Postgraduate Medicine

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Acute Kidney Injury: Current Perspectives

Devasmita Choudhury MD

To cite this article: Devasmita Choudhury MD (2010) Acute Kidney Injury: Current Perspectives,
Postgraduate Medicine, 122:6, 29-40, DOI: 10.3810/pgm.2010.11.2220

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Published online: 13 Mar 2015.

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Acute Kidney Injury: Current Perspectives

Devasmita Choudhury, MD1,2
1
VA North Texas Health Care
Systems, Dallas VA Medical Center,
Dallas, TX; 2UT Southwestern Medical
Center at Dallas, Dallas, TX
Abstract: Acute kidney injury (AKI) increases morbidity and mortality, particularly for the
critically ill. Recent definitions standardizing AKI to reflect graded changes in serum creatinine
and urine output (per the Risk, Injury, Failure, Loss, and End-stage renal failure [RIFLE] and
Acute Kidney Injury Network [AKIN] criteria) with severity of renal injury and developments
in AKI pathobiology are being utilized to identify biomarkers of early kidney injury. These
developments may be useful in the early intervention of preventing AKI. Although there has
been progress in the management of AKI, therapeutic challenges include appropriate prophylaxis
prior to contrast administration, use of diuretics, vasopressors, and the type and dose of renal
replacement therapy. Future use of bioartificial dialyzers, plasma therapies, and the possibility
of stem cell regeneration of injured kidney tissue are being actively investigated to provide
alternative treatment options for AKI. This review aims to provide an overview of current
practices, available therapies, and continued research in AKI therapy.
Keywords: acute kidney injury; renal failure; kidney failure; critically ill; comorbidities

Introduction
Acute kidney injury (AKI), also known as acute renal failure, delineates a sudden loss
of renal function over hours, days, and weeks as opposed to months and years. Early
detection is imperative to prevent this catastrophic event and initiate treatment that
may mitigate renal injury. Categorizing AKI into extrarenal and intrarenal processes
helps navigate the numerous events that cause a decline in renal function. Reversibility
of extrarenal processes, pre-renal and/or post-renal, is frequently more satisfactory
than intrarenal etiologies, although prolonged hypovolemia and/or obstruction can
also lead to intrarenal damage.
Intrarenal processes that occur in-hospital are often the most challenging and dev-
astating. Of the intrarenal processes, the most frequent include ischemic injury from
renal hypoperfusion, sepsis, hemorrhage, and surgery, and nephrotoxic injury from
tubular toxins, such as aminoglycosides, contrast agents, chemotherapy, malignancy-
associated tumor lysis, or light chains (as in myeloma). Acute kidney injury-associated
in-hospital mortality can increase up to 10-fold or higher in comparison with patients
without AKI, particularly if dialysis is necessary.1 Serum creatinine changes as little as
0.3 to 0.4mg/dL suggest a 70% greater multivariate adjusted odds of death compared
with patients who have no change in serum creatinine during hospitalization.2 In this
Correspondence: Devasmita Choudhury,
MD, article, we discuss the current treatment options and therapeutic challenges for AKI
Dallas VA Medical Center, and provide an overview of future research.
4500 South Lancaster Rd.,
111G1,
Dallas, TX 75216 Methods
Tel: 214-857-1593
The main focus of this article is an update on AKI/acute renal failure. A PubMed litera-
Fax: 214-857-1514
E-mail: devasmita.dev@va.gov ture search was performed using the terms acute kidney injury and acute renal failure,

Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260 29
71508e
Devasmita Choudhury
which were cross-referenced with associated topics, including
epidemiology, definition, pathophysiology, biomarkers, con-
trast agents, diuretics, vasopressors, dialysis modality, dialysis
dose, stem cells, bioartificial devices, and plasma therapies.
Original articles, randomized controlled trials, observational
studies, meta-analyses, case reports, and topic reviews pub-
lished in the English language over the past 10years comprised
90% of the information used to summarize the current treatment
options for AKI. Approximately 10% of the remaining articles
dated back 30years for completeness and to compare current
with former treatment.
Defining AKI
A closer look at acute renal failure suggests that this entity
comprises a sudden loss of renal function at various stages
and grades of injury, which may be reversible. An early
diagnosis is necessary for early intervention. In a consensus
statement published in 2004, experts on acute renal failure
proposed that the name be changed from acute renal fail-
ure to acute kidney injury. This group established the Progress in AKI Pathobiology
Acute Dialysis Quality Initiatives (ADQI), which proposed
the Risk, Injury, Failure, Loss, and End-stage renal failure
[RIFLE] criteria for standardizing and staging AKI. The
RIFLE criteria uses the common clinical parameters of serum
creatinine and urine output to formulate 3severity categories
(Risk, Injury, Failure) of AKI and 2 clinical outcomes catego-
ries (Loss and End-stage renal failure) (Figure1). In 2007,
the Acute Kidney Injury Network (AKIN), which is com-
posed of nephrologists and intensivists worldwide, suggested
refinements to the RIFLE criteria to increase its sensitivity
by using smaller changes in serum creatinine for identifying
patients in the stage 1 category (Risk). In addition, a 48-hour
period for diagnosing AKI was suggested to reinforce the
acuity of the diagnostic process within a clinically relevant
timeline.3,4 It also proposed classifying any patients receiving
renal replacement therapy (RRT) as stage 3.3,4
The clinical utility of this definition and staging has been
validated in numerous clinical outcomes studies.48 Changing
the name and standardizing the staging criteria shifted clas-
sification into grades of injury in the effort that acting earlier
would ameliorate poor outcomes. In addition, standardized
criteria now allows AKI data from various parts of the world
to be compared. A recent study comparing the utility of both
these criteria looked at a large database of the Australian
New Zealand Intensive Care Society Adult Patient Data-
base (ANZICSAPD) over the course of 5years to assess
how the RIFLE and AKIN criteria fared in the diagnosis
and classification of AKI and in the prediction of hospital
30 Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260
mortality. Classification of patients by either the AKIN or
RIFLE criteria was similar, with only a 2% difference in the
earliest stages. Sixteen percent were classified in the Risk
category by the RIFLE criteria versus 18% classified as stage
1 injury by the AKIN criteria. However, this decreased the
number of patients then classified as stage 2 AKIN (Injury
stage by RIFLE) from 13.6% to 10.1%. Comparison of the
predictive capability of the 2-stage criteria using receiver
operator curves (ROC), which plot sensitivity (proportion
of true positives results) and specificity (proportion of false-
positive results), shows the area under the curve (AUC) for
hospital mortality was 0.66 for RIFLE and 0.67 for AKIN in
all patients.4 The AUC was 0.65 for both when only septic
patients from the database were considered,4 suggesting
similar diagnostic accuracy of both criteria. Thus, the RIFLE
and AKIN criteria, which are relatively easy to remember
and utilize, seem to be appropriate as clinical tools in the
diagnosis of AKI.
Basic studies in various experimental models of AKI
have gradually delineated the response of the vasculature,
tubules, and interstitial renal tissue to acute insult.9 Cur-
rent understanding suggests that marked microvascular
vasoconstriction from ischemia (ie, increased endothe-
lial angiotensin II, sympathetics, endothelin, adenosine,
thromboxane A2, leukotrienes) disrupts counter endothelial
vasodilatory responses (acetylcholine, bradykinin, nitric
oxide, prostaglandin E2 [PGE2]), leading to vascular smooth
muscle injury and activation of mediators of coagula-
tion and inflammation via leukocyte adhesion. Resultant
hypoxia and decreased nutrient delivery to downhill tubular
epithelial cells leads to increases in reactive oxygen spe-
cies, calcium, and phospholipases, causing breakdown of
the epithelial cytostructure with loss of cell polarity. This
signals apoptosis and initiation of cell necrosis with tubular
epithelial desquamation, obstruction that increases intra-
tubular pressure and decreases glomerular transcapillary
hydrostatic pressure, and backleak of glomerular filtrate.10,11
However, pathologic changes observed in animal mod-
els of ischemia reperfusion do not always translate to similar
pathology in human renal tissue.12 In addition, physiological
and phenotypic changes can vary widely in patients with
AKI, particularly with varying etiologies of AKI. This has
prompted further query and generation of newer animal
models that try to mimic clinical settings and outcomes
found in hospital settings. Some have suggested that
regional hypoxia during AKI leads to tubular oxygen supply
 Acute Kidney Injury

Figure 1. RIFLE/AKIN consensus classification.4

RIFLE/AKIN UO
GFR Criteria
Classification Criteria

1.5- to 2-fold increase in

UO < 0.5 mL/kg/h for
Risk/Stage 1 serum or > 0.3 mg/dL (> 26.4
6h
mol/L) from baseline

/AKIN Classification > 2- to 3-fold increase in serum

Injury/Stage 2 UO < 0.5 mL/kg/h for
creatinine from baseline 12 h

> 3-fold rise in serum UO < 0.3 mL/kg/h

creatinine or > 4.0 mg/dL
Failure/Stage 3 for 24 h or anuria for
(> 354 mol/L) with an acute
12 h
increase of > 0.5 mg/dL (44 mol/L)

Persistent ARF: complete loss

Loss of renal function > 4 weeks
(28 days)

End-stage renal
disease > 3 months
Failure

Abbreviations: AKIN, Acute Kidney Injury Network; ARF, acute renal failure; GFR, glomerular filtration rate; RIFLE, Risk, Injury, Failure, Loss, and End-stage renal failure; UO, urine output.
Adapted from the ADQI.

and demand mismatch, thus altering regional renal blood
flow. This may be important in signaling tubuloglomerular
feedback to decrease filtration, prevent increased injury,
and promote recovery during AKI.1317 A KCl-induced
mouse cardiac arrest model19 is being utilized to probe
crosstalk between the ischemic kidney and other organs
that can affect renal outcomes. Cecal ligation to induce
polymicrobial sepsis in mice with volume resuscitation
and antibiotic treatment is being used to interrogate events
of sepsis-associated AKI.18 Hemodynamic monitoring in a
live sheep model of continuous Escherichia coli sepsis has
simulated the hyperdynamic state of sepsis with onset of
oliguric acute renal failure. This model suggests decreased
glomerular filter pressure with subsequent mismatch of
medullary energy use requiring high needs for oxygen
consumption but inadequate oxygen extraction.19 Prob-
ing the microenvironment in AKI has made it feasible to
understand the role of inflammation and crosstalk between
injured organs.20 In addition, progress in understanding
pathobiology has allowed for the investigation of markers
of early kidney injury.
Search for Early Injury Biomarkers
of AKI
Blood urea nitrogen and serum creatinine appear to be rela-
tively good markers for progressive kidney injury; however,
they may not be specific or sensitive to detect early kidney
injury. With early kidney injury, various biomolecules,
including cytokines, inflammatory markers, tubular enzymes,
and proteins, can be detected in the urine and serum.21 The
optimal renal biomarker should detect injury as early as pos-
sible and be clinically useful in grading the severity of the
injury as it relates to outcome. Several biomolecules are under
scrutiny as injury markers for AKI, including urinary inter-
leukin-18 (IL-18), neutrophil gelatinase-associated lipocalin
(NGAL), kidney injury molecule-1 (KIM-1), and cystatin C.
Urinary IL-18, a cytokine released after acute ischemic
injury, is noted in the urine of mice and humans in high con-
centrations. It was reported as being highest in patients with
acute tubular necrosis and delayed renal transplant function
when levels were compared between patients with prerenal
azotemia, acute tubular necrosis, urinary tract infections,
chronic kidney disease (CKD), transplant evaluation, and

Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260 31
Devasmita Choudhury
healthy controls.22 A prospective analysis of urine collected
in a nested case-control cohort of critically ill patients with
serum creatinine levels of ,1.2mg/dL on intensive care
unit admission of the Acute Respiratory Distress Syndrome
(ARDS) Network trial found higher levels in the patients
developing AKI, which was predictive of mortality. In its
utility as a diagnostic marker of kidney injury 24hours prior
to AKI diagnosis, an AUC-ROC of 0.73 was noted.23 Higher
urinary IL-18 levels after pediatric surgery were predictive
of AKI, compared to increases in serum creatinine within
48 to 72 hours for the detection of AKI. Current evaluation
of the urinary IL-18 as a predictive biomarker of AKI sug-
gests low sensitivity but high specificity. Thus, while many
patients with AKI may not have elevations in urinary IL-18
levels, those who have elevations are rarely false-positive
elevations.24
The iron-transporting protein NGAL (other names
include lipocalin-2 and siderocalin), found in neutrophils
granules, may be measured by enzyme-linked immunosor-
bent assay (ELISA) or quantitative immunoblotting meth-
ods. Urinary NGAL levels by ELISA increased significantly
within 2hours after cardiopulmonary bypass in children with
congenital heart repair who subsequently developed AKI in
24 to 72hours.25 Comparative analysis using ELISA urine
NGAL levels of delayed or prompt transplanted kidney func-
tion suggested trends in serum creatinine after multivariate
adjustments, suggesting a role for urinary NGAL in detecting
delayed graft function.26 Urinary NGAL levels measured by
quantitative immunoblotting at various time points in adults
after cardiac surgery also increased in those who develop
AKI, although these levels greatly overlapped with those not
developing AKI.27 Whether differing measurement meth-
odology or age explains variable results of urinary NGAL
needs further clarification. Standardized methodologies to
measure plasma and urine NGAL for rapid results are being
investigated.28 Serum NGAL levels have not been useful in
predicting AKI.
KIM-1, a type-1 transmembrane glycoprotein involved
in cell-to-cell and cell-to-matrix interaction, is markedly
upregulated in proximal renal tubular cells in response to
ischemic or nephrotoxic AKI. KIM-1sheds its ectodomain
into the urine after proximal tubular injury.29 In patients
with established AKI, urinary KIM-1 levels showed a
significant association with the outcomes of dialysis or
death; however, this association was no longer significant
when adjusted for covariates.30 In a case-control study of
20 pediatric patients with and without AKI, a prospective
evaluation of KIM-1 level normalized to urinary creatinine
32 Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260
concentration at 12hours after cardiopulmonary bypass
surgery.31 The AUC was 0.83, suggesting possible use-
fulness as an early injury marker. Further investigation
continues to combine this and other markers as panels for
evaluation of AKI.31
Cystatin C is an endogenous cysteine proteinase inhibitor
produced at a constant rate and released in the plasma by all
nucleated cells in the body. Filtered freely by the kidney,
it is nearly completely catabolized by the proximal tubule.
It has been reported that postoperative serum cystatin C
levels in cardiac bypass surgery patients at various time points
had a trend toward higher composite values in those with AKI
noted 24hours prior to the diagnosis of AKI.32 However, plasma
cystatin C was not useful in predicting the development of
AKI.32 Urinary cystatin C postoperatively was predictive for
those requiring RRT. However, levels were not different for
those with AKI not requiring RRT and those without AKI.32
Thus, early kidney injury markers in both serum and urine
are being actively investigated. It is possible that a combi-
nation of markers will soon be available to determine early
injury and need for intervention. In the interim, changes in
therapy are being pursued to prevent, minimize, or support
the recovery of renal injury and recovery based on current
definitions.
Therapeutic Challenges in AKI
Management
Preventive Management in Contrast-
Induced AKI
We continue to progress in refining the prevention and treatment
of AKI. One instance where an improvement can be noted is
with contrast-induced nephropathy (CIN). The general incidence
of CIN reported has decreased some over the past decade,
from approximately 15% to 7%,33,34 suggesting perhaps better
awareness in addition to some therapeutic changes. However,
given the increased number of procedures in high-risk patient
groups, this entity remains the third-leading cause of AKI.35
Decreased renal perfusion and nephrotoxic agents are the first-
and second-leading causes.35 High-risk patient characteristics for
AKI include the elderly, patients with diabetes, recent kidney
injury, recent contrast load, a volume-depleted state (including
cardiac or liver failure), concurrent nephrotoxic antibiotics, non-
steroidal or chemotherapy agents, myeloma, and CKD. A large
retrospective review of patients receiving low-osmolar contrast
media in Rochester, MN from 2004 to 2006suggested higher
mortality for the group that developed CIN at 30days (15.6% vs
5.2% of the non-CIN group; P,0.001), with CIN defined as a
serum creatinine increase of $25% or an increase of 0.5% mg/

dL within 7days of exposure.36 Contrast-induced nephropathy
has been associated with a 5.5% increased odds for death.37
Although expected renal recovery occurs over days to weeks
in 75% of patients, nearly 10% become dialysis dependent.38
Type of Contrast Agent
Various aspects of CIN, such as type of contrast agent and
patient management before and after contrast administration,
continue to be evaluated. The proposed pathogenesis encom-
passes an aspect of both renal ischemia and direct tubular
toxicity. An initial brief renal vasodilatory response after
contrast administration leads to significant vasoconstriction
altering blood flow to the renal medulla. Subsequent medul-
lary hypoxia with impaired adaptive response leads to cyto-
toxic tubular damage with increased oxidant stress and loss of
renal function. Cell culture studies also imply direct tubular
cell toxicity with loss of cellular proteins and a decrease in
transepithelial resistance, permeability, and possible comple-
ment activation.39 While avoidance of iodinated contrast is
optimal, patients in need of specific diagnostic studies pro-
pose a therapeutic challenge. Although magnetic resonance
imaging (MRI) and magnetic resonance angiography (MRA)
studies are an option for those without underlying renal dys-
function, magnetic resonance studies with gadolinium should
not be considered in patients AKI or with moderate-to-severe
CKD given the risk of nephrogenic systemic fibrosis. Use
of low- and iso-osmolar iodinated contrast agents is more
frequent in the current decade, with a suggested benefit over
first-generation higher osmolar contrast agents.4042 Benefit
of iso-osmolar agent to that of low-osmolar contrast agents
has been suggested but not definitively shown.43 If contrast
must be given, then the most important preventive therapy
appears to be avoidance of volume depletion,4446 and/or
adequate volume repletion for those deemed to be volume
depleted.47 For this reason, pre- and post-procedure diuretics
should be avoided if possible.48
Volume Replacement
Trials have addressed the importance isotonic fluid replace-
ment in CIN compared with hypotonic solutions. Fluid
administered pre-procedure over longer periods of time rather
than bolus administration resulted in better outcomes.49,50 Oral
saline (NaCl) administration of (1g/10kg) over 2days (240
mEq in 70-kg patient) compared with 6hours of intravenous
(IV) 0.9% saline NaCl suggested no difference between these
2 groups, and was better than NaCl infusion plus furosemide
administration.51 Recent randomized trials have suggested
benefit of isotonic bicarbonate infusion over isotonic saline
Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260 33
Acute Kidney Injury
infusion before and after contrast exposure;52,53 however,
small patient numbers in these trials cannot exclude the
possibility of a type 1 error. Use of bicarbonate solution
for volume repletion in the prevention of CIN nephropa-
thy perhaps reinforces the hypothesis that improving the
hypoxic renal medullary pH may protect from mitochondrial
reactive oxygen species generation and subsequent oxidant
injury.52,54,55 Further randomized studies evaluating the benefit
of bicarbonate infusion or alkalinization of the urine may be
useful to further clarify the use of bicarbonate in CIN. While
firm conclusions may not be available from these studies as
to what type, how much, and when to administer volume,
there is little debate for the role of adequate volume repletion
prior to contrast administration.
N-acetylcysteine
With oxidant injury playing a possible role in contrast-
induced AKI, the antioxidant with vasodilatory effect,
N-acetylcysteine (NAC), has also been used and tested for the
prevention of CIN. Tepel etal56 initially suggested that use
of 600mg twice daily of oral NAC on the day prior and day
of contrast administration decreased the incidence from 21%
in the placebo group to 2% in the treatment group. Others
have subsequently suggested similar benefit, with some not-
ing higher doses of NAC 1200mg twice daily as being more
effective.57 However, these studies lacked effective sample
sizes needed to make definitive conclusions. Furthermore,
meta-analyses of the studies evaluating NAC for CIN has
resulted in conflicting results.58,59 Given the relatively low
cost and low toxicity noted with use of NAC, it is being
frequently used as prophylaxis. No conclusive data recom-
mends routine use at this time.
Periprocedural Blood Purification
Because the pathogenesis of CIN may be from direct tubu-
lar toxicity, a basic inclination to remove contrast from
the body may seem appropriate. One dialysis treatment
removes approximately 60% to 90% of contrast agents.60
Therefore, several studies have looked at periprocedural
blood purification techniques, including hemofiltration
and hemodialysis, for decreasing CIN.6163 Using change in
serum creatinine to define CIN becomes a problem when
these techniques are used because creatinine is decreased
with these blood purification techniques. Lee etal62 looked a
high-risk population of CKD stage 5 with an eGFR 12.8mL/
min/1.73m2 undergoing coronary angiography and performed
prophylactic hemodialysis after IV saline administration after
contrast. The serum creatinine level at day 4 was higher than
Devasmita Choudhury
the control group, and more patients required temporary
dialysis in the saline control group. With dialysis there is
removal of the very marker that is being used to determine
disease. Even after 4days, it will take time for those hav-
ing undergone dialysis to reach the same level of serum
creatinine as the group that did not have serum creatinine
removed with dialysis. When added to spontaneous recov-
ery, improvement in serum creatinine can be misleading.
Thus, the conclusions of a better renal outcome with blood
purification after contrast administration can be misleading.
Recent meta-analyses of 6 randomized studies using hemo-
dialysis suggested that there was no decrease in CIN with
periprocedural hemodialysis in comparison with a standard
medical therapy (relative risk, 1.35 for hemodialysis; 95%
confidence interval, 0.931.94).63 Given these findings, there
appears to be no convincing evidence for a clear benefit for
periprocedural hemodialysis in CIN.
Diuretic Dilemma
Diuretic use is relatively common in critically ill patients with
AKI. A multinational, multicenter survey of intensivists and
nephrologists composed of academic institutions (77.5%) and
other private, regional, and metropolitan hospitals from 16
countries reported use of IV furosemide as the most com-
mon (71.9%) medication given in bolus dosing.64 Serum
creatinine, urine output, blood pressure, central venous pres-
sure, and risk of toxicity determined dose. Most commonly,
diuretics were used just prior to RRT or during recovery.64
The question remains whether there is benefit or harm in
using diuretics in the setting of AKI.
The rationale for diuretic use during AKI is often to main-
tain urine flow, flush out debris, and convert from an oliguric
to a nonoliguric state to prevent further renal injury. The other
rationale is for volume management. Data in both animal and
human studies support use of loop diuretics to decrease renal
oxygen consumption by decreasing active sodium transport,
thereby limiting potential ischemic tubular damage.65,66 In
addition, loop diuretics inhibit prostaglandin dehydrogenase,
which can then prevent breakdown of renal vasodilator PGE2,67
thereby increasing renal blood flow. Similarly, various studies
have suggested that nonoliguric patients with AKI have better
outcomes.68,69 However, studies evaluating the use of diuretics
in AKI have suggested little benefit, and 1 retrospective study
suggests increased mortality. Kleinknecht etal70 randomized
66 patients with oliguric renal failure to IV furosemide rang-
ing from 1.5 to 6.0mg/kg given every 4hours in 33 patients
and no diuretics in 33 control patients. A persistent diuresis
was observed in 5 of the treated group and 2 of the controls.
34 Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260
Hemodialysis was required in most patients, with no differ-
ences noted in mean time of oliguria, number of dialysis ses-
sions, and mean time with renal insufficiency.
Brown etal71 conducted a randomized study in 58 estab-
lished acute renal failure patients assigned to either a 1-g
bolus of furosemide over 4hours, or IV or oral dosing of
3 g/24hours to obtain a sustained urine output of 200mL/hour
or serum creatinine decreased , 300 mol/L. Oliguria
reversed in 24 of 28 patients given sustained furosemide but
in only 2 given a single injection. No difference in dialysis
treatment session number, duration of renal failure, or mor-
tality was found. Deafness was noted in 2 patients, with 1
case being permanent.
Ninety-two patients with acute renal failure (ARF) were
studied by Schilliday etal.72 Patients were randomized to 3mg/
kg of torsemide (n=30), furosemide (n=32), or placebo IV
(n=30) once every 6hours for 21 days or until renal recovery
or death. All patients also received 2 g/kg/min dopamine and
20% mannitol for 3days prior to randomization. The Acute
Physiology and Chronic Health Evaluation II (APACHE II)
score for severity of illness was similar in each group, with
similar creatinine clearance and urine volumes noted at ini-
tiation. While recovery of renal function or need for dialysis
did not differ between diuretic or placebo groups, urine flow
rates were significantly greater in the group of patients using
loop diuretics.
A larger randomized, double-blind, placebo-controlled
study of 388 acute renal failure patients requiring dialysis eval-
uated patients randomized to either intravenous (25 mg/kg/d)
or oral furosemide (35 mg/kg/d) versus placebo to determine
survival and need for dialysis.73 Patients in the diuretic group
had greater renal impairment at baseline and greater serum
creatinine at randomization, which was not evident at RRT
initiation. No differences were noted between the 2 groups for
overall mortality, number of dialysis sessions, time on dialysis,
and time to recovery of renal function, although the diuretic
group reached urine output of 2 L/day over a shorter period.
Problems with this study were that all patients received a test
dose of furosemide 15mg/kg prior to randomization, which
may have affected outcome. In addition, increased diuresis
of a recovering kidney may have led to slower return to the
endpoint of evaluating recovery.
A cohort analysis of the large, multicenter Project to
Improve Care in Acute Renal Disease (PICARD) data set
in critically ill AKI evaluated 552 patients, 326 of whom
had used diuretics before renal consultation. The group
using diuretics was older, had more patients with con-
gestive heart failure, higher pulmonary capillary wedge

pressure, lower cardiac output, higher vascular resistance,
and more cardiorespiratory organ failure. The differences
between groups were addressed using propensity scores in
the study. The calculated risk of death was 25% and the
risk of nonrecovery of renal function was 36%, with the
conclusion that widespread diuretic use should be discour-
aged.74 However, this was a group of patients in whom renal
consultation was requested, suggesting perhaps more severe
renal failure and nonrecovery of function.
A larger prospective, multicenter, multinational
observational study, Beginning and Ending Support-
ive Therapy for the Kidney (BEST), also reviewed this
topic and evaluated . 1700 patients in the intensive
care unit using diuretics (furosemide used in 98% of
patients), with groups adjusted for covariates and pro-
pensity scores as done in the prior retrospective PICARD
cohort. This study found no risk of higher mortality
and therefore could not discourage use of diuretics. 75
A phase 2, randomized, controlled trial evaluating furo-
semide in the critically ill patient with AKI is currently
underway and will be useful to further clarify current
diuretic use in this population.76
Despite theoretical benefit in the use of diuretics to
decrease AKI, studies in CIN have suggested possible
increase of CIN with the use of diuretics. Postoperative
cardiac patients have an increase in serum creatinine,
with increased urine output when loop diuretics are used.
Therefore, avoidance has been suggested when used for
protection of renal function after cardiac surgery. These
data suggest that diuretic use to prevent AKI is not useful.
Diuretic use in established acute renal failure offers little
benefit in changing outcome of mortality or need for RRT,
particularly in the presence of oliguria. Given the current
literature, use of diuretics for volume management when
necessary in patients with AKI can be considered. How-
ever, diuretic use to prevent oliguria in the AKI setting is
not indicated.77
Vasopressors in AKI
When renal autoregulatory capacity is compromised, the
ability to maintain renal perfusion is lost, and blood flow
decreases in linear fashion. Loss of blood flow leads to
renal ischemia. This can occur at higher than expected
mean arterial pressures for patients (usually 80 mm Hg)
with significant vascular disease.78 Therefore, restoring
blood pressure becomes critical. Vasopressors that optimize
renal perfusion should improve patient outcomes. As such,
several vasopressors have been under study.
Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260 35
Acute Kidney Injury
Dopamine
Dopamine, an endogenous catecholamine, has dopaminer-
gic effects at low doses of 2 to 5 g/kg/min, as opposed
to having -adrenergic and -adrenergic effects at higher
dosages. When used at lower doses in healthy individuals
and experimental animals, renal vasodilation with increased
renal blood flow and natriuresis are seen.79 Some studies have
also suggested a blunting of endogenous norepinephrine-
associated vasoconstriction.80 As a result, low-dose dopamine
infusion in AKI has frequently been utilized to maintain renal
blood flow. However, some reviews of trials using low-dose
dopamine in patients with AKI have shown little benefit.8183
Norepinephrine
Norepinephrine acts via -adrenergic stimulation as a potent
vasopressor. Marked splanchnic and renal vasoconstriction
can occur in the presence of hypovolemic hypotension, essen-
tial hypertension, and with normal circulation. Reversible
AKI can be induced when norepinephrine is injected into
the renal artery.84 In undervasodilated states such as sepsis,
there is significant nitric oxide release, downregulation of
-adrenergic receptor responsiveness, endothelial damage,
and loss of vascular smooth muscle tone; therefore, the use
of IV norepinephrine may improve renal blood flow.78 Nor-
epinephrine used in the short term in clinically relevant doses
of 0.2 to 0.4 g/kg/min in conscious dogs showed improved
increased renal blood flow and decreased renal vascular
resistance, with improvement in mean arterial pressure.78,85
Pretreatment with indomethacin, propranolol, and
angiotensin did not change this response, suggesting that
these changes were not attributable to prostaglandins,
-receptor stimulation, or angiotensin mediation, but may
actually be from restoring systemic blood pressure. Nor-
epinephrine also did not decrease renal blood flow of dogs
during endotoxic shock.86 More detailed physiologic studies
in endotoxemic dogs suggest an increase in both dynamic
renal blood flow and perfusion pressure.87 Other clinical
studies have also reported improvement in renal clearance
and urine output with norepinephrine use in patients with
septic shock.88 Compared with high-dose dopamine, nor-
epinephrine fared better in restoring mean arterial pressure
and urine output.89
Vasopressin
Vasopressin is a peptide hormone rapidly released with
acute shock, acting via V1 receptors to increase mean arte-
rial pressure and decrease cardiac output. Levels decrease
over time with prolonged hypotension.90 It can potentiate the
Devasmita Choudhury
effect of norepinephrine. In the face of marked vasodilation,
as in septic shock, there may be a relative deficiency and
therefore exogenous administration has been considered.91 In
observational studies, low-dose vasopressin infusion has been
show to improve blood pressure; however, given a possible
decrease in blood flow to other vital organs, including kidney,
heart, and gut, it has been used with caution. When used in
conjunction with norepinephrine, improved blood pressure
allowed for decreasing norepinephrine dose in patients with
vasodilatory shock.90 A recent multicenter, double-blind,
randomized controlled trial compared the use of vasopres-
sin plus low-dose norepinephrine versus norepinephrine
alone in patients with septic shock and found no significant
difference in primary outcome of mortality or secondary
outcomes, including days free of RRT or ventilator use.
There was also no difference in adverse events.91
Terlipressin
Terlipressin is glycine-modified vasopressin, which has a
longer half-life and can be given intermittently. Its use as
a vasoconstrictor for marked splanchnic vasodilation of
hepatorenal syndrome has shown some improvement in renal
blood flow and urine output when used with albumin.92,93
While it is available for use for hepatorenal syndrome
type 1 internationally, it is under phase 3 clinical trials in
the United States.
RRT in the Critically Ill and Patients
with Multiorgan Failure
While presence of AKI already heralds an increase in mor-
tality, prognosis in the critically ill usually with multiorgan
failure can be dismal, with a 50% reported mortality.94 There-
fore, supportive management issues need critical analysis
to impact therapy. Several studies have therefore evaluated
the delivery and dose of RRT.
Renal replacement therapy can be offered to the critically
in several different forms, among which the most popular
modalities include intermittent hemodialysis, continuous
RRT (CRRT), or a hybrid of slow, continuous dialysis given
intermittently with a conventional hemodialysis machine,
termed sustained low-efficiency dialysis. Continuous RRT
can usually be provided as hemofiltration alone as continu-
ous venovenous hemofiltration, dialysis alone or with com-
bination of both hemofiltration and dialysis (CVVHDF). The
utility of these modalities and treatment dose is often based
on patient need, hemodynamic status, and modality avail-
ability. However, both modality and dose are factors that
may affect outcome in the critically ill patient. Therefore,
36 Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260
both have recently been carefully evaluated to determine
the best therapeutic approach in RRT.
Intermittent Versus CRRT
Single-center and multicenter randomized trials evaluating
the effect of modality suggest that there is little difference in
mortality outcome when either intermittent or CRRT is used
in the critically ill population when similar amounts of dialy-
sis are provided. Uehlinger etal95 randomized intensive care
unit patients with AKI to either intermittent hemodialysis
(N=55) or CVVHDF (N=70) and standardized for solute
clearance 25mL/min/day and found no difference in patient
mortality between groups. Larger multicenter randomized
studies by both Vinsonneau etal96 (N=360 patients), and
Lin etal97 (N=316) confirmed findings of single-center tri-
als. Selecting the clinical modality of choice is done at the
bedside and depends on availability.
Dialysis Dose
The dialysis dose is measured as the amount of urea clear-
ance (small solute clearance) that occurs over time with each
dialysis session. With continuous renal therapies, the dose is
frequently evaluated by the total ultrafiltration effluent rate.
Earlier studies suggested that increasing the dialysis dose
by either increasing the number of dialysis treatments or
increasing the dialysis effluent rate with CRRT may improve
mortality in the critically ill.98100 However, more recent
randomized controlled trials, including the Veterns Affairs/
National Institutes of Health ATN trial and Randomized
Evaluation of Normal versus Augmented Level of Replace-
ment Therapy (RENAL) trial, evaluating intensity of renal
support in critically ill patients, suggest that achieving a
dose of 1.2 KT/V (solute clearance to the volume of solute
distribution time) during intermittent hemodialysis or at
least 20 to 25mL/kg/hour of dialysis effluent during CRRT
should be targeted for renal support, with no added benefit
in mortality by increasing the treatment dose.101,102
Therapies on the Horizon
Bioartificial Kidney
A combination of cell therapy and tissue engineering have
launched into early clinical testing the bioartificial kidney
or renal tubule assist device (RAD). This is composed of
a hemodialysis filter and bioreactor containing living renal
proximal tubular cells. Renal proximal tubular cells isolated
from deceased donor kidneys are cultured for integration
into a filtration device. Because these proximal tubular cells
have stem cell-like characteristics, they are grown in con-

fluent monolayers on the inner surface of hollow fibers of
a hemofiltration cartridge.103 Studies using RAD in acutely
uremic dogs with bilateral nephrectomy suggested added
metabolic and endocrine and transport replacement to filtra-
tion. Animals treated with RAD actively absorbed potassium,
HCO3, and glucose; they excreted NH3 and had appropriate
small solute and fluid control.104 In addition, treated animals
were able to reach normal vitamin D levels compared with
sham animals. Furthermore, septic animals treated with RAD
maintained mean arterial pressure and cardiac output for a
longer time period than sham animals.105,106 Ten AKI patients
with an expected mortality of 85% were evaluated in a phase
1/2study. Six of 10 survived past 30days, and the RAD device
maintained viability up to 24 hours.107 A multicenter phase
2 trial in 58 patients with AKI from multiorgan failure were
randomized 2:1 for RAD 72hours or CRRT alone and sug-
gested some benefit in survival with RAD treatment. However,
the groups may have been unbalanced, with greater numbers
of African Americans in the RAD-treated group and higher
APACHE II scores in the CRRT patient group.108 We look
forward to larger clinical studies to bring this technology to
the forefront to improve RRT.109
Plasma Therapies and Adsorption
Techniques in Septic AKI
Removal of inflammatory mediators with plasma exchange,
plasmapheresis alone, or combination with hemodiafiltration, as
well use of polymyxin B hemoperfusion, are being actively inves-
tigated for AKI associated with sepsis or multiorgan dysfunction.
Although concentrations of various septic mediators decrease,
results indicating survival are mixed and clear indications for
use of these therapies require results from large randomized
trials. Similarly, hemadsorption techniques using charcoal110
and polymyxin B beads111,112 in small trials have suggested
improved monocyte responsiveness, decrease in plasma tumor
necrosis factor levels, and decreased proapoptotic activity of
filtered plasma from septic patients when tested on cultured renal
cells.110,113 Polymyxin B hemoperfusion is available in Japan for
septic patients; however, not widely available outside of Japan.114
Larger clinical trials using this methodology are needed to clarify
its role in the septic AKI patient with high mortality.
Stem Cell and Renal Regeneration
for AKI
Hematopoietic stem cells have been shown to locate to the
injured kidney when kidney injury is induced in animal mod-
els.115,116 In addition, resident stem cells have also been located
in the kidney, as in some other organs, and have been shown
Postgraduate Medicine, Volume 122, Issue 6, November 2010, ISSN 0032-5481, e-ISSN 1941-9260 37
Acute Kidney Injury
to undergo dedifferentiation in the face of AKI.117 Studies
have suggested that intrarenal cells are primarily responsible
for the regenerative role after ischemic injury.118,119 Resident
mesenchymal cells may affect injury repair via differentiation
into and endothelial lineage with paracrine effects to prevent
microvascular dropout after renal injury.120 Furthermore, the
possibility of deriving pluripotent embryonic stem-like cells
from cultured somatic cells is also being investigated.121 The
ultimate goal will be to have the therapeutic option and ability
to repair renal injury once it occurs.
Summary
Acute kidney injury remains a significant cause of morbidity
and mortality for hospitalized patients. Recent standardized
clinical definitions have broadened this entity from failure
and loss of function to risk and injury, incorporating a shift
in thinking toward early diagnosis and preventive therapies.
Critical analyses of currently available therapies for supportive
management stress the importance of appropriate renal perfu-
sion, volume management, and adequate dosing with RRTs.
Active clinical investigations toward early diagnosis and more
cell-based therapies for AKI treatment will hopefully improve
patient outcomes in the future.
Conflict of Interest Statement
Devasmita Choudhury, MD discloses no conflicts of interest.
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