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. 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