Southwestern Internal Medicine Conference: Ischemic Acute Renal Failure STEVEN R. HAYS, MD
ABSTRACT: Underperfusion of the kidneys often results in the development of ischemic acute renal failure. This review summarizes the recent developments in the understanding of the pathophysiology, diagnosis, and treatment of this serious and costly disorder that affects almost 5% of hospitalized patients. KEY INDEXING TERMS: Acute renal failure; Ischemia; Acute tubular necrosis. [Am J Med Sci 1992; 304(2): 93-108.]
A
cute renal failure is commonly encountered in hospitals. Approximately 5% of patients admitted to the hospital develop acute renal failure during their hospital stay. I The development of acute renal failure is associated with a sixfold increase in risk of dying and an average 16-23 day increase in length of hospital stay.2 Despite major advances in the management of patients with acute renal failure, severe underlying illnesses and complications currently limit survival to 50%, a figure not substantially improved since 1950.3-7 To manage or prevent this serious and costly disorder, the physician must understand the pathophysiologic principles involved in the development of acute renal failure. Ischemic acute renal failure is defined as a syndrome triggered by underperfusion of the kidneys that results in the rapid deterioration of renal function and accumulation of nitrogenous wastes. Renal underperfusion plays an important pathophysiologic role in the development of all nonnephrotoxic-mediated acute renal failure. ·From the The University of Texas Southwestern Medical Center at Dallas, Dept. of Internal Medicine, Dallas, Texas. This review was presented for Internal Medicine Grand Rounds at The University of Texas Southwestern Medical Center at Dallas on September 5, 1991. The author is grateful to Robert J. Alpern for his helpful suggestions on this review. The author also gratefully acknowledges the excellent secretarial work of Dedrian Copeland and the library research of Rebecca Aricheta, Ebtesam M. Shawky, and Tommie W. Friday of Merck Sharp & Dohme, Rahway, New Jersey. Steven Hays is a recipient of a Clinical Investigator Award K08 DK 01859. Correspondence: Steven R. Hays, MD, The University of Texas Southwestern Medical Center at Dallas, Dept. of Internal Medicine, Room H5.112, 5323 Harry Hines Blvd., Dallas, TX 75235-8856. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Pathophysiology
Normally, renal blood flow to the kidney is high and the oxygen supply greatly exceeds the requirement for oxygen use.s However, when the kidney is underperfused, it is highly susceptible to injury. As shown in Figure 1, renal underperfusion is manifested by a syndrome characterized by a decrease in glomerular filtration rate (GFR). This can occur in the absence of hypotension, which is documented in less than 50% of the cases of postsurgical hypotension. 3 When the underperfusion is corrected, the GFR returns to normal (prerenal azotemia) or remains markedly depressed for a prolonged time (ischemic acute renal failure, ie, acute tubular necrosis). Thus, underperfusion of the kidney is manifested by a continuum of disorders ranging from prerenal azotemia to acute tubular necrosis (acute renal failure). Alterations in Renal Blood Flow. In human studies, renal blood flow, measured by a variety of techniques, has been shown to be decreased for a prolonged time after the initial precipitating event (during the so-called maintenance phase9~IS). Renal blood flow may remain depressed for up to 4 weeks. 1l•13 The a-adrenergic blocking agents phenoxybenzamine or phentolamine do not effectively block the renal vasoconstriction associated with acute renal failure. IO.19 The lack of effect of these agents implies that vasoconstriction is not mediated by mechanisms involving circulating catecholamines or renal nerve activity. Even when renal blood flow is increased by vasodilators, GFR remains markedly depressed. 1O,12 In addition, in most animal studies, GFR is reduced disproportionately in relation to renal blood flow,20 and renal blood flow returns to normal while GFR remains markedly depressed. 21 ,22 Thus, reduced renal blood flow seems an unlikely cause of the sustained reduction in GFR. In fact, superficial cortical blood flow rapidly returns to normal after an ischemic event. However, regional changes in perfusion may be more important than changes in total renal blood flow. Medullary blood flow is decreased to a greater extent than cortical flow and remains reduced for a longer time. After an ischemic event, medullary blood flow is decreased by at least two-thirds at a time when cortical flow is reduced by only one-third.23 These data recently have been confirmed by single-fiber laser
93
Ischemic Acute Renal Failure
Renal Underperfusion (Ischemia)
~ Glomerular
Filtration Rate
Correct Hypoperfusion
t Glomerular Filtration Rate (prerenal Azotemia)
~ Glomerular Filtration Rate (Ischemic Acute Renal Failure, i.e., Acute Tubular Necrosis)
Figure 1. Clinical pathophysiology of ischemic acute renal failure.
Doppler flowmetry.24 The decrease in medullary blood flow occurs predominantly in the outer medulla, while inner medullary blood flow is paradoxically increased. 24 This exaggerated reduction in outer medullary blood flow has been shown to be secondary to aggregated erythrocytes in the medullary inner stripe capillaries. 25,26 Cell swelling in the corticomedullary proximal straight tubules27,28 or polymorphonuclear leukocytemediated post-ischemic capillary leakage of fluid29 have been proposed as possible mechanisms for this erythrocyte aggregation. The erythrocyte aggregation in the outer medulla leads to preferential shunting of blood to the inner medulla. In these studies, a direct relationship between medullary congestion and decreased renal function was found. The renal medulla is supplied by blood from the efferent arterioles of the juxtamedullary nephrons. 3o These vessels turn downward toward the medulla, forming the descending vasa recta. At the junction between the inner and outer stripe, the descending vasa recta coalesce to form the vascular bundle. The sparse, elongated mesh of capillaries in the outer stripe of the outer medulla is supplied mainly by branches off the efferent arterioles and by relatively few branches off the descending vasa recta. The inner stripe of the outer medulla is supplied only from branches of the descending vasa recta to form a dense capillary plexus that provides blood to the tubules of the interbundle region, an area occupied predominately by the thick ascending Limbs of Henle. Blood to the inner meiulla is supplied by the descending vasa recta, which have traversed the outer medulla in the vascular bundles. This anatomic arrangement allows blood not previously exposed to tubules to be delivered to the inner medulla. The capillaries from the inner stripe form the ascending vasa recta, which do not rejoin the vascular bundle but instead drain toward the outer stripe between the vascular bundles. In contrast, in the inner medulla, the capillaries form ascending vasa recta that
94
return to the vascular bundle before ascending through the outer medulla. Thus, blood returning from the inner medulla is in a countercurrent relationship with blood that supplies the inner stripe region (Figure 231 ). This countercurrent relationship of the vasa recta prevents the dissipation of the cortico-medullary gradient of osmolality. It occurs at the cost of countercurrent diffusion of oxygen between the arterial and venous limbs of the vasa recta. Under hypoxic conditions, blood flow in pathway 2 of the diagram may be severely impaired, whereas blood flow in pathway 1 remains relatively intact. 32,33 A characteristic pattern of cell injury occurs in the isolated perfused kidney, a model useful for examining renal ischemia. 34 The medullary thick ascending Limb of Henle in the outer and inner stripe of the outer medulla suffers severe ischemic damage. The S3 segment
/
I
\
\
I
I
I I
-os -
---.. \ \ \
\
\ \ \
-
IS
--
-
1M
Figure 2. Blood supply to the outer and inner medulla of the kidney. C = cortical. OS = outer stripe. IS = inner stripe. 1M = inner medulla. From reference 30. August 1992 Volume 304 Number 2
Hays
of the proximal tubule in the outer stripe also suffers ischemic damage. The injury is most pronounced in those tubules supplied by pathway 2, which are located away from the vascular bundle.32-34 The capillary-like ascending vasa recta of pathway 2 are extremely susceptible to compression by ischemic tubular swelling.25,35 Under normal conditions, the partial pressure of oxygen has been found to be about 10 mm Hg in the medullary region. 36,37 The low oxygen pressures are secondary to the countercurrent diffusion of oxygen between the limbs of the vasa recta. Because of its reliance on aerobic and anaerobic glycolysis, the medulla appears to function adequately,38 but it operates on the verge of anoxia. Optical spectroscopic measurements of the redox state of cytochrome a,a3, the terminal electron carrier of the mitochondrial chain, which transports electrons directly to oxygen, has been estimated to be reduced by at least 20% in the renal medulla even under normal conditions,39 and is reduced even further (30-40%) when the kidney is excised and perfused in vitro. 40 Inhibitors of transport in the thick ascending Limb of Henle (furosemide and bumetanide) produce a significant increase in the oxidized state of cytochrome a,a3, suggesting that the medullary thick ascending Limb of Henle is an important site for this reduced cytochrome oxidase.40 Thus, the medullary thick ascending Limb of Henle, with its high rate of metabolism (oxygen consumption) and low oxygen supply (imposed by the anatomic arrangement of the medullary vascular system), is extremely vulnerable to ischemic damage. 33,36 The S3 segment of the proximal tubule, which also is located in this area of the kidney and relies largely on aerobic glycolysis,38,41 also is susceptible to ischemic damage (Figure 342 ). Cellular Characteristics of Ischemia. Tubular injury: The term "acute tubular necrosis" is a misnomer. Early biopsy series of acute renal failure described widespread tubular necrosis. 43 In addition, fairly extensive tubular necrosis has been described in ischemic models of acute renal failure. 44-47 However, much of the necrosis described in early autopsy series was a direct result of autolysis. 48 Only patchy necrosis of individual cells on biopsy and autopsy specimens has been reported in more recent studies performed with more modern cell preservation techniques. 49-52 Only recently has any attempt been made to quantify the difference between cortical and medullary lesions in human ischemic acute renal failure. 50-52 Individual desquamated cells (presumably loci for previous necrotic cells) were increased fivefold in the medullary thick ascending Limb of Henle compared to proximal tubular sites.52 Thus, the term "acute tubular necrosis" is misleading, because only areas of focal necrosis of individual cells are found, and these are predominantly localized to the distal nephron (mTALH). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
CORTEX
PST
OMCD
MEDULLA
DLH ALH
Figure 3. Initial nephron segments damaged in ischemic acute renal failure. PCT = proximal convoluted tubule. PST = proximal straight tubule. DLH = descending limb of Henle. ALH = ascending limb of Henle. TALH = thick ascending limb of Henle. DCT = distal convoluted tubule. CCD = cortical collecting duct. OMCD = outer medullary collecting duct. IMCD = inner medullary collecting duct.
Thus, the profound decline in renal function is disproportionate to the extent of tubular cell death. Although the tubular cells are not irreversibly injured, they exhibit striking changes in their morphology, especially in proximal tubule segments (S3 > SbS2)' After an ischemic episode, there is a significant reduction in the proximal tubule brush-border membrane49,51-53 and extensive changes in the proximal medullary thick ascending Limb of Henle and distal tubular basolateral infoldings.51 ,52 These studies suggest that major changes in the apical (urinary surface) and basolateral (blood surface) membranes occur in ischemic acute renal failure and that extensive tubular necrosis is not required for the development of acute renal failure. Nature of the cellular dysfunction: Central to the issue of cellular dysfunction in ischemic acute renal failure is the depletion of cellular adenosine triphosphate (ATP). Renal ischemia results in a rapid depletion of cellular ATP.54- 56 ATP breakdown products are highly permeative across the cell membrane and diffuse out of the cell. Upon correction of the ischemia, a biphasic mode of correction of ATP metabolism has been noted, characterized by an initial rapid recovery of ATP, followed by a slower, more gradual return toward preischemic levels.54-56 The rate of the initial rapid recovery of ATP is a good index of the residual adenine nucleotide pool in the kidney after ischemia. Renal ATP content 2 hours after the ischemic insult is a good indicator of the recovery of GFR at 24 hours. 55 Loss of ATP leads to several events that ultimately result in cellular dysfunction (Figure 4).57 Some ofthe~e abnormalities become apparent only after the kidney has regained its perfusion pressure. Depletion of cel-
95
Ischemic Acute Renal Failure
REPERFUSION
ISCHEMIA
/ Disruplion of cytoskeleton and tight irction Lo~s o~
eplth~hal -
polanty
I ATP _
J
Nucle~tide
~ deplellon
Phospholipase activalion
J
MEMBRANE ALTERATIONS • ~
I Hypoxanthine I Xanthine oxidase
,
l
·
---.l. Ca
2'
_
O2: OW
I ATP rege,eration Mitochondrial dysfunction
\
Lipid peroxidation and protein alterations
CELLULAR DYSFUNCTION
Figure 4. Pathophysiology of ischemia-induced proximal tubular cell injury. From reference 57.
lular ATP leads to the disruption of microfilaments and loss of the functional integrity of tight junctions, resulting in a loss of surface membrane polarity. This, coupled with the activation of phospholipases, results in alterations of surface membranes, which are clinically manifest by a reduction in proximal tubule transepithelial transport. Ischemia also results in increased production of nucleotide breakdown products. Some of these diffuse out of the cell, whereas others are further broken down to hypoxanthine, leading to the cellular accumulation of hypoxanthine. Ischemia also leads to the conversion of xanthine dehydrogenase to xanthine oxidase, which becomes important when oxygen levels are increased during reperfusion. After reperfusion, cellular energy stores cannot be regenerated because of nucleotide depletion and mitochondrial dysfunction. Oxygen reacts with hypoxanthine in the presence of xanthine oxidase to form reactive oxygen species (free radicals). These free radicals, combined with increased mitochondrial calcium content, lead to further mitochondrial dysfunction. Increased cellular calcium and free radicals also may lead to lipid peroxidation, causing further membrane alterations. Alterations in membrane lipids and proteins result in cellular dysfunction and the cessation of the normal transepithelial transport of ions, water, and macromolecules between blood and urine. Loss of cellular polarity: Depletion of ATP results in a loss of polarity of the proximal tubule cell.58 The proximal tubule is a polar epithelium involved in the vectorial movement of ions, water, and macromolecules between the luminal (urinary) and blood compartments. To accomplish this task, the polar epithelial cell must have certain fundamental characteristics. These include: (1) distinct apical and basolateral membrane surface domains;59,6o (2) a functional junctional complex in the lateral membrane, including tight junctions that maintain the lipid and protein differences of the two surface membranes, intermediate junctions, desmosomes, gap junctions, and cell adhesion proteins;61,62 (3) a functional cytoskeleton;63,64 and
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(4) adequate ATP stores. This arrangement allows each surface membrane (apical and basolateral) to have defined tasks dictated by its specific proteins and lipids. In the normal polar proximal tubule cell, sodium is transported across the apical membrane into the cell via Na/H antiport. Sodium is transported across the basolateral membrane out of the cell via the Na-KATPase. Na-K-ATPase is tethered to the basolateral membrane by the actin cytoskeleton.65 After ischemia, the combination of a "leaky" tight junction complex and a disrupted actin cytoskeleton allows the lateral migration of proteins such as Na-K-ATPase and lipids within the bilayer from one membrane domain to the other.66-70 Thus, duration-dependent ischemia in the proximal tubule leads to the disarrangement of surface transport proteins and the inefficient transepithelial transport of ions. This subject has been reviewed recently.58.71,72 Additional Pathophysiologic Characteristics. Tubular obstruction and backleak· Portions of the proximal tubule brush border membrane and a few necrotic cells are sloughed into the lumen after ischemia. These may coalesce in the distal portion of the proximal tubule or combine with Tamm-Horsfall proteins in the distal nephron to form obstructing plugs.42,73-76 Tubular obstruction results in an increase in intraluminal proximal tubule pressure, which dissipates the hydraulic pressure driving glomerular filtration. 73,77,78 In addition, depressed urine production and creatinine excretion can be partially attributed to the sequestration of tubular fluid within obstructed tubules. 73,79 Finally, altered membrane permeability and increased tubular pressure can lead to the backleak of fluid from the tubular lumen to the blood, which also decreases glomerular filtration. This has been confirmed in experimental models of ischemic acute renal failure by the inability to fully recover inulin that has been injected into the tubular lumen from the urine. 73,77,8o Using dextran molecules of varying sizes, Myers and colleagues have calculated that approximately 50% of inulin used for clearance studies is lost by transtubular backleak in human ischemic renal failure. 78,81-83 Thus, tubular obstruction and backleak play important roles in the prolonged depression of GFR in ischemic acute renal failure. Cellular Repair. Shortly after the onset of ischemia, cellular" repair processes begin. After ischemia, several genes, including the heat shock protein family and early response genes, are induced and proteins are synthesized anew or in greater quantities.84-87 HSP 72: Emami et al,86 using a specific monoclonal anti-HSP 72 antibody, found accumulation of HSP 72 protein in kidney tissue after transient ischemia. HSP 72 accumulation initially was found 3 hours after reperfusion of the ischemic kidney and remained detectable for up to 5 days. The pattern of HSP 72 accumulation was independent of the duration of the ischemia, and as little as 15 minutes of total ischemia August 1992 Volume 304 Number 2
Hays
was sufficient to result in the above pattern of HSP 72 accumulation. Whether the prolonged accumulation of HSP 72 after ischemia is the result of slow degradation, persistent synthesis, or both was not determined in this study. In addition, the function of HSP 72 in the cellular repair process is not yet known. In general, the heat shock family of proteins protects, preserves, and recovers the function of various protein complexes within the cell that may be injured after a stress. 88•89 This may be accomplished by HSP 72 acting as a cytosolic chaperon to transport proteins in a partially unfolded state and to target them to specific organelle sites within the ceI1.88•89 After ischemia, the heat shock family of proteins may have a cytoprotective effect within the cell by salvaging denatured proteins through solubilization and by facilitating their refolding or chaperoning them to a degradative system.89 Further study of HSP 72 synthesis and accumulation in relation to the cellular repair process is critical to the understanding of renal ischemia. Early response genes: Epithelial growth and regeneration may be integral to recovery from renal ischemia. Accordingly, several laboratories have investigated the induction of immediate early response genes (c-fos, cjun, Egr-1) after renal ischemia. 84 •85•87 Egr-1 mRNA detected by Northern analysis was found to be abundant 1 hour after a 30 minute exposure to ischemia. It persisted for more than 24 hours. 87 The pattern of elevation was independent of the duration of ischemia. In contrast, c-fos mRNA levels accumulated in proportion to the duration of ischemia, rising quickly (at 1 hour) and returning to control levels at 24 hours. 87 Thus, induction of early response genes occurs after ischemia, and investigation of their role in tissue recovery or cell regeneration may be important in understanding ischemic acute renal failure and in developing strategies for facilitating recovery from ischemic renal damage. Summary. Transient ischemia results in afferent arteriolar vasoconstriction and a persistent decrease in renal plasma flow, which is greater in the renal medulla than in the cortex (Figure 5). This results in medullary hypoxia. ATP becomes markedly depressed, resulting in a series of events that eventually lead to cellular damage in the medullary section of the proximal tubule (proximal straight tubule) and in the medullary portion of the thick ascending Limb of Henle. Cellular debris is released into the tubular lumen, where it may coalesce or combine with Tamm-Horsfall proteins secreted from the thick ascending Limb of Henle to form obstructing casts. Raised intratubular pressure in the proximal tubule dissipates the hydraulic filtration pressure necessary for glomerular filtration, and GFR falls. In addition, altered tubular membrane permeability, combined with raised intratubular pressures, allows backleak of filtered fluid, leading to further decreases in GFR. Also possible is that transient ischemia THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
__-
Transient Ischemia
.
+
Persistent ~ Renal Plasma Flow (Medullary > Cortical)
+
Medullary Hypoxia
t
, ,
Tubular Damage (PST, mTALH)
~
GFR, Backleak
Further Tubular Damage (PCT, PST, cTALH, mTALH, CCD) Figure 5. Summary of pathophysiologic mechanisms of ischemic acute renal failure. PST = proximal straight tubule. mTALH = medullary thick ascending limb of Henle. GFR = glomerular filtration rate. PCT = proximal convoluted tubule. cTALH = cortical thick ascending limb of Henle. CCD = cortical collecting duct.
per se leads to hypoxic cellular damage without a prolonged decrease in renal blood flow. Loss of transport activity by the proximal tubule and thick ascending Limb of Henle may flood the macula densa with solute, activating tubuloglomerular feedback. Tubuloglomerular feedback-activated renal afferent arteriole vasoconstriction then may lead to the depression of renal blood flow sometimes found in ischemic acute renal failure. Diagnosis
There is a long list of possible etiologies for a decline in renal function in patients. To facilitate a rapid clinical approach to the diagnosis and to expedite therapy, it has been convenient to classify these various causes of acute renal failure into prerenal, renal, and post renal etiologies. This distinction is important, because rapid intervention in the case of prerenal and postrenal acute renal failure can prevent further renal damage. Urine volume: Assessment of urine volume is important in the differential diagnosis of acute renal failure. Anuria is defined as less than 100 ml/day of urine output via a Foley catheter. Oliguria is defined as less than 400 ml/day of urine output via a Foley catheter. Urine output of greater than 500 mljday is classified
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Ischemic Acute Renal Failure
as nonoliguria. The prolonged absence of urine after bladder catheterization is unusual and implies: (1) absence of urine delivery to the bladder, as seen with bilateral ureteral obstruction; (2) absence of perfusion of the glomeruli, as seen with bilateral renal artery or vein occlusion; or (3) complete lack of cortical function, as seen with bilateral cortical necrosis. Less commonly, anuria is secondary to severe vasoconstrictive states (shock syndromes) or severe glomerular dysfunction (rapidly progressive glomerulonephritis). Oliguria suggests acute tubular necrosis, an intrinsic renal disease process, but it also is characteristic of prerenal azotemia when it occurs in association with avid sodium and water absorption. Nonoliguria is commonly seen with intrinsic renal disease, usually associated with nephrotoxic-mediated acute renal failure. 1 Nonoliguric acute renal failure also can be seen with incomplete urinary tract obstruction. In ischemic acute renal failure, there is no difference in the prevalence of nonoliguric versus oliguric states. 4 Urinary tract obstruction: Acute renal failure secondary to obstruction accounts for less than 10% of all cases of acute ischemic renal failure. 1 However, because relief of the obstruction potentially can restore renal function, it always should be considered. Acute renal failure secondary to urinary tract obstruction can present as anuria, oliguria, fluctuating oliguria, or nonoliguria.90 The amount of urine produced with urinary tract obstruction depends on the underlying etiology and duration and degree of obstruction. Evaluation of obstruction should begin with catheterization of the bladder after the patient has voided. This permits the diagnosis of lower urinary tract obstruction and testing of the post-void residual of urine, which may be increased in partial lower urinary tract obstruction. Ultrasonography in experienced hands has a 98% sensitivity and 74% specificity for detecting obstruction, compared to intravenous pyelography, and avoids the risk of contrast. 90-92 Sonography also allows kidney size to be determined, and the finding of small bilaterally shrunken kidneys suggests a more chronic irreversible process. The false positive rate for detecting obstruction with sonography is about 15%.92,93 The sonogram may fail to detect obstruction if the patient has been obstructed for less than 1-3 days or if the collecting system is encased with tumor or fibrosis. 94 Computed tomography (CT) also is useful for detecting obstruction, especially if visualization by sonography is inadequate because of obesity or the presence of congenital collecting system abnormalities.92 ,93 Thus, ultrasound and occasionally CT are extremely useful for diagnosing obstruction in most patients. When a high suspicion for obstruction is entertained, and ultrasound or CT detect normal or increased kidney size but no obstruction, further urologic work-up may be needed. 92 High-grade obstructive nephropathy may present with minimal or no dilation of the collecting system, especially if an infiltrative process pre-
98
vents dilation of the renal structures.93- 95 This has been documented in as many as 11 % of all patients with obstruction. 96 Retrograde pyelography and antegrade pyelography often can be used for diagnosis and treatment in this situation. Despite improvements in renal ultrasound, retrograde pyelography remains the gold standard for the diagnosis of urinary tract obstructions. 97 Distinguishing prerenal azotemia from oliguric acute tubular necrosis: Prerenal azotemia probably is the most common cause of acute renal failure 3 ,5,6,98 and is potentially reversible. However, prolonged prerenal azotemia can lead to ischemic acute tubular necrosis. Thus, recognition and prompt therapy of prerenal azotemia in the setting of acute renal failure is important. Prerenal azotemia and oliguric acute tubular necrosis typically present with oliguria and acute renal failure. Because the treatment and prognosis are very different, distinguishing between the two disorders is important. Effective arterial blood volume: Evaluation of effective arterial blood volume is important in distinguishing prerenal azotemia from oliguric acute tubular necrosis. Effective arterial blood volume refers to that part of the extracellular fluid in the vascular space that effectively perfuses the tissues. It is not a measurable entity, but rather refers to the rate of perfusion of the capillary circulation. 99 Effective arterial blood volume can be assessed by physical examination and blood and urine chemistries (Table 1). Although effective arterial blood volume varies with the extracellular volume in normal people, it may be independent of the extracellular volume, the plasma volume, or even the cardiac output in a variety of disease states. Effective arterial blood volume even may be decreased in a patient with increased total body sodium, ie, in congestive heart failure, cirrhosis, and nephrosis. Multiple effectors, including the sympathetic nervous system, angiotensin II release, and an increase in tubular sodium and water absorption, are stimulated by a decrease in effective arterial blood volume. Physical examination: It is important to look for changes in skin color and temperature, which might reflect inadequate tissue perfusion. In addition, a decrease in effective arterial blood volume is manifested by orthostatic increases in pulse rate and decreases in blood pressure. BUNfer ratio: In normal subjects and patients with intrinsic renal disease, the blood urea nitrogen/creatTable 1. Assessment of Effective Arterial Blood Volume 1. Physical examination
a. Skin color b. Temperature of extremities (sympathetic overactivity) c. Orthostatic pulse and blood pressure changes 2. Blood urea nitrogen/creatinine ratio a. >20/1 Prerenal azotemia b. 90%) for prerenal azotemia, but the sensitivity in distinguishing between the two disorders is limited by the fairly high overlap of values that occur in the 20-40 mEqjL range.lOl-l05 Generally, urine CI- varies with urine Na+, except in cases when Na+ is excreted with another anion.106 This is most often seen in metabolic alkalosis, where the need to excrete excess HC03 may raise urine Na+ despite volume depletion. In this setting, urine CI- may be low and is a better index of volume status.107 Thus, urine CI- always should be measured with urine Na+. Urine osmolality is highly specific for determining prerenal azotemia, but it suffers from a relatively low sensitivity for distinguishing between the two disorders. l03 Another index with a high specificity for detecting prerenal azotemia but a low sensitivity for distinguishing between the two disorders is the urineto-plasma ratio of creatinine.103 Determining the urineto-plasma osmolality ratio increased the sensitivity for distinguishing between the two disorders, but overlap of values between the two disorders was common. l08 Although their tests (Uos m , U jP creatinine, and osmolality ratio) have a fairly low sensitivity for distinguishing between prerenal azotemia and oliguric acute tubular necrosis, they provide a subtle indication of relative medullary ischemia. The two best tests for distinguishing prerenal azotemia from oliguric acute tubular necrosis are the renal failure index (RFI), which combines the urine Na+ and the urine-to-plasma creatinine ratio, and the fractional excretion of Na+ (FE Na ). Handa found an RFI of
ABSTRACT: Underperfusion of the kidneys often results in the development of ischemic acute renal failure. This review summarizes the recent developments in the understanding of the pathophysiology, diagnosis, and treatment of this serious and costly disorder that affects almost 5% of hospitalized patients. KEY INDEXING TERMS: Acute renal failure; Ischemia; Acute tubular necrosis. [Am J Med Sci 1992; 304(2): 93-108.]
A
cute renal failure is commonly encountered in hospitals. Approximately 5% of patients admitted to the hospital develop acute renal failure during their hospital stay. I The development of acute renal failure is associated with a sixfold increase in risk of dying and an average 16-23 day increase in length of hospital stay.2 Despite major advances in the management of patients with acute renal failure, severe underlying illnesses and complications currently limit survival to 50%, a figure not substantially improved since 1950.3-7 To manage or prevent this serious and costly disorder, the physician must understand the pathophysiologic principles involved in the development of acute renal failure. Ischemic acute renal failure is defined as a syndrome triggered by underperfusion of the kidneys that results in the rapid deterioration of renal function and accumulation of nitrogenous wastes. Renal underperfusion plays an important pathophysiologic role in the development of all nonnephrotoxic-mediated acute renal failure. ·From the The University of Texas Southwestern Medical Center at Dallas, Dept. of Internal Medicine, Dallas, Texas. This review was presented for Internal Medicine Grand Rounds at The University of Texas Southwestern Medical Center at Dallas on September 5, 1991. The author is grateful to Robert J. Alpern for his helpful suggestions on this review. The author also gratefully acknowledges the excellent secretarial work of Dedrian Copeland and the library research of Rebecca Aricheta, Ebtesam M. Shawky, and Tommie W. Friday of Merck Sharp & Dohme, Rahway, New Jersey. Steven Hays is a recipient of a Clinical Investigator Award K08 DK 01859. Correspondence: Steven R. Hays, MD, The University of Texas Southwestern Medical Center at Dallas, Dept. of Internal Medicine, Room H5.112, 5323 Harry Hines Blvd., Dallas, TX 75235-8856. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Pathophysiology
Normally, renal blood flow to the kidney is high and the oxygen supply greatly exceeds the requirement for oxygen use.s However, when the kidney is underperfused, it is highly susceptible to injury. As shown in Figure 1, renal underperfusion is manifested by a syndrome characterized by a decrease in glomerular filtration rate (GFR). This can occur in the absence of hypotension, which is documented in less than 50% of the cases of postsurgical hypotension. 3 When the underperfusion is corrected, the GFR returns to normal (prerenal azotemia) or remains markedly depressed for a prolonged time (ischemic acute renal failure, ie, acute tubular necrosis). Thus, underperfusion of the kidney is manifested by a continuum of disorders ranging from prerenal azotemia to acute tubular necrosis (acute renal failure). Alterations in Renal Blood Flow. In human studies, renal blood flow, measured by a variety of techniques, has been shown to be decreased for a prolonged time after the initial precipitating event (during the so-called maintenance phase9~IS). Renal blood flow may remain depressed for up to 4 weeks. 1l•13 The a-adrenergic blocking agents phenoxybenzamine or phentolamine do not effectively block the renal vasoconstriction associated with acute renal failure. IO.19 The lack of effect of these agents implies that vasoconstriction is not mediated by mechanisms involving circulating catecholamines or renal nerve activity. Even when renal blood flow is increased by vasodilators, GFR remains markedly depressed. 1O,12 In addition, in most animal studies, GFR is reduced disproportionately in relation to renal blood flow,20 and renal blood flow returns to normal while GFR remains markedly depressed. 21 ,22 Thus, reduced renal blood flow seems an unlikely cause of the sustained reduction in GFR. In fact, superficial cortical blood flow rapidly returns to normal after an ischemic event. However, regional changes in perfusion may be more important than changes in total renal blood flow. Medullary blood flow is decreased to a greater extent than cortical flow and remains reduced for a longer time. After an ischemic event, medullary blood flow is decreased by at least two-thirds at a time when cortical flow is reduced by only one-third.23 These data recently have been confirmed by single-fiber laser
93
Ischemic Acute Renal Failure
Renal Underperfusion (Ischemia)
~ Glomerular
Filtration Rate
Correct Hypoperfusion
t Glomerular Filtration Rate (prerenal Azotemia)
~ Glomerular Filtration Rate (Ischemic Acute Renal Failure, i.e., Acute Tubular Necrosis)
Figure 1. Clinical pathophysiology of ischemic acute renal failure.
Doppler flowmetry.24 The decrease in medullary blood flow occurs predominantly in the outer medulla, while inner medullary blood flow is paradoxically increased. 24 This exaggerated reduction in outer medullary blood flow has been shown to be secondary to aggregated erythrocytes in the medullary inner stripe capillaries. 25,26 Cell swelling in the corticomedullary proximal straight tubules27,28 or polymorphonuclear leukocytemediated post-ischemic capillary leakage of fluid29 have been proposed as possible mechanisms for this erythrocyte aggregation. The erythrocyte aggregation in the outer medulla leads to preferential shunting of blood to the inner medulla. In these studies, a direct relationship between medullary congestion and decreased renal function was found. The renal medulla is supplied by blood from the efferent arterioles of the juxtamedullary nephrons. 3o These vessels turn downward toward the medulla, forming the descending vasa recta. At the junction between the inner and outer stripe, the descending vasa recta coalesce to form the vascular bundle. The sparse, elongated mesh of capillaries in the outer stripe of the outer medulla is supplied mainly by branches off the efferent arterioles and by relatively few branches off the descending vasa recta. The inner stripe of the outer medulla is supplied only from branches of the descending vasa recta to form a dense capillary plexus that provides blood to the tubules of the interbundle region, an area occupied predominately by the thick ascending Limbs of Henle. Blood to the inner meiulla is supplied by the descending vasa recta, which have traversed the outer medulla in the vascular bundles. This anatomic arrangement allows blood not previously exposed to tubules to be delivered to the inner medulla. The capillaries from the inner stripe form the ascending vasa recta, which do not rejoin the vascular bundle but instead drain toward the outer stripe between the vascular bundles. In contrast, in the inner medulla, the capillaries form ascending vasa recta that
94
return to the vascular bundle before ascending through the outer medulla. Thus, blood returning from the inner medulla is in a countercurrent relationship with blood that supplies the inner stripe region (Figure 231 ). This countercurrent relationship of the vasa recta prevents the dissipation of the cortico-medullary gradient of osmolality. It occurs at the cost of countercurrent diffusion of oxygen between the arterial and venous limbs of the vasa recta. Under hypoxic conditions, blood flow in pathway 2 of the diagram may be severely impaired, whereas blood flow in pathway 1 remains relatively intact. 32,33 A characteristic pattern of cell injury occurs in the isolated perfused kidney, a model useful for examining renal ischemia. 34 The medullary thick ascending Limb of Henle in the outer and inner stripe of the outer medulla suffers severe ischemic damage. The S3 segment
/
I
\
\
I
I
I I
-os -
---.. \ \ \
\
\ \ \
-
IS
--
-
1M
Figure 2. Blood supply to the outer and inner medulla of the kidney. C = cortical. OS = outer stripe. IS = inner stripe. 1M = inner medulla. From reference 30. August 1992 Volume 304 Number 2
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of the proximal tubule in the outer stripe also suffers ischemic damage. The injury is most pronounced in those tubules supplied by pathway 2, which are located away from the vascular bundle.32-34 The capillary-like ascending vasa recta of pathway 2 are extremely susceptible to compression by ischemic tubular swelling.25,35 Under normal conditions, the partial pressure of oxygen has been found to be about 10 mm Hg in the medullary region. 36,37 The low oxygen pressures are secondary to the countercurrent diffusion of oxygen between the limbs of the vasa recta. Because of its reliance on aerobic and anaerobic glycolysis, the medulla appears to function adequately,38 but it operates on the verge of anoxia. Optical spectroscopic measurements of the redox state of cytochrome a,a3, the terminal electron carrier of the mitochondrial chain, which transports electrons directly to oxygen, has been estimated to be reduced by at least 20% in the renal medulla even under normal conditions,39 and is reduced even further (30-40%) when the kidney is excised and perfused in vitro. 40 Inhibitors of transport in the thick ascending Limb of Henle (furosemide and bumetanide) produce a significant increase in the oxidized state of cytochrome a,a3, suggesting that the medullary thick ascending Limb of Henle is an important site for this reduced cytochrome oxidase.40 Thus, the medullary thick ascending Limb of Henle, with its high rate of metabolism (oxygen consumption) and low oxygen supply (imposed by the anatomic arrangement of the medullary vascular system), is extremely vulnerable to ischemic damage. 33,36 The S3 segment of the proximal tubule, which also is located in this area of the kidney and relies largely on aerobic glycolysis,38,41 also is susceptible to ischemic damage (Figure 342 ). Cellular Characteristics of Ischemia. Tubular injury: The term "acute tubular necrosis" is a misnomer. Early biopsy series of acute renal failure described widespread tubular necrosis. 43 In addition, fairly extensive tubular necrosis has been described in ischemic models of acute renal failure. 44-47 However, much of the necrosis described in early autopsy series was a direct result of autolysis. 48 Only patchy necrosis of individual cells on biopsy and autopsy specimens has been reported in more recent studies performed with more modern cell preservation techniques. 49-52 Only recently has any attempt been made to quantify the difference between cortical and medullary lesions in human ischemic acute renal failure. 50-52 Individual desquamated cells (presumably loci for previous necrotic cells) were increased fivefold in the medullary thick ascending Limb of Henle compared to proximal tubular sites.52 Thus, the term "acute tubular necrosis" is misleading, because only areas of focal necrosis of individual cells are found, and these are predominantly localized to the distal nephron (mTALH). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
CORTEX
PST
OMCD
MEDULLA
DLH ALH
Figure 3. Initial nephron segments damaged in ischemic acute renal failure. PCT = proximal convoluted tubule. PST = proximal straight tubule. DLH = descending limb of Henle. ALH = ascending limb of Henle. TALH = thick ascending limb of Henle. DCT = distal convoluted tubule. CCD = cortical collecting duct. OMCD = outer medullary collecting duct. IMCD = inner medullary collecting duct.
Thus, the profound decline in renal function is disproportionate to the extent of tubular cell death. Although the tubular cells are not irreversibly injured, they exhibit striking changes in their morphology, especially in proximal tubule segments (S3 > SbS2)' After an ischemic episode, there is a significant reduction in the proximal tubule brush-border membrane49,51-53 and extensive changes in the proximal medullary thick ascending Limb of Henle and distal tubular basolateral infoldings.51 ,52 These studies suggest that major changes in the apical (urinary surface) and basolateral (blood surface) membranes occur in ischemic acute renal failure and that extensive tubular necrosis is not required for the development of acute renal failure. Nature of the cellular dysfunction: Central to the issue of cellular dysfunction in ischemic acute renal failure is the depletion of cellular adenosine triphosphate (ATP). Renal ischemia results in a rapid depletion of cellular ATP.54- 56 ATP breakdown products are highly permeative across the cell membrane and diffuse out of the cell. Upon correction of the ischemia, a biphasic mode of correction of ATP metabolism has been noted, characterized by an initial rapid recovery of ATP, followed by a slower, more gradual return toward preischemic levels.54-56 The rate of the initial rapid recovery of ATP is a good index of the residual adenine nucleotide pool in the kidney after ischemia. Renal ATP content 2 hours after the ischemic insult is a good indicator of the recovery of GFR at 24 hours. 55 Loss of ATP leads to several events that ultimately result in cellular dysfunction (Figure 4).57 Some ofthe~e abnormalities become apparent only after the kidney has regained its perfusion pressure. Depletion of cel-
95
Ischemic Acute Renal Failure
REPERFUSION
ISCHEMIA
/ Disruplion of cytoskeleton and tight irction Lo~s o~
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MEMBRANE ALTERATIONS • ~
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CELLULAR DYSFUNCTION
Figure 4. Pathophysiology of ischemia-induced proximal tubular cell injury. From reference 57.
lular ATP leads to the disruption of microfilaments and loss of the functional integrity of tight junctions, resulting in a loss of surface membrane polarity. This, coupled with the activation of phospholipases, results in alterations of surface membranes, which are clinically manifest by a reduction in proximal tubule transepithelial transport. Ischemia also results in increased production of nucleotide breakdown products. Some of these diffuse out of the cell, whereas others are further broken down to hypoxanthine, leading to the cellular accumulation of hypoxanthine. Ischemia also leads to the conversion of xanthine dehydrogenase to xanthine oxidase, which becomes important when oxygen levels are increased during reperfusion. After reperfusion, cellular energy stores cannot be regenerated because of nucleotide depletion and mitochondrial dysfunction. Oxygen reacts with hypoxanthine in the presence of xanthine oxidase to form reactive oxygen species (free radicals). These free radicals, combined with increased mitochondrial calcium content, lead to further mitochondrial dysfunction. Increased cellular calcium and free radicals also may lead to lipid peroxidation, causing further membrane alterations. Alterations in membrane lipids and proteins result in cellular dysfunction and the cessation of the normal transepithelial transport of ions, water, and macromolecules between blood and urine. Loss of cellular polarity: Depletion of ATP results in a loss of polarity of the proximal tubule cell.58 The proximal tubule is a polar epithelium involved in the vectorial movement of ions, water, and macromolecules between the luminal (urinary) and blood compartments. To accomplish this task, the polar epithelial cell must have certain fundamental characteristics. These include: (1) distinct apical and basolateral membrane surface domains;59,6o (2) a functional junctional complex in the lateral membrane, including tight junctions that maintain the lipid and protein differences of the two surface membranes, intermediate junctions, desmosomes, gap junctions, and cell adhesion proteins;61,62 (3) a functional cytoskeleton;63,64 and
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(4) adequate ATP stores. This arrangement allows each surface membrane (apical and basolateral) to have defined tasks dictated by its specific proteins and lipids. In the normal polar proximal tubule cell, sodium is transported across the apical membrane into the cell via Na/H antiport. Sodium is transported across the basolateral membrane out of the cell via the Na-KATPase. Na-K-ATPase is tethered to the basolateral membrane by the actin cytoskeleton.65 After ischemia, the combination of a "leaky" tight junction complex and a disrupted actin cytoskeleton allows the lateral migration of proteins such as Na-K-ATPase and lipids within the bilayer from one membrane domain to the other.66-70 Thus, duration-dependent ischemia in the proximal tubule leads to the disarrangement of surface transport proteins and the inefficient transepithelial transport of ions. This subject has been reviewed recently.58.71,72 Additional Pathophysiologic Characteristics. Tubular obstruction and backleak· Portions of the proximal tubule brush border membrane and a few necrotic cells are sloughed into the lumen after ischemia. These may coalesce in the distal portion of the proximal tubule or combine with Tamm-Horsfall proteins in the distal nephron to form obstructing plugs.42,73-76 Tubular obstruction results in an increase in intraluminal proximal tubule pressure, which dissipates the hydraulic pressure driving glomerular filtration. 73,77,78 In addition, depressed urine production and creatinine excretion can be partially attributed to the sequestration of tubular fluid within obstructed tubules. 73,79 Finally, altered membrane permeability and increased tubular pressure can lead to the backleak of fluid from the tubular lumen to the blood, which also decreases glomerular filtration. This has been confirmed in experimental models of ischemic acute renal failure by the inability to fully recover inulin that has been injected into the tubular lumen from the urine. 73,77,8o Using dextran molecules of varying sizes, Myers and colleagues have calculated that approximately 50% of inulin used for clearance studies is lost by transtubular backleak in human ischemic renal failure. 78,81-83 Thus, tubular obstruction and backleak play important roles in the prolonged depression of GFR in ischemic acute renal failure. Cellular Repair. Shortly after the onset of ischemia, cellular" repair processes begin. After ischemia, several genes, including the heat shock protein family and early response genes, are induced and proteins are synthesized anew or in greater quantities.84-87 HSP 72: Emami et al,86 using a specific monoclonal anti-HSP 72 antibody, found accumulation of HSP 72 protein in kidney tissue after transient ischemia. HSP 72 accumulation initially was found 3 hours after reperfusion of the ischemic kidney and remained detectable for up to 5 days. The pattern of HSP 72 accumulation was independent of the duration of the ischemia, and as little as 15 minutes of total ischemia August 1992 Volume 304 Number 2
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was sufficient to result in the above pattern of HSP 72 accumulation. Whether the prolonged accumulation of HSP 72 after ischemia is the result of slow degradation, persistent synthesis, or both was not determined in this study. In addition, the function of HSP 72 in the cellular repair process is not yet known. In general, the heat shock family of proteins protects, preserves, and recovers the function of various protein complexes within the cell that may be injured after a stress. 88•89 This may be accomplished by HSP 72 acting as a cytosolic chaperon to transport proteins in a partially unfolded state and to target them to specific organelle sites within the ceI1.88•89 After ischemia, the heat shock family of proteins may have a cytoprotective effect within the cell by salvaging denatured proteins through solubilization and by facilitating their refolding or chaperoning them to a degradative system.89 Further study of HSP 72 synthesis and accumulation in relation to the cellular repair process is critical to the understanding of renal ischemia. Early response genes: Epithelial growth and regeneration may be integral to recovery from renal ischemia. Accordingly, several laboratories have investigated the induction of immediate early response genes (c-fos, cjun, Egr-1) after renal ischemia. 84 •85•87 Egr-1 mRNA detected by Northern analysis was found to be abundant 1 hour after a 30 minute exposure to ischemia. It persisted for more than 24 hours. 87 The pattern of elevation was independent of the duration of ischemia. In contrast, c-fos mRNA levels accumulated in proportion to the duration of ischemia, rising quickly (at 1 hour) and returning to control levels at 24 hours. 87 Thus, induction of early response genes occurs after ischemia, and investigation of their role in tissue recovery or cell regeneration may be important in understanding ischemic acute renal failure and in developing strategies for facilitating recovery from ischemic renal damage. Summary. Transient ischemia results in afferent arteriolar vasoconstriction and a persistent decrease in renal plasma flow, which is greater in the renal medulla than in the cortex (Figure 5). This results in medullary hypoxia. ATP becomes markedly depressed, resulting in a series of events that eventually lead to cellular damage in the medullary section of the proximal tubule (proximal straight tubule) and in the medullary portion of the thick ascending Limb of Henle. Cellular debris is released into the tubular lumen, where it may coalesce or combine with Tamm-Horsfall proteins secreted from the thick ascending Limb of Henle to form obstructing casts. Raised intratubular pressure in the proximal tubule dissipates the hydraulic filtration pressure necessary for glomerular filtration, and GFR falls. In addition, altered tubular membrane permeability, combined with raised intratubular pressures, allows backleak of filtered fluid, leading to further decreases in GFR. Also possible is that transient ischemia THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
__-
Transient Ischemia
.
+
Persistent ~ Renal Plasma Flow (Medullary > Cortical)
+
Medullary Hypoxia
t
, ,
Tubular Damage (PST, mTALH)
~
GFR, Backleak
Further Tubular Damage (PCT, PST, cTALH, mTALH, CCD) Figure 5. Summary of pathophysiologic mechanisms of ischemic acute renal failure. PST = proximal straight tubule. mTALH = medullary thick ascending limb of Henle. GFR = glomerular filtration rate. PCT = proximal convoluted tubule. cTALH = cortical thick ascending limb of Henle. CCD = cortical collecting duct.
per se leads to hypoxic cellular damage without a prolonged decrease in renal blood flow. Loss of transport activity by the proximal tubule and thick ascending Limb of Henle may flood the macula densa with solute, activating tubuloglomerular feedback. Tubuloglomerular feedback-activated renal afferent arteriole vasoconstriction then may lead to the depression of renal blood flow sometimes found in ischemic acute renal failure. Diagnosis
There is a long list of possible etiologies for a decline in renal function in patients. To facilitate a rapid clinical approach to the diagnosis and to expedite therapy, it has been convenient to classify these various causes of acute renal failure into prerenal, renal, and post renal etiologies. This distinction is important, because rapid intervention in the case of prerenal and postrenal acute renal failure can prevent further renal damage. Urine volume: Assessment of urine volume is important in the differential diagnosis of acute renal failure. Anuria is defined as less than 100 ml/day of urine output via a Foley catheter. Oliguria is defined as less than 400 ml/day of urine output via a Foley catheter. Urine output of greater than 500 mljday is classified
97
Ischemic Acute Renal Failure
as nonoliguria. The prolonged absence of urine after bladder catheterization is unusual and implies: (1) absence of urine delivery to the bladder, as seen with bilateral ureteral obstruction; (2) absence of perfusion of the glomeruli, as seen with bilateral renal artery or vein occlusion; or (3) complete lack of cortical function, as seen with bilateral cortical necrosis. Less commonly, anuria is secondary to severe vasoconstrictive states (shock syndromes) or severe glomerular dysfunction (rapidly progressive glomerulonephritis). Oliguria suggests acute tubular necrosis, an intrinsic renal disease process, but it also is characteristic of prerenal azotemia when it occurs in association with avid sodium and water absorption. Nonoliguria is commonly seen with intrinsic renal disease, usually associated with nephrotoxic-mediated acute renal failure. 1 Nonoliguric acute renal failure also can be seen with incomplete urinary tract obstruction. In ischemic acute renal failure, there is no difference in the prevalence of nonoliguric versus oliguric states. 4 Urinary tract obstruction: Acute renal failure secondary to obstruction accounts for less than 10% of all cases of acute ischemic renal failure. 1 However, because relief of the obstruction potentially can restore renal function, it always should be considered. Acute renal failure secondary to urinary tract obstruction can present as anuria, oliguria, fluctuating oliguria, or nonoliguria.90 The amount of urine produced with urinary tract obstruction depends on the underlying etiology and duration and degree of obstruction. Evaluation of obstruction should begin with catheterization of the bladder after the patient has voided. This permits the diagnosis of lower urinary tract obstruction and testing of the post-void residual of urine, which may be increased in partial lower urinary tract obstruction. Ultrasonography in experienced hands has a 98% sensitivity and 74% specificity for detecting obstruction, compared to intravenous pyelography, and avoids the risk of contrast. 90-92 Sonography also allows kidney size to be determined, and the finding of small bilaterally shrunken kidneys suggests a more chronic irreversible process. The false positive rate for detecting obstruction with sonography is about 15%.92,93 The sonogram may fail to detect obstruction if the patient has been obstructed for less than 1-3 days or if the collecting system is encased with tumor or fibrosis. 94 Computed tomography (CT) also is useful for detecting obstruction, especially if visualization by sonography is inadequate because of obesity or the presence of congenital collecting system abnormalities.92 ,93 Thus, ultrasound and occasionally CT are extremely useful for diagnosing obstruction in most patients. When a high suspicion for obstruction is entertained, and ultrasound or CT detect normal or increased kidney size but no obstruction, further urologic work-up may be needed. 92 High-grade obstructive nephropathy may present with minimal or no dilation of the collecting system, especially if an infiltrative process pre-
98
vents dilation of the renal structures.93- 95 This has been documented in as many as 11 % of all patients with obstruction. 96 Retrograde pyelography and antegrade pyelography often can be used for diagnosis and treatment in this situation. Despite improvements in renal ultrasound, retrograde pyelography remains the gold standard for the diagnosis of urinary tract obstructions. 97 Distinguishing prerenal azotemia from oliguric acute tubular necrosis: Prerenal azotemia probably is the most common cause of acute renal failure 3 ,5,6,98 and is potentially reversible. However, prolonged prerenal azotemia can lead to ischemic acute tubular necrosis. Thus, recognition and prompt therapy of prerenal azotemia in the setting of acute renal failure is important. Prerenal azotemia and oliguric acute tubular necrosis typically present with oliguria and acute renal failure. Because the treatment and prognosis are very different, distinguishing between the two disorders is important. Effective arterial blood volume: Evaluation of effective arterial blood volume is important in distinguishing prerenal azotemia from oliguric acute tubular necrosis. Effective arterial blood volume refers to that part of the extracellular fluid in the vascular space that effectively perfuses the tissues. It is not a measurable entity, but rather refers to the rate of perfusion of the capillary circulation. 99 Effective arterial blood volume can be assessed by physical examination and blood and urine chemistries (Table 1). Although effective arterial blood volume varies with the extracellular volume in normal people, it may be independent of the extracellular volume, the plasma volume, or even the cardiac output in a variety of disease states. Effective arterial blood volume even may be decreased in a patient with increased total body sodium, ie, in congestive heart failure, cirrhosis, and nephrosis. Multiple effectors, including the sympathetic nervous system, angiotensin II release, and an increase in tubular sodium and water absorption, are stimulated by a decrease in effective arterial blood volume. Physical examination: It is important to look for changes in skin color and temperature, which might reflect inadequate tissue perfusion. In addition, a decrease in effective arterial blood volume is manifested by orthostatic increases in pulse rate and decreases in blood pressure. BUNfer ratio: In normal subjects and patients with intrinsic renal disease, the blood urea nitrogen/creatTable 1. Assessment of Effective Arterial Blood Volume 1. Physical examination
a. Skin color b. Temperature of extremities (sympathetic overactivity) c. Orthostatic pulse and blood pressure changes 2. Blood urea nitrogen/creatinine ratio a. >20/1 Prerenal azotemia b. 90%) for prerenal azotemia, but the sensitivity in distinguishing between the two disorders is limited by the fairly high overlap of values that occur in the 20-40 mEqjL range.lOl-l05 Generally, urine CI- varies with urine Na+, except in cases when Na+ is excreted with another anion.106 This is most often seen in metabolic alkalosis, where the need to excrete excess HC03 may raise urine Na+ despite volume depletion. In this setting, urine CI- may be low and is a better index of volume status.107 Thus, urine CI- always should be measured with urine Na+. Urine osmolality is highly specific for determining prerenal azotemia, but it suffers from a relatively low sensitivity for distinguishing between the two disorders. l03 Another index with a high specificity for detecting prerenal azotemia but a low sensitivity for distinguishing between the two disorders is the urineto-plasma ratio of creatinine.103 Determining the urineto-plasma osmolality ratio increased the sensitivity for distinguishing between the two disorders, but overlap of values between the two disorders was common. l08 Although their tests (Uos m , U jP creatinine, and osmolality ratio) have a fairly low sensitivity for distinguishing between prerenal azotemia and oliguric acute tubular necrosis, they provide a subtle indication of relative medullary ischemia. The two best tests for distinguishing prerenal azotemia from oliguric acute tubular necrosis are the renal failure index (RFI), which combines the urine Na+ and the urine-to-plasma creatinine ratio, and the fractional excretion of Na+ (FE Na ). Handa found an RFI of
