CONTEMPO UPDATES
LINKING EVIDENCE AND EXPERIENCE
Acute Renal Failure
Naveen Singri, MD
Shubhada N. Ahya, MD
Murray L. Levin, MD
A
CUTE RENAL FAILURE (ARF)
remains a common and criti-
cal clinical entity affecting 5%
to 7% of all hospitalized pa-
tients.1,2 It is associated with various
medical problems, treatments, and pro-
cedures. Despite advances in medical
care, ARF still carries a significant mor-
bidity and a 20% to 70% mortality rate.
Unfortunately, this has not improved
during the past 50 years because of a
sicker and older population.
Epidemiology
Acute renal failure is characterized by
an abrupt decline in renal function re-
sulting in an inability to excrete meta-
bolic wastes and maintain proper fluid
and electrolyte balance. Although there
is no universal laboratory definition, it
is reasonable to define ARF as an in-
crease in serum creatinine for 2 weeks
or less of 0.5 mg/dL (44.2 µmol/L) if the
baseline is less than 2.5 mg/dL (221
µmol/L) or an increase in serum creati-
nine by more than 20% if the baseline
is more than 2.5 mg/dL (221 µmol/L).
The incidence of ARF during hospi-
talization has remained stable over the
last 20 years.1,2 This is due not only to
the higher acuity of illnesses and ag-
gressive treatment of an aging popula-
tion, but also to the impact of newer
nephrotoxic medications, treatments,
diagnostic testing, and procedures.
When mild cases are included, the
overall outcome of ARF leads to a 20%
mortality rate. 2 Patients with more
severe renal insufficiency (an increase
of serum creatinine ⬎3.0 mg/dL [265
µmol/L]) and those requiring renal re-
placement therapy have mortality rates
approaching 40% to 50%.2 In the inten-
©2003 American Medical Association. All rights reserved.
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sive care unit (ICU), patients with ARF
carry the highest mortality rate of 50%
to 70%. This rate has remained un-
changed during the past 50 years, be-
cause patients in the ICU have more
complicated ARF and may be elderly
with multiple comorbidities.3 The sub-
set of patients who develop ARF during
the first 24 hours after cardiogenic shock
from a myocardial infarction have a mor-
tality rate of 87% vs 53% in those pa-
tients who did not develop ARF.4 The de-
velopment of ARF increases the mortality
associated with any primary disease.
Presentation
Most patients are asymptomatic and are
diagnosed with renal failure based on
laboratory data. Patients may present
with malaise, hematuria, flank pain,
dyspnea, edema, hypertension, or en-
cephalopathy. Acute renal failure is ei-
ther oliguric (⬍400 mL of urine/d) or
nonoliguric. Oliguria indicates a more
severe insult to the kidney compared
with nonoliguria. Affected patients with
contrast nephropathy and aminogly-
coside toxicity commonly present with
nonoliguric ARF. Anuria is defined as
less than 100 mL of urine/d. Only a few
conditions lead to complete anuria, in-
cluding vascular lesions, total obstruc-
tion, severe acute tubular necrosis
(ATN), or severe glomerulonephritis.
As toxins accumulate, patients be-
come lethargic, nauseated, confused, and
then comatose. Seizures and death may
ensue. Salt and water excess can lead to
vascular congestion, pulmonary edema,
and hypoxia. Hyperkalemia may cause
life-threatening arrhythmias. Acidosis
can compromise cardiac contractility
and cellular enzyme function.
Causes
The etiology of ARF is best divided into
prerenal, intrarenal, and postrenal
causes (TABLE 1).1,2,5,6 Prerenal azote-
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6
CLINICIAN’S CORNER
mia describes any condition leading to
decreased renal perfusion, including in-
travascular volume depletion, relative
hypotension, compromised cardiac out-
put, or hepatorenal syndrome. Intra-
renal diseases affect structures of the
nephron such as the glomeruli, tu-
bules, vessels, or interstitium. The most
common condition is ATN induced by
ischemia or toxins; ATN occurs when
the reduction in renal blood flow is se-
vere or prolonged enough to lead to cell
death. Prerenal azotemia and ische-
mic tubular necrosis occur on a con-
tinuum of the same pathophysiologic
process. These 2 conditions account for
75% of the cases of ARF.2 Postrenal dis-
ease signifies obstruction of urinary flow
anywhere from the renal pelvis to the
urethra and accounts for 5% of all cases
of ARF in the hospital.2
Patients who present with ARF in the
outpatient setting typically have drug
toxicity (angiotensin-converting en-
zyme inhibitors, nonsteroidal anti-
inflammatory drugs), acute interstitial
nephritis, volume depletion, obstruc-
tion, glomerulonephritis, vasculitis, or
sepsis. Inpatients tend to experience vol-
ume depletion, drug toxicity, contrast
nephropathy, hypotension, and sepsis.
Multiple etiologies frequently contrib-
ute to the development of ARF.
Diagnosis
The history and physical examination
remain invaluable tools in the workup
of ARF. A history of nephrotoxic medi-
cations, intravenous contrast, or hypo-
Author Affiliations: Division of Nephrology/
Hypertension, Department of Medicine, Northwest-
ern University Feinberg School of Medicine, Chi-
cago, Ill.
Corresponding Author and Reprints: Shubhada N.
Ahya, MD, Division of Nephrology/Hypertension, De-
partment of Medicine, Feinberg School of Medicine,
Olson Pavilion, 4-500, 710 N Fairbanks St, Chicago,
IL 60611 (e-mail: sahya@nmff.org).
Contempo Updates Section Editor: Sarah Pressman
Lovinger, MD, Fishbein Fellow.
747
ACUTE RENAL FAILURE

tension from rigorous chart review (in- A blood urea nitrogen/creatinine ra- nitrogen/creatinine ratio of only 10:1.
cluding intraoperative flowsheets) can tio of more than 15:1 to 20:1 suggests If glomerular filtration falls to less than
be found. Examination can show evi- hypoperfusion of the kidney leading to 10 mL/min, serum creatinine should in-
dence of orthostasis, edema, conges- increased reabsorption of urea by the crease by 0.5 to 1.5 mg/dL (44-133
tive heart failure, bladder distension, li- renal tubules. Patients with cirrhosis or µmol/L) per day depending on age,
vedo reticularis, petechiae, or palpable other protein deficient states may have muscle mass, and muscle injury. Blood
purpura (TABLE 2). renal hypoperfusion with a blood urea urea nitrogen should increase by 10 to
20 mg/dL (3.6-7.1 mmol/L) per day but
can be higher in hypercatabolic states
Table 1. Causes of Acute Renal Failure like sepsis, gastrointestinal bleeding, or
Cases of Acute Renal with corticosteroid use.
Failure, %
A urinalysis examined immediately
Causes Inpatient Outpatient after voiding is essential in the workup
Prerenal (renal hypoperfusion) of ARF (TABLE 3).7 A bland sediment
Hypovolemia: gastrointestinal, urinary, or skin losses;
hemorrhage; third-spacing; inadequate cardiac output without casts and protein suggests an
Hypotension: sepsis; anesthesia and medication-induced; underperfused state or obstructive
hepatorenal syndrome; relative hypotension below patient’s 35-401,2 705 uropathy. Once ATN has developed,
autoregulatory level
brownish granular casts with renal tu-
Pharmacologic: nonsteroidal anti-inflammatory drugs,
angiotensin-converting enzyme inhibitors bular epithelial cells may be present. In
Large vessel: thrombosis, embolus, dissection the setting of glomerulonephritis and
Intrarenal vasculitis, proteinuria, dysmorphic red
Small vessel: atheroembolism, malignant hypertension, blood cells, and red blood cell casts may
scleroderma, thrombotic thrombocytopenic
purpura/hemolytic-uremic syndrome, disseminated be observed. Red urine in the absence
intravascular coagulation of red blood cells suggests rhabdomy-
Glomeruli: acute or rapidly progressive glomerulonephritis, olysis or hemolysis.
vasculitis
The urinalysis also measures specific
Tubules
Acute tubular necrosis 55-60 11
gravity, which estimates urine osmolal-
Ischemic: hypovolemia, hypotension, sepsis ity. A urine osmolality of more than 400
Toxic (eg, intravenous contrast, aminoglycosides, mOsm/kg is frequently associated with
amphotericin B, cisplatin, myoglobin, hemoglobin) prerenal azotemia or glomerulonephri-
Obstruction (uric acid, calcium oxalate, acyclovir, indinavir, tis.7 A specific gravity of 1.010 indicates
light chains)
a urine osmolality of 300 mOsm/kg or
Interstitium: acute interstitial nephritis, infection (bilateral
pyelonephritis), infiltration (lymphoma, sarcoidosis),
isosthenuria. This occurs in normal states
aristolochic acid (Chinese herb)6 but also with ATN, where it reflects the
Postrenal loss of concentrating and diluting abili-
Ureteral: tumors, calculi, clot, sloughed papillae, ties of the renal tubules.
retroperitoneal fibrosis, lymphadenopathy
Bladder neck: tumors, thromboemboli, calculi, prostatic 2-5 17
Urine electrolytes are helpful in dif-
hypertrophy or carcinoma, neurogenic ferentiating prerenal azotemia from
Urethral: strictures, tumors, obstructed indwelling catheters ATN. The urine sodium concentra-
tion is usually less than 20 mEq/L with
renal hypoperfusion and more than 30
Table 2. History and Physical Examination in Acute Renal Failure
to 40 mEq/L with ATN (Table 3).7 The
fractional excretion of sodium (FENa)
History Physical Examination
is the percentage of filtered sodium that
Prerenal
Vomiting, diarrhea, hemorrhage, Orthostatic hypotension, poor skin turgor, dry is excreted in the urine. In the setting
overdiuresis, burns, pancreatitis, fevers, buccal mucosa, congestive heart failure, of oliguria, a FENa of less than 1% sug-
intraoperative hypotension, history of edema (these signs can also be seen in acute
heart failure or liver disease tubular necrosis resulting from severe gests hypoperfusion while a value of
prerenal azotemia), signs of liver disease more than 1% is usually due to intrin-
Intrarenal sic renal disease. 7 However, an el-
Nephrotoxic medications, intravenous Edema, livedo reticularis, petechiae, palpable
contrast, invasive angiography, purpura, muscle tenderness evated FENa may be misleading if di-
hemoptysis, sinusitis, pharyngitis, or uretics or intravenous fluids were given
other infection, muscle trauma with before the urine collection. Other causes
rhabdomyolysis, red urine
Postrenal
of a low FENa include glomerulone-
Decreased urinary stream, nocturia, Distended bladder, enlarged prostate, abdominal phritis, contrast nephropathy, myoglo-
anuria, frequency, dribbling, flank pain or pelvic masses binuria, hemoglobinuria, and early ATN
748 JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted) ©2003 American Medical Association. All rights reserved.

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Table 3. Urinalysis, Urine Chemistries, and Osmolality in Acute Renal Failure
Hypovolemia
Sediment Bland
Protein None or low
Urine sodium, mEq/L* ⬍20
Urine osmolality, ⬎400
mOsm/kg
Fractional excretion of ⬍1
sodium, %†
Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.
*The sensitivity and specificity of urine sodium of less than 20 in differentiating prerenal azotemia from acute tubular necrosis are 90% and 82%, respectively (N = 85).7
†Fractional excretion of sodium is the urine to plasma (U/P) of sodium divided by U/P of creatinine ⫻ 100. The sensitivity and specificity of fractional excretion of sodium of less than
1% in differentiating prerenal azotemia from acute tubular necrosis are 96% and 95%, respectively (N = 85).7
(transition from prerenal azotemia to
ischemic tubular necrosis).
Other laboratory studies may also be
helpful in the workup of ARF. A com-
plete blood cell count with coagulation
studies may reveal evidence of platelet
consumption, red blood cell mem-
brane damage, or both, indicating
thrombotic thrombocytopenic purpura/
hemolytic-uremic syndrome, or dissemi-
nated intravascular coagulation. Eosino-
philia may suggest acute interstitial
nephritis or atheroembolic disease. Eo-
sinophiluria (⬎1%) can be seen in some
forms of acute interstitial nephritis but
has poor sensitivity and specificity. An
elevated creatine phosphokinase may
suggest rhabdomyolysis.
Ultrasonography is the safe, readily
available radiologic procedure for as-
sessing obstruction, kidney size, and
echogenicity.8 Unless a clear inciting fac-
tor is found, a renal ultrasound should
be performed early in the evaluation of
ARF. Small kidneys with increased cor-
tical echogenicity imply chronic medi-
cal disease, but a component of acute re-
nal deterioration may also be present.
Renal Doppler blood flows are helpful if
renovascular compromise is suspected
clinically. Kidney biopsy is used in the
evaluation of ARF if a nephritic or ne-
phrotic syndrome, or unexplained re-
cent onset of renal failure exists.
Treatment
Once renal failure occurs, the physi-
cian should attempt to reverse the un-
©2003 American Medical Association. All rights reserved.
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Acute Tubular Acute Interstitial
Necrosis Nephritis
Broad, brownish White blood cells,
granular casts eosinophils,
cellular casts
None or low Minimal but may be
increased with
NSAIDs
⬎30 ⬎30
⬍350 ⬍350
⬎1 Varies
derlying cause. The intravascular vol-
ume and mean arterial pressure (MAP)
should be returned to baseline, and elec-
trolyte abnormalities should be cor-
rected. Further damage should be pre-
vented by avoiding nephrotoxic agents.
The ICU mortality rate has been shown
to be increased when renal consulta-
tion was delayed for more than 48 hours;
thus, the nephrologist should become in-
volved early in the course of ARF.9
Hyperkalemia can be treated medi-
cally. Inhaled ␤-agonists, insulin/
glucose (5-10 U intravenously fol-
lowed by 1 ampule 50% dextrose), and
sodium bicarbonate (to neutralize ac-
ids) shift potassium intracellularly but
will not lower total body potassium. So-
dium polystyrene sulfonate (SPS), a po-
tassium-binding resin, can be used to
decrease total body potassium through
gastrointestinal potassium transport-
ers. As most of these transporters lie in
the rectosigmoid colon, rectal admin-
stration of SPS can result in immedi-
ate potassium reduction. Sorbitol has
been used to hasten kayexalate deliv-
ery. Due to recent reports of gastroin-
testinal ulcerations with its use,10 SPS
may be mixed with ginger ale for oral
administration or suspended in dex-
trose with water or saline for rectal ad-
ministration. A diet low in potassium
is also recommended.
Some physicians still use renal-dose
dopamine (0.5-2.0 µg/kg per minute)
for prophylaxis or treatment of ARF. In
healthy patients, dopamine improves
(Reprinted) JAMA, February 12, 2003—Vol 289, No. 6
ACUTE RENAL FAILURE
Glomerulonephritis Obstruction
Red blood cells, red Bland or bloody
blood cell casts
Increased, ⬎100 Low
mg/dL
⬍20 ⬍20 (Acute)
⬎40 (Few days)
⬎400 ⬍350
⬍1 ⬍1 (Acute)
⬎1 (Few days)
renal blood flow, glomerular filtration
rate (GFR), and sodium excretion.
However, recent studies and a meta-
analysis have shown no benefit in the
prevention or early treatment of
ARF.11-13 Furthermore, dopamine may
be harmful by shifting oxygen con-
sumption to the renal medulla from
deep cortical structures and by sup-
pressing anterior pituitary hormone
concentrations.14
Renal replacement therapy is initi-
ated for hyperkalemia, volume over-
load, or metabolic acidosis refractory
to medical therapy. It is also started for
uremic complications such as pericar-
ditis or encephalopathy. Intensive daily
dialysis leading to decreased mortality
and faster recovery of renal function has
been recently described.15 However, be-
cause lower surface area dialyzers were
used and desired dialysis clearances
were not achieved, further data need to
be acquired before daily dialysis can be
recommended. Continuous renal re-
placement therapy is initiated in pa-
tients with hemodynamic instability and
has not been shown to be superior to
conventional hemodialysis.16
Patients recovering from oliguric ARF
may have an increase in urine output
before stabilization or improvement of
serum chemistries is noted. The GFR
may have improved slightly but insuf-
ficiently to clear metabolic wastes. Con-
tinued renal replacement therapy may
be necessary despite resumption of uri-
nary output.
749
ACUTE RENAL FAILURE
Conversion of oliguric to nonol-
iguric ARF with the use of high-dose di-
uretics has not been shown to improve
mortality or lessen the need for hemo-
dialysis.17,18 Recently, a cohort study of
ICU patients with ARF suggested that
patients treated with diuretics had an in-
creased risk of death and nonrecovery
of renal function.19 Despite adjustment
for age, comorbidities, and urine out-
put, the group who received diuretics
still appeared to have a poorer progno-
sis. An age- and comorbidity-matched
prospective trial is probably the best way
to determine whether these variables in-
fluenced the study’s results. If these truly
were negative effects of diuretics, they
could have occurred because of a di-
rect toxic effect or because of a delay in
obtaining nephrology consultation and
dialysis while awaiting a potential salu-
tary effect of the diuretics, or perhaps
other factors not yet elucidated. None-
theless, it appears that diuretics rarely
have a beneficial effect on established
ARF and may be harmful. Nephrologic
consultation should be obtained as soon
as possible.
In ARF, medications need to be ad-
justed for a GFR of less than 10 mL /
min to avoid overdosing, regardless of
the serum creatinine. Any formula used
to calculate GFR is accurate only in the
presence of stable renal function.
Prevention
Because of the high morbidity, mortal-
ity, and costs associated with ARF, pre-
vention of ARF is most important. En-
dothelin antagonists, atrial natriuretic
peptides, prostaglandins, nitric oxide in-
hibitors, thyroxine, and human insulin-
like growth factor 1 have been studied
for the prophylaxis and treatment of
ATN without clinical benefit.20-23
The prevention or immediate correc-
tion of hypotension and stabilization of
the MAP may preclude ARF. This re-
quires volume replacement with iso-
tonic saline. Elderly patients have a di-
minished ability to autoregulate renal
blood flow in the face of low blood pres-
sure. Although an MAP of 70 mm Hg
may be tolerated in a younger patient,
it can lead to azotemia in an older pa-
750 JAMA, February 12, 2003—Vol 289, No. 6 (Reprinted)
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tient. This is especially important in the
intraoperative setting under general an-
esthesia.
Identifying patients who are at
increased risk for developing ARF is cru-
cial. Increased age, chronic renal insuf-
ficiency (CRI), diabetes mellitus, obe-
sity, and jaundice are important risk
factors. In patients with stable baseline
renal function, the creatinine clear-
ance, an estimate of GFR, can be calcu-
lated using the Cockcroft-Gault for-
mula24: creatine clearance = (140 − age)
⫻ ideal weight (kg) (⫻ 0.85 for women)/
72 ⫻ serum creatinine (mg/dL).
Older individuals and those with low
muscle mass (eg, patients with end-
stage liver disease) may have compro-
mised renal function despite normal or
near-normal serum creatinine levels.
Acute renal failure can be prevented by
appropriate dosing of medications and
the use of prophylactic measures for
contrast nephropathy in patients with
known CRI.
Radiographic contrast still accounts for
10% of hospital-acquired ARF. Re-
cently, several groups have studied the
combination of acetylcysteine and 0.45%
saline in preventing ARF in high-risk pa-
tients. Two trials using an oral acetyl-
cysteine regimen with 0.45% saline
reduced the incidence of contrast ne-
phropathy in patients with CRI (serum
creatinine, 1.6-2.4 mg/dL [141-212
µmol/L]) undergoing computed tomog-
raphy scans (90% risk reduction; 21% to
2% incidence)25 and coronary angio-
grams (82% risk reduction; 45% to 8%
incidence).26 Another study27 of pa-
tients with CRI (serum creatinine ⬎1.2
mg/dL [⬎106 µmol/L] or creatinine
clearance ⬍60 mL/min [⬍1.0 mL/s] un-
dergoing coronary angiography re-
vealed that patients given oral acetylcys-
teine regimen experienced a reduction
in contrast nephropathy (67% risk re-
duction; 12% to 4% incidence) com-
pared with those given 0.9% saline alone.
However, another study28 of patients
(mean serum creatinine, 1.5 mg/dL [133
µmol/L]) undergoing coronary or pe-
ripheral angiography who were given
more than 140 mL of contrast did not
show renal protection with acetylcyste-
©2003 American Medical Association. All rights reserved.
ine and 0.45% saline. Given all of these
results, the oral acetylcysteine regimen
(600 mg twice daily the day before and
the day of the radiographic study) with
0.45% saline at 1 mL/kg 6 to 12 hours
before and after contrast infusion should
be administered.29 The choice of fluids
needs to be reinvestigated, as a recent
trial30 found that isotonic saline was su-
perior to 0.45% saline in the prevention
of contrast nephropathy in patients with
normal renal function undergoing coro-
nary angioplasty. To minimize the
amount of contrast administered, when
possible, left ventriculograms should be
avoided during cardiac catheterizations
and magnetic resonance angiography
substituted for computed tomography
scans with contrast.
Fenoldopam mesylate is a selective
dopamine (D1) receptor agonist ap-
proved for use in hypertensive urgen-
cies and emergencies. Dopamine re-
ceptor activation in the kidney leads to
vasodilation and increased renal blood
flow. Several nonrandomized studies
have shown a lower incidence of con-
trast nephropathy with fenoldopam and
hydration when compared with his-
torical controls.31,32 Recently, a ran-
domized, double-blinded, placebo-
controlled study of 45 patients with CRI
(mean serum creatinine, 2.6 mg/dL
[230 µmol/L]) undergoing coronary an-
giography showed that fenoldopam
with 0.45% saline was superior to 0.45%
saline alone in preventing contrast ne-
phropathy (50% risk reduction; 41% to
21% incidence).33 These results are
promising and larger multicenter trials
are currently taking place.
Medications that frequently cause
ARF, especially in patients with hemo-
dynamic compromise, include ampho-
tericin B, aminoglycosides, and non-
steroidal anti-inflammatory drugs. Risk
factors leading to amphotericin B neph-
rotoxicity include male sex, CRI, daily
dose of more than 35 mg, total cumu-
lative dose, duration of therapy, and
concurrent use of cyclosporine or
aminoglycosides.34,35 Therefore, am-
photericin B should be dosed at 0.6
mg/kg per day and, if tolerated, iso-
tonic saline given prior to each dose.

Aminoglycoside toxicity usually oc-
curs after 1 week of therapy but can pre-
sent as early as 1 to 2 days after start-
ing therapy if another renal insult
coexists. Renal dysfunction can occur
even with close monitoring of levels due
to continued accumulation in the proxi-
mal tubular cells. The risk is higher in
patients with elevated drug levels,
longer duration of therapy, divided
doses, jaundice, and obesity but can be
reduced with single daily dosing (79%
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