Acute Renal Failure

M. Michele Mariscalco

Acute renal failure (ARF) is defined as an abrupt decline in the renal regulation of water, electrolytes, and acid-base balance of a magnitude sufficient to result in the retention of nitrogenous waste. Often, acute oliguria is the earliest sign of impaired renal function. Oliguria in adults is defined as an output of less than 400 mL of urine per day. In infants and children, oliguria is based on body size. Most sources use a urine volume of less than 0.5 mL per kilogram of body weight per hour in infants and urine volumes of less than 500 mL/m²/day in children. The occurrence of nonoliguric renal failure in adults is recognized increasingly. It is thought to be secondary to the increased use of nephrotoxic drugs (in particular, aminoglycosides and nonsteroidal antiinflammatory agents), improved resuscitation, and the improved survival of trauma victims. The pediatric series reflect a very low incidence of nonoliguric renal failure, with most cases occurring in postoperative patients.

In the clinical setting, the terms acute renal failure (ARF) and acute tubular necrosis (ATN) are used interchangeably. ATN was described first during World War II as acute loss of kidney function that occurred in severely injured crush victims. Histologically, patchy necrosis of renal tubules was noted at autopsy. However, subsequent studies have demonstrated that tubular necrosis often is seen only in occasional tubule cells and, in some cases, tubular necrosis is not demonstrated at all. What is clear is that the glomeruli are morphologically normal. In this chapter, ARF is differentiated from reversible vasoconstriction, such as occurs with prerenal azotemia or urinary obstruction (post renal azotemia). Here, ARF will include the entity of ATN, as it often is called in the clinics.

The process of ARF can be divided into three phases:

Initiation phase. Ischemia or a toxin sets in motion a sequence of events that produces an injury to tubular epithelial cells, and glomerular filtration rate (GFR) declines.
Maintenance phase. The GFR remains relatively low for several days or weeks, depending on the severity of the initiating insult.
Recovery phase. Recovery is characterized by gradual and progressive restoration of GFR and tubule function.

During an acute renal injury, both renal vascular and tubular abnormalities occur. Increasing evidence indicates that inflammation also is involved in the pathogenesis of the decreased GFR. With ischemic injury and that due to sepsis, nephron autoregulation occurs. With ischemia, rather than the normal autoregulatory vasodilation that occurs as a result of decreased
renal perfusion, autoregulation appears to be lost, and renal vasoconstriction occurs. Increased vasoconstrictor response to endogenous norepinephrine occurs. In adult patients with sepsis, renal arteriolar vasodilation occurs at a time when perfusion is compromised because of systemic vasodilation. The afferent arteriole may not be responsive to endogenous norepinephrine, leading to decreased transglomerular pressure and ischemia.

With ARF, tubular epithelial injury results in altered reabsorption of solute and water in the proximal nephron. In ARF, proximal tubule brush border membranes and epithelial tubule cells are shed and excreted into the urine, and this debris ultimately can obstruct the lumen. Concomitantly, a loss of tubular integrity occurs. Solute and fluid that should be retained within the tubule lumen leak back across the damaged membrane into the peritubular fluid and eventually into the plasma. The progressive necrosis of epithelial cells can result in the obstruction of some nephrons and the loss of tubular integrity in others. However, the “backleak” hypothesis can account for only about a 10% decrease in GFR in ARF. The other mechanisms for decreased GFR that result from tubular injury remain to be elucidated. Vasoactive compounds, such as the renin-angiotensin-aldosterone system, nitric oxide, vasodilatory prostaglandins, and adenosine, have been implicated as the mediators in this cycle.

EPIDEMIOLOGY

A relative paucity of published reports exists covering ARF in pediatrics. In work by Williams, encompassing the years 1989 to 1998, the age distribution of 125 children with ARF was 37%, younger than 1 year old; 20%, 2 to 4 years old; and 43%, 5 to 15 years old. The overall survival rate was 73%. Survival rates for the three age groups were 60%, 96%, and 80%, respectively. Forty-one percent of the patients received renal replacement therapies. In developing countries, the most common causes of ARF include hemolytic uremic syndrome (HUS, 31%), glomerulonephritis (23%), and postoperative sepsis and ischemic/prerenal events (18% each). In work by Williams from the United States, hemolytic-uremic syndrome (HUS) accounts for only 16% of cases of ARF. The other etiologies include heart surgery (18%), hematologic-oncologic complications (17%), sepsis (15%), ischemic/prerenal causes (5%), pulmonary (3%), and “others” (24%).

The most frequent cause of ARF in newborns is perinatal asphyxia, which results in underperfusion of the kidneys. Other causes in the newborn include hemorrhage, necrotizing enterocolitis, and increased insensible fluid loss through the skin, especially while under radiant warmers and during bilirubin phototherapy. Oliguria does not result from occlusion of the artery, the vein, or the ureter of a single kidney unless the contralateral kidney is absent or not functioning. Renal artery stenosis and renal vein thrombosis are rare findings in children, but they do occur in the newborn period. Usually, renal artery stenosis occurs as a complication of umbilical artery catheterization and presents with hypertension. Renal vein thrombosis should be suspected in neonates with hematuria, proteinuria, or an enlarging abdominal mass. An early ultrasonographic diagnosis is imperative in establishing this diagnosis and other causes of obstruction, such as bilateral ureteral obstruction or bladder outlet obstruction. One should rule out obstruction of these anatomic sites before considering other medical reasons for ARF.

ARF can be caused by renal or other intrinsic events, including small-vessel vasculitis or acute glomerulonephritis caused by connective-tissue disease, poststreptococcal glomerulonephritis, and rapidly progressive glomerulonephritis. Other causes include interstitial nephritis caused by drugs, infection, or cancer. ARF may result from exposure to nephrotoxic antibiotics, heavy metals, solvents, radiographic contrast dyes, intratubular crystals (uric acid or oxalate), or intratubular pigments (hemoglobinuria or myoglobinuria).

HUS is defined by the presence of anemia (hemolysis), thrombocytopenia, and impaired renal function. The most common form has been associated with diarrheal prodromes, especially hemorrhagic colitis, caused by Escherichia coli (O157:H7). In the classic form of the disease, toxins are released by those infectious agents that cause glomerular endothelial damage. A thrombotic microangiopathy develops, with platelet aggregation and fibrin deposition in small vessels of the kidney but also in other sites such as the gastrointestinal tract and central nervous system. Other infectious agents (i.e., Streptococcus pneumoniae, Shigella, and Salmonella, human immunodeficiency virus [HIV]) also have been associated with the development of HUS.

Acute poststreptococcal glomerulonephritis and HUS also occur in adults. Thrombotic thrombocytopenic purpura is a syndrome with features similar to those of HUS. Thrombotic thrombocytopenic purpura occurs in adults to a greater extent than in children. Other clinical syndromes that occur in all ages, but more commonly in adults, include crescentic rapidly progressive glomerular nephritis, renal vasculitic diseases (polyarteritis nodosa, Wegener granulomatosis), and immune-mediated diseases (Goodpasture disease and systemic lupus erythematosus).

Drugs can induce kidney injury in all age groups. Several mechanisms of drug-induced injury have been described. The most common pattern is tubular toxicity, which occurs with many medications, including antibiotics, cisplatinum, certain anesthetics, and radiocontrast agents. Tubular injury may occur either via direct toxicity or via changes in intrarenal blood flow patterns. Acute tubulointerstitial nephritis is characterized by inflammation of the renal interstitium accompanied by interstitial edema and renal tubular injury. Although drugs often are associated with this type of nephritis, it also may be caused by infectious agents. The usual toxicity profile of a drug may be enhanced in critically ill patients because of the use of multiple, potentially nephrotoxic, medications in addition to hemodynamic insults.

Finally, oligoanuria may be the result of an anatomic obstruction of the kidneys. Unilateral obstruction rarely causes ARF unless only one kidney is present or the other kidney is diseased. Unrelieved obstruction results in changes in renal blood flow characteristics that ultimately redistribute blood flow from the outer to the inner cortex, with resultant relative ischemia of the renal medulla. Causes of urinary tract obstruction include tumors, cystic disease, calculi, prune belly syndrome, and neurogenic bladder.

DIAGNOSIS

The renal failure indices listed in Table 456.1 can be helpful in distinguishing between oliguric patients with decreased perfusion to the kidneys and those with intrinsic renal failure. Clinical conditions associated with a decreased effective intravascular volume in children include dehydration secondary to vomiting, diarrhea, or nasogastric drainage in addition to that caused by peripheral pooling of fluid from sepsis or third-spacing from acute abdominal processes. In such a clinical setting, repletion of the intravascular volume through appropriate fluid therapy results in an increased urine output. Occasionally, children with the nephrotic syndrome become oliguric because of a decreased circulating volume secondary to a reduced plasma oncotic pressure. Conversely, children with myocardial failure may have an adequate blood volume but diminished cardiac output, with a consequent decrease in their renal blood
flow. Therapy in such children is aimed at improving cardiac function.

TABLE 456.1. CLINICAL EVALUATION OF ACUTE RENAL FAILURE IN ADOLESCENTS, CHILDREN, AND NEONATES

	Prerenal (Hypovolemia or Decreased Perfusion)	Acute Renal Failure
U_Na (mEq/L)	<10 (<30 in neonate)	>50
FE_Na%*	<1 (<2.5 in preterm infants)	>2 (>2.5 in preterm infants)
U_osm(mOsm/L)	>500 (>400 in neonate)	<350 (<400 in neonate)
U/P_osm	>2 (>1.5 in neonate)	<1
BUN/Cr	>20	Progressive increases in both BUN and Cr
BUN, blood urea nitrogen; U, urea; p, plasma; Cr, creatinine; FE_Na, percent fractional excretion of sodium. *FE_Na % = (U/P)_Na ÷ (U/P)_(Cr) × 100.