INTRODUCTION

Acute tubular necrosis (ATN) is clinically characterized by acute kidney injury (AKI), 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.(3,4,5,6) The various etiologies of AKI can be grouped into 3 broad categories : prerenal, intrinsic renal, and postrenal. Prerenal AKI (55% of AKI cases) is a functional response of structurally normal kidneys to hypoperfusion, whereas postrenal AKI (< 5% of AKI cases) is a consequence of mechanical or functional obstruction to urine flow. Intrinsic AKI (40% of AKI cases) is the result of structural damage to the renal tubules, glomeruli, interstitium, or renal vasculature.(7) Most intrinsic AKI 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 AKI.(8) Pathologically, ATN is characterized by varying degrees of tubule cell damage and by cell death that usually results from prolonged renal ischemia, nephrotoxins, or sepsis. Its clinical course may be divided into initiation, maintenance, and recovery phases.(7) Patients with hospital-acquired ATN frequently have no specific symptoms. Careful evaluation of the hospital course usually reveals the cause of ATN. In patients with communityacquired ATN, a thorough history and physical examination are invaluable in pinpointing the etiology.(7) Laboratory evaluation confirms the diagnosis; ultrasonography of the kidneys and bladder with Doppler flow is essential. Serum creatinine is the current criterion standard for the diagnosis of AKI; however, important limitations are noted.(7) Treatment of pediatric patients with ATN requires correction of imbalances in fluid volume, electrolytes, and acid-base balance. Dialysis may be indicated. Patients must be monitored for the development of complications, including infection and hematologic, neurologic, and metabolic disorders.(7)

Furosemide may convert the oliguric ATN to a nonoliguric type, which is managed more easily. In addition, ATN is frequently complicated by hyperphosphatemia and hypocalcemia, which respond to calcium-containing oral phosphate binders.(7)

THE RENAL TUBULES

The renal tubules, commencing in the renal corpuscles, present, during their course, many changes in shape and direction, and are contained partly in the medullary and partly in the cortical substance. At their junction with the glomerular capsule they exhibit a somewhat constricted portion, which is termed the neck. Beyond this the tubule becomes convoluted, and pursues a considerable course in the cortical substance constituting the proximal convoluted tube. After a time the convolutions disappear, and the tube approaches the medullary substance in a more or less spiral manner; this section of the tubule has been called the spiral tube. Throughout this portion of their course the renal tubules are contained entirely in the cortical substance, and present a fairly uniform caliber. They now enter the medullary substance, suddenly become much smaller, quite straight in direction, and dip down for a variable depth into the pyramids, constituting the descending limb of Henles loop. Bending on themselves, they form what is termed the loop of Henle, and reascending, they become suddenly enlarged, forming the ascending limb of Henles loop, and reenter the cortical substance. This portion of the tubule ascends for a short distance, when it again becomes dilated, irregular, and angular. This section is termed the zigzag tubule; it ends in a convoluted tube, which resembles the proximal convoluted tubule, and is called the distal convoluted tubule. This again terminates in a narrow junctional tube, which enters the straight or collecting tube.(1) The straight or collecting tubes commence in the radiate part of the cortex, where they receive the curved ends of the distal convoluted tubules. They unite at short intervals with one another, the resulting tubes presenting a considerable increase in caliber, so that a series of comparatively large tubes passes from the bases of the rays into the renal pyramids. In the medulla the tubes of each pyramid converge to join a central tube (duct of Bellini) which finally opens on the summit of one of the papilla; the contents of the tube are therefore discharged into one of the calyces.(1) The renal tubules consist of a basement membrane lined with epithelium. The epithelium varies considerably in different sections of the tubule. In the neck the epithelium is continuous with that lining the glomerular capsule, and like it consists of flattened cells each containing an

oval nucleus . The two convoluted tubules, the spiral and zigzag tubules and the ascending limb of Henles loop, are lined by a type of epithelium which is histologically the same in all. The cells are somewhat columnar in shape and dovetail into one another of their lateral aspect. Each has a striated border next the lumen of the tube, its inner part is granular and its outer portion vertically striated. The nucleus is spherical and situated about the center of the cell. In the descending limb of Henles loop the epithelium resembles that found in the glomerular capsule and the commencement of the tube, consisting of flat, clear epithelial plates, each with an oval nucleus. The nuclei alternate on opposite surfaces of the tubule so that the lumen remains fairly constant. In the straight tube the epithelium is clear and cubical: in its papillary portion the cells are distinctly columnar and transparent. (1)

TUBULAR FUNCTION
Water and electrolytes are freely filtered at the level of the glomerulus. Thus, the electrolyte content of "ultrafiltrate" at the beginning of the proximal tubule is similar to that of plasma. Carefully regulated processes of tubular reabsorption and/or tubular secretion determine final water content and electrolyte composition of urine. As a general principle, "bulk" movement of solute tends to occur in the proximal portions of the nephron, whereas fine adjustments tend to occur distally. Modern advances in molecular biology have helped to delineate the role of specific nephron segments in regulating ion and water transport and the diseases that occur as a result of abnormalities in these processes.(2)

Sodium Sodium is essential in maintaining extracellular fluid balance and, thus, volume status. The kidney is capable of effecting large changes in sodium excretion in a variety of normal and pathologic states. There are four main sites of sodium transport. Approximately 60% of sodium is absorbed in the proximal tubule by coupled transport with glucose or amino acids, 25% in the ascending loop of Henle (bumetanide-sensitive sodium-potassium 2 chloride transporter, NKCC2), and 15% in the distal tubule (thiazide-sensitive sodium chloride cotransporter, NCCT) and collecting tubule (epithelial sodium channel, ENaC). Under normal circumstances, the urinary excretion of sodium approximates the sodium intake (80-250 mEq/24 hr for an adult who consumes a typical American diet) minus 1-2 mEq/kg/24 hr required for normal metabolic processes. However, in states of volume depletion (e.g., dehydration, blood loss) or decreased effective circulating blood volume (e.g., septic shock, hypoalbuminemic states, or congestive heart failure), there may be a dramatic decrease in urinary sodium excretion to as low as 1 mEq/L. Changes in volume status are detected by baroreceptors in the atria, afferent arteriole, and the carotid sinus and by the macula densa, which detects changes in chloride delivery. The major hormonal mechanisms mediating sodium balance include the renin-angiotensinaldosterone (RAA) axis, atrial natriuretic factor (ANF), and norepinephrine. Angiotensin II and aldosterone increase sodium reabsorption in the proximal tubule and distal tubules, respectively. Norepinephrine, released in response to volume depletion, does not directly act on tubular
5

transport mechanisms but impacts on sodium balance by decreasing renal blood flow and thus decreasing the filtered load of sodium, as well as stimulating renin release. With more severe volume depletion antidiuretic hormone (ADH) is also released (see Chapter 522). Sodium excretion is promoted by atrial natriuretic factor (ANF) and suppression of renin.(2)

Potassium Extracellular potassium homeostasis is very tightly regulated, because small changes in plasma potassium concentrations have dramatic effects on cardiac, neural, and neuromuscular function. Essentially all filtered potassium is fully reabsorbed in the proximal tubule. Therefore, urinary excretion of potassium is completely dependent on tubular secretion by potassium channels present in the principal cells of the collecting tubule. Factors that promote potassium secretion include aldosterone, increased sodium delivery to the distal nephron, and increased urine flow rate.(2)

Calcium A significant portion of filtered calcium (65%) is reabsorbed in the proximal tubule. Additional calcium is reabsorbed in the ascending loop of Henle by passive movement between cells (paracellular absorption) in a process driven by sodium chloride reabsorption and potassium recycling into the lumen. Calcium uptake in this nephron segment is regulated by an extracellular calcium receptor (CaR). Factors that promote calcium reabsorption include parathyroid hormone (PTH, released in response to hypocalcemia), thiazide diuretics, and volume depletion. Factors that promote calcium excretion include sodium intake (either orally or by infusion of sodiumcontaining intravenous fluids) and loop diuretics such as furosemide.(2)

Phosphate

The majority of filtered phosphate is reabsorbed in the proximal tubule. Reabsorption is increased by endogenous or exogenous calcitriol (1,25-dihydroxyvitamin D) and inhibited by PTH.(2)

Magnesium

About 25% of filtered magnesium is reabsorbed in the proximal tubule. Modulation of renal magnesium excretion occurs primarily in the ascending loop of Henle, with some contribution of the distal convoluted tubule. Although specific magnesium transporters have been identified, the precise mechanisms by which they are regulated remain unclear.(2)

ACUTE TUBULAR NECROSIS

PATHOPHYSIOLOGY The current understanding of the pathophysiology of acute tubular necrosis (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 metalinduced nephrotoxic ATN.(9) The typical findings in humans include the following: (7)

Patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded basement membrane. Diffuse effacement and loss of proximal tubule cell brush border. 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. Tubular dilatation and intraluminal casts in the distal nephron segments. 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.

The clinical course of ATN may be divided into the following 3 phases (7) Initiation Maintenance Recovery

Initiation phase 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 glomerular filtration rate (GFR) starts to fall, and urine output decreases.(7)

Maintenance phase 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. Acute kidney injury (AKI) due to nephrotoxins is typically nonoliguric. The second phase of ATN usually lasts for 1-2 weeks but may extend to a few months.(7)

Recovery phase The recovery phase of ATN is characterized by polyuria and gradual normalization of the GFR. This 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.(7) In the absence of multiorgan failure, most patients with ATN regain most renal function. 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 significant scientific and technological advances.(7) 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), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF).(7) In animals, exogenous administration of several of these growth factors has been shown to accelerate recovery from ischemic AKI ; however, in a single human trial, IGF-1 did not prove

to be beneficial when given to adults with AKI of various etiologies. Additional human studies with growth factors are currently under way.(7) Heat shock proteins (HSPs) 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.(7) 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.(7)

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ETIOLOGY The following are prevalent causes of ATN in neonates : (10) 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 angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (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.

Causes of ATN in Older Children The following are prevalent causes of ATN in older children :(7) 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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EPIDEMIOLOGY Frequency varies widely, depending on the clinical context. ATN is the most frequent cause of hospital acquired AKI. In adults, prevalence of ATN is approximately 1% at admission, 2-5% during hospitalization, and 4-15% after cardiopulmonary 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%. ATN is more common in neonates than in other pediatric populations because of the high frequency of comorbid conditions.(11)

PROGNOSIS The 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.(7) Mortality rates widely vary according to the underlying cause and associated medical condition. The most common causes of death are sepsis, cardiovascular and pulmonary dysfunction, and withdrawal of life support measures.(7) For patients with community-acquired ATN without other serious comorbid conditions, mortality is approximately 5% and has decreased over the past decades because of the availability of efficient renal replacement therapies.[25] Mortality jumps to 80% in patients in the ICU with multiorgan failure, although death is almost never caused by renal failure.(7) 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.(7)

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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 blood urea nitrogen (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.(7) 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.(7)

Conditions Resulting in Fluid Loss 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 the nephrotic syndrome.(7) 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. Refer to the illustration shown below.(7)

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Medication use 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.(7) 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.(7) 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.(7)

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Conditions associated with 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.(7) 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.(7) Hyperuricosuric ATN is primarily observed during treatment of lymphoproliferative or myeloproliferative malignancies and presents as tumor lysis syndrome.(7)

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.(7)

PHYSICAL EXAMINATION Signs of acute kidney injury (AKI) include hypertension, edema, anemia, and signs of heart failure, 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.(7)

DIFFERENTIAL DIAGNOSIS Although oliguria is a criterion used to diagnose and stage acute kidney injury (AKI), AKI 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.(7)

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Differentials (7) Dehydration Oliguria Renal Cortical Necrosis Tumor Lysis Syndrome

LABORATORY FINDING The following studies are indicated in patients with acute tubular necrosis (ATN): (7) Urinalysis Urinary indexes Blood urea nitrogen (BUN) and serum creatinine Serum electrolytes (sodium, potassium, phosphate, and calcium) Arterial blood gases Complete blood cell count

Although acute kidney injury (AKI) is usually secondary to ischemic or nephrotoxic injury, other causes of intrinsic AKI 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.(7)

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 red blood cells (RBCs). Broad, brown granular casts are typically found in ischemic or nephrotoxic ATN. Heme-positive urine in the absence of erythrocytes in the sediment suggests ATN due to hemolysis or rhabdomyolysis.(7)
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Urinary Indices 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).(7) In prerenal failure, urine specific gravity and the ratio of urine to plasma creatinine levels are high, and the urinary sodium concentration is low (see Table, below). In contrast, the urine in ATN is isosthenuric with a low urine-to-plasma creatinine ratio and high urine sodium concentration.(7) The fractional excretion of sodium (FENa) is the percentage of filtered sodium that is excreted. It is easily calculated 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.(7) 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 (see Table, below).(7) Table : Urinary Indexes in Acute Tubular Necrosis vs Prerenal Failure (7) ATN Urine specific gravity Urine sodium (mEq/L) Urine/plasma creatinine FENa (%) 1010 >40 < 20 >2 Prerenal >1020 < 10 >40 <1

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Measurement of Blood Urea Nitrogen and Serum Creatinine Levels The hallmark of established AKI 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-to-creatinine ratio is usually around 10, as opposed to a ratio of more than 20 that is commonly observed in prerenal failure (due to enhanced proximal tubular reabsorption of urea). However, the BUN-to-creatinine ratio may be misleading in patients whose conditions are wasting or in infants with physiologically low muscle mass.(12) Elevations of BUN can also result from steroid therapy, parenteral nutrition, gastrointestinal (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.(7) Serum creatinine is the current criterion standard for the diagnosis of AKI. However, important limitations have been noted, as follows: (7) First, serum creatinine levels can widely vary with age, sex, lean muscle mass, muscle metabolism, and hydration status. Second, serum creatinine levels may not change until about 50% of kidney function has been lost. Third, at lower glomerular filtration rates (GFRs), the amount of tubular secretion of creatinine results in overestimation of renal function. Finally, during acute changes in glomerular filtration, serum creatinine does not accurately depict kidney function until steady-state equilibrium has been reached, which may require several days. In the future, defining AKI by either a predictive biomarker of kidney damage or a sensitive measure of decrease in kidney function may be appropriate. Fortunately, novel biomarkers are currently undergoing evaluation and validation.(13,14)

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Determination of Serum Electrolyte Concentrations Hyponatremia is a common finding in ATN and is usually dilutional secondary to fluid retention and administration of hypotonic fluids.(7) 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 promptly and aggressively treated, primarily because of its depolarizing effect on cardiac conduction pathways.(7) 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.(7) Hypocalcemia results predominantly from hyperphosphatemia and impaired absorption of calcium from the GI tract because of inadequate 1,25-hydroxyvitamin D3 production by the diseased kidneys. Severe hypocalcemia results in tetany, seizures, and cardiac arrhythmias.(7) 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.(7) Hypomagnesemia is a prominent finding in nephrotoxic ATN, particularly associated with gentamicin, amphotericin B, cisplatinum, or pentamidine administration.(7)

Evaluation of 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

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to the metabolic acidosis. Severe acidosis can develop in children who are hypercatabolic (shock, sepsis) or who have inadequate respiratory compensation.(7)

Complete Blood Cell 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, because it can result in hemoglobinuric ATN. These patients usually display elevated serum lactate dehydrogenase levels.(7) Microangiopathic hemolytic anemia with schistocytes and thrombocytopenia are indicative of possible hemolytic-uremic syndrome (HUS), which is an important cause of intrinsic ARF in children. Prolonged ATN also can result in bleeding due to dysfunctional platelets.(7)

Tests for Rhabdomyolysis and Tumor Lysis Syndrome 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 also usually display marked increases in serum potassium and phosphate.(7) In the tumor lysis syndrome following cancer chemotherapy, a marked elevation in serum uric acid occurs along with hyperkalemia and hyperphosphatemia.(7)

Determination of Serum Nephrotoxin levels Serum levels of nephrotoxins should be determined and serially followed, particularly when using gentamicin, vancomycin, cyclosporine, or tacrolimus.(7)

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Renal Ultrasonography Ultrasonography 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.(7) Ultrasonography 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.(7) Congenital disorders, such as polycystic kidney disease and multicystic dysplasia, are easily detected, and calculi and tumors are also evident. Hydronephrosis is suggestive of urinary tract obstruction, and accompanying hydroureter and a thickened bladder wall are consistent with bladder outlet obstruction. A Doppler study is important in the evaluation of vascular obstruction.(7)

Radionuclide Scanning 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 post transplant period, when scans can help differentiate between ATN and transplant rejection.(15)

Electrocardiography Perform electrocardiography (ECG) if hyperkalemia is suspected or detected by laboratory tests. The following are sequential ECG changes in hyperkalemia: (7) Tall peaked T waves
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Prolongation of PR interval Widening of QRS complex ST segment changes Ventricular tachycardia Terminal ventricular fibrillation

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, renal biopsy findings may be valuable in establishing the diagnosis, guiding therapy, and assessing prognosis. Renal biopsy findings may be also useful in the immediate post transplant period for differentiating between ATN and acute rejection.(7)

Histologic Findings Typical histologic findings in ATN include the following: (7) Patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded basement membrane Diffuse effacement and loss of proximal tubule cell brush border 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 the loop of Henle are located Tubular dilatation and intraluminal casts in the distal nephron segments 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.

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TREATMENT
Recognition of the circumstances that place children at risk for acute tubular necrosis (ATN) and institution of corrective measures may prevent the development of this disorder. Treatment of pediatric patients with ATN requires correction of imbalances in fluid volume, electrolytes, and acid-base balance. Children with ATN who are hemodynamically unstable or require acute dialysis should be transferred to an intensive care unit (ICU).(7)

Fluid Management
The major goal of fluid management is to restore and maintain intravascular volume. ATN may manifest itself 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 fractional excretion of sodium (FENa).(7) 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.(7) 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 such cases, consider fluid removal by dialysis or hemofiltration, especially if signs of pulmonary edema are evident.(7) 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
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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.(7)

Correction of Electrolyte Abnormalities and Acid-Base Imbalance

ATN may lead to hyperkalemia, hyponatremia, hyperphosphatemia, hypocalcemia, and metabolic acidosis.(7) Hyperkalemia 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.(7) When serum potassium exceeds 6.5 mEq/L or tall peaked T waves are evident on the ECG, emergency treatment of hyperkalemia is indicated. 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 potassium level. Such therapy should be used with caution because it can precipitate hypocalcemia and sodium overload.(7) 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.(7) The presence of electrocardiographic (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.(7)
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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.(7) Hyponatremia The primary treatment of hyponatremia is free water restriction. Patients with a serum sodium level below 120 mEq/L may require hypertonic (3%) sodium chloride infusion, especially if central nervous system (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.(7) Hyperphosphatemia and hypocalcemia 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.(7) Metabolic acidosis 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.(7) Bicarbonate administration may precipitate hypernatremia or hypocalcemia. Children who cannot tolerate a large sodium load (ie, those with heart failure) may be treated in an ICU setting with intravenous tromethamine (THAM), pending institution of dialysis.(7)

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

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severity of the abnormality to be corrected. Common indications for dialysis in ATN are as follows: (16) 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 )

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.(16) Hemodialysis has the distinct advantage of rapid correction of fluid, electrolyte, and acidbase imbalances, and it 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.(16) 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 is generally recommended in children with AKI, although not all studies have documented beneficial effects.(16) Continuous venovenous hemofiltration (CVVH) has emerged as an alternative therapy primarily for children with ATN who require fluid removal and 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
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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. (16) Some concern remains that dialysis may actually 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.(16)

Adjustment of Medications
Avoid nephrotoxic agents, as they may worsen the renal injury and delay recovery of function. Such agents include contrast media, aminoglycosides, and nonsteroidal antiinflammatory drugs (NSAIDs).(7) 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 glomerular filtration rate (GFR) of less than 10 mL/min, irrespective of the serum creatinine value.(7)

Administration of Calcium Channel Blockers

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.(7) 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 AKI following cadaveric
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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.(7) In addition, CCB administration prior to radio contrast 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.(7)

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.(7)

Dietary Measures
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. Children who are nauseous or anorexic may benefit from parenteral feedings or intravenous hyperalimentation.(7) 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. If adequate nutrition cannot be achieved because of fluid restriction, consider early institution of ultrafiltration or dialysis.(7)

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Restriction of Activity
Children with ATN are usually hospitalized, and activity is restricted; however, strict bed rest does not accelerate recovery.(7)

Consultations
Children with ATN are best treated in a tertiary care institution with pediatric nephrology consultants.(7)

PREVENTION OF ACUTE TUBULAR NECROSIS

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, radio contrast administration, amphotericin B therapy, and cisplatin infusion.(17) 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 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.(17) 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 acute kidney injury (AKI), they may convert an oliguric to a nonoliguric AKI, which is more easily managed because it eliminates the need for fluid restriction and allows for maximal nutritional support.(17)

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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.(17)

MEDICATION Diuretic treatment may convert oliguric acute tubular necrosis (ATN) to nonoliguric ATN, although diuretics do not appear to alter the course of acute kidney injury (AKI).(7) Hyperkalemia in 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 intravenous (IV) calcium.(7) 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.(7)

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.(7)

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Furosemide (Lasix) Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. It is used for ATN prevention in children with oliguria duration less than 48 hours who have not responded to adequate hydration. It may also be considered for oliguria in the presence of volume overload. Furosemide is also used for hyperkalemia to increase potassium excretion in the urine.(7)

Alkalizing agents

Intravenous sodium bicarbonate 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.(7) Sodium bicarbonate Sodium bicarbonate is used to treat hyperkalemia. It causes a rapid shift of potassium into cells. The magnitude of the potassium intracellular shift varies; thus, bicarbonate is not reliable in lowering the potassium level by itself. It is also used emergently to manage severe metabolic acidosis.(7) Sodium citrate (Bicitra, Oracit) Sodium citrate manages mild metabolic acidosis and is used as an alkalinizing agent when long-term maintenance of an alkaline urine is desirable.(7)

Myocardium stabilizers

Intravenous calcium is primarily used to protect the myocardium from the deleterious effects of hyperkalemia (ie, arrhythmias) by antagonizing the potassium actions on the myocardial cell membrane. It does not lower serum potassium levels.(7)
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Calcium gluconate (Kalcinate) Calcium gluconate is given intravenously to provide myocardial protection from hyperkalemia. It is indicated if hyperkalemia is accompanied by ominous electrocardiographic (ECG) changes beyond peaked T waves or if ECG changes persist after bicarbonate therapy.(7)

Intracellular transporters

Insulin and glucose (dextrose) cause a transcellular shift of potassium into muscle cells, thereby lowering (temporarily) potassium serum levels.(7) Dextrose and insulin infusion Dextrose and insulin infusion is used as an adjunct to bicarbonate therapy to promote intracellular shift of potassium.(7)

Exchange resins

Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-tomoderate hyperkalemia. Each 1 mEq of potassium is exchanged for 1 mEq of sodium.(7) Sodium polystyrene sulfonate (Kayexalate) Sodium polystyrene sulfonate is indicated in all cases of hyperkalemia because it is the only modality (other than diuretics and dialysis) that actually removes excessive potassium from the body. It exchanges sodium for potassium and binds it in the gut, primarily in the large intestine, and decreases total body potassium. Its onset of action after oral administration ranges from 2-12 hours and is longer when rectally administered.(7)

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Phosphate binders

ATN is frequently complicated by hyperphosphatemia and hypocalcemia, which respond to calcium-containing oral phosphate binders.(7) Calcium carbonate (Oystercal, Caltrate) Calcium carbonate combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in feces.(7)

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1. Gray H. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918; Bartleby.com, 2000. www.bartleby.com/107/. 2. Kliegman R, Nelson W. Nelson Textbook of Pediatric. 19th ed. Philadelphia : Elsevier & Saunders; 2011:1757-58.. 3. American Society of Nephrology. American Society of Nephrology Renal Research Report. J Am Soc Nephrol. Jul 2005;16(7):1886-903. 4. Andreoli SP. Management of acute renal failure. In: Barratt TM, Avner ED, Harmon W, eds. Pediatric Nephrology. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1999:1119-34. 5. Devarajan P, Goldstein SL. Acute renal failure. In: Kher KK, Schnaper HW, Makker SP. Clinical Pediatric Nephrology. 2nd ed. Oxon, UK: Informa Healthcare; 2007:363376. 6. Warnock DG. Towards a definition and classification of acute kidney injury. J Am Soc Nephrol. Nov 2005;16(11):3149-50. 7. Devarajan P, Langman C. Pediatric Acute Tubular necrosis. 2010. Cited from : http://emedicine.medscape.com/article/980830 8. Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for change?. J Am Soc Nephrol. Aug 2003;14(8):2178-87. 9. Devarajan P. Update on Mechanisms of Ischemic Acute Kidney Injury. J Am Soc Nephrol. Jun 2006;17(6):1503-1520. 10. Devarajan P. Cellular and molecular derangements in acute tubular necrosis. Curr Opin Pediatr. Apr 2005;17(2):193-9. 11. Chertow GM, Burdick E, Honour M, et al. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. Nov 2005;16(11):3365-70.
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12. Rabb H, Colvin RB. Case records of the Massachusetts General Hospital. Case 31-2007. A 41-year-old man with abdominal pain and elevated serum creatinine. N Engl J Med. Oct 11 2007;357(15):1531-41. 13. Devarajan P. The future of pediatric acute kidney injury management-biomarkers. Semin Nephrol. Sep 2008;28(5):493-8. 14. Parikh CR, Devarajan P. New biomarkers of acute kidney injury. Crit Care Med. Apr 2008;36(4 Suppl):S159-65. 15. Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. Nov 13-19 2004;364(9447):1814-27. 16. Himmelfarb J, Tolkoff Rubin N, Chandran P, et al. A multicenter comparison of dialysis membranes in the treatment of acute renal failure requiring dialysis. J Am Soc Nephrol. Feb 1998;9(2):257-66. 17. Lameire NH, De Vriese AS, Vanholder R. Prevention and nondialytic treatment of acute renal failure. Curr Opin Crit Care. Dec 2003;9(6):481-90.

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