Rudolph's Pediatrics, 22nd Ed.

CHAPTER 471. Acute Renal Failure

Prasad Devarajan

Acute renal failure (ARF) is classically defined as a rapid decline in glomerular filtration rate (GFR), leading to accumulation of nitrogenous wastes such as blood urea nitrogen (BUN) and creatinine. ARF is a common condition, associated with serious consequences and unsatisfactory therapeutic options.1-18 Oliguria, defined as a urine output of less than 0.5 ml/kg/hour, is an important clinical sign but occurs in only about half the cases. ARF may be classified as (1) prerenal azotemia, due to a functional response of structurally normal kidneys to hypoperfusion; (2) intrinsic ARF, due to structural damage to the kidneys from prolonged ischemia, nephrotoxins, sepsis, or intrinsic renal disease; and (3) postrenal ARF, due to obstruction of the urinary tract.

Prerenal azotemia is usually rapidly reversed by restoration of renal perfusion, but early treatment is essential in order to prevent the progression to intrinsic ARF. Once established, there is no effective treatment for ARF, and the clinician can provide only supportive care with dialysis. While the worst outcomes are encountered in patients requiring dialysis, even mild degrees of ARF, such as occurs with only a small increases in serum creatinine, is predictive of an increase in mortality and morbidity rate, irrespective of the underlying cause.19-22


Pediatric studies from the 1980s and 1990s report hemolytic uremic syndrome, other primary renal causes, and infections as the most prevalent causes leading to acute renal failure (ARF).23 More recent studies in developed countries show a dramatic shift in the epidemiology of ARF such that it is primarily a hospital-acquired illness, with the most common causes being renal ischemia, nephrotoxin use, congenital heart disease, bone marrow transplantation, and sepsis.24,25 In contrast, in the undeveloped world of Africa and tropical Asia, children are most likely to develop ARF secondary to gastroenteritis, septicemia, acute glomerulonephritis, or falciparum malaria. Hemolytic uremic syndrome and leptospirosis are common in Latin America, and ARF due to snakebites is often encountered in rural Asia.

Hospital-acquired pediatric ARF rates are escalating at an alarming rate, over ninefold from the 1980s through 2004.26 The incidence of the most severe forms of ARF, defined by dialysis requirement, ranges from 1% to 2% of all critically ill children.26,27 When less strict criteria for ARF are used, such as doubling of serum creatinine, the incidence rises to 21% of children in intensive care units.28 The incidence jumps to 82% in critically ill children who receive invasive mechanical ventilation and at least one vasoactive medication.28 ARF also complicates up to 24% of neonatal intensive care unit admissions and is present in 60% of neonates with severe asphyxia.29 Approximately 40% of patients with sepsis develop ARF, with 20% requiring dialysis.7

In children undergoing cardiopulmonary bypass, the incidence of ARF is in the range of 10% to 40%, depending on the definition used.30-34 In children receiving stem cell transplants, the incidence of ARF (defined by doubling of serum creatinine) is about 20%.35



Prerenal acute renal failure (ARF), or azotemia, is an appropriate functional response of structurally normal kidneys to hypoperfusion. The oliguria in this situation represents a renal mechanism for preserving intravascular volume. Table 471-1 lists the common causes of prerenal azotemia. A reduction in circulatory volume evokes a systemic response aimed at normalizing intravascular volume at the expense of glomerular filtration rate (GFR). Baroreceptor-mediated activation of the sympathetic nervous system and renin-angiotensin axis results in afferent renal vasoconstriction and the consequent reduction in GFR (Fig. 471-1). However, in response to renal hypoperfusion, several intrarenal autoregulatory mechanisms help maintain GFR (Fig. 471-2). Prolonged reduction in renal perfusion pressure (eg, due to dehydration or systemic hypotension) can overwhelm these compensatory mechanisms, and intrinsic ARF can ensue.

Table 471-1. Causes of Acute Renal Failure

The most effective compensatory mechanism involves the intrarenal generation of vasodilatory prostaglandins that dilate the afferent arterioles.36 Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit this response and can precipitate ARF, especially in the presence of decreased circulatory volume.37 Small children who are febrile and then become dehydrated are at particular risk for developing ARF when treated with NSAIDs unless hydration is maintained when these drugs are used. A second mechanism results from a differential in the constrictor effect of angiotensin II on the efferent versus afferent arteriole. Angiotensin II constricts both the afferent and efferent arteriole, but this effect is more marked in the efferent arteriole, leading to increased hydrostatic pressure across the glomerulus and maintenance of GFR.38 Angiotensin-converting enzyme inhibitor (ACEI) therapy can interfere with this compensatory mechanism. If patients taking ACEIs become dehydrated, GFR will decline and ARF can develop. A third mechanism, termed myogenic autoregulation, refers to the unique ability of the afferent arterioles to rapidly vasodilate in response to a decrease in lateral stretch caused by hypoperfusion. Immunosuppressant medications commonly used in patients after kidney transplantation (eg, cyclosporine) can interfere with the myogenic mechanism.

FIGURE 471-1. Pathophysiological mechanisms leading to decreased glomerular filtration rate (GFR) in prerenal acute renal failure. Baroreceptor-mediated activation of the sympathetic nervous system and renin-angiotensin axis results in afferent renal vasoconstriction and a resultant reduction in GFR.

FIGURE 471-2. Renal compensatory mechanisms that maintain glomerular filtration rate (GFR) in prerenal acute renal failure. Intrarenal generation of vasodilatory prostaglandins and intrinsic myogenic mechanisms dilate the afferent arterioles. This effect combined with a differential greater constrictor effect of angiotensin on the efferent arteriole versus the afferent arteriole leads to an increased hydrostatic glomerular arteriole pressure with a resultant increase in GFR. Iatrogenic interference with these mechanisms can precipitate a reduction in GFR.


Intrinsic acute renal failure (ARF) is most frequently caused by prolonged ischemia, nephrotoxins, or sepsis (Table 471-1) In clinical practice, it is frequently multifactorial, often occurring concomitantly, and there are overlapping pathogenetic mechanisms. Intrinsic ARF is associated pathologically with acute tubular necrosis (ATN); therefore, the terms intrinsic ARF and ATN are often used interchangeably. However, ATN is a misnomer, since frank tubular cell necrosis is rarely found in human ARF. Instead, there is effacement and loss of proximal tubule brush border, patchy loss of tubule cells, focal proximal tubular dilatation and distal tubular casts, and areas of cellular regeneration. Necrotic cell death is restricted to the highly susceptible outer medullary regions (the S3 segment of the proximal tubule and medullary thick ascending limb of Henle’s loop). More recently, apoptosis has been reported in both distal and proximal tubules, in both ischemic and nephrotoxic forms of human ARF.40,41 In addition, peritubular capillaries in the outer medulla have been shown to display a striking vascular congestion and leukocyte accumulation.42-47The mechanisms underlying these morphological changes are detailed below.

There is evidence for hemodynamic alterations in intrinsic ARF. Total renal blood flow is reduced to about 50% of normal due to persistent intense renal vasoconstriction, as shown in Figure 471-3. Cellular mechanisms underlying these hemodynamic alterations relate primarily to endothelial damage.43-46 This leads to a local imbalance of vasoactive substances, including enhanced release of the vasoconstrictor endothelin and reduced release of vasodilatory endothelium-derived nitric oxide. However, these hemodynamic abnormalities do not account for the profound loss of renal function, and several human trials of vasodilators such as dopamine have failed to demonstrate improvement in GFR in established ARF despite augmentation of total renal blood flow.48

Proposed alterations in tubular dynamics in established ARF include obstruction, back-leak, and activation of tubuloglomerular feedback. Their interplay is illustrated in Figure 471-3. It is unlikely that obstruction alone can account for the profound dysfunction in clinical ARF, since human studies using forced diuresis with furosemide or mannitol do not show an impact on the survival and renal recovery rate of patients with established ARF.49,50Similarly, although movement of the glomerular filtrate back into the circulation has been shown to occur, this accounts for only a very minor component of the decrease in glomerular filtration rate (GFR) in human ARF.

The role for activating tubuloglomerular feedback is controversial.

In injured kidney tubule cells, a rapid and profound reduction in intracellular ATP content occurs, which triggers several metabolic events (see eFig. 471.1 ).

There is now substantial evidence for the role of reactive oxygen species in the pathogenesis of ARF.55 During reperfusion, hydrogen peroxide and superoxide are generated in tubule cells. In the presence of iron, hydrogen peroxide forms the highly reactive hydroxyl radical. Several scavengers of reactive oxygen molecules protect against ARF in animals, but human studies have been inconclusive. Two major advances have recently emerged in the area of iron chelation. The first is the availability of human apotransferrin, an iron-binding protein, which protects against renal ischemia-reperfusion injury in animals by abrogating renal superoxide formation.56 The second is the discovery of neutrophil gelatinase-associated lipocalin (NGAL), an endogenous iron-transporting protein. NGAL is one of the most highly induced genes and proteins in the kidney following early ischemic and nephrotoxic injury.57Exogenous administration of NGAL provides significant functional protection in animal models of ARF.58 The potential use of these endogenous agents in human ARF is currently under investigation.

FIGURE 471-3. Pathophysiological mechanisms leading to decreased glomerular filtration rate in intrinsic acute renal failure.

The tubule cell’s biological response to acute injury is multifaceted and includes loss of cell polarity and brush borders, cell death, dedifferentiation of viable cells, proliferation, and restitution of a normal epithelium (see eFig. 471.2 ).

Following kidney injury, the mode of tubule cell death depends primarily on the severity of the insult and the resistance of the cell type. Necrosis occurs following more severe injury and in the more susceptible proximal tubules, whereas apoptosis predominates after less severe injury and especially in the ischemia-resistant distal nephron segments. Considerable attention has recently been directed toward unraveling the molecular pathways involved in renal tubule cell apoptosis (eFig. 471.3 ).1,11 Inhibition of apoptosis holds promise in ARF.

Renal tubule cells possess a remarkable ability to regenerate and proliferate after acute injury.72 Understanding the molecular mechanisms of repair may provide clues toward accelerating recovery from ARF. The potential use of progenitor cells and stem cells as therapeutic strategies in ARF is currently in the initial stages of investigation.74,75

Inflammation plays an important role in the pathogenesis of ARF. The major components of this response include endothelial injury, leukocyte recruitment, and production of inflammatory mediators by tubule cells (eFig. 471.4 ).

Strategies that modulate the inflammatory response may provide significant beneficial effects in human ARF.


Postrenal ARF is a result of bilateral obstruction of the outflow tracts and is uncommon beyond the neonatal period. Postrenal azotemia is usually reversed by relief of the obstruction but is accompanied by a very significant postobstructive diuresis. The common causes of postrenal ARF are listed in Table 471-1.


Acute renal failure most commonly presents with a progressive accumulation of nitrogenous wastes in a predisposed patient. Less frequently, one encounters an unexplained rise in blood urea nitrogen (BUN) and creatinine. The evaluation of patients requires a complete history, physical examination, laboratory evaluation, renal imaging, and (very rarely) a kidney biopsy. It is important to recognize that early in the course of acute renal failure (ARF), changes in BUN and creatinine do not provide an accurate reflection of renal function. Despite the characteristically precipitous reduction in glomerular filtration rate that occurs in ARF, the BUN usually rises by only about 20 mg/dl per day and the serum creatinine by 1 to 2 mg/dl per day, until the values reach a steady state that more accurately represents the actual degree of renal dysfunction. This relationship is important from several perspectives: (1) it distinguishes ARF from chronic renal failure (CRF), since the BUN and creatinine in CRF do not progressively increase but display a steady high value; (2) the timing of the original insult that leads to the development of ARF can be estimated; and (3) the BUN and serum creatinine are delayed and unreliable biomarkers of ARF. In the case of BUN, an increase can be encountered in the absence of ARF, especially in patients undergoing steroid therapy, total parenteral nutrition, and bleeding within the gastrointestinal tract. For serum creatinine measurements, even normal individuals can display significant variations, depending on age, diet, medications, hydration status, muscle mass, and muscle metabolism. Furthermore, a substantial loss of GFR may occur before an increase in serum creatinine can be measured.

In patients with suspected ARF, the diagnostic evaluation is directed toward identifying the underlying cause, distinguishing between prerenal and intrinsic ARF, and discriminating between ARF and chronic renal failure (CRF).


A detailed history and physical examination directed toward the salient aspects listed in Table 471-2, combined with a careful urinalysis, will yield the etiology of ARF in the majority of cases. Typically, the urine in prerenal azotemia contains only a few hyaline and fine granular casts, with little protein or blood. In contrast, proteinuria and hematuria are prominent in intrinsic ARF. Heme-positive urine in the absence of RBCs in the sediment suggests hemolysis or rhabdomyolysis. Urine microscopy reveals dysmorphic RBCs in primary glomerular disease and reveals WBCs in pyelonephritis or interstitial nephritis. Broad brown granular casts are typically encountered in ischemic or toxic ATN, whereas RBC casts are characteristic of acute glomerulonephritis, and WBC casts indicate interstitial nephritis or pyelonephritis.


This distinction is based on the principle that prerenal azotemia is associated with maximal reabsorption of solutes and water by the intact proximal tubule, whereas the tubule cell damage typical of intrinsic ARF results in impaired reabsorptive capacity of the proximal tubule. Urinary indices based on this principle are shown in Table 471-3. The fractional excretion of sodium (FENa) is reportedly the most accurate in making this distinction. It is calculated from measured concentrations of sodium (Na) and creatinine (Cr) in the urine (U) and plasma (P), as follows:

Table 471-2. Evaluation of Acute Renal Failure


Fluid loss

Diarrhea, vomiting




Nephrotoxic agents

Nonsteroidal anti-inflammatory drugs


Contrast agents

Glomerular disease

Streptococcal infection (poststreptococcal glomerulonephritis)

Bloody diarrhea (hemolytic-uremic syndrome)

Fever, joint complaints, rash (systemic lupus erythematosus)


Complete anuria

Poor urinary stream

Physical Signs

Signs of intravascular volume depletion

Signs of ARF (edema, hypertension)

Signs of underlying renal disease

Butterfly rash, joint swelling (systemic lupus erythematosus)

Purpuric rash (Henoch-Schonlein purpura)

Fever, macular rash (interstitial nephritis)

Palpably enlarged kidneys (polycystic/multicystic kidney disease, renal vein thrombosis)

Signs of obstruction

Poor urinary stream

Palpably enlarged bladder

Therapeutic catheterization

FENa = ([U/P]Na)/([U/P]Cr) × 100

In prerenal ARF, the FENa is typically less than 1, whereas it is greater than 3 in intrinsic ARF. Interpretation of these indices must take into account any abnormal presence of substances in the urine such as protein, glucose, mannitol, contrast agents, and diuretic therapy. By the same principle of increased solute reabsorption, the BUN/creatinine ratio in the serum is markedly elevated (> 20) in prerenal azotemia.


A kidney and bladder ultrasound is a sensitive, noninvasive modality that can differentiate between acute renal failure (ARF) and chronic renal failure (CRF) and that can rule out a postrenal etiology. Typically, the kidneys in ARF are normal or enlarged, with increased echogenecity, whereas those in CRF are frequently small and shrunken. Other distinguishing features are shown in Table 471-3.

Table 471-3. Distinguishing Type of Acute Renal Failure (ARF)*


Common complications of acute renal failure are listed in Table 471-4. Hyponatremia is a common laboratory finding and is usually dilutional (secondary to fluid retention and administration of hypotonic fluids) but can be due to sodium depletion or associated hyperglycemia (see Chapter 466). Hypernatremia in ARF is usually a result of excessive sodium administration (inappropriate fluid therapy or overzealous sodium bicarbonate administration). Hyperkalemia is due to the reduction in glomerular filtration rate (GFR) and in tubular secretion, increased catabolism, and metabolic acidosis (each 0.1 unit reduction in arterial pH raises serum potassium by 0.3 mEq/L). Hyperkalemia is most pronounced in patients with excessive endogenous production (rhabdomyolysis, hemolysis, and tumor lysis syndrome). Symptoms are nonspecific and may include malaise, nausea, and muscle weakness. EKG changes should be looked for in all patients suspected of having hyperkalemia (see Chapter 466). A high anion gap metabolic acidosis is common and is secondary to the impaired renal excretion of acid and the impaired reabsorption and regeneration of bicarbonate. Hypocalcemia in ARF is due to increased serum phosphate and impaired renal conversion of vitamin D to the active form. Hypocalcemia is most pronounced in patients with rhabdomyolysis. Metabolic acidosis increases the fraction of ionized calcium (the active form). Therefore, overzealous bicarbonate therapy can decrease the concentration of ionized calcium and precipitate symptoms of hypocalcemia, including tetany, seizures, and cardiac arrhythmias. Hyperphosphatemia is primarily due to impaired renal excretion and can aggravate the hypocalcemia. During recovery from ARF, the vigorous diuretic phase may be accompanied by significant volume depletion, hypernatremia, hypokalemia, and hypophosphatemia.

The genesis of nonrenal complications is complex, and ARF per se is a major risk factor for their development. The accumulation of unidentified “uremic toxins” is postulated to play a major role in the cardiac, pulmonary, gastrointestinal, neuropsychiatric, and infectious disturbances. ARF is also clearly associated with an increase in mortality rate, irrespective of the underlying cause.19-22 A long-held concept that patients died “with” and not “from” ARF has recently been challenged.77-82 Even small increases in serum creatinine, much less than would be considered indicative of the need for dialysis, are now recognized as contributing to poor outcomes. In adults, an increase in serum creati-nine of only 0.3 mg/dL was associated with increased mortality, even when outcome was controlled for significant patient comorbidity.8 Similar results were noted in pediatric patients with acute decompensated heart failure, in whom a 0.3-mg/dL or greater rise in serum creatinine demonstrated a sevenfold increased mortality risk.78 These findings highlight the need for a focus on earlier detection and treatment of ARF, well before the serum creatinine begins to rise and other nonrenal complications ensue.

Table 471-4. Complications of Acute Renal Failure



Metabolic acidosis





Pulmonary edema

Cardiac arrhythmias


Myocardial infarction








Gastrointestinal ulcers


Altered mental status







Bleeding (platelet dysfunction)




Infected intravenous (IV) sites



Acute renal failure (ARF) associated with intravascular volume depletion requires prompt and vigorous fluid resuscitation with normal saline (20 ml/kg over 30 to 60 minutes, repeated twice if necessary). This should result in urine output within about 4 hours; if not, the bladder should be catheterized to confirm the anuria. Potassium is contraindicated until urine flow is well established and the serum potassium begins to normalize. Patients who are oliguric should be provided with fluids to equal insensible water loss plus replacement of output. Oliguria with fluid overload is managed with fluid restriction and diuretics. Resistance to diuretics (typical of intrinsic ARF) may necessitate dialysis. Aggressive nutritional support is crucial to enhance the recovery process. Adequate calories to account for maintenance requirements and supplemental calories to combat excessive catabolism should be administered by oral, enteral, or parenteral routes as appropriate. If adequate nutrition cannot be achieved because of fluid restriction, early institution of dialysis should be strongly considered. The management of fluid and electrolyte disorders, especially hyperkalemia, is discussed in Chapter 466.


Nephrotoxic agents should be avoided in ARF, as they may worsen the injury and delay recovery of function. The dose of all medications should be adjusted based on residual renal function. Importantly, patients with ARF in the early phase of a rising creatinine should be assumed to have a GFR of less than 10 ml/min, regardless of the absolute value of the serum creatinine, since this value may not reflect actual renal function.


The common indications for acute dialytic therapy in ARF include (1) fluid overload that is unresponsive to diuretics or is a hindrance to adequate nutrition; (2) hyperkalemia that is unresponsive to nondialytic therapy; (3) refractory hypertension; and (4) symptomatic uremia, including pericarditis, pleuritis, and neurological symptoms. The choices available include hemo-dialysis (HD), peritoneal dialysis (PD), and continuous renal replacement therapy (CRRT). The choice of dialysis modality depends on the patient’s clinical status, the physician’s expertise, and the availability of appropriate resources. Hemodialysis requires central vascular access, specialized equipment and technical personnel, anticoagulation (except in patients with coagulopathy), and the ability to tolerate a large extracorporeal volume. Critically ill patients frequently require pressor support for effective hemodialysis. The advantage of hemodialysis in the setting of ARF lies in its ability to rapidly correct imbalances in fluid, electrolyte, and acid-base status.

The advantages of peritoneal dialysis include ease of performance and no requirement for specialized equipment, personnel, or systemic anticoagulation. Peritoneal dialysis is frequently the preferred therapy for neonates and small infants. Accurate ultrafiltration and blood flow rates are crucial for pediatric CRRT, since the extracorpo-real circuit volume can comprise more than 15% of a child’s total blood volume. Small inaccuracies in ultrafiltration may represent a large percentage of the patient’s total body water. The advent of hemofiltration machines with volumetric control allowing for accurate ultrafiltration flows has led to an increased use of CRRT compared to peritoneal dialysis as the preferred modality for treating pediatric ARF, especially in the intensive care setting. CRRT is especially useful in the presence of hemodynamic instability and multiorgan dysfunction, since it allows for gentle, continuous management of fluid overload.


Children who appear to recover from ARF secondary to hemolytic-uremic syndrome exhibit a 10% to 25% rate of progression to chronic renal insufficiency or end-stage renal failure.79 Long-term follow-up of premature infants with neonatal ARF has shown a 45% rate of renal insufficiency.80 In children who had an episode of ARF, 34% had either reduced kidney function or were dialysis-dependent upon hospital discharge.24 Long-term (3 to 5 years) follow-up of children who survived an episode of ARF found patient survival to be 57%, with the majority of mortality occurring within 2 years of the ARF episode.81 In addition, approximately 60% of the patients studied in a follow-up clinic visit demonstrated evidence of chronic kidney disease. Collectively, these data strongly suggest that long-term follow-up is warranted for children who survive an ARF episode.


Taking fluids and avoiding hypotension and nephrotoxins appear to be the most effective strategies in preventing ARF in critically ill patients. Vigorous fluid administration has been successfully employed to prevent ARF in patients at high risk, including those who have undergone cardiac surgery or renal transplantation; those with hemoglobinuria, myoglobinuria, early tumor lysis syndrome; and those who received nephrotoxic agents such as radio-contrast, cisplatin, and amphotericin. Adjunctive pharmacological agents for the prevention of ARF, including diuretics and “renal dose” dopamine, are still widely used in the intensive care setting, even though they have been shown to be ineffective and perhaps even deleterious.53,54 Administering these agents early in the course of ARF does not alter the natural history of the disease but can potentially convert the syndrome from an oliguric to a nonoliguric form, therefore simplifying fluid, electrolyte, and nutritional therapy. One common and reasonably safe clinical approach is to use high-dose furosemide (2 to 5 mg/kg per dose bolus followed by a continuous drip) for oliguria of less than 48 hours’ duration that has not responded to adequate hydration.