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Acute Tubular Necrosis

Residents conference
Presented by Dr Gagandeep K Heer, MD
(PGY-2)

Background
Definition: ARF is defined as an abrupt or

rapid decline in the renal function.


A rise in serum BUN or creatinine
concentration, with or without decrease in
urine output, usually is evidence of ARF.
ARF is often transient and completely
reversible.

Background

The causes of ARF are divided into 3 categories:


Prerenal
Renal
Postrenal
ATN is the most common cause of ARF in the renal category.
ATN is the 2nd most common cause of all categories of ARF in
hospitalized patients, with only prerenal azotemia occurring
more frequently.
In outpatients, obstruction (ureteric, bladder neck or urethral)
is the 2nd most common cause of ARF after prerenal azotemia.
Other causes of ARF include acute interstitial nephritis, acute
glumerulonephtitis, vasculitis, HUS, TTP, DIC, accelerated HTN,
radiation nephritis, acute on chronic renal failure, renovascular
obstruction (bilateral or unilateral in the setting of single
functioning kidney), renal allograft rejection, intratubular
deposition and obstruction (myeloma proteins, urate, oxalate
crystals, etc.)

Pathophysiology

ATN usually occurs after an acute ischemic or


toxic event, and it has a well-defined sequence of
events.
Initiation phase characterized by acute decrease
in GFR to very low levels, with a sudden increase
in serum Cr and BUN concentrations.
Maintenance phase is characterized by sustained
severe reduction in GFR and the BUN and Cr
continue to rise.
Recovery phase, in which the tubular function is
restored, is characterized by an increase in urine
volume (if oliguria was present) and gradual
decrease in Cr and BUN to their pre-injury level.

Ischemic ATN

Ischemic ATN is often described as a continuum of prerenal


azotemia. Response to fluid repletion can help distinguish
between the two: return of renal function within 24-72
hours usually indicate prerenal disease although short-lived
ATN can recover within similar timeframe (e.g. self limited
insult such as transient aortic clamping during suprarenal
aortic aneurysm surgery).
Initiation phase: Hypoperfusion initiates cell injury that
often leads to cell death. It is most prominent in straight
portion of the proximal tubules and thick ascending limb of
loop of Henle. The reduction in the GFR occurs not only
from reduced filtration due to hypoperfusion but also from
casts and debris obstructing the lumen, causing back leak
of filtrate through the damaged epithelium (ineffective
filtration). In addition, ischemia leads to decreased
production of vasodilators (i.e. nitric oxide, prostacyclin) by
tubular epithelial cells, leading to further vasoconstriction
and hypoperfusion.

Ischemic ATN

Maintenance phase is characterized by stabilization of


GFR at a very low level, and it typically lasts 1-2 weeks.
Uremic complications typically develop during this
phase. In addition to the above mentioned mechanism of
injury, tubulo-glomerular feedback also plays a role by
causing constriction of afferent arterioles by the macula
densa cells, which detect and increased salt load in the
distal tubules.
During Recovery phase, there is regeneration of tubular
epithelial cells. An abnormal diuresis sometimes occurs,
causing salt and water loss and volume depletion. The
mechanism of the diuresis is not completely understood,
but it may in part be due to delayed recovery of tubular
cell function in the setting of increased glomerular
filtration. In addition, continued use of diuretics (often
administered during initiation and maintenance phases)
may also add to the problem.

Nephrotoxic ATN

Most of the pathophysiological features of


ischemic ATN are shared by the
nephrotoxic forms and it has the same
three phases.
Nephrotoxic injury to tubular cells occurs
by multiple mechanisms including direct
toxicity, intrarenal vasoconstriction, and
intratubular obstruction.

At cellular level

Ischemic ATN:
Cellular ischemia results in series of alterations in energetics,
ion transport and membrane integrity that ultimately leads to cell
injury or necrosis. These changes include depletion of ATP,
inhibition of active sodium transport and transport of other
solutes, impairment of cell volume regulation, cytoskeletal
disruption and loss of cell polarity, cell-cell and cell-matrix
attachment, accumulation of intracellular calcium, altered
phospholipid metabolism, oxygen free radical formation and
peroxidation of membrane lipids.
A characteristic feature of ischemic ATN is the absence of
widespread necrosis of tubular epithelial cells. Necrosis is more
subtle and is reflected in individual necrotic cells within some
proximal or distal tubules. These single cells shed into tubular
lumen, with resulting focal denudation of the tubular basement
membrane. Interstitial edema is common.

Ischemic ATN

Histology (continued)

Toxic ATN: The morphology differs from ischemic


ATN in that the former is characterized by more
extensive necrosis of the tubular epithelium. In
most cases, however, the necrosis is limited to
certain segments that are most sensitive to the
toxin. ATN caused by hemoglobin or myoglobin
has added feature of numerous red-brown
tubular casts, colored by heme pigments.
During the recovery phase of ATN, the tubular
epithelium regenerates, leading to the
appearance of mitoses, increased size of cells and
nuclei, and cell crowding. Survivors eventually
display complete restoration of normal renal
architecture.

Nephrotoxic ATN

Frequency

In the US: ARF is seen in 5% of all


hospital admissions and upto 30% of
patients admitted to the ICU. Prerenal
causes account for about half of all cases.
ATN is most common cause out of the
intrinsic renal diseases.

History

A good history is very important in diagnosis of


ATN.
Find out about:
Recent hypotension
Sepsis
Muscle necrosis (e.g. h/o seizure, cocaine use)
Exposure to contrast or nephrotoxic medications
Hypovolumia
Other risk factors for development of ATN like
underlying renal disease from DM, HTN, etc.

Physical Exam

Physical exam may be unremarkable because


ARF is often found incidentally during routine
laboratory studies (i.e. elevated BUN and Cr).
Look for pericardial friction rub (pt may have
pericarditis), asterixis and/or excoriation marks
related to uremic pruritis.
Hypertension or edema may be noted.
Physical findings related to the underlying
disease.

Causes of ATN
ATN is usually caused by an acute event,
either ischemic or toxic.

Causes of Ischemic ATN

It may be considered part of the spectrum


of prerenal azotemia and they have the
same causes and risk factors
Hypovolumic states hemorrhage,
volume depletion from GI or renal losses,
burns, fluid sequestration.
Low cardiac output states CHF and other
diseases of the myocardium, valvulopathy,
arrhythmia, pericardial diseases,
tamponade.

Causes of Ischemic ATN

Systemic vasodilation sepsis,


anaphylaxis
DIC
Renal vasoconstriction cyclosporine,
norepinephrine, epinephrine, amphotericin
B, etc
Hyperviscosity syndrome
Impaired renal autoregulatory responses
cyclooxygenase inhibitors

Causes of Nephrotoxic ATN


The kidney is a good target for toxins. Not
only does it have a rich blood supply,
receiving 25% of CO, but it also helps in
the excretion of these toxins by
glomerular filtration and tubular secretion.

Exogenous toxins
Aminoglycosides:
10-30% of patients getting aminoglycosides
develop ATN.
Risk factors include preexisting liver disease,
renal disease, concomitant use of other
nephrotoxins, advanced age, shock, female sex
and a higher level 1 hr after the dose.
Toxicity presumably more common with 3
doses/day than a single daily dose (as the drug
uptake by tubules is saturable phenomenon).
Amphotericin B: The likelihood of toxicity is in
direct proportion to the total dose administered
and is more common if > 3 grams is
administered.

Exogenous Toxins
Radiocontrast media:

Contrast-induced nephropathy has become a frequent


occurrence with increased number of studies requiring
contrast media like angiography, CT scan, etc

Iodinated contrast media causes vasoconstriction as well as


a direct toxic effects on tubular cells.

Patients at increased risk include diabetes, baseline renal


insufficiency, large contrast load, history of HTN, older age
and presence of proteinuria.
Cyclosporine and tacrolimus: Can cause ARF as well as chronic
interstitial nephritis.
Sulfa drugs, acyclovir and indinavir cause ARF by tubular
obstruction due to crystal formation in the tubular lumen
Others: Cisplatin, methotrexate and foscarnet, etc.

Endogenous toxins
Myoglobinuria

The breakdown of muscle (rhabdomyolysis), leading to


myoglobinuria, occurs in many clinical settings like crush injuries,
viral illness, cocaine, heavy exercise, alcoholism, seizures and
certain medications. ATN can develop in small proportion of these
patients.

The exact mechanism of renal failure is not clearly understood,


but several theories include direct toxic injury, development of
DIC, mechanical tubular obstruction by the pigment and intrarenal
ischemia from vasomediator release.

Factors that increase the risk of ATN in this setting include


extracellular fluid volume depletion, liver dysfunction and
hypotension.
Hemoglobinuria
ARF is a rare complication of hemolysis and hemoglobinuria and is
most often associated with transfusion reactions. Hemoglobin has
no apparent direct toxicity on the cells and the renal failure in this
setting is probably related to hypotension and decrease renal
perfusion.

Endogenous Toxins
Crystals:
Acute crystal-induced nephropathy is encountered in
conditions where crystals are produced endogenously due
to high cellular turnover (i.e. uric acid, calcium phosphate),
as seen in certain malignancies or the treatment of these
malignancies (tumor lysis syndrome). However, this
condition is also associated with ingestion of certain toxic
substances, such as ethylene glycol.
Multiple myeloma:
This condition causes renal failure by several mechanisms,
such as prerenal azotemia due to volume contraction, cast
nephropathy due to increased light chain proteins
precipitated into the tubular lumen, hypercalcemia and uric
acid nephropathy.

Workup
Lab studies

Serum chemistries: By definition, BUN and serum Cr


concentrations are increased. In addition, hyponatremia,
hyperkalemia, hypermagnesemia, hypocalcemia,
hyperphosphatemia and metabolic acidosis may be present.
Remember that hypercalcemia and hyperuricemia may
suggest a malignant condition as a cause.
CBC: Pt may be anemic. Not only is erythropoietin
production decreased but platelet dysfunction from uremia
also makes bleeding more likely.
Urinalysis: May reveal muddy brown, granular casts and
epithelial cell casts. In addition, checking urine lytes may
also help differentiate ATN from prerenal azotemia.

Laboratory Findings Used to


Differentiate Prerenal Azotemia
from ATN

Finding

Prerenal
Azotemia

ATN

>500

<350

<20

>40

Fraction excretion
of sodium(%)

<1

>2

Fraction excretion
of Urea(%)

<35

>50

Plasma BUN/Cr
ratio

>20

<10-15

Urine Cr/Plasma Cr
ratio

>40

<20

Bland and/or
nonspecific

May show muddy


brown granular
casts

Urine osmolarity
(mOsm/kg)
Urine sodium
(mmol/d)

Urine sediment

Lab (continued)

Loss of concentrating ability is an early and


almost universal finding in ATN.
None of the above criteria for the diagnosis of
prerenal disease may be present in a patient with
underlying renal disease. Hence, a cautious trial
of fluids may be given.

Imaging Studies

Abdominal radiograph is of limited benefit


in ARF except in diagnosing (or excluding)
nephrolithiasis.
Ultrasound, CT scan, or MRI very useful,
both to exclude obstructive uropathy and
measure renal size and cortical thickness.
Renal US is a simple, relatively
inexpensive and non-invasive imaging
modality and should be done in all
patients presenting with ARF.

Renal biopsy

Biopsy is rarely necessary. It should only be performed when the


exact renal cause of ARF is unclear, the course is protracted and
knowing the exact cause is possibly going to change the
management.
Needless to say, prerenal and postrenal causes must be ruled out
before subjecting a patient to this invasive procedure. The
diagnosis of ATN is made on a clinical basis, i.e. with the help of
detailed and accurate history, thorough physical exam, and
pertinent lab tests and imaging studies.
A more urgent indication for renal biopsy is in the setting of
clinical and urinary findings suggestive of renal vasculitis rather
than ATN and the diagnosis needs to be established quickly so
that appropriate immunomodulatory therapy can be initiated.
Biopsy may also be more critically important in a renal transplant
patient to rule out rejection.
Other indications for biopsy include suspected glomerulonephritis,
HUS, TTP and acute interstitial nephritis.
The biopsy is performed under ultrasound or CT guidance after
ascertaining the safety of the procedure.

Complications
Patients with ATN can have several complications.

Electrolyte abnormalities
Hyperkalemia: Higher levels are associated with ECG
abnormalities (e.g. peaked T waves, prolonged PR interval, P
wave flattening, widened QRS) and risk of developing lifethreatening arrhythmias (e.g. ventricular tachycardia or
fibrillation, complete heart block, bradycardia, asystole).
Arrhythmias have been reported in up to 30% of patients. In
addition to these worrisome cardiac effects, hyperkalemia can
also lead to neuromuscular dysfunction and, potentially,
respiratory failure.
Hyponatremia
Hyperphosphatemia
Hypermagnesemia
Hypocalcemia: Hypocalcemia may be secondary to both
deposition of calcium phosphate and reduced levels of 1,25
dihydroxyvitamin D. It is usually asymptomatic, but
hypocalcemia may result in nonspecific ECG changes, muscle
cramps, or seizures.
Metabolic acidosis

Complications

Intravascular volume overload: It is characterized by weight gain,


raised jugular venous pressure and dependent edema. In its most
severe manifestation, this may lead to respiratory failure from
pulmonary edema.
Hypertension: Hypertension is suspected to mainly be due to salt
and water retention. About 25% of patients with ARF develop
some hypertension.
Uremic syndrome/Uremia: Uremia results from the accumulation
of nitrogenous waste. It is a potentially life-threatening
complication associated with ARF.
Platelet dysfunction is common and can lead to life-threatening
hemorrhage.
This may manifest as pericardial disease (uremic
pericarditislisten for a rub on exam)
GI symptoms (i.e. nausea, vomiting, cramping)
Neurological symptoms (i.e. lethargy, confusion, asterixis,
seizures).
Anemia: Anemia may develop from many possible causes.
Erythropoiesis is reduced in ARF, but platelet dysfunction is also
observed in the setting of uremia, which may predispose to
hemorrhage. In addition, volume overload may lead to
hemodilution, and red cell survival time may be decreased.

Complications

Polyuric phase of ATN: This complication can lead


to hypovolemia and create a setting for prerenal
azotemia and perpetuation of ATN.
Infections: Infections is the leading cause of
morbidity and mortality and can occur in 30-70%
of patients with ARF. Infections are more likely in
these patients because of an impaired immune
system and because of increased use of
indwelling catheters and intravenous needles.

Prevention
Ischemic ATN: Be attentive to optimizing
cardiovascular function as well as maintaining
intravascular volume, especially in patients
with preexisting risk factors or those taking
nephrotoxic medications. Medicines that
reduce systemic resistance (e.g. afterload
reducers) may cause renal vasoconstriction or
affect the kidneys autoregulatory response
(e.g. ACE inhibitors, cyclooxygenase inhibitors)
and also should be used with caution.
Dopamine, mannitol and furosemide, etc have
been tried within 24 hrs of ischemic insult to
prevent progression to ATN, but have no
proven benefit.

Prevention
Nephrotoxic ATN
Aminoglycosides: Once daily dosing of
aminoglycosides decreases the
incidence of nephrotoxicity.
Amphotericin B: Minimize the use of
this drug and assure that ECF volume
is adequate.
Cyclosporin and tacrolimus: Regular
monitoring of blood levels.
Alkalinization of the urine should be
tried in patients with marked
myoglobinuria and hemoglobinuria.

Prevention
Radiocontrast dye: Out of all the agents/modalities
that have been investigated for prevention of CIN, only
the following have been shown to be of some benefit:
1.Hydration with isotonic saline infusion has proven
benefits in prevention of contrast-induced nephropathy.
Typically, half isotonic sodium chloride solution
(0.45%) administered at a rate of 50-100 mL/h 12
hours before and 12 hours after the administration of
the dye load is most effective, especially in the setting
of prior renal insufficiency and diabetes mellitus.
2. Low osmolal and iso-osmolal nonionic contrast media
are also associated with lower incidence of CIN.
3. N-acetylcysteine has been used with success in highrisk patients to prevent contrast-induced
nephrotoxicity.
4. Using lower doses of contrast media, avoiding volume
depletion and NSAIDs, both of which can cause renal
vasoconstriction are some other useful measures.
5. A new modality recently investigated is use of
prophylactic hemofiltration in patients who need
contrast and have baseline renal insufficiency.

The Prevention of Radiocontrast-AgentInduced


Nephropathy by Hemofiltration
Giancarlo Marenzi, M.D., et al.
NEJM October 2nd, 2003.
114 consecutive patients with chronic renal failure (serum creatinine
concentration, >2 mg/dl, who were undergoing coronary interventions, were
Randomly assigned to either hemofiltration in an intensive care unit (ICU) or
isotonic-saline hydration at a rate of 1 ml per kilogram of body weight per
hour given in a step-down unit. Hemofiltration and saline hydration were
initiated 4 to 8 hours before the coronary intervention and were continued for
18 to 24 hours after the procedure was completed.
Results: Compared with intravenous saline, hemofiltration was associated
with the following significant benefits
1. A lesser likelihood of an increase in the serum creatinine concentration of
greater than 25 percent from baseline values (5 versus 50 percent)
2. A lesser likelihood of requirement for temporary renal replacement
therapy (3 versus 25 percent)
3. A reduction in both in-house mortality (2 versus 14 percent) and one-year
mortality (10 versus 30 percent).
4. Greatest benefit was seen in patients with higher Cr (>4 mg/dl).
Until additional data are available, routine use of hemofiltration for prevention of
CIN is not recommended. However, consideration should be given to the use of
hemofiltration (in combination with other preventive measures) among patients at highest
risk of contrast nephropathy, particularly the diabetic patient with a baseline serum
creatinine concentration of 4 mg/dL or greater.

Treatment
General treatment

The main goal of treatment is to prevent further injury to


the kidney. ECF volume should be assessed promptly,
either on clinical grounds or by invasive means (SwanGanz catheter), and repletion of any deficit should be
initiated promptly. A renal ultrasound should be performed
to exclude obstruction.
All possible nephrotoxic drugs should be stopped.
In general, an attempt is made to increase the urine output
if oliguria is present, by using loop diuretics, although there
is some controversy about this in the literature. One
retrospective study showed that diuretics may even
increase the risk of death and non-recovery of renal
function. Only use diuretics if ECF volume and cardiac
function are first carefully assessed and found adequate.
The only true indication for diuretic use is volume overload.
Furosemide and bumetanide are the commonly used
diuretics.

Treatment

Aggressively treat any complications that develop.


Remember that sepsis is a common cause of death
with severe ARF, so aggressive treatment of
infections is prudent. However, prophylactic antibiotic
has not been proven to be of any benefit.
Also, adjust doses of all medications if the kidney
eliminates them.
Various agents have been studied for their possible
role in hastening tubular regeneration and functional
recovery in ATN including growth factors (IGF-I), low
dose DA, combination of DA and ANP and anaritide (a
synthetic form of ANP) but have shown no benefit in
recovery or survival.

Treatment
Dialysis treatment
In general, no clear consensus is established on when
or how often to perform hemodialysis in the setting
of ARF. Some studies have suggested that early
initiation may be beneficial, but, in one prospective
trial, aggressive dialysis did not improve recovery or
survival rates. However, hemodialysis is still
considered standard therapy in severe ARF. In
addition, continuous hemodialysis (continuous
venovenous hemofiltration [CVVHD] and continuous
arteriovenous hemofiltration with dialysis (CAVHD)
and peritoneal dialysis are also available. No
compelling studies suggest that one mode is better
than another. In general, patients with multiorgan
failure and hemodynamic instability may benefit from
a continuous mode because it is typically less taxing
on the hemodynamics.
Indications for dialysis: Clinical evidence of uremia,
intractable intravascular volume overload,
hyperkalemia or severe acidosis resistant to
conservative measures.

Treatment of Complications

Volume overload: Salt and water restriction, diuretics.


Dialysis for refractory cases.
Hyperkalemia: Restrict potassium intake, glucose and
insulin, sodium bicarbonate, kayexalate, calcium gluconate,
dialysis.
Metabolic acidosis: Sodium bicarb (only if HCO3
<15mmol/L or pH<7.2) or dialysis.
Hypocalcemia: Calcium carbonate, calcium gluconate.
Infections: Antibiotics, assess the IV sites.
Hyponatremia: Free water restriction.
Hyperphosphatemia: Restrict phosphate intake, phosphate
binding agents.
Hypermagnesemia: Avoid Mg containing antacids.
Anemia: Blood transfusion may be required.

Nutrition

Clearly, the maintenance of fluid and electrolyte


balance is critical. Aggressive and early
nutritional support also improves survival rates.
Adequate caloric intake is essential to avoid
catabolism and starvation ketoacidosis, while
minimizing production of nitrogenous waste. This
is best achieved by restricting dietary protein to
approximately 0.6g/kg/day of protein of high
biologic value (rich in essential amino acids) and
provide most calories as carbohydrate
(approximately 100 g/day).
Enteral hyperalimentation or parenteral nutrition
if recovery prolonged or if patient very catabolic.

Mortality and Morbidity

The in-hospital survival rate of patients with ATN


is about 50%, with 30% surviving for 1 year.
Factors associated with increased mortality
include: poor nutrition status, male sex, the
presence of oliguria, need for mechanical
ventilation, chronic immunosuppression, acute
MI, stroke or seizures.
The presence of renal failure itself seems to be a
prognostic factor in survival since it weakens
immune system and impairs platelet function
thus predisposing the patient to sepsis and
bleeding.

Mortality and Morbidity

Infections remain the leading cause of death.


For ARF the mortality rate is 20-50% in patients with
underlying medical illnesses, but the mortality rate is as
high as 60-70% with patients in a surgical setting or with
severe trauma. If multiorgan failure is present, especially
severe hypotension or acute respiratory distress syndrome,
the mortality rate ranges from 50-80%.
With dialysis intervention, the frequency of uremia,
hyperkalemia, and volume overload as causes of death
have decreased. The most common causes of death now
are sepsis, cardiovascular and pulmonary dysfunction, and
withdrawal of life support.
The type of dialysis membrane utilized during HD may also
affect prognosis.

Prognosis

Patients with oliguric ATN have a worse prognosis


than patients with nonoliguric ATN. This probably
is related to more severe necrosis and more
significant disturbances in electrolyte balance.
Rapid increase in serum creatinine (i.e. >3
mg/dL) probably also indicates a poorer
prognosis. Again, this probably reflects more
serious underlying disease.
Of the survivors of ATN, approximately 50% have
residual subclinical impairment of renal function,
about 5% continue to undergo a decline in renal
function following an initial recovery phase and
about 5% never recover kidney function and
require dialysis.

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