AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acute tubular necrosis (ATN) is characterized pathologically by varying degrees of tubule cell damage and by cell death usually resulting from prolonged renal ischemia, nephrotoxins, or sepsis. ATN is characterized clinically by acute renal failure (ARF), which is defined as a rapid (hours to days) decline in the glomerular filtration rate (GFR) that leads to retention of waste products such as BUN and creatinine.

The various etiologies of ARF can be grouped into 3 broad categories: prerenal, intrinsic renal, and postrenal. Prerenal ARF (55% of ARF) is a functional response of structurally normal kidneys to hypoperfusion, whereas postrenal ARF (<5% of ARF) is a consequence of mechanical or functional obstruction to urine flow. Intrinsic ARF (40% of ARF) is the result of structural damage to the renal tubules, glomeruli, interstitium, or renal vasculature.

Most intrinsic ARF cases are associated with ATN from prolonged ischemia or toxic injury, and the terms ischemic and nephrotoxic ATN are frequently used synonymously with ischemic or nephrotoxic ARF. The focus of this article is ischemic and nephrotoxic ATN. Other important causes of intrinsic ARF in children, such as hemolytic-uremic syndrome (HUS) and immunologic glomerular diseases, are not discussed.

The clinical course of ATN may be divided into initiation, maintenance, and recovery phases. The initiation phase corresponds to the period of exposure to ischemia or nephrotoxins. Renal tubule cell damage begins to evolve (but is not yet established) during this phase. GFR starts to fall, and urine output decreases.

During the maintenance phase, renal tubule injury is established, the GFR stabilizes at the level well below normal, and the urine output is low or absent. Although oliguria (or anuria) is one of the clinical landmarks of ATN, it is absent in a minority of patients with so-called nonoliguric ATN. ARF due to nephrotoxins is typically nonoliguric. The second phase of ATN lasts usually for 1-2 weeks but may extend to a few months.

The recovery phase of ATN is characterized by polyuria and gradual normalization of GFR; however, when ATN occurs (as it often does) in the context of multiorgan dysfunction, regeneration of renal tissue may be severely impaired and renal function may not return. Morbidity and mortality in such situations remains dismally high in spite of significant scientific and technological advances.

Pathophysiology

The current understanding of the pathophysiology of ATN is the result of intensive scientific studies performed over many decades. Despite the nomenclature, frank necrosis of tubule cells is relatively inconspicuous in ischemic ATN, whereas it can be more extensive in heavy metal-induced nephrotoxic ATN. The typical findings in humans include (1) patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded basement membrane; (2) diffuse effacement and loss of proximal tubule cell brush border; (3) patchy necrosis, most typically in the outer medulla where the straight (S3) segment of the proximal tubule and the medullary thick ascending limb (mTAL) of Henle loop; (4) tubular dilatation and intraluminal casts in the distal nephron segments; and (5) evidence of cellular regeneration. Regenerating cells are often detected in biopsies together with freshly damaged cells, suggesting the occurrence of multiple cycles of injury and repair.

Alterations in renal hemodynamics

Decreases in effective intravascular volume, in cardiac output, or in renal blood flow trigger compensatory mechanisms that result in afferent arteriolar dilatation via myogenic responses, tubuloglomerular feedback, and prostaglandins), efferent arteriolar constriction (via angiotensin II), and enhanced tubular salt and water reabsorption (stimulated by angiotensin II and sympathetic nervous system).

When the renal hypoperfusion is prolonged, a shift from compensation to decompensation occurs. Excessive stimulation of the sympathetic nervous system and the renin-angiotensin system causes profound renal vasoconstriction that eventually results in tubular damage. Iatrogenic interference with renal compensation by administration of vasoconstrictors (cyclosporine or tacrolimus), inhibitors of prostaglandin synthase (nonsteroidal anti-inflammatory drugs [NSAIDs]), or inhibitors of the renin-angiotensin system, such as ACE inhibitors or angiotensin receptor antagonists, can precipitate ATN in individuals with reduced renal perfusion.

Severe renal vasoconstriction (25-50% of normal) has been documented in experimental and clinical ARF and has been considered in the past as a dominant causative factor. That explains the name of vasomotor nephropathy given to this condition; however, reduction in total renal blood flow alone does not appear to account for the profound reduction in GFR since improvement of renal blood flow by volume expansion or administration of vasodilators does not correct GFR.

Recent studies suggest that persistent abnormalities in intrarenal blood flow involving the outer medullary region may contribute to the reduction in GFR. The outer medulla is relatively hypoxic even under normal conditions, with a partial pressure of oxygen being 10-20 mm Hg (compared to 50-60 mm Hg in the cortex), rendering the tubular segments in this region (namely the S3 segment of the proximal tubule and the mTAL) highly susceptible to ischemia. For reasons that are incompletely understood, hypoxia and vasoconstriction persist in the outer medullary region even after total renal blood flow returns to normal, resulting in further tubular injury.

Mediators of both the renal vasoconstriction and the persistent reduction in medullary blood flow most likely include endothelin-1, angiotensin II, prostaglandins, adenosine, and nitric oxide. Elevated levels of endothelin-1, a potent renal vasoconstrictor, have been demonstrated in patients with ARF of various etiologies, and endothelin receptor antagonists have been shown to ameliorate experimental ARF. A role for angiotensin II, another potent renal vasoconstrictor, has been proposed because hyperplasia of the juxtaglomerular apparatus with increased renin granule content and increased plasma renin activity have been demonstrated in patients with ARF. However, inhibition of angiotensin II does not diminish the extent of renal injury in experimental ARF and may precipitate ARF in patients with diminished effective blood volume. This makes the role of angiotensin II in human ATN uncertain.

Adenosine has been incriminated as a renal vasoconstrictor in contrast nephropathy. Pretreatment with adenosine receptor antagonists, such as theophylline, can blunt the abrupt reduction in GFR induced by contrast agents, but these agents are ineffective once ATN is established.

A deficiency of renal vasodilators, such as endothelium-derived nitric oxide and prostaglandins, may also play a role in the initiation of ATN, but no evidence exists that administration of either mediator alters the course of established ATN. The inability of nitric oxide donors, such as nitroprusside, to improve the course of ischemic ARF may be related to the paradoxical toxic effects of nitric oxide on proximal tubule cells via generation of reactive oxygen species. Although a deficiency of vasodilatory atrial natriuretic peptide (ANP) has not been demonstrated in ATN, ANP has been reported to increase renal blood flow, GFR, natriuresis and diuresis in experimental ischemic and toxic ARF, when infused shortly after the onset of renal ischemia. In human trials, ANP offered no benefit when administered to critically ill adults with ATN but did appear to improve the overall survival in a subset of patients with oliguric ATN.

Alterations in tubule function

The tubular segments located within the medullary region (S3 segment of proximal tubule and mTAL) are particularly vulnerable to ischemia because the oxygen tension in this region is low even under normal conditions, and both segments have a high rate of oxygen consumption. The active transport of sodium that occurs at this level depends on oxidative phosphorylation for energy. Consequently, these tubular segments are extremely susceptible to ischemia and to those nephrotoxins that disrupt energy production or mitochondrial function.

Tubular obstruction also contributes to the reduction in GFR. Recent studies revealed that tubular obstruction is produced predominantly by the exfoliation of viable (rather than necrotic) tubule cells, leaving behind denuded areas of the basement membrane. Another factor leading to the reduction of GFR is the combination of exposed basement membrane and the loss of tight junctions in the attached proximal tubule cells that result in tubular back leak of a variety of substances, including creatinine and urea. The back leak renders these substances unsuitable for the estimation of GFR. Activation of the tubuloglomerular feedback system may also contribute to the reduction in GFR.

The increased delivery of sodium chloride to the distal nephron segments, specifically the macula densa, due to cellular abnormalities in the ischemic proximal tubule would be expected to induce afferent arteriolar constriction via A1 adenosine receptor (A1AR) activation and thereby decrease GFR. However, recent animal studies have shown that a knockout of the A1AR resulted in a paradoxical worsening of ischemic renal injury, and exogenous activation of A1AR was protective. Thus, tubuloglomerular feedback activation following ischemic injury may indeed represent a beneficial phenomenon that limits wasteful delivery of ions and solutes to the damaged proximal tubules, thereby reducing the demand for ATP-dependent reabsorptive processes. Any salutary effect of exogenous A1AR activation in human ATN remains to be determined.

Alterations in tubule cell metabolism

Adenosine triphosphate (ATP) depletion plays a pivotal role in renal cell injury. In general, cellular ATP is produced by mitochondrial oxidative phosphorylation and by glycolysis in the endoplasmic reticulum. Proximal tubule cells are dependent predominantly on mitochondria for ATP synthesis, rendering them especially susceptible to oxygen deprivation in ischemic ATN and to nephrotoxins that cause mitochondrial damage. Oxygen deprivation results in rapid catabolism of ATP to adenosine diphosphate (ADP) and adenosine monophosphate (AMP).

Restoration of oxygen allows for rapid rephosphorylation of these adenine nucleotides to ATP; however, prolonged ischemia results in further catabolism of adenine nucleotides to adenosine and hypoxanthine, which can diffuse passively out of the cell and deplete the adenine nucleotide pool for ATP synthesis. Prolonged cellular ATP depletion initiates a sequence of events including inhibition of ATP-dependent transport mechanisms, activation of proteases, and cytoskeletal alterations. The importance of ATP depletion has been underscored by the demonstration in animal models that provision of exogenous adenine nucleotides partially ameliorates cellular injury following ischemia.

Reactive oxygen species (ROS), such as hydroxyl radical, peroxynitrite, and hypochlorous acid, are generated from several sources during reperfusion of ischemic kidneys. The hydroxyl radical can be formed from superoxide and hydrogen peroxide, which under normal circumstances are produced continually by tubule cells. The final conversion of hydrogen peroxide to hydroxyl radical requires ferrous iron. Naturally occurring antioxidants, such as superoxide dismutase, catalyze the conversion of superoxide to hydrogen peroxide, which, in turn, is converted to water by catalase or glutathione peroxidase, thereby conferring cryoprotection.

Prolonged ischemia results in the catabolism of cellular ATP to hypoxanthine, and the concomitant calcium-dependent activation of xanthine oxidase. During reperfusion, xanthine oxidase uses molecular oxygen as an electron receptor while converting hypoxanthine to xanthine, thereby generating excessive superoxide that can overwhelm the tubule cell's defenses against hydroxyl radical production. Other sources of ROS include mitochondria that are damaged during ischemia-reperfusion, neutrophils that are activated following ischemia-reperfusion, and peroxynitrite production from an interaction of superoxide with nitric oxide (the proximal tubular synthesis of which is induced by ischemic and toxic injury).

ROS-mediated injury is also encountered in conditions associated with the availability of excessive free ferrous iron, such as hemoglobinuria, myoglobinuria, gentamicin, and cisplatin nephrotoxicity. Once generated, ROS can damage cells in many ways, including direct oxidation of membrane proteins, peroxidation of membrane lipids, and DNA damage. Yet, the role of ROS in ATN remains controversial. While several animal studies provided evidence of ROS generation during renal ischemia-reperfusion injury and a protective effect of exogenously administered antioxidants, other studies failed to reveal a protective effect of antioxidants. These contradictory results may be due to factors such as the duration of injury and timing of the intervention. Controlled trials using antioxidants in human ATN have not been done.

Intracellular free calcium rises following ATP depletion due to impairment of pumps that normally extrude calcium from the cell or sequester calcium within the endoplasmic reticulum. This can result in mitochondrial damage, activation of proteases and phospholipases, generation of ROS, and cytoskeletal disruption. Calcium channel blockers (CCBs) have been shown to ameliorate ischemic renal injury in a variety of animal studies, although the mechanisms conferring the protection are unclear. They may include an improvement in renal hemodynamics, a membrane stabilizing effect on tubule epithelial cells, and a calmodulin antagonizing effect, in addition to the prevention of calcium overloading of cells.

CCBs have also yielded encouraging results in human ATN. Administration of CCBs to both donors and recipients has been shown to reduce the prevalence of ARF following cadaveric kidney transplants; however, the beneficial effect of CCBs in this setting may be because of their ability to blunt the nephrotoxicity of the concomitantly administered cyclosporine. In addition, CCB administration prior to radiocontrast materials confers protection against nephrotoxicity. It appears, therefore, that the prophylactic use of CCBs prior to a potential renal insult, such as cold ischemia in cadaveric transplants or administration of contrast material, is beneficial but that CCBs are unlikely to be effective in established ATN.

Activation of phospholipase has been demonstrated in hypoxia-induced injury to proximal tubules in animal models, presumably as a result of ATP depletion and increase in intracellular calcium. Phospholipase activation can result in breakdown of membrane phospholipids, disruption of cellular membranes, and subsequent cell death. Inhibitors of phospholipase A2 have been shown to confer protection against tubule cell injury in experimental ATP depletion.

Activation of neutrophils recruited during reperfusion of ischemic kidneys has been implicated in subsequent renal cell injury. Activated neutrophils loosely adhere to the vascular endothelium via P-selectin-mediated interactions, become immobilized via interactions between the leukocyte adhesion molecule CD11/18 and the endothelial receptor intercellular adhesion molecule-1 (ICAM-1), and induce direct endothelial and tubule cell injury via release of reactive oxygen species. In experimental models, depletion of neutrophils or inhibition of neutrophil adhesion to endothelial cells (via administration of soluble P-selectin glycoprotein ligand or neutralizing antibodies to either ICAM-1 or CD11/18) significantly reduced the severity of ischemia-reperfusion injury.

Alterations in tubule cell morphology

ATN is characterized by heterogeneity in the morphologic response of various nephron segments. The cells lining the collecting duct tubules within the inner medulla and cortical ascending limbs are frequently not injured. Proximal tubule and mTAL cells display changes commensurate with the severity of the insult, with the majority of cells being injured sublethally and capable of complete recovery. More severely affected cells are lost by apoptosis, while the most severely injured cells undergo necrosis; however, even the sublethally injured cells undergo significant alterations in the actin-based cytoskeleton, which account for several of the functional consequences of ATN.

The integrity of the actin-based cytoskeleton is crucial to several aspects of renal tubule epithelial cell biology, including the maintenance of asymmetric (polarized) distribution of integral membrane proteins, maintenance of the tight junctions, structure of microvilli, and cell-cell and cell-substratum interactions. Disruption of actin microfilaments following ischemic renal injury results in a series of cellular changes that have been demonstrated primarily in cultured cells and in animal models.

First, loss of microvillus structure results in exfoliation of the brush border into the tubule lumen, which contributes to tubular obstruction.

Second, loss of the barrier function of proximal tubule tight junctions contributes to the back-leak of glomerular filtrate.

Third, loss of basolateral localization of the sodium, potassium–adenosine triphosphatase (Na, K-ATPase) and its redistribution to the apical membrane domain results in impaired transport of sodium, water, and other cotransported solutes. The apical mislocation of Na, K-ATPase has also been demonstrated in human ATN, and normalization of solute transport is dependent on reestablishment of the polarized phenotype.

Fourth, loss of basal domain distribution of beta1-integrins and their redistribution to the apical domain results in loss of cell adherence to the substratum and the exfoliation of viable cells. This contributes not only to the cast formation and tubular obstruction but also to the back-leak via denuded areas of basement membrane. In addition, it may contribute to the abnormal adhesion between exfoliated cells, thereby promoting cast formation and obstruction.

The explanation for the latter hypothesis lies in the finding that the detached viable cells contain receptor fragments of matrix proteins that bind avidly to the beta1-integrins expressed apically on neighboring exfoliated cells. This interaction requires the presence of the arginine-glycerol-asparaginase (Arg-Gly-Asp, or RGD) motif on the integrin receptors. In experimental ATN, infusion of short peptides containing the RGD motif significantly ameliorated cast formation and functional impairment, by preventing adhesion between exfoliated cells.

Lethally injured tubule cells die via 2 distinct mechanisms. The most severely injured cells display a profound decrease in ATP levels and undergo necrosis. This is characterized by cell swelling, mitochondrial disruption, and loss of plasma membrane integrity, leading to the chaotic release of intracellular components into the extracellular space and activation of an inflammatory response.

Less severely injured cells exhibit a partial ATP depletion, and activate apoptotic pathways. Apoptosis or programmed cell death is an energy-requiring process characterized by progressive cell shrinkage, nuclear condensation and fragmentation, plasma membrane blebbing, and disintegration of the cell into membrane-bound vesicles that are phagocytized rapidly without eliciting an inflammatory response. Apoptosis is best viewed as a packaging mechanism, whereby the cell essentially commits suicide and quietly exits the stage. Apoptotic cells can be detected in histologic sections only by specific techniques. A large body of evidence now exists attesting to the critical role of apoptosis, both in experimental ARF and in human ATN.

Following brief periods of renal ischemia, apoptotic cells become evident within 24 hours of reflow. A second wave of apoptotic cells has been observed during the recovery phase of ARF, when it likely represents a mechanism for removal of unwanted or excessively proliferating cells, thereby facilitating the remodeling of injured tubules. The molecular mechanisms underlying the first wave of apoptosis are currently under intense investigation because selective inhibition of these pathways may constitute a powerful novel strategy for diminishing cell death in ATN.

Factors influencing recovery

In the absence of multiorgan failure, most patients with ATN regain most of the renal function. The recovery phase involves the restitution of cell polarity and tight junction integrity in sublethally injured cells, removal of dead cells by apoptosis, removal of intratubular casts by reestablishment of tubular fluid flow, and regeneration of lost renal epithelial cells. Following ischemia-reperfusion, there is a marked up-regulation of a number of genes that play important roles in renal tubule cell proliferation occurs, including epidermal growth factor (EGF), insulinlike growth factor-1 (IGF-1), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In animals, exogenous administration of several of these growth factors has been shown to accelerate recovery from ischemic ARF; however, in a single human trial, IGF-1 did not prove to be beneficial when given to adults with ARF of various etiologies. Additional human studies with growth factors currently are under way.

Heat shock proteins (HSP) are a group of highly conserved proteins that are expressed constitutively in normal cells and markedly induced in cells injured by heat, hypoxia, or toxins. They act as intracellular chaperones, allowing proper folding, targeting, and assembly of newly synthesized and denatured proteins. At least 2 families of HSPs, namely HSP-70 and HSP-25, have been shown to be overexpressed in renal tubule cells following ischemia-reperfusion injury in animals. HSP-70 may play a role in the restitution of cell polarity, and HSP-25 is an actin-capping protein that may assist in the repair of actin microfilaments in sublethally injured cells. The role for HSPs in human ATN remains to be elucidated.

Frequency

United States

Frequency varies greatly depending on the clinical context. ATN is the most frequent cause of hospital acquired ARF. In adults, prevalence of ATN is approximately 1% at admission, 2-5% during hospitalization, and 4-15% after cardio-pulmonary bypass. ATN occurs in approximately 5-10% of newborn ICU patients and 2-3% of pediatric ICU patients. Prevalence in children undergoing cardiac surgery is 5-8%.

Mortality/Morbidity

• Mortality rates vary widely according to the underlying cause and associated medical condition. For patients with community-acquired ATN without other serious comorbid conditions, the mortality rate is approximately 5%, and it has decreased over the past decades because of the availability of efficient renal replacement therapies. The mortality rate jumps to 80% among ICU patients with multiorgan failure, although death almost never is caused by renal failure.
• The most common causes of death are sepsis, cardiovascular and pulmonary dysfunction, and withdrawal of life support measures.

Race

No significant racial predilection exists.

Sex

Both sexes are affected equally.

Age

ATN affects all age groups, although the causes differ from group to group. ATN is encountered more commonly in neonates and elderly persons because of the high frequency of comorbid conditions.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients with hospital-acquired ATN frequently have no specific symptoms. The diagnosis is at times suspected when urine output diminishes and is usually made by the documentation of successive elevations in BUN and serum creatinine levels. Careful evaluation of the hospital course usually reveals the cause of ATN. In patients with community-acquired ATN, a thorough history and physical examination are invaluable in pinpointing the etiology. In children, the most common form is ischemic ATN caused by severe hypovolemia, shock, trauma, sepsis, burns, and major surgery. Also common is nephrotoxic ATN, caused by a variety of drugs. Their deleterious effect is markedly enhanced by hypovolemia, renal ischemia, or other renal insults.

• Fluid losses
• • Severe vomiting and/or diarrhea are common causes of renal hypoperfusion in children. Significant fluid loss may also result from hemorrhage or burns. Loss of intravascular volume into the interstitial compartment accompanies major surgery, shock syndromes, and nephrotic syndrome.
  • Children with fluid losses may complain of thirst, dizziness, palpitations, and fatigue. A history of acute weight loss and oliguria may be documented; however, ATN resulting from nephrotoxic drugs and from perinatal events are frequently of the nonoliguric type.
• Drugs
• • In the presence of mild prerenal insufficiency, ingestion of seemingly innocuous medications that impair renal autoregulation can precipitate oliguric ATN; for example, NSAIDs inhibit the renal synthesis of vasodilator prostaglandins and can precipitate ATN when administered to febrile children with intercurrent dehydration.
  • Cyclosporine, tacrolimus, and contrast agents are afferent arteriolar constrictors. Their nephrotoxicity is potentiated by preexisting hypovolemia because they inhibit the myogenic response of the afferent arteriole to renal hypoperfusion.
  • Drugs that induce direct tubule cell damage include aminoglycosides; amphotericin B; cyclosporine; tacrolimus; antineoplastic agents, such as cisplatin and methotrexate; and contrast agents.
  • Acyclovir and sulfonamides can precipitate and obstruct the tubular lumens, especially in children with diminished tubular fluid flow.
• Release of endogenous tubular toxins
• • Myoglobinuric ATN may be encountered in a variety of clinical situations, including muscle trauma, prolonged seizures, malignant hyperthermia, snake and insect bites, myositis, severe hypokalemia and hypophosphatemia, and infections such as severe influenza.
  • Hemoglobinuric ATN can accompany various states of hemolysis, including transfusion reactions, malaria, snake and insect bites, glucose 6-phosphate dehydrogenase deficiency, and mechanical causes such as extracorporeal circulation and cardiac valvular prostheses.
  • Hyperuricosuric ATN is observed primarily during treatment of lymphoproliferative or myeloproliferative malignancies and presents as tumor lysis syndrome.
• Hypoxia
• • In infants, ATN frequently complicates severe perinatal asphyxia, respiratory distress syndrome, hemorrhage, and cyanotic congenital heart disease.
  • Older children with severe pulmonary or cardiac disease also are prone to ATN.

Physical

• Signs of ARF include hypertension; edema; anemia; and signs of congestive heart failure (CHF), such as hepatomegaly, gallop rhythm, and pulmonary edema.
• Signs of intravascular volume depletion include tachycardia, orthostatic hypotension, decreased skin turgor, dry mucous membranes, and changes in sensorium.

Causes

• Prevalent causes of ATN in neonates
• • Ischemia - Perinatal asphyxia, respiratory distress syndrome, hemorrhage (eg, maternal, twin-twin transfusion, intraventricular), congenital cyanotic heart disease, shock/sepsis
  • Exogenous toxins - Aminoglycosides, amphotericin B, maternal ingestion of ACE inhibitors or NSAIDs
  • Endogenous toxins - Hemoglobin following hemolysis, myoglobin following seizures
  • Kidney disease - Renal venous thrombosis, renal artery thrombosis; renal hypoplasia and dysplasia; autosomal recessive polycystic kidney disease; bladder outlet obstruction
• Prevalent causes of ATN in older children
• • Ischemia - Severe dehydration; hemorrhage; shock/sepsis; burns; third space losses in major surgery, trauma, nephrotic syndrome; cold ischemia in cadaveric kidney transplant; near drowning; severe cardiac or pulmonary disease
  • Exogenous toxins - Drugs that impair autoregulation (eg, cyclosporine, tacrolimus, ACE inhibitors, NSAIDs), direct nephrotoxins (eg, aminoglycosides, amphotericin B, cisplatin, contrast agents, cyclosporine, tacrolimus)
  • Endogenous toxins - Hemoglobin release (eg, transfusion reactions, malaria, snake and insect bites, glucose 6-phosphate dehydrogenase deficiency, extracorporeal circulation, cardiac valvular prostheses), myoglobin release (crush injuries, prolonged seizures, malignant hyperthermia, snake and insect bites, myositis, hypokalemia, hypophosphatemia, influenza)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urinalysis
• • Careful examination of freshly voided urine is a rapid and inexpensive way of distinguishing prerenal failure from ATN. In prerenal failure, a few hyaline and fine granular casts may be observed with little protein, heme, or RBCs.
  • Heme-positive urine in the absence of erythrocytes in the sediment suggests ATN from hemolysis or rhabdomyolysis.
  • Broad, brown granular casts are typically found in ischemic or nephrotoxic ATN.
• Urinary indexes
• • Simultaneous measurement of urinary and serum sodium, creatinine, and osmolality can help differentiate between prerenal azotemia (in which the reabsorptive capacity and concentrating ability of the kidney are preserved or enhanced) and ATN (in which these functions are impaired).
  • In prerenal failure, urine specific gravity and the ratio of urine to plasma creatinine levels are high, and the urinary sodium concentration is low (Table 1). In contrast, the urine in ATN is isosthenuric with a low urine-to-plasma creatinine ratio and high urine sodium concentration.
  • The fractional excretion of sodium (FeNa) is the percentage of filtered sodium that is excreted. It is calculated easily by the formula FeNa(%) = ([U/P]Na)/([U/P]Cr) x 100, where Na and Cr represent concentrations of sodium and creatinine in the urine (U) and plasma (P), respectively. The FeNa is typically more than 1% in ATN and less than 1% in prerenal azotemia. Be alert to the fact that FeNa may be low in intrinsic renal failure from glomerular diseases.
  • Interpretation of urinary indexes requires caution.
  • Collect blood and urine specimens before the administration of fluids, mannitol, or diuretics.
  • Urine should be free of glucose, contrast material, or myoglobin.
  • Urinary indexes suggestive of prerenal failure (FeNa <1) may be observed in the ATN of contrast nephropathy and rhabdomyolysis.

    Table 1. Urinary Indexes in ATN vs Prerenal Failure

    	ATN	Prerenal
    Urine specific gravity	1010	>1020
    Urine sodium (mEq/L)	>40	<10
    Urine/plasma creatinine	<20	>40
    FeNa	>2%	<1%

• Blood urea nitrogen and serum creatinine
• • The hallmark of established ARF is a daily increase in serum creatinine (by 0.5-1.5 mg/dL/d) and BUN (by 10-20 mg/dL/d) levels. In ATN, the BUN/creatinine ratio is usually around 10, as opposed to a ratio more than 20 commonly observed in prerenal failure (due to enhanced proximal tubular reabsorption of urea). However, the BUN/creatinine ratio may be misleading in patients whose conditions are wasting or in infants with physiologically low muscle mass.
  • Elevations of BUN also can result from steroid therapy, parenteral nutrition, GI bleeding, and catabolic states. A spurious elevation in serum creatinine may be observed following the use of drugs that interfere with the tubular secretion of creatinine (cimetidine, trimethoprim) or drugs that provide chromogenic substrates (cephalosporins) that interfere with the Jaffe reaction for the determination of serum creatinine.
• Serum sodium: Hyponatremia is a common finding in ATN and is usually dilutional, secondary to fluid retention and administration of hypotonic fluids.
• Serum potassium
• • Hyperkalemia is a common and often serious complication of ATN. Contributing factors include reduced GFR, reduced tubular secretion, metabolic acidosis (each 0.1 unit reduction in arterial pH raises serum potassium by 0.3-0.4 mEq/L), and associated catabolic state.
  • Hyperkalemia is most pronounced in individuals with excessive endogenous potassium production, such as in rhabdomyolysis, hemolysis, and tumor lysis syndrome.
  • Symptoms are nonspecific and may include malaise, nausea, and muscle weakness.
  • Hyperkalemia represents a life-threatening emergency that must be treated promptly and aggressively, primarily because of its depolarizing effect on cardiac conduction pathways.
• Serum phosphate and calcium
• • Hyperphosphatemia and hypocalcemia frequently complicate ATN. The phosphate excess is secondary to reduced renal excretion and can lead to hypocalcemia and calcium phosphate deposition in various tissues.
  • Hypocalcemia results predominantly from hyperphosphatemia and impaired absorption of calcium from the GI tract because of inadequate 1,25-hydroxy vitamin D-3 production by the diseased kidneys.
  • Determining ionized calcium concentration may be important because this unbound form of serum calcium determines physiologic activity.
  • Acidosis increases the fraction of serum calcium that is in the ionized form, while correction of acidosis may decrease it; thus, overzealous bicarbonate therapy can acutely decrease ionized calcium.
  • Severe hypocalcemia results in tetany, seizures, and cardiac arrhythmias.
• Acid-base balance
• • The high anion gap metabolic acidosis of ATN is a consequence of impaired renal excretion of nonvolatile acids. Decreased tubular reabsorption of bicarbonate further contributes to the metabolic acidosis.
  • Severe acidosis can develop in children who are hypercatabolic (shock, sepsis) or who have inadequate respiratory compensation.
• Complete blood count
• • A mild-to-moderate anemia is commonly observed as a result of dilution and decreased erythropoiesis. Severe anemia should prompt a search for hemolysis from a variety of causes; it can result in hemoglobinuric ATN. These patients usually display elevated serum lactate dehydrogenase levels.
  • Microangiopathic hemolytic anemia with schistocytes and thrombocytopenia are indicative of possible HUS, which is an important cause of intrinsic ARF in children.
  • Prolonged ATN also can result in bleeding due to dysfunctional platelets.
• Other tests
• • A suspicion of rhabdomyolysis may be confirmed by direct determination of urinary myoglobin and elevation of serum creatine kinase (specifically the CK3 isoenzyme).
  • Children with rhabdomyolysis usually also display marked increases in serum potassium and phosphate.
  • In the tumor lysis syndrome following cancer chemotherapy, a marked elevation in serum uric acid occurs along with hyperkalemia and hyperphosphatemia.
  • Hypomagnesemia is a prominent finding in nephrotoxic ATN, particularly associated with gentamicin, amphotericin B, cisplatinum or pentamidine administration.
  • Serum levels of nephrotoxins should be determined and serially followed, particularly when using gentamicin, vancomycin, cyclosporine, or tacrolimus.
  • Although ARF is usually secondary to ischemic or nephrotoxic injury, other causes of intrinsic ARF should be kept in mind and excluded by history, physical examination, and laboratory evaluation. Laboratory evaluation should include urine cultures and serologic tests (including C3 and C4 in all patients) and lupus serologies and hepatitis profiles when appropriate.

Imaging Studies

• Renal ultrasound
• • An ultrasound examination of the kidneys and bladder with Doppler flow is essential in the workup of ARF. Exceptions to this rule may include children with unmistakable prerenal failure from well-documented dehydration who respond promptly to fluid therapy or children with renal insufficiency secondary to obvious glomerular disease, hypoxia-ischemia, or exposure to nephrotoxins.
  • Ultrasound provides important information regarding kidney size, contour, echogenicity, corticomedullary differentiation, and blood flow.
  • In ischemic or nephrotoxic ATN, the kidneys are of normal size or slightly enlarged, with increased echogenicity.
  • With prolonged ATN, renal cortical necrosis may result in decreased kidney size.
  • Bilateral small scarred kidneys are indicative of chronic renal disease.
  • Congenital disorders, such as polycystic kidney disease and multicystic dysplasia, are easily detected.
  • Calculi and tumors are also evident.
  • Hydronephrosis is suggestive of urinary tract obstruction, and accompanying hydroureter and thickened bladder wall are consistent with bladder outlet obstruction.
  • A Doppler study is important in the evaluation of vascular obstruction.
• Radionuclide scans
• • Radionuclide scans (functional scans with mercaptotriglycylglycine [MAG-3] or diethylenetriamine penta-acetic acid [DTPA]) are useful in the assessment of obstruction and may provide additional information regarding GFR, renal blood flow, and tubule function.
  • Their major clinical use in children with ATN is in the immediate posttransplant period, when scans can help differentiate between ATN and transplant rejection.

Other Tests

• Perform an ECG if hyperkalemia is suspected or detected by laboratory tests. The following are sequential ECG changes in hyperkalemia:
• • Tall peaked T waves
  • Prolongation of PR interval
  • Widening of QRS complex
  • ST segment changes
  • Ventricular tachycardia
  • Terminal ventricular fibrillation

Procedures

• Renal biopsy
• • In general, a kidney biopsy is not necessary in the initial evaluation; however, if prerenal and postrenal causes of ARF have been ruled out and an intrinsic renal disease other than ischemic ATN, nephrotoxic ATN, HUS, or postinfectious glomerulonephritis is a possibility, a renal biopsy may be valuable in establishing the diagnosis, guiding therapy, and assessing prognosis.
  • Renal biopsy may be also useful in the immediate posttransplant period for the differentiation between ATN and acute rejection.

Histologic Findings

See Pathophysiology.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

In this section, strategies for preventing ATN and managing fluid and electrolyte disturbances are briefly described. Short accounts of dialytic modalities and newer experimental therapeutic approaches are also included. Treatment of hypertension in ATN is considered in a separate article (see Hypertension).

• Prevention of ATN
  • In clinical situations in which renal hypoperfusion or toxic injury is anticipated, administration of fluids, diuretics, mannitol, and low-dose dopamine have been used to prevent or reverse renal injury. Vigorous prophylactic fluid administration has been used successfully to prevent ATN following cardiac surgery, cadaveric kidney transplantation, major trauma, burns, hemoglobinuria, myoglobinuria, tumor lysis syndrome, radiocontrast administration, amphotericin B therapy, and cisplatin infusion.
  • Ensuring adequate hydration prior to any of the above procedures is now an established standard of care. However, the role of diuretics, mannitol, and low-dose dopamine is more controversial. In one recent well-designed study using either low-dose dopamine or furosemide prior to cardiac surgery in adults, no renoprotective effect could be documented. The prophylactic use of diuretics or dopamine prior to the above procedures is not recommended at this time.
  • Several studies, albeit uncontrolled, suggest that diuretics may be beneficial when administered during the early phase of ATN. Although they do not appear to alter the course of the ARF, they may convert an oliguric to a nonoliguric ARF, which is more easily managed because it obviates the need for fluid restriction and allows for maximal nutritional support.
  • The current recommendation is that a trial of intravenous furosemide should be attempted in children with oliguria of less than 48 hours duration who have not responded to adequate hydration. The dose of furosemide should be in the high range (2-5 mg/kg). Some evidence suggests that in the prevention of crush syndrome, early administration of mannitol, before muscle toxins and breakdown products are released into the circulation, may protect from the development of ATN.
• Fluid management
  • The major goal of fluid management is to restore and maintain intravascular volume. ATN may manifest with hypovolemia, euvolemia, or volume overload, and an estimation of fluid status is a prerequisite for initial and ongoing therapy. This is accomplished by measuring input and output, serial body weights, vital signs, skin turgor, capillary refill, serum sodium, and FeNa.
  • Children with intravascular volume depletion require prompt and vigorous fluid resuscitation. Initial therapy includes normal saline or lactated Ringer solution at 20 mL/kg over 30 minutes. It can be repeated twice if necessary, after careful monitoring to avoid possible fluid overload. Potassium administration is contraindicated until urine output is established. If anuria persists after 3 fluid boluses (confirmed by bladder catheterization), central venous monitoring may be required to guide further management.
  • Oliguria in the presence of volume overload requires fluid restriction and possibly intravenous administration of furosemide. Children with established ATN may not respond to furosemide; in which case, consider fluid removal by dialysis or hemofiltration, especially if signs of pulmonary edema are evident.
  • Input and output records, daily weights, physical examination, and serum sodium concentration guide ongoing therapy. A bedside indicator of appropriate fluid therapy is a body weight decrease of approximately 0.5% per day as a result of caloric deprivation; serum sodium concentration should remain stable. A more rapid weight loss and increasing serum sodium indicate inadequate fluid replacement. An absence of weight loss with decreasing serum sodium suggests excess free water replacement.
  • During the recovery phase, children develop significant polyuria and natriuresis and may become dehydrated if appropriate adjustments in fluid requirements are not made.
• Electrolytes and acid-base balance
  • If serum potassium levels exceed 5.5-6.5 mEq/L, eliminate all sources of potassium from the diet or intravenous fluids and administer a cation exchange resin such as sodium polystyrene sulfonate (Kayexalate). Kayexalate requires several hours of contact with the colonic mucosa to be effective; the rectal route of administration is preferred. Complications of this therapy include hypernatremia and constipation. An attempt can be made to lower serum potassium concentration by increasing the dose of diuretics in those patients responding to them.
  • Emergency treatment of hyperkalemia is indicated when serum potassium exceeds 6.5 mEq/L or tall peaked T waves are evident on the ECG. In addition to Kayexalate, administer intravenous sodium bicarbonate, which causes a rapid shift of potassium into cells. The magnitude of the potassium intracellular shift is variable, and thus bicarbonate is not reliable in lowering the K level. Such therapy should be used with caution because it can precipitate hypocalcemia and sodium overload. Sodium bicarbonate uptake of potassium by cells can also be stimulated by infusion of glucose and insulin or by beta-agonists (albuterol by nebulizer). The efficacy and convenience of nebulized albuterol has been well described in chronic hemodialysis patients with hyperkalemia; however, it can cause tachycardia, and the overall pediatric experience is limited.
  • The presence of ECG changes requires the immediate administration of calcium gluconate (with continuous ECG monitoring) to counteract the effects of hyperkalemia on the myocardium. This therapy may precipitate bradycardia and other cardiac arrhythmias.
  • The definitive therapy for significant hyperkalemia in oliguric ATN frequently includes dialysis. The forms of therapy outlined above serve to tide over the crisis while arrangements are being made for dialysis.
  • The primary treatment of hyponatremia is free water restriction. Serum sodium of less than 120 mEq/L may require hypertonic (3%) sodium chloride infusion, especially if CNS dysfunction is present. Administration of hypertonic sodium chloride could precipitate CNS dysfunction and may be used only with extreme caution in critical care settings.
  • Management of hyperphosphatemia includes dietary restriction and oral phosphate binders (calcium carbonate or calcium acetate). Hypocalcemia usually responds to oral calcium salts used for control of hyperphosphatemia but may require 10% calcium gluconate infusion or intravenous Calcitrol if severe.
  • Metabolic acidosis of ATN is usually mild and does not require treatment. Moderate acidosis (pH <7.3) should be treated with oral sodium bicarbonate or sodium citrate. Severe acidosis (pH <7.2), especially in the presence of hyperkalemia, requires intravenous bicarbonate therapy. Adequate ventilation is necessary in order to exhale the carbon dioxide produced. Bicarbonate administration may precipitate hypernatremia or hypocalcemia. Children who cannot tolerate a large sodium load (ie, those with CHF) may be treated in an intensive care unit (ICU) setting with intravenous tromethamine (THAM), pending institution of dialysis.
• Medications
  • Avoid nephrotoxic agents, as they may worsen the renal injury and delay recovery of function. Such agents include contrast media, aminoglycosides, and NSAIDs.
  • Prescribing medication in ATN requires knowledge of the route of elimination, and modifications in dose or frequency should be made based on residual renal function. When making these adjustments, patients in the early phase of ATN with a rising serum creatinine level should be assumed to have a GFR of less than 10 mL/min, irrespective of the serum creatinine value.
• Dialysis
  • The goal of dialysis is to remove endogenous and exogenous toxins and to maintain fluid, electrolyte, and acid-base balance until renal function returns. Indications for acute dialysis are not absolute, and the decision to use this therapy depends on the rapidity of onset, duration, and severity of the abnormality to be corrected. See Common indications for dialysis in ATN.
  • The choice between hemodialysis and peritoneal dialysis depends on the overall clinical condition, availability of technique, etiology of the ATN, institutional preferences, and specific indications or contraindications.
    • In general, peritoneal dialysis is a gentler and preferred method in infants and younger children. Specific contraindications include abdominal wall defects, bowel distention, perforation or adhesions, and communications between the abdominal and chest cavities.
    • Hemodialysis has the distinct advantage of rapid correction of fluid, electrolyte, and acid-base imbalances, and may be the treatment of choice in hemodynamically stable patients, especially older children. Disadvantages include the requirement for vascular access, large extracorporeal blood volume, heparinization, and skilled personnel. An important advance has been the use of biocompatible synthetic dialysis membranes, such as polysulfone. These membranes should minimize complement activation and neutrophil infiltration into the kidney. Their use generally is recommended in children with ARF, although not all studies have documented beneficial effects.
  • Over the past decade, continuous venovenous hemofiltration (CVVH) has emerged as an alternative therapy primarily for children with ATN who require fluid removal who are unstable or critically ill. The major advantage of this technique lies in the ability to remove fluid in a hypotensive child in whom hemodialysis may be relatively contraindicated and peritoneal dialysis inefficient. The patient requires the continuous presence of trained personnel and specialized equipment that are currently available only at select tertiary care centers. CVVH also can be modified easily to allow for significant solute removal, and as experience accumulates, this continuous but gentle modality may emerge as the dialytic therapy of choice for patients with ATN in the ICU.
  • Some concern remains that dialysis actually may be detrimental to recovery of renal function in ATN. Institution of dialysis may decrease any residual urine output (which exacerbates intratubular obstruction), may induce episodes of hypotension (which further compromises renal perfusion), and may activate complement (which increases neutrophil infiltration into the kidney). Complement activation may be minimized by the use of biocompatible membranes, and CVVH may allow for dialysis with better hemodynamic control.
• Common indications for dialysis in ATN
• • Fluid overload that is unresponsive to diuretics
  • Fluid overload that hinders adequate nutritional support
  • Hyperkalemia with oliguria
  • Symptomatic acid-base imbalances
  • Refractory hypertension
  • Symptomatic uremia (pleuritis, pericarditis, CNS symptoms)

Surgical Care

• Patients with ATN secondary to obstruction frequently require urologic care. The site of obstruction determines the therapy.
• In neonates, obstruction of the bladder neck caused by posterior urethral valves must be immediately relieved by gentle insertion of a fine urethral catheter. The subsequent management of choice is endoscopic ablation of the valves. A temporary cutaneous vesicostomy may be required in a small infant.

Consultations

• Management of ATN requires specialized care by a pediatric nephrologist.

Diet

• Children with ATN are frequently in a highly catabolic state. Aggressive nutritional support is important.
• Adequate calories to account for maintenance requirements and supplements to combat excessive catabolism must be provided.
• Oral feeding is the preferred route of administration.
• Infants should receive a low-phosphorus diet (Similac PM 60/40), and older children should be placed on a low-potassium, low-phosphorus diet. Additional calories may be supplied by fortifying foods with Polycose and medium-chain triglyceride (MCT) oils.
• Children who are nauseous or anorexic may benefit from parenteral feedings or intravenous hyperalimentation.
• If adequate nutrition cannot be achieved because of fluid restriction, consider early institution of ultrafiltration or dialysis.

Activity

• Children with ATN are usually hospitalized, and activity is restricted; however, strict bed rest does not accelerate recovery.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In this section, the use of medications for prevention of ARF and treatment of hyperkalemia, hyperphosphatemia, and metabolic acidosis are described. For the treatment of hypertension, see Hypertension.

Hyperkalemia in oliguric ATN is a medical emergency that may be managed by shifting potassium into cells with sodium bicarbonate, glucose/insulin infusion, or beta-agonists; by increasing potassium excretion with exchange resins (sodium polystyrene) or loop diuretics (furosemide); or by dialysis. Protecting the myocardium from hyperkalemia is managed with IV calcium. Hyperphosphatemia may be initially managed with oral calcium to bind dietary phosphate. Oral citrate salts may be used to manage mild metabolic acidosis, whereas IV sodium bicarbonate is needed for severe metabolic acidosis.

Drug Category: Loop diuretics

In children with recent-onset oliguria from prerenal or toxic injury who are unresponsive to hydration, a trial of furosemide may convert the oliguric ATN to a nonoliguric type, which is managed more easily. These agents have a direct vasodilatory action and additionally may prevent tubular obstruction by increasing intratubular fluid flow.

Drug Category: Alkalizing agents

Sodium bicarbonate IV and oral sodium citrate are used as buffers that break down to water and carbon dioxide after picking up free hydrogen ions, thus counteracting acidosis by raising blood pH. IV sodium bicarbonate is also used to manage hyperkalemia.

Drug Name	Sodium citrate (Bicitra, Oracit)
Description	Manages mild metabolic acidosis and used as an alkalinizing agent when long-term maintenance of an alkaline urine is desirable.
Adult Dose	1-2 mEq/kg/d PO divided bid
Pediatric Dose	Administer as in adults
Contraindications	Renal insufficiency and patients in sodium restricted diet
Interactions	Decreases therapeutic levels of lithium, chlorpropamide, methotrexate, tetracyclines and salicylates due to urinary alkalinization; increases toxicity of amphetamines, ephedrine, quinine and quinidine due to urinary alkalinization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dilute with water or juice and administer after meals; may cause diarrhea.

Drug Category: Myocardium stabilizers

The use of IV calcium does not lower serum potassium levels. It is used primarily to protect the myocardium from the deleterious effects of hyperkalemia (ie, arrhythmias) by antagonizing the potassium actions on the myocardial cell membrane.

Drug Category: Intracellular transporters

Insulin and glucose (dextrose) cause a transcellular shift of potassium into muscle cells, thereby lowering (temporarily) potassium serum levels.

Drug Category: Exchange resins

Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-moderate hyperkalemia. Each mEq of potassium is exchanged for 1 mEq of sodium.

Drug Category: Phosphate binders

ATN is frequently complicated by hyperphosphatemia and hypocalcemia, which respond to calcium-containing oral phosphate binders.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Transfer

• Children with ATN are best treated in a tertiary care institution with pediatric nephrology consultants.
• Transfer children with ATN who are hemodynamically unstable or require acute dialysis to an ICU.

Deterrence/Prevention

• Children with ATN should avoid foods high in potassium, phosphate, and sodium content. See Medical Care.

Complications

• Infections develop in 30-70% of patients with ATN. These include infections of the respiratory system, urinary tract, and indwelling catheters. Impaired defenses due to uremia and excessive use of antibiotics and invasive maneuvers may contribute to the high rate of infectious complications.
• Cardiovascular complications are primarily a result of fluid and sodium retention. They include hypertension, CHF, and pulmonary edema.
• Hyperkalemia results in ECG abnormalities and cardiac arrhythmias.
• Other complications
• • Gastrointestinal (eg, anorexia, nausea, vomiting, ileus, bleeding)
  • Hematologic (eg, anemia, platelet dysfunction)
  • Neurologic (eg, confusion, asterixis, somnolence, seizures)
  • Electrolyte disturbances (eg, hyponatremia, hyperkalemia, hypocalcemia, hyperphosphatemia)
  • Metabolic acidosis

Prognosis

• Despite significant advances in supportive care and renal replacement therapy, the high mortality rates with multiorgan failure have not improved in the past few decades. Patients die, not because of renal failure but because of serious involvement of other systems during the period of ATN.
• On the other hand, prognosis for children with ATN from prerenal causes or in the absence of significant comorbid conditions is usually quite good if appropriate therapy is instituted in a timely fashion. Most patients recover adequate renal function to lead normal lives. Some are left with permanent renal damage. In those left with mild-to-moderate renal damage further deterioration in kidney function may occur later in childhood; therefore, long-term follow-up is required in these patients.

Patient Education

• For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article Acute Kidney Failure.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose nephrotoxin-induced renal failure and discontinue the offending agent
• Failure to adjust dose of medications

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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