1. health and fitness
2. disease

Best Practice & Research Clinical Anaesthesiology
Vol. 18, No. 1, pp. 1 –20, 2004
doi:10.1016/S1521-6896(03)00077-6, available online at http://www.sciencedirect.com
1
Clinical and laboratory diagnosis of acute
renal failure
Robert J. Anderson*
MD
Professor of Medicine
Department of Medicine, University of Colorado Health Science Center, 4200 East 9th Avenue, Box B-180,
Denver, CO 80262, USA
Daniel W. Barry
MD
Assistant Professor
Department of Medicine, University of Colorado, 1635 North Ursula St, Box F-729, Aurora, CO 80045, USA
Acute renal failure (ARF) is defined in general terms as an abrupt decrease in renal function
sufficient enough to result in retention of nitrogenous waste and disrupt fluid and electrolyte
homeostasis. There is no consensus regarding a quantifiable definition of ARF. Prompt evaluation
of ARF is vital because ARF can be the end result of diverse processes which can often be
reversed or attenuated through therapy directed at the underlying condition. Evaluation begins
with careful review of the patient’s history, previous medical records, physical examination,
urinalysis, and available laboratory data. Routine urine chemical indices, calculation of the
fractional excretion of sodium, and examination of the urine sediment are valuable in
characterizing the cause of ARF. When this evaluation fails to yield a diagnosis, further testing
may be required to evaluate intravascular volume status or diagnose a systemic disorder or
glomerular cause of ARF. Response to therapeutic trials may provide a diagnosis. When a
diagnosis cannot be made with reasonable certainty through this evaluation renal biopsy should
be considered.
Key words: kidney failure, acute; kidney function test; diagnosis; urinalysis; kidney; biopsy; kidney
tubular necrosis, acute; nephritis, interstitial; kidney calculi; urinary calculi.
Acute renal failure (ARF) is defined in general terms as an abrupt decrease in renal
function sufficient enough to result in retention of nitrogenous waste and disrupt fluid
and electrolyte homeostasis.1 – 4 Although this qualitative definition is agreed upon, there
is no consensus regarding the quantification of the decline in renal function to warrant a
diagnosis of ARF.2 Commonly used definitions include an increase in serum creatinine
(SCr) concentration of 0.5 mg/dl or more over the base-line value or a reduction in the
calculated creatinine clearance of 50%. The clinician must remember that in patients with
normal renal function, SCr is a poor marker of change in kidney function. Large reductions
in glomerular filtration rate (GFR) initially produce only small increases (0.1 –0.3 mg/dl)
* Corresponding author. Tel.: þ1-303-372-9092; Fax: þ1-303-372-9082.
E-mail address: [email protected] (R.J. Anderson).
1521-6896/$ - see front matter Q 2003 Published by Elsevier Ltd.
2 R. J. Anderson and D. W. Barry
in SCr concentration.5 Therefore, even small increases in SCr should be carefully
evaluated.
ARF is encountered frequently in modern medical practice, especially in the inpatient
setting.6 – 12 A wide range of pathophysiological events produce identical clinical pictures
of ARF.1 – 6,8 – 15 Alleviation or attenuation of ARF requires prompt identification and
treatment of the underlying condition. Mild forms of ARF are often reversible, and
several studies have found a direct relationship between the magnitude of rise in SCr
concentration and ARF mortality.6 – 11,16 Thus, clinicians should thoroughly evaluate even
mild increases in SCr concentration. In this chapter we review the clinical and laboratory
features of various causes of ARF and suggest an approach to timely diagnosis.
PRESENTING MANIFESTATIONS OF ACUTE RENAL FAILURE
ARF is most commonly diagnosed when there is an increased concentration of SCr or
blood urea nitrogen (BUN). Typically, the BUN/SCr ratio is approximately 15:1. In the
complete absence of glomerular filtration, BUN and SCr increase 10 –15 mg/dl and 1.0 –
1.5 mg/dl per day, respectively. However, there are several situations that disproportionately affect either the BUN or SCr concentration (Table 1) thereby altering this
relationship.17 Moreover, factors other than a reduction in GFR can lead to increased
concentrations of BUN (e.g. a catabolic state) or SCr (e.g. rhabdomyolysis or
medications that interfere with creatinine excretion or measurement) as shown in
Table 1.
The SCr concentration is usually a better marker of GFR than is the BUN. In a steady
state, the SCr approximately doubles each time the GFR is reduced by 50%. For
example, steady state GFRs of 100, 50, 25 and 12.5 ml/minute correlate with SCr
concentrations of 1.0, 2.0, 3.0 and 4.0, respectively. However, ARF usually is not a
steady-state setting as the determinants of the SCr concentration (production, volume
of distribution, and renal clearance) vary.18 Also, the rise in SCr lags behind the process
leading to ARF. Unfortunately, techniques for monitoring real-time GFR are expensive
and are not routinely available.19 In some intensive care settings, frequent, brief, timed
urine samples are collected to assess GFR. The reliability of this approach remains to be
carefully validated.
The development of ARF may also be recognized through a decrease in urine output.
The presence of oliguria (, 400 ml/24 hours) or anuria (absence of urine output)
indicates the presence of ARF.13 Most cases of ARF encountered in contemporary
clinical practice are non-oliguric in nature.8 Recent clinical studies have found that urine
output correlates strongly with residual glomerular filtration and poorly with renal
tubular function.20 The higher level of residual glomerular filtration in non-oliguric
patients is compatible with less severe renal failure and lower mortality than is seen in
oliguric ARF.
A third way ARF may be detected is through evaluation of either laboratory results
(hyperkalaemia, acidaemia, hypocalcaemia, hyperphosphataemia, hypermagnesaemia,
anaemia) or clinical findings (fluid overload, altered mental status, nausea, anorexia,
pericarditis) that are secondary to ARF.
In clinical practice, it can be difficult to determine whether an elevated SCr or BUN
concentration is due to an acute or chronic process. Reviewing previous records is
essential in this setting. If previous values are unavailable, the clinician should assume the
presence of potentially treatable conditions.21 Small kidney size (, 10 cm) on renal
imaging supports the diagnosis of chronic renal disease. Non-enzymatic carbamylation
Diagnosis of acute renal failure 3
Table 1. Causes of an abnormal BUN/
creatinine ratio.
BUN:Cr . 15
Increased formation of urea
High intake of protein
Catabolic states
Fever
Tissue necrosis
Corticosteroid use
Tetracyclines
Sepsis
Decreased elimination of urea
Volume loss
Decreased cardiac output
Obstructive uropathy
BUN:Cr , 15
Decreased formation of urea
Starvation
Advanced liver disease
Hereditary deficiency of urea-cycle enzymes
Relative increased removal of urea
Post-dialysis
Increased formation of creatinine
Rhabdomyloysis
Decreased secretion of creatinine
Cimetidine
Trimethoprim
Pyrimethamine
Interference with assay
Ketones
Cefoxitin
Ascorbic acid
Methyldopa
Flucytosine
Barbiturates
of the terminal valine of haemoglobin occurs in direct relationship to the duration and
magnitude of the increase in BUN. A recent study of 28 patients with ARF and 13
patients with CRF found a value , 80 mg of carbamyl valine per gramme of haemoglobin
had a sensitivity and specificity of 96 and 84.2%, respectively for differentiating acute
from chronic renal failure.22
CAUSES OF ACUTE RENAL FAILURE
Traditionally, ARF is categorized as pre-renal, intrarenal or post-renal as shown in
Table 2.1 Pre-renal refers to factors associated with renal hypoperfusion as the cause of
filtration failure. Pre-renal processes are the most commonly encountered causes of
ARF.1,6 – 8,11,12 If not reversed, pre-renal ARF can progress to ischaemic acute tubular
necrosis (ATN). In pre-renal ARF, decreased renal perfusion pressure, afferent
4 R. J. Anderson and D. W. Barry
Table 2. Differential diagnosis of acute renal failure.
Pre-renal (40 –80%)
Volume loss or sequestration
Decreased cardiac output
Hypotension
Post-renal (5–15%)
Intrarenal
Crystals
Proteins
Extrarenal
Pelvis
Ureter
Bladder
Urethra
Renal (10 –30%)
Vascular disorder
Small vessel
Large vessel
Glomerulonephritis
Interstitial disorders
Inflammation
Space-occupying process
Tubular necrosis
Ischaemia
Toxin
Pigmenturia
arteriolar constriction, or efferent arteriolar dilation acts to decrease glomerular
hydrostatic pressure.23 Events that decrease renal perfusion pressure include loss of
extracellular fluid (e.g. vomiting, diarrhoea, haemorrhage, nasogastric suctioning, burns,
heat stroke, diuresis), sequestration of extracellular fluid (e.g. muscle crush injury,
pancreatitis, early sepsis, intra-abdominal surgery), impaired cardiac output, and
antihypertensive medications. Afferent arteriolar constriction can be caused by
enhanced vasoconstrictive influences (e.g. circulating adrenalin (epinephrine), angiotensin II, endothelin, enhanced renal adrenergic neural traffic) or by a decrease in
vasodilators (nitric oxide, bradykinin, eicosanoids). These changes can be due to
medications such as non-steroidal anti-inflammatory drugs (NSAIDs), cyclosporin,
radiocontrast medium, and amphotericin B23 – 25 or are seen in the post-operative
state, early sepsis, advanced liver disease, oedematous disorders, or volume-depleted
states. Efferent arteriolar vasodilation occurs with the use of angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers.
An unusual cause of ‘pre-renal’ ARF is a hyperoncotic state. Glomerular filtration
pressure is glomerular hydrostatic pressure minus plasma colloid oncotic pressure.
Infusion of either osmotically active substances—such as mannitol, dextran or
protein—can increase oncotic pressure enough to exceed the glomerular capillary
hydrostatic pressure.26 – 28 This stops glomerular filtration leading to an anuric form of
ARF, that usually is alleviated by removal of the offending substance.
Diagnosis of acute renal failure 5
Post-renal (after formation of the glomerular filtrate) causes of ARF are
less commonly encountered than pre-renal causes, but they are nearly always
treatable.6,7,10,29 – 37 Post-renal forms of ARF are divided into intrarenal (tubular) or
extrarenal. Tubular precipitation of insoluble crystals (methotrexate, acyclovir,
sulphonamides, indinavir, uric acid, triamterene, oxalic acid)32 – 36 or protein (plasma
cell dyscrasia)37 can increase intratubular pressure. If sufficiently high, this opposes
glomerular filtration pressure and can decrease GFR. Similarly, obstruction of the
extrarenal collecting system at any level (renal pelvis, ureters, bladder or urethra) can
also lead to post-renal ARF.
After considering pre-renal and post-renal causes, the clinician should turn to
intrarenal causes of ARF. Considering renal causes in terms of renal anatomic
compartments is helpful. Disorders of the smaller renal vasculature, (e.g. vasculitis,
thrombotic thrombocytopenic purpura (TTP), haemolytic – uraemic syndrome (HUS),
malignant hypertension, eclampsia, disseminated intravascular coagulation (DIC),
scleroderma, post-partum states) the large arteries (e.g. thrombosis, emboli), and
the renal veins (acute occlusion) can all result in ARF.38 – 47 All forms of acute
glomerulonephritis can present as ARF.48 Acute inflammation and space-occupying
processes of the renal interstitium (e.g. drug-induced, infectious, and autoimmune
disorders, leukaemia, lymphoma, sarcoidosis) can result in ARF.49 Finally, tubular
damage or ATN, which usually results from renal ischaemia due to prolonged pre-renal
ARF, nephrotoxins (e.g. radiocontrast medium, aminoglycosides, pentamidine,
foscarnet, cisplatin, amphotericin, NSAIDs, heavy metals, hydrocarbons), and
pigmenturia (e.g. intravascular haemolysis, rhabdomyolysis) are relatively common
causes of ARF.1 – 6,8 – 12,32
DIAGNOSTIC APPROACH TO ACUTE RENAL FAILURE
History and record review
A suggested diagnostic approach to patients with ARF is shown in Figure 1. Considering
the setting in which ARF has developed may be helpful. For example, communityacquired ARF can usually be attributed to a single cause (usually pre-renal, post-renal,
or medication-induced) and has a good prognosis.1,2,7 – 10,50 ARF acquired on a hospital
ward, however, occurs in the setting of co-morbidity, is often multifactorial, and is
associated with higher mortality.1 – 4,6 – 10,12,50 Acute renal failure acquired in the
intensive care unit is almost always multifactorial and is associated with sepsis, multiorgan failure and even higher mortality2,3,8,9,11,16).
Causes of ARF can also be considered in the context of the underlying disease or
process in which it occurs (Figure 2). Unique causes of ARF can be seen in the setting of
malignancy, immunodeficiency virus (HIV) infection, pregnancy, and the post-operative
or intensive care state.2,6 – 8,11,12,16,32,37,46,51 – 53 Two settings not shown in Figure 2 in
which ARF is frequently encountered are the elderly population and patients with liver
disease. The effect of advancing age in decreasing functional renal reserve and the
associated co-morbidities increases the risk of ARF. Researchers have demonstrated
that there is a dramatic (three- to eightfold), age-dependent increase in the incidence of
community-acquired ARF in patients older than 60 years.10 Although this group is
subject to all forms of ARF, pre-renal and post-renal causes are especially common.54,55
Patients with liver disease are susceptible to several renal insults, including those
of pre-renal (e.g. aggressive diuresis, large-volume paracentesis, gastrointestinal
6 R. J. Anderson and D. W. Barry
EVALUATION OF
ACUTE RENAL FAILURE
SUBSEQUENT EVALUATION
TO CONSIDER
INITIAL EVALUATION
l
l
l
l
l
History
Review of records
Physical examination
Urinalysis
Consider bladder catheterization
DIAGNOSTIC
TESTING
l
l
l
l
l
Urinary diagnostic
indices and special
urinalysis
Evaluation to
exclude urinary tract
obstruction
Assessment of
cardiac/intravascular
volume status
Assessment of
renal vasculature
Additional blood
work or cultures
THERAPEUTIC
TRIALS
l
l
l
l
l
Volume
expansion
Improvement of
cardiac function
Discontinuation
of nephrotoxins
Relief of urinary
tract obstruction
Empiric trial of therapy
for specific disorders
(immunosuppression,
plasmapheresis)
Figure 1. Approach to evaluation of acute renal failure.
TISSUE
EVALUATION
l
l
Renal biopsy
Other tissue
biopsy
CAUSES OF ACURE RENAL FAILURE
BY CLINICAL SETTING
Malignancy
Pre-renal
l Drug induced
l Pericardial tamponade
l Cardiac dysfunction
HIV
Pre-renal
l Hypodipsia
l Diarrhoea
Pregnancy
Pre-renal
l
Hyperemesis gravidarum
Post-renal
Post-renal
ICU/Post-operative states
Pre-renal
l Volume depletion or
sequestration
l Impaired cardiac output
Figure 2. Causes of acute renal failure by clinical setting.
Diagnosis of acute renal failure 7
l Gravid uterus blocking ureters
Post-renal
l
Uretal
blockage
Post-renal
l Ureteral blockage
Renal
(lymphoma)
l
Bladder outlet obstruction
(surgery metastasis,
l Sepsis
l Crystalluria (sulphonamides,
retro-peritoneal fibrosis)
l Ureteric ligation
protease inhibitors, acyclovir) l Thrombotic microangiopathy
l Bladder neck obstruction
Renal
l HELLP syndrome/eclampsia
(Prostate/bladder cancer)
l Protein deposition
l Sepsis
l Cortical necrosis
l Crystalluria (uric acid,methotrexate)
(B-cell lymphoma)
l Toxins (aminoglycosides,
l Protein deposition
contrast dye, vancomycin
Renal
(plasma cell dyscrasia)
amphotericin, converting
l Toxins (aminoglycosides,
Renal
enzyme inhibitors)
l Toxins (chemotherapeutic agents,
foscarnet, pentamidine, amphotericin B,
l
Multiple organ failure
antimicrobials, contrast dye)
vancomycin, contrast dye)
l
Rhabdomyolysis
l Light chain toxicity
l Sepsis
l Tumour-lysis/hyperuicaemia
l HIV-associated glomerulopathy
l Hypercalcaemia
l Thrombotic microangiopathy
l Tumour infiltration
l Tumour glomerulopathy
l Thrombotic microangiopathy
8 R. J. Anderson and D. W. Barry
Table 3. Drugs and toxins associated with renal failure.
Decreased renal perfusion
NSAIDs, ACE inhibitors, contrast media, amphotericin B, cyclosporin, tacrolimus
Direct tubular injury
Aminoglycosides, contrast media, amphotericin B, methotrexate, cipslatin, foscarnet, pentamidine,
heavy metals, myoglobin, haemoglobin, intravenous immune globulin, HIV protease inhibitors
Intratubular obstruction
Contrast media, methotrexate, acyclovir, sulphonamides, ethylene glycol, uric acid, cocaine, lovastatin
Immunological –inflammatory
Penicillin, cephalosporins, allopurinol, NSAIDs, sulphonamides, diuretics, rifampin, ciprofloxacin,
cimetidine, tetracyclines, phenytoin
haemorrhage, sepsis) and renal (e.g. glomerulopathy, ischaemic and toxic ATN, acute
interstitial nephritis) aetiologies.50 Additionally, a significant portion of patients with
advanced liver disease develop intense renal vasoconstriction and a form of ARF (the
hepatorenal syndrome) that responds poorly to treatment and is associated with high
mortality.56,57
The clinical history with regard to events associated with intravascular volume loss
or sequestration and impaired cardiac function is important in determining the cause of
ARF. A history of thirst, orthostatic lightheadedness, and symptoms of congestive heart
failure supports a pre-renal aetiology of ARF.
Post-renal causes of ARF are common at the extremes of age, with a history of
changes in the size and force of urine stream, the presence of bladder, prostate, or
pelvic cancer; the use of anticholinergic and alpha-adrenergic medications; the presence
of anuria, suprapubic pain, or urolithiasis; or exposure to medications known to cause
hyperuricaemia or crystalluria.32 – 36,58 Patients with either a single kidney or a
significant baseline decrease in the function of one kidney should make the clinician
even more concerned about the possibility of post-renal ARF because a single lesion
may obstruct the good kidney.
A history of factors that predispose to vascular disease (smoking, hypertension,
diabetes mellitus, hyperlipidaemia, claudication, stroke, myocardial infarction, peripheral vascular disease, arterial catheterization involving the aorta, aortic aneurysm, and
atrial fibrillation) is compatible with a vascular embolic event leading to ARF. A history
of systemic infection or the presence of systemic symptoms may support a glomerular
cause of ARF. Medication exposure, symptoms of systemic infection, or a history of
acute pyelonephritis may point to acute interstitial nephritis as the cause of ARF. The
presence of disorders associated with either rhabdomyolysis or intravascular
haemolysis suggests the possibility of pigmenturia contributing to ARF.32,59
In all cases of ARF, careful review of medication and exposure to toxin is critical.
Several studies have demonstrated that up to 25% of all cases of ARF can be attributed
to exposure to nephrotoxin.6 – 8,10 – 12,24,25,49,51,60,61 Drugs and toxins associated with
ARF are reviewed in Table 3.
Physical examination
Physical examination remains an important diagnostic tool for determining the cause of
ARF. Assessing the volume status of patients with ARF is critical but sometimes difficult.
Diagnosis of acute renal failure 9
A meta-analysis of physical findings suggests that 1-minute orthostatic tachycardia
(. 30 beats/minute) or decrease in systolic blood pressure (. 20 mm Hg), dry axillae,
dry oral mucous membranes, and longitudinal tongue furrows are of diagnostic value in
detecting hypovolaemia. Decreased skin turgor or impaired capillary refill time have
limited sensitivity and specificity.62
Ophthalmic examination may reveal Hollenhorst plaques suggestive of atheroemboli42 or other findings compatible with bacterial endocarditis, vasculitis or malignant
hypertension. Neck examination for jugular venous pressure and carotid pulses and
sounds may be helpful in detecting heart failure, aortic valve disease or vascular disease.
Cardiovascular examination for rate, rhythm, murmurs, gallops and rubs may be helpful
in detecting the presence of heart failure and possible sources of emboli (e.g. atrial
fibrillation, endocarditis). Lung examination can assist in determining the presence of
either heart failure or a pulmonary –renal syndrome associated with ARF. Abdominal
examination can reveal findings compatible with vascular disease (e.g. bruits, palpable
abdominal aortic aneurysm), masses that could be malignant, a distended bladder which
could be indicative of outlet obstruction, or possible sources of bacteraemia, evidence
of liver disease (e.g. ascites, collateral venous pattern, hepatosplenomegaly).
Examination of the extremities for symmetry and strength of pulses (vascular disease)
and oedema can be helpful. Skin examination may reveal palpable purpura (vasculitis), a
fine maculpapular rash (drug-induced interstitial nephritis), or livedo reticularis and
embolic stigmata (atheroemboli). If neurological signs are present, systemic disorders
such as vasculitis, TTP, subacute bacterial endocarditis, and malignant hypertension
warrant consideration. Peripheral neuropathy in the presence of ARF raises the
possibility of nerve compression caused by rhabdomyolysis, ischaemia, heavy metal
intoxication, or plasma cell dyscrasia. Pelvic examination in females and rectal
examination may detect an obstructive cause of ARF.
Laboratory data
Reviewing the haemogram can be helpful in determining the cause of ARF. Anaemia
could indicate recent haemorrhage or intravascular haemolysis as factors contributing
to the ARF. A microangiopathic state (thrombocytopenia, reticulocytosis, elevated
lactate dehydrogenase, deformed red blood cells on peripheral smear) with ARF points
to TTP, HUS, eclampsia, vasculitis, malignant hypertension, HIV infection, and various
medications as possible causes.39,45,47 Anaemia with rouleaux formation and ARF
suggests a plasma cell dyscrasia. Eosinophilia is compatible with atheroemboli, acute
interstitial nephritis or polyarteritis nodosa. Leukopenia is common in patients with
systemic lupus erythematosus (SLE) and ARF. Thrombocytopenia in the setting of ARF
is compatible with a thrombotic microangiopathy, SLE, DIC, rhabdomyolysis, advanced
liver disease with hypersplenism, and ‘white clot syndrome’ resulting from heparin
administration as causes of the ARF.39,45,47,63 – 65 Coagulopathy, such as prolongation of
the international normalized ratio (INR) or partial thromboplastin time (PTT), suggests
underlying liver disease (increased INR), DIC (increased INR and PTT), or antiphospholipid antibody syndrome (increased PTT), all of which can lead to ARF.51,51,63 – 65
Hyperkalaemia of a modest degree (, 5.5 mEq/l) is a common finding in ARF. More
marked hyperkalaemia suggests the possibility of rhabdomyolysis, tumour lysis
syndrome, intravascular hemolysis, or the use of NSAIDs or angiotensin-converting
enzyme inhibitors as contributing factors.32,59 Elevations of creatine kinase, serum
glutamic-oxaloacetic transaminase, and LDH often occur with rhabdomyolysis or
tumour lysis syndrome. Modest hyperuricaemia (, 10 mg/dl) usually accompanies ARF,
10 R. J. Anderson and D. W. Barry
but much higher levels of uric acid occur with tumour lysis syndrome, rhabdomyolysis
and heat stroke.66 Mild metabolic acidosis occurs frequently as a consequence of ARF
and is often associated with a modest (5 –10 mEq/l) increase in the anion gap. Marked
acidosis with larger anion gaps should raise suspicion for ethylene glycol poisoning,
rhabdomyolysis, and lactic acidosis from sepsis as contributing factors.32,67
Urine flow and urinalysis
Analysing the quality and quantity of urine is vital in evaluating ARF (Table 4). Anuria is
seen with cessation of glomerular filtration (e.g. rapidly progressive glomerulonephritis,
acute cortical necrosis, or renal arterial occlusion) or complete urinary tract
obstruction. Brief (, 24– 48 hour) episodes of severe oliguria (, 100 ml/day) occur
in some cases of ATN, especially in the context of heat stroke.66 Pre-renal forms of ARF
nearly always present with oliguria (, 400 ml/day), although non-oliguric forms have
been reported.68 Post-renal and renal forms of ARF can present with any pattern of
urine flow ranging from anuria through polyuria. As noted previously, most cases of
ARF seen in contemporary medical practice that result from ATN are non-oliguric.8
Routine dipstick and microscopic analysis of urine is often helpful in determining the
cause of ARF. In an older study6, diagnostically useful information was obtained from
routine urinalysis in about 75% of ARF cases. Generally, a normal urinalysis in the setting
Table 4. Urinalysis in acute renal failure.
Normal
Pre-renal
Post-renal
High plasma oncotic pressure
Abnormal
RBC, RBC casts, proteinuria
Glumerulonephritis
Vasculitis
Thrombotic microangiopathy
WBC, WBC casts
Pyelonephritis
Interstitial nephritis
Eosinphiluria
Allergic interstitial nephritis
Atheroemboli
Glomerulonephritis
Pigmented casts, renal tubular epithelial cells
ATN
Myoblobinuria
Haemoglobinuria
Crystalluria
Uric acid
Drugs/toxins
Non-albumin proteinuria
Plasma cell dyscrasia
Diagnosis of acute renal failure 11
of ARF suggests a pre-renal or post-renal cause. An abnormal urinalysis suggests a renal
cause. Two studies6,69, but not a third70, suggest a direct relationship between the
presence and the degree of abnormalities seen on routine urinalysis and the prognosis
of ARF. In the study of ARF patients by Hou and coworkers6, a normal urinalysis
(probable pre-renal cause) was associated with a mortality of 15%, and an abnormal
urinalysis (probable renal cause) had a mortality of 35%. More recent studies indicate,
however, that patients with a clinical course typical of pre-renal forms of ARF can have a
significant number of casts and cellular elements on microscopic examination of their
urine.69
The ‘dipstick’ orthotoludine reaction for blood is sensitive for about three red blood
cells/high-power field. If no blood cells are present, this reaction is positive in the
setting of either myoglobinuria or haemoglobinuria, both of which can lead to ATN.
The dipstick protein measurement detects only albumin. Acid precipitation with
sulphosalicylic acid (Exton’s reagent) detects all types of protein. Thus, small amounts of
protein found by dipstick measurement, with larger amounts found by acid
precipitation, suggest the presence of light chains, and urine protein electrophoresis
should be ordered to evaluate further. If the dipstick reaction for protein is moderately
or strongly positive in the setting of ARF, quantification (timed sample or spot urine
albumin/creatinine ratio) is indicated. The presence of more than 1 – 2 g/day of urine
protein suggests a glomerular cause of ARF.
Examination of the urine sediment is of great value in ARF. The presence of gross
or microscopic haematuria suggests a glomerular, vascular, interstitial, or other
structural renal cause (e.g. stone, tumour, infection or trauma) of ARF and is rarely
seen with ATN.71 Recently, considerable attention has been focused on urinary red
blood cell (RBC) morphology as a clue to the cause of haematuria. Initially,
dysmorphic urinary RBCs found with phase-contrast microscopy, scanning or electron
microscopy, or Coulter counter, were felt to be diagnostic of a glomerular process.
More recently, routine bright-field microscopy was found to be capable of
demonstrating G1 RBCs (doughnut-shaped RBCs with one or more circular blebs
or protrusions), which are highly suggestive of a glomerular process.72 There are,
however, no data examining the morphology of urinary RBCs in the setting of ARF of
diverse causes. The presence of a large number of white blood cells (WBCs) on
urinalysis in ARF suggests the presence of either pyelonephritis or interstitial
nephritis. Recently, cytodiagnostic quantitative assessment of urine demonstrated that
patients with ARF due to ATN have significantly more collecting duct cells and total
casts on urinalysis than those patients with ARF resulting from other causes.
However, a large overlap was seen, which limits the sensitivity, specificity and
predictive power.69
Eosinophiluria in the setting of ARF is an area of great interest. Hansel’s stain is
superior to Wright’s stain in detecting eosinophiluria.73 The presence of eosinophiluria
(. 1% urine WBCs) is non-specific. It occurs with acute interstitial nephritis, many
forms of glomerulonephritis, atheroembolic disease, urinary tract infections,
prostatitis, acute rejection of renal allografts, and obstructive uropathy.42,73 However,
this finding is diagnostically valuable when the ARF occurs in a setting compatible with
either allergic interstitial nephritis (drug exposure, fever, rash, peripheral eosinphiluria)49 or atheroembolic disease (vascular catheterization, Hollenhorst plaques, livedo
reticularis, purples toes).41,42
Red blood cell casts in the urine sediment strongly suggest a glomerular or vascular
cause of ARF but have also been observed with acute interstitial nephritis. White blood
12 R. J. Anderson and D. W. Barry
cell casts may indicate the presence of either pyelonephritis or other forms of acute
interstitial nephritis.49,74
The observation of crystals in the urine sediment of patients with ARF may yield
diagnostic clues.24,25,32 – 36,58 Such evaluation is maximized with the use of fresh warm
urine, polarizing microscopy, knowledge of the urine pH, and an experienced
microscopist.58 The presence of a large number of uric acid crystals suggests acute
uric acid nephropathy, tumour lysis syndrome, or catabolic ARF. Oxalate crystals are
compatible with ethylene glycol, jejunoileal bypass, or massive doses of vitamin C
underlying ARF. 24,25,35,58 Pharmacological-agent crystals from the use of
sulphonamides, indinavir and triamterene may suggest a causal role in the development
of ARF.24,25,32 – 36,58
Urinary chemical indices and other markers
Randomized, prospective studies have clearly established the diagnostic helpfulness of
measuring selected urinary concentrations of electrolytes, uric acid and creatinine in
the setting of ARF (Figure 3).75 – 77 The major use of such spot urine chemistries is to
URINARY DIAGNOSTIC INDICES
IN ACUTE RENAL FAILURE
PRE-RENAL
Hyaline casts
>1.020
>500
<20
<1
<7
<7
RENAL
Urinalysis
Specific gravity
Uosm (mOsm/Kg H2O)
UNa (mEqu/l)
FE Na
FE uric acid (%)
FE lithium (%)
Abnormal
~1.010
>300
>40
>2
>15
>20
low
Low-molecularweight proteins
(β-2microglobulins,
amylase,
α1-microglobulin)
high
low
Brush-border
enzymes
(eg. alkaline phosphatase,
N-acetyl-β-glucosaminidase
alanine aminopeptidase)
high
Figure 3. Urinary diagnostic indices in acute renal failure.
Diagnosis of acute renal failure 13
differentiate pre-renal from renal (especially ATN) forms of ARF. Basically, pre-renal
disorders are characterized by intact tubular function with avid re-absorption of filtered
salts and water and selective organic acids resulting in low urine concentrations of
sodium, chloride, lithium and uric acid and relatively high urine/plasma (U/P) ratios of
osmolality, urea nitrogen, and creatinine.1,75,77 Contrastingly, ATN is associated with
impaired tubular function resulting in higher concentrations of sodium, chloride, trace
lithium, uric acid, and lower U/P ratios of osmolality, urea nitrogen and creatinine. In
general, the fractional excretion of sodium [FENa ¼ (UNa/PNa)/(UCr/PCr) £ 100]
appears to be more sensitive than these other urinary indices for differentiating prerenal ARF from ATN.75 However, a recent study found that a low fractional excretion
of urea (, 0.35) may be more sensitive and specific than the fractional excretion of
sodium in differentiating between pre-renal and renal causes of ARF, especially when
diuretics have been administered.78
Using urinary indices to assist in the differential diagnosis of ARF requires the
application of several caveats. First, there is no ‘gold standard’ for ATN, which makes
definitive conclusions about the sensitivity and specificity of indices difficult. Second,
despite routine use, no study has demonstrated that these indices alter either
management or outcome of ARF. Third, recent administration of diuretics may give
misleading urine sodium values. Fourth, nearly all studies have been based on indices
obtained at a single point relatively late in the course of ARF. The process of ARF is
undoubtedly dynamic in nature.23,79,80 For example, the early phases of the pre-renal
forms of ARF are associated with intact tubular function. If the cause or causes of the
pre-renal insult cannot be rapidly reversed, then ischaemic ATN can develop with
impaired tubular function. Such a consequence of events has been clearly documented
in experimental ARF settings and may explain the low FENa reported early in the course
of ARF accompanying rhabdomyolyis, sepsis, administration of radiocontrast medium,
non-oliguric forms of ARF and exposure to NSAIDs.81 – 84 Finally, the specificity of
urinary biochemical indices is limited. Thus, early in the course of urinary tract
obstruction, glomerulonephritis and thrombotic microangiopathies, the FENa can
resemble that seen in pre-renal ARF.85,86 Acute interstitial nephritis and acute renal
artery occlusion can result in indices indistinguishable form those of ATN.87,88 Also,
indices identical to those seen with ATN occur when pre-renal forms of ARF are
associated with impaired renal tubular re-absorption of sodium, as occurs with diuretic
use, bicarbonaturia, glycosuria, mineralocorticoid deficiency and salt-wasting nephropathy.89 Finally, while the fractional excretion of trace lithium appears to be a reliable
index for differentiating pre-renal forms of ARF, the special analytical techniques
required limit its use. Many of the urinary diagnostic indices depicted in Figure 3 are
used as an aid in determining the cause of ARF and also provide prognostic data on the
outcome in ARF patients.
Two additional types of urinary marker have been applied as diagnostic aids in ARF.
The first type is urinary excretion of enzymes found in the brush borders of nephron
segments (e.g. intestinal form of alkaline phosphatase, N-acetyl-b-glucosaminidase,
alanine aminopeptidase). The second type is urinary excretion of small-molecularweight proteins (e.g. b2-microglobulin, amylase, lysozyme, retinol-binding protein, a1macroglobulin) that are readily filtered and usually re-absorbed by the proximal tubule.
If the tubules are damaged, then re-absorptive capacity is diminished and increased
urinary excretion of these filtered enzymes and small-molecular-weight proteins would
be expected. While this generally occurs, the urinary excretion of selected enzymes
and small proteins has not been sufficiently sensitive or specific to warrant their routine
use in determining the cause of ARF.90,91
14 R. J. Anderson and D. W. Barry
Examination of urine may also be helpful if a monoclonal gammopathy is suspected.
Urinary electrophoresis for light chains may be helpful. Immunofluorescence of urine
sediment with antisera to light chains appears to be sensitive and specific for diagnosing
light-chain nephropathy.92
Recent research has found another marker that may be of value in distinguishing
ATN from other causes of ARF. Kidney Injury Molecule-1 (KIM-1) is a transmembrane
protein made by cells of the proximal tubule. Increased urinary levels of KIM-1 were
observed in the setting of ATN.93 Further research is needed to confirm the clinical
utility of this biomarker.
Possible urinary tract obstruction
Post-renal ARF is especially common in the elderly and patients with communityacquired ARF.10,29 Bladder catheterization and renal ultrasonography are commonly
used to screen for obstruction. Hydronephrosis may be minimal or absent on renal
imaging if the obstruction is very acute or if there is extensive retroperitoneal
fibrosis.29,31 Renal CT scanning may be useful in evaluating for urinary tract obstruction
and delineating its cause and extent.
Other testing
Intravascular volume status and cardiac output are sometimes hard to assess even
after careful review of the medical record, physical examination, and laboratory data.
In these cases, tests such as chest radiographs and echocardiograms may be helpful.
The utility of pulmonary artery catheterization in the management of acutely ill
patients has been brought into question.94 In carefully selected patients, this
procedure may, however, provide useful information in assessing volume status and
filling pressures.
When glomerular or systemic disorders are suspected as the cause of ARF,
additional testing may be indicated. Blood cultures, echocardiography and CT scanning
may help to detect the presence and source of sepsis. Measurement of antineutrophil
cytoplasmic antibodies, as well as antibodies to DNA, glomerular basement membrane,
and streptolysin-O may be helpful in certain situations. Testing for hepatitis viruses,
complement components, and circulating immune complexes (cryoglobulins, rheumatoid factor, C1q binding) may also be valuable. If vascular disease is suspected, duplex
Doppler ultrasonongraphy or magnetic resonance angiography can be diagnostically
helpful.38 – 40
Therapeutic trials
A patient’s response to a therapeutic intervention can lead to a diagnosis. Improvement
in renal function with either volume resuscitation or improvement in cardiac output
(inonotropic support, afterload or pre-load reduction) supports a pre-renal cause of
ARF. Improvement after bladder catheterization, ureteral stenting, or placement of a
percutaneous nephrostomy tube suggests a post-renal cause.10,29 – 31 Improvement
after discontinuing NSAIDs or converting enzyme inhibitors suggests a causal role for
these agents in the development of ARF.24,25 When renal function improves in response
to corticosteroid or other immunosuppressive therapies, it may indicate a diagnosis of
allergic interstitial nephritis or glomerulonephritis.
Diagnosis of acute renal failure 15
Analysis of renal tissue
Despite careful evaluation, the cause of ARF cannot always be determined with
reasonable certainty. Clinical evaluation, as discussed previously, yields a diagnosis in
75 – 80% of cases.95 If a diagnosis cannot be made, renal biopsy should be
considered.95 – 100 Although there is no consensus for renal biopsy indications,
nephrologists consider biopsy when pre-renal and post-renal causes have been
excluded and ATN cannot be diagnosed on the basis of the clinical and laboratory
evaluation.95 – 99 Signs and symptoms suggesting a systemic disorder, heavy proteinuria
and RBC casts are potential indications for performing renal biopsy in the setting of
ARF. Anuria without obstruction, prolonged (2 –3 weeks) oliguria, and marked
hypertension are also possible indications for biopsy.
Several studies have examined the utility of renal biopsy in the evaluation and
management of ARF.95 – 100 In an older series, investigators performed renal biopsies in
84 patients who were thought to have ATN. Of these patients, 52% were found to have
glomerular pathology, 30% had a tubulointerstitial disorder, and 18% a vascular
disorder. A clinical diagnosis of acute tubulointerstitial disease was 77% sensitive and
86% specific, while a clinical diagnosis of acute glomerular disease was 56% sensitive and
66% specific.98 In a separate series, 91 consecutive patients believed to have a renal
cause of ARF underwent biopsy. Overall, about 20% of these patients had a glomerular
cause of ARF. The clinical diagnosis was about 86% sensitive for identifying an acute
tubulointerstitial disorder and 67% sensitive for identifying a glomerular disorder as the
cause of ARF.95
Cohen and coworker97 found that, of 21 biopsies done for ARF, the pre-biopsy
clinical diagnosis was correct in only one-third of cases and the results of the biopsy
resulted in a significant change in therapy more than half the time.
Haas and coworkers reviewed the results of 259 consecutive renal biopsies done
for ARF in patients age 60 years or greater. They found that the most common
diagnoses were pauci-immune glomerulonephritis (31%) and acute interstitial
nephritis (18%), and the cause of acute renal failure was identified in more than
90% of biopsy specimens.100
The timing of renal biopsy in ARF remains a key issue. Historically, a lack of recovery
of renal function and anuria persisting for several days were considered indications for
biopsy. Presently, however, concerns about the irreversibility of many forms of
glomerulonephritis and untreated acute interstitial disorders have lead to a much more
timely approach to renal biopsy when the cause of ARF in unclear after a careful clinical
evaluation.
SUMMARY
Early detection and prompt, thorough evaluation of even small increases in the SCr
concentration is vital, as early intervention may alleviate renal failure. Evaluation
begins with obtaining the history, reviewing the medical record, and considering the
clinical setting. Together with physical examination, urinalysis and other routine
laboratory tests, the cause of ARF can be determined in 40 –60% of cases. Additional
diagnostic testing and therapeutic trials reveal the diagnosis in another 20 –30% cases
of ARF. In the remaining cases, renal biopsy may be required to determine a
diagnosis.
16 R. J. Anderson and D. W. Barry
Practice points
† even small increases in SCr represent significant decreases in GFR and should be
evaluated promptly
† acute renal failure is divided into pre-renal, post-renal and renal categories
† pre-renal processes are the most common
† renal causes should be considered in terms of renal anatomic compartments
† patients with a single functioning kidney are at increased risk of post-renal
ARF
† community-acquired ARF has lower mortality and is less likely to be
multifactorial than ICU or hospital-acquired forms of ARF
† evaluation of ARF requires careful review of previous laboratory data, recent
events, and medication exposures
† dry axillae, longitudinal tongue furrows and dry mucous membranes are
reliable signs of hypovolaemia
† examination of urine sediment and calculation of the FENa are valuable in
differentiating between pre-renal and renal causes of ARF
† a normal routine urinalysis suggests a pre-renal cause of ARF
† eosinophiluria occurs with acute interstitial nephritis, atheroemboli, infection
and some forms of glomerulonephritis
† pigmented granular casts are consistent with ATN
† renal biopsy may be required to make a definite diagnosis
Research agenda
† further research is needed to identify biomarkers to distinguish ATN from
other causes of ARF
† improve understanding of risk factors for the development of ARF
† development of early or ‘real-time’ markers of acute renal dysfunction
† find new methods to differentiate among the various causes of ARF
† apply electronic or other means to notify clinicians of modest increases in
serum creatinine to encourage early evaluation
REFERENCES
1. Thadhani R, Pascual M & Bonventure JV. Acute renal failure. New England Journal of Medicine 1996; 334:
1448– 1460.
2. Elasy T & Anderson RJ. Changing demography of acute renal failure. Seminars in Dialysis 1996; 9:
438–446.
* 3. Nolan CR & Anderson RJ. Hospital-acquired renal failure. Journal of the American Society of Nephrology
1998; 9: 710– 718.
4. Stewart CL & Barnen R. Acute renal failure in infants, children, and adults. Critical Care Clinics 1997; 13:
575–590.
5. Obialo CI, Okonofua EC, Tayade et al. Epidemiology of denovo acute renal failure in hospitalized
African–Americans. Archives of Internal Medicine 2000; 160: 1309– 1313.
6. Hou SH, Bushinsky DA, Wish JB et al. Hospital-acquired renal insufficiency: a prospective study. American
Journal of Medicine 1983; 74: 243–248.
7. Liano F & Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based
study. Kidney International 1996; 50: 811–818.
Diagnosis of acute renal failure 17
8. Anderson RJ, Linas SL, Berns AS et al. Noliguric acute renal failure. New England Journal of Medicine 1977;
296: 1134–1138.
9. Levy EM, Viscoli CM & Horwitz RI. The effect of acute renal failure on mortality: a cohort analysis. Journal
of the American Medical Association 1996; 275: 1489–1494.
10. Feest TG, Round A & Hamad S. Incidence of severe acute renal failure in adults: results of a communitybased study. British Medical Journal 1993; 306: 481 –483.
11. Brivet FG, Kleinknecht DJ, Loriat P et al. Acute renal failure in intensive care units: causes, outcome, and
prognostic factors of hospital mortality: a prospective, multicenter study. Critical Care Medicine 1996; 24:
192– 198.
12. Hoste EA, Lameire NH, Vanholder RC et al. Acute renal failure in patients with sepsis in a surgical ICU:
predictive factors, incidence, comorbidity, and outcome. Journal of the American Society of Nephrology
2003; 14: 1022–1031.
13. Klahr S & Miller SB. Acute oliguria. New England Journal of Medicine 1998; 338: 671– 675.
14. Mindell JA & Chertow GM. A practical approach to acute renal failure. Medical Clinics of North America
1997; 81: 731 –748.
15. Zand MS & Steinman TI. Identifying the cause of acute renal failure. Contemporary Internal Medicine 1997;
9: 20–26.
16. Hamel MB, Phillips RS, Davis RB et al. Outcomes and cost-effectiveness of initiating dialysis and
continuing aggressive care in seriously ill hospitalized adults. Annals of Internal Medicine 1997; 127:
195– 202.
17. Jurado R & Mattix H. The decreased serum urea nitrogen–creatinine ratio. Archives of Internal Medicine
1998; 158: 2509–2511.
18. Moran SM & Meyers BD. Course of acute renal failure studied by a model of creatinine kinetics. Kidney
International 1985; 27: 928–937.
19. Rabito CA, Panico F, Rubin R et al. Noninvasive, real-time monitoring of renal function during critical
care. Journal of the American Society of Nephrology 1994; 4: 1421–1428.
20. Rahman SN & Conger JD. Glomerular and tubular factors in urine flow ratios of acute renal failure
patients. American Journal of Kidney Diseases 1994; 23: 788–793.
21. Rahman M & Smith MC. Chronic renal insufficiency. Archives of internal Medicine 1998; 158: 1743–1752.
22. Wynckel A, Randoux C, Millart H et al. Kinetics of carbamylated haemoglobin in acute renal failure.
Nephrology Dialysis Transplant 2000; 15: 1183–1188.
23. Badr KF & Ichikawa I. Pre-renal failure: a deleterious shift from renal compensation to decompensation.
New England Journal of Medicine 1998; 319: 623–629.
* 24. Choudhury D & Abmed Z. Drug-induced nephrotoxicity. Medical clinics of North America 1997; 81:
705 –717.
25. Bennett WM. Drug nephrotoxicity: an overview. Renal Failure 1997; 19: 221–224.
26. Moran M & Kapsner C. Acute real failure associated with elevated plasma oncotic pressure. New England
Journal of Medicine 1987; 317: 150– 153.
27. Dorman HR, Sondheimer JH & Cadnapaphornchai P. Mannitol-induced acute renal failure. Medicine
1990; 69: 153.
28. Cayco AV, Perazella MA & Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a
report of two cases and an analysis of the literature. Journal of the American Society of Nephrology 1997; 8:
1788–1794.
* 29. Klahr S. Urinary tract obstruction. In Schrier RW (ed.) Diseases of the Kidney, 7th edn. Philadelphia:
Lippencott Williams and Wilkins, 2001, pp 757–788.
30. Chapman ME & Reid JH. Use of percutaneous nephrostomy in malignant ureteric obstruction. British
Journal of Radiology 1991; 64: 318–320.
31. Bhandari S, Johnston P, Fowler RC et al. Non-dilated bilateral ureteric obstruction. Nephrology Dialysis
Transplant 1995; 10: 2337– 2339.
32. Don BR, Rodriguez RA & Humphries MA. Acute renal failure associated with pigmenturia or crystal
deposits. In Schrier RW (ed.) Diseases of the Kidney, 7th edn. Philadelphia: Lippencott Williams and
Wilkins, 2001, pp 1299–1328.
33. Becker BN & Schulman G. Nephrotoxicity of antiviral therapies. Current Opinion in Nephrology and
Hypertension 1996; 5: 375 –379.
34. Roy LF, Villeneuve JP, Dumont A et al. Irreversible renal failure associated with triamterene. American
Journal of Nephrology 1991; 11: 486–488.
35. Ramaswamy CR, Williams JD & Griffiths DF. Reversible acute renal failure with calcium oxalate cast
nephropathy: possible role of ascorbic acid. Nephrology Dialysis Transplant 1993; 8: 1387–1389.
36. Kopp JB, Miller KD, Mican JA et al. Crystalluria and urinary tract abnormalities associated with indinavir.
Annals of Internal Medicine 1997; 127: 119 –125.
18 R. J. Anderson and D. W. Barry
37. Blade J, Fernandez-Llama P, Bosch F et al. Renal failure in multiple myeloma. Archives of Internal Medicine
1998; 158: 1889–1893.
38. Hays SR. Ischemic acute renal failure. American Journal of the Medical Sciences 1992; 304: 93 –108.
* 39. Abuelo JG. Diagnosing vascular causes of acute renal failure. Annals of internal Medicine 1995; 123:
601 –614.
40. Sandy D & Vidt DO. How to identify and limit ischemic nephropathy: presentation, screening tests,
therapeutic approaches. Journal of Critical Illness 1998; 13: 503 –512.
41. Bell SP, Frankel A & Brown EA. Cholesterol emboli: uncommon or unrecognized. Journal of the Royal
Society of Medicine 1997; 90: 543–546.
42. Wilson DM, Salazer TL & Farkouth ME. Eosinophiluria in atheroembolic renal disease. American Journal of
Medicine 1991; 91: 186–189.
43. Rudnick MR, Berns JS, Cohen RM et al. Nephrotoxic risks of renal angiography contrast media-asociated
nephrotoxicity and atheroembolism: a critical review. American Journal of Kidney Diseases 1994; 24:
713–727.
44. McCullough PA, Wolyn R, Rocher LL et al. Acute renal failure after coronary intervention: incidence,
risk factors, and relationship to mortality. American Journal of Medicine 1997; 103: 368–375.
45. Remuzzi G & Ruggenenti P. The hemolytic-uremic syndrome. Kidney International 1998; 66: S54–S57.
46. Marwah D & Howe S. Renal disease in pregnancy. Current Opinion in Nephrology and Hypertension 1996; 5:
147–150.
47. Gordon LI & Kwaan HC. Cancer- and drug-associated thrombotic thrombocytopenic purpura and
hemolytic uremic syndrome. Seminars in Hematology 1997; 34: 140 –147.
48. Hricik DE, Chung-Park M & Sedor JR. Glomerulonephritis. New England Journal of Medicine 1998; 339:
888–899.
* 49. Eknoyan G. Acute tubulointerstitial nephritis. In Schrier RW (ed.) Diseases of the Kidney, 7th edn.
Philadelphia: Lippencott Williams and Wilkins, 2001, pp 1273–1298.
50. Welage LS, Walawander CA, Timm EG et al. Risk factors for acute renal insufficiency in patients with
suspected or documented bacterial pneumonia. Annals of Pharmacotherapy 1994; 28: 515–522.
51. Liano F, Junco E, Pascual J et al. The spectrum of acute renal failure in the intensive care unit compared
with that seen in other settings. The Madrid Acute Renal Failure Study Group. Kidney International 1998;
66: S16– S24.
52. Weinman EJ & Patak RV. Acute renal failure in cancer patients. Oncology 1992; 6: 47–52.
53. Turney JH, Marshall DH, Brownjohn AM et al. The evolution of acute renal failure. Quarterly Journal of
Medicine 1990; 74: 83–104.
54. Andreucci VE, Fuiano G, Russo D et al. Vasomotor nephropathy in the elderly. Nephrology Dialysis
Transplant 1998; 13: 17–24.
55. Pascual J & Liano F. Causes and prognosis of acute renal failure in the very old. Journal of the American
Geriatrics Society 1998; 46: 721– 725.
56. Gines P & Rodes J. Clinical disorders of renal function in cirrhosis with ascites. In Arroyo V, Gines P &
Schrier RW (eds) Ascites and Renal Dysfunction in Liver Disease. Malden, MA: Blackwell Science, 1996, pp
36–57.
* 57. Bataller R, Sort P, Gines P et al. Hepatorenal syndrome: definition, pathophysiology, clinical features, and
management. Kidney International 1998; 53: S47–S53.
58. Fogazzi GB. Crystalluria: a neglected aspect of urinary sediment analysis. Nephrology Dialysis Transplant
1996; 11: 379– 387.
59. Zager RA. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney International 1996; 49:
314–326.
60. Abuelo JG. Renal failure caused by chemicals, foods, plants, animal venoms and misuse of drugs. Archives
of Internal Medicine 1990; 150: 505–510.
61. Davidman M, Olson P, Kohen J et al. Iatrogenic renal disease. Archives of Internal Medicine 1991; 151:
1809– 1812.
* 62. McGee S, Abernathy WB & Timel DL. Is this patient hypovolemic? Journal of the American Medical
Association 1999; 281: 1022–1029.
63. Rysava R, Zabka J, Peregrin JH et al. Acute renal failure due to bilateral renal artery thrombosis associated
with primary antiphospholipid syndrome. Nephrology Dialysis Transplant 1998; 13: 2645–2647.
64. Hughson MD, Nadasedy T & McCarty GA. Renal thrombotic microangiopathy in patients with systemic
lupus erythematosus and the antiphospholipid syndrome. American Journal of Kidney Disorders 1992; 20:
150–158.
65. Somers DL, Sotolongo C & Bertolatus IA. White clot syndrome associated with renal failure. Journal of
American Society of Nephrology 1993; 4: 137–141.
66. Schrier RW, Henderson HS, Tisher CC et al. Nephropathy associated with heat stress and exercise.
Annals in Internal Medicine 1967; 67: 356.
Diagnosis of acute renal failure 19
67. Oster JR, Sanger I, Contreras GN et al. Metabolic acidosis with extreme elevation of anion gap: case
report and literature review. American Journal of the Medical Sciences 1999; 317: 38–49.
68. Miller PD, Krebs RA, Neal BJ et al. Polyuric pre-renal failure. Archives of Internal Medicine 1980; 140:
907– 909.
69. Marcussen N, Schumann J, Campbell P et al. Cytodiagnostic urinalysis is very useful in the differential
diagnosis of acute renal failure and can predict severity. Renal Failure 1995; 17: 721–729.
70. Minuth AN, Terrell JB & Suki WN. Acute renal failure: a study of the course and prognosis of 104
patients and of the role of furosemide. American Journal of the Medical Sciences 1976; 271: 317–324.
71. Duflot J, Cohen AN & Adler S. Macroscopic hematuria as the presenting manifestation of acute renal
failure. American Journal of Kidney Diseases 1993; 22: 607 –610.
72. Dinda AK, Saxena S, Guleria S et al. Diagnosis of glomerular haematuria: role of dysmorphic red cell, G1
cell, and bright-field microscopy. Scandinavian Journal of Clinical and Laboratory Investigation 1997; 57:
203– 208.
73. Nolan CR & Kelleher SP. Eosinophiluria. Clinics in Laboratory Medicine 1988; 8: 555–565.
74. Jones BE, Nanra RS & White KH. Acute renal failure due to acute pyelonephritis. American Journal of
Nephrology 1991; 11: 257– 259.
75. Miller TR, Anderson RJ, Linas SL et al. Urinary diagnostic indices in acute renal failure: a prospective
study. Annals of Internal Medicine 1978; 88: 47– 50.
* 76. Rabb H. Evaluation of urinary markers in acute renal failure. Current Opinions in Nephrology and
Hypertension 1988; 7: 681–685.
77. Steinhausen F. Fractional excretion of trace lithium and uric acid in acute renal failure. Journal of the
American Society of Nephrology 1994; 4: 1429–1437.
* 78. Carvounis CP, Nisar S & Guro-Razuman S. Significance of the fractional excretion of urea in the
differential diagnosis of acute renal failure. Kidney International 2002; 62: 2223–2229.
79. Bock HA. Pathophysiology of acute renal failure in septic shock failure. Kidney International 1998; 53:
S15–S18.
80. Lam M & Kaufman CE. Fractional excretion of sodium as a guide to volume depletion during recovery
from acute renal failure. American Journal of Kidney Diseases 1985; 6: 18–21.
81. Fang LS, Siroa RA, Ebert TH et al. Low fractional excretion of sodium with contrast media-inducted
acute renal failure. Archives of Internal Medicine 1980; 140: 531 –533.
82. Vaz AJ. Low fractional excretion of urinary sodium in acute renal failure due to sepsis. Archives of Internal
Medicine 1983; 143: 738 –739.
83. Corwin HL, Schrieber MI & Fang LS. Low fractional excretion of sodium: occurrence with
hemoglobinuric and myoglobinuric-induced acute renal failure. Archives of Internal Medicine 1984; 144:
981–982.
84. Diamond IR & Yoburn DC. Nonoliguric acute renal failure associated with a low fractional excretion of
sodium. Annals of Internal Medicine 1982; 96: 597 –600.
85. Hoffman LM & Suki WN. Obstructive uropathy mimicking volume depletion. Journal of the American
Medical Association 1976; 236: 2096–2097.
86. Hilton PJ, Jones NF, Barraclough MA et al. Urinary osmolality in acute renal failure due to
glomerulonephritis. Lancet 1969; ii: 655–656.
87. Lins RL, VeTooten GA, DeClerk DS et al. Urinary indicies in acute interstitial nephritis. Clinical
Nephrology 1986; 26: 131– 133.
88. Liano F, Gamey C, Pascual J et al. Use of urinary parameters in the diagnoses of total acute renal artery
occlusion. Nephron 1994; 66: 170– 175.
89. Anderson RJ, Gross PA & Gabow PA. Urinary chloride concentration in acute renal failure. Mineral and
Electrolyte Metabolism 1984; 10: 92–97.
90. Chew SL, Lins RL, Daelemans R et al. Urinary enzymes in acute renal failure. Nephrology Dialysis
Transplant 1993; 8: 507–511.
91. Hoffmann W, Regenbogen C, Edel H et al. Diagnostic strategies in urinalysis. Kidney International 1994;
46S: 111–114.
92. Fogazzi GB, Pazzi C, Passenni P et al. Utility of immunofluorescence of urine sediment for identifying
patients with renal disease due to monoclonal gammopathies. American Journal of Kidney Diseases 1991;
17: 211–217.
93. Han VK, Bailly V, Abichandani R et al. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human
renal proximal tubule injury. Kidney International 2002; 62: 237 –244.
94. Connors AF, Speroif T & Dawson NV. The effectiveness of right heart catheterization in the initial care of
critically ill patients. Journal of the American Medical Association 1996; 276: 889 –897.
95. Mustonen J, Pasternak A, Helm H et al. Renal biopsy in acute renal failure. American Journal of Nephrology
1984; 4: 27–31.
20 R. J. Anderson and D. W. Barry
* 96. Andreucci VE, Fuiano G, Stanzcate P et al. Role of renal biopsy in the diagnosis and prognosis of acute
renal failure. Kidney International 1998; 53: S91–S95.
97. Cohen AH, Nast CC, Adler SB et al. Clinical utility of kidney biopsies in the diagnosis and management of
renal disease. American Journal of Nephrology 1989; 9: 309 –315.
98. Wilson DM, Turner DR, Cameron JS et al. Value of renal biopsy in acute intrinsic renal failure. British
Medical Journal 1976; 2: 459–461.
99. Richards NT, Darby S, Howie AJ et al. Knowledge of renal histology alters patient management in over
40% of cases. Nephrology Dialysis Transplant 1994; 9: 1255– 1259.
100. Haas M, Spargo BH, Wit EJ et al. Etiologies and outcome of acute renal insufficiency in older adults: a
renal biopsy study of 259 cases. American Journal of Kidney Diseases 2000; 35: 433–447.