Alterations of Renal and Urinary Tract Function in Children
Renal and urinary disorders occur in children as well as adults. In childhood, however, the kidney and genitourinary structures are continuing to develop, so renal dysfunction may be associated with mechanisms and manifestations that are different from those in adults. In addition, some renal and urinary disorders are congenital and involve structural anomalies of the kidney and urinary drainage system.
The embryonic urinary system develops as three sets of sequentially replaced organs: the pronephros, mesonephros, and metanephros. The pronephros is a nonfunctional structure that arises at the level of the cervical and upper thoracic regions during the third fetal week and connects the primitive wolffian duct to the cloaca as the foundation for male sexual development (Figure 39-1). The development of the mesonephros and metanephros is described in Figure 39-1. The Wilms tumor 1 (WT1) gene plays an important role at all stages of kidney development and maintenance of kidney function. The wingless type signaling (WNT signaling) transduction pathway also is important for mesenchyme growth and differentiation.1,2
After glomeruli and tubules form, the tissues organize and progressively differentiate over approximately 30 days. Initial glomerular development is staggered, so there are glomeruli in various stages. In fact, a few of the first glomeruli formed degenerate and disappear during the later stages of fetal development. Progressive development continues into the ninth fetal month, when all metanephrogenic tissue then disappears.
As the embryo develops and the vertebral column straightens, the kidneys appear to ascend to the sacral area at about 6 weeks, to the third lumbar area by the third month, and to the first lumbar area at term. The kidneys rotate 90 degrees as they ascend so that renal tissue is lateral and the collecting system is medial.
While the kidneys mature, the cloaca becomes the urogenital sinus. It then differentiates into the vesicourethral canal, which forms the bladder and the upper urethra, and the urogenital sinus, which forms the main part of the urethra.
At birth the kidneys occupy a large portion of the posterior abdominal wall, and the ureters are proportionately shorter than those of an adult. All the nephrons are present at birth, and their number does not increase as the kidney grows and matures. The kidney reaches adult size by adolescence and, because of maturation of the tubular system, increases in weight 10-fold from the time of birth.
Urine formation and excretion begin by the third month of gestation, contributing to the amniotic fluid. In infancy the bladder lies close to the abdominal wall, making urinary bladder aspiration for diagnostic purposes a relatively simple procedure. The bladder descends into the pelvis with growth, changing from a cylindrical organ to the adult pyramidal shape. Although small amounts of urine are found in the bladder at birth, the newborn may not void for 12 to 24 hours.
Immediately at birth the renal blood flow and glomerular filtration rate (GFR) increase because of a decrease in vascular resistance and the need to perform excretory functions no longer performed by the placenta. Renal vascular resistance remains higher in newborns and infants, however, which may be attributed to increased levels of circulating renin. The resistance progressively declines during the first year of development, with an increasing fraction of the cardiac output going to the kidney. The GFR continues to increase, achieving adult levels by 2 years of age.
Because the kidney develops from the center toward the periphery, renal distribution of blood flow during the newborn period is primarily to the renal medulla. The result is a preferential flow to the medullary nephrons, which have comparatively short loops at this stage of development. The combination of higher blood flow and shorter loops produces a more dilute urine-approximately 600 to 700 mOsm (compared with 800 to 1200 mOsm in adults) (see Chapter 3). The immature kidney is also less responsive to the actions of antidiuretic hormone (vasopressin) (see Figure 3-5).3 The dilute urine is accentuated by a low rate of urea excretion, which is necessary to establish the concentration gradient in the medulla. Urea excretion is low primarily because infants are in a high anabolic state and use their protein for growth.
Because of a high hydrogen ion concentration, limited ability to regulate the internal environment, and lowered osmotic pressure, the infant’s renal system has a narrow chemical safety margin. The immaturity and smaller surface area of the tubules also may diminish the water reabsorption response to antidiuretic hormone (ADH). An immature tubular transport capacity means that the ability to excrete a potassium load, reabsorb bicarbonate, or buffer hydrogen with ammonia does not become efficient until approximately 2 years of age. Consequently, any disturbance such as diarrhea, infection, fasting for diagnostic tests, or improper feeding can rapidly lead to severe acidosis and fluid imbalance because the infant can rapidly develop over- or underhydration, or edema (see Chapter 3).4
After birth the proportion of total body water to body weight does not change markedly. Considerable change occurs, however, in the location of that body water as the child matures (see Chapter 3). Compared to an adult, the percentage of extracellular fluid volume of the newborn infant is nearly double. Decrease in extracellular fluid volume occurs in two different periods of rapid growth-infancy and adolescence.
An infant has not only a greater content of extracellular fluid but also a greater rate of fluid exchange. The adult consumes and excretes approximately 2000 ml of water daily, representing 5% of the total body fluid and 14% of the extracellular fluid. In contrast, the infant’s daily exchange of 600 to 700 ml represents about 20% of the total body water or nearly 60% of the extracellular volume, making control of dehydration and overhydration more difficult.
The composition of body fluids differs slightly with age. The total electrolyte concentration in extracellular fluids is greater in the newborn than in the adult. The concentrations of sodium, chloride, phosphates, and organic acids are also greater. The concentration of bicarbonate ions is lower in the infant than in the older child, with a mild acidosis evidenced by a lowered pH. These variations, combined with a lowered plasma protein level, cause a reduced oncotic pressure of the vascular compartment and favor accumulation of fluid in the tissue spaces and an increased GFR. In the healthy child these differences remain for a few weeks or months. The premature infant and the normal newborn infant are usually in a state of well-compensated acidosis and potential edema.
Congenital abnormalities of the kidney and urinary tract occur in about 1 out of 500 newborns.5 Structural abnormalities range from minor, nonpathologic, or easily correctable anomalies to those that are incompatible with life. For example, the kidneys may fail to ascend from the pelvis to the abdomen, causing ectopic kidneys-which usually function normally. The kidneys also may fuse in the midline as they ascend, causing a single U-shaped horseshoe kidney, with an incidence rate of 0.25 to 0.61 per 10,000 births.6 Approximately one third of individuals with horseshoe kidneys are asymptomatic, and the most common problems are hydronephrosis, infection, stone formation, and tumors.7 Collectively, structural anomalies of the renal system account for approximately 45% of cases of renal failure in children.
Hypospadias is a congenital condition in which the urethral meatus is located on the ventral side or undersurface of the penis. The meatus can be located anywhere on the glans, the penile shaft, the base of the penis, the penoscrotal junction, or the perineum (Figure 39-2). This is the most common anomaly of the penis and occurs in about 1 in 125 infant boys. The etiology is multifactorial and related to disruptions in male hormones, including testosterone biosynthesis defects, steroid 5α-reductase type 2 mutations, genes associated with penile and urethral development, hormones administered for in vitro fertilization, advanced maternal age, and other environmental factors.9 Chordee, or penile torsion, may accompany hypospadias. In chordee a shortage of skin on the ventral surface causes the penis to bend or to “bow” ventrally (Figure 39-3). Penile torsion is a counterclockwise twist of the penile shaft. Partial absence of the foreskin, inguinal hernia, and cryptorchidism (undescended testes; see Chapter 25) are associated with the anomaly.10
The goals for corrective surgery on the child with hypospadias are: (1) a straight penis when erect to facilitate sexual intercourse as an adult, (2) a uniform urethra of adequate caliber to prevent spraying during urinations, (3) a cosmetic appearance satisfactory to the individual, and (4) repair completed in as few procedures as possible. Formerly performed in two or more stages, hypospadias repairs are now done in one stage. Improvements in microsurgical techniques have enhanced outcomes and decreased complications and the need for follow-up surgery. Surgery is usually performed between 4 and 12 months of age.11
Epispadias and exstrophy of the bladder are the same congenital defect but expressed to a different degree. The dorsal urethra is not fused in epispadias and has failed to form into a tube. In male epispadias the urethral opening is on the dorsal surface of the penis. In females a cleft along the ventral urethra usually extends to the bladder neck. The incidence of epispadias is about 1 in 40,000 to 118,000 births. About twice as many boys as girls present with this defect.
In boys the urethral opening may be small and situated behind the glans (anterior epispadias), or a fissure may extend the entire length of the penis and into the bladder neck (posterior epispadias). The majority of children with epispadias can achieve urinary continence, although surgical intervention may be necessary.12
Exstrophy of the bladder is a rare extensive congenital anomaly of herniation of the bladder through the abdominal wall with failure of the abdominal muscles, pelvic ring, and pelvic floor musculature to fuse in the midline (Figure 39-4). The posterior portion of the bladder mucosa is exposed and appears bright red. The prevalence of exstrophy of the bladder is about 2.07 in 100,000 live births. Boys are predominant with a ratio of about 2:1 and this complication is more common in whites.13
Exstrophy of the bladder is caused by intrauterine failure of the abdominal wall and the mesoderm of the anterior bladder to fuse. Urine seeps onto the abdominal wall from the ureters, causing a constant odor of urine and excoriation of the surrounding skin. The rectus muscles below the umbilicus are separated, and the pubic rami (bony projections of the pubic bone) are not joined. The clitoris in girls is divided into two halves with the urethra between them. The penis in boys is epispadic. In addition, the posterior aspect of the pelvis is externally rotated, which retroverts the acetabula and causes external rotation of the feet. This causes a waddling gait when the child first learns to walk, but most children quickly learn to compensate. Surgical intervention may be required.14 Because the exposed bladder mucosa becomes hyperemic and edematous, it bleeds easily and is painful. It should be covered with Silastic or a plastic dressing (e.g., kitchen plastic wrap) for protection from diaper irritation while permitting urine drainage. The unrepaired exstrophic bladder is cosmetically unacceptable and prone to cancerous changes as soon as 1 year after birth. Ideally the bladder and pubic defect should be closed before the infant is 72 hours old. Surgical reconstruction is usually performed within the first year either as a complete primary repair or as staged procedures. Staged procedures may include bladder augmentation and bladder neck and epispadias repair.15 Objectives of management include preservation of renal function, attainment of urinary control, prevention of infection, reconstructive repair of the defect, and improvement of sexual function and quality of life.
Cloacal exstrophy is the most rare and severe form of bladder exstrophy. The intestines, genitourinary tract, and spine may be involved, and reconstruction with restored urine and fecal control is difficult.
Ureteropelvic junction (UPJ) obstruction is a blockage of the tapered point where the renal pelvis transitions into the ureter.16 An intrinsic malformation of smooth muscle hypertrophy and fibrosis produces obstruction in 90% of cases.17 It is the most common cause of hydronephrosis in neonates.18 Diagnosis is made by ultrasound. Open or endoscopic surgery to relieve the obstruction occurs if there is decline of renal drainage or function.19 During infancy or childhood, secondary ureteropelvic junction obstruction is caused by kinking or secondary scarring in the presence of high-grade vesicoureteral reflux. Children with UPJ obstruction have an increased risk of vesicoureteral reflux. Other defects are sometimes associated with ureteral duplication including complete ureteral duplication (abnormal growth of two ureters and ureteral orifices draining a single kidney), incomplete duplication (bifurcation of the ureter terminates into one ureteral orifice and serves a single kidney), and ureterocele (cystic dilation of the intravesical ureter). Obstruction of the distant ureter (ureterovesical junction obstruction) causes dilation of the entire ureter, renal pelvis, and calyceal system (megaureter). Megaureter can occur when a short acontractile segment of the ureter develops just above the ureterovesical junction or from ureteral reflux.20
Congenital causes of bladder outlet obstruction are rare and include urethral valves, urethral polyps, and urethral atresia. A urethral valve is a thin membrane that occludes the urethral lumen and obstructs urinary outflow in males. It is the most common cause of congenital lower urinary tract obstruction and renal failure. Most valves occur in the posterior urethra, although a few arise from the embryologically distinct anterior urethra.21 Urethral polyps arising from the prostatic urethra are rare. Symptoms of polyps may include hematuria; voiding issues, such as urinary retention or straining to void; and dilation of the upper tracts.22 Urethral atresia is absence of the urethra and is rare.
Congenital urethral valves or polyps can be diagnosed with prenatal ultrasound and treated with prenatal bladder shunting or with resection during the first days of life.23 Infants with significant renal (and pulmonary) hypoplasia who are unable to undergo primary resection may be managed with a vesicostomy, a small opening created between the bladder wall and the abdomen.24
During embryologic development the ureteric duct grows into the metanephric tissue, triggering the formation of the kidneys. If this growth does not occur, the kidney is absent-a condition called renal aplasia. A hypoplastic kidney is small with a decreased number of nephrons. These conditions may be unilateral or bilateral; the occurrence may be incidental or familial.24 Bilateral hypoplastic kidneys are a common cause of chronic renal failure in children. Segmental hypoplasia (the Ask-Upmark kidney) may be congenital or secondary to vesicoureteral reflux.25
Renal dysplasia usually results from abnormal differentiation of the renal tissues; for example, primitive glomeruli and tubules, cysts, and nonrenal tissue (such as cartilage) are found in the dysplastic kidney. Dysplasia may be secondary to antenatal obstruction of the urinary tract from ureteroceles, posterior urethral valves, or prune-belly syndrome (congenital absence of abdominal muscles).
Renal agenesis (the absence of one or both kidneys) may be unilateral or bilateral, and may occur randomly or be hereditary. It may be an isolated entity or associated with anomalies in other organs.26
Unilateral renal agenesis occurs in approximately 1 of 1000 live births in the United States. Males are more often affected, and it is usually the left kidney that is absent. The single kidney is often completely normal so that the child can expect a normal, healthy life. The normal solitary kidney grows because of compensatory hypertrophy before27 and after birth. By the time the child is several years older, the volume of this kidney may approach twice the normal size. In some instances the single kidney is abnormally formed and associated with abnormalities of its collecting system.28 Extrarenal congenital abnormalities are relatively more common with unilateral renal agenesis.
Bilateral renal agenesis (also called Potter syndrome) is a rare disorder incompatible with extrauterine life.29 Approximately 75% of affected infants are male. Bilateral renal agenesis results from either an abnormal development of the normal progression from pronephros to mesonephros to metanephros or an isolated bilateral failure of development of the ureteral buds. The term Potter syndrome refers to the association with a specific group of facial anomalies (wide-set eyes, parrot-beak nose, low-set ears, and receding chin). Oligohydramnios (low amount of amniotic fluid) leads to underdeveloped lungs. Affected infants rarely live more than a few hours because of pulmonary insufficiency. Approximately 40% of affected infants are stillborn. Renal agenesis can be detected prenatally by ultrasound.
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder that occurs in about 1 in 1000 live births in the United States. Mutations of two genes, PKD-1 (chromosome 16) and PKD-2 (chromosome 4), account for the disease most often presenting in late childhood or adulthood. The gene products (polycystins) regulate growth and differentiation of the tubular epithelium.30 Defects in the formation of epithelial cells and their cilium result in cyst formation and obstruction accompanied by destruction of renal parenchyma, interstitial fibrosis, and loss of functional nephrons. Cysts may occur in other organs including the liver, ovaries, and pancreas. Hypertension, heart valve defects, and cerebral and aortic aneurysms may develop. Urinary tract infection, hematuria, and flank pain may occur. Diagnosis is usually confirmed by ultrasound. Individuals may live for decades before developing symptoms of renal disease and not all progress to end-stage disease.31 Autosomal recessive PKD (ARPKD) with cystic changes in the kidney and liver is often first suspected on a prenatal ultrasound. The gene mutation for ARPKD (PKHD1) encodes a protein important to maintaining structural integrity and cellular function of the kidneys and liver. Renal replacement therapy is usually required during childhood or adolescence. Biomarkers and therapies to slow the progression of cyst development and renal failure are being studied.32
The most common glomerular disorders in children are glomerulonephritis, nephrotic syndrome, and hemolytic uremic syndrome. Most glomerular diseases are acquired and immunologically mediated. The disease can be acute or chronic. The likelihood of developing renal failure depends on the specific condition. The most common glomerular disorders in children are presented below.
Acute glomerulonephritis includes a number of renal disorders in which proliferation and inflammation of the glomeruli are secondary to an immune mechanism (Table 39-1). (The major glomerulopathies and their histologic characteristics can be reviewed in Chapter 38 and Table 38-7.) The symptoms usually include the sudden onset of hematuria with red blood cell casts and proteinuria, and can be accompanied by renal salt and water retention, edema, hypertension, and in severe cases azotemia (i.e., decreased glomerular filtration rate). Chronic glomerulonephritis is the causative factor for 30% to 50% of renal failure in children and is the condition responsible for most school-age and teenage children requiring dialysis and kidney transplantation.
Related to other bacterial or viral infection
|Immunologic mechanism||Antigen-antibody complex deposition|
Planted antigens with immune complex formed in situ
Formation of antiglomerular basement membrane antibodies (rare)
No immunologic cause established
Diffuse, focal, or segmented
Membranous, proliferative, or combination of types
Lobular, exudative, necrotizing, and other types
Chronic with glomerular proliferation
|Clinical manifestations of disease||Acute glomerulonephritis|
Persistent (chronic) glomerulonephritis
Idiopathic nephrotic syndrome
Acute poststreptococcal glomerulonephritis (PSGN) is one of the most common immune complex-mediated renal diseases in children ages 5 to 15 years and it is representative of acute glomerulonephritis. It most commonly occurs after a throat (pharyngitis) or skin (impetigo) infection with nephritogenic strains of group A beta-hemolytic streptococci, although other bacteria (e.g., Staphylococcus) and viruses also may be responsible. Sporadic occurrences of infectious glomerulonephritis have been observed after bacterial endocarditis, which may be associated with streptococcal or staphylococcal microorganisms, or after viral diseases, such as varicella and hepatitides B and C. Glomerulonephritis develops with the deposition of antigen-antibody complexes (immunoglobulin G [IgG], IgA, and C3 complement) (see Chapter 8) in the glomerulus or the antigen may be trapped within the glomerulus and immune complexes formed in situ.33 The exact mechanism of immune complex formation is unknown. The immune complexes initiate inflammation and glomerular injury. Immunofluorescence microscopy shows lumpy deposits of immunoglobulin (IgG) and complement (C3) on the glomerular basement membrane (Figure 39-5). The thickened glomerular membrane contributes to decreased GFR. Activated complement, inflammatory cytokines, oxidants, proteases, and growth factors attack epithelial cells, alter membrane permeability, and cause hematuria and proteinuria. More severe renal disease is observed after a prolonged infection and before antibiotic therapy. Hypertension occurs primarily because of fluid retention.34
Symptoms usually begin 1 to 2 weeks after an upper respiratory tract infection (more common during cold weather) and up to 6 weeks after skin infections, such as impetigo (more common during warm, humid weather). The onset of symptoms in the child is abrupt, varying with disease severity. The urine is usually smoky brown or cola colored because of the presence of red blood cells. The child may complain of flank or midabdominal pain, irritability, general malaise, and fever. Acute hypertension may cause headache, vomiting, somnolence, and other central nervous system (CNS) manifestations, including seizures. Cardiovascular symptoms are related to circulatory overload and are compounded by hypertension. These include dyspnea, tachypnea, and an enlarged, tender liver. The most severely affected children develop acute renal failure with oliguria. As many as half the children affected are asymptomatic. The disease is usually mild and runs its course in 1 month, but urine abnormalities may be found up to 1 year after the onset. Less than 5% of children become oliguric or develop rapidly progressive glomerulonephritis, or progress to chronic glomerulonephritis. Prolonged proteinuria and abnormal GFR indicate an unfavorable prognosis. More than 95% recover completely.
Acute glomerulonephritis (AGN) may be accompanied by a positive throat or skin culture for Streptococcus. Antistreptolysin-O titers confirm a recent streptococcal infection. Antihyaluronidase, antideoxyribonuclease B, and antistreptokinase antibody are other diagnostic markers. Serum complement level is decreased, and serum creatinine concentration and blood urea nitrogen level are elevated. The urine usually contains red blood cells and proteins. Treatment is supportive and symptom specific. For severe disease oliguria and hypertension are common, and fluid, sodium, and potassium intakes are restricted. Antihypertensive medication and diuretic agents may be indicated during the acute phase.
Henoch-Schönlein purpura (HSP) nephritis (anaphylactoid purpura) is an immune-mediated IgA vasculitis that affects glomerular blood vessels, causing inflammation and damage to the vessel wall (see Chapter 38 for the pathophysiology of IgA nephropathy). The disease also involves small vessels in the skin and gut. Classic symptoms of HSP include palpable purpura, arthritis, abdominal pain, and renal disease characterized by gross or microscopic hematuria with mild or no proteinuria. Kidney biopsy demonstrates IgA deposition in the mesangium35 (see Table 38-7 in Chapter 38). The development of interstitial fibrosis and crescent formation from subepithelial immune deposits along the glomeruli increases the risk of chronic renal failure.36 Most children recover with supportive care, although some progress to kidney failure. Severe symptoms require corticosteroids and other immunosuppressant drugs.37
Hemolytic uremic syndrome (HUS) is an acute disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. It is the most common community-acquired cause of acute renal failure in young children. The disease occurs most frequently in infants and children younger than 4 years of age. The prognosis has improved dramatically in recent years, with more than 90% of children surviving and most regaining normal renal function.
HUS has been associated with both bacterial and viral agents, as well as endotoxins, especially those from Escherichia coli 0157:H7 and recently Escherichia coli 0104:H4 (Shiga toxins).38 Potential sources of exposure include animals, unpasteurized beverages, and contaminated meat and vegetables. The disease also occurs with cancer and use of chemotherapeutic agents.39 In HUS, verotoxin (Shiga toxin) from E. coli is absorbed from the intestines into the blood, binds to polymorphonuclear leukocytes, and is transported to the kidney, causing a cascade of effects, including lysis of glomerular capillary endothelial cells, separation of endothelial cells from the basement membrane, activation and aggregation of platelets, and activation of the coagulation cascade. The glomerular arterioles become swollen and occluded with platelets and fibrin clots. There is decreased glomerular filtration, and the damaged glomerular membrane results in hematuria and proteinuria. Oliguria with renal failure occurs in up to 50% of children. Narrowed vessels damage passing erythrocytes. These damaged red blood cells, identified as burr cells, helmet cells, and fragmented red blood cells, are removed by the spleen, causing acute hemolytic anemia. Fibrinolysis, the process of dissolution of a clot, acts on precipitated fibrin, causing the fibrin split products to appear in serum and urine. The platelet clustering within damaged vessels, combined with the damage and removal of platelets, produces thrombocytopenia. Fibrin-rich thrombi can be found throughout the microcirculation.40 Other tissues, including the brain, liver, heart, and intestines, are often involved, which portends a poorer prognosis.
Typical HUS is preceded by a prodromal gastrointestinal (GI) illness with diarrhea (usually caused by Shiga toxin-producing E. coli) and is known as D+ HUS. Less frequently atypical or sporadic HUS is preceded by an unknown event or an upper respiratory tract infection and is known as D− HUS. A rare familial form is associated with mutations in complement proteins. P-hemolytic-uremic syndrome is associated with Streptococcus pneumoniae respiratory tract infection and is mediated by neuraminidase that injures glomerular epithelial cells. It occurs without diarrhea. The onset of D+ HUS occurs about 1 to 2 weeks after a GI illness with a symptom-free 1- to 5-day period. There is sudden onset of pallor, bruising or purpura, irritability, and oliguria. Slight fever, anorexia, vomiting, diarrhea (with the stool characteristically watery and blood stained-hemorrhagic diarrhea), abdominal pain, mild jaundice, and circulatory overload are accompanying symptoms. Seizures and lethargy indicate CNS involvement. Renal failure is apparent within 2 days to 2 weeks of onset. The renal failure causes metabolic acidosis, uremia, hyperkalemia, and often hypertension.
Clinical evaluation includes history of preexisting illness, presenting symptoms, and urine and blood analysis. Antibiotics are not used in the initial treatment because they increase Shiga toxin release and increase the risk of HUS. Management consists of maintaining nutrition and hydration (to dilute toxins) and controlling hypertension, hyperkalemia, and seizures.41 When renal failure occurs, dialysis is indicated. Blood transfusions with packed red blood cells are needed to maintain reasonable hemoglobin levels. Most children recover; however, some will develop hypertension, proteinuria, or renal insufficiency or failure. Death usually occurs from complications related to CNS or myocardial involvement.42 Preventing Shiga toxin-producing bacterial infection (i.e., E. coli) prevents HUS.