The mammalian embryo progressively develops three sets of excretory organs, all of which might be termed the “embryonic kidney.” The pronephros and mesonephros regress in the human but induce the metanephros, the direct precursor of the adult kidney (Figure 25-1). The pronephros, a solid mass of cells along the nephrogenic cord, is located at the cervical level at approximately 3 weeks’ gestation. Degeneration of the pronephros begins soon after its formation, and regression has completely occurred by week 5. The pronephros has no excretory function but plays an important role in the formation of the mesonephros. The primitive ureter of the pronephros forms the wolffian, or mesonephric, duct via fusion of the pronephric tubular buds. The mesonephric duct then induces the formation of the second kidney, the mesonephros, at approximately 4 weeks of gestation. The mesonephros develops from the nephrogenic cord and forms 40 pairs of thin-walled tubules and glomeruli with excretory function. Portions of the mesonephric duct system are retained in the male fetus and form the ducts of the epididymis, the ductus deferens, and the ejaculatory duct. The remainder of the mesonephric duct system in the male infant has degenerated by the 4th month of gestation as the metanephric kidney develops. In the female, near-complete degeneration has occurred by the 3rd month of gestation.

The metanephros appears at 4½ to 5 weeks’ gestation. The metanephric kidney is the product of a series of inductive interactions between the metanephric mesenchyme and epithelial ureteric bud. Initially, the ureteric bud grows from the mesonephric duct into the mesenchymal portion of the urogenital ridge; concomitantly, the metanephric mesenchyme changes, becoming histologically distinct from the surrounding tissue. When the metanephric mesenchyme and ureteric bud make contact, a condensation of cells begins along the surface of the bud. These cells are the beginnings of pretubular aggregates that undergo mesenchymal-to-epithelial transformation to become the segmented nephron. The condensed mesenchyme is also thought to produce a number of stem cells, which remain undifferentiated and proliferative. These cells serve to maintain a supply of precursor cells until the completion of nephron development. Thus the epithelial portion of the adult kidney is derived from both the metanephric mesenchyme, via the stem cells ultimately responsible for individual nephron formation, and the ureteric bud, whose migration and division determine the pattern of formation of the urinary collecting system via its pretubular aggregates. The ureteric bud migrates to the most caudal end of the nephrogenic cord and finally to the lumbar region by week 8 of gestation. The ureteric bud also rotates 90 degrees medially along the longitudinal axis. Abnormalities in ascent or rotation can lead to pelvic kidneys, horseshoe kidneys, or crossed fused ectopia. Anomalies of the kidney often accompany anomalies of the ureter, as well as other portions of the urinary tract. Congenital anomalies of the kidney and urinary tract (CAKUT) are a family of diseases with a diverse anatomic spectrum of kidney anomalies (agenesis, dysplasia, hypoplasia) and ureteropelvic anomalies (megaureter, agenesis, hydronephrosis, vesicoureteric reflux, posterior urethral valves, and ureteral duplications).⁴⁸

Nephrogenesis is the process of nephron formation via growth and differentiation of multiple cell types and leads to formation of the overall renal architecture. The process begins in the renal cortex closest to the medulla (juxtamedullary nephrons) and proceeds in a dichotomous branching centrifugal pattern with the outermost (superficial cortical) nephrons forming last. There are multiple phases of growth and structural reorganization following the interactions between the mesonephric mesenchyme and the ureteric bud. The formation of the collecting system is controlled by the branching pattern of the ureteral bud, and this occurs at the same time as the formation of functional nephron units. Four progressive phases of nephrogenesis occur during which the nephron proceeds through several intermediate forms. By the fourth stage, there is a definitive glomerulus with highly differentiated visceral and parietal epithelial cells. The vascular system development occurs in concert with nephron formation. The surrounding major vessels and spinal ganglia grow into the metanephros to complete the remaining cell types, and vessel architecture is similar to the newborn kidney by 15 weeks of gestation.

Although newborn kidneys are usually described as “immature,” they are perfectly suited to their usual responsibilities. During the latter part of gestation, their primary role is maintenance of amniotic fluid volume. This requires a large volume of urine with a relatively high concentration of sodium. Thus fetal urine output is on the order of 10 mL/kg/hr of sodium-rich urine. Fetal fractional excretion of sodium (FENa) (i.e., the fraction of sodium in glomerular filtrate that appears in urine) is especially high, approximately 15%. This compares with less than 1% in a growing infant born after a full-term pregnancy.

The next major responsibility is during the first week of life. Fetuses have a large amount of extracellular fluid (ECF). ECF as a percentage of body weight progressively diminishes throughout gestation: (1) approximately 65% of body weight at 26 weeks of gestation; (2) 40% at full-term; and (3) 25% by 1 year of age. Most of the postnatal reduction occurs in the first week of life and is the primary reason that body weight may decrease by up to 10% in breast-fed term infants and even more in premature infants. The newborn kidney can handle this challenge without difficulty. Finally, in subsequent weeks, the kidney has no trouble retaining the electrolytes needed for growth and no trouble producing dilute urine to accommodate the large water load presented by breast milk. Growth itself is a powerful homeostatic ally. A substantial portion of carbohydrates, electrolytes, and nitrogenous wastes from protein absorbed from breast milk are never presented to the kidney for excretion. They are incorporated into the growing body.

Only when the neonatal kidney has to cope with unexpected derangements of water, electrolyte, or acid-base status secondary to premature birth or illness, especially illness accompanied by cessation of growth, does its relative lack of ability to concentrate urine, excrete extra sodium and potassium loads, conserve sodium (in preterm infants), and regulate acid-base status become problematic. In older children and adults, normal kidneys can correct for substantial errors in clinical judgment as to water and electrolyte administration or creation and correction of acid-base abnormalities. This is not so with neonatal kidneys, especially in smaller preterm infants.

With that in mind, it is helpful to review specific aspects of neonatal renal function.

The process of forming the adult complement of approximately 600,000 nephrons in each kidney is complete by 34 to 36 weeks gestational age (GA). Development proceeds in centrifugal fashion, with juxtamedullary nephrons developing first and superficial cortical nephrons last. ⁵In general, nephron development continues at approximately the same rate even if the infant is born prematurely. In other words, development continues whether in utero or ex utero. For example, a premature infant born at 28 weeks of gestation will not complete nephrogenesis for another 6 to 8 weeks (Figure 25-2). Despite continued nephrogenesis, infants with intrauterine growth restriction and those born with extremely low birth weights may never achieve a normal number of nephrons. This has been termed congenital oligophrenia. Compromised renal function and elevated blood pressures have been reported on long-term follow-up of small preterm infants.

Glomerular filtration rate (GFR) is the rate at which filtrate of renal blood, or more precisely of renal plasma, appears in proximal renal tubules. A primary physiologic limitation of the neonatal kidney, increasingly so with decreasing gestational age, is limited GFR. For the fetus, the placenta serves to maintain fluid and electrolyte composition and clearance of metabolic wastes. Thus renal arterial blood flow is approximately 5% of fetal cardiac output as compared with 25% later on. After full-term birth, GFR doubles to triples in the first weeks of life (see Figure 25-2) and then further increases to adult levels between 1 and 2 years of life.

The situation is different in infants born before 34 to 36 weeks GA. For example, GFR is approximately 5 mL/min/1.73 m² or approximately 0.5 mL/kg/min (30 mL/kg/hr) in a 24-week infant. That increases little in absolute terms until 34 to 36 weeks of gestation (see Figure 25-2). Thereafter GFR increases rapidly, as it does in full-term infants although, as just mentioned, it may never reach normal adult values.

In clinical settings, GFR may be estimated using the clearance of creatinine. For this to be accurate, serum creatinine concentration must be constant, creatinine in the urine must represent creatinine in glomerular filtrate with no creatinine added or taken away during passage through renal tubules, and urine collection must be carefully timed and complete. Because serum creatinine concentrations change after birth, filtered creatinine is reabsorbed by tubules, especially in small preterm infants, and urine collection in newborns is difficult without bladder catheterization; therefore determination of creatinine clearance is uncommon in neonatal intensive care units (NICUs).

Under ideal steady-state conditions, serum creatinine concentrations should provide an accurate indirect indication of GFR, eliminating the need to collect urine. Creatinine production rate is roughly constant. In a steady state, creatinine excretion in urine is equal to creatinine production and likewise constant. The equation for measurement of GFR with creatinine is as follows:

Serum creatinine concentration is thus equal to a constant divided by GFR. Therefore a true increase in creatinine concentration from 0.4 to 0.5 mg/dL, a 25% increase, indicates a reduction in GFR of 20%; the inverse of 1.25 is 0.80.

As mentioned, strict steady-state conditions are often absent in the neonatal period. Nevertheless, serum creatinine concentration is useful as a general indicator of renal function. In full-term infants, as GFR increases, creatinine concentration falls during the first week of life from 0.8 to 1.2 mg/dL, reflecting maternal creatinine concentrations, to neonatal levels of 0.2 to 0.3 mg/dL. The rate of decrease depends on hydration and clinical status. Rising or stable serial serum creatinine concentrations or an isolated value exceeding 0.5 mg/dL after 1 week of age indicates renal dysfunction.

In preterm infants, the steep increase in GFR does not occur until nephrogenesis is complete at 34 to 36 weeks postmenstrual age (PMA). Furthermore, filtered creatinine is reabsorbed along the tubule. This increases with decreasing gestational age and PMA. As a result, creatinine concentrations often rise in the first 24 to 48 hours and are then slow to fall. Gestational-age– and postnatal-age–based graphs are needed to identify abnormal values. ^6,107 After the initial increase in creatinine concentration, concentration should slowly fall. A secondary rise indicates renal dysfunction.

Urine flow depends on both GFR and tubular reabsorption. Fetal GFR is approximately 30 mL/kg/hr, yet fetal urine output is 10 mL/kg/hr. GFR in full-term infants is approximately 90 mL/kg/hr, yet urine output is 2 to 3 mL/kg/hr. The difference is the activity of the renal tubule.

Oliguria is ordinarily defined as urine output of less than 1 mL/kg/hr. However, urine output may transiently decrease immediately after birth to less than 1 mL/kg/hr because tubular reabsorption of water increases because of an increase in fetal antidiuretic hormone (ADH) during labor. Nevertheless, 50% of full-term infants void by 12 hours, 92% by 24 hours, and 99% by 48 hours of life. Causes for prolonged failure to void include poor cardiac output or blood pressure, primary renal dysfunction, and obstruction to urine flow. After transient oliguria/anuria, urine flow rate increases as the newborn excretes his or her physiologically expanded fetal extracellular fluid volume as described earlier.

The proximal tubule is responsible for reabsorbing glucose, amino acids, and most of the bicarbonate, sodium chloride, and water in glomerular filtrate. In smaller preterm infants, tubular transport mechanisms are insufficient to prevent spillage of each of these in varying degrees.

Physiologic diuresis in the first week of life is accompanied by physiologic natriuresis. The kidney is then responsible for conserving sufficient dietary sodium for growth. This is a challenge for preterm infants (Figure 25-3).Thus premature infants often require extra sodium intake to compensate for what amounts to obligatory sodium wastage. Conversely, in the presence of a sodium load (e.g., from administration of large amounts of sodium chloride), the neonatal kidney cannot compensate with a rapid increase in FENa. The result is edema and possibly circulatory overload.

The kidney is an important site for regulation of potassium balance. In the adult, it is responsible for maintaining zero balance. In contrast, to sustain the neonate, the kidney must maintain positive potassium balance. In this context, it is less surprising that mechanisms for potassium excretion are underdeveloped at birth.

Serum potassium concentrations tend to be high in neonates (5.5 to 6 mEq/L).⁵⁹ The levels are not of pathologic significance and perhaps play a role in supporting growth. This serves to point out the importance of growth as a homeostatic mechanism. Some clinicians have the impression that nonoliguric hyperkalemia in small preterm infants is less common since routine institution of early parenteral protein administration.

By adult standards, serum bicarbonate concentrations are low in full-term newborns (19-21 mEq/L) and even lower (16-20 mEq/L) in premature infants. Lower serum bicarbonate concentrations reflect limited ability to cope with the higher acid load from high protein intake and acid generated with formation of new bone. The capacity of the neonatal proximal tubule to reabsorb filtered bicarbonate is one-third that of an adult. Proximal tubular bicarbonate reabsorption is further compromised if ECF is over-expanded with crystalloid solutions; because proximal tubular sodium and bicarbonate reabsorption are closely linked, bicarbonate is wasted as sodium reabsorption decreases to rid the body of excess sodium chloride. The capacities of the collecting duct to secrete hydrogen ions and of the proximal tubule to make ammonia to buffer secreted hydrogen ion are also limited. The net result is limited capacity to correct metabolic acidosis. Limited ability to achieve minimal urine pH values is relative. If serum bicarbonate is low enough (e.g., 14 to 15 mEq/L), the kidney can completely reabsorb the smaller amount of filtered bicarbonate and achieve a urine pH of 5. Serum bicarbonate concentrations increase to adult levels of 24 to 26 mEq/L by the end of the first year.

Metabolic acidemia (see Chapter 8) with low bicarbonate and high chloride concentrations is seen in premature infants with transient proximal renal tubular acidosis and in infants who have received excessive amounts of chloride in normal saline. It can also be seen during recovery from acute renal failure and with renal vein thrombosis and nephrocalcinosis.

Serum uric acid concentrations are elevated in the newborn because production from nucleotide breakdown is increased just after birth, especially in premature infants. This is accompanied by increased uric acid excretion. High urinary uric acid concentrations leave reddish uric acid crystals in the diaper and may be mistaken for blood.

Although lower urinary tract and renal anomalies are seldom the presenting feature of chromosomal disorders, they frequently form part of a multisystem malformation syndrome caused by chromosomal anomalies. Renal disorders seen with chromosomal disturbance include fused kidneys, duplication defects, renal agenesis or hypoplasia, hydronephrosis and hydroureter, renal dysplasia or cystic disease, hypospadias, micropenis, and cryptorchidism.

The overall pattern of malformation with individual chromosomal disorders is usually sufficient for diagnosis; however, variation can be seen from one individual to another, even for patients with aneuploidy. Although certain renal anomalies are characteristic of certain chromosomal disorders, no one renal malformation is unique to any particular chromosomal disorder.

Consequences of obstruction of the developing nephron unit include hydronephrosis, hydroureter, and cortical cysts. Severe obstruction leads to renal dysplasia or agenesis. Dysplasia and agenesis may also be secondary to developmental growth failure and may be unilateral or bilateral. In the case of the multicystic dysplastic kidney, there may be no evidence of obstruction, whereas in other cases, dysplasia may be secondary to lower tract dysfunction and obstruction. Typically, the dysplastic kidney does not keep up with somatic growth and gradually shrinks and disappears.

Furosemide may cause electrolyte and acid-base disturbances, including hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis. It increases calcium excretion and may be associated with nephrocalcinosis and less commonly with nephrolithiasis, secondary hyperparathyroidism, and osteopenia. Although nephrocalcinosis can occur without furosemide, there is little doubt that furosemide increases the risk. Calcification and the additional complication of renal tubular acidosis may be ameliorated or reversed by promotion of calcium reabsorption by addition of a thiazide diuretic. ^93,97 The long-term effects of nephrocalcinosis in preterm infants are not clear. Ototoxicity is another complication of furosemide, especially when used in combination with aminoglycosides.

Aminoglycosides have long been one of the commonest causes of drug-induced nephrotoxicity. Pharmacokinetic monitoring can achieve desired concentrations (peak 6 to 8 mcg/mL and trough <2 mcg/mL) and reduce risk. The neonate may be at less risk for nephrotoxicity from aminoglycosides than is the mature kidney. However, gentamicin-induced renal toxicity was recently confirmed in the neonatal kidney without any relationship to peak and trough serum levels. In fact, the long-term effects of neonatal aminoglycoside exposure on renal development have yet to be adequately evaluated. Ototoxicity is the second main adverse effect of aminoglycosides and, in contrast to nephrotoxicity, is irreversible.

The nephrotoxicity induced by aminoglycosides manifests clinically as nonoliguric renal failure, with a slow rise in serum creatinine and a hypo-osmolar urine developing after several days of treatment. The nephrotoxicity of the aminoglycosides is believed to be secondary to a small percentage of retained drug within the kidney’s proximal epithelial cells. At low or appropriate doses, tubular alterations can generate proteinuria, hypo-osmotic urine, and increases in blood urea nitrogen (BUN) and creatinine reflecting a decrease in GFR. At higher doses of aminoglycosides, tubular wasting of potassium, magnesium, and calcium, along with decreased water reabsorption, bicarbonate, and glucose concomitantly with tubular necrosis, can be seen.

Since the 1970s, premature infants with symptomatic patent ductus arteriosus (PDA) have been treated with indomethacin, a nonspecific prostaglandin inhibitor. Indomethacin, as well as other NSAIDs, has been shown to have various side effects including hemodynamic changes in cerebral, mesenteric, and renal circulations. The renal side effects seen with indomethacin appear to be related to three phenomena, as follows:

The fragile balance of vasoconstrictor (mediated by angiotensin II, endothelin) and vasodilatory (atrial natriuretic peptide, nitric oxide, prostaglandins, kallikrein-kinin) forces is now altered in favor of vasoconstriction and further reduction of the already low GFR.

For preterm infants and newborns, the administration of NSAIDs should be done with care and frequent monitoring of renal function, even though these changes often are reversible. When a change or decline in GFR is noted (e.g., plasma creatinine increase), then the administration of NSAIDs should be halted. Indomethacin has been shown to have clinically important renal side effects including proteinuria, oliguria, renal failure, hyperkalemia, and hyponatremia. Patients at higher risk include those with persistent patent ductus arteriosus, dehydration, and simultaneous administration of other nephrotoxic drugs. Unfortunately, the combined use of furosemide and indomethacin does not improve outcome. At this time, in the absence of large randomized and controlled trials, guidelines for NSAID administration must rely on animal studies. In addition, there are no studies on the effect of selective COX inhibitors on PDA closure.

The neonatal patient, particularly the low-birth-weight infant, is now exposed to an increased use of invasive procedures and broad-spectrum antimicrobial therapy and therefore is at a higher risk for systemic fungal sepsis. Agents for therapy include amphotericin B, which is associated with adverse effects, including infusion reactions with hemodynamic instability and nephrotoxicity with electrolyte disturbances.

Multiple studies have indicated that maintenance of adequate fluid and electrolyte balance before amphotericin B administration may prevent nephrotoxicity. In particular, two strategies, use of a liposomal amphotericin system and salt-loading before amphotericin B administration, are employed. To date, no definitive controlled data exist that show an ameliorated risk for liposomal amphotericin B. Salt-loading, on the other hand, before amphotericin B therapy, of greater than 4 mEq/kg/day may reduce nephrotoxicity; the exact mechanism by which sodium reduces the incidence and severity of amphotericin B–induced nephrotoxicity has not been shown. Suggestions have been made that amphotericin B–enhanced tubuloglomerular feedback is reversed by high sodium intake.

A complete family history of renal disease or syndromes that involve the kidneys is important. Prenatal exposures to maternal infection, drugs, toxin, or medication intake are risk factors. Paternal smoking and advanced age may also be associated with an increased risk for urinary tract anomalies.

The quantity of amniotic fluid is an indicator of fetal renal function since fetal urination is responsible for most of the amniotic fluid volume beginning in the second trimester of pregnancy. Normally, amniotic fluid volume increases during gestation, peaking at 34 weeks of gestation. Severe fetal genitourinary abnormalities result in oligohydramnios (Table 25-1). Severe urinary concentrating defects (e.g., diabetes insipidus and Bartter syndrome) have been associated with polyhydramnios. Perinatal asphyxia is a risk factor for renal damage.

Physical findings that are indicators of genitourinary tract abnormalities are outlined in Table 25-1.

Acute renal failure (ARF) in the newborn is a relatively common problem. Although the precise incidence and prevalence of acute renal failure in the NICU is unknown, several studies have shown an incidence between 6% and 24%. ^3,4,103ARF is defined as the sudden deterioration of the kidney’s baseline function and is usually characterized by an increase in the blood concentration of creatinine and nitrogenous waste products, by a decrease in the GFR, and by the inability of the kidney to appropriately regulate fluid and electrolyte homeostasis.

After birth, the serum creatinine in the newborn is a reflection of maternal renal function and cannot be used as a measure of renal function in the newborn shortly after birth. ^4,20,22,96In full-term healthy newborns, the serum creatinine declines to about 0.4 to 0.6 mg/dL at about 2 weeks of age. In premature infants, this postnatal decline in serum creatinine is at a slower rate. As a general rule, the more premature the infant, the higher the serum creatinine. Any rising serum creatinine from initial baseline or a serum creatinine greater than 1.5 mg/dL with normal maternal function should be investigated.

A decline in urine output is a common clinical manifestation of ARF (e.g., prerenal failure, hypoxic-ischemic insults, or cortical necrosis), but many forms of ARF are associated with normal urine output (e.g., nephrotoxic renal insults).

There are many different causes of renal failure in the newborn (Box 25-1). These causes are typically classified as prerenal, intrinsic renal disease including vascular insults, and obstructive uropathy. The preponderance of factors causing ARF in the newborn are prerenal in nature (e.g., hypoxia, hypovolemia, hypotension); primary intrinsic renal disease and obstructive uropathy are much less common.