Clin and Lab Diagnosis in Arf

7/30/2019 Clin and Lab Diagnosis in Arf

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1

Clinical and laboratory diagnosis of acute

renal failure

Robert J. Anderson* MDProfessor 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 MDAssistant 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 functionsufficient enough to result in retention of nitrogenous waste and disrupt fluid and electrolytehomeostasis. There is no consensus regarding a quantifiable definition of ARF. Prompt evaluationof ARF is vital because ARF can be the end result of diverse processes which can often bereversed or attenuated through therapy directed at the underlying condition. Evaluation beginswith careful review of the patients history, previous medical records, physical examination,urinalysis, and available laboratory data. Routine urine chemical indices, calculation of thefractional excretion of sodium, and examination of the urine sediment are valuable incharacterizing the cause of ARF. When this evaluation fails to yield a diagnosis, further testingmay be required to evaluate intravascular volume status or diagnose a systemic disorder orglomerular cause of ARF. Response to therapeutic trials may provide a diagnosis. When adiagnosis cannot be made with reasonable certainty through this evaluation renal biopsy shouldbe 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 renalfunction sufficient enough to result in retention of nitrogenous waste and disrupt fluidand electrolyte homeostasis.14 Although this qualitative definitionis agreed upon, thereis no consensus regarding the quantification of the decline in renal function to warrant adiagnosis 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 thecalculated creatinine clearance of 50%. Theclinicianmust remember that in patients withnormal renal function, SCr is a poor marker of changein kidney function.Largereductionsin glomerular filtration rate (GFR) initially produce only small increases (0.10.3 mg/dl)

1521-6896/$ - see front matter Q 2003 Published by Elsevier Ltd.

Best Practice & Research Clinical AnaesthesiologyVol. 18, No. 1, pp. 120, 2004doi:10.1016/S1521-6896(03)00077-6, available online at http://www.sciencedirect.com

*Corresponding author. Tel.:

1-303-372-9092; Fax:

1-303-372-9082.E-mail address: [email protected] (R.J. Anderson).
http://www.sciencedirect.com/http://www.sciencedirect.com/


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in SCr concentration.5 Therefore, even small increases in SCr should be carefully

evaluated.ARF isencountered frequently in modern medical practice, especially in the inpatient

setting.612 A wide range of pathophysiological events produce identical clinical picturesof ARF.16,815 Alleviation or attenuation of ARF requires prompt identification andtreatment of the underlying condition. Mild forms of ARF are often reversible, andseveral 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 evenmild increases in SCr concentration. In this chapter we review the clinical and laboratoryfeatures 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 orblood urea nitrogen (BUN). Typically, the BUN/SCr ratio is approximately 15:1. In thecomplete absence of glomerular filtration, BUN and SCr increase 10 15 mg/dl and 1.01.5 mg/dl per day, respectively. However, there are several situations that dispropor-tionately affect either the BUN or SCr concentration (Table 1) thereby altering thisrelationship.17 Moreover, factors other than a reduction in GFR can lead to increasedconcentrations of BUN (e.g. a catabolic state) or SCr (e.g. rhabdomyolysis ormedications that interfere with creatinine excretion or measurement) as shown inTable 1.

The SCr concentration is usually a better marker of GFR than is the BUN. In a steadystate, the SCr approximately doubles each time the GFR is reduced by 50%. Forexample, steady state GFRs of 100, 50, 25 and 12.5 ml/minute correlate with SCrconcentrations of 1.0, 2.0, 3.0 and 4.0, respectively. However, ARF usually is not asteady-state setting as the determinants ofthe SCr concentration (production, volumeof distribution, and renal clearance) vary.18 Also, the rise in SCr lags behind the processleading to ARF. Unfortunately, techniques for monitoring real-time GFR are expensiveand are not routinely available.19 In some intensive care settings, frequent, brief, timedurine samples are collected to assess GFR. The reliability of this approach remains to becarefully 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 contemporaryclinical practice are non-oliguric in nature.8 Recent clinical studies have found that urineoutput correlates strongly with residual glomerular filtration and poorly with renaltubular function.20 The higher level of residual glomerular filtration in non-oliguricpatients is compatible with less severe renal failure and lower mortality than is seen inoliguric 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 BUNconcentration is due to an acute or chronic process. Reviewing previous records isessential in this setting. If previous values are unavailable, the clinician should assume thepresence of potentially treatable conditions.21 Small kidney size (,10 cm) on renalimaging supports the diagnosis of chronic renal disease. Non-enzymatic carbamylation

2 R. J. Anderson and D. W. Barry


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of the terminal valine of haemoglobin occurs in direct relationship to the duration andmagnitude of the increase in BUN. A recent study of 28 patients with ARF and 13patients with CRF found a value,80 mg of carbamyl valine per gramme of haemoglobinhad a sensitivity and specificity of 96 and 84.2%, respectively for differentiating acutefrom chronic renal failure.22

CAUSES OF ACUTE RENAL FAILURE

Traditionally, ARF is categorized as pre-renal, intrarenal or post-renal as shown inTable 2.1 Pre-renal refers to factors associated with renal hypoperfusion as the cause offiltration failure. Pre-renal processes are the most commonly encountered causes ofARF.1,6 8,11,12 If not reversed, pre-renal ARF can progress to ischaemic acute tubularnecrosis (ATN). In pre-renal ARF, decreased renal perfusion pressure, afferent

Table 1. Causes of an abnormal BUN/

creatinine ratio.

BUN:Cr. 15

Increased formation of urea

High intake of protein

Catabolic states

FeverTissue 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-dialysisIncreased formation of creatinine

Rhabdomyloysis

Decreased secretion of creatinine

Cimetidine

Trimethoprim

Pyrimethamine

Interference with assay

Ketones

Cefoxitin

Ascorbic acid

Methyldopa

Flucytosine

Barbiturates

Diagnosis of acute renal failure 3


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arteriolar constriction, or efferent arteriolar dilation acts to decrease glomerularhydrostatic pressure.23 Events that decrease renal perfusion pressure include loss ofextracellular 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 byenhanced vasoconstrictive influences (e.g. circulating adrenalin (epinephrine), angio-tensin II, endothelin, enhanced renal adrenergic neural traffic) or by a decrease invasodilators (nitric oxide, bradykinin, eicosanoids). These changes can be due tomedications such as non-steroidal anti-inflammatory drugs (NSAIDs), cyclosporin,radiocontrast medium, and amphotericin B2325 or are seen in the post-operativestate, early sepsis, advanced liver disease, oedematous disorders, or volume-depletedstates. Efferent arteriolar vasodilation occurs with the use of angiotensin-convertingenzyme inhibitors or angiotensin receptor blockers.

An unusual cause of pre-renal ARF is a hyperoncotic state. Glomerular filtrationpressure is glomerular hydrostatic pressure minus plasma colloid oncotic pressure.Infusion of either osmotically active substancessuch as mannitol, dextran orproteincan increase oncotic pressure enough to exceed the glomerular capillaryhydrostatic pressure.2628 This stops glomerular filtration leading to an anuric form ofARF, that usually is alleviated by removal of the offending substance.

Table 2. Differential diagno-

sis of acute renal failure.

Pre-renal(4080%)

Volume loss or sequestration

Decreased cardiac output

Hypotension

Post-renal (515%)

Intrarenal

Crystals

Proteins

Extrarenal

Pelvis

Ureter

Bladder

Urethra

Renal(1030%)

Vascular disorder

Small vessel

Large vessel

Glomerulonephritis

Interstitial disordersInflammation

Space-occupying process

Tubular necrosis

Ischaemia

Toxin

Pigmenturia



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Post-renal (after formation of the glomerular filtrate) causes of ARF areless commonly encountered than pre-renal causes, but they are nearly alwaystreatable.6,7,10,29 37 Post-renal forms of ARF are divided into intrarenal (tubular) orextrarenal. Tubular precipitation of insoluble crystals (methotrexate, acyclovir,sulphonamides, indinavir, uric acid, triamterene, oxalic acid)3236 or protein (plasmacell dyscrasia)37 can increase intratubular pressure. If sufficiently high, this opposesglomerular filtration pressure and can decrease GFR. Similarly, obstruction of the

extrarenal collecting system at any level (renal pelvis, ureters, bladder or urethra) canalso lead to post-renal ARF.

After considering pre-renal and post-renal causes, the clinician should turn tointrarenal causes of ARF. Considering renal causes in terms of renal anatomiccompartments is helpful. Disorders of the smaller renal vasculature, (e.g. vasculitis,thrombotic thrombocytopenic purpura (TTP), haemolyticuraemic syndrome (HUS),malignant hypertension, eclampsia, disseminated intravascular coagulation (DIC),scleroderma, post-partum states) the large arteries (e.g. thrombosis, emboli), andthe renal veins (acute occlusion) can all result in ARF.3847 All forms of acuteglomerulonephritis can present as ARF.48 Acute inflammation and space-occupyingprocesses of the renal interstitium (e.g. drug-induced, infectious, and autoimmunedisorders, leukaemia, lymphoma, sarcoidosis) can result in ARF.49 Finally, tubulardamage or ATN, which usually results from renal ischaemia due to prolonged pre-renalARF, nephrotoxins (e.g. radiocontrast medium, aminoglycosides, pentamidine,

foscarnet, cisplatin, amphotericin, NSAIDs, heavy metals, hydrocarbons), andpigmenturia (e.g. intravascular haemolysis, rhabdomyolysis) are relatively commoncauses 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. Consideringthe setting in which ARF has developed may be helpful. For example, community-acquired 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 hospitalward, however, occurs in the setting of co-morbidity, is often multifactorial, and isassociated with higher mortality.1 4,6 10,12,50 Acute renal failure acquired in theintensive care unit is almost always multifactorial and is associated with sepsis, multi-organ failure and even higher mortality2,3,8,9,11,16).

Causes of ARF can also be considered in the context of the underlying disease orprocess in which it occurs (Figure 2). Unique causes of ARF can be seen in the setting ofmalignancy, immunodeficiency virus (HIV) infection, pregnancy, and the post-operativeor intensive care state.2,6 8,11,12,16,32,37,46,51 53 Two settings not shown in Figure 2 inwhich ARF is frequently encountered are the elderly population and patients with liverdisease. The effect of advancing age in decreasing functional renal reserve and theassociated co-morbidities increases the risk of ARF. Researchers have demonstratedthat there is a dramatic (three- to eightfold), age-dependent increase in the incidence ofcommunity-acquired ARF in patients older than 60 years.10 Although this group issubject 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 thoseof pre-renal (e.g. aggressive diuresis, large-volume paracentesis, gastrointestinal



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Figure 1. Approach to evaluation of acute renal failure.

l History

l

Review of records

l

Physical examination

l

Urinalysis

l

Consider bladder catheterization

INITIAL EVALUATION

EVALUATION OF

ACUTE RENAL FAILURE

SUBSEQUENT EVALUATION

TO CONSIDER

DIAGNOSTIC

TESTING

THERAPEUTIC

TRIALS

TISSUE

EVALUATION

l

Urinary diagnostic

indices and special

urinalysis

l Evaluation to

exclude urinary tract

obstruction

l

Assessment of

cardiac/intravascularvolume status

l

Assessment of

renal vasculature

l

Additional blood

work or cultures

l

Volume

expansion

l Improvement of

cardiac function

l Discontinuation

of nephrotoxins

l Relief of urinary

tract obstruction

l

Empiric trial of therapy

for specific disorders

(immunosuppression,

plasmapheresis)

l

Renal biopsy

l

Other tissue

biopsy


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CAUSES OF ACURE RENAL FAILURE

BY CLINICAL SETTING

Malignancy

Pre-renal

l

Drug induced

l

Pericardial tamponade

l Cardiac dysfunction

Pre-renal

l

Hypodipsia

l Diarrhoea

Pre-renal

l

Hyperemesis gravidarum

Pre-renal

l

Volume depletion or

sequestration

l

Impaired cardiac output

Post-renal

l Bladder outlet obstruction

l

Ureteric ligation

Post-renal

l

Gravid uterus blocking uretersPost-renall

Uretal blockage

(lymphoma)

l

Crystalluria (sulphonamides,

protease inhibitors, acyclovir)

l

Protein deposition

(B-cell lymphoma)

Post-renall

Ureteral blockage

(surgery metastasis,

retro-peritoneal fibrosis)

l

Bladder neck obstruction

(Prostate/bladder cancer)

l Crystalluria (uric acid,methotrexate)

l

Protein deposition

(plasma cell dyscrasia) Renal

l Toxins (aminoglycosides,

foscarnet, pentamidine, amphotericin B,

vancomycin, contrast dye)

l

Sepsis

l

HIV-associated glomerulopathyl Thrombotic microangiopathy

Renal

l Toxins (chemotherapeutic agents,

antimicrobials, contrast dye)

l Light chain toxicity

l

Tumour-lysis/hyperuicaemia

l

Hypercalcaemia

l

Tumour infiltration

l

Tumour glomerulopathy

l

Thrombotic microangiopathy

Renal

l

Sepsis

l Toxins (aminoglycosides,

contrast dye, vancomycin

amphotericin, converting

enzyme inhibitors)

l Multiple organ failure

l

Rhabdomyolysis

Renal

l

Sepsis

l Thrombotic microangiopathy

l

HELLP syndrome/eclampsia

l

Cortical necrosis

Pregnancy ICU/Post-operative statesHIV

Figure 2. Causes of acute renal failure by clinical setting.


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haemorrhage, sepsis) and renal (e.g. glomerulopathy, ischaemic and toxic ATN, acuteinterstitial nephritis) aetiologies.50 Additionally, a significant portion of patients withadvanced liver disease develop intense renal vasoconstriction and a form of ARF (thehepatorenal syndrome) that responds poorly to treatment and is associated with highmortality.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 ofARF. A history of thirst, orthostatic lightheadedness, and symptoms of congestive heartfailure supports a pre-renal aetiology of ARF.

Post-renal causes of ARF are common at the extremes of age, with a history ofchanges in the size and force of urine stream, the presence of bladder, prostate, orpelvic cancer; the use of anticholinergic and alpha-adrenergic medications; the presenceof anuria, suprapubic pain, or urolithiasis; or exposure to medications known to causehyperuricaemia or crystalluria.32 36,58 Patients with either a single kidney or asignificant baseline decrease in the function of one kidney should make the clinicianeven more concerned about the possibility of post-renal ARF because a single lesionmay obstruct the good kidney.

A history of factors that predispose to vascular disease (smoking, hypertension,diabetes mellitus, hyperlipidaemia, claudication, stroke, myocardial infarction, periph-eral vascular disease, arterial catheterization involving the aorta, aortic aneurysm, and

atrial fibrillation) is compatible with a vascular embolic event leading to ARF. A historyof systemic infection or the presence of systemic symptoms may support a glomerularcause of ARF. Medication exposure, symptoms of systemic infection, or a history ofacute pyelonephritis may point to acute interstitial nephritis as the cause of ARF. Thepresence of disorders associated with either rhabdomyolysis or intravascularhaemolysis 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 attributedto exposure to nephrotoxin.68,10 12,24,25,49,51,60,61 Drugs and toxins associated withARF are reviewed in Table 3.

Physical examination

Physical examination remains an important diagnostic tool for determining the cause ofARF. Assessing the volume status of patients with ARF is critical but sometimes difficult.

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

Immunologicalinflammatory

Penicillin, cephalosporins, allopurinol, NSAIDs, sulphonamides, diuretics, rifampin, ciprofloxacin,

cimetidine, tetracyclines, phenytoin



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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 indetecting hypovolaemia. Decreased skin turgor or impaired capillary refill time havelimited sensitivity and specificity.62

Ophthalmic examination may reveal Hollenhorst plaques suggestive of atheroem-boli42 or other findings compatible with bacterial endocarditis, vasculitis or malignant

hypertension. Neck examination for jugular venous pressure and carotid pulses andsounds may be helpful in detecting heart failure, aortic valve disease or vascular disease.Cardiovascular examination for rate, rhythm, murmurs, gallops and rubs may be helpfulin detecting the presence of heart failure and possible sources of emboli (e.g. atrialfibrillation, endocarditis). Lung examination can assist in determining the presence ofeither heart failure or a pulmonaryrenal syndrome associated with ARF. Abdominalexamination can reveal findings compatible with vascular disease (e.g. bruits, palpableabdominal aortic aneurysm), masses that could be malignant, a distended bladder whichcould be indicative of outlet obstruction, or possible sources of bacteraemia, evidenceof 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), afine maculpapular rash (drug-induced interstitial nephritis), or livedo reticularis andembolic stigmata (atheroemboli). If neurological signs are present, systemic disorders

such as vasculitis, TTP, subacute bacterial endocarditis, and malignant hypertensionwarrant consideration. Peripheral neuropathy in the presence of ARF raises thepossibility of nerve compression caused by rhabdomyolysis, ischaemia, heavy metalintoxication, or plasma cell dyscrasia. Pelvic examination in females and rectalexamination may detect an obstructive cause of ARF.

Laboratory data

Reviewing the haemogram can be helpful in determining the cause of ARF. Anaemiacould indicate recent haemorrhage or intravascular haemolysis as factors contributingto the ARF. A microangiopathic state (thrombocytopenia, reticulocytosis, elevatedlactate dehydrogenase, deformed red blood cells on peripheral smear) with ARF pointsto TTP, HUS, eclampsia, vasculitis, malignant hypertension, HIV infection, and variousmedications as possible causes.39,45,47 Anaemia with rouleaux formation and ARFsuggests a plasma cell dyscrasia. Eosinophilia is compatible with atheroemboli, acuteinterstitial nephritis or polyarteritis nodosa. Leukopenia is common in patients withsystemic lupus erythematosus (SLE) and ARF. Thrombocytopenia in the setting of ARFis compatible with a thrombotic microangiopathy, SLE, DIC, rhabdomyolysis, advancedliver disease with hypersplenism, and white clot syndrome resulting from heparinadministration as causes of the ARF.39,45,47,6365 Coagulopathy, such as prolongation ofthe international normalized ratio (INR) or partial thromboplastin time (PTT), suggestsunderlying liver disease (increased INR), DIC (increased INR and PTT), or antipho-spholipid 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. Moremarked hyperkalaemia suggests the possibility of rhabdomyolysis, tumour lysissyndrome, intravascular hemolysis, or the use of NSAIDs or angiotensin-convertingenzyme inhibitors as contributing factors.32,59 Elevations of creatine kinase, serumglutamic-oxaloacetic transaminase, and LDH often occur with rhabdomyolysis ortumour lysis syndrome. Modest hyperuricaemia (,10 mg/dl) usually accompanies ARF,



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but much higher levels of uric acid occur with tumour lysis syndrome, rhabdomyolysisand heat stroke.66 Mild metabolic acidosis occurs frequently as a consequence of ARFand is often associated with a modest (510 mEq/l) increase in the anion gap. Markedacidosis 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 isseen with cessation of glomerular filtration (e.g. rapidly progressive glomerulonephritis,acute cortical necrosis, or renal arterial occlusion) or complete urinary tractobstruction. Brief (,2448 hour) episodes of severe oliguria (,100 ml/day) occurin some cases of ATN, especially in the context of heat stroke.66 Pre-renal forms of ARFnearly always present with oliguria (,400 ml/day), although non-oliguric forms havebeen reported.68 Post-renal and renal forms of ARF can present with any pattern ofurine flow ranging from anuria through polyuria. As noted previously, most cases ofARF 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 thecause of ARF. In an older study6, diagnostically useful information was obtained fromroutine 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

PyelonephritisInterstitial 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



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of ARF suggests a pre-renal or post-renal cause. An abnormal urinalysis suggests a renalcause. Two studies6,69, but not a third70, suggest a direct relationship between thepresence and the degree of abnormalities seen on routine urinalysis and the prognosisof 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 abnormalurinalysis (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 theirurine.69

The dipstick orthotoludine reaction for blood is sensitive for about three red bloodcells/high-power field. If no blood cells are present, this reaction is positive in thesetting of either myoglobinuria or haemoglobinuria, both of which can lead to ATN.

The dipstick protein measurement detects only albumin. Acid precipitation withsulphosalicylic acid (Extons reagent) detects all types of protein. Thus, small amounts ofprotein found by dipstick measurement, with larger amounts found by acidprecipitation, suggest the presence of light chains, and urine protein electrophoresisshould be ordered to evaluate further. If the dipstick reaction for protein is moderatelyor strongly positive in the setting of ARF, quantification (timed sample or spot urinealbumin/creatinine ratio) is indicated. The presence of more than 12 g/day of urineprotein suggests a glomerular cause of ARF.

Examination of the urine sediment is of great value in ARF. The presence of grossor microscopic haematuria suggests a glomerular, vascular, interstitial, or otherstructural renal cause (e.g. stone, tumour, infection or trauma) of ARF and is rarelyseen with ATN.71 Recently, considerable attention has been focused on urinary redblood cell (RBC) morphology as a clue to the cause of haematuria. Initially,dysmorphic urinary RBCs found with phase-contrast microscopy, scanning or electronmicroscopy, or Coulter counter, were felt to be diagnostic of a glomerular process.More recently, routine bright-field microscopy was found to be capable ofdemonstrating G1 RBCs (doughnut-shaped RBCs with one or more circular blebsor 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 ofdiverse causes. The presence of a large number of white blood cells (WBCs) onurinalysis in ARF suggests the presence of either pyelonephritis or interstitialnephritis. Recently, cytodiagnostic quantitative assessment of urine demonstrated that

patients with ARF due to ATN have significantly more collecting duct cells and totalcasts on urinalysis than those patients with ARF resulting from other causes.However, a large overlap was seen, which limits the sensitivity, specificity andpredictive power.69

Eosinophiluria in the setting of ARF is an area of great interest. Hansels stain issuperior to Wrights stain in detecting eosinophiluria.73 The presence of eosinophiluria(.1% urine WBCs) is non-specific. It occurs with acute interstitial nephritis, manyforms 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 witheither allergic interstitial nephritis (drug exposure, fever, rash, peripheral eosinphi-luria)49 or atheroembolic disease (vascular catheterization, Hollenhorst plaques, livedoreticularis, purples toes).41,42

Red blood cell casts in the urine sediment strongly suggest a glomerular or vascularcause of ARF but have also been observed with acute interstitial nephritis. White blood



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cell casts may indicate the presence of either pyelonephritis or other forms of acuteinterstitial nephritis.49,74

The observation of crystals in the urine sediment of patients with ARF may yielddiagnostic clues.24,25,32 36,58 Such evaluation is maximized with the use of fresh warmurine, polarizing microscopy, knowledge of the urine pH, and an experiencedmicroscopist.58 The presence of a large number of uric acid crystals suggests acuteuric acid nephropathy, tumour lysis syndrome, or catabolic ARF. Oxalate crystals are

compatible with ethylene glycol, jejunoileal bypass, or massive doses of vitamin Cunderlying ARF.24,25,35,58 Pharmacological-agent crystals from the use ofsulphonamides, indinavir and triamterene may suggest a causal role in the developmentof ARF.24,25,32 36,58

Urinary chemical indices and other markers

Randomized, prospective studies have clearly established the diagnostic helpfulness ofmeasuring selected urinary concentrations of electrolytes, uric acid and creatinine inthe setting of ARF (Figure 3).7577 The major use of such spot urine chemistries is to

URINARY DIAGNOSTIC INDICESIN ACUTE RENAL FAILURE

PRE-RENAL RENAL

Hyaline casts

>1.020

>500

15>20

Low-molecular-

weight proteins

(-2microglobulins,

amylase,

1-microglobulin)

Brush-border

enzymes

(eg. alkaline phosphatase,

N-acetyl--glucosaminidase

alanine aminopeptidase)

low

low high

high

Urinalysis

Figure 3. Urinary diagnostic indices in acute renal failure.



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differentiate pre-renal from renal (especially ATN) forms of ARF. Basically, pre-renaldisorders are characterized by intact tubular function with avid re-absorption of filteredsalts and water and selective organic acids resulting in low urine concentrations ofsodium, chloride, lithium and uric acid and relatively high urine/plasma (U/P) ratios ofosmolality, urea nitrogen, and creatinine.1,75,77 Contrastingly, ATN is associated withimpaired tubular function resulting in higher concentrations of sodium, chloride, tracelithium, uric acid, and lower U/P ratios of osmolality, urea nitrogen and creatinine. In

general, the fractional excretion of sodium [FENa (UNa/PNa)/(UCr/PCr) 100]appears to be more sensitive than these other urinary indices for differentiating pre-renal ARF from ATN.75 However, a recent study found that a low fractional excretionof urea (,0.35) may be more sensitive and specific than the fractional excretion ofsodium in differentiating between pre-renal and renal causes of ARF, especially whendiuretics have been administered.78

Using urinary indices to assist in the differential diagnosis of ARF requires theapplication of several caveats. First, there is no gold standard for ATN, which makesdefinitive conclusions about the sensitivity and specificity of indices difficult. Second,despite routine use, no study has demonstrated that these indices alter eithermanagement or outcome of ARF. Third, recent administration of diuretics may givemisleading urine sodium values. Fourth, nearly all studies have been based on indicesobtained at a single point relatively late in the course of ARF. The process of ARF isundoubtedly 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 thepre-renal insult cannot be rapidly reversed, then ischaemic ATN can develop withimpaired tubular function. Such a consequence of events has been clearly documentedin experimental ARF settings and may explain the low FENa reported early in the courseof ARF accompanying rhabdomyolyis, sepsis, administration of radiocontrast medium,non-oliguric forms of ARF and exposure to NSAIDs.8184 Finally, the specificity ofurinary biochemical indices is limited. Thus, early in the course of urinary tractobstruction, glomerulonephritis and thrombotic microangiopathies, the FENa canresemble that seen in pre-renal ARF.85,86 Acute interstitial nephritis and acute renalartery 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 areassociated with impaired renal tubular re-absorption of sodium, as occurs with diureticuse, bicarbonaturia, glycosuria, mineralocorticoid deficiency and salt-wasting nephro-pathy.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 techniquesrequired limit its use. Many of the urinary diagnostic indices depicted in Figure 3 areused as an aid in determining the cause of ARF and also provide prognostic data on theoutcome 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 nephronsegments (e.g. intestinal form of alkaline phosphatase, N-acetyl-b-glucosaminidase,alanine aminopeptidase). The second type is urinary excretion of small-molecular-weight proteins (e.g. b2-microglobulin, amylase, lysozyme, retinol-binding protein, a1-macroglobulin) that are readily filtered and usually re-absorbed by the proximal tubule.If the tubules are damaged, then re-absorptive capacity is diminished and increasedurinary excretion of these filtered enzymes and small-molecular-weight proteins wouldbe expected. While this generally occurs, the urinary excretion of selected enzymesand small proteins has not been sufficiently sensitive or specific to warrant their routineuse in determining the cause of ARF.90,91



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Examination of urine may also be helpful if a monoclonal gammopathy is suspected.Urinary electrophoresis for light chains may be helpful. Immunofluorescence of urinesediment with antisera to light chains appears to be sensitive and specific for diagnosinglight-chain nephropathy.92

Recent research has found another marker that may be of value in distinguishingATN from other causes of ARF. Kidney Injury Molecule-1 (KIM-1) is a transmembraneprotein 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 clinicalutility of this biomarker.

Possible urinary tract obstruction

Post-renal ARF is especially common in the elderly and patients with community-acquired ARF.10,29 Bladder catheterization and renal ultrasonography are commonlyused to screen for obstruction. Hydronephrosis may be minimal or absent on renalimaging if the obstruction is very acute or if there is extensive retroperitonealfibrosis.29,31 Renal CT scanning may be useful in evaluating for urinary tract obstructionand delineating its cause and extent.

Other testing

Intravascular volume status and cardiac output are sometimes hard to assess evenafter 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 illpatients has been brought into question.94 In carefully selected patients, thisprocedure may, however, provide useful information in assessing volume status andfilling pressures.

When glomerular or systemic disorders are suspected as the cause of ARF,additional testing may be indicated. Blood cultures, echocardiography and CT scanningmay help to detect the presence and source of sepsis. Measurement of antineutrophilcytoplasmic 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, rheuma-

toid factor, C1q binding) may also be valuable. If vascular disease is suspected, duplexDoppler ultrasonongraphy or magnetic resonance angiography can be diagnosticallyhelpful.3840

Therapeutic trials

A patients response to a therapeutic intervention can lead to a diagnosis. Improvementin renal function with either volume resuscitation or improvement in cardiac output(inonotropic support, afterload or pre-load reduction) supports a pre-renal cause ofARF. Improvement after bladder catheterization, ureteral stenting, or placement of apercutaneous nephrostomy tube suggests a post-renal cause.10,29 31 Improvementafter discontinuing NSAIDs or converting enzyme inhibitors suggests a causal role forthese agents in the development of ARF.24,25 When renal function improves in responseto corticosteroid or other immunosuppressive therapies, it may indicate a diagnosis ofallergic interstitial nephritis or glomerulonephritis.



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Analysis of renal tissue

Despite careful evaluation, the cause of ARF cannot always be determined withreasonable certainty. Clinical evaluation, as discussed previously, yields a diagnosis in7580% of cases.95 If a diagnosis cannot be made, renal biopsy should beconsidered.95100 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 laboratoryevaluation.9599 Signs and symptoms suggesting a systemic disorder, heavy proteinuriaand RBC casts are potential indications for performing renal biopsy in the setting ofARF. Anuria without obstruction, prolonged (2 3 weeks) oliguria, and markedhypertension are also possible indications for biopsy.

Several studies have examined the utility of renal biopsy in the evaluation andmanagement of ARF.95100 In an older series, investigators performed renal biopsies in84 patients who were thought to have ATN. Of these patients, 52% were found to haveglomerular pathology, 30% had a tubulointerstitial disorder, and 18% a vasculardisorder. A clinical diagnosis of acute tubulointerstitial disease was 77% sensitive and86% specific, while a clinical diagnosis of acute glomerular disease was 56% sensitive and66% specific.98 In a separate series, 91 consecutive patients believed to have a renalcause of ARF underwent biopsy. Overall, about 20% of these patients had a glomerularcause of ARF. The clinical diagnosis was about 86% sensitive for identifying an acute

tubulointerstitial disorder and 67% sensitive for identifying a glomerular disorder as thecause of ARF.95

Cohen and coworker97 found that, of 21 biopsies done for ARF, the pre-biopsyclinical diagnosis was correct in only one-third of cases and the results of the biopsyresulted in a significant change in therapy more than half the time.

Haas and coworkers reviewed the results of 259 consecutive renal biopsies donefor ARF in patients age 60 years or greater. They found that the most commondiagnoses were pauci-immune glomerulonephritis (31%) and acute interstitialnephritis (18%), and the cause of acute renal failure was identified in more than90% of biopsy specimens.100

The timing of renal biopsy in ARF remains a key issue. Historically, a lack of recoveryof renal function and anuria persisting for several days were considered indications forbiopsy. Presently, however, concerns about the irreversibility of many forms ofglomerulonephritis 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 clinicalevaluation.

SUMMARY

Early detection and prompt, thorough evaluation of even small increases in the SCrconcentration is vital, as early intervention may alleviate renal failure. Evaluationbegins with obtaining the history, reviewing the medical record, and considering theclinical setting. Together with physical examination, urinalysis and other routinelaboratory tests, the cause of ARF can be determined in 4060% of cases. Additionaldiagnostic testing and therapeutic trials reveal the diagnosis in another 2030% casesof ARF. In the remaining cases, renal biopsy may be required to determine adiagnosis.



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Practice points

even small increases in SCr represent significant decreases in GFR and should beevaluated 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-renalARF

community-acquired ARF has lower mortality and is less likely to bemultifactorial than ICU or hospital-acquired forms of ARF

evaluation of ARF requires careful review of previous laboratory data, recentevents, and medication exposures

dry axillae, longitudinal tongue furrows and dry mucous membranes arereliable signs of hypovolaemia

examination of urine sediment and calculation of the FENa are valuable indifferentiating 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 fromother 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

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Clin and Lab Diagnosis in Arf