CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

24. Kidney & Urinary Tract

Gary M. Lum, MD

EVALUATION OF THE KIDNEY & URINARY TRACT

HISTORY

When renal disease is suspected, the history should include

1. Family history of cystic disease, hereditary nephritis, deafness, dialysis, or renal transplantation

2. Preceding acute or chronic illnesses (eg, urinary tract infection [UTI], pharyngitis, impetigo, or endocarditis)

3. Rashes or joint pains

4. Growth delay or failure to thrive

5. Polyuria, polydipsia, enuresis, urinary frequency, or dysuria

6. Documentation of hematuria, proteinuria, or discolored urine

7. Pain (abdominal, costovertebral angle, or flank) or trauma

8. Sudden weight gain or edema

9. Drug or toxin exposure

10. Data pertaining to the newborn with suspected urinary tract disease: prenatal ultrasonographic studies, birth asphyxia, Apgar scores, oligohydramnios, dysmorphic features, abdominal masses, voiding patterns, anomalous development, and umbilical artery catheterization

PHYSICAL EXAMINATION

Important aspects of the physical examination include the height, weight, skin lesions (café au lait or ash leaf spots), pallor, edema, or skeletal deformities. Anomalies of the ears, eyes, or external genitalia may be associated with renal anomalies or disease. The blood pressure should be measured in a quiet setting. The cuff should cover two-thirds of the child’s upper arm, and peripheral pulses should be noted. The abdomen should be palpated, with attention to the kidneys, abdominal masses, musculature, and the presence of ascites. An ultrasonic device is useful for measurements in infants.

LABORATORY EVALUATION OF RENAL FUNCTION

Serum Analysis

The standard indicators of renal function are serum levels of urea nitrogen and creatinine; their ratio is normally about 10:1. This ratio may increase when renal perfusion or urine flow is decreased, as in urinary tract obstruction or dehydration. Because serum urea nitrogen levels are more affected by these and other factors (eg, nitrogen intake, catabolism, use of corticosteroids) than are creatinine levels, the most reliable single indicator of glomerular function is the serum level of creatinine. For example, an increase in serum creatinine from 0.5 to 1.0 mg/dL represents a 50% decrease in glomerular filtration rate. The serum creatinine level of small children should be well under 0.8 mg/dL. Only larger adolescents should have levels exceeding 1 mg/dL. Less precise but nonetheless important indicators of possible renal disease are abnormalities of serum electrolytes, pH, calcium, phosphorus, magnesium, albumin, or complement.

Glomerular Filtration Rate

The endogenous creatinine clearance (Ccr) in milliliters per minute estimates the glomerular filtration rate (GFR). A 24-hour urine collection is the “classic” approach for determining creatinine clearance; however, it is often difficult to obtain in the pediatric population. The procedure for collecting a timed urine specimen should be explained carefully so that the parent or patient understands fully the rationale of (1) first emptying the bladder (discarding that urine) and noting the time; and (2) putting all urine subsequently voided into the collection receptacle, including the last void, 24 hours later. Reliability of the 24-hour collection can be checked by measuring the total 24-hour creatinine excretion in the specimen. Total daily creatinine excretion (creatinine index) should be 14–20 mg/kg. Creatinine indices on either side of this range suggest collections that were either inadequate or excessive. Calculation by the following formula requires measurements of plasma creatinine (Pcr) in mg/mL, urine creatinine (Ucr) in mg/mL, and urine volume (V) expressed as mL/min:

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Creatinine is a reflection of body muscle mass. Because accepted ranges of normal Ccr are based on adult parameters, correction for size is needed to determine normal ranges in children. Clearance is corrected to a standard body surface area of 1.73 m2 in the formula:

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Although 80–125 mL/min/1.73 m2 is the normal range for Ccr, estimates at the lower end of this range may indicate problems.

The Schwartz formula is a reliable formula for quick approximation of Ccr based on plasma creatinine level and length in centimeters:

Ccr (mL/min/1.73 m2) = k × height (cm)/Pcr (mg/dL)

where k is a constant: 0.45 for infants 1–52 weeks old, 0.55 for children 1–13 years old, 0.55 for females 1–18 years old, and 0.7 for males 13–18 years old.

Urine Concentrating Ability

Inability to concentrate urine causes polyuria, polydipsia, or enuresis and is often the first sign of chronic renal failure, and, in some cases, raises the possibility of diabetes insipidus. The first morning void should be concentrated (specific gravity 1.020 or higher), presuming cessation of drinking anything through the night. Thus, determination of the specific gravity of a first morning void is an easy and helpful test of the kidney’s concentrating ability.

Urinalysis

Commercially available dipsticks can be used to screen the urine for blood leukocytes, nitrites, protein, and specific gravity and to approximate the urine pH. Positive results for blood should always be confirmed by microscopy, which is also the only way to determine if there is significant crystalluria. Significant proteinuria (> 150 mg/dL) detected by dipstick should be confirmed by quantitation, either with a 24-hour urine collection or by the protein/creatinine ratio of a random specimen.

In children with asymptomatic hematuria or proteinuria, the search for renal origins will yield the most results. Isolated proteinuria may also reflect urologic abnormalities, benign excretion, or glomerular alterations. RBC casts suggest glomerulonephritis (GN), but the absence of casts does not rule out this disease. Anatomic abnormalities such as cystic disease may also cause hematuria.

Benign hematuria, including benign familial hematuria, is diagnosed by exclusion. In this group are children whose hematuria is caused by asymptomatic hypercalciuria. Figure 24–1 suggests an approach to the renal workup of hematuria. GN is discussed in more detail later in this chapter.

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Image Figure 24–1. Approach to the renal workup of hematuria. (Exclude UTI, lithiasis, trauma, bleeding disorders, sickle cell disease.) Complement is depressed in acute poststreptococcal type of glomerulonephritis (about 30 days), chronic glomerulonephritis (persistent), and lupus. ANA, antinuclear antibody; ASO, antistreptolysin antibody; BP, blood pressure; BUN, blood urea nitrogen; C3, complement; Ca, calcium; CBC, complete blood count; Cr, creatinine; IgA, immunoglobulin A; RBC, red blood cell; SLE, systemic lupus erythematosus; U/A, urinalysis.

Combined proteinuria and hematuria is characteristic of more significant glomerular disease. Quantitation of proteinuria is customarily accomplished by a timed collection (eg, over a 24-hour period). However, given the frequency of errors in collection in the pediatric population, the degree of proteinuria may be estimated by the ratio of protein mg/dL/creatinine mg/dL in a random urine sample. A protein/creatinine ratio above 0.2 is abnormal. If the laboratory reports this as mg protein/gram of creatinine, normal is 200 or less.

In the evaluation of asymptomatic proteinuria, orthostatic or postural proteinuria should be ruled out. This can be accomplished simply by comparing the protein/creatinine ratio of urine formed in the supine position (the first morning void accumulated in the bladder while sleeping) to a sample obtained during daily ambulation. If the “supine” sample is normal and proteinuria is occurring only during upright posture, this demonstrates postural (benign) proteinuria. If both samples are abnormal, proteinuria would be considered “persistent.”

An approach to the workup of isolated proteinuria, including nephrotic syndrome, is shown in Figure 24–2. Note that corticosteroid therapy is included in the algorithm because this may be initiated for nephrotic syndrome prior to referral. Other renal lesions with proteinuric manifestations are discussed later in this chapter.

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Image Figure 24–2. Approach to the workup of isolated proteinuria. BP, blood pressure; Cr, creatinine; hpf, high-power field; RBC, red blood cell; U/A, urinalysis; VCUG, voiding cystourethrogram. Rules out benign postural proteinuria with urine protein/creatine ratio of first morning void (recumbent urine) versus day void (upright). Will normalize within a month in poststreptococcal glomerulonephritis.

Special Tests of Renal Function

Measurements of urinary sodium, creatinine, and osmolality are useful in differentiating prerenal from renal causes of renal insufficiency, such as acute tubular necrosis. Prolonged underperfusion causes varying increases in serum creatinine and blood urea nitrogen (BUN) concentrations, prompting the need to differentiate between this state and acute tubular necrosis (see section Acute Renal Failure). The physiologic response to decreased renal perfusion is decreased urinary output, increased urine osmolality, increased urinary solutes (eg, creatinine), and decreased urinary sodium (usually < 20 mEq/L).

The presence of certain substances in urine may suggest tubular dysfunction. For example, urine glucose should be less than 5 mg/dL. Hyperphosphaturia occurs with significant tubular abnormalities (eg, Fanconi syndrome). Measurement of the phosphate concentration of a 24-hour urine specimen and evaluation of tubular reabsorption of phosphorus (TRP) will help document renal tubular diseases as well as hyperparathyroid states. TRP (expressed as percentage of reabsorption) is calculated as follows:

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where Scr = serum creatinine; Ucr = urine creatinine; SPO4 = serum phosphate; and UPO4 = urine phosphate. All values for creatinine and phosphate are expressed in milligrams per deciliter for purposes of calculation. A TRP value of 80% or more is considered normal, although it depends somewhat on the value of SPO4.

The urinary excretion of amino acids in generalized tubular disease reflects a quantitative increase rather than a qualitative change. Diseases affecting proximal tubular reabsorption of bicarbonate—including isolated renal tubular acidosis (RTA), Fanconi syndrome (which occurs in diseases such as cystinosis), and chronic renal failure—are discussed later in the chapter.

LABORATORY EVALUATION OF IMMUNOLOGIC FUNCTION

Many parenchymal renal diseases are thought to have immune causation, although the mechanisms are largely unknown. Examples include (1) deposition of circulating antigen-antibody complexes that are directly injurious or incite injurious responses and (2) formation of antibody directed against the glomerular basement membrane (rare in children).

C3 and C4 complement components should be measured when immune-mediated renal injury or chronic GN is suspected. Where clinically indicated, antinuclear antibodies, hepatitis B surface antigen, and rheumatoid factor should be obtained. In rare cases, cold-precipitable proteins (cryoglobulins), C3 “nephritic” factor, or antiglomerular basement membrane (anti-GBM) antibody measurements may help confirm a specific diagnosis. At some point in the workup, the diagnosis may be supported or confirmed by histologic examination of renal tissue.

RADIOGRAPHIC EVALUATION

Renal ultrasonography is a useful noninvasive tool for evaluating renal parenchymal disease, urinary tract abnormalities, or renal blood flow. Excretory urography is used to assess the anatomy and function of the kidneys, collecting system, and bladder. Radioisotope studies provide information about renal anatomy, blood flow, and integrity and function of the glomerular, tubular, and collecting systems. Renal stones are best seen by computed tomography.

Voiding cystourethrography or cystoscopy is indicated when vesicoureteral reflux (VUR) or bladder outlet obstruction is suspected. Cystoscopy is rarely useful in the evaluation of asymptomatic hematuria or proteinuria in children.

Renal arteriography or venography is indicated to define vascular abnormalities (eg, renal artery stenosis) prior to surgical intervention or transluminal angiography. Less invasive measures such as ultrasonography and Doppler studies can demonstrate renal blood flow or thromboses. More specific identification of stenoses of the renal artery is accomplished by magnetic resonance arteriography.

RENAL BIOPSY

Histologic information is valuable for diagnosis, to guide treatment, and to inform prognosis. Satisfactory evaluation of renal tissue requires examination by light, immunofluorescence, and electron microscopy. The need for a renal biopsy should be determined by a pediatric nephrologist.

CONGENITAL ANOMALIES OF THE URINARY TRACT

RENAL PARENCHYMAL ANOMALIES

About 10% of children have congenital anomalies of the genitourinary tract, which range in severity from asymptomatic to lethal. Some asymptomatic abnormalities may have significant complications. For example, patients with “horseshoe” kidney (kidneys fused in their lower poles), although not representing renal parenchymal disease or reduction in kidney function, have a higher incidence of renal calculi. Unilateral agenesis or multicystic dysplasia is usually accompanied by compensatory hypertrophy of the contralateral kidney and thus should be compatible with normal renal function, requiring no specific nephrology referral or follow-up. Supernumerary and ectopic kidneys are usually of no significance. Abnormal genitourinary tract development is associated with varying degrees of renal dysgenesis and dysfunction ranging from mild to severe; an example of the latter is in utero bilateral renal agenesis, which is associated with severe oligohydramnios, pulmonary hypoplasia, abnormal (Potter) facies, and perinatal death.

1. Renal Dysgenesis

Renal dysgenesis is a spectrum of anomalies. In simple hypoplasia, which may be unilateral or bilateral, the affected kidneys are smaller than normal. In some forms of dysgenesis, immature, undifferentiated renal tissue persists. In some situations, the number of normal nephrons is insufficient to sustain life once the child reaches a critical body size. The lack of adequate renal tissue may not be readily discernible in the newborn period in the presence of normal urine production. Often, discovery of renal insufficiency in an infant is coincident with blood work drawn for other purposes showing an elevated serum creatinine.

Other forms of renal dysgenesis include oligomeganephronia (characterized by the presence of only a few large glomeruli) and the cystic dysplasias (characterized by the presence of renal cysts). This group includes microcystic disease (congenital nephrosis). A simple cyst within a kidney, different from either autosomal recessive or dominant polycystic kidney disease, is clinically unimportant. An entire kidney lost to multicystic development with concomitant hypertrophy and normal function of the contralateral side should also be of no clinical consequence.

2. Polycystic Kidney Disease

Both forms of polycystic kidney disease (autosomal dominant [ADPKD] or recessive [ARPKD]) are increasingly diagnosed by prenatal ultrasound. In its most severe form (ARPKD), the cystic kidneys are nonfunctional in utero, and, therefore, newborns can have Potter facies and other complications of oligohydramnios. In infancy and childhood, kidney enlargement by cysts may initially be recognized by abdominal palpation of renal masses. Hypertension is an early problem in ARPKD. The rate of the progression of renal insufficiency varies, as does growth failure, other complications of chronic renal failure, and early development of end-stage renal disease. In ADPKD, two genes, ADPKD1 and ADPKD2, account for 80% and 10% of cases, respectively. Susceptibility of family members is detected by gene linkage studies. Renal ultrasound identifies cysts in about 80% of affected children by age 5 years. Children with this diagnosis need monitoring for the development and treatment of hypertension, which usually develops in the teenage years. These patients would not be expected to develop renal insufficiency, if any, until later in adult years.

3. Medullary Cystic Disease (Juvenile Nephronophthisis)

Medullary cystic disease is characterized by cysts of varying sizes in the renal medulla with tubular and interstitial nephritis. Children present with renal failure and signs of tubular dysfunction (decreased concentrating ability, Fanconi syndrome). This lesion should not be confused with medullary sponge kidney (renal tubular ectasia), a frequently asymptomatic disease occurring in adults.

DISTAL URINARY TRACT ANOMALIES

1. Obstructive Uropathy

Obstruction at the ureteropelvic junction may be the result of intrinsic muscle abnormalities, aberrant vessels, or fibrous bands. The lesion can cause hydronephrosis and usually presents as an abdominal mass in the newborn. Obstruction can occur in other parts of the ureter, especially at its entrance into the bladder, causing proximal hydroureter and hydronephrosis. Renal radionuclide scan with furosemide “wash-out” will reveal or rule out obstruction as the cause of the hydronephrosis. Whether intrinsic or extrinsic, urinary tract obstruction should be relieved surgically as soon as possible to minimize damage to the kidneys.

Severe bladder malformations such as exstrophy are clinically obvious and a surgical challenge. More subtle—but urgent in terms of diagnosis—is obstruction of urine flow from vestigial posterior urethral valves. This anomaly, which occurs almost exclusively in males, usually presents in newborns with anuria or a poor voiding stream secondary to severe obstruction of urine flow. The kidneys and bladder may be easily palpable. Leakage (ureteric perforation, although rare) proximal to the obstruction may produce urinary ascites. Surgical drainage of urine is urgently required to prevent irreversible damage.

Prune belly syndrome is an association of urinary tract anomalies with cryptorchidism and absent abdominal musculature. Although complex anomalies, especially renal dysplasia, usually cause early death or the need for dialysis or transplantation, some patients have lived into the third decade with varying degrees of renal insufficiency. Timely urinary diversion is essential to sustain renal function.

Other complex malformations and external genital anomalies such as hypospadias are beyond the scope of this text. The challenge presented by urologic abnormalities resulting in severe compromise and destruction of renal tissue is to preserve all remaining renal function and treat the complications of progressive chronic renal failure. Involvement of a specialist in pediatric urology in early management is essential.

2. Reflux Nephropathy

The retrograde flow of urine from the bladder into the ureter (vesicoureteral reflux) may cause renal scarring and subsequent renal insufficiency or hypertension, or both, especially in the presence of UTI. A finding of hydronephrosis on renal ultrasound is suggestive of vesicoureteral reflux. Its presence can be confirmed or eliminated by a voiding cystourethrogram, which would also be obtained to rule out reflux in the evaluation of UTI. Low-grade reflux may resolve in the absence of infection, in which case antibiotic prophylaxis (advised with any degree of reflux) is undertaken while awaiting signs of spontaneous resolution. Surgery may be required for chronic severe reflux.

HEMATURIA & GLOMERULAR DISEASE

MICROHEMATURIA

Children with painful hematuria should be investigated for UTI or direct injury to the urinary tract. Dysuria is common in cystitis or urethritis; associated back pain suggests the possibility of pyelonephritis; colicky flank pain may indicate the passage of a stone. Bright red blood or clots in the urine are associated with bleeding disorders, trauma, and arteriovenous malformations. Abdominal masses suggest the presence of urinary tract obstruction, cystic disease, or tumors of the renal or perirenal structures.

Asymptomatic hematuria is a challenge because clinical and diagnostic data are required to decide whether to refer the child to a nephrologist. The diagnosis of hematuria should not rely solely on a urine “dipstick” evaluation, but should be verified by a microscopic RBC count. Ruling out hypercalciuria as a cause of hematuria by a random urine calcium/creatinine ratio is one of the initial steps in the evaluation of hematuria. A value above 0.2 requires verification with a 24-hour collection. Hypercalciuria is excretion of calcium in excess of 4 mg/kg/d. Figure 24–1 delineates the outpatient approach to renal hematuria. The concern regarding the differential diagnosis is the possible presence of glomerular disease.

GLOMERULONEPHRITIS

The various types of glomerulonephritis (GN) have similar manifestations. Table 24–1 lists the most commonly encountered disorders in the differential diagnosis of childhood GN, including their clinical and histopathologic abnormalities. Severe glomerular histopathologic and clinical entities, such as anti-GBM antibody disease (Goodpasture syndrome), Wegener granulomatosis, and idiopathic, rapidly progressive GN, may be considered in the differential diagnosis of acute GN, but these disorders are exceedingly rare in children.

Table 24–1. Glomerular diseases encountered in childhood.

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1. Acute Poststreptococcal Glomerulonephritis

The diagnosis of acute poststreptoccocal glomerulonephritis is supported by a recent history (7–14 days previously) of group A β-hemolytic streptococcal infection, typically involving the pharynx or skin. If a positive culture is not available, recent infection may be supported by an elevated antistreptolysin O titer or by high titers of other antistreptococcal antibodies. Other infections can cause similar glomerular injury; thus, “postinfection” glomerulonephritis (GN) may be a better term for this type of acute glomerulonephritis (AGN). In most cases, recovery is expected and usually complete within weeks. If the diagnosis is in question, or if the renal function of a patient with postinfection GN progressively deteriorates, a renal biopsy should be performed and treatment with corticosteroids initiated.

The clinical presentation of GN is gross hematuria generally accompanied by varying degrees of increase in serum creatinine, edema, and hypertension. Urine may be coffee-colored or tea-colored. Microscopic examination of urine reveals RBCs too numerous to count. Microscopy may reveal RBC casts. If present, these are diagnostic of GN, but their absence does not exclude the diagnosis. Edema is often seen (periorbital, facial, extremities), caused by sodium and water retention resulting from alteration in glomerular function. Symptoms are usually nonspecific. In cases accompanied by hypertension (a common finding), headache may be present. Fever is uncommon. Severe glomerular injury (which usually occurs in severe, acute presentations of the more chronic or destructive forms of GN) may be accompanied by massive proteinuria (nephrotic syndrome), anasarca, ascites, and severe compromise of renal function.

Typical poststreptococcal GN has no specific treatment. Antibiotic therapy is indicated if an infection is still present. Disturbances in renal function and resulting hypertension may require close monitoring, reduction in salt intake, diuretics, or other antihypertensive drugs. In severe cases of renal failure, hemodialysis or peritoneal dialysis may be necessary. Corticosteroids may also be administered in an attempt to influence the course of the GN.

The acute abnormalities generally resolve in 2–3 weeks. Low levels of serum complement (C3) may normalize as early as 24 hours or as late as 30 days after onset. Other complement-consuming glomerulonephritides include membranoproliferative GN (chronic GN with persistent complement depression) and lupus GN. In poststreptococcal GN, although microscopic hematuria may persist for as long as a year, 85% of children recover completely. Persistent deterioration in renal function, urinary abnormalities beyond 18 months, persistent hypocomplementemia, and nephrotic syndrome are ominous signs. If any of these is present, a renal biopsy is indicated.

2. IgA Nephropathy

When asymptomatic gross hematuria appears to accompany a minor acute febrile illness or other stressful occurrence, the diagnosis of IgA nephropathy may be entertained. In contrast to postinfection GN, IgA nephropathy is not associated with prior streptococcal infection, complement is not depressed, and in 50% of cases, serum immunoglobin A is elevated. Often there are no associated symptoms or signs. Gross hematuria resolves within days, and there are no serious sequelae in 85% of cases. Treatment is not indicated, and the prognosis is good in most cases. Prognosis is guarded, however, if severe proteinuria, hypertension, or renal insufficiency is present or develops. In such instances, although no treatment is universally accepted, corticosteroids and other immunosuppressive drugs are used. Omega-3 fatty acids from fish oils are thought to be helpful.

3. Henoch-Schönlein Purpura

The diagnosis of Henoch-Schönlein purpura rests on the presence of a typical maculopapular and purpuric rash found primarily, but not exclusively, on the dorsal surfaces of the lower extremities and buttocks. Most children have abdominal pain, and bloody diarrhea may be present. Joint pain is common, and, depending on the extent of renal involvement, hypertension may be present. Joint and abdominal pain responds to treatment with corticosteroids. Renal involvement ranges from mild GN with microhematuria to severe GN and varying degrees of renal insufficiency. GN with massive proteinuria and renal insufficiency carries a poor prognosis. Twenty percent of such cases result in end-stage renal failure. There is no universally accepted treatment, but corticosteroids are often administered (see Chapter 30).

4. Membranoproliferative Glomerulonephritis

The most common “chronic” form of GN in childhood is membranoproliferative GN. The diagnosis is established from the histologic appearance of the glomeruli on biopsy tissue. There are two major histologic types of membranoproliferative GN. Clinically, type II carries the worse prognosis, as end-stage renal failure develops in most cases. Type I more often responds to treatment with corticosteroids. C3 is depressed (in both types) and may be useful as a marker of response to treatment.

5. Lupus Glomerulonephritis

The diagnosis of systemic lupus erythematosus (SLE) is based on its numerous clinical features and abnormal laboratory findings that include a positive antinuclear antibody test, depressed serum complement, and increased serum double-stranded DNA. Renal involvement is indicated by varying degrees of hematuria and proteinuria. More severe cases are accompanied by renal insufficiency and hypertension. Significant renal involvement requires treatment with various combinations of immunosuppressive drugs including prednisone (as a primary drug), azathioprine, cyclophosphamide, mycophenalate, tacrolimus, and rituximab, a monoclonal antibody against the B-cell surface antigen CD20. End-stage renal failure develops in 10%–15% of patients with childhood SLE.

6. Hereditary Glomerulonephritis

The most commonly encountered hereditary GN is Alport syndrome, characterized by hearing loss and GN, occurring predominantly in males. It is a chronic form of GN and thus does not present with the clinical features typically seen in patients with acute processes. A family history is generally present, but there is a spontaneous mutation rate of about 18%. In individuals with the progressive form of GN, end-stage renal failure occurs, usually in the second to third decade of life. Although currently there is no treatment for this disorder, careful management of associated hypertension may slow the process.

Ahn SY, Ingulli E: Acute poststreptococcal glomerulonephritis: An update. Curr Opin Pediatr 2008;20:157–162 [PMID: 18332711].

Sanders JT, Wyatt RJ: IgA nephropathy and Henoch-Schönlein purpura nephritis. Curr Opin Pediatr 2008;20:163–170 [PMID: 18332712].

ACUTE INTERSTITIAL NEPHRITIS

Acute interstitial nephritis is characterized by diffuse or focal inflammation and edema of the renal interstitium and secondary involvement of the tubules. The condition is most commonly drug related (eg, β-lactam–containing antibiotics, such as methicillin).

Fever, rigor, abdominal or flank pain, and rashes may occur in drug-associated cases. Urinalysis usually reveals leukocyturia and hematuria. Hansel staining of the urinary sediment often demonstrates eosinophils. The inflammation can cause significant deterioration of renal function. If the diagnosis is unclear because of the absence of a history of drug or toxin exposure or the absence of eosinophils in the urine, a renal biopsy may be performed to demonstrate the characteristic tubular and interstitial inflammation. Immediate identification and removal of the causative agent is imperative and may be all that is necessary. Treatment with corticosteroids is helpful in patients with progressive renal insufficiency or nephrotic syndrome. Severe renal failure requires supportive dialysis.

Gonzalez E et al: Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney Int 2008;73:940–946 [PMID: 18185501].

PROTEINURIA & RENAL DISEASE

Urine is rarely completely protein-free, but the average excretion is well below 150 mg/24 h. Small increases in urinary protein can accompany febrile illnesses or exertion and in some cases occur while in the upright posture.

An algorithm for investigation of isolated proteinuria is presented in Figure 24–2. In idiopathic nephrotic syndrome without associated features of GN, treatment with corticosteroids may be initiated. Nephrologic advice or follow-up should be sought, especially in patients with difficult or frequently relapsing unexplained proteinuria.

CONGENITAL NEPHROSIS

Congenital nephrosis is a rare autosomal recessive disorder. The kidneys are pale and large and may show microcystic dilations (microcystic disease) of the proximal tubules and glomerular abnormalities, including proliferation, crescent formation, and thickening of capillary walls. The pathogenesis is not well understood.

Infants with congenital nephrosis commonly have low birth weight, a large placenta, wide cranial sutures, and delayed ossification. Mild edema may be seen after the first few weeks of life. Anasarca follows, and the abdomen can become greatly distended by ascites. Massive proteinuria associated with typical-appearing nephrotic syndrome and hyperlipidemia is the rule. Hematuria is common. If the patient lives long enough, progressive renal failure occurs. Most affected infants succumb to infections by a few months of life.

Treatment prior to dialysis and transplantation has little to offer other than nutritional support and management of the chronic renal failure.

IDIOPATHIC NEPHROTIC SYNDROME OF CHILDHOOD (MINIMAL CHANGE DISEASE)

Nephrotic syndrome is characterized by proteinuria, hypoproteinemia, edema, and hyperlipidemia. It may occur as a result of any form of glomerular disease and may rarely be associated with a several extrarenal conditions. In young children, the disease usually takes the form of idiopathic nephrotic syndrome of childhood (nil disease, lipoid nephrosis, minimal change disease), which has characteristic clinical and laboratory findings, but no well-understood cause.

image Clinical Findings

Affected patients are generally younger than age 6 years at onset. Typically, periorbital swelling and oliguria are noted, often following an influenza-like syndrome. Within a few days, increasing edema—even anasarca—becomes evident. Most children have few complaints other than vague malaise or abdominal pain. With significant “third spacing” of plasma volume, however, some children may present with hypotension. With marked edema, dyspnea due to pleural effusions may also occur.

Despite heavy proteinuria, the urine sediment is usually normal, although microscopic hematuria may be present. Plasma albumin concentration is low, and lipid levels increased. When azotemia occurs, it is usually secondary to intravascular volume depletion.

Glomerular morphology is unremarkable except for fusion of foot processes of the glomerular basement membrane. This nonspecific finding is associated with many proteinuric states.

image Complications

Infections (eg, peritonitis) sometimes occur, and Streptococcus pneumoniae is frequently the cause. Hypercoagulability may be present, and thromboembolic phenomena are commonly reported. Hypertension can be noted, and renal insufficiency can result from decreased renal perfusion.

image Treatment & Prognosis

As soon as the diagnosis of idiopathic nephrotic syndrome is made, corticosteroid treatment should be started. Prednisone, 2 mg/kg/d (maximum, 60 mg/d), is given for 6 weeks as a single daily dose. The same dose is then administered on an alternate-day schedule for 6 weeks; thereafter, the dose is tapered gradually and discontinued over the ensuing 2 months. The goal of this regimen is the disappearance of proteinuria. If remission is not achieved during the initial phase of corticosteroid treatment, additional nephrologic consultation should be obtained. If remission is achieved, only to be followed by relapse, the treatment course may be repeated. A renal biopsy is often considered when there is little or no response to treatment. One should take into account that the histologic findings may not alter the treatment plan, which is designed to eliminate the nephrotic syndrome regardless of underlying renal histology.

Unless the edema causes symptoms such as respiratory compromise due to ascites, diuretics should be used with extreme care. Patients may have decreased circulating volume and are also at risk for venous thrombosis. Careful restoration of compromised circulating volume with intravenous 25% albumin infusion and administration of a diuretic such as furosemide is helpful in mobilizing edema. Infections such as peritonitis should be treated promptly to reduce morbidity. Immunization with pneumococcal conjugate and polysaccharide vaccines is advised.

A favorable response of proteinuria to corticosteroids and subsequent favorable response during relapse suggests a good prognosis. Failure to respond or early relapse usually heralds a prolonged series of relapses. This not only may indicate the presence of more serious nephropathy, but presents a challenge in choosing future therapy for those either severely corticosteroid “dependent” and/or in danger of increasing steroid side effects. Historically, chlorambucil or cyclophosphamide drug therapy added to corticosteroid treatment have been utilized in an attempt to achieve corticosteroid discontinuance while maintaining remission. Such drugs are often used effectively, but only in children who respond well to corticosteroids in the first place. Because of potential significant side effects associated with these drugs, tacrolimus or cyclosporine is now added instead for the treatment of steroid dependent cases. Increasing reports and experience suggest that cases in which nephrotic syndrome is poorly responsive to or “dependent” upon corticosteroids, even with an added agent such as tacrolimus, may respond to rituximab. Patients who do not respond to corticosteroids or who relapse frequently should be referred to a pediatric nephrologist, if such referral was not made earlier in the course.

FOCAL GLOMERULAR SCLEROSIS

Focal glomerular sclerosis is one cause of corticosteroid-resistant or frequent relapsing nephrotic syndrome. The cause is unknown. The diagnosis is made by renal biopsy, which shows normal-appearing glomeruli as well as some partially or completely sclerosed glomeruli. The lesion has serious prognostic implications because as many as 15%–20% of cases can progress to end-stage renal failure. The response to corticosteroid treatment is variable. In difficult cases, especially when prolonged use of steroids is resulting in significant undesirable side effects, other immunosuppressive agents such as cyclosporin A or tacrolimus have been used in addition to corticosteroids to try to achieve longer remission with corticosteroid discontinuance. Recurrence of focal glomerular sclerosis resulting in nephrotic syndrome may occur after renal transplantation. The recurrence is usually treated with plasmapheresis and/or rituximab; the latter agent is also showing encouraging utility in treating the nephrotic syndrome of membranous or mesangial nephropathy as well as refractory nephrotic syndrome associated with other forms of glomerular disease or vasculitis.

MESANGIAL NEPHROPATHY (MESANGIAL GLOMERULONEPHRITIS)

Mesangial nephropathy is another form of corticosteroid-resistant nephrotic syndrome. The renal biopsy shows a distinct increase in the mesangial matrix of the glomeruli. Very often the expanded mesangium contains deposits of IgM demonstrable on immunofluorescent staining. The cause is unknown. Corticosteroid therapy may induce remission, but relapses are common. Choices for treating this type of nephrotic syndrome are the same as noted earlier.

MEMBRANOUS NEPHROPATHY (MEMBRANOUS GLOMERULONEPHRITIS)

Although largely idiopathic in nature, membranous nephropathy can be found in association with hepatitis B antigenemia, SLE, congenital and secondary syphilis, renal vein thrombosis; with immunologic disorders such as autoimmune thyroiditis; and with administration of drugs such as penicillamine. The pathogenesis is unknown, but the glomerular lesion is thought to be the result of prolonged deposition of circulating antigen-antibody complexes.

The onset of membranous nephropathy may be insidious or may resemble that of idiopathic nephrotic syndrome of childhood (see earlier section). It occurs more often in older children and adults. The proteinuria of membranous nephropathy responds poorly to corticosteroid therapy, although low-dose corticosteroid therapy may reduce or delay development of chronic renal insufficiency. The diagnosis is made by renal biopsy.

Fine RN: Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children. Pediatr Nephrol 2007;22:496 [PMID: 17186280].

Gipson DS et al: Management of childhood onset nephrotic syndrome. Pediatrics 2009;124:747–757 [PMID: 19651590].

DISEASES OF THE RENAL VESSELS

RENAL VEIN THROMBOSIS

In newborns, renal vein thrombosis may complicate sepsis or dehydration. It may be observed in infants of diabetic mothers, may be associated with umbilical vein catheterization, or may result from any condition that produces a hypercoagulable state (eg, clotting factor deficiency, SLE, or thrombocytosis). Renal vein thrombosis is less common in older children and adolescents. It may develop following trauma or without any apparent predisposing factors. Spontaneous renal vein thrombosis has been associated with membranous glomerulonephropathy. Nephrotic syndrome may either cause or result from renal vein thrombosis.

image Clinical Findings

Renal vein thrombosis in newborns is generally characterized by the sudden development of an abdominal mass. If the thrombosis is bilateral, oliguria may be present; urine output may be normal with a unilateral thrombus. In older children, flank pain, sometimes with a palpable mass, is a common presentation.

No single laboratory test is diagnostic of renal vein thrombosis. Hematuria usually is present; proteinuria is less constant. In the newborn, thrombocytopenia may be found, but it is rare in older children. The diagnosis is made by ultrasonography and Doppler flow studies.

image Treatment

Anticoagulation with heparin is the treatment of choice in newborns and older children. In the newborn, a course of heparin combined with treatment of the underlying problem is usually all that is required. Management in other cases is less straightforward. The tendency for recurrence and embolization has led some to recommend long-term anticoagulation. If an underlying membranous GN is suspected, biopsy should be performed.

image Course & Prognosis

The mortality rate in newborns from renal vein thrombosis depends on the underlying cause. With unilateral renal venous thromboses at any age, the prognosis for adequate renal function is good. Renal vein thrombosis may rarely recur in the same kidney or occur in the other kidney years after the original episode of thrombus formation. Extension into the vena cava with pulmonary emboli is possible.

RENAL ARTERIAL DISEASE

Arterial disease (eg, fibromuscular hyperplasia, congenital stenosis) is a rare cause of hypertension in children. Although few clinical clues are specific to underlying arterial lesions, they should be suspected in children with severe hypertension, with onset at or before age 10 years, or with delayed visualization on nuclear scan of the kidneys. The diagnosis is established by renal arteriography with selective renal vein renin measurements. Some of these lesions may be approached by transluminal angioplasty or surgery (see section Hypertension), but repair may be technically impossible in small children. Although thrombosis of renal arteries is rare, it should be considered in a patient with acute onset of hypertension and hematuria in an appropriate setting (eg, in association with hyperviscosity or umbilical artery catheterization). Early diagnosis and treatment provides the best chance of reestablishing renal blood flow.

Tullus K: Renovascular hypertension in children. Lancet 2008;371: 1453–1463 [PMID: 18440428].

HEMOLYTIC-UREMIC SYNDROME

Hemolytic-uremic syndrome is the most common glomerular vascular cause of acute renal failure in childhood. The diarrhea-associated form is usually the result of infection with Shiga toxin–producing (also called verotoxin-producing) strains of Shigella or Escherichia coli. Ingestion of under-cooked ground beef or unpasteurized foods is a common source. There are many serotypes, but the most common pathogen in the United States is E coliO157:H7. Bloody diarrhea is the usual presenting complaint, followed by hemolysis and renal failure. Circulating verotoxin causes endothelial damage, which leads to platelet deposition, microvascular occlusion with subsequent hemolysis, and thrombocytopenia. Similar microvascular endothelial activation may also be triggered by drugs (eg, cyclosporin A); by viruses (human immunodeficiency virus [HIV]); and by pneumococcal infections, in which bacterial neuraminidase exposes the Thomsen-Friedenreich antigen on RBCs, platelets, and endothelial cells, thereby causing platelet aggregation, endothelial damage, and hemolysis. Rare cases are caused by genetic factors (eg, congenitally depressed C3 complement and factor H deficiency).

image Clinical Findings

Hemolytic-uremic syndrome due to Shigella or E coli begins with a prodrome of abdominal pain, diarrhea, and vomiting. Oliguria, pallor, and bleeding manifestations, principally gastrointestinal, occur next. Hypertension and seizures develop in some children—especially those who develop severe renal failure and fluid overload. There may also be significant endothelial involvement in the central nervous system (CNS).

Anemia is profound, and RBC fragments are seen on blood smears. A high reticulocyte count confirms the hemolytic nature of the anemia, but may not be noted in the presence of renal failure. Thrombocytopenia is profound, but other coagulation abnormalities are less consistent. Serum fibrin split products are often present, but fulminant disseminated intravascular coagulation is rare. Hematuria and proteinuria are often present. The serum complement level is normal except in those cases related to congenital predisposition.

image Complications

These usually result from renal failure. Neurologic problems, particularly seizures, may result from hyponatremia, hypertension, or CNS vascular disease. Severe bleeding, transfusion requirements, and hospital-acquired infections must be anticipated.

image Treatment

Meticulous attention to fluid and electrolyte status is crucial. The use of antimotility agents and antibiotics for hemolytic-uremic syndrome caused by gastrointestinal infection is believed to worsen the disease. Antibiotics may upregulate and cause the release of large amounts of bacterial Shiga toxin. Timely dialysis improves the prognosis. Since prostacyclin-stimulating factor, a potent inhibitor of platelet aggregation, may be absent in some cases, plasma infusion or plasmapheresis has been advocated in severe cases (generally in those cases with severe CNS involvement). Platelet inhibitors have also been tried, but the results have not been impressive, especially late in the disease. Nonetheless, using a platelet inhibitor early in the disease in an attempt to halt platelet consumption and microvascular occlusion may obviate the need for platelet transfusions and reduce the progression of renal failure. RBC and platelet transfusions may be necessary. Although the risk of volume overload is significant, this can be minimized by dialysis. Erythropoietin (epoetin alfa) treatment may reduce RBC transfusion needs. Although no therapy is universally accepted, strict control of hypertension, adequate nutrition support, and the timely use of dialysis reduce morbidity and mortality. If renal failure is “nonoliguric,” and if urine output is sufficient to ensure against fluid overload and electrolyte abnormalities, management of renal failure without dialysis is possible.

image Course & Prognosis

Most commonly, children recover from the acute episode within 2–3 weeks. Some residual renal disease (including hypertension) occurs in about 30%, and end-stage renal failure occurs in about 15%. Thus, follow-up of children recovering from hemolytic-uremic syndrome should include serial determinations of renal function for 1–2 years and monitoring of blood pressure for 5 years. Mortality (about 3%–5%) is most likely in the early phase, primarily resulting from CNS or cardiac complications.

Copelovitch L, Kaplan BS: Streptococcus pneumoniae–associated hemolytic uremic syndrome. Pediatr Nephrol 2008;23:1951–1956 [PMID: 17564729].

Iijima K et al: Management of diarrhea-associated hemolytic uremic syndrome in children. Clin Exp Nephrol 2008;12:16–19 [PMID: 18175052].

RENAL FAILURE

ACUTE RENAL FAILURE

Acute renal failure is the sudden inability to excrete urine of sufficient quantity or composition to maintain body fluid homeostasis. Explanations include quickly reversible problems such as dehydration or urinary tract obstruction, as well as new-onset renal disease (eg, acute glomerulonephritis), drug-related toxic nephropathies, or renal ischemia; the latter is primarily suspected in settings of significant hemodynamic instability or other circumstances resulting in decreased renal perfusion. Table 24–2 lists prerenal, renal, and postrenal causes of acute renal failure.

Table 24–2. Classification of renal failure.

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image Clinical Findings

The hallmark of early acute renal failure is oliguria with subsequent variable rise in serum creatinine and BUN; these observations are more likely to be the initial concern in a hospitalized patient. Although an exact etiologic diagnosis may be unclear at the onset, classifying oliguria as outlined in Table 24–2 is helpful in determining if an immediately reversible cause is present.

Entities that should be quickly addressed and corrected, for example, volume depletion, urinary tract obstruction or hypotension should be considered first. Once normal renal perfusion and lack of urinary tract obstruction is ensured, if there is no clinical evidence for de novo renal disease or exposure to nephrotoxic agents, a diagnosis of acute tubular necrosis (vasomotor nephropathy, ischemic injury) may be entertained.

A. Prerenal Causes

The most common cause of acute decreased renal function in children is compromised renal perfusion. It is usually secondary to dehydration, although abnormalities of renal vasculature and poor cardiac performance may also be considered. Table 24–3 lists the urinary indices helpful in distinguishing these “prerenal” conditions from true renal parenchymal insult, such as in acute tubular necrosis.

Table 24–3. Urine studies.

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B. Renal Causes

Causes of renal failure intrinsic to the kidneys include acute glomerulonephritides, hemolytic-uremic syndrome, acute interstitial nephritis, and nephrotoxic injury. The diagnosis of acute tubular necrosis (vasomotor nephropathy)—which is reserved for those cases in which renal ischemic insult is believed to be the likely cause—should be considered when correction of prerenal or postrenal problems does not improve renal function and there is no evidence of de novo renal disease.

C. Postrenal Causes

Postrenal failure, usually found in newborns with urologic anatomic abnormalities, is accompanied by varying degrees of renal insufficiency. One should always keep in mind the possibility of acute urinary tract obstruction in acute renal failure, especially in the setting of anuria of acute onset. Whatever the cause, ensuring urine drainage is the first step toward reversibility of oliguria.

image Complications

The severity of the complications of acute renal failure depends on the degree of renal functional impairment and oliguria. Common complications include (1) fluid overload (hypertension, congestive heart failure, and pulmonary edema), (2) electrolyte disturbances (hyperkalemia), (3) metabolic acidosis, (4) hyperphosphatemia, and (5) elevations in BUN and creatinine.

image Treatment

Prerenal and/or postrenal factors should be excluded or rectified. Normal circulating volume should be maintained and normal blood pressure and cardiac performance established with appropriate fluids. Strict measurement of input and output must be maintained, with input adjusted as reduction in output dictates. Placement of a Foley bladder catheter can aid in timely measurement of and adjustment to changes in output. However, in cases where oligo/anuric renal failure is well established (ie, insignificant urine volume), the foreign body should be removed to minimize bladder infection risk. Measurement of central venous pressure may be indicated. Administration of pressor drugs to correct hypotension may be needed. Increasing urine output with diuretics, such as furosemide (1–5 mg/kg, per dose, intravenously, maximum of 200 mg), can be attempted. The effective dose will depend on the amount of functional compromise (if < 50% function, initiate attempt at diuresis with maximum dose). If a response does not occur within 1 hour and the urine output remains low (< 0.5 mL/kg/h), the furosemide dose, if not already maximized, should be increased up to 5 mg/kg. In some cases, the addition of a long-acting thiazide diuretic, such as metolazone, may improve the response. If no diuresis occurs with maximum dosing, further administration of diuretics should cease.

If these maneuvers stimulate some urine flow but biochemical evidence of acute renal failure persists, the resulting nonoliguric acute renal failure should be more manageable. Fluid overload and dialysis may be averted. However, if the medications and nutrients required exceed the renal capacity for excretion, and there is no increase in urine output with the use of maximum doses of diuretics (loop diuretic plus a thiazide diuretic) dialysis is indicated. Institution of dialysis before more severe complications of acute renal failure develop is likely to improve clinical management and outcome. It is important to adjust medication dosage according to the degree of renal function.

A. Acute Dialysis: Indications

Immediate indications for dialysis are (1) severe hyperkalemia; (2) unrelenting metabolic acidosis (usually in a situation where fluid overload prevents sodium bicarbonate administration); (3) fluid overload with or without severe hypertension or congestive heart failure (a situation in which volume concerns would seriously compromise administration of adequate nutritional support or of necessary intravenous medications); and (4) symptoms of uremia, usually manifested in children by CNS depression. In cases in which one is concerned about the so called “uremic” bleeding, it is important to keep in mind that despite the use of the clinical term uremia, it is not the blood urea nitrogen which contributes to platelet dysfunction in renal failure. Accumulation of metabolic end products that contribute to bleeding correlate better with the amount of renal function as reflected by the serum creatinine. This is especially true in cases in which the BUN, which is potentially affected by many things in an ill patient, appears to be disproportionately elevated with respect to the serum creatinine.

B. Methods of Dialysis

Peritoneal dialysis is generally preferred in children because of ease of performance and patient tolerance. Although peritoneal dialysis is technically less efficient than hemodialysis, hemodynamic stability and metabolic control can be better sustained because this technique can be applied on a relatively continuous basis. Hemodialysis should be considered (1) if rapid removal of toxins is desired, (2) if the size of the patient makes hemodialysis less technically cumbersome and hemodynamically well tolerated, or (3) if impediments to efficient peritoneal dialysis are present (eg, ileus, adhesions). Furthermore, if vascular access and usage of anticoagulation are not impediments, a slow, continuous hemodialytic process, continuous renal replacement therapy (CRRT), may be applied, with either heparin or citrate used for anticoagulation. CRRT is also a very useful approach in patients already being supported with extracorporeal membrane oxygenation (ECMO).

C. Complications of Dialysis

Complications of peritoneal dialysis include peritonitis, volume depletion, and technical complications such as dialysate leakage and respiratory compromise from intra-abdominal dialysate fluid. Peritonitis can be avoided by strict aseptic technique. Peritoneal fluid cultures are obtained as clinically indicated. Leakage is reduced by good catheter placement technique and appropriate intra-abdominal dialysate volumes. Adjustment of the electrolyte concentration of dialysate is important to maintain electrolyte balance. Potassium (absent from standard dialysate solutions) can be added to the dialysate as required. Phosphate is also absent because hyperphosphatemia is an expected problem in renal failure. Nonetheless, if phosphate intake is inadequate, hypophosphatemia must be addressed. Correction of fluid overload is accomplished by using high osmolar dialysis fluids. Higher dextrose concentrations (maximum 4.25%) can correct fluid overload rapidly at the risk of causing hyperglycemia. Fluid removal may also be increased with more frequent exchanges of the dialysate, but rapid osmotic transfer of water may result in hypernatremia.

Even in small infants, hemodialysis can rapidly correct major metabolic and electrolyte disturbances as well as volume overload. The process is highly efficient, but the speed of the changes can cause problems such as hemodynamic instability. Anticoagulation with heparin is required. Careful monitoring of the appropriate biochemical parameters is important. Note that during or immediately following the procedure, blood sampling will produce misleading results because equilibration between extravascular compartments and the blood will not have been achieved. Vascular access must be obtained and carefully monitored. Hemodialysis is generally intermittent and utilized as clinically indicated. If need be, CRRT may be used to maintain more minute-to-minute, continuous metabolic and fluid control especially in the very hemodynamically unstable or septic patient. With this technique, either heparin or citrate may be used for anticoagulation, with the choice based upon which is more suitable for the situation.

image Course & Prognosis

The course and prognosis of acute renal failure vary with the etiology. If severe oliguria occurs in acute tubular necrosis, it usually lasts about 10 days. Anuria or oliguria lasting longer than 3 weeks makes the diagnosis of acute tubular necrosis unlikely and favors alternative diagnoses such as vascular injury, severe ischemia (cortical necrosis), GN, or obstruction. The diuretic phase begins with an increase in urinary output to large volumes of isosthenuric urine containing sodium levels of 80–150 mEq/L. During the recovery phase, signs and symptoms subside rapidly, although polyuria may persist for several days or weeks. Urinary abnormalities usually disappear completely within a few months. If renal recovery does not ensue, arrangements are made for chronic dialysis and eventual renal transplantation.

Andreoli SP: Acute kidney injury in children. Pediatr Nephrol 2009;24:253–263 [PMID: 19083019].

Walters S et al: Dialysis and pediatric acute kidney injury: choice of renal support modality. Pediatr Nephrol 2009;24:37–48 [PMID: 18483748].

CHRONIC RENAL FAILURE

Chronic renal failure in children most commonly results from developmental abnormalities of the kidneys or urinary tract. Infants with renal agenesis are not expected to survive. Depending on the degree of dysgenesis (including multicystic development), the resulting renal function will determine outcome. Abnormal development of the urinary tract may not permit normal renal development. Obstructive uropathy or severe VUR nephropathy, without (or despite) surgical intervention, continues to cause a significant amount of progressive renal insufficiency in children. In older children, the chronic glomerulonephritides and nephropathies, irreversible nephrotoxic injury, or hemolytic-uremic syndrome may also cause chronic renal failure. Early evaluation and close follow-up by a nephrologist in these situations is advised.

image Complications

Any remaining unaffected renal tissue can compensate for gradual loss of functioning nephrons in progressive chronic renal failure, but complications of renal insufficiency appear when compensatory ability is overwhelmed. In children who have developmentally reduced function and are unable to concentrate the urine, polyuria and dehydration are more likely to be problems than fluid overload. Output may be expected to gradually diminish as renal failure progresses to end stage; however, some children can continue to produce generous quantities of urine (but not of good quality) even though they require dialysis. A salt-wasting state can also occur. In contrast, children who develop chronic renal failure due to glomerular disease or renal injury will characteristically retain sodium and water and develop hypertension.

Metabolic acidosis and growth retardation occur early in chronic renal failure. Disturbances in calcium, phosphorus, and vitamin D metabolism leading to renal osteodystrophy and rickets require prompt attention. Increases in parathyroid hormone occur in response to decreased serum calcium from lack of renally activated vitamin D and/or rising serum phosphorus. The increase in parathyroid hormone, which improves renal tubular excretion of phosphorous, can maintain a normal serum calcium and serum phosphate level early in the course, but at the expense of the skeleton. The increase in parathyroid hormone will also be reflected in an increase in alkaline phosphatase. Anemia due to decreased erythropoietin production can occur relatively early on as well.

Symptoms such as anorexia, nausea, and malaise occur late in chronic renal failure (generally less than 30% renal function). These symptoms can be avoided if chronic renal failure has been detected early and associated complications treated, but may require initiation of renal replacement therapy. CNS abnormalities such as confusion and lethargy are very late symptoms, followed even later by stupor and coma. Other late complications of untreated renal failure are platelet dysfunction and bleeding tendencies. Pericarditis, congestive heart failure, pulmonary edema, and hypertension may occur.

image Treatment

A. Management of Complications

Treatment of chronic renal failure is primarily aimed at controlling the associated complications. Hypertension, hyperkalemia, hyperphosphatemia, acidosis, and anemia are among the early problems. Acidosis may be treated with sodium citrate solutions, as long as the added sodium will not aggravate hypertension. Sodium restriction is advisable when hypertension is present. Hyperphosphatemia is controlled by dietary restriction and dietary phosphate binders (eg, calcium carbonate). Vitamin D should be given to maintain normal serum calcium. When the BUN level exceeds approximately 50 mg/dL, or if the child is lethargic or anorexic, dietary protein should be restricted. Potassium restriction will be necessary as the GFR falls to a level where urinary output decreases sharply. Diet must be maintained to provide the child’s daily requirements.

Renal function must be monitored regularly (creatinine and BUN), and serum electrolytes, calcium, phosphorus, alkaline phosphatase, and hemoglobin and hematocrit levels monitored to guide changes in fluid and dietary management as well as dosages of phosphate binder, citrate buffer, vitamin D, blood pressure medications, and epoetin alfa. Growth failure may be treated with human recombinant growth hormone. These treatments require careful monitoring to minimize symptoms while the need for chronic dialysis and transplantation continues to be assessed.

Care must be taken to avoid medications that aggravate hypertension; increase the body burden of sodium, potassium, or phosphate; or increase production of BUN. Successful management relies greatly on education of the patient and family.

Attention must also be directed toward the psychosocial needs of the patient and family as they adjust to chronic illness and the eventual need for dialysis and kidney transplantation.

B. Dialysis and Transplantation

Chronic peritoneal dialysis (home-based) and hemodialysis provide life-saving treatment for children prior to renal transplantation. The best measure of the success of chronic dialysis in children is the level of physical and psychosocial rehabilitation achieved, such as continued participation in day-to-day activities and school attendance. Although catch-up growth rarely occurs, patients can grow at an acceptable rate even though they may remain in the lower percentiles. Use of epoetin alfa, growth hormone, and better control of renal osteodystrophy contribute to improved outcome.

At present, the graft survival rate for living-related kidney transplants is 90% at 1 year, 85% at 2 years, and 75% at 5 years. With cadaveric transplantation, graft survivals are 76%, 71%, and 62%, respectively. Overall, the mortality rate is 4% for recipients of living-related donors and 6.8% for recipients of cadaver organs. These percentages are affected by the increased mortality, reported to be as high as 75%, in infants younger than age 1 year, primarily due to technical issues and complications of immunosuppression. A body weight of at least 15 kg is associated with a significantly improved survival rate. Adequate growth and well-being are directly related to acceptance of the graft, the degree of normal function, and the side effects of medications.

Carey WA et al: Outcomes of dialysis initiated during the neonatal period for treatment of end-stage renal disease: a North American Pediatric Renal Trials and Collaborative Studies special analysis. Pediatrics 2007;119:468 [PMID: 17224455].

Rees L: Long-term outcome after renal transplantation in childhood. Pediatr Nephrol 2009;24:475–484 [PMID: 17687572].

Shroff R, Ledermann S: Long-term outcome of chronic dialysis in children. Pediatr Nephrol 2009;24:463–474 [PMID: 18214549].

HYPERTENSION

Hypertension in children is commonly of renal origin. It is anticipated as a complication of known renal parenchymal disease, but it may be found on routine physical examination in an otherwise normal child. Increased understanding of the roles of water and salt retention and overactivity of the renin-angiotensin system has done much to guide therapy; nevertheless, not all forms of hypertension can be explained by these two mechanisms.

The causes of renal hypertension in the newborn period include (1) congenital anomalies of the kidneys or renal vasculature, (2) obstruction of the urinary tract, (3) thrombosis of renal vasculature or kidneys, and (4) volume overload. Some instances of apparent paradoxic elevations of blood pressure have been reported in clinical situations in which chronic diuretic therapy is used, such as in bronchopulmonary dysplasia. Hypertensive infants and older children should be examined for renal, vascular, or aortic abnormalities (eg, thrombosis, neurofibromatosis, coarctation) as well as some endocrine disorders, including pheochromocytoma, glucocorticoid-remedial aldosteronism, primary hyperaldosteronism, pseudoaldosteronism (Liddle syndrome), and pseudohypoaldosteroism (Gordon syndrome).

image Clinical Findings

A child is normotensive if the average recorded systolic and diastolic blood pressures are lower than the 90th percentile for age and sex. The 90th percentile in the newborn period is approximately 85–90/55–65 mm Hg for both sexes. In the first year of life, the acceptable levels are 90–100/60–67 mm Hg. Incremental increases with growth occur, gradually approaching young adult ranges of 100–120/65–75 mm Hg in the late teens. Careful measurement of blood pressure requires correct cuff size and reliable equipment. The cuff should be wide enough to cover two-thirds of the upper arm and should encircle the arm completely without an overlap in the inflatable bladder. Although an anxious child may have an elevation in blood pressure, abnormal readings must not be too hastily attributed to this cause. Repeat measurement is helpful, especially after the child has been consoled.

Routine laboratory studies include serum BUN, creatinine and electrolytes, a complete blood count, urinalysis, and urine culture. Abnormal BUN and creatinine would support underlying renal disease as the cause and serum electrolytes demonstrating hypokalemic alkalosis may represent either hyperaldosteronism or pseudoaldosteronism in which case urine sodium and chloride should be measured. Renal ultrasonography with Doppler flow is helpful in determining the possible presence of renal scarring, urinary tract obstruction or renovascular flow disturbances as a cause of hypertension. A renal biopsy (which rarely reveals the cause of hypertension unless clinical evidence of renal disease is present) should be undertaken with special care in the hypertensive patient and preferably after pressures have been controlled by therapy. Figure 24–3 presents a suggested approach to the outpatient workup of hypertension.

Image

Image Figure 24.3. Approach to the outpatient workup of hypertension. ANA, antinuclear antibody; BP, blood pressure; BUN, blood urea nitrogen; C3, complement; Cr, creatinine; MRA, magnetic resonance angiography; U/A, urinalysis.

image Treatment

A. Acute Hypertensive Emergencies

A hypertensive emergency exists when CNS signs of hypertension appear, such as papilledema or encephalopathy. Retinal hemorrhages or exudates also indicate a need for prompt and effective control. In children, end-organ abnormalities secondary to hypertension commonly are not present. Treatment varies with the clinical presentation. The primary classes of useful antihypertensive drugs are (1) diuretics, (2) α- and β-adrenergic blockers, (3) angiotensin-converting enzyme inhibitors, (4) calcium channel blockers, and (5) vasodilators.

Whatever method is used to control emergent hypertension, medications for sustained control should also be initiated so that normal blood pressure will be maintained when the emergent measures are discontinued (Table 24–4). Acute elevations of blood pressure not exceeding the 95th percentile for age may be treated with oral antihypertensives, aiming for progressive improvement and control within 48 hours.

Table 24–4. Antihypertensive drugs for emergency treatment.

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1. Sublingual nifedipine—This calcium channel blocker is rapid acting, and, in appropriate doses, should not result in hypotensive blood pressure levels. The liquid from a 10-mg capsule can be drawn into a syringe and the dosage approximated. The exact dosage for children who weigh less than 10–30 kg is difficult to ascertain by this method, but 5 mg is a safe starting point. Because the treatment is given for rising blood pressure, it is unlikely that the effects will be greater than desired. Larger children with malignant hypertension require 10 mg. In such cases, the capsule may simply be pierced and the medication squeezed under the patient’s tongue. In children who are able to swallow capsules, and are large enough for a 10-mg dose, the child may bite the capsule, then swallow it for rapid onset of the drug. IV medication to achieve sustained control should be initiated as soon as possible.

2. Sodium nitroprusside—Sodium nitroprusside is considered one of the most rapidly effective IV medications to gain control of malignant hypertension but long-term usage is limited by fear of possible thiocyanate toxicity especially in renal failure. As with other vasodilators, it will result in reflex tachycardia requiring the addition of a β-blocker, and fluid retention requiring addition of a diuretic.

3. Furosemide—Administered at 1–5 mg/kg intravenously, this diuretic reduces blood volume and enhances the effectiveness of antihypertensive drugs.

4. Labetalol or Esmolol—IV forms of β-blockers can be very effective if there are no cardiac or respiratory contraindications to their use.

5. Intravenous hydralazine—This vasodilator is sometimes effective. Dosage varies according to the severity of the hypertension and should begin at about 0.15 mg/kg. Will cause physiologic responses requiring addition of β-blocker and diuretic.

B. Sustained Hypertension

Several choices are available for treatment (Table 24–5). A single drug such as a β-blocker (unless contraindicated, eg, in reactive airway disease) may be adequate to treat mild hypertension. Diuretics are useful to treat renal insufficiency, but the disadvantages of possible electrolyte imbalance must be considered. Single-drug therapy with an angiotensin-converting enzyme inhibitor is useful, especially because most hypertension in children is renal in origin. Calcium channel blockers are increasingly useful, and appear well tolerated in children. The use of the vasodilator type of antihypertensive drug requires concomitant administration of a diuretic to counter the effect of vasodilation on increasing renal sodium and water retention and a β-blocker to counter reflex tachycardia. Minoxidil, considered the most powerful of the orally administered vasodilators, can be extremely efficacious in the treatment of severe, sustained hypertension, but its effect is greatly offset by these other effects. Hirsutism is also a significant side effect. Hydralazine hydrochloride may still be the most common vasodilator in pediatric use—but, again, the necessity of using two additional drugs for maximum benefit relegates use to severe situations calling for management with three or four drugs. The advice of a pediatric nephrologist should be sought.

Table 24–5. Antihypertensive drugs for ambulatory treatment.

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Flynn JT: Hypertension in the young: epidemiology, sequelae and therapy. Nephrol Dial Transplant 2009;24:370 [PMID: 18996836].

Hogg RJ et al: A multicenter study of the pharmacokinetics of lisinopril in pediatric patients with hypertension. Pediatr Nephrol 2007;22:695 [PMID: 17216247].

INHERITED OR DEVELOPMENTAL DEFECTS OF THE KIDNEYS

There are many developmental, hereditary, or metabolic defects of the kidneys and collecting system. The clinical consequences include metabolic abnormalities, failure to thrive, nephrolithiasis, renal glomerular or tubular dysfunction, and chronic renal failure. Table 24–6 lists some of the major entities.

Table 24–6. Inherited or developmental defects of the urinary tract.

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DISORDERS OF THE RENAL TUBULES

Three subtypes of renal tubular acidosis (RTA) are recognized: (1) the classic form, called type I or distal RTA; (2) the bicarbonate-wasting form, called type II or proximal RTA; and (3) type IV, or hyperkalemic RTA (rare in children), which is associated with hyporeninemic hypoaldosteronism. Types I and II and their variants are encountered most frequently in children. Type III is a combination of types I and II.

Other primary tubular disorders in childhood, such as glycinuria, hypouricemia, or renal glycosuria, may result from a defect in a single tubular transport pathway (see Table 24–6).

1. Distal Renal Tubular Acidosis (Type I)

The most common form of distal RTA in childhood is the hereditary form. The clinical presentation is one of failure to thrive, anorexia, vomiting, and dehydration. Hyperchloremic metabolic acidosis, hypokalemia, and a urinary pH exceeding 6.5 are found. Acidosis is more severe in the presence of a bicarbonate “leak.” This variant of distal RTA with bicarbonate wasting has been called type III but for clinical purposes need not be considered as a distinct entity. Concomitant hypercalciuria may lead to rickets, nephrocalcinosis, nephrolithiasis, and renal failure.

Other situations that may be responsible for distal RTA are found in some of the entities listed in Table 24–6.

Distal RTA results from a defect in the distal nephron, in the tubular transport of hydrogen ion, or in the maintenance of a steep enough gradient for proper excretion of hydrogen ion. This defect can be accompanied by degrees of bicarbonate wasting.

The classic test for distal RTA is an acid load from NH4Cl. The test is cumbersome and can produce severe acidosis. A clinical trial of alkali administration should be used to rule out proximal (type II) RTA. The dose of alkali required to achieve a normal plasma bicarbonate concentration in patients with distal RTA is low (seldom exceeding 2–3 mEq/kg/24 h)—in contrast to that required in proximal RTA (> 10 mEq/kg/24 h). Higher doses are needed, however, if distal RTA is accompanied by bicarbonate wasting. Correction of acidosis can result in reduced complications and improved growth.

Distal RTA is usually permanent, although it sometimes occurs as a secondary complication. If the defect is not caused by a significant tubular disorder and renal damage is prevented, the prognosis with treatment is good.

2. Proximal Renal Tubular Acidosis (Type II)

Proximal RTA, the most common form of RTA in childhood, is characterized by an alkaline urine pH, loss of bicarbonate in the urine, and mildly reduced serum bicarbonate concentration. This occurs as a result of a lower than normal bicarbonate threshold, above which bicarbonate appears in the urine. Thus, urinary acidification can occur when the concentration of serum bicarbonate drops below that threshold, and bicarbonate disappears from the urine; this ability to eventually acidify the urine thus reflects normal distal tubular function.

Proximal RTA is often an isolated defect, and in the newborn can be considered an aspect of renal immaturity. Onset in infants is accompanied by failure to thrive, hyperchloremic acidosis, hypokalemia, and, rarely, nephrocalcinosis. Secondary forms result from reflux or obstructive uropathy or occur in association with other tubular disorders (see Table 24–6). Proximal RTA requires more than 3 mEq/kg of alkali per day to correct the acidosis. Serum bicarbonate should be monitored weekly until a level of at least 20 mEq/L is attained.

Citrate solutions (eg, Bicitra, Polycitra) are somewhat more easily tolerated than sodium bicarbonate. Bicitra contains 1 mEq/mL of Na+ and citrate. Polycitra contains 2 mEq/mL of citrate and 1 mEq each of Na+ and K+. The required daily dosage is divided into three doses. Potassium supplementation may be required, because the added sodium load presented to the distal tubule may exaggerate potassium losses.

The prognosis is excellent in cases of isolated defects, especially when the problem is related to renal immaturity. Alkali therapy can usually be discontinued after several months to 2 years. Growth should be normal, and the gradual increase in the serum bicarbonate level to greater than 22 mEq/L heralds the presence of a raised bicarbonate threshold in the tubules. If the defect is part of a more complex tubular abnormality (Fanconi syndrome with attendant phosphaturia, glycosuria, and amino aciduria), the prognosis depends on the underlying disorder or syndrome.

OCULOCEREBRORENAL SYNDROME (LOWE SYNDROME)

Lowe syndrome results from various mutations in the ORCL1 gene, which codes for a Golgi apparatus phosphatase. Affected males have anomalies involving the eyes, brain, and kidneys. The physical stigmata and degree of mental retardation vary with the location of the mutation. In addition to congenital cataracts and buphthalmos, the typical facies includes prominent epicanthal folds, frontal prominence, and a tendency to scaphocephaly. Muscle hypotonia is a prominent finding. The renal abnormalities are of tubule function and include hypophosphatemic rickets with low serum phosphorus levels, low to normal serum calcium levels, elevated serum alkaline phosphatase levels, RTA, and aminoaciduria. Treatment includes alkali therapy, phosphate replacement, and vitamin D. Antenatal diagnosis is possible.

HYPOKALEMIC ALKALOSIS (BARTTER SYNDROME, GITELMAN SYNDROME, & LIDDLE SYNDROME)

Bartter syndrome is characterized by severe hypokalemic, hypochloremic metabolic alkalosis, extremely high levels of circulating renin and aldosterone, and a paradoxic absence of hypertension. On renal biopsy, a striking juxtaglomerular hyperplasia is seen.

A neonatal form of Bartter syndrome is thought to result from mutations in two genes affecting either Na+–K+ or K+ transport. These patients have life-threatening episodes of fever and dehydration with hypercalciuria and early-onset nephrocalcinosis. Classic Bartter syndrome presenting in infancy with polyuria and growth retardation (but not nephrocalcinosis) is thought to result from mutations in a chloride channel gene. Gitelman syndrome occurs in older children and features episodes of muscle weakness, tetany, hypokalemia, and hypomagnesemia. These children have hypocalciuria. In Liddle syndrome, the presenting significant clinical abnormality may at first be hypertension, although hypokalemia may also be evident. Serum renin and aldosterone are low and serum sodium is elevated.

Treatment with prostaglandin inhibitors and potassium-conserving diuretics (eg, amiloride combined with magnesium supplements) and potassium and magnesium where indicated is beneficial in Bartter syndrome and Gitelman syndrome. Although the prognosis is guarded, a few patients seem to have less severe forms of the disease that are compatible with long survival times. Treatment in Liddle syndrome is with a low sodium diet and potassium sparing diuretics, excluding spironolactone, since it acts by regulation of aldosterone.

CYSTINOSIS

There are three types of cystinosis: adult, adolescent, and infantile. The adolescent type is characterized by cystine deposition, which, if not treated with phosphocysteamine (Cystagon) which aids in the metabolic conversion of cystine (unable to exit cells) to cysteine (able to exit cells), is accompanied by the development of the renal Fanconi syndrome (renal tubular dysfunction) and varying degrees of renal failure. Growth is usually normal. The infantile type is the most common and the most severe. Characteristically, children present in the first or second year of life with Fanconi syndrome and, without the metabolic benefit of Cystagon treatment, progress to end-stage renal failure.

Cystinosis results from mutations in the CTNS gene, which codes for a cystine transporter. About 50% of patients share an identical deletion. Inheritance is autosomal recessive. Cystine is stored in cellular lysosomes in virtually all tissues. Eventually, cystine accumulation results in cell damage and cell death, particularly in the renal tubules. Renal failure between ages 6 and 12 years is common in the infantile form.

Whenever the diagnosis of cystinosis is suspected, slit-lamp examination of the corneas should be performed. Cystine crystal deposition causes an almost pathognomonic ground-glass “dazzle” appearance. Increased white cell cystine levels are diagnostic. Hypothyroidism is common.

Cystagon therapy is helpful in the treatment of cystinosis and can retard progression of renal failure and the accumulation of cystine in other organs. Depending on the progression of chronic renal failure, management is directed toward all side effects of renal failure, with particular attention paid to the control of renal osteodystrophy. Dialysis and transplantation may be needed.

Nesterova G, Gahl W: Nephropathic cystinosis: late complications of a multisystem disease. Pediatr Nephrol 2008;32:863–878 [PMID: 18008091].

NEPHROGENIC DIABETES INSIPIDUS

The congenital X-linked recessive form of nephrogenic (no response to vasopressin) diabetes insipidus results from mutations in the vasopressin receptor, AVPR2. Autosomal (recessive and dominant) forms of nephrogenic diabetes insipidus are caused by mutations of the AQP2 gene that codes for a water channel protein, aquaporin-2. Genetic counseling and mutation testing are available.

Urine concentrating ability is impaired in a number of other conditions—sickle cell anemia, pyelonephritis, potassium depletion, hypercalcemia, cystinosis and other renal tubular disorders, and obstructive uropathy—and as a result of nephrotoxic drugs. Children receiving lithium treatment should be monitored for the development of nephrogenic diabetes insipidus.

The symptoms of nephrogenic diabetes insipidus are polyuria, polydipsia, and failure to thrive. In some children, particularly if the solute intake is unrestricted, adjustment to an elevated serum osmolality may develop. These children are particularly susceptible to episodes of dehydration, fever, vomiting, and convulsions.

The diagnosis can be suspected on the basis of a history of polydipsia and polyuria insensitive to the administration of vasopressin, desmopressin acetate, or lypressin. The diagnosis is confirmed by performing a vasopressin test. Carefully monitored water restriction does not increase the tubular reabsorption of water (TcH2O) to above 3 mL/min/m2. Urine osmolality remains lower than 450 mOsm/kg, whereas serum osmolality rises and total body weight falls. Before weight reduction of more than 5% occurs or before serum osmolality exceeds 320 mOsm/kg, vasopressin should be administered.

In infants, it is usually best to allow water as demanded and to restrict salt. Serum sodium levels should be evaluated at intervals to avoid hyperosmolality from inadvertent water restriction. In later childhood, sodium intake should continue to be restricted to 2.0–2.5 mEq/kg/24 h.

Treatment with hydrochlorothiazide is helpful, and many patients show improvement with administration of prostaglandin inhibitors such as indomethacin or tolmetin.

Linshaw MA: Back to basics: congenital nephrogenic diabetes insipidus. Pediatr Rev 2007;28:372–380 [PMID: 17908859].

NEPHROLITHIASIS

Renal calculi in children may result from inborn errors of metabolism, such as cystine in cystinuria, glycine in hyperglycinuria, urates in Lesch-Nyhan syndrome, and oxalates in oxalosis. Stones may occur secondary to hypercalciuria in distal tubular acidosis, and large stones are quite often seen in children with spina bifida who have paralyzed lower limbs or any situation where immobilization promotes calcium mobilization from bones. Treatment is limited to that of the primary condition, if possible. Most cases of nephrolithiasis have no basis in a metabolic disturbance, however, and are initially addressed with attention toward maintaining optimal hydration. Surgical removal of stones or lithotrypsy should be considered only for obstruction, intractable severe pain, and chronic infection.

Tanaka ST, Pope JC 4th: Pediatric stone disease. Curr Urol Rev 2009;10:138–143 [PMID: 19239819].

1. Cystinuria

Cystinuria, like Hartnup disease and several other disorders, is primarily an abnormality of amino acid transport across both the enteric and proximal renal tubular epithelium. There are at least three biochemical types. In the first type, the bowel transport of basic amino acids and cystine is impaired, but transport of cysteine is not impaired. In the renal tubule, basic amino acids are again rejected by the tubule, but cystine absorption appears to be normal. The reason for cystinuria remains obscure. Heterozygous individuals have no aminoaciduria. The second type is similar to the first except that heterozygous individuals excrete excess cystine and lysine in the urine, and cystine transport in the bowel is normal. In the third type, only the nephron is involved. The only clinical manifestations are related to stone formation: ureteral colic, dysuria, hematuria, proteinuria, and secondary UTI. Urinary excretion of cystine, lysine, arginine, and ornithine is increased.

The most reliable way to prevent stone formation is to maintain a constantly high free-water clearance. This involves generous fluid intake. Alkalinization of the urine is helpful. If these measures do not prevent significant renal lithiasis, the use of tiopronin (Thiola) is recommended.

Ahmed K et al: Management of cystinuric patients: an observational, retrospective, single-centre analysis. Urol Int 2008;80P: 141–144 [PMID: 18362482].

2. Primary Hyperoxaluria

Oxalate in humans is derived from the oxidative deamination of glycine to glyoxylate, from the serine-glycolate pathway, and from ascorbic acid. At least two enzymatic blocks have been described. Type I is a deficiency of liver-specific peroxisomal alanine–glyoxylate aminotransferase. Type II is glyoxylate reductase deficiency.

Excess oxalate combines with calcium to form insoluble deposits in the kidneys, lungs, and other tissues, beginning during childhood. The joints are occasionally involved, but the main effect is on the kidneys, where progressive oxalate deposition leads to fibrosis and eventual renal failure.

Pyridoxine supplementation and a low-oxalate diet have been tried as therapy, but the overall prognosis is poor, and most patients succumb to uremia by early adulthood. Renal transplantation is not very successful because of destruction of the transplant kidney. However, encouraging results have been obtained with concomitant liver transplantation, correcting the metabolic defect.

Hyperoxaluria may also be a consequence of severe ileal disease or ileal resection.

URINARY TRACT INFECTIONS

It is estimated that 8% of girls and 2% of boys will acquire UTIs in childhood. Girls older than age 6 months have UTIs far more commonly than boys, whereas uncircumcised boys younger than 3 months of age have more UTIs than girls. Circumcision reduces the risk of UTI in boys. The density of distal urethral and periurethral bacterial colonization with uropathogenic bacteria correlates with the risk of UTI in children. Most UTIs are ascending infections. Specific adhesins present on the fimbria of uropathogenic bacteria allow colonization of the uroepithelium in the urethra and bladder and increase the likelihood of UTI. The organisms most commonly responsible for UTI are fecal flora, most commonly E coli (> 85%), KlebsiellaProteus, other gram-negative bacteria, and, less frequently, Enterococcus or coagulase-negative staphylococci.

image Pathogenesis

Dysfunctional voiding, which is uncoordinated relaxation of the urethral sphincter during voiding, leads to incomplete emptying of the bladder, increasing the risk of bacterial colonization. Similarly, any condition that interferes with complete emptying of the bladder, such as constipation, vesicoureteral reflux, urinary tract obstruction, or neurogenic bladder, increases the risk of UTI. Poor perineal hygiene, structural abnormalities of the urinary tract, catheterization, instrumentation of the urinary tract, and sexual activity increase the risk as well.

The inflammatory response to pyelonephritis may produce renal parenchymal scars. Such scars in infancy and childhood may contribute to hypertension, renal disease, and renal failure later in life.

image Clinical Findings

A. Symptoms and Signs

Newborns and infants with UTI have nonspecific signs, including fever, hypothermia, jaundice, poor feeding, irritability, vomiting, failure to thrive, and sepsis. Strong, foul-smelling or cloudy urine may be noted. Preschool children may have abdominal or flank pain, vomiting, fever, urinary frequency, dysuria, urgency, or enuresis. School-aged children commonly have classic signs of cystitis (frequency, dysuria, and urgency) or pyelonephritis (fever, vomiting, and flank pain). Costovertebral tenderness is unusual in young children, but may be demonstrated by school-aged children. Physical examination should include attention to blood pressure determination, abdominal examination, and a genitourinary examination. Urethritis, poor perineal hygiene, herpes simplex virus, or other genitourinary infections may be apparent on examination.

B. Laboratory Findings

Screening urinalysis indicates pyuria (> 5 WBCs/high-power field) in most children with UTI, but some children can have sterile pyuria without UTI. White cells from the urethra or vagina may be present in urine or may be in the urine because of a renal inflammatory process. The leukocyte esterase test correlates well with pyuria, but has a similar false-positive rate. The detection of urinary nitrite by dipstick is highly correlated with enteric organisms being cultured from urine. Most young children (70%) with UTI have negative nitrite tests, however. They empty their bladders frequently, and it requires several hours for bacteria to convert ingested nitrates to nitrite in the bladder.

The gold standard for diagnosis remains the culture of a properly collected urine specimen. Collection of urine for urinalysis and culture is difficult in children due to frequent contamination of the sample. In toilet-trained, cooperative, older children, a midstream, clean-catch method is satisfactory. Although cleaning of the perineum does not improve specimen quality, straddling of the toilet to separate the labia in girls, retraction of the foreskin in boys, and collecting midstream urine significantly reduce contamination. In infants and young children, bladder catheterization or suprapubic collection is necessary in most cases to avoid contaminated samples. Bagged urine specimens are helpful only if negative. Specimens that are not immediately cultured should be refrigerated and kept cold during transport. Any growth is considered significant from a suprapubic culture. Quantitative recovery of 105cfu/mL or more is considered significant from clean-catch specimens, and 104–105 is considered significant from catheterized specimens. Usually the recovery of multiple organisms indicates contamination.

Asymptomatic bacteriuria is detected in 0.5%–1.0% of children who are screened with urine culture. Asymptomatic bacteriuria, as seen commonly in children requiring chronic bladder catheterization, is believed to represent colonization of the urinary tract with nonuropathogenic bacteria. Treatment in such cases may increase the risk of symptomatic UTI by eliminating nonpathogenic colonization. Screening urine cultures in asymptomatic children are, therefore, generally discouraged.

C. Imaging

Because congenital urologic abnormalities increase the risk of UTI, a renal ultrasound, which is a noninvasive study, is recommended for children with UTI. In cases where hydronephrosis and/or frank evidence of urinary tract obstruction is demonstrated, a voiding cystourethrogram (VCUG) is performed to demonstrate vesicoureteral reflux or a renal scan can be done to confirm obstruction and demonstrate the amount of functioning renal tissue. VUR is a congenital abnormality present in about 1% of the population beyond infancy and is graded using the international scale (I—reflux into ureter; II—reflux to the kidneys; III—reflux to kidneys with dilation of ureter only; IV—reflux with dilation of ureter and mild blunting of renal calyces; V—reflux with dilation of ureter and blunting of renal calyces). Reflux is detected in 30%–50% of children presenting with a UTI at 1 year of age and younger. The natural history of reflux is to improve, and 80% of reflux of grades I, II, or III will resolve or significantly improve within 3 years following detection provided there is prophylaxis against infection.

VCUG should be done selectively on children with a first UTI; candidates for VCUG should include those in whom a urologic abnormality is suspected due to weak stream, dribbling, or perineal abnormalities. Boys with a first UTI may have posterior urethral valves, an important congenital abnormality that requires surgery. Children older than 3 years of age who are otherwise healthy and growing well usually can be followed clinically and do not need an immediate VCUG for a first UTI, but a renal ultrasound is recommended. The yield of VCUG in sexually active teenagers is very low.

Ultrasonographic examination of kidneys should be done acutely in children presenting with pyelonephritis and repeated in those who have not improved after 3–5 days of antimicrobial treatment appropriate for the susceptibility of the organism. The examination is done to detect renal or perirenal abscesses or obstruction of the kidneys.

image Treatment

A. Antibiotic Therapy

Management of UTI is influenced by clinical assessment. Very young children (younger than 3 months) and children with dehydration, toxicity, or sepsis should be admitted to the hospital and treated with parenteral antimicrobials. Older infants and children who are not seriously ill can be treated as outpatients. Initial antimicrobial therapy is based on prior history of infection and antimicrobial use, as well as location of the infection in the urinary tract.

Uncomplicated cystitis can be treated with amoxicillin, trimethoprim–sulfamethoxazole, or a first-generation cephalosporin. These antimicrobials are concentrated in the lower urinary tract, and high cure rates are common. There are significant differences in the rates of antimicrobial resistance, so knowledge of the rates in the local community is important. More seriously ill children are initially treated parenterally with a third-generation cephalosporin or aminoglycoside. The initial antimicrobial choice is adjusted after culture and susceptibility results are known. The recommended duration of antimicrobial therapy for uncomplicated cystitis is 7–10 days. For sexually mature teenagers with cystitis, fluoroquinolones such as ciprofloxacin and levofloxacin for 3 days are effective and cost-effective. Short-course therapy of cystitis is not recommended in children, because differentiating upper and lower tract disease may be difficult and higher failure rates are reported in most studies of short-course therapy.

Acute pyelonephritis is usually treated for 10 days. In nontoxic children older than 3 months of age who are not vomiting, oral treatment with an agent such as cefixime can be used. In sicker children, parenteral therapy may be required initially. Most of these children can complete therapy orally once symptomatic improvement has occurred. A repeat urine culture 24–48 hours after beginning therapy is not needed if the child is improving and doing well.

B. Follow-Up

Children with UTI should be followed with screening urinalysis 1 and 2 months after resolution of UTI. Dipstick nitrite determination can be used at home by parents on first morning voided urine in children with frequently recurring UTI.

C. Prophylactic Antimicrobials

Selected children with frequently recurring UTI may benefit from prophylactic antimicrobials. In children with high-grade VUR, prophylactic antimicrobials may be beneficial in reducing UTI, as an alternative to surgical correction, or in the interval prior to surgical therapy. Many experts recommend surgical correction of higher-grade reflux, particularly grade V. Trimethoprim-sulfamethoxazole and nitrofurantoin are approved for prophylaxis. The use of broader-spectrum antimicrobials leads to colonization and infection with resistant strains.

Children with dysfunctional voiding generally do not benefit from prophylactic antimicrobials; rather, addressing the underlying dysfunctional voiding is most important.

DeMuri GP, Wald ER: Imaging and antimicrobial prophylaxis following the diagnosis of urinary tract infection in children. Pediatr Infect Dis J 2008;27:553–554 [PMID: 18520594].

Geary DF, Schaefer F: Comprehensive Pediatric Nephrology, 1st ed. Mosby, Inc; 2008.

Williams G, Craig JC: Prevention of recurrent urinary tract infection in children. Curr Opin Infect Dis 2009;22:72–76 [PMID: 19532083].