Although the exact prevalence of acute renal failure (ARF) in the neonate is difficult to determine precisely, patients who have mild-to-severe ARF are common in most neonatal intensive care units (NICUs). In most instances, the cause of failure is prerenal, in which cardiac output or renal blood flow are diminished, but intrinsic renal injury or postrenal obstructive processes also occur. By considering normal renal physiology, the mechanisms through which renal failure develops can be understood. This understanding is important in limiting the extent of injury and in developing therapies to control the effects of renal dysfunction on fluid and electrolyte balance, acidosis, and nutrition. Outcome and prognosis depend on comorbidities and the presence of failure in other organs as well as the cause and severity of ARF. Permanent effects may not be apparent until later in childhood, mandating careful follow-up and monitoring.
After completing this article, readers should be able to:
Define renal failure in the neonate.
Discuss the epidemiology, pathophysiology, and diagnosis of renal failure.
Develop a differential diagnosis for the cause of renal failure.
Describe the management strategies for renal failure and potential complications.
Discuss the prognosis and long-term outcome of neonates who have renal failure.
Acute renal failure (ARF) is defined as the rapid elevation in the concentration of blood urea nitrogen (BUN), creatinine, and other cellular waste products in the blood resulting from diminished glomerular filtration rate (GFR) in the kidney. (1) Frequently, it involves abnormal tubular function, including reduced sodium resorption and increased loss of bicarbonate, as well as diminished excretion of water. Unlike in older patients, it is difficult to define neonatal ARF on the basis of a specific serum creatinine value, in part because concentrations measured immediately after birth reflect the maternal rather than infant's renal function. As shown in Table 1, normal creatinine values are dependent on gestational age, with higher values normally seen in more immature babies, and on postnatal age. In term babies, the concentration normally rises somewhat in the first 24 to 36 hours after birth, subsequently decreasing and stabilizing at about 0.4 mg/dL (35.4 mcmol/L) by 5 days of age. (2) In preterm infants, the peak value occurs between 2 and 3 days after birth, and stabilization typically is delayed until about 6 days of age. It is important to consider these normal patterns for creatinine in assessing the meaning of any particular value, which makes it very difficult to use a single value to diagnose renal failure, except that a clearly elevated value beyond the normal range indicates decreased glomerular function. Often, ARF can be diagnosed by monitoring changes in the creatinine value because during a period of intrinsic renal failure, it usually increases between 0.5 and 1.0 mg/dL (44.2 and 88.4 mcmol/L) per day. (3)
Urine output is another key indicator of renal function. Commonly, ARF is suspected when oliguria is present, defined as a period during which urine output is less than 0.5 mL/kg per hour. This is not a universal finding, however, and the urine output remains normal or even may be increased during ARF in many patients. (4)(5)
The underlying process leading to renal failure may be categorized as: 1) prerenal, due to a diminution of systemic circulation to the kidney as a result of a contraction in the intravascular volume or failure of the cardiac output; 2) renal, which results from damage or necrosis of the parenchyma of the kidney; or 3) postrenal due to distal obstruction to urine flow in the kidney or collecting system. These distinctions are somewhat artificial, and some processes include elements from more than one of these general categories. (6)
The incidence of ARF in the neonatal period is greater than during later childhood, but exact numbers have been difficult to determine accurately because many mild cases characterized by transient oliguria never are recognized, and cases of nonoliguric failure, even those that are severe, may be undiagnosed. In addition, most studies that have attempted to define the incidence have focused only on babies transferred for care, making true incidence within the population impossible to determine. Older studies identified a prevalence as high as 24% of admissions to neonatal intensive care units (NICUs), but more recent analyses have found a prevalence of 3% to 8% among NICU admissions, (4) numbers comparable to those seen in adult patients. Newborns who have undergone cardiac surgery appear to be at highest risk in most series, but one recent large series found that the underlying causes most often are asphyxia (40% of cases, primarily severe asphyxia) sepsis (22%), or feeding problems (18%); another series noted that as many as one third of patients who have ARF are preterm. The underlying cause does not necessarily predict urine output during ARF. In one series of neonates who had ARF following severe asphyxia, 60% of cases were nonoliguric, with oliguric and anuric cases accounting for 25% and 15%, respectively. (7)
Outside the newborn period, most cases of renal failure in infants and children are due to intrinsic renal disease, but in newborns, 60% to 90% of cases are prerenal in origin. (6) For a given clinical circumstance, however, there may be genetic factors that predispose some babies to develop ARF. This has been evaluated most fully among infants who develop renal failure following significant infection. Some of these infants have been found to have polymorphisms of tumor necrosis factor-alpha and interleukins-1b, -6, or -10. (8) The risk of ARF is not increased among those who have a single polymorphism, but it is among the babies who have more than one. It is postulated that this group of infants is more likely to develop ARF following infection because the multiple polymorphisms result in an exaggerated inflammatory response. In other studies, polymorphisms in the angiotensin-converting enzyme gene and one of the angiotensin receptors (AT1) result in changes in the renin-angiotensin system, but to date these factors do not appear to predispose infants to renal failure. In contrast, variation in the density of AT2 receptors, which may be due to either genetics or physiologic immaturity, may predispose certain babies to ARF (9) by altering their response to decreased renal blood flow.
Among neonates, most cases due to insufficient vascular volume (prerenal) recover with appropriate management, although some patients develop long-term problems. Mortality from renal failure in the newborn has been reported to be as high as 25% to 50%, with the risk being highest in babies who have intrinsic renal disease, those needing dialysis or mechanical ventilation, and those who have prolonged anuria or absent uptake on renal radionuclide scans. Interestingly, there is no correlation between peak creatinine values and mortality risk. (3)
Differential Diagnosis of ARF
As noted previously, the underlying causes of ARF generally can be divided into prerenal, renal (intrinsic), and postrenal categories. Table 2 lists the major causes within each group. Early identification of the possible cause is important for both management and longer-term outcome, especially because most renal failure in the neonate begins with a prerenal problem, which can be corrected successfully if recognized and treatment is begun. If renal failure remains unrecognized and untreated, there is a greater risk that it may progress from a readily treatable disorder to intrinsic renal injury, which is more difficult to treat and has a higher risk of long-term consequences. Understanding the cause also makes it possible to focus treatment on both the underlying cause and the renal disorder itself and is helpful in determining the prognosis and long-term outcome for a particular case. For better understanding of how each potential diagnosis affects renal function, it is worthwhile to review the pathophysiologic mechanisms that result in decreased glomerular filtration.
The kidney is comprised of individual nephrons, each of which is supplied by blood via the afferent arteriole and drained by the efferent arteriole. Glomerular filtration depends on four parameters (Figure): 1) plasma flow rate in the afferent arteriole, 2) transcapillary hydraulic pressure within the glomerulus (the difference between pressure within the capillary bed and that in the proximal tubule of the collecting system), 3) the colloid osmotic pressure of the plasma, and 4) the inherent permeability of the glomerular capillaries themselves.
Decreased plasma flow rate is the hallmark of prerenal failure, resulting from volume contraction or impaired cardiac output. Correction of these conditions often is effective in completely reversing renal hypoperfusion and restoring normal function. When uncorrected for longer periods, the inherent damage to the kidneys alters vascular responsiveness and can result in impaired renal plasma flow, even after the total systemic volume is replete. In healthy babies and adults, renal blood flow and perfusion normally can be maintained even in the presence of a decrease in systemic blood pressure. Such renal autoregulation occurs through dilation of the afferent arteriole and constriction of the efferent one, thereby preserving renal blood flow. This is mediated by the increase in catecholamine secretion that is triggered by decreased renal perfusion, which results in the generation of vasodilator prostaglandins and prostacyclin, a mechanism that can be affected by several drugs. The catecholamines also activate the renin-angiotensin system, which mediates efferent vasoconstriction. This autoregulation system is functional in the healthy newborn, despite normally low systemic blood pressure and renal blood flow. In the face of volume contraction, however, the factors diminish the capacity for autoregulation, thereby putting the newborn at higher risk of developing inherent renal injury and continued restriction of renal plasma flow, even after systemic volume or cardiac output is restored.
Potential disruption of autoregulation also can occur because of the dependence of glomerular filtration on transcapillary hydraulic pressure, the difference between the pressure in the capillaries and that in the proximal tubule. These pressures, or more importantly the difference between them, normally remain stable over a wide clinical range. In studies in adult rats, however, when systemic hypotension was severe enough to drop below the autoregulatory range, the processes that sustain glomerular filtration began to fail, and the glomerular capillary pressure fell, ultimately resulting in hypofiltration and decreased renal function. (10) Both volume contraction and congestive heart failure, two common prerenal causes of ARF, exacerbate the process. When either or both occur, any decrease in renal perfusion pressure results in a similar decrease in GFR. In contrast, when these conditions are absent, a decrease in renal perfusion pressure as large as 30% can be tolerated with only a small reduction in GFR.
Physiologic immaturity appears to accentuate the impact of reduced transcapillary hydraulic pressure, making it even more significant than volume contraction or diminished cardiac output. In one study, the 30% decrease in renal perfusion pressure that minimally affected glomerular filtration in healthy adults resulted in a more than 80% decrease in the GFR of young rats, almost three times the effect of volume contraction alone. This was attributed primarily to a decrease in glomerular capillary pressure, as a result of diminished arteriolar pressure. Young animals lack the ability to respond to volume contraction with adequate vasoconstriction in the efferent arteriole. This is due to a diminished vasoconstrictive response to angiotensin II, as a consequence of decreased receptor number and density. The loss of this important component of the autoregulatory system leads to decreased transcapillary pressure by lowering glomerular capillary pressure.
Transcapillary pressure also depends on the hydraulic pressure in the proximal tubules. When the tubules are injured, some cells die and glycoproteins in the membranes of others are redistributed, disrupting the basement membrane and causing tubular obstruction. This raises intratubular pressure, thereby decreasing transcapillary pressure and glomerular filtration. Tubular damage also alters sodium and potassium flux, contributing to electrolyte abnormalities in renal failure. In addition, the loss or damage to the intracellular junctions results in “backleak” by which creatinine leaks from the tubules back into the circulation that, in turn, increases serum concentrations. (11) It is not known to what extent this contributes to the peak creatinine concentration or how much this affects the magnitude of the apparent decrease in calculated GFR.
If plasma colloid osmotic pressure were increased, glomerular filtration would be decreased. In newborns, this factor is never more than a theoretical consideration because newborns have normally low plasma protein concentrations compared with adults. Alterations in the properties of the glomerular membrane, on the other hand, could be expected to alter filtration, and it is likely that this factor is important in the changes that occur with gestational maturation. Most of the causes of ARF in neonates, however, do not significantly alter glomerular morphology. Although subtle changes may occur, the impact on filtration remains unclear.
At its core, assessment of ARF begins with history and physical examination, which represent the first step in identifying clinical conditions that may predispose or lead to the condition. In the neonate, most renal failure is due, at least initially, to prerenal factors, and early identification of these factors can prevent progression of renal injury. Perhaps the most common early sign of prerenal failure is oliguria or anuria. When decreased urine output is noted, initial treatment can begin while the specific cause of decreased systemic circulation to the kidneys is identified.
Dehydration resulting in decreased intravascular volume may result from poor feeding due to immaturity, difficulty in establishing breastfeeding, or because of some underlying illness. This process usually evolves over a period of days (and, thus, rarely is seen earlier than this) and can be identified by a careful history, often before it reaches a serious state. True volume contraction significant enough to impair renal function more often results from gastrointestinal losses or in association with electrolyte losses in salt-wasting disorders. Hemorrhage is another prominent cause of marked volume contraction. It is important to recognize that although the history and presentation often are revealing and conclusive in demonstrating hemorrhage severe enough to affect renal function, some cases of even massive hemorrhage may be hidden and discovery delayed unless they are contemplated. A large fetomaternal hemorrhage can occur during the later stages of the birth process but be outwardly inapparent, resulting in marked volume contraction because the fluid equilibration that might otherwise occur via the placenta does not have time to occur before birth. Subgaleal hemorrhages can occur rapidly during the birth process and can become very large, leading to significant volume contraction before the extent of the hemorrhage can be appreciated clinically. (12) Physical examination is helpful in distinguishing this entity from an exaggerated caput or loculated cephalohematoma. Typically, a subgaleal hematoma is mobile and has a “bag of worms” feel, and the blood slips down toward the neck as the baby is positioned upright.
Possible third space losses due to sepsis or trauma should be considered when history or physical examination findings are consistent with such disorders. Sepsis also may result in marked peripheral vasodilation or “warm shock,” leading to hypotension and reduced renal perfusion even while cardiac function and blood volume are normal. Although much less common, diabetes insipidus can be the cause of excess water loss and volume contraction.
Congestive Heart Failure
In congestive heart failure or cases of obstructed cardiac output, the blood volume actually may be normal or even increased, but renal perfusion is decreased. This may occur after surgical correction of a heart defect but more often is related to other causes of cardiac compromise, including sepsis, hypoxic–ischemic injury, or especially in a preterm infant, a patent ductus arteriosus with large left-to-right flow. (13) Hyperviscosity of the blood is related to abnormally high hematocrit, often manifesting as plethora, and is more common in infants of mothers who have diabetes or infants who experience growth restriction. This process can result in decreased renal perfusion by reducing flow in the arterioles and capillaries.
Hypoxic-ischemic injury may lead to renal failure through several mechanisms, which bridge the categories of prerenal and intrinsic renal disease. Ultimately, intrinsic renal damage can occur directly from tissue hypoxia and ischemia, to which the metabolically active kidney is sensitive. In the early stages, however, renal hypoperfusion results from pump failure and diminished cardiac output due to bradycardia and cardiac depression. The normal autoregulation mechanisms fail, and kidney perfusion is compromised. Like other prerenal disorders, if the problem is not corrected, the injury may progress as vasoconstriction and reduced capillary perfusion result in acute tubular necrosis (ATN) and diminished function. (10)
Unlike many other causes, hypoxic-ischemic injury often precedes birth, and the extent and severity can be significant and progressive before intervention can be implemented to improve cardiac function or vascular supply. As a result, this shift from prerenal to intrinsic renal disease is more difficult to prevent, and ATN can occur. When ARF follows potential hypoxic injury, it is important to try to differentiate the underlying mechanism, so appropriate therapy and management can be instituted. Several tests can be helpful in this endeavor.
Intrinsic Renal Injury
Once intrinsic renal injury has occurred, urinalysis results may be abnormal, showing granular casts and some variable degree of proteinuria. As the capacity to conserve sodium and water is lost in the injured kidney, urine osmolality decreases and urine sodium concentration and fractional excretion of sodium increase. As shown in Table 3, measurement of these urinary indices (urine osmolality, sodium, and the fractional excretion of sodium) may be helpful in differentiating ATN from prerenal disease. The utility is limited in more preterm infants, in whom tubular immaturity alone can result in the same findings. Radiographically, the kidneys are normal in size, but radionuclide scanning demonstrates delayed uptake in the parenchyma and diminished excretion.
In addition to hypoxia, many drugs may cause nephrotoxicity, particularly when underlying renal function already is compromised. Common agents with this potential include the aminoglycosides, the toxicity of which is related to dose, the interval between doses, and the length of the antibiotic course. If the serum concentration cannot decrease to a safe trough level, injury to the proximal tubules can occur. This process is reversible over several days, but it is much less likely to occur when concentrations and dosing intervals are monitored carefully. Studies in adults have demonstrated that once-daily dosing of these drugs decreased the potential for toxicity while providing equal efficacy, and this practice has become standard in neonates as well. (14) Amphotericin is another commonly used agent that has the potential to cause dose-related toxicity, but this occurs infrequently in newborns, especially when the newer liposomal formulations are used.
Renal dysfunction also is common after therapy with nonsteroidal anti-inflammatory agents (NSAIDs), with some evidence indicating a lower risk with ibuprofen than indomethacin. (15)(16)(17)(18) These drugs are administered to treat a hemodynamically significant patent ductus arteriosus, the presence of which compromises the already lower GFRs in neonates. Renal function is maintained via the autoregulatory processes of afferent arteriolar dilation and efferent arteriolar constriction. These mechanisms are mediated through prostaglandins, the synthesis of which is blocked by NSAIDs. Therapy with indomethacin commonly results in ARF, occurring more frequently when larger doses are used. The renal effect is manifested by significant reductions in GFR and urinary output, free water excess, and derangement in electrolyte concentrations. Ibuprofen can cause renal dysfunction by the same mechanism, although in some studies it has been reported to result in less renal compromise.
Many other drugs have the potential to cause intrinsic renal failure, such as angiotensin-converting enzyme inhibitors. (19) These drugs block autoregulation of renal blood flow by disrupting vasoconstriction in the efferent arterioles of the glomerulus. They are not a major cause of ARF in neonates, however, because they rarely are used therapeutically in these patients. If used to treat the mother during gestation, these and other drugs can have an impact on the fetus and newborn.
Renal Vascular Disease
Renal vascular disease also can result in clinically apparent renal failure if it is bilateral. Arterial thrombosis, in either the renal arteries themselves or in the aorta, may occur spontaneously, but it is strongly associated with placement of an umbilical artery catheter. In addition to oliguric renal failure, this thrombosis typically results in hypertension and hematuria. Therapy includes immediate removal of the catheter and the judicious use of anticoagulation. (20)
The risk of renal vein thrombosis (RVT) is increased in infants of diabetic mothers and in all babies in whom perinatal asphyxia, polycythemia, or infrequently, severe dehydration is diagnosed. (21) RVT occurs more frequently in males, and in almost 50% of reported cases, the thrombus is so extensive that it extends back into the inferior vena cava. Some patients (as many as 53% in one major review) have hereditary prothrombotic factors, and the presence of these may increase the risk of recurrence later in childhood. (22)(23)(24) Because the recurrence risk is low, even among these patients, routine screening for these factors in patients who have RVT is not recommended. Patients typically present with macroscopic hematuria, a palpable abdominal mass, or thrombocytopenia, with all three forming a “classic triad” in many patients. Ultrasonography demonstrates enlarged, echogenic kidneys with attenuation of corticomedullary differentiation, and it is a useful adjunctive diagnostic study. Kidney size or length is correlated inversely with outcome; severely affected kidneys develop scarring and atrophy.
Treatment for RVT ranges from supportive care alone to anticoagulation or fibrinolytic therapy. (25) Supportive care alone frequently is effective, and renal outcomes in many reports are similar to those obtained when anticoagulation with heparin or low-molecular weight heparin is used. Success is limited; more than 70% of patients have irreversible kidney damage and renal atrophy and about 20% develop persistently elevated blood pressures. As a result, infants who have RVT require careful follow-up assessment as they grow.
Transient Renal Dysfunction
In some cases of intrinsic renal failure in the neonate, the exact cause cannot be determined before it resolves spontaneously. Such transient renal dysfunction of the neonate has been reported in case studies. Patients present in the first few days after birth with oliguria, elevated creatinine and BUN, and characteristic echogenicity in the kidneys, all of which resolve over several days.
ARF also can result from postrenal or obstructive causes. Such anatomic conditions typically now are identified by ultrasonography, often after suggestive findings on physical examination. The increase in tubular pressure due to obstruction results in decreased transcapillary pressures, directly leading to diminished glomerular function. If the process continues over a long time period, such as during gestation, irreversible injury to the kidney may result.
The management of ARF in the newborn is outlined in Table 4. A conservative approach may be appropriate, including taking measures to maintain urine output, keeping fluids and electrolytes in balance, providing appropriate nutrition, and correcting acidosis. Doses of drugs that normally are excreted by the kidneys must be adjusted. Such actions may prevent the need for more invasive measures such as peritoneal or hemodialysis.
Management of renal failure is much easier when there is urine output, even though the overall outcome may not be changed. Unfortunately, therapies often used in older children and adults, such as mannitol infusion, generally are not suitable for newborns because the high osmotic load can be associated with untoward effects such as intracranial hemorrhage, especially in the preterm infant. Diuretics, especially furosemide, frequently are used to increase urine output, and they offer the theoretical advantage of decreasing metabolic rate in damaged tubules by inhibiting sodium-potassium-ATPase. Unfortunately, clinical response often requires the use of high doses or continuous infusions, which can result in direct nephrotoxicity. In general, therefore, if these drugs do not result in a clinical response, they should be discontinued.
Adequate support of blood pressure, including the use of catecholamines such as dopamine, is important in ensuring that renal blood flow is optimized. Although low doses of dopamine have been advocated for their direct effect in dilating renal vasculature, use of this therapy has not been shown to improve outcome or reduce the need for dialysis in adults and actually may cause some harm.
Most therapy revolves around careful management of fluid and electrolytes by monitoring and adjusting intake to match output. Potassium should be removed from all fluids until adequate output is assured, and administered fluid volumes should be adjusted based on output, including an estimation of insensible losses.
Fluid restriction often complicates the provision of adequate nutrition, which is hampered further by the need to provide adequate energy without causing nitrogen overload and uremia. Caloric intake should be maximized by using carbohydrate and fat and tailoring protein intake via measurements of BUN. Fluids also must be adjusted to compensate for increased blood acids when normal renal excretion is compromised. Sodium bicarbonate, acetate, or citrate can be used as buffering agents, as long as the baby has normal ventilation.
If these therapies fail to control uremia, hyperkalemia, acidosis, or fluid balance, dialysis may be indicated. Most neonates are treated with peritoneal dialysis, which typically is accomplished by manual exchange of small fluid volumes and can be performed in most NICUs. (26)(27)(28) Standard recipes for solutions are used and adjusted based on clinical response. Hemodialysis in the newborn requires special expertise and is particularly difficult in preterm infants, but new devices have been developed that have the potential to extend this therapy to more patients.
The major determinants of outcome include the presence of comorbidities and other organ failure as well as the underlying cause of the ARF. Mortality ranges as high as 61% in babies who experience multiple organ failure. Reversible insults, such as drug toxicity, and cases of nonoliguric failure have good prognosis for survival and recovery. Among those babies who have oliguric or anuric renal failure, especially those who require peritoneal dialysis, the mortality is high. Severe intrinsic renal damage, such as cortical necrosis following ischemia or severe injury from postrenal obstruction, is more likely to lead to chronic renal failure in as many as two thirds of patients. All patients who have ARF should be monitored adequately with follow-up assessments, including periodic measurements of serum creatinine, blood pressure, and evaluation for proteinuria, with careful attention to the fact that some abnormalities may not be apparent for several years.
American Board of Pediatrics Neonatal-Perinatal Medicine Content Specifications
Know the causes of renal failure in the neonate.
Know the clinical manifestations, imaging, and laboratory features of renal failure in the neonate.
Know the management of renal failure in the neonate, including the use of hemofiltration, peritoneal dialysis, and hemodialysis.
Dr Ringer has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/ device.
- Copyright © 2010 by the American Academy of Pediatrics
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