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Multiprofessional Critical Care Review Course - 2005
267
OBJECTIVES
• Differentiate features of the major causes of renal failure
in the critically ill patient
• Generate an appropriate differential diagnosis for acute
renal failure in this setting
• Describe the general management of the various causes
of acute renal failure
• Defi ne the various dialysis modalities available and their
applications
INTRODUCTION
Acute renal failure (ARF) is an abrupt decrease in glomerular
fi ltration rate (GFR) resulting in the accumulation of
nitrogenous waste products in the blood (acute azotemia).
ARF comprises a spectrum of disorders and usually is due to
an alteration in systemic or intrarenal hemodynamics, acute
renal parenchymal disease, or urinary tract obstruction, and
it generally carries the expectation of complete recovery.
Acute azotemia also may be due to nonrenal factors (“pseudorenal”
failure). Elevations in blood urea nitrogen (BUN) without
a change in GFR may occur with corticosteroid use, gastrointestinal
bleeding, tetracyclines, severe catabolic states,
or hyperalimentation. Similarly, the serum creatinine may
increase with inhibition of renal tubular creatinine secretion
(trimethoprim and cimetidine), or due to interference with the
creatinine assay (cefoxitin, acetone, alpha-methyldopa) (1)
(Table 1). Conversely, malnutrition and severe liver disease
may result in decreased BUN levels, and severe muscle wasting
will be associated with low creatinine concentrations as
muscle is the major source of creatinine production. These
nonrenal factors always should be considered when using
BUN and creatinine to evaluate kidney function. Due to
these and other factors, estimating glomerular fi ltration rate
with the Cockcroft-Gualt (2) or modifi cation of diet in renal
disease (MDRD) formulas(3, 4) may allow for more accurate
assessment of kidney function.
Prerenal azotemia occurs when renal perfusion is compromised
by an absolute decrease in extracellular fl uid volume
(ECV) (e.g., hemorrhage, gastrointestinal fl uid losses, burns),
a decrease in the “effective” circulating volume (heart failure,
ascites, nephrotic syndrome), or the accumulation of fl uid
in a “third space” (e.g., pancreatitis, acute abdomen, bowel
surgery, muscle trauma). It may occur occasionally with high
intra-abdominal pressures (>15 mm Hg bladder pressure) after
trauma or surgery. Correction of the intravascular volume
defect or abdominal pressure should result in improved renal
perfusion and resolution of azotemia. In most series, prerenal
azotemia has a 90% survival rate, but, if unrecognized or
untreated, it can evolve into ischemic acute tubular necrosis
(ATN) with a signifi cantly worse prognosis.
The diagnosis of prerenal azotemia is based on a physical
examination demonstrating ECV depletion and on several
urinary indices (Table 2). Of these, the fractional excretion
of sodium (FENa) is used most frequently (5). The FENa
measures the ratio of the sodium excreted (urinary sodium
x volume) to the sodium fi ltered (serum sodium x GFR) by
the following formula:
FENa = (UNa / SNa)/(Ucr /Scr) x 100,
where U indicates urine; S, serum; and cr, creatinine. The test
can be done with a spot sample of urine and blood.
The FENa is less than 1% when acute azotemia is prerenal
due to volume depletion but greater than 1% with ATN, where
tubular dysfunction associated with the ATN does not allow
appropriate sodium reabsorption. A few exceptions must be
kept in mind. Rhabdomyolysis, contrast nephropathy, acute
glomerulonephritis, and sepsis are all causes of ARF in which
the FENa may be low, particularly early in the clinical course
. In addition, patients with severe heart failure or cirrhosis
where there is a low renal perfusion also have a FENa of
less than 1% (7). Diuretics, glucosuria, or preexisting renal
insuffi ciency will falsely elevate the FENa in a patient with
prerenal azotemia. When diuretics increase the FENa, a
fractional excretion of urea (FEurea) of less than 35% more
accurately indicates prerenal azotemia than the FENa (8,9).
The clinician must be alert to these potential pitfalls of the
FENa when approaching the acutely azotemic patient.
ACUTE RENAL FAILURE IN THE CRITICALLY ILL
Derek M. Fine, MD
Table 1. Causes of “Pseudorenal Failure”
Nonrenal causes of elevated urea
Corticosteroids
Hyperalimentation
Gastrointestinal bleeding
Nonrenal causes of elevated creatinine
Interference with creatinine assay:
Acetone
Cefoxitin
Flucytosine
Alpha-Methyldopa
Blocked tubular creatinine secretion:
Cimetidine
Trimethoprim
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Table 2. Diagnostic Indices of Prerenal Azotemia (PRA)
and Acute Tubular Necrosis (ATN).
Prerenal Azotemia ATN
BUN: Creatinine 20 10
Urine Osmolality (mOsm/
L)
> 350 ~ 300
Urinelasma Osmolality > 1.5 1.0
Urine Sodium (mEq/L) < 30 > 30
Fractional excretion of Na < 1% > 1%
Fractional Excretion of
Urea
< 35% > 50%
It is important to recognize that in many instances a trial of
fl uid infusion, the gold standard used to diagnose prerenal
azotemia in the FeNa studies, is the easiest way to assess for
this etiology. Therefore, prerenal azotemia can be confi rmed
and simultaneously treated if the urinary output improves and
the azotemia resolves with administration of isotonic fl uids,
improvement in the underlying heart failure, or correction
of the third space defect.
Table 3. Causes of Acute onset Anuria
Acute bilateral urinary tract or catheter obstruction
Unilateral obstruction with solitary kidney
Shock with severe ATN
Acute vascular events
Aortic or renal artery dissection
Renal artery or vein thrombosis
An obstruction to urine fl ow may cause postrenal azotemia.
Although anuria is expected and often present, fl uctuating
or even high urine volumes may result if the blockage is
partial. The acute onset of anuria (vs oliguria) should raise
concern for bilateral urinary tract or catheter obstruction,
acute vascular events, such as aortic or renal artery dissection,
or acute thrombotic or embolic events involving renal
arteries or veins. If the obstruction is relatively recent (days
to weeks), correcting it usually will resolve the azotemia.
A catheter and a renal ultrasound are required steps in diagnosing
any patient with acute azotemia. With urethral or
prostatic obstruction, a urinary catheter will suffi ce in treating
the obstruction. Upper tract obstruction may require a
ureteral stent or percutaneous nephrostomy. For patients with
a solitary kidney, a retrograde pyelogram may be necessary
to positively exclude obstruction.
After excluding prerenal and postrenal azotemia, one must
consider the various renal parenchymal or hemodynamic
derangements responsible for ARF. These include diseases
that primarily affect the glomerulus (glomerulonephritis),
interstitium (interstitial nephritis), renal vasculature (vascular
occlusion or vasculitis), or tubules (acute tubular necrosis
[ATN]).
The initial step in evaluating acute renal failure is determining
the setting in which it develops. In those who develop ARF
in the hospital, one must fi rst consider prerenal renal failure,
ATN, obstruction and acute interstitial nephritis as causes.
Though these conditions still are common considerations
in the outpatient setting, glomerular and vascular diseases
become more important considerations.
DIFFERENTIAL DIAGNOSIS OF ARF IN THE
INTENSIVE CARE UNIT (ICU)
Although ATN is the most common cause of ICU-acquired
ARF (10), important glomerular, interstitial, and vascular
diseases must be considered (Table 4).
Glomerular
Fulminant glomerulonephritides due to bacterial endocarditis,
lupus erythematosus, staphylococcal septicemia, visceral
abscesses, Goodpasture syndrome, or pauci-immune antineutrophil
cytoplasmic antibodies [ANCA] associated)
glomerulonephritis are not infrequent causes of ARF in the
ICU. Once considered, these diagnoses are not diffi cult to
make. The urinalysis will show hematuria, red blood cell
casts, and moderate to heavy proteinuria. Hypertension is
variably present. Blood cultures, serologic testing (ANCA,
hepatitis C antibodies, and antiglomerular basement membrane
[Anti-GBM] antibody), and a search for visceral abscess
may be rewarding. Complement levels (C3 and C4) are
particularly helpful as they will be decreased in the majority
of cases of endocarditis, post-streptococcal and other infection-
related glomerulonephritides, cryoglobulinemic GN, and
lupus nephritis. An urgent renal biopsy should be considered
whenever acute glomerulonephritis is suspected, as aggressive
specifi c therapy (e.g., plasma exchange, corticosteroids
and/or cyclophosphamide) often is required.
Alterations in glomerular hemodynamics are recognized
increasingly as a cause of ARF. These include afferent arteriolar
vasoconstriction (hepatorenal syndrome) or efferent
arteriolar vasodilatation (angiotensin-converting enzyme
inhibitors). The latter as a cause of ARF usually is seen when
severe cardiac failure, ECV depletion, or bilateral renal artery
stenosis already compromises renal blood fl ow. In addition,
less well-defi ned derangements in intrarenal hemodynamics
are likely to contribute to the ARF of sepsis, potent vasodilators
(nitroprusside and nifedipine) (11), and the nonsteroidal
anti-infl ammatory drugs (NSAIDs). In these cases, the urine
sediment is usually bland, and the renal biopsy (if performed)
is normal. Recovery of renal function is expected, provided
the offending drug is removed or the underlying condition
is corrected.
Hepatorenal syndrome (HRS) refers to ARF that occurs in
the setting of severe liver failure after other obvious causes
are excluded. The patient demonstrates avid sodium retention
(UNa <10 mEq/L; FENa <1%) and oliguria not responding
to ECV expansion. The urine sediment is usually benign.
Onset may be insidious or abruptly precipitated by ECV
depletion (gastrointestinal [GI] bleeding, diuretics, paracentesis)
or sepsis. Because the liver is critical to both urea
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269
and creatinine generation, patients with cirrhosis and ascites
may have signifi cant renal compromise despite normal serum
values. Furthermore, those with end-stage disease frequently
have diminished muscle mass with associated low creatinine
production. In one study, the incidence of HRS was 18% at
1 year and 39% at 5 years in these patients (12). HRS likely
results from nitric oxide-induced splanchnic vasodilatation
with consequent activation of the renin angiotensin and
sympathetic nervous systems (13). Thus, cardiac output
is high and systemic vascular resistance is low (“septic
physiology”) despite elevated peripheral and renal vascular
resistance. Other pathogenesis theories include an imbalance
of vasoconstrictor/vasodilator prostaglandins (supported by
elevated urinary 20-HETE, a vasoconstrictor prostaglandin),
endotoxemia, endothelin induced renal vasoconstriction, release
of false neurotransmitters, or an increase in sympathetic
tone due to elevated hepatic sinusoidal pressure.
The preferred treatment of HRS is liver transplantation. As
a “bridge” to transplant, various medical therapies may be
tried. The sympatholytic agent clonidine may transiently
improve GFR. Data on misoprostol and n-acetyl cysteine are
confl icting. There are promising preliminary reports using
both terlipressin (an ADH analog) given with albumin infusions
(14) and the combination of midodrine and octreotide
(15). Portovenous shunting and transjugular intrahepatic
portosystemic shunt (TIPS) have high complication rates and
generally are reserved as a last resort in refractory patients.
Interstitial
Acute interstitial nephritis (AIN) usually is due to allergy.
Although the list of agents reported to cause AIN is legion,
the most common offending agents are fl uoroquinolones,
penicillins, cephalosporins, sulfonamides and NSAIDs. The
development of AIN is associated temporally with the drug
exposure, occurring 7 to 10 days after a fi rst exposure and 3
to 5 days on a re-exposure.
Table 4. Differential Diagnosis of Acute Renal Failure.
I. Glomerular
A. Altered glomerular hemodynamics.
1. Hepatorenal syndrome
2. ACE Inhibitors / ARBs
3. Nifedipine / nitroprusside
4. Cyclosporine / tacrolimus
5. NSAIDs
6. Hypercalcemia
B. Glomerulonephritis (GN)
1. Infectious
a. Bacterial endocarditis
b. “Shunt” nephritis
c. Visceral abscess
d. Hepatitis C-associated cryoglobulinemia
e. Poststreptococcal GN
2. Lupus erythematosus
3. ANCA related GN
4. Goodpasture syndrome
II. Interstitial
A. Allergic interstitial nephritis
B. Bacterial pyelonephritis
C. Viral (CMV, measles, mumps)
D. Tumor lysis
E. Urate / oxalate nephropathy
F. Multiple myeloma
G. Infi ltrative (lymphoma, leukemia)
H. Sarcoidosis
III. Vascular
A. Hypertensive crisis
B. Renal artery thrombosis / thromboembolism
C. Cholesterol emboli syndrome (CES)
D. Vasculitis
1. Wegener (usually C-ANCA pos)
2. Polyarteritis nodosa
3. Microscopic polyangiitis (usually P-ANCA pos)
4. Hypersensitivity vasculitis
5. Henoch Schonlein Purpura
6. Cryoglobulinemia
E. Thrombotic Microangiopathy
1. Thrombotic thrombocytopenic purpura (TTP)
2. Hemolytic uremic syndrome (HUS)
IV. Tubular (ATN)
A. Toxic
1. Aminoglycosides
2. Platinum
3. Radiographic contrast agents
4. Amphotericin B
5. Solvents (CCl4, ethylene glycol)
6. Rhabdomyolysis / myoglobinuria
7. Intravascular hemolysis
B. Ischemic
1. Hypotension / shock
2. Hemorrhage
3. Sepsis
The presence of sterile pyuria with eosinophiluria on urine
analysis strongly suggests AIN in the context of an exposure.
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The presence of fever, rash, arthralgias, and eosinophilia is
likewise suggestive. Nevertheless, contrary to commonly
held beliefs, these clinical features generally are not present
in the post-methicillin era (16). Early cases of antibioticinduced
AIN were described with the use of methicillin (17)
and typically featured pyuria, fever and fl ank pain. However,
each of these symptoms is usually present in fewer than 50%
of patients with AIN(16). Therefore, in the context of a possible
culprit drug, one must not exclude AIN based solely on
the absence of these features. NSAID-induced AIN is less
likely than other forms to have eosinophiluria and generally
is associated with signifi cant levels of proteinuria.
Tumor lysis syndrome (TLS) refers to a variety of metabolic
complications associated with lymphoid or rarely solid malignancies.
Though usually associated with lytic therapy, TLS
may occur spontaneously in the presence of a large tumor
burden. Hyperuricemia (usually >15 mg/dL) or hyperphosphatemia
(usually >8 mg/dL) may cause ARF. Hypocalcemia
and hyperkalemia often complicate the early clinical course.
Patients usually are oligoanuric, and the urinary sediment
frequently reveals amorphous rates or urate crystals. Once
TLS has occurred, urinary alkalinization is not recommended
routinely, as it actually may enhance renal parenchymal
calcium phosphate deposition. ECV expansion with isotonic
crystalloid or mannitol has prophylactic benefi t. Although
allopurinol has not eliminated tumor lysis ARF, it does help
(at dosages of 600 to 900 mg daily, if possible).
Other causes of ARF involving the interstitial are less common
and include bacterial pyelonephritis, multiple myeloma,
uric acid nephropathy, and occasionally infi ltrative disorders,
such as lymphoma, leukemia, and sarcoidosis. Oxalate nephropathy
may complicate acute ethylene glycol ingestion
(with elevated anion and osmolar gap).
Vascular
Vascular disease frequently is overlooked as a cause of ARF.
Malignant hypertension usually accompanied by retinopathy,
thrombocytopenia, and thrombotic microangiopathy, can cause
ARF. Thrombotic microangiopathy and thrombocytopenia also
accompany hemolytic uremic syndrome (HUS), thrombotic
thrombocytopenic purpura (TTP) and scleroderma renal crises.
Renal infarction due to trauma, thrombosis or thromboembolism
can cause ARF with fever, hematuria, acute fl ank pain,
ileus, leukocytosis, and an elevated LDH level, a syndrome that
may mimic an acute abdomen. Thromboemboli usually arise
from the heart in patients with severe left ventricular failure
or atrial fi brillation. Renal artery vasculitis most commonly
due to polyarteritis nodosa (PAN) and renal artery dissections
need to be considered when infarction is noted.
Renal vasculitis (Wegener granulomatosus, micropolyangiitis
(MPA), Goodpasture syndrome and cryoglobulinemic-associated
GN) often cause ARF with rapidly progressive
glomerulonephritis. These disorders are identifi ed by their
multisystem manifestations, active urine sediment (hematuria,
pyuria, RBC and WBC casts, and proteinuria), and
in the case of Wegener and MPA, the presence of ANCA in
the serum. Polyarteritis nodosa, a medium vessel vasculitis,
which generally is not ANCA-positive, affects the renal
arteries and arterioles causing renovascular hypertension or
renal infarction.
Cholesterol emboli syndrome (CES), also known as atheroembolic
disease, refers to renal atherosclerotic or cholesterol
microemboli, which may occur after aortic manipulation
(surgery or catheterization) and occasionally occurs spontaneously.
Urine sediment usually is bland. Besides ARF, gastrointestinal
bleeding (due to microinfarcts), livedo reticularis
of the lower extremities, patchy areas of ischemic necrosis
in the toes, transient hypocomplementemia, and eosinophilia
may be present. It is important to distinguish CES from a
thromboembolic event, as therapeutic anticoagulation is
dangerous to the former but necessary for the latter.
Tubular
The most common cause of hospital-acquired and ICU-acquired
ARF is acute tubular necrosis (ATN) (10), which is
broadly divided into toxic and ischemic causes. In fact, ATN
in the ICU setting usually is due to a “conspiracy” of factors
including hypovolemia, poor cardiac output, nephrotoxins,
and sepsis.
Among the more common toxins causing ATN are the aminoglycoside
antibiotics. Used in severe Gram-negative sepsis,
these antibiotics have been associated with nephrotoxicity
in 10% to 20 % of therapeutic courses (18). Aminoglycoside
nephrotoxicity characteristically presents 5 days to 10
days after initiation of treatment with nonoliguric features.
Aminoglycoside nephrotoxicity risk factors include volume
contraction, long treatment duration, advanced age, hypokalemia,
concomitant use of other nephrotoxins, and a short
dosing interval. After an initial loading dose, the maintenance
dose should be adjusted based on the patient’s estimated
GFR. Careful monitoring of serum drug levels is helpful to
avoid toxicity, although nephrotoxicity can occur even with
appropriate monitoring (19).
Radiographic contrast agents may cause ARF in patients with
preexisting renal insuffi ciency, diabetes mellitus, and poor
left ventricular function or when multiple studies are done in
a 24-hour period. It is important to recognize that the primary
mechanism of nephrotoxicity is ischemia due to vasoconstriction
of the afferent arteriole, and, therefore, concurrent
use of agents that also vasoconstrict at this level place the
patient at signifi cant risk; these agents include amphotericin
B, calcineurin inhibitors and NSAIDs. The volume of contrast
used (>1.5 mL/kg) appears related directly to nephrotoxicity.
Nonionic and isosmolar contrast appears less nephrotoxic
(20). Prophylaxis with intravenous crystalloid (1 mL/ kg of
normal saline (NS), 12 hours precontrast and postcontrast
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administration) is well established. However, a recent study
supports the use of sodium bicarbonate (3 mL/kg per hour for
1 hour before and 1 mL/kg per hour for 6 hours after contrast
use) as better prophylaxis than sodium chloride (21). N-acetyl
cysteine has been shown to be effective in some studies (600
mg by mouth every 12 hours; 2 doses before and 2 doses after
the procedure) (22), and its use is widespread due to the low
risk profi le. Intravenous mannitol, furosemide (either before
or after contrast), dopamine and calcium channel blockers
do not appear to lessen nephrotoxicity. Theophylline and
fenoldopam may decrease nephrotoxicity in patients at very
high risk, particularly those in whom fl uid is contraindicated.
Although most cases of contrast nephrotoxicity occur within
24 hours to 48 hours and usually resolve within a few days,
the condition signifi cantly increases hospital mortality rates
and cost. Patients may require acute dialysis, but permanent
loss of renal function is rare. In patients where recovery does
not occur or where renal failure occurs more than 48 hours
after a cardiac catheterization, cholesterol emboli must be
suspected.
Massive intravascular hemolysis or rhabdomyolysis may
produce ARF. Common causes of rhabdomyolysis include
drugs (e.g., heroin, cocaine, statins), major crush injuries,
alcohol, seizures, vascular occlusion due to thrombi or dissection,
and muscle compression syndromes. All have the
potential of producing myoglobinuria and ARF, particularly
if ECV depletion or shock exist simultaneously. Hyperkalemia
is the most ominous feature, while hyperuricemia,
hyperphosphatemia, and acidosis also result. Hypocalcemia
often occurs early, but hypercalcemia (as high as 14 mg/dL)
appears during recovery (23). Elevated creatine phosphokinase
(CPK) and dark heme-positive urine without RBCs are
major diagnostic clues. Prophylaxis against ATN depends on
aggressive intravenous crystalloid. The addition of mannitol
and bicarbonate (