eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Acute Tubular Necrosis

Author: Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Coauthor(s): Robert P Woroniecki, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Nephrology, Albert Einstein College of Medicine, Children's Hospital of Montefiore
Contributor Information and Disclosures

Updated: Oct 16, 2008

Introduction

Background

Acute tubular necrosis (ATN) is pathologically characterized by varying degrees of tubule cell damage and by cell death that usually results from prolonged renal ischemia, nephrotoxins, or sepsis. ATN is clinically characterized 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.1

The various etiologies of ARF can be grouped into 3 broad categories: prerenal, intrinsic renal, and postrenal. Prerenal ARF (55% of ARF cases) is a functional response of structurally normal kidneys to hypoperfusion, whereas postrenal ARF (<5% of ARF cases) is a consequence of mechanical or functional obstruction to urine flow. Intrinsic ARF (40% of ARF cases) 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. The 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 usually lasts for 1-2 weeks but may extend to a few months.

The recovery phase of ATN is characterized by polyuria and gradual normalization of the 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 despite 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). These mechanisms initially maintain the GFR despite a reduction in renal perfusion pressure, as shown in Media file 2.

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 because improvement of renal blood flow by volume expansion or administration of vasodilators does not correct the GFR. The genesis and potential consequences of intense persistent renal vasoconstriction are illustrated in Media file 3.

Studies suggest that persistent abnormalities in intrarenal blood flow involving the outer medullary region may contribute to the reduction in the GFR. The outer medulla is relatively hypoxic even under normal conditions, with a partial pressure of oxygen being 10-20 mm Hg (compared with 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 the 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 suggests 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 the GFR. Studies have reported that tubular obstruction is predominantly produced by the exfoliation of viable (rather than necrotic) tubule cells, leaving behind denuded areas of the basement membrane. Another factor that leads to the reduction of the 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 the GFR. Activation of the tubuloglomerular feedback system may also contribute to the reduction in the 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, 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

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 predominantly depend 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 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 passively diffuse 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 continually produced by tubule cells. The final conversion of hydrogen peroxide to hydroxyl radical requires ferrous iron. These changes are shown in Media file 4. 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. Although 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 conclusive.

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 various animal studies, although the mechanisms that confer 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. Therefore, the prophylactic use of CCBs prior to a potential renal insult, such as cold ischemia in cadaveric transplants or administration of contrast material, appears to be beneficial; however, 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; most cells are sublethally injured and capable of complete recovery. More severely affected cells are lost by apoptosis, and 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 changes in tubule cell morphology characteristic of ATN are shown in Media file 5.

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 primarily demonstrated 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 rapidly phagocytized 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 suggests 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 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, a marked up-regulation of numerous 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.2 Additional human studies with growth factors are currently underway.

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 widely varies 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 patients in the ICU and 2-3% of pediatric patients in the ICU. Prevalence in children undergoing cardiac surgery is 5-8%.

Mortality/Morbidity

Mortality rates widely vary 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 has decreased over the past decades because of the availability of efficient renal replacement therapies. The mortality rate jumps to 80% among patients in the ICU with multiorgan failure, although death is almost never 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 is observed.

Sex

Both sexes are equally affected.

Age

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

Clinical

History

Patients with hospital-acquired acute tubular necrosis (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. Nephrotoxic ATN is also common and is caused by various 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 nonoliguric.
  • Drugs
    • In the presence of mild prerenal insufficiency, ingestion of seemingly innocuous medications that impair renal autoregulation can precipitate oliguric ATN; for example, nonsteroidal anti-inflammatory drugs (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 (eg, cisplatin, 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 various 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 primarily observed 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 are also 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.
  • Although oliguria is a criterion used to diagnose and stage acute renal failure (ARF), ARF can be present without oliguria, especially in patients with nephrotoxic kidney injury, interstitial nephritis, or perinatal asphyxia. Oliguria may be defined as urine output less than 1 mL/kg/h in children and less than 400 mL/d in adults.

Causes

The most common causes of ATN in children, their associated mechanisms and clinical signs (urine output) are shown in Table 1.

  • 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 (eg, crush injuries, prolonged seizures, malignant hyperthermia, snake and insect bites, myositis, hypokalemia, hypophosphatemia, influenza)

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References
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Further Reading

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Keywords

acute tubular necrosis, ATN, acute renal failure, ARF, acute intrinsic renal failure, acute vasomotor nephropathy, oliguria, anuria, ischemic ATN, nephrotoxic ATN, renal ischemia, hemolytic-uremic syndrome, HUS, immunologic glomerular disease, polyuria, severe renal vasoconstriction, nephrotic syndrome, muscle trauma, prolonged seizures, malignant hyperthermia, snake bites, insect bites, myositis, severe hypokalemia, hypophosphatemia, influenza, malaria, glucose 6-phosphate dehydrogenase deficiency, tumor lysis syndrome, severe perinatal asphyxia, respiratory distress syndrome, hemorrhage, cyanotic congenital heart disease, congestive heart failure, CHF, hepatomegaly, gallop rhythm, pulmonary edema, nephrotoxic kidney injury, interstitial nephritis, perinatal asphyxia, renal venous thrombosis, renal artery thrombosis, renal dysplasia, autosomal recessive polycystic kidney disease, bladder outlet obstruction

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Contributor Information and Disclosures

Author

Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Prasad Devarajan, MD is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Robert P Woroniecki, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Nephrology, Albert Einstein College of Medicine, Children's Hospital of Montefiore
Robert P Woroniecki, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Richard Neiberger, MD, PhD, Director of Pediatric Renal Stone Disease Clinic, Associate Professor, Department of Pediatrics, Division of Nephrology, University of Florida College of Medicine and Shands Hospital
Richard Neiberger, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Medical Association, American Society of Nephrology, American Society of Pediatric Nephrology, Christian Medical & Dental Society, Florida Medical Association, International Society for Peritoneal Dialysis, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Shock Society, Sigma Xi, Southern Medical Association, Southern Society for Pediatric Research, and Southwest Pediatric Nephrology Study Group
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Adrian Spitzer, MD, Professor, Department of Pediatrics, Albert Einstein College of Medicine; Director of NIH Training Program, Children's Hospital at Montefiore Medical Center
Adrian Spitzer, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Pediatric Society, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine
Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD, The Isaac A Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University; Division Head of Kidney Diseases, Children's Memorial Hospital, Chicago
Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology
Disclosure: Amgen Grant/research funds None; Abbott Honoraria Speaking and teaching; Altus Pharmaceuticals Grant/research funds None; Genzyme Grant/research funds None; Merck Grant/research funds None; NIH Grant/research funds None

 
 
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