Fluid, Electrolyte, Acid–Base, and Renal-Developmental Physiology and Disorders

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Chapter 9

Fluid, Electrolyte, Acid–Base, and Renal-Developmental Physiology and Disorders

During fetal life the placenta is responsible for fetal water and electrolyte homeostasis. The principal function of the fetal kidney is the continuous excretion of water and electrolytes into the amniotic cavity, which is essential for maintenance of amniotic fluid volume. Normal amniotic fluid volume is essential for normal lung development. After birth the kidneys assume responsibility for maintenance of appropriate total body water and electrolyte homeostasis ( Fig. 9-1).

Urine is made by the fetus in increasing amounts as gestation advances. In fact, fetal urine output is quite high—in the range of 25% of body weight per day, approximately 750 to 1000 mL per day near term. Fetal urine, along with pulmonary secretions, is an important contributor to amniotic fluid. The process is dynamic, with amniotic fluid being produced continuously, then swallowed and reabsorbed from the gastrointestinal tract ( Fig. 9-2). Fetal oliguria may produce oligohydramnios. Obstruction in the gastrointestinal tract or neurologic impairment of swallowing may result in polyhydramnios.

The first definitive nephrons form at 8 weeks of gestation. Renal function adequate to sustain extrauterine life develops by approximately 23 weeks of gestation. Nephrogenesis is complete at 36 weeks.

By 22 weeks’ gestation 95% of fetal kidneys are detectable.

Fetal renal blood flow (RBF) increases steadily from approximately 4% at 17 to 18 weeks of gestation to 6% at term. Adult kidneys receive between 20% and 25% of cardiac output. The low RBF in the fetus is due to high renovascular resistance caused by increased activity of the renin-angiotensis-aldosterone and sympathetic nervous systems.

RBF increases sharply after birth at term to between 8% and 10% of cardiac output. Adult levels of RBF are not achieved until approximately 2 years of age.

Fetal GFR slowly increases during fetal life until approximately 36 weeks, when nephrogenesis is complete. Thereafter little increase occurs until birth, at which time there is a dramatic increase in GFR. The increase in GFR with birth is less dramatic in preterm infants ( Fig. 9-3).

See Table 9-1.

The answer to this question is complicated. In fact, it is the change in serum [Cr]—not a single value—after birth that is relevant. At birth serum [Cr] is largely a function of maternal serum [Cr]. The subsequent change varies with gestational age. In infants younger than 30 weeks’ gestation, serum [Cr] either does not change or it increases 30% to 40% before declining to the birth level during the first 5 to 8 days of age, then subsequently declines before reaching a steady state by 7 to 10 weeks of age. The duration of the plateau is inversely related to gestational age; the rate of decline is directly related to gestational age. In infants at 30 weeks’ gestation or older, serum [Cr] declines from birth to reach a steady value at 3 to 6 weeks of age. The rate of decline is directly related to gestational age.

The volume of urine in the postnatal period is determined by water and sodium intake, GFR, the ability to maintain a concentration gradient in the renal medullary interstitium, and the presence or absence of antidiuretic hormone (ADH).

12. What are the important differences in the regulation of sodium ion (Na+) and potassium ion (K+) balance?

image The vast majority of total body Na+ is extracellular, whereas the vast majority of total body K+ is intracellular.

image Serum [Na+] is solely a function of total body water and sodium balance. Serum [K+] is a function of internal (the distribution of K+ across cell membranes) and total body (or external) potassium balance. Urinary Na+ excretion is a function of the amount of Na+ filtered (which depends on the GFR and serum [Na+]) and the amount of Na+ which is reabsorbed along the renal tubules. The amount of K+ filtered has little effect on urinary potassium because 5% to 10% of the filtered K+ is delivered to the distal nephron regardless of serum [K+] or total body potassium balance. Urinary K+ excretion, then, is a function of the amount of potassium secreted or reabsorbed in the distal nephron.

Potassium uptake by cells is stimulated by the following:

Potassium movement from the intracellular to extracellular space is stimulated by the following:

Term infants conserve sodium effectively after the first few hours of life (after contraction of the extracellular fluid space). Preterm infants conserve sodium less effectively for the following reasons:

No. Their ability to excrete a sodium load is limited by their low GFR.

Concentrating ability is limited in infants for several reasons. Protein intake by the infant is used to make new cells during this period of rapid growth, and relatively little nitrogen is diverted to urea. Urea is an important component of the tonicity of the medullary interstitium and the osmolality of urine. Additional factors include (1) the relatively short loops of Henle in the neonatal nephrons that limit the surface area available for equilibration with the interstitium and (2) a high level of prostaglandins that can increase medullary blood flow and “wash out” the medullary concentration gradient. The maximum urine concentration in the preterm infant is approximately 600 mOsm/L, in the full term infant is 800 mOsm/L, and in the adult is 1500 mOsm/L.

Not primarily. Preterm infants are capable of diluting their urine to 75 mOmol/L, compared with that of full-term infants and adults of 50 mOsm/L. The capacity of the newborn to excrete a free water load is limited by their lower GFR.

Data in animals suggest that potassium secretion by the immature distal nephron is limited by the following:

Fluid and Electrolyte Management

Ninety-seven percent of infants pass urine in the first 24 hours of life and 100% by 48 hours. During the first 2 days of life, infants urinate two to six times per day ( Table 9-2).

TABLE 9-2

TIME OF FIRST VOID IN 500 INFANTS ∗

image

∗In 395 term infants, 80 preterm infants, and 25 postterm infants.

Adapted from Clark DA. Time of first void and first stool in 500 newborns. Pediatrics 1977;60:457.

This decrease in weight is the result of catabolism secondary to low caloric intake and a physiologic decrease in the extracellular water (ECW) volume that is independent of caloric intake. Most premature babies manifest a natriuretic diuresis in the first few days of life, which results in negative net total body water and sodium balance and, therefore, a decrease in extracellular fluid (ECF) volume.

21. Why is the reduction in ECW volume in preterm infants considered physiologic?

The clinician should use what the attending physician requests. After the first day of life, however, it is important to understand that it is the absolute fluid and electrolyte intake (milliliters or millimoles per day) relative to that in the previous 8 to 24 hours that is relevant. In other words, should the absolute fluid or electrolyte intake be more or less than it was previously? The answer depends on what fluid and electrolyte balances resulted from the previous intakes and on what water and electrolyte losses are anticipated. There is no magic amount of water per kg/day that is appropriate for all infants, even infants at the same weight, gestational age, postnatal age, and in the same environment. If the infant loses more water (and therefore weight) than you judge to be appropriate and you anticipate that water losses will remain approximately the same, the absolute amount of water (milliliters per day) given should be increased. However, if the current weight is used to calculate fluid requirements, the absolute amount of water administered may be only slightly more or even less than the amount given the day before. For example, an 860-g infant loses 110 g (approximately 13% of birth weight) in the first day of life after receiving 100 mL/kg/day (86 mL/day). You decide this rate of weight loss is too great and increase water intake by 20% to 120 mL/kg/day. Based on the current weight of 750 gm, however, this is only 90 mL/day, which is barely more than that given the previous day. If water losses remain the same, weight loss will be only slightly less over the next 24 hours despite an increase in water intake per kilogram current body weight.

The most important determinants of IWL are gestational age, postnatal age, antenatal steroids, and environment. IWL decreases with increasing gestational and postnatal age ( Fig. 9-5), exposure to antenatal steroids, and increasing ambient humidity.

The concentration of dextrose in the intravenous solution is an irrelevant number. The relevant variable is the dextrose administration rate. Neonates normally produce 4 to 8 mg/kg/min of glucose endogenously. Administration at this rate usually maintains serum glucose concentration in the normal range and conserves glycogen stores. Once the rate of water administration is determined, a dextrose concentration is selected that provides somewhere between 4 and 8 mg/kg/min. In some infants higher glucose infusion rates may be necessary, occasionally exceeding even 12 to 14 mg/kg/min in some circumstances to maintain appropriate blood glucose levels.

image

Yes.

image

No. Although plasma blood glucose concentrations are approximately 10% to 18% higher than whole blood concentrations (because the water content of plasma is higher than that of blood cells), most POC analyzers are calibrated to plasma and therefore provide plasma glucose concentrations. However, POC analyzers have limited accuracy, with a tendency to read falsely lower than the actual plasma glucose concentration. Variation from the actual plasma glucose concentration may be as much as 10 to 20 mg/dL, with the greatest variation at low glucose concentrations. Because of limitations with rapid POC testing methods, any abnormal plasma glucose concentration must be confirmed by laboratory testing.

In the absence of unusual Na+ losses (e.g., loss of gastrointestinal or cerebrospinal fluid), no Na+ should be given. Under these conditions the kidney is the principal route of Na+ loss. During the first day of life, urine Na+ excretion is low (0.5 to 2 mEq/kg/day). With the onset of the postnatal diuresis (when the rate of net water loss often exceeds net Na+ loss), the serum sodium [Na+] level often rises. Therefore it is usually best to withhold Na+ initially, especially in extremely premature infants, in whom IWL is quite high and quite variable, therefore placing these infants at particular risk for developing significant hypernatremia in the first few days of life.

The main route of potassium loss is in the urine. Urine potassium losses are low initially because GFR and urine output are relatively low after birth. Moreover, serum potassium concentration ([K+]) may rise in extremely premature infants even in the absence of exogenous potassium. Therefore potassium should be withheld until it can be ascertained that renal function is normal and, in extremely premature babies, the serum [K+] is normal and not increasing.

Not necessarily. Serum [Na] is the concentration, not the amount, of sodium in the ECF space. If it is abnormally low, the amount of sodium in the ECF space is “insufficient” for the amount of water in the ECF space. Thus serum [Na] may be low because there is too little extracellular sodium, too much ECW, or both. The most common cause of hyponatremia in neonates in the first 1 or 2 days of life is excessive fluid administration. In such situations free water intake should be restricted. 789101112131415161718192021222324252627282930313233343536

image KEY POINTS: FLUIDS AND ELECTROLYTES

Nonoliguric Hyperkalemia in Premature Infants

Hyperkalemia is defined as a serum potassium concentration that is equal to or greater than 6.7 mEq/L from a nonhemolyzed whole blood sample.

Hyperkalemia is caused by perturbations in internal or external K+ balance:

and/or

Nonoliguric hyperkalemia is a rise in the serum potassium concentration equal to or greater than 6.7 mEq/L in the absence of a falling or low urine output.

Nonoliguric hyperkalemia may develop in the first 24 to 36 hours of life even in the absence of potassium intake. In fact, most infants who develop nonoliguric hyperkalemia are in negative potassium balance. Therefore nonoliguric hyperkalemia is caused by a shift of potassium from the intracellular fluid to the extracellular space. Although the mechanisms responsible for this shift are unknown, infants with nonoliguric hyperkalemia are believed to have lower levels of Na+/K+ ATPase. It is noteworthy that serum [K+] increases after birth in nearly all extremely preterm infants, even those who do not develop hyperkalemia. The etiology of this shift is unknown, but it is only clinically significant in very preterm infants.

When originally reported in the literature in the early 1980s, the prevalence of nonoliguric hyperkalemia ranged from 25% to 50% of infants below 1000 g birth weight or younger than 28 weeks’ gestational age. However, it is much less common now, even in infants younger than 25 weeks’ gestational age. This is probably the result of the increased prevalence of antenatal steroid therapy and more aggressive nutrition, which have been shown to reduce the risk of nonoliguric hyperkalemia.

Hyperkalemia increases the ratio of extracellular [K+] to intracellular [K+], depolarizing cells with excitable membranes, most importantly myocardial cells. This may causes bradyarythmias. These are uncommon with serum [K+]s lower than 7 to 8 mmol/L. If serum [K+] continues to rise, asystole may occur. However, asystole is uncommon with serum [K+]s lower than 8 to 9 mmol/L.

There is no consensus regarding this issue. Treatment may be considered if serum [K+] is equal to or greater than 7 meq/L or there are electrocardiographic changes resulting from hyperkalemia. It is important to know that nonoliguric hyperkalemia normally resolves without treatment with the onset of physiologic natriuretic diuresis.

Nonoliguric hyperkalemia is managed in the following ways:

image By antagonizing the arrythmagenic effect of hyperkalemia

image By stimulating cellular uptake of potassium

image By increasing renal potassium secretion

image Peritoneal dialysis is rarely required except with hyperkalemia caused by renal failure.

Use of this method to treat hyperkalemia is no longer considered safe and effective.

Insulin therapy has been shown as more effective in lowering serum [K+] in extremely premature infants with nonoliguric hyperkalemia in a randomized controlled trial. Moreover, cation exchange resins have been associated with intestinal injury.

image KEY POINTS: HYPERKALEMIA

1. Nonoliguric hyperkalemia (potassium >6.7 mEq/L in plasma from a nonhemolyzed whole blood specimen) still occurs in extremely premature infants, but the current prevalence is less than originally reported (15% to 50%). This probably results from the increased prevalence of antenatal steroid exposure. Therefore the clinician should be particularly vigilant in checking for nonoliguric hyperkalemia in extremely preterm infants whose mothers have not received antenatal steroids before their birth.

2. Other causes of hyperkalemia of which to be cognizant are oliguric acute renal failure and drugs that inhibit K excretion (e.g., spironolactone and enalapril).

3. Hyperkalemia may be a life-threatening emergency. In this circumstance inhalation treatment with albuterol is most rapidly effective.

373839404142434445

Acid–Base Balance

Hydrogen ion concentration ([H+]) is measured potentiometrically using a complicated system that employs two electrodes (usually Ag/AgCl) designed such that the potential between them is sensitive to the [H+] in the intervening medium. [H+] is expressed as pH, which equals the negative logarithm of [H+] (−log[H+]). Because pH is defined as the negative log [H+], pH decreases as [H+] increases and increases when [H+] decreases.

Note: Unfortunately, as a result of expressing pH as −log[H+], the proportional change in [H+] is masked. To understand logarithm, think of “power.” Thus 103 = 1000 and log (1000) = 3. When the pH changes by 0.3 units (e.g., from 7.4 to 7.1), the hydrogen ion concentration nearly doubles from 40 to 79 nanoMol/L.

The partial pressure of oxygen is measured amperometrically by the Clark electrode. The reduction reaction of interest is: 4e− + O2 + 2H2O = 4OH−. Current flows in linear proportion to the activity of dissolved oxygen.

The partial pressure of carbon dioxide (CO2) is measured using an electrode with a semipermeable membrane that allows only CO2 to diffuse into the electrode compartment, where it is converted to carbonic acid. The hydrogen ions produced by this reaction are then measured as previously described. The semipermeable membrane ensures that this measurement is completely independent of blood pH.

Plasma bicarbonate concentration image is not measured; it is calculated from the Henderson–Hasselbalch equation:

image

The concentration of carbonic acid ([H2CO3]) is not measured, but it is proportional to the dissolved carbon dioxide (CO2), with which it is in equilibrium. Dissolved carbon dioxide equals the product of the solubility coefficient of carbon dioxide in plasma at 37° C (0.031) and the partial pressure of carbon dioxide (pCO2), which is measured. Therefore the image can be calculated from the measured pH and measured pCO2 as follows:

image

The equation uses pK′ (the apparent pK), to account for the equilibrium between dissolved CO2 and image. The pK′ for H2CO3 dissociation in adult human plasma is 6.1.

The blood buffer bases of human adults are plasma image, plasma proteins, image in red blood cells, and hemoglobin (Hgb). The effect of these buffers is to establish and stabilize a pH of blood at approximately 7.4.

When measured, buffer base is the number of millimoles of strong base or strong acid needed to titrate 1 L of blood (Hgb = 15 g/dL) to pH = 7.4 at 37° C while pCO2 is held at 40 mmHg (at which point the addition of base or acid has restored the total blood buffers to normal values). Base excess (BE) in the blood (actual BE) is the difference between what actually is measured in the test sample and the sum of these values.

In clinical practice it is the BE in the extended extracellular space (red blood cells + plasma + interstitial fluid [ISF]) that is of interest. The concentration of buffer base in the ISF is lower than whole blood, primarily because ISF contains no Hgb. Therefore the algorithm used in blood gas autoanalyzers to calculate ECF BE uses a model of the blood volume diluted with ISF. There are minor variations in the algorithm used to calculate ECF BE, but the most common one is as follows:

image

The normal total of extracellular buffers for infants is 3 to 4 mEq/L lower, so infants normally have a base deficit in this range.

This has been subject of some debate for some time. However, BE is easier to interpret than serum image because it is less dependent on pCO2. When an increase in [H+] is not due to an increase in respiratory acid (i.e., carbonic acid produced from the combination of CO2 and H2O), the added H+ is bound by the buffer anions and base excess falls in direct proportion to the added H+. However, when an increase in [H+] is due to an increase in CO2, serum image increases (because it is in equilibrium with CO2) and the other buffer anions decrease in direct proportion; thus BE remains unchanged. Therefore at a pH of 7.4, what serum image is normal depends on the measured pCO2 ( Table 9-3).

The serum image in preterm infants is normally 17 ± 1.2 mEq/L, with two standard deviations encompassing values as low as 14.5 mEq/L. During the first week of life, term infants have a serum image of 20 ± 2.8 mEq/L. During the first year of life, the serum image is still only approximately 22 ± 1.9 mEq/L, compared with 23 ± 1 mEq/L and 26 ± 1 mEq/L in older children and adults.

These differences in normal serum bicarbonate levels with maturation result from the increased capacity of the mature kidney to conserve bicarbonate and to excrete [H+]. These factors also impair the capacity of the newborn to excrete acid loads. This is the result of immaturity of carbonic anhydrase in the renal tubules and the intercalated cells of the collecting duct.

Titratable acid is a term to describe acids such as phosphoric acid and sulfuric acid, which are involved in acid excretion. It excludes ammonium (NH4+) as a source of acid and is part of the calculation for net acid excretion. The titratable acid excretion rate in term infants younger than 1 month old is about one half of adult values, and the ammonium excretion rate about two thirds that of older children and adults. Preterm infants have even lower rates. After 1 month of age the net acid excretion rate in term infants is similar to that in older children and adults when expressed per 1.73 m2. Preterm infants also increase their rates of titratable acid and ammonium excretion with maturation, but these rates still remain lower than in term infants, even up to the age of 4 months. After 1 month of age the amount of ammonia excreted also depends on diet (ammonia production is increased in infants fed cow’s milk compared with that of infants fed breast milk).

During the first 3 weeks of life a premature infant can reduce the urine pH only to 6 ± 0.1. After 1 month, the urine pH can be reduced to 5.2 ± 0.4.

It is not useful. The oxygen saturation reported with the blood gas is calculated from the measured pO2 using an algorithm based on the adult oxygen–Hbg desaturation curve.

Acid–base measurements are made in the blood, but they are the same in the ISF space. Because image is calculated from pH and pCO2, it represents the plasma concentration of image. As calculated by blood gas autoanalyzers, the reported BE reflects the difference between the normal and actual buffer base concentrations. However, intracellular acid–base status cannot be measured in clinical practice. Because CO2 diffuses across cell membranes much more rapidly than image, it is possible for rapid changes in pCO2 to change the acid–base profile of the two compartments in different directions and at different rates. When attempting to treat acid-base disorders, the clinician must consider the possible consequences, such as worsening intracellular acidosis in the face of alkalinization of the ECF with infusions of bicarbonate.

Strictly speaking, acidemia and alkalemia refer to the actual pH of the blood relative to a pH of 7.4. A lower pH indicates acidemia; a higher pH indicates alkalemia. Acidosis and alkalosis refer to the respiratory and metabolic components of acid–base status compared with normal:

After a known amount of solute is introduced into a solution, the concentration is measured, and the apparent volume in which the solute is distributed is calculated. This volume is called the volume of distribution, and it is used to estimate how much solute is needed to change the measured concentration of that solute. For simple single compartments and inert solutes, the calculation measures the true volume. For multicompartment systems and unstable solutes, the solute may be distributed unevenly (i.e., either concentrated in or excluded from various compartments), metabolized, or otherwise eliminated. In these systems the calculated volume is different from the true volume in which the solute is distributed. Because of its interaction with a number of buffer systems, both intracellular and extracellular, and its elimination as CO2 through the lungs, the volume of distribution of bicarbonate is larger than the ECF space. For metabolic acidosis in neonates the dosage should be based on the following formula if blood gases and pH measurements are available: image(mEq) = 0.3 × weight (kg) × base deficit (mEq/L). The usual dosage is 1 to 2 mEq/kg/dose.

The anion gap is the difference in the serum between the concentrations of cations and anions. It its calculated as follows:

image

The [K+] may be excluded from the calculation because wide variation in serum potassium is lethal. With [K+] in the equation the normal anion gap is approximately 12, and without [K+] in the equation it is approximately 8.

If there is an increase in unmeasured cations, the anion gap will be increased. If there is an increase in unmeasured anions, the anion gap will be decreased.

Theoretically, it should be. Distinguishing between metabolic acidosis caused by bicarbonate loss and metabolic acidosis caused by increases in organic acid (an unmeasured cation) is a common and important problem. The anion gap will be normal when acidosis is caused by bicarbonate loss (because it is associated with increased renal tubular reabsorption of Cl− and therefore increases in serum [Cl−] without change in unmeasured anions. On the other hand, when metabolic acidosis results from an increase in organic acid (e.g., lactic acid), the sum of unmeasured cations will be higher. Unfortunately, there is so much overlap between a normal anion gap (no change in unmeasured cations or anions) and abnormal anion gaps resulting from a change in unmeasured cations or anions that the anion gap is clinically useful only in cases of extreme changes in unmeasured cations and anions. Because the serum lactic acid concentration can be readily measured clinically and because it is by far the organic acid most likely to be increased, the anion gap has fallen into disuse. It can be helpful, though, with marked elevation in organic acids whose measurements are less readily available.

As a general rule, replacement of bicarbonate when body losses of bicarbonate are excessive (e.g., through the stool or urine) is appropriate. On the other hand, there is minimal evidence documenting the value of sodium bicarbonate infusions to correct acidemia resulting from many, if not most, other causes (e.g. lactic acidosis). In fact, data in animals, children, and adults suggest that correction of lactic acidosis with sodium bicarbonate infusions may be detrimental. Although it is relatively easy to make the pH of the ECF change in the desired direction, it is much more difficult to know in what direction the associated change in intracellular pH will be, which is the relevant issue for cell function. Moreover, if the cause of the acidemia is ongoing, the improvement in pH will be temporary; the primary cause of the acidemia must be corrected. Therefore sodium bicarbonate treatment should be used cautiously, if at all. 464748495051525354

image KEY POINTS: ACID–BASE BALANCE

Diuretics

Hyponatremia is the result of too little sodium relative to water in the ECW compartment; therefore it may be caused by a deficit of sodium or an excess of water in the ECW compartment. The primary action of loop diuretics is to inhibit chloride (and thereby sodium) reabsorption in the loop of Henle. Therefore hyponatremia with loop diuretics could be caused by a sodium deficit resulting from excessive diuretic therapy or from excessive administration of free water. The former is managed by decreasing the frequency of loop diuretic administration, the latter by decreasing free water intake.

Loop diuretics induce hypercalciuria by inhibiting renal tubular calcium reabsorption. Therefore chronic administration of these agents can cause nephrocalcinosis, calcium nephrolithiasis, or both.

Diuretics cause metabolic alkalosis by increasing potassium secretion. This results from the increased delivery of water and sodium to the distal tubule and is treated with potassium chloride (KCl) supplementation. Diuretic therapy also induces a reduction in effective intraarterial volume and thereby activates the renin-angiotensin-aldosterone system, which stimulates secretion of potassium in the distal tubule. Blocking the effect of aldosterone on the distal tubule therefore counteracts the metabolic consequences of pharmacologic diuresis. Accordingly, adding spironolactone, a competitive inhibitor of aldosterone, to the diuretic regimen may prevent or improve derangements in serum bicarbonate and potassium concentrations. Caution should be used in adding spironolactone to the diuretic regimen and supplementing with KCl. 100

image KEY POINTS: DIURETICS

Differential Diagnosis and Evaluation of Oliguria

Your question is not so naïve, given the wide range of urine volumes from the most dilute to the most concentrated. The nurse likely responds on the basis of physical evidence; for example, he or she may say that the infant had only three wet diapers over the past 24 hours. If the baby is in an intensive care unit and the urine volume is being quantified, urine flow rate can be calculated. Within the first 24 hours after delivery the volume may be as low as 0.5 to 0.7 mL/kg/h, but beyond this period it is usually greater than 1 mL/kg/h. Oliguria is defined as a urine output persistently below 1 mL/kg/h.

In considering what the causes of oliguria are, you need to remember the determinants of urine flow rate (see Question 6). The primary causes of oliguria are as follows:

image Dehydration. Dehydration is defined as an inappropriately negative decrease in total body water, sodium, or both caused by insufficient water and sodium intake. If urine can be obtained for analysis, urine [Na+] will be low and urine osmolality will be high with dehydration. Treatment depends on the cause but always includes replenishment of total body water and sodium.

image Acute renal failure (ARF). Renal failure by definition is a decrease in GFR below normal for gestational and postnatal age. Evaluation of serum [Cr] is required to judge whether GFR is reduced. However, a single value, especially in the first days of life when serum [Cr] is largely a function of maternal serum [Cr], will not be sufficient. The pattern of change over time, taking into account gestational and postnatal age, is more relevant. Treatment of ARF depends on the underlying etiology, but the principles of management are shown in Table 9-4.

TABLE 9-4

PRINCIPLES OF MANAGEMENT FOR ACUTE RENAL FAILURE

Monitor weight.

Monitor urine output and fluid balance.

Monitor serum electrolytes, blood urea nitrogen, and creatinine.

Remove potassium from intravenous fluids until renal output is adequate.

Adjust doses of drugs excreted by the kidney.

Provide adequate nutrition.
 Adjust protein intake based on blood urea nitrogen to avoid overload.
 Add calories as carbohydrate and fat.

Correct acidosis with supplemental acetate, citrate, or bicarbonate.

Attempt a trial of furosemide to promote and maintain urine output.

Support blood pressure with dopamine.

Attempt dialysis, if necessary.

From Ringer SA. Acute renal failure in the newborn. Neoreviews 2010;11:e243.

image Syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH is the secretion of antidiuretic hormone by the hypothalamus in the absence of volume or osmolar stimuli. Treatment is restriction of free water.

It is important to note that all the aforementioned causes may occur without associated oliguria, but urine output should be relatively low. There is an extensive differential diagnosis for each of these primary causes, and the clinical context is important in narrowing the differential diagnosis.

This would be consistent with ARF because serum [Cr] should fall after birth in a term newborn.

Urinary indices to separate prerenal ARF from intrarenal ARF are not as useful in neonates as in older children and adults. However, the best index is the fractional excretion of sodium (FENa), which is calculated as follows:

image

In prerenal failure in which renal tubular function is normal, FENa is 2.5% to 3%. A FENa above 2.5% to 3% indicates intrarenal ARF with associated renal tubular injury. Because of overlap between the two groups, specificity is limited. Note that during postnatal natriuretic diuresis or extracellular volume (ECV) expansion, FENa will be high; in this case, however, urine output should also be high. However, in the polyuric phase of ARF, urine output and FENa are abnormally high. The former and the latter can be differentiated by urine osmolality. With ECV expansion the urine is hypoosmolar; in the polyuric phase of ARF the urine is isoosmolar ( Table 9-5).

TABLE 9-5

URINE INDICES IN PRERENAL AND INTRINSIC RENAL FAILURE

image

Data from Ringer SA. Acute renal failure in the newborn. Neoreviews 2010;11:e243

The most likely diagnosis is oligohydramnios sequence.

The most helpful initial test would be abdominal sonography concentrating on the kidneys, ureters, and bladder. 555657585960

Differential Diagnosis and Evaluation of Polyuria

A urine flow rate greater than 4 to 5 mL/kg/h qualifies as polyuria.

Polyuria can be physiologic in response to excessive water and sodium intake or ECV expansion.

Pathologic causes of polyuria include the following:

image Impaired reabsorption of Na+ by the kidney. This is often the result of renal tubular injury or disease.

image Osmotic diuresis. This is caused by the filtration of either a substance that is not reabsorbed by the renal tubules or a substance whose filtration rate greatly exceeds the capacity of the renal tubules to reabsorb it (e.g., glucose with marked hyperglycemia). In this case the offending substance impairs reabsorption of water and sodium, primarily in the proximal tubule. Because of the increased delivery of water and Na+ to the distal tubule, K+ secretion will also be stimulated, resulting in an inappropriate increase in urinary potassium excretion (or kaliuresis) and potassium depletion.

image Diabetes insipidus (DI). This results from the inability to concentrate the urine because of deficient production of antidiuretic hormone by the hypothalamus (central DI) or lack of responsiveness of the cortical collecting tubule to antidiuretic hormone.

66. A newborn male infant is found to have renal failure caused by obstructive uropathy as the result of posterior urethral valves. A catheter is inserted into the bladder through the urethra. There is a large diuresis. The ARF gradually subsides with normalization of the serum creatinine level. Months later, the mother complains that her infant requires many more changes of diapers than did her other children. What is the likely explanation?

Severe obstruction of the urinary tract during nephrogenesis may lead to renal maldevelopment and can result in renal dysplasia. An early sign of dysplasia is a renal concentrating defect that manifests as polyuria and polydipsia. Some affected children maintain a normal GFR throughout their lives, but others have a slowly progressive decline in renal function, resulting in end-stage renal disease, often during the teenage years.

The neonatal form of Bartter syndrome, also known as hyperprostaglandin E syndrome, may present this way. In such cases the mother has polyhydramnios caused by increased fetal urine excretion; affected infants are often born prematurely. Postnatally, polyuria and renal sodium wasting continue, resulting in hypovolemia and prerenal ARF. Infants with Bartter syndrome also have hypercalciuria and increased excretion of prostaglandin E2. Additional findings may include hypokalemia and an elevated serum bicarbonate level, but this is not as common in infants as it is in older children with Bartter syndrome.

The defect appears to be in the ascending limb of the loop of Henle involving the NaCl, KCl cotransporter, or the potassium channel. There are two genetic forms of neonatal Bartter syndrome, one involving the gene that codes for the cotransporter (locus SLC12A1 on chromosome bands 15q–21) and one that results from mutation in the ROMK gene (locus KCNJ1 on chromosome bands 11q24–25), which controls the potassium channel.

Treatment with a prostaglandin synthetase inhibitor (e.g., indomethacin, ibuprofen) reverses many of the abnormalities. Salt-losing adrenal insufficiency must be excluded, but it is usually associated with hyperkalemia and acidosis. 61

image KEY POINTS: OLIGURIA AND POLYURIA

Renal Tubular Acidosis

All four types are associated with a hyperchloremic, normal anion gap acidosis.

RTA usually presents with nonspecific symptoms such as failure to thrive, lethargy, vomiting, and tachypnea. The hallmark of this syndrome is the presence of a normal anion gap hyperchloremic metabolic acidosis.

In type I (distal) RTA the neonate presents with hypocitraturia, hypercalciuria, nephrocalcinosis, and failure to thrive with growth retardation. There are both dominant and recessive forms of distal RTA. The dominant form usually presents at an older age. The recessive form of distal RTA that presents in the neonatal period is associated with early onset bilateral sensorineural hearing loss. These patients often have vomiting and dehydration and can present with rickets.

Type II (proximal) RTA can present in infancy with ocular abnormalities such as band keratopathy, cataracts, and glaucoma. In addition to presenting with metabolic acidosis, these patients have growth restriction, defective dental enamel, developmental delay, and calcium deposits in the basal ganglia.

Type III RTA (combined proximal and distal) presents in infancy with osteopetrosis. These patients often have early nephrocalcinosis with blindness and deafness.

Obstructive Uropathy

The most common finding is resolution of hydronephrosis (48%). Another 15% will show a nonobstructed, enlarged pelvis. The remaining will show the following:

Less common causes of hydronephrosis include ectopic ureter, prune-belly syndrome, urethral atresis, retrocaval ureter, ureteral stricture, hydrocolpos, pelvic tumor, and cloacal anomaly.

In fetal hydronephrosis 50% of cases improve, 40% remain stable, and 10% progress.

Criteria for prenatal intervention are as follows:

Prenatal intervention is generally limited to males with posterior urethral valves.

The goals of intervention are to restore sufficient amniotic fluid volume to allow normal pulmonary development and maximize ultimate renal function.

Renal and bladder ultrasound is the first imaging needed in a neonate with an abnormal prenatal ultrasound. A normal 48-hour postnatal ultrasound is probably sufficient to exclude clinically significant disease, although some physicians will obtain an ultrasound later.

If unilateral hydronephrosis is present, a voiding cystourethrogram (to exclude vesicoureteral reflux) and serial ultrasounds are recommended. If there is progression of hydronephrosis, then a nuclear medicine scan (MAG-3 or DMSA) is indicated to assess kidney function. If there is bilateral hydronephrosis on the postnatal ultrasound, the neonate should have a vesicoureterogram (VCUG) within the first week of life.

Ureteropelvic junction obstruction is the most common cause of hydronephrosis in children. Diagnosis requires the presence of hydronephrosis (ultrasound with dilated renal pelvis in the absence of a dilated ureter). Pyeloplasty, excision of the stenotic segment, is usually necessary in neonates with an abdominal mass, bilateral hydronephrosis, or a solitary kidney.

A ureterocele is a cystic dilation of the distal end of the ureter. It is obstructive because it may extend through the bladder neck (ectopic), but it may remain entirely within the bladder (intravesical). This condition affects girls more often than boys and is usually associated with the upper pole of a completely duplicated collecting system. Ultrasound commonly shows hydronephrosis in the upper pole, a dilated ureter, and a ureterocele in the bladder. 6465666768697071

Posterior Urethral Valves

PUV is usually caused by an obstructing membrane extending from the verumontanum at the base of the prostatic urethra to the more distal anterior portion of the membranous urethra. This membrane contains only a small opening through which urine can pass; as the urine flows, the membrane billows out in a windsock fashion as a one-way flap valve, causing obstruction. The degree of obstruction varies depending on the size of the opening of the membrane.

The most common presentation of PUV is poor urinary stream during the postnatal period. The antenatal ultrasound often demonstrates bilateral hydroureteronephrosis, a dilated, thick-walled bladder with poor emptying, and occasionally oligohydramnios. A more severe clinical presentation of PUV in the postnatal period is with respiratory distress secondary to pulmonary hypoplasia, renal insufficiency, urosepsis, and heart failure. Depending on the degree of obstruction, PUV may also present after the neonatal period with an abdominal mass, which indicates a distended bladder, ureter, or renal pelvis.

81. What are the short- and long-term consequences of PUV?

82. Does intervention after fetal diagnosis ultimately improve renal function?

Fetal intervention, including vesicoamniotic shunt placement, is performed when progressive oligohydramnios is noted on serial fetal ultrasounds to improve amniotic fluid levels. Oligohydramnios is detrimental to pulmonary development and may cause pulmonary hypoplasia. Correcting oligohydramnios is thought to allow better expansion of the chest wall and lung development, lessening the chance of pulmonary hypoplasia. Survival without intervention is 0% with a urinalysis consistent with a poor prognosis and 40% with a good prognosis. Prenatal intervention increases the chance of survival to 38% with a poor prognosis and 69% with a good prognosis.

Conditions that allow decompression of the urinary tract (i.e., “pop-off” mechanism) have a better prognosis. Such conditions include bladder diverticular formation, urinary ascites, and unilateral vesiculoureteral reflux dysplasia (VURD) syndrome. Urinary ascites is caused by transudation of urine across a renal calyceal fornix into the peritoneal cavity; this transudation relieves the obstruction. VURD syndrome occurs when one kidney refluxes with subsequent renal dysplasia on that side, offering protection for the contralateral kidney. 7273

image KEY POINTS: OBSTRUCTIVE UROPATHY

Hematuria

No. Hematuria is never physiologic, but it can be a common finding in sick premature infants.

Hematuria is defined as more than five red blood cells per high power field.

86. What are the causes of hematuria in the newborn infant?

87. How should infants with hematuria be evaluated?

Congenital Nephrotic Syndrome

The term congenital nephrotic syndrome is used to describe a patient who develops the nephrotic syndrome during the first 3 months of life. Nephrotic syndrome is a constellation of abnormalities that includes (1) nephrotic-range proteinuria, defined as a urinary protein excretion greater than 100 mg/m2 body surface area/24 h, calculated from a timed urine collection, or a ratio of urine protein concentration (mg/dL)/urine creatinine concentration (mg/dL) greater than 2, calculated from a single-spot urine sample; (2) nephrotic-range hypoalbuminemia with serum albumin concentrations less than 2.5 g/dL; (3) hyperlipemia, determined from the results of measurements of serum cholesterol or triglyceride concentrations (or both); and (4) peripheral edema that may be present in many patients.

Abnormal proteinuria is defined as urine protein excretion greater than 100 mg/m2 body surface area/24 h, calculated from a timed urine collection, or a ratio of urine protein (mg/dL)/urine creatinine (mg/dL) greater than 0.5, calculated from a single-spot urine specimen. Preterm infants are more likely to exhibit proteinuria than are term infants. Abnormal proteinuria can occur in newborns as a result of various pathologic processes, including chronic volume depletion, congestive heart failure, and interstitial nephritis caused by antibiotic administration. However, nephrotic-range proteinuria, as defined previously, suggests significant damage to glomerular epithelial cells caused by some pathologic process. Therefore discovery of nephrotic-range proteinuria, even in the absence of the full nephrotic syndrome, should prompt an evaluation.

The most common cause of nephrotic syndrome in the first 3 months of life is congenital nephrotic syndrome of the Finnish type, an autosomal recessive disease that is most common among Finns, although cases have been reported from all over the world. A less common cause of congenital nephrotic syndrome is diffuse mesangial sclerosis (DMS). DMS seems to have a genetic basis, but the exact mode of inheritance is unknown. Patients with DMS tend to develop nephrotic syndrome between 3 months and 2 years of age. Other renal lesions that can cause neonatal nephrotic syndrome may be associated with malformations that are not inherited in a known mendelian fashion. An example is Denys–Drash syndrome, a combination of ambiguous or female external genitalia with gonadal dysgenesis, a 46,XY genotype, and a predilection for the development of nephroblastoma.

Congenital infections may also cause nephrotic syndrome in a neonate. Congenital syphilis is the most common infectious association, but hepatitis B, C, human immunodeficiency virus (HIV), and cytomegalovirus (CMV) infections are also associated with congenital nephrotic syndrome. Many patients with congenital nephrotic syndrome resulting from a congenital infection demonstrate depressed serum concentrations of one or more components of the complement system.

Infants with congenital nephrotic syndrome of the Finnish type (CNF gene map locus 19q13.1) generally have a large placenta (mean placental/fetal weight, 0.4) and are born preterm and small for gestational age. Prenatal evaluation of the mother of a patient with congenital nephrosis, Finnish variant (CNF), commonly demonstrates elevated concentrations of alpha-fetoprotein in both the amniotic fluid and the mother’s blood. These abnormalities are not observed in mother–infant pairs afflicted with other forms of congenital nephrotic syndrome.

The evaluation should be, as usual, driven by the differential diagnosis. Although the most likely underlying diagnosis is congenital primary glomerular disease, causes of secondary nephrotic syndrome should be pursued. A careful physical examination and renal/pelvic imaging (ultrasonogram) are helpful to identify any abnormalities of the external genitalia, the internal reproductive organs, or the kidneys (such as a Wilms tumor) that may suggest Denys–Drash syndrome or other malformation syndromes associated with congenital nephrotic syndrome. A family history of consanguinity, fetal or neonatal demise, or renal failure may be useful in suggesting a genetic cause for the nephrotic syndrome. Blood should be drawn to measure the levels of serum complement and complement components and to uncover evidence of prenatal infection with syphilis, hepatitis B or C, HIV, CMV, Toxoplasma gondii, or malaria. If the imaging and serologic evaluations reveal nothing, a renal biopsy should be performed to help make a diagnosis and guide future management.

As a group, patients who develop nephrotic syndrome in the newborn period have a guarded prognosis. With the initiation of renal replacement therapy (usually peritoneal dialysis) in these neonates, the long-term survival rates have increased dramatically in the past few decades. Possible causes of increased morbidity and mortality in this population include the development of bacterial infections, developmental delay, growth failure, thrombotic events, acute or chronic renal failure, complications of renal transplantation, and Wilms tumor among patients with Denys–Drash syndrome. 75

Nephrocalcinosis

Nephrocalcinosis is usually suggested by the findings on a renal ultrasound of a hyperechoic renal medulla, commonly in a very-low-birth-weight infant. Nephrocalcinosis results from microscopic calcification in the medullary portion of the kidney but often is accompanied by hyperechoic foci in the calyces, which represent renal calculi as well. Nephrocalcinosis can present with hematuria or urinary tract infection, but it is usually an incidental finding.

Yes. The association of long-term furosemide therapy and nephrocalcinosis has been well recognized since the original description by Hufnagle et al. in 1982. There are, however, other diagnostic considerations for infants with nephrocalcinosis, which are outlined in Table 9-6.

TABLE 9-6

DIFFERENTIAL DIAGNOSIS OF NEPHROCALCINOSIS IN INFANTS

NORMOCALCEMIC HYPERCALCEMIC NORMOCALCIURIC
HYPERCALCIURIA HYPERCALCIURIA NEPHROCALCINOSIS
Furosemide therapy Hyperparathyroidism Primary hyperoxaluria
Bartter syndrome Hypophosphatasia Enteric hyperoxaluria
Distal renal tubular acidosis Williams syndrome Renal candidiasis
Hyperprostaglandin E Idiopathic infantile Long-term hypercalcemia
Subcutaneous fat necrosis Acetazolamide therapy
Dystrophic calcifications		  

Adapted from Karlowicz MG, Adelman RD. Renal calcification in the first year of life. Pediatr Clin North Am 1995;42:1397–1413.

The value for hypercalciuria, if defined as calcium excretion of greater than the 95th percentile for an age-matched cohort, is different in infants than it is in older children. In infants younger than 7 months old the 95th percentile for urinary calcium/creatinine (mg/mg) was reported by Sargent et al. to be 0.86, and in children 7 to 18 months old the value was 0.60. In another study very-low-birth-weight infants with nephrocalcinosis had a mean urinary calcium/creatinine of 0.49 compared with 0.11 in control subjects.

Treatment of the primary cause can be important in cases not caused by long-term furosemide therapy. In infants being given furosemide, substitution of a thiazide diuretic for furosemide can decrease the calcium excretion and result in shrinkage of calculi and improvement of the medullary nephrocalcinosis. The long-term prognosis has been correlated with the course of the urinary calcium excretion.

Long-term studies of premature infants with nephrocalcinosis have suggested that 30% to 50% of the children continue to have evidence of renal calcification up to 5 years after diagnosis. There is some evidence of a slightly decreased GFR in patients with nephrocalcinosis, but these findings may be the result of prematurity and not specific for the history of nephrocalcinosis. 76777879

Hypertension

Various factors can alter the relationship between blood pressure as recorded on the NICU flow sheet and the patient’s true average baseline blood pressure. For example, blood pressure readings are affected by the patient’s position (pressures measured when the patient is supine are slightly higher than those obtained when the patient is prone), by recent medical manipulations, and by recent feedings. Cuff inflation, by itself, can stimulate the startle response, which can cause a transient increase in blood pressure. In addition, body geography has an impact on blood pressure measurements: Pressures measured in the legs are normally somewhat higher than those measured in the arms.

This question is often difficult to answer. Data regarding the normal ranges of systolic and diastolic blood pressures for term newborns and premature infants at various gestational ages have been published. Studies have shown that blood pressure in the neonatal period increases with gestational age, birth weight, and postmenstrual age.

A single random recording of elevated blood pressure may not be clinically significant because it may not exemplify the patient’s average blood pressure. A more representative blood pressure measurement is recorded when the infant has not been fed or manipulated for 90 minutes before the evaluation; further refinement is achieved when several blood pressure measurements are made over a period of 5 to 10 minutes.

The diagnosis of hypertension should be made only if the systolic and diastolic blood pressures are above the 95th percentile on at least three separate blood pressure measurements recorded at 2-minute intervals during a time when the infant is quiet and otherwise undisturbed ( Table 9-7).

The majority of hypertension in the NICU is renovascular in etiology. Umbilical artery catheter (UAC)–associated thrombosis can release thrombotic emboli to the aorta, the renal arteries, or both and thus induce the release of renin leading to hypertension. Thrombus formation at the time of UAC line placement is most likely secondary to disruption of the vascular endothelium of the umbilical artery.

Extremely-low-birth-weight infants with bronchopulmonary dysplasia appear to develop hypertension in the absence of clear evidence of renal artery occlusion at a rate higher than that seen with renal thrombosis. The etiology in many of these cases cannot be determined, although it is postulated that hypoxemia might be involved. Over 50% of these infants with bronchopulmonary dysplasia develop elevated blood pressures after discharge from the NICU. Extremely-low-birth-weight infants who have been hospitalized for a prolonged period should therefore have routine blood pressure measurements made during their well-baby visits throughout the first year of life. Blood pressure measurement is often neglected by pediatricians because of the difficulty in obtaining an accurate determination in these tiny babies. Other causes of neonatal hypertension are listed in Table 9-8.

TABLE 9-8

DIFFERENTIAL DIAGNOSIS OF NEONATAL HYPERTENSION

AORTIC OBSTRUCTION

Coarctation of the aorta
Aortic arch interruption
Descending aorta thrombosis

RENAL AND RENOVASCULAR PROBLEMS

Renal artery thrombosis or embolus
Renal artery stenosis
Renal vein thrombosis (late)
Cystic renal disease
Obstructive uropathy

PHARMACOLOGIC ADVERSE EFFECTS

Catecholamines
Cocaine
Dexamethasone
Theophylline

OTHER CAUSES

Exogenous fluid administration
Environmental cold or noise stress
Seizures
Chronic lung disease

Most patients who develop hypertension as a result of complications from a UAC are normotensive until the UAC is pulled. When the UAC is removed, hypertension often develops abruptly. The onset of hypertension in this situation coincides with the embolization of renal vessels by clots that are sheared from the tip of the catheter during its withdrawal. Hypertension associated with UAC thrombosis usually resolves by 2 years of age.

UAC-related hypertension is generated by high circulating concentrations of angiotensin II. Angiotensin II production can be blocked by use of drugs that inhibit angiotensin-converting enzyme (ACE) inhibitors. Captopril is usually the ACE inhibitor of choice, with a starting dose of 0.01 to 0.5 mg/kg/dose given three times a day. The daily dose may be increased to a maximum of 6 mg/kg/day, if needed. Other ACE inhibitors such as enalapril or lisinopril may be used with equally beneficial effects, but dosing of these drugs for very small patients may be problematic for pharmacists. The use of ACE inhibitors is somewhat controversial because they may cause an exaggerated fall in blood pressure in the preterm infant. In addition, ACE inhibitors may hinder the final stages of renal maturation. For both those reasons, some clinicians do not use an ACE inhibitor until the infant has reached 44 weeks’ postmenstrual age. For other causes of hypertension, calcium channel blockers are recommended. Table 9-9 summarizes the dosing for the commonly used antihypertensive agents.

TABLE 9-9

DOSING OF SELECTED ANTIHYPERTENSIVE AGENTS IN NEONATES

image

image

∗Avoid use in preterm infants until 44 weeks’ postmenstrual age

Data from Dione JM, Flynn JT. Hypertension in the neonate. Neoreviews 2012;13:e401.

Most cases of hypertension in newborns are caused by excessive circulating concentrations of hormones that cause hypertension as a result of their ability to increase peripheral vascular resistance and/or their ability to cause salt and water retention.

Renin produced by the kidney in response to either UAC-related renal artery thrombosis or to congenital renal artery stenosis generates angiotensin I. Angiotensin I is converted to angiotensin II by the action of ACE that is present in the kidney, lung, placenta, brain, and other organs. Angiotensin II has multiple effects when it circulates in the blood, including increased peripheral vascular resistance, augmented production and release of aldosterone by the adrenal glands, and stimulation of thirst and salt craving. All of these angiotensin II actions can increase blood pressure.

Rare endocrine disorders such as virilizing adrenal hyperplasia caused by 11β-hydroxylase deficiency and primary hyperaldosteronism may cause neonatal hypertension owing to overproduction of mineralocorticoid (desoxycorticosterone in the case of 11β-hydroxylase deficiency; aldosterone in patients with hyperaldosteronism). The overproduction of mineralocorticoid in these diseases causes hypertension by way of inappropriate renal salt and water retention. There may also be a mineralocorticoid-mediated hypokalemic metabolic alkalosis.

Prenatal or postnatal exposure to exogenous steroids (e.g., betamethasone, prednisone, or methylprednisolone) can likewise cause hypertension in newborns.

Despite the conventional wisdom that coarctation of the aorta is associated with a cardiac murmur and absent femoral pulses, many newborns with aortic coarctation do not fit the mold. In hypertensive infants measurement of blood pressure in both upper and lower extremities is crucial. Coarctation of the aorta should be suspected if the systolic pressure in the leg is more than 10 mmHg lower than the systolic pressure in the arms. It is also important to note that hypertension may persist in these infants even after the coarctation has been surgically repaired. 808182

image KEY POINTS: HYPERTENSION

Renal Vein Thrombosis

Maternal factors known to increase the risk of RVT in the newborn include diabetes mellitus, elevated levels of immunoglobulin G anticardiolipin antibody, and activated protein C resistance. In addition, infants born to mothers who have required anticoagulation during pregnancy for thrombotic disorders should be treated with special caution.

Infants with inherited thrombophilic disorders, such as a deficiency of protein S, protein C, or antithrombin III, have an increased risk of RVT. Newborns who are otherwise healthy may develop RVT if they have experienced perinatal asphyxia, an episode of sepsis, or hyperosmolarity and dehydration caused by, for example, administration of intravenous radiocontrast or fluid losses as a result of vomiting or diarrhea.

Clinicians should suspect the diagnosis of RVT if a newborn develops hematuria (often gross hematuria) in association with a swollen kidney, palpable as a flank mass, and abrupt or progressive elevation of the plasma creatinine concentration. Suspicion of RVT is especially warranted if these abnormalities are accompanied by thrombocytopenia. RVT may not, however, always induce dramatic clinical or laboratory changes. For example, a newborn with RVT may produce urine that is clear yellow; microscopic hematuria with or without proteinuria may be the only urinary abnormality. Even when the RVT does not cause major changes in the urinalysis, however, there is usually a measurable deterioration of renal function, thrombocytopenia, and perhaps a transient elevation of blood pressure.

Renal ultrasonography is a useful tool. It is noninvasive and usually identifies areas of the kidney that are affected by RVT. The renal parenchyma that experiences obstruction to venous drainage appears swollen and hyperechoic.

Renal scans using intravenous injections of technetium diethylenetriaminepentaacetic acid (DTPA) or technetium dimercaptosuccinic acid demonstrate perfusion defects in the areas that are drained by the thrombosed renal vessels. These scans, however, do not provide anatomic detail, nor are they able to differentiate between arterial and venous renovascular disease. Furthermore, the utility of renal scans is limited by the fact that they generally require the sick infant to be transported from the neonatal unit to the nuclear medicine department.

Because RVT may be caused by serum hyperosmolarity, intravenous administration of hypertonic radiocontrast agents may be ill-advised. Therefore the clinician should not order studies that may require administration of intravenous contrast agents (e.g., intravenous pyelography, computed tomography).

Infants with RVT commonly experience a period of renal insufficiency that results in the following fluid and electrolyte abnormalities:

Neither thrombectomy nor nephrectomy has a role. Thrombectomy is unlikely to provide benefit because most cases of RVT begin in the peripheral renal venous circulation; therefore removal of a clot present in the main renal vein is not likely to restore venous drainage to the bulk of the affected renal parenchyma. Some experts advocate attempting thrombectomy when bilateral RVT also involves the inferior vena cava; however, there is little evidence to support the notion that the procedure, even in the direst circumstances, improves either long-term patient survival or ultimate renal function.

Because many, if not most, kidneys with RVT ultimately recover some function as a result of recanalization of thrombosed vessels, nephrectomy of the affected kidney in the acute or subacute phase of RVT should be discouraged. Evidence that nephrectomy improves patient survival is unsubstantiated, and this procedure certainly leads to a decrease in functional nephron mass.

The usefulness of thrombolytic or anticoagulant therapy must be qualified by such terms as maybe or sometimes. Infusion of thrombocytic agents, either locally or systemically, has been used with some success in patients with RVT or renal arterial thrombosis. The risk of hemorrhagic complications, however, is significant. Because thrombolysis and venous recanalization occur as part of the normal resolution of RVT, it is not clear that pharmacologic thrombolytic therapy carries a favorable risk-to-benefit ratio.

Anticoagulant intervention that aims to prevent extension of RVT into previously uninvolved venous structures may be appropriate for some patients, particularly those who have congenital thrombophilic disorders. The prothrombotic factors that lead to RVT formation and propagation in most newborns can be eliminated without anticoagulant therapy (e.g., hyperosmolarity, dehydration). However, anticoagulants may protect infants with intrinsic abnormalities of the coagulation cascade from experiencing secondary thrombotic events. 83

Prune-Belly Syndrome

Prune-belly syndrome is a rare congenital anomaly that consists of genital (usually undescended testes) and urinary tract abnormalities with absent or decreased abdominal wall musculature ( Fig. 9-6). Prune-belly syndrome is caused by urethral outlet obstruction early in development.

From bottom to top, the most common urinary tract anomalies are as follows:

It is important to note that the anatomic abnormalities of the urinary tract in patients with prune-belly syndrome may be caused by primary, intrinsic, and diffuse defects of embryologic development of the structures involved, which are different from the discrete lesions of obstruction or reflux that may occur in the urinary tract of otherwise normal newborns. However, the abnormalities may appear similar to those that occur in prune-belly syndrome. For example, the large, thick-walled bladder of patients with prune-belly syndrome may occur in the absence of bladder outlet obstruction, although the bladder may bear a resemblance to that of a patient with PUV. Similarly, although ureteral dilation in otherwise normal infants is commonly associated with vesicoureteral reflux or obstruction, a similar ureteral lesion in a patient with prune-belly syndrome may occur in the absence of reflux or obstruction.

Patients with prune-belly syndrome often have additional problems, including pulmonary hypoplasia and Potter facies (flattening of the nose, redundant skin, receding chin, ocular hypertelorism, and low-set ears); hip dislocation or subluxation; talipes equinovarus; congenital cardiac disease, especially atrial septal defect, ventricular septal defect, and tetralogy of Fallot; and gastrointestinal anomalies.

The urologic/renal dysfunction in patients with prune-belly syndrome is almost certainly responsible for some of the nonurologic complications. For example, oligohydramnios, a common complication of prune-belly syndrome pregnancies, accounts for the pulmonary hypoplasia, the hip dislocation or subluxation, and the talipes equinovarus that may be seen in these newborns. It has been suggested that the underlying defect in prune-belly syndrome is abnormal mesoderm development.

The initial work-up should include (1) abdominal and pelvic ultrasonography to provide a basic road map of the genitourinary anomalies and (2) voiding cystourethrography to diagnose vesicoureteral reflux and reflux into a patent urachus. Either of these two diagnoses mandates initiation of antibiotic prophylaxis. If the infant is stable enough to be transported, other imaging studies significantly enhance understanding of the genitourinary pathology. Computerized axial tomograms of the abdomen, performed before and after intravenous administration of radiocontrast material, will usually reveal more anatomic detail than ultrasound; in addition, they provide a qualitative assessment of comparative renal function (i.e., right versus left kidney). A renal scan using DTPA or MAG3 will localize any points of obstruction between the kidneys and the bladder and provides a quantitative estimate of the comparative function of the two kidneys.

Because an infant with prune-belly syndrome may also harbor gastrointestinal and cardiac anomalies, an upper gastrointestinal tract series with small bowel follow-through, a barium enema, an electrocardiogram, and an echocardiogram are also needed as part of the initial work-up.

Every newborn with prune-belly syndrome should be evaluated by a pediatric urologist. However, intervention during the newborn period should be limited to the least invasive procedures available and should be used only when necessary to relieve high-grade obstruction in the urinary tract. More extensive genitourinary reconstructive procedures should be postponed to a later date and, in fact, may not be necessary at all. There is considerable controversy about whether surgical intervention is appropriate in boys with prune-belly syndrome when their genitourinary anomalies are not associated with obstruction or vesicoureteral reflux.

At some point the surgeon must deal with the intraabdominal cryptorchidism. Orchidectomy, as a means to prevent testicular neoplasia, is an option because the reproductive potential of boys with prune-belly syndrome is probably low. An alternate approach is to relocate the abdominal testes into the scrotum by one of a variety of complex surgeries. In any case these surgical interventions can wait until the infant is several months old.

Surgical plication of the lax abdominal musculature is important for the psychological well-being of patients with prune-belly syndrome, but this cosmetic reconstruction should probably not be performed in a newborn. 848586

Cystic Kidney Disease

A multicystic kidney is the result of abnormal metanephric differentiation. There is no continuity between glomeruli and calyces, and the kidney does not function. The contralateral kidney may be normal, absent, hydronephrotic, ectopic, or dysplastic.

Renal cystic dysplasia may be unilateral or bilateral. The kidneys are usually cystic and exhibit disorganized architecture. They often contain ectopic tissue (e.g., cartilage, muscle) and do not function normally.

In polycystic renal disease there are many cysts in both kidneys, no dysplasia, and continuity between glomeruli and calyces. The kidneys are often large.

121. Describe the management of autosomal recessive polycystic kidney disease in a neonate.

122. What are some complications that can occur in infants with autosomal recessive polycystic disease?

123. Can autosomal dominant polycystic kidney disease occur in the neonate?

Yes. Affected neonates have extremely large cystic kidneys and respiratory distress, and they usually manifest significant renal failure immediately after birth.

There are no indications for biopsies in these patients. Careful evaluation with ultrasonography is sufficient for diagnostic and treatment purposes.

ExStrophy of the Bladder

The correct terms for the developmental defect shown in Figure 9-7 are bladder exstrophy and epispadias.

Bladder closure takes place between the sixth and eighth weeks of fetal life.

Bladder exstrophy should be closed in the first 48 hours of life to ensure the best possible technical results for achieving long-term continence.

The upper urinary tract is almost always normal in these children. Evaluation of these children should include assessment of the hips, however, because some of them will have hip dysplasia.

The risk is no greater than that for the general population, which is 1:50,000 live births.

The reasons are not entirely clear; however, it appears that the widespread use of prenatal ultrasonography and elective termination have had a significant impact on the incidence of bladder exstrophy worldwide. 9293

Hypospadias

The developmental defect shown in Figure 9-8 is called hypospadias.

133. Does the child shown in Figure 9-8 need immediate surgical attention?

No. Surgical correction is best done somewhere between 6 and 12 months of life, assuming there are no additional medical issues.

Penile development takes place between 12 and 15 weeks of gestation.

Chromosomal evaluation is mandatory in infants with hypospadias and nonpalpable gonads. The clinician must rule out virilizing congenital adrenal hyperplasia to prevent errors in gender assignment and avoid the risk of a salt-losing crisis in the infant.

Rare. There is no greater incidence of other genital urinary anomalies in infants with distal hypospadias than in other infants.

The incidence of hypospadias is increasing nationwide. The reason is not entirely clear, but it may have to do with increased use of in vitro fertilization or exposure to environmental estrogens and antiandrogens. 94959697

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