Pediatric Acute Tubular Necrosis Treatment & Management

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).^{[33, 34, 35, 36, 37, 38]}

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).

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 such cases, consider fluid removal by dialysis or hemofiltration,^[39] 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.

ATN may lead to hyperkalemia, hyponatremia, hyperphosphatemia, hypocalcemia, and metabolic acidosis.

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.

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.

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 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.

The definitive therapy for significant hyperkalemia in oliguric ATN frequently includes dialysis (see Dialysis, below). The forms of therapy outlined above serve to tide over the crisis while arrangements are being made for dialysis.

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.

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.

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.

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.

The goal of dialysis is to remove endogenous and exogenous toxins and to maintain fluid, electrolyte, and acid-base balance until renal function returns.^{[40, 41]} 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. Common indications for dialysis in ATN are as follows:

• 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.

Hemodialysis has the distinct advantage of rapid correction of fluid, electrolyte, and acid-base 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.

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 ARF, although not all studies have documented beneficial effects.^{[40, 41]}

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.^{[42, 39]} 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 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.

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

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.

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.

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.

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.

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

Children with ATN are best treated in a tertiary care institution with pediatric nephrology consultants.

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.^{[43, 44, 45]}

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.

Several studies, albeit uncontrolled, suggest that diuretics may be beneficial when administered during the early phase of ATN.^[43] Although they do not appear to alter the course of the acute renal failure (ARF), they may convert an oliguric to a nonoliguric ARF, which is more easily managed because it eliminates 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).^[46] 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.