Kt/V
greater than 1.2 and a URR greater than 65%.16,39 Despite these
recommendations, consideration of adequate clearance should still
be given on a case-by-case basis, taking into account patient residual
renal function, uremic symptoms, nutrition markers, and overall func-
tional status.
1.8 | Dialysis delivery
Outpatient HD predominantly occurs within a dialysis treatment facil-
ity, though home HD treatments have grown in popularity in recent
years, with 2.5-fold higher use of home HD in 2014 compared to
1
2000. In-center HD typically consists of thrice weekly treatments
lasting 3.5-4.5 hours, though alternative options such as extended
HD treatments and in-center nocturnal dialysis are also available in
some settings. With home HD, patients may opt for thrice weekly,
longer, or more frequent treatments. To perform home HD, patients
must be trained in self-cannulation of their dialysis access and the
basic functions of the dialysis machine. Selection of in-center versus
home HD is dependent on regional availability, patient home support,
functional status, and patient preference.16 While interest is growing
in home HD, rigorous outcome data comparing home HD to more
traditional RRT modalities do not exist. In the Frequent Hemodialysis
Network Nocturnal Trial, participants were randomized to thrice
weekly in-center HD versus 6 nights a week home nocturnal HD.41
This failed to demonstrate a survival difference but was limited by
lack of power; patients receiving frequent HD, however, have
reported a better health-related quality of life.42
abdominal surgeries or uncorrected hernias may preclude PD, and
the inherent biologic properties of the peritoneal membrane may
render some patients less suitable for this modality.
PD catheters are tunneled from an entry point from either below
the beltline or the presternal region and are coiled internally in the pel-
vis (Figure 2). Ideally, one should wait 2-4 weeks before instilling dialy-
sate to minimize leaks at the insertion site.46 Fundamentally, PD utilizes
the parietal peritoneum as a biological filter to exchange solute and
fluid. Solute exchange is described according to the 3-pore model, in
which ultrasmall pores (aquaporin-1) mediate water flux along osmotic
gradients, small pores (40-60 !
A) transport readily dialyzable molecules
such as sodium and urea, and large pores (100-200 !
A) are responsible
for movement of macromolecules such as b-2 microglobulin.47 As the
biology of the peritoneum differs for each patient, so does the length of
time the dialysate must dwell to allow for efficient and effective dialy-
sis. A peritoneal equilibration test (PET) is performed to categorize
patients as low, low average, high average, or high transporters.
Most patients perform automated peritoneal dialysis (APD) utiliz-
ing a cycler, in which a machine (Figure 3) performs approximately
4-6 exchanges of 1.5-3 L of dialysate while the patient is sleeping.
Variations on the mode of delivery allow PD to be individualized to

2 | CONTINUOUS RENAL REPLACEMENT

THERAPY

2.1 | Peritoneal dialysis

There exist several forms of continuous renal replacement therapy
(CRRT), of which peritoneal dialysis (PD) is the only modality appro-
priate for outpatient management of ESRD. PD was also the CRRT
modality for unstable hospitalized patients with acute kidney injury F I G U R E 2 AP abdominal radiograph of a patient on peritoneal
dialysis. The tip (arrow) of the catheter is coiled in the pelvic cavity
until the introduction of continuous arteriovenous (CAV) therapy in
the 1980s. While there is a growing interest again in the use of
urgent-start PD for hospitalized patients, virtually all hemodynami-
cally unstable inpatients in the United States are currently managed
with continuous venovenous (CVV) therapy.43 PD is often continued
for hospitalized ESRD patients already on this modality, although
strong consideration should be given to the use of CVV in such
patients who are critically ill in the ICU.44,45
PD offers several advantages over in-center HD: (1) patients
have greater control over their therapy, (2) dialysis is performed on a
daily basis, (3) volume shifts are less as compared to thrice weekly
HD and as such potentially better tolerated in the setting of signifi-
cant cardiovascular disease, and (4) it is bloodless. At the same time,
successful PD requires a motivated, attentive patient. Prior intra- FIGURE 3 Automated peritoneal dialysis cycler with dialysate
6 | FOY AND SPERATI

T A B L E 3 Peritoneal dialysis modalities

Abbreviation Modality Description Comments
Automated PD (APD)
NIPD Nocturnal intermittent PD Machine performs automated exchanges Minimizes disruption to patient’s schedule while awake.
over 8-10 hr while patient is sleeping Best for “high transporters,” but may not achieve
adequate clearance of unmeasured “middle molecules.”
CCPD Continuous cycling PD At the conclusion of nocturnal cycling, the Convenience of nocturnal exchanges with the addition
machine leaves a “last fill” in the of at least 1 longer daytime exchange to augment
peritoneal cavity. The patient may or may middle molecule clearance. Fewer nocturnal exchanges
not manually drain the effluent prior to with longer daytime dwells are better suited to slower
the next night’s cycling. transporters.
Manual
CAPD Continuous ambulatory PD Patient performs multiple manual Provides best clearance for low transporters but
exchanges during waking hours. requires significant time commitment from patients.

the needs of the patient (Table 3). Ultrafiltration is achieved by the
osmosis of water along osmotic gradients established by the dex-
trose concentration of dialysate. Patients adjust their ultrafiltration
goal based on their weight and will typically refer to the dextrose
concentration by color—yellow (1.5%), green (2.5%), and red
(4.25%). The use of 4.25% dextrose will result in larger and more
sustained ultrafiltration, although frequent use leads to sclerosis and
failure of the peritoneal membrane over time. Less commonly,
icodextrin rather than dextrose-based dialysate will be utilized; it can
falsely elevate blood glucose values with certain glucometers.48,49
This effect may persist for 2 weeks after the discontinuation of
icodextrin-based PD.
Importantly, residual renal function (urine output > 100 mL/day)
is critical for achieving adequate solute and fluid clearance in
patients on PD and is associated with lower mortality.50,51 Renin-
angiotensin-aldosterone system antagonists, commonly prescribed,
may help slow the loss of residual renal function. Potential nephro-
toxins such as NSAIDs and iodinated intravenous contrast should be
avoided when possible.52,53
PD is associated with several potential complications. Hyper-
glycemia from the high dextrose content (2.5% exchange =2500 mg/
dL dextrose) of the dialysate may worsen or induce diabetes mellitus.
Transient dysfunction of the catheter is common, often due to intralu-
minal fibrin or patient constipation. Abdominal hernias develop at a
rate of 0.04-0.08 hernias/patient/year and are more common in
patients utilizing larger dwell volumes or performing ambulatory PD
while upright.54,55 In patients in whom the PD catheter may have been
internally sutured, bowel obstruction due to an internal hernia may
develop, requiring a high index of suspicion and, at times, laparoscopic
evaluation for diagnosis.
Exit site infections and peritonitis are worrisome complications.
When performed with optimal technique, PD peritonitis rates should
be <0.39 per patient year.56 Abdominal pain and/or cloudy effluent
should prompt evaluation for peritonitis.57 The catheter can often be
preserved, at least initially, with exit site infections and most cases
of peritonitis. Fungal peritonitis is one indication for which the PD
catheter should almost universally be removed.
In 1-2% of patients, hydrothorax may develop due to transuda-
tion of dialysate through pleuroperitoneal connections.58 In such
cases, the glucose concentration in the pleural fluid should approach
that of the dialysate, and technetium-99 m scintigraphy may aid in
diagnosis. Lastly, patients should avoid submerging the catheter in a
bath or swimming in freshwater. Swimming in the ocean or a chlori-
nated pool is possible, although should be done with the approval of
the PD program.
2.2 | Continuous venovenous therapy
In critically ill patients requiring renal replacement therapy, CVV
therapies are the modality of choice. By design, CVV therapies run
at slower blood and dialysate flow rates to permit slower solute
clearance with less destabilizing effects on patient hemodynamics.
As shown in Table 4, dialysate flow rates with continuous venove-
nous hemodialysis (CVVHD) may be 20-fold slower than typically
prescribed in intermittent HD. CVVHD requires approximately
24 hours of therapy to approach the small solute clearance achieved
in 3-4 hours with intermittent HD. CVV therapies are particularly
well-suited for patients with unstable hemodynamics, increased
intracranial pressure, severe hypo- or hypernatremia, acute liver fail-
ure, and poisonings with dialyzable substances that possess a large
volume of distribution. CVV therapies require the use of a central
venous catheter, and while a small report describes successful use of
AVF/AVG for CVV delivery, it can lead to significant access compli-
cations.59 Of note, in patients currently undergoing extracorporeal
membrane oxygenation (ECMO), the CVV machine can be placed in
series such that a separate vascular access is not required.
There exist several variations on CVV therapy. With CVVHD,
clearance is achieved by the diffusion of solutes between blood and
dialysate across the semipermeable filter. In contrast, continuous
venovenous hemofiltration (CVVH) does not utilize dialysate, but
rather achieves solute clearance by ultrafiltration of large volumes of
plasma (500-5000 mL/h) with simultaneous administration of physio-
logically balanced replacement fluid to maintain fluid balance. Solute
clearance is achieved through convection, or “solvent drag,” across
FOY AND SPERATI
T A B L E 4 Continuous hemodialysis modalities
Blood flow
Abbreviation Modality (mL/min)
CVVHD Continuous venovenous hemodialysis 200-300
CVVH Continuous venovenous hemofiltration 200-300
CVVHDF Continuous venovenous hemodiafiltration 200-300
SCUF Slow continuous ultrafiltration 200-300
SLED Slow low-efficiency hemodialysis 200-300
a
Typical dialysate rates are shown. Maximum rates vary by machine and clinical indication.
b
Typical prescription is 20-25 mL/kg/h. In CVVHDF, the total rate will be split between the dialysate and hemofiltration rates.
the filter. Both modalities may be combined to provide hemodiafil-
tration (CVVHDF). No data support a meaningful difference in out-
come across the different therapies.60
In all modalities, the sodium, potassium, and calcium within the
dialysate/replacement fluid can be altered to meet the clinical need.
In light of the slower blood flow rates characteristic of CVV thera-
pies, catheter and filter clotting are frequent complications. To
reduce clotting, intravenous heparin is often used. As many critically
ill patients are not candidates for systemic heparin therapy, alterna-
tive interventions may be required. Frequent replacement of filters
and catheters, utilizing blood flows ≥300 mL/min, and the use of
citrate anticoagulation can be helpful interventions. Regional citrate
anticoagulation entails the prefilter administration of citrate followed
by chelation and inactivation by postfilter administration of intra-
venous calcium. While this approach minimizes the risk for systemic
anticoagulation and bleeding, it requires constant attention to avoid
61
citrate toxicity as well as hypo- or hypercalcemia. The use of regio-
nal citrate anticoagulation is limited by the need for specialty solu-
tions, complex protocols, and lack of familiarity at many institutions
among nurses and nephrologists.62
Slow continuous ultrafiltration (SCUF) or continuous venovenous
ultrafiltration (CVVU) is utilized for management of refractory volume
overload. As dialysate is not utilized and hourly UF rates are slower
than with CVVH, this results primarily in volume removal without
appreciable convective clearance. In a randomized controlled trial
comparing isolated UF to diuretics in the management of decompen-
sated congestive heart failure, isolated UF led to a higher creatinine
and similar weight loss.63 Thus, while isolated UF (and specifically
SCUF in patients hemodynamically inappropriate for intermittent ther-
apy) has a role in the management of volume overload that has failed
maximal medical therapy, it is inappropriate as initial therapy.
Importantly, CVV therapies are typically monitored by an ICU
nurse, and as such, permit simultaneous delivery of RRT to more
patients than could otherwise be accomplished with a limited dialysis
nursing staff. This requires appropriate training of critical care nurs-
ing staff and may impose limitations on nurse:patient ratios. An alter-
native is slow low-efficiency hemodialysis (SLED), in which a dialysis
nurse performs a 6-8 hour dialysis session at blood and dialysate
flows intermediate between CVVHD and intermittent HD. This is an
emerging arena within renal replacement therapy with multiple
implementations, sometimes referred to as prolonged intermittent
| 7
Ultra/
Dialysate hemofiltration
ratea,b (mL/h) rate (mL/h) Dialysis staff Nursing staff
1000-5000 Variable + +++
n/a 1000-5000b + +++
b
1000-5000 1000-5000b + +++
n/a Variable + +++
1000-2000 Variable ++++ +
renal replacement therapy (PIRRT).64 These modalities require less
critical care nursing resources but limit the number of dialysis treat-
ments that can be provided on a daily basis.
Hypophosphatemia develops in many patients and requires sup-
plementation or dialysis dose reduction. Thrombocytopenia presum-
ably due to platelet-filter interactions may also be seen.65
3 | OUTCOME DATA
According to 2016 United States Renal Data System data, the unad-
justed 5-year survival rate of ESRD patients who initiated therapy
on intermittent HD was 41.6% and 51.5% for patients on PD.1 It is
unclear if PD or HD offers a relative survival advantage, but in prop-
erly selected candidates, the mortality rate appears similar between
the modalities out to 5 years.56
In critically ill patients, there is no compelling evidence that CVV
therapy versus intermittent HD impacts mortality or regain of renal
function, provided the patient is hemodynamically appropriate for
the selected modality.66 Based on several randomized clinical trials,
the dialysate rate in CVVHD or ultrafiltration rate in CVVH for
patients with AKI is generally prescribed at 20-25 mL/kg/h, with
additional adjustments based on clinical circumstances.67-70 In criti-
cally ill patients receiving intermittent HD, thrice weekly HD was
associated with similar outcomes compared to a more intensive
treatment strategy.67 A common problem with CVV therapy is treat-
ment interruption for medical procedures or system clotting. As
such, the prescriber must be attentive to the cumulative “down-
time” and adjust the prescription as needed to ensure adequate
solute/fluid clearance. For critically ill patients with AKI, the optimal
timing of dialysis initiation is unknown; a delayed initiation strategy
(ie, awaiting an indication for dialysis) may be as beneficial in regard
to mortality as an early start strategy.71 For AKI patients treated by
intermittent HD, a typical prescription is 9-12 hours per week, often
delivered over 3-4 sessions.
4 | MEDICATION DOSING
Appropriate dose adjustment for medications administered to
patients on dialysis is understudied and of significant importance to
8 |
clinical outcomes and patient safety. For many medications, guideli-
nes for dosing on intermittent HD are often available, although not
always rigorously derived. For example, the package insert for apixa-
ban does not recommend dose reduction for most patients on dialy-
sis, a recommendation provided by a study of 8 patients receiving a
dose lower than the prescribing instructions.72,73 A postmarketing
study, however, has revealed significant drug accumulation at recom-
mended doses, suggesting the dose on intermittent HD should
potentially be 50% less.74
For CRRT, dose adjustments are often not available. In the absence
of guidelines, medications in patients on CVV therapies are often
dosed for a creatinine clearance equivalent to the dialysate (CVVHD)
or ultrafiltration (CVVH) rate. For example, at a dialysate flow rate of
2000 mL/h on CVVHD, medications are often dosed for a creatinine
clearance of approximately 30 mL/min (2000 mL/h " 60 min/
h = 33 mL/min). This assumes the medication is freely dialyzable, an
assumption that may not be accurate. As such, when possible, drug
levels should be followed and doses adjusted accordingly. Significant
potential exists for both over and under-dosing medications, in partic-
ular antibiotics such as cefepime.75-77 Moreover, data are largely
nonexistent regarding the quantity of medication removed by convec-
tion typical of lower volume isolated ultrafiltration. Thus, while supple-
mental doses are generally not required after an IUF session, the true
impact on drug concentration is often unknown. Close coordination
with pharmacists and prescribers is required whenever the nephrolo-
gist alters the dialysis prescription and/or modality.
In summary, multiple strategies exist for the safe and life-saving
delivery of dialysis therapies. While the specifics of dialysis prescrip-
tion are the responsibility of the nephrologist, providers from all dis-
ciplines will potentially care for patients with ESRD. Familiarity with
dialysis modalities and the therapeutic concerns specific to these
technologies may facilitate improved multidisciplinary patient care.
REFERENCES
1. United States Renal Data System. 2016 USRDS annual data report:
epidemiology of kidney disease in the United States. Bethesda, MD:
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases; 2016.
2. Abel JJ, Rowntree LG, Turner BB. On the removal of diffusible sub-
stances from the circulating blood of living animals by dialysis. J
Pharmacol Exp Ther. 1914;5:275-316.
3. Kolff WJ, Berk HTJ. The artificial kidney: a dialyser with a great area.
Acta Med Scand. 1944;117:121-134.
4. Blagg CR. The early history of dialysis for chronic renal failure in the
United States: a view from Seattle. Am J Kidney Dis. 2007;49:482-
496.
5. Boen ST, Mulinari AS, Dillard DH, Scribner BH. Periodic peritoneal
dialysis in the management of chronic uremia. Trans Am Soc Artif
Intern Organs. 1962;8:256-262.
6. Peitzman SJ. Chronic dialysis and dialysis doctors in the United
States: a nephrologist-historian’s perspective. Semin Dial. 2001;14:
200-208.
7. Brescia MJ, Cimino JE, Appel K, Hurwich BJ. Chronic hemodialysis
using venipuncture and a surgically created arteriovenous fistula. N
Engl J Med. 1966;275:1089-1092.
FOY AND SPERATI
8. Institute of Medicine (US) Committee for the Study of the Medicare
End-Stage Renal Disease Program; Rettig RA, Levinsky NG, editors.
Kidney Failure and the Federal Government. Washington, DC: National
Academies Press (US); 1991.
9. Rettig RA. Special treatment—the story of Medicare’s ESRD entitle-
ment. N Engl J Med. 2011;364:596-598.
10. Kucirka LM, Grams ME, Lessler J, et al. Association of race and age
with survival among patients undergoing dialysis. JAMA. 2011;306:
620-626.
11. Johns TS, Estrella MM, Crews DC, et al. Neighborhood socioeco-
nomic status, race, and mortality in young adult dialysis patients. J
Am Soc Nephrol. 2014;25:2649-2657.
12. Hecking M, Bieber BA, Ethier J, et al. Sex-specific differences in
hemodialysis prevalence and practices and the male-to-female mor-
tality rate: the Dialysis Outcomes and Practice Patterns Study
(DOPPS). PLoS Med. 2014;11:e1001750.
13. Sperati CJ. Hemodialysis: Initiation and Complications. In: Lerma EV,
Rosner M, eds. Clinical Decisions in Nephrology, Hypertension, and Kid-
ney Transplantation. New York: Springer; 2013:333-348.
14. Daugirdas JT, Blake PG, Ing TS. Handbook of dialysis, 5th ed.
Philadelphia: Wolters Kluwer Health; 2015.
15. Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial
of early versus late initiation of dialysis. N Engl J Med. 2010;363:
609-619.
16. National Kidney Foundation. KDOQI Clinical Practice Guideline for
Hemodialysis Adequacy: 2015 update. Am J Kidney Dis. 2015;66:
884-930.
17. Neri M, Villa G, Garzotto F, et al. Nomenclature for renal replace-
ment therapy in acute kidney injury: basic principles. Crit Care.
2016;20:318.
18. Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears
to be safe and effective for dialysis-induced hypotension: a system-
atic review. Nephrol Dial Transplant. 2004;19:2553-2558.
19. Ronco C, Ghezzi PM, Brendolan A, Crepaldi C, La Greca G. The
haemodialysis system: basic mechanisms of water and solute trans-
port in extracorporeal renal replacement therapies. Nephrol Dial
Transplant. 1998;13(Suppl 6):3-9.
20. Nistor I, Palmer SC, Craig JC, et al. Convective versus diffusive dialy-
sis therapies for chronic kidney failure: an updated systematic
review of randomized controlled trials. Am J Kidney Dis. 2014;63:
954-967.
21. Locatelli F, Manzoni C, Di Filippo S. The importance of convective
transport. Kidney Int Suppl. 2002;80:115-120.
22. Boure T, Vanholder R. Which dialyser membrane to choose? Nephrol
Dial Transplant. 2004;19:293-296.
23. Schiffl H. High-flux dialyzers, backfiltration, and dialysis fluid quality.
Semin Dial. 2011;24:1-4.
24. Coulliette AD, Arduino MJ. Hemodialysis and water quality. Semin
Dial. 2013;26:427-438.
25. Bommer J, Jaber BL. Ultrapure dialysate: facts and myths. Semin Dial.
2006;19:115-119.
26. ANSI/AAMI/ISO. Water for Hemodialysis and Related Therapies. ANSI/
AAMI 13959: 2014. Arlington, VA: Association for the Advancement
of Medical Instrumentation; 2014.
27. Weijmer MC, Vervloet MG, ter Wee PM. Compared to tunnelled
cuffed haemodialysis catheters, temporary untunnelled catheters are
associated with more complications already within 2 weeks of use.
Nephrol Dial Transplant. 2004;19:670-677.
28. Nguyen DB, Shugart A, Lines C, et al. National Healthcare Safety
Network (NHSN) dialysis event surveillance report for 2014. Clin J
Am Soc Nephrol. 2017;12:1139-1146.
29. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for
the diagnosis and management of intravascular catheter-related
infection: 2009 Update by the Infectious Diseases Society of Amer-
ica. Clin Infect Dis. 2009;49:1-45.
FOY AND SPERATI
30. Rose DA, Sonaike E, Hughes K. Hemodialysis access. Surg Clin North
Am. 2013;93:997-1012.
31. Vascular Access Work Group. Clinical practice guidelines for vascular
access. Am J Kidney Dis. 2006;48(Suppl 1):S176-247.
32. Shechter SM, Skandari MR, Zalunardo N. Timing of arteriovenous
fistula creation in patients with CKD: a decision analysis. Am J Kid-
ney Dis. 2014;63:95-103.
33. Ellingson KD, Palekar RS, Lucero CA, et al. Vascular access hemor-
rhages contribute to deaths among hemodialysis patients. Kidney Int.
2012;82:686-692.
34. Shrestha B, Boyes S, Brown P. Innocuous-looking skin scab over an
arteriovenous fistula: case report and literature review. World J
Nephrol. 2014;3:118-121.
35. Huber TS, Carter JW, Carter RL, Seeger JM. Patency of autogenous
and polytetrafluoroethylene upper extremity arteriovenous
hemodialysis accesses: a systematic review. J Vasc Surg. 2003;38:
1005-1011.
36. Saha M, Allon M. Diagnosis, treatment, and prevention of hemodial-
ysis emergencies. Clin J Am Soc Nephrol. 2017;12:357-369.
37. Zepeda-Orozco D, Quigley R. Dialysis disequilibrium syndrome. Pedi-
atr Nephrol. 2012;27:2205-2211.
38. Davenport A. Antibodies to heparin-platelet factor 4 complex:
pathogenesis, epidemiology, and management of heparin-induced
thrombocytopenia in hemodialysis. Am J Kidney Dis. 2009;54:361-
374.
39. Hemodialysis Adequacy Work Group. Clinical practice guidelines for
hemodialysis adequacy, update 2006. Am J Kidney Dis. 2006;48
(Suppl 1):S2-90.
40. Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and
membrane flux in maintenance hemodialysis. N Engl J Med.
2002;347:2010-2019.
41. Rocco MV, Lockridge RS Jr., Beck GJ, et al. The effects of frequent
nocturnal home hemodialysis: the Frequent Hemodialysis Network
Nocturnal Trial. Kidney Int. 2011;80:1080-1091.
42. Garg AX, Suri RS, Eggers P, et al. Patients receiving frequent
hemodialysis have better health-related quality of life compared to
patients receiving conventional hemodialysis. Kidney Int.
2017;91:746-754.
43. Alkatheeri AM, Blake PG, Gray D, Jain AK. Success of urgent-start
peritoneal dialysis in a large Canadian renal program. Perit Dial Int.
2016;36:171-176.
44. Phu NH, Hien TT, Mai NT, et al. Hemofiltration and peritoneal dialy-
sis in infection-associated acute renal failure in Vietnam. N Engl J
Med. 2002;347:895-902.
45. Gabriel DP, Caramori JT, Martim LC, Barretti P, Balbi AL. High vol-
ume peritoneal dialysis vs daily hemodialysis: a randomized, con-
trolled trial in patients with acute kidney injury. Kidney Int Suppl.
2008;108:S87-93.
46. Ranganathan D, John GT, Yeoh E, et al. A randomized controlled
trial to determine the appropriate time to initiate peritoneal dialysis
after insertion of catheter (Timely PD Study). Perit Dial Int.
2017;37:420-428.
47. Perl J, Bargman JM. Peritoneal dialysis: from bench to bedside and
bedside to bench. Am J Physiol Renal Physiol. 2016;311:F999-F1004.
48. Wens R, Taminne M, Devriendt J, et al. A previously undescribed
side effect of icodextrin: overestimation of glycemia by glucose ana-
lyzer. Perit Dial Int. 1998;18:603-609.
49. Extraneal full prescribing information. http://www.baxterpi.com/pi-
pdf/Extraneal_PI.pdf. Accessed July 6, 2017.
50. Bargman JM, Thorpe KE, Churchill DN, CANUSA Peritoneal Dialysis
Study Group. Relative contribution of residual renal function and
peritoneal clearance to adequacy of dialysis: a reanalysis of the
CANUSA study. J Am Soc Nephrol. 2001;12:2158-2162.
51. Paniagua R, Amato D, Vonesh E, et al. Effects of increased peri-
toneal clearances on mortality rates in peritoneal dialysis: ADEMEX,
| 9
a prospective, randomized, controlled trial. J Am Soc Nephrol.
2002;13:1307-1320.
52. Htay H, Cho Y, Pascoe EM, et al. Predictors of residual renal func-
tion decline in peritoneal dialysis patients: the balANZ Trial. Perit
Dial Int. 2017;37:283-289.
53. Zhang L, Zeng X, Fu P, Wu HM. Angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers for preserving residual
kidney function in peritoneal dialysis patients. Cochrane Database
Syst Rev. 2014;23:CD009120.
54. Del Peso G, Bajo MA, Costero O, et al. Risk factors for abdominal
wall complications in peritoneal dialysis patients. Perit Dial Int.
2003;23:249-254.
55. Yang SF, Liu CJ, Yang WC, et al. The risk factors and the impact of
hernia development on technique survival in peritoneal dialysis
patients: a population-based cohort study. Perit Dial Int. 2015;35:
351-359.
56. Mehrotra R, Devuyst O, Davies SJ, Johnson DW. The current state
of peritoneal dialysis. J Am Soc Nephrol. 2016;27:3238-3252.
57. Li PKT, Szeto CC, Piraino B, et al. ISPD peritonitis recommendations:
2016 update on prevention and treatment. Perit Dial Int. 2016;36:
481-508.
58. Nomoto Y, Suga T, Nakajima K, et al. Acute hydrothorax in continu-
ous ambulatory peritoneal dialysis—a collaborative study of 161
centers. Am J Nephrol. 1989;9:363-367.
59. Al Rifai A, Sukul N, Wonnacott R, Heung M. Safety of arteriovenous
fistulae and grafts for continuous renal replacement therapy: the
Michigan experience. Hemodial Int. Mar 13 2017. https://doi.org/10.
1111/hdi.12550.
60. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney
Injury Work Group. KDIGO clinical practice guideline for acute kid-
ney injury. Kidney Int Suppl 2012; 2: 1-138.
61. Bai M, Zhou M, He L, et al. Citrate versus heparin anticoagulation
for continuous renal replacement therapy: an updated meta-analysis
of RCTs. Intensive Care Med. 2015;41:2098-2110.
62. Morabito S, Pistolesi V, Tritapepe L, Fiaccadori E. Regional citrate
anticoagulation for RRTs in critically ill patients with AKI. Clin J Am
Soc Nephrol. 2014;9:2173-2188.
63. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompen-
sated heart failure with cardiorenal syndrome. N Engl J Med.
2012;367:2296-2304.
64. Edrees F, Li T, Vijayan A. Prolonged intermittent renal replacement
therapy. Adv Chronic Kidney Dis. 2016;23:195-202.
65. Bellomo R, Cass A, Cole L, et al. The relationship between
hypophosphataemia and outcomes during low-intensity and high-
intensity continuous renal replacement therapy. Crit Care Resusc.
2014;16:34-41.
66. Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the
intensive care unit: a systematic review of the impact of dialytic
modality on mortality and renal recovery. Am J Kidney Dis. 2002;40:
875-885.
67. VI NIH, Acute Renal Failure Trial Network, Palevsky PM, Zhang JH,
et al. Intensity of renal support in critically ill patients with acute
kidney injury. N Engl J Med. 2008;359:7-20.
68. RENAL Replacement Therapy Study Investigators, Bellomo R, Cass
A, et al. Intensity of continuous renal-replacement therapy in criti-
cally ill patients. N Engl J Med. 2009;361:1627-1638.
69. Prowle JR, Schneider A, Bellomo R. Clinical review: optimal dose of
continuous renal replacement therapy in acute kidney injury. Crit
Care. 2011;15:207.
70. Fayad AI, Buamscha DG, Ciapponi A. Intensity of continuous renal
replacement therapy for acute kidney injury. Cochrane Database Syst
Rev. 2016;10:CD010613.
71. Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for
renal-replacement therapy in the intensive care unit. N Engl J Med.
2016;375:122-133.
10 | FOY AND SPERATI

72. Eliquis full prescribing information. http://packageinserts.bms.com/ 77. Huwyler T, Lenggenhager L, Abbas M, et al. Cefepime plasma con-
pi/pi_eliquis.pdf. Accessed July 6, 2017. centrations and clinical toxicity: a retrospective cohort study. Clin
73. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharma- Microbiol Infect. 2017;23:454-459.
codynamics, and safety of apixaban in subjects with end-stage renal
disease on hemodialysis. J Clin Pharmacol. 2016;56:628-636.
74. Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixa-
ban pharmacokinetics at steady state in hemodialysis patients. J Am How to cite this article: Foy M, Sperati CJ. What the non-
Soc Nephrol. 2017;28:2241-2248. nephrologist needs to know about dialysis? Semin Dial.
75. Hobbs AL, Shea KM, Roberts KM, Daley MJ. Implications of aug-
2018;00:1–10. https://doi.org/10.1111/sdi.12671
mented renal clearance on drug dosing in critically ill patients: a
focus on antibiotics. Pharmacotherapy. 2015;35:1063-1075.
76. Nolin TD, Aronoff GR, Fissell WH, et al. Pharmacokinetic assessment
in patients receiving continuous RRT: perspectives from the Kidney
Health Initiative. Clin J Am Soc Nephrol. 2015;10:159-164.