Chapter 24: Kidney & Urinary Tract

HISTORY

When renal disease is suspected, the history should include the following:

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

2. Rashes or joint pain/swelling

3. Growth delay or failure to thrive

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

5. Documentation of hematuria, proteinuria, or discolored urine

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

7. Sudden weight gain or loss or edema

8. Drug or toxin exposure

9. Birth history including prenatal ultrasonographic studies, oligo- or polyhydramnios, birth asphyxia, dysmorphic features and other congenital anomalies, abdominal masses, voiding patterns, and umbilical artery catheterization

10. Family history of cystic renal disease, hypertension including early-onset, hereditary nephritis, deafness, dialysis, or renal transplantation

PHYSICAL EXAMINATION

Important aspects of the physical examination include the height, weight, growth percentiles, skin lesions (café au lait, ash leaf spots, or rash), 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 with a manual cuff of the appropriate size in the right upper extremity, ideally with the child seated with feet flat on the ground. The cuff should cover two-thirds of the child’s upper arm, and peripheral pulses should be assessed. The abdomen should be palpated and auscultated, with attention to nephromegaly, abdominal masses, musculature, ascites, or bruits.

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 GFR (glomerular filtration rate). Norms for serum creatinine relate to muscle mass. Therefore, only larger adolescents should have levels exceeding 1 mg/dL. Serum cystatin C is an additional indicator of glomerular function, independent of muscle mass. Cystatin C is a cysteine protease inhibitor that is produced by all nucleated cells and released in the blood. It is reabsorbed and catabolized by renal tubular cells. Currently, Cystatin C is less widely available, and is less reliable in certain clinical settings, such as with corticosteroid administration or thyroid disease. 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 (C_Cr) in milliliters per minute estimates the GFR. A 24-hour urine collection is the “classic” approach for determining C_Cr; however, it is often difficult to accurately obtain in the pediatric population, particularly in children who are not continent. 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 assessed in individuals with normal muscle mass by measuring the total 24-hour creatinine excretion in the specimen. Total daily creatinine excretion (creatinine index) should be 15–25 mg/kg, with normal values higher in males that in females, reflective of differences in muscle mass. 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 or serum creatinine (P_Cr) in mg/dL, urine creatinine (U_Cr) in mg/dL, and urine volume (V) expressed as mL/min:

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

As 80–125 mL/min/1.73 m² is the normal range for C_Cr (for children older than 1 year), estimates at the lower end of this range may indicate problems.

A quick approximation of estimated GFR in children, the “bedside Schwartz” equation, based on plasma or serum creatinine level and length in centimeters, can be obtained as follows:

eGFR(mL/min/1.73 m²) = 0.413 × height (cm)/P_Cr(mg/dL)

This formula was developed in children with chronic kidney disease (CKD) and has more recently been validated in children with normal renal function. When cystatin C (cysC) has been assessed, the creatinine-Cystatin C-based CKiD equation may be utilized to include this variable and blood urea nitrogen (BUN):

This more extensive calculation may be useful as a confirmatory test in specific circumstances when eGFR based on serum creatinine is less accurate (eg, low muscle mass) or when the clinical scenario warrants a secondary test. Online tools can be utilized to facilitate this calculation.

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), presuming cessation of fluid intake overnight. 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 or casts. Hematuria is present with > 5 RBC/high-powered field (hpf). Significant proteinuria (≥ 30 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, although urologic etiologies require consideration. Urinary red blood cell (RBC) casts suggest glomerulonephritis (GN), but the absence of casts does not exclude this disease. Urine RBC morphology may be helpful, with dysmorphic RBC arising from the kidneys. Anatomic abnormalities such as cystic disease with cyst rupture may also cause hematuria. Benign hematuria, including benign familial hematuria/thin glomerular basement membrane disease, is diagnosed by exclusion. Hematuria can also be observed in the setting of hypercalciuria or urolithiasis. Note that hypercalciuria is not associated with proteinuria. Figure 24–1 suggests an approach to the renal workup of hematuria. GN is discussed in more detail later in this chapter.

Combined proteinuria and hematuria is characteristic of more significant glomerular disease. Quantification 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 and the potential difficulties in timed collection in children who are not toilet trained, the degree of proteinuria may be estimated by the ratio of protein (mg/dL)/creatinine (mg/dL) in a random urine sample. A urine protein/creatinine ratio above 0.2 is abnormal. In the evaluation of asymptomatic proteinuria, orthostatic or postural proteinuria should be excluded. 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 proteinuria. Such patients typically show resolution of orthostatic proteinuria over time, but rarely an orthostatic pattern can be seen initially in GN, so ongoing follow-up is warranted. 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. The presence of significant hematuria (> 20 RBC/hpf) or RBC casts should raise concern for GN (see Figure 24–1). Other renal lesions with proteinuric manifestations are discussed later in this chapter.

Special Tests of Renal Function

Measurements of urinary sodium, creatinine, and osmolality are useful in differentiating prerenal from renal causes of acute kidney injury (AKI). The physiologic response to decreased renal perfusion is decreased urinary output, increased urine osmolality, increased urinary solute concentration (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 in the setting of normal serum glucose concentration. Hyperphosphaturia occurs with significant proximal 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:

where S_Cr = serum creatinine, U_Cr = 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 85% or more is considered normal in children, although it depends somewhat on the value of Spo₄.

A quantitative increase in urinary excretion of amino acids is seen in generalized proximal tubular disease. Defective proximal tubular reabsorption of bicarbonate can be seen in isolated renal tubular acidosis (RTA), Fanconi syndrome, and chronic renal failure.

Novel Urinary Biomarkers

Urinary markers of AKI, most often of tubular damage, have become more clinically available in recent years. They include, among others, Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL), an iron transporting protein that is almost completely reabsorbed by normal renal tubules. NGAL levels increase after acute ischemic/nephrotoxic insults and have been found to be sensitive markers of AKI, especially in intensive care settings.

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).

Serum C3 and C4 complement concentrations should be measured when immune-mediated renal injury or chronic GN is suspected. Where clinically indicated, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), hepatitis B surface antigen, and hepatitis C antibody should be obtained. In rare cases, cryoglobulins (very rare in childhood), C3 nephritic factor and other assessment of complement function, or antiglomerular basement membrane (anti-GBM) antibody measurements may help confirm a specific diagnosis. At some point in the workup, the diagnosis should, if possible, be confirmed by histologic examination of renal tissue.

RADIOGRAPHIC EVALUATION

Renal ultrasonography is a useful noninvasive tool for evaluating renal parenchymal disease, urinary tract abnormalities, and renal blood flow. Radioisotope studies provide information about renal anatomy, blood flow, and integrity and function of the glomerular, tubular, and collecting systems. Renal stones are often visualized by ultrasonography but are best delineated by computed tomography (CT) without contrast. Due to lack of radiation, ultrasonography is usually used for screening and follow-up of urolithiasis. Voiding cystourethrography (VCUG) is indicated when vesicoureteral reflux (VUR) or bladder outlet obstruction (eg, to visualize the posterior urethra) is suspected. Cystoscopy is rarely useful in the evaluation of asymptomatic hematuria or proteinuria in children. Abdominal magnetic resonance imaging (MRI) or CT are useful for the identification and delineation of renal or adrenal masses. Doppler ultrasound is helpful to exclude renal arterial or venous thrombosis but of variable sensitivity and specificity in the diagnosis of renal artery stenosis; the latter condition is better assessed by MR or CT angiography. Intrarenal arterial stenosis may require direct renal arteriography.

RENAL BIOPSY

Histologic information is valuable in select cases to diagnose, guide treatment, and 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.

RENAL PARENCHYMAL ANOMALIES

About 10% of children have congenital anomalies of the genitourinary tract, which range in severity from asymptomatic to lethal. Recent findings suggest that congenital anomalies of the kidney and urinary tract (CAKUT) may arise from mutations in a multitude of different single gene causes. Some asymptomatic abnormalities may have significant implications. For example, patients with “horseshoe” kidney (kidneys fused in their lower poles), although very rarely associated with 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 is typically associated with normal renal function. Supernumerary and ectopic kidneys are often of no significance. Abnormal genitourinary tract development can be associated with varying degrees of renal dysplasia and dysfunction ranging from mild to severe; an example of the latter is in utero bilateral renal agenesis, which, without prenatal intervention to support lung development, is associated with oligoanhydramnios, abnormal facies and limb anomalies (eg, talipes equinovarus) from fetal compression, and perinatal death from pulmonary hypoplasia (Potter syndrome).

Renal Dysplasia

Renal dysplasia constitutes a spectrum of anomalies. In simple hypoplasia, which may be unilateral or bilateral, the affected kidneys are smaller than normal. In some forms of dysplasia, immature undifferentiated renal tissue persists. In some situations, the number of functional nephrons is insufficient to sustain normal renal function once the child reaches a critical body size. The lack of adequate renal tissue is not always readily discernible in the newborn period in the presence of normal or often increased urine production.

Other forms of renal dysplasia include oligomeganephronia (characterized by the presence of only a few large glomeruli) and the cystic dysplasias (characterized by the presence of renal cysts). Simple renal cysts are rare in children and are typically observed in children with a history of significant chronic medical illness. The presence of multiple “simple” cysts should raise concern for possible underlying polycystic kidney disease.

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 kidneys are dysfunctional in utero, and therefore newborns may demonstrate Potter sequence. In less severe cases, kidney enlargement by cysts may initially be recognized when nephromegaly is noted on physical examination. Hypertension is an early problem in ARPKD. The rate of progression of renal insufficiency varies in ARPKD, but many children with a neonatal renal presentation reach end-stage renal disease (ESRD) by school age. Recent studies suggest wide variation in phenotype, even within families. Some patients present in early adulthood with liver dysfunction from congenital hepatic fibrosis with moderate nephromegaly and mild-to-moderate chronic kidney disease.

With advances in radiographic imaging, ADPKD is being diagnosed earlier in life, including prenatally. Children with ADPKD can manifest many of the same findings as adults with ADPKD, such as enlarged kidneys, pain, hematuria, proteinuria, hypertension, kidney stones, and extrarenal cysts (pancreas, spleen, liver), although renal insufficiency and intracranial aneurysms are rare in childhood. Routine monitoring for hypertension is indicated in children with or known to be at-risk for ADPKD. Because cysts grow over time, a normal renal ultrasound does not exclude ADPKD in an at-risk child (ie, parent known to have ADPKD). Approximately half of patients with ADPKD reach ESRD by 60 years of age. Rarely ADPKD can present with Potter sequence or severe neonatal manifestations.

Medullary Cystic Disease/Nephronophthisis

Medullary cystic disease and nephronophthisis are inherited conditions with similar renal morphology characterized by bilateral small corticomedullary cysts in normal to small kidneys with tubulointerstitial scarring leading to ESRD. Numerous causative genes have been identified in nephronophthisis, all of which encode for proteins expressed in the primary cilia of renal epithelial cells, leading to classification as “ciliopathies.” Children with nephronophthisis manifest impaired urinary concentration leading to polyuria and polydipsia with progressive renal insufficiency in childhood or adolescence. Extrarenal involvement including retinitis pigmentosa, hepatic fibrosis, skeletal defects, cerebellar vermis aplasia, or other abnormalities can help target specific gene analysis. Several forms of autosomal-dominant medullary cystic disease exist, usually presenting with adult-onset renal failure and no extrarenal involvement. However, uromodulin-associated kidney disease with hyperuricemia and renal failure can be seen in adolescents.

DISTAL URINARY TRACT ANOMALIES

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 prenatal hydronephrosis, an abdominal mass in the newborn, or recurrent abdominal pain with vomiting in an older child (Dietl’s crisis). Obstruction can occur in other parts of the ureter, especially at the ureterovesical junction, causing proximal hydroureter and hydronephrosis. Renal radionuclide scan with furosemide “wash-out” will reveal or rule out ureteral obstruction as the cause of the hydronephrosis. Whether intrinsic or extrinsic, urinary tract obstruction should be relieved as soon as possible to minimize damage to the kidneys and warrants referral to a pediatric urologist.

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 (PUV). This anomaly, which occurs almost exclusively in males, may be detected prenatally with an enlarged muscular bladder and hydroureteronephrosis. Neonates may demonstrate a poor voiding stream or eventual UTI. The kidneys and bladder may be easily palpable. Leakage (ureteric perforation, although rare) proximal to the obstruction may produce urinary ascites. Decompression of the bladder, most often accomplished via urethral catheterization, is critical in children with PUV to prevent irreversible kidney damage.

Eagle-Barrett (Prune Belly) syndrome is an association of urinary tract anomalies with cryptorchidism and absent abdominal musculature. Renal dysplasia and/or functional urinary tract obstruction may lead to ESRD. Timely urinary diversion is essential to sustain renal function.

Other complex malformations and external genital anomalies 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, prevent UTI and potential related renal scarring, and treat the complications of progressive chronic renal failure. Collaboration between the pediatric urologist and nephrologist, ideally in a multidisciplinary clinic, in early management is essential.

Reflux Nephropathy

The retrograde flow of urine from the bladder into the ureter (vesicoureteral reflux, VUR), when high grade, may cause renal scarring and subsequent renal insufficiency or hypertension, or both, especially in the setting of UTIs. Hydronephrosis on renal ultrasound suggests the possibility of VUR or obstruction. Absence of hydronephrosis on ultrasonography does not, however, rule out the possibility of VUR. VUR is most often diagnosed with a voiding cystourethrogram. Low-grade VUR typically resolves spontaneously over time. Prophylactic antibiotics may be administered depending on the child’s age, degree of VUR, and frequency of UTI while awaiting spontaneous resolution. Surgery may be required for chronic severe reflux. Appropriate management of reflux nephropathy includes prevention and prompt treatment of UTI, monitoring and management of hypertension and complications of chronic renal insufficiency, and consideration of angiotensin-converting enzyme (ACE) inhibition to prevent glomerular hyperfiltration.

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 and/or fever suggests the possibility of pyelonephritis; and colicky flank pain may indicate the passage of a stone. Bright red blood or clots in the urine can also be 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 nephrology evaluation is needed. The diagnosis of hematuria should not rely solely on a urine “dipstick” evaluation, but it must be verified by a microscopic RBC count (normal < 5 RBC/hpf). Ruling out hypercalciuria as a cause of hematuria with a random urine calcium/creatinine ratio (both values in mg/dL) is one of the initial steps in the evaluation of hematuria. A value above 0.2 requires verification with a 24-hour urine collection when possible, and should prompt referral to pediatric nephrology. Hypercalciuria is present with excretion of calcium in excess of 4 mg/kg/day. Figure 24–1 delineates the outpatient approach to renal hematuria. The primary concern in the differential diagnosis of hematuria is the possible presence of glomerular disease.

GLOMERULONEPHRITIS

The various types of glomerulonephritis (GN) have similar clinical manifestations. The defining features of GN include hematuria, urinary RBC casts, hypertension, and edema. Hematuria may be microscopic or gross (often coffee- or tea-colored) in nature. While RBC casts are often present, their absence does not exclude the diagnosis of GN. Urine protein excretion may range from normal (Pr/Cr ratio < 0.2) to nephrotic range (Pr/Cr ratio > 2). Edema (periorbital, facial, extremities, ascites) occurs due to salt and water retention with impaired glomerular function and contributes to systemic hypertension, which is further exacerbated by the glomerular inflammation and associated renin production. Therefore, diuretics followed by blockade of the renin-angiotensin-aldosterone system are the pillars of hypertension management. Affected children require evaluation of blood pressure, renal function, serum albumin, and urine protein excretion. Serum C3 concentration is helpful to distinguish certain types of GN (depressed in postinfectious and membranoproliferative (MPGN)/C3 glomerulopathy (C3GN), GN due to SLE, and GN related to ventriculoatrial shunt infection or endocarditis [the latter two conditions are rarely seen in childhood but are typically evident by history and examination]). Renal biopsy may be indicated when the etiology of GN is not otherwise clear from history and preliminary testing.

Severe glomerular histopathologic and clinical entities such as anti-GBM antibody disease (Goodpasture syndrome), granulomatosis with polyangiitis, microscopic polyangiitis, and crescentic IgA nephropathy may be considered in the differential diagnosis of acute GN; it should be recognized that these disorders are unusual in children. Many of these diagnoses may be rapidly progressive in nature.

Acute Postinfectious Glomerulonephritis

The diagnosis of acute poststreptococcal GN is supported by a recent history (typically within the preceding 7–14 days, with range of 1 day to 6 weeks) of group A β-hemolytic streptococcal infection, usually as pharyngitis or, less commonly, impetigo. If a positive culture is not available, recent infection may be supported by an elevated titer of antistreptococcal antibodies. However, documentation of elevated antistreptococcal antibodies alone does not confirm that GN is poststreptococcal in nature. Other infections can cause similar glomerular injury; thus “postinfectious” GN may be a preferred term for this type of acute glomerulonephritis (AGN). Postinfectious GN is associated with depressed serum C3 complement. The manifestations range from asymptomatic microhematuria to gross hematuria with nephrotic range proteinuria and marked renal insufficiency. However, in most cases, full recovery occurs and is usually complete within weeks.

Typical postinfectious GN has no specific treatment. Antibiotic therapy is indicated if an active infection is documented. Disturbances in renal function and resulting hypertension may require close monitoring, reduction in salt intake, diuretics, or other antihypertensive drugs such as ACE inhibitors. In cases of severe renal failure, hemodialysis or peritoneal dialysis may be necessary. Corticosteroids may also be considered in an attempt to influence the course of severe GN. Serum C3 may normalize as early as 24 hours or as late as 8 weeks after onset. In postinfectious GN, microscopic hematuria may persist for as long as a year; 85% of children recover completely. Persistent deterioration in renal function, chronic proteinuria, and presentation complicated by nephrotic syndrome are concerning signs for long-term prognosis.

IgA Nephropathy

When asymptomatic gross hematuria with or without proteinuria occurs concurrently with a minor acute illness or other stressful occurrence, the diagnosis of IgA nephropathy may be entertained. IgA nephropathy is the most common cause of GN. Serum complement is normal in this condition. IgA nephropathy may be accompanied by flank pain or dysuria. Gross hematuria typically resolves within days, and there are no serious sequelae in 85% of children. Treatment is not generally 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 after confirmatory kidney biopsy solidifies the diagnosis. Omega-3 fatty acids from fish oils are also thought to be helpful by inhibiting macrophage infiltration of the glomerular mesangium.

Henoch-Schönlein Purpura

The diagnosis of Henoch-Schönlein purpura (HSP) rests on the presence of a typical maculopapular and purpuric rash found primarily, but not exclusively, on the dependent surfaces of the lower extremities and buttocks. Many children have abdominal pain, and bloody diarrhea may be present. Joint pain and swelling are common. Hypertension may be present. Kidney biopsy is rarely required due to the constellation of clinical findings, but lupus and ANCA-mediated vasculitis should be considered in the appropriate setting, particularly in adolescents. The renal histologic lesion of HSP is identical to that of IgA nephropathy. The condition is usually self-limited. Joint and abdominal pain responds to treatment with short courses of corticosteroids. Renal involvement ranges from none to mild GN with microhematuria to severe GN with associated nephrosis and renal insufficiency. More severe renal involvement is associated with worse long-term prognosis, including potential for progression to ESRD. There is no universally accepted treatment, but corticosteroids and other immunosuppressive agents are often administered (see Chapter 30).

Membranoproliferative Glomerulonephritis/C3 Glomerulopathy

The most common “chronic” form of GN in childhood is membranoproliferative GN (MPGN). The diagnosis is established from the histologic appearance of the glomeruli on biopsy. Recent studies have led to reclassification of these conditions, recognizing that abnormalities of complement regulation may be the primary etiology. There is a wide phenotypic spectrum of these conditions. These conditions typically are associated with depressed serum C3. Immunosuppressive treatment, including targeted blockade of components of the complement system, is recommended but response may vary depending on the underlying etiology.

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 antibodies to double-stranded DNA. Renal involvement is indicated by varying degrees of hematuria and proteinuria and should be assessed via renal biopsy. More severe cases are accompanied by renal insufficiency and hypertension. Significant renal involvement requires treatment with various combinations of immunosuppressive drugs, including prednisone, azathioprine, cyclophosphamide, mycophenolate, tacrolimus, and rituximab, a monoclonal antibody against the B-cell surface antigen CD20. ESRD develops in 10%–15% of patients with childhood SLE.

Hereditary Glomerulonephritis

The most commonly encountered hereditary GN is Alport syndrome. This condition is due to mutations in type IV collagen found in basement membranes of the glomeruli, cochlea, and lens, and is characterized by progressive GN, high-frequency sensorineural hearing loss, and lens abnormalities. Although the condition can be inherited in autosomal dominant or recessive manners, the vast majority of cases are X-linked in transmission. Thus, males are typically more severely affected. Such boys present very early in life, even in infant and toddler years, with persistent microhematuria and recurrent gross hematuria associated with intercurrent illness, followed by chronic proteinuria and then deterioration in renal function. A family history may be present, but there is a spontaneous mutation rate of about 20%. In males with X-linked or children with autosomal recessive disease, ESRD usually occurs in the second to third decade of life. Females with X-linked Alport syndrome show a wide spectrum of disease manifestation from asymptomatic hematuria to ESRD. Although currently there is no treatment for this disorder, careful management of associated hypertension may slow the process.

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 or nonsteroidal anti-inflammatory drugs [NSAIDs]), but infectious etiologies, including Epstein-Barr virus, also occur.

Fever, rash, and eosinophilia may occur in drug-associated cases. Urinalysis usually reveals leukocyturia and, potentially, mild hematuria and proteinuria. Hansel staining of the urinary sediment may demonstrate eosinophils. The inflammation can cause significant deterioration of renal function and systemic hypertension. The association between tubulointerstitial nephritis and uveitis (TINU) is occasionally seen in childhood. If the diagnosis is unclear because of the absence of a history of drug or toxin exposure or acute infection, 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 whenever possible is imperative and may be all that is necessary. Treatment with corticosteroids or other immunomodulatory agents may be helpful in patients with progressive renal insufficiency or associated nephrotic syndrome. Dialysis support is occasionally required.

Urine is rarely completely protein free, but the average excretion is well below 150 mg/24 h. As noted previously, small increases in urinary protein can accompany febrile illnesses or exertion and in some cases occur while in the upright posture (orthostatic proteinuria).

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 after a comprehensive evaluation is completed in consultation with a pediatric nephrologist.

CONGENITAL NEPHROSIS (FINNISH TYPE)

Congenital nephrosis of the Finnish type is a rare autosomal recessive disorder characterized by microcystic dilations of the proximal tubules and glomerular abnormalities including proliferation, crescent formation, and thickening of capillary walls. The condition is associated with genetic mutations in NPHS1, which codes for nephrin, a transmembrane protein and structural component of the glomerular basement membrane.

Infants with congenital nephrosis commonly have markedly elevated maternal serum α-fetoprotein concentration, a large placenta, wide cranial sutures, and delayed ossification. Progressive edema may be seen after the first few weeks of life. Massive urine protein losses lead to other risks, including recurrent infection due to hypogammaglobulinemia (urinary loss of immunoglobulin G), thrombosis (urinary loss of antithrombin III, Protein C and S), and eventual clinical hypothyroidism (urinary loss of thyroid-binding globulin). Such children usually require nightly high-dose albumin infusions and once to twice weekly intravenous immunoglobulin (IVIG) infusions. Nephrectomies may be required to prevent complications of the high-grade protein losses. Progressive renal failure requiring dialysis and transplantation are anticipated, although historically affected infants often succumbed to serious bacterial infection in the first year of life.

IDIOPATHIC NEPHROTIC SYNDROME OF CHILDHOOD

Clinical Findings

Affected patients are generally younger than 10 years at onset. Typically, periorbital swelling and oliguria are noted, often following intercurrent illness. Within a few days, increasing edema—even anasarca—becomes evident. Most children have few complaints other than vague malaise or abdominal pain. With significant hypoalbuminemia, some children experience symptoms of intestinal malabsorption. With marked edema, dyspnea due to pleural effusions or massive ascites may also occur.

Despite heavy proteinuria, the urine sediment is usually normal, although microscopic hematuria may be present. Gross hematuria is occasionally seen but more often with FSGS than minimal change disease (MCD). Plasma albumin concentration is low and lipid levels increased. When azotemia occurs, it is usually secondary to intravascular volume depletion from “third space” leak and low oncotic pressure.

Complications

Infections (eg, peritonitis, sepsis) sometimes occur, and encapsulated bacteria such as Streptococcus pneumoniae are frequently the cause. Hypercoagulability may be present, and thromboembolic phenomena such as deep venous thrombosis, renal vein thrombosis, or sagittal sinus thrombosis are reported. Hypertension can occur, and renal insufficiency can result from decreased renal perfusion. Hyperlipidemia resolves when affected children enter remission but is of concern in treatment-resistant nephrotic syndrome.

Treatment & Prognosis

When the diagnosis of idiopathic nephrotic syndrome is made, corticosteroid treatment should be started as the vast majority of children will enter remission in response to such treatment, thus avoiding the need for kidney biopsy that neither predicts response to treatment nor long-term renal function. Prednisone, 60 mg/m² or 2 mg/kg/day (maximum, 60 mg/day), is given for 6 weeks as a single daily dose. A dose of 40mg/m² or 1.5 mg/kg/day is then administered on an alternate-day schedule for 6 weeks. Thereafter, the corticosteroids are discontinued or the dose tapered gradually and discontinued over the ensuing few months depending on local practice. The goal of this regimen is the disappearance of proteinuria. If remission is not achieved during the initial 4 weeks of corticosteroid treatment, steroid-sparing therapy and kidney biopsy should be considered. 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, however, that the histologic findings may not necessarily alter the treatment plan, which is designed to eliminate the nephrotic syndrome regardless of underlying renal histology.

Careful clinical assessment of intravascular volume status is indicated to guide diuretic therapy in children with idiopathic nephrotic syndrome. While those with obvious evidence of volume overload will benefit from diuretics, some children, particularly those with MCD, will show evidence of intravascular volume depletion due to third space fluid leak. The latter group of children will experience hypotension and prerenal azotemia with aggressive diuresis; thus, careful restoration of compromised circulating volume with intravenous 25% albumin infusion with consideration of a diuretic such as furosemide is most helpful in mobilizing edema. Infections such as peritonitis should be treated promptly to reduce morbidity. Immunization with pneumococcal conjugate and polysaccharide vaccines is advised due to the increased risk of invasive pneumococcal disease with active relapse.

Resolution of proteinuria with corticosteroid treatment suggests a good prognosis. Early relapse usually heralds a prolonged series of relapses; frequent relapses increase corticosteroid exposure and should lead to consideration of alternate immunosuppressive therapy to maintain remission. Historically, chlorambucil or cyclophosphamide was added to corticosteroid treatment in steroid-responsive but-dependent children to achieve corticosteroid discontinuance while maintaining remission. Because of potential significant side effects associated with these drugs, calcineurin inhibitors (most commonly tacrolimus) or mycophenylate mofetil are now added instead in steroid-dependent cases. Children who fail to respond to corticosteroids have a more guarded long-term prognosis for renal function yet may still attain remission with alternative immunosuppressive agents. 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, although no controlled trials have been conducted and the long-term effects of repeated courses of rituximab in this setting are not known.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Focal segmental glomerulosclerosis (FSGS) is a cause of idiopathic nephrotic syndrome in children but can also cause chronic asymptomatic proteinuria. The condition is concerning as up to 15%–20% of cases can progress to end-stage renal failure. The response to corticosteroid treatment is variable. Treatment in the setting of active nephrotic syndrome is reviewed above, but the benefits of chronic immunosuppressive therapy are less clear in the asymptomatic child.

Recurrence of FSGS is common following renal transplantation. Fortunately, most children respond well to treatment with plasmapheresis and/or rituximab after kidney transplantation; 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.

MEMBRANOUS NEPHROPATHY (MEMBRANOUS GLOMERULONEPHRITIS)

Although largely idiopathic in nature, membranous nephropathy can be found in association with infections, including hepatitis B, hepatitis C, and congenital syphilis; with immunologic disorders such as autoimmune thyroiditis and SLE (in contrast to other forms of lupus nephritis, serum C3 is often normal with membranous lupus); and with administration of drugs such as penicillamine. Recent studies suggest a high frequency of antibodies to podocyte antigens in affected patients.

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 may respond poorly to corticosteroid therapy and secondary immunomodulatory agents are often prescribed. Historically, alkylating agents such as cyclophosphamide were used in conjunction with corticosteroid therapy, while more recently calcineurin inhibitors, mycophenylate mofetil and rituximab have been explored with some success. The diagnosis is made by renal biopsy.

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, or thrombocytosis). Renal vein thrombosis is less common in older children and adolescents. It may develop following trauma, with a procoagulant state (such as antiphospholipid antibody positivity in SLE or treatment-resistant nephrotic syndrome), or without any apparent predisposing factors. Spontaneous renal vein thrombosis has been associated with membranous nephropathy.

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. 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 and may occasionally be gross in nature; 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.

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; the risks of systemic anticoagulation in the newborn, particularly if preterm, must be considered. Evaluation for thrombophilia may be needed. In children with a known tendency for recurrence, more long-term anticoagulation may be required.

Course & Prognosis

The mortality rate in newborns from renal vein thrombosis depends on the underlying cause. With unilateral renal venous thrombosis at any age, the prognosis for adequate renal function is good. Bilateral disease is of course more concerning, and long-term renal follow-up focusing on renal function and growth is warranted in such children. Renal vein thrombosis may rarely recur in the same kidney or 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 dysplasia, congenital renal artery or midaortic stenosis, Takayasu arteritis) 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 in children who demonstrate increasingly difficult to control hypertension. The diagnosis is established by MR or CT angiography and confirmed by renal arteriography or direct intraoperative visualization. When vasculitis is present, immunosuppressive treatment is the first approach. Other lesions may be approached by transluminal angioplasty or surgery (see section Hypertension), but repair may be technically impossible in small children. In such cases, medical management of hypertension pending somatic growth is indicated. 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.

HEMOLYTIC-UREMIC SYNDROME

Hemolytic-uremic syndrome (HUS) is the most common glomerulovascular cause of acute renal failure in childhood. The diarrhea-associated form is usually the result of infection with Shiga toxin–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 coli O157:H7. Bloody diarrhea is the usual presenting complaint, followed by hemolysis, thrombocytopenia, and renal failure. Circulating toxin causes endothelial damage, which leads to platelet deposition/consumption and microvascular occlusion with subsequent hemolysis. Similar microvascular endothelial activation may also be triggered by drugs (eg, calcineurin inhibitors or mammalian target of rapamycin inhibitors); 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, with associated cell lysis. Rare cases are caused by genetic factors causing complement dysregulation (eg, factor H deficiency).

Clinical Findings

HUS 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. Children with pneumococcal-associated HUS typically have documented pneumococcal pneumonia, sepsis, or meningitis. Children with atypical HUS associated with complement dysregulation often develop an episode of HUS following intercurrent illness and present with malaise and pallor. 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), heart, and pancreas. Anemia may be 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 often severe, 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. Hemoglobinuria is occasionally observed due to marked RBC hemolysis.

Complications

Complications of AKI occur. Neurologic problems, particularly seizures, may result from hyponatremia, hypertension, or CNS vascular disease. Despite thrombocytopenia, many children are prone to thrombosis due to the underlying endothelial damage.

Treatment

Meticulous attention to fluid and electrolyte status is crucial. The use of antimotility agents and antibiotics for HUS caused by gastrointestinal infection is believed to worsen the disease. Antibiotics may upregulate and increase the release of large amounts of bacterial Shiga toxin. Timely dialysis improves the prognosis. RBC transfusions are often necessary. Platelet transfusions should be avoided unless there is active bleeding. Erythropoietin (epoetin alfa) treatment may reduce RBC transfusion needs and is indicated in the setting of renal failure. Atypical HUS due to complement dysregulation may benefit from plasmapheresis or plasma infusion (by replacing missing factors or removing factor H autoantibodies), but these therapies have been more recently replaced by the anti-C5a monoclonal antibody, eculizumab. Whether eculizumab may be of benefit in other forms of HUS remains to be determined. Plasma therapy should be avoided in pneumococcal HUS as it provides the patient with anti–Thomsen-Friedenreich antibody and thereby drives the HUS process. Although no therapy is universally accepted, strict control of hypertension and fluid balance, 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.

Course & Prognosis

Most commonly, children recover from the acute episode within 2–3 weeks. Some residual renal disease (including hypertension, proteinuria, or chronic renal insufficiency) occurs in about 30%, and end-stage renal failure occurs in about 15%. The risk of ESRD is higher in children with atypical or pneumococcal-induced HUS. Follow-up of children recovering from HUS should include serial determinations of renal function with frequency dictated by the etiology, course, and subsequent findings and routine monitoring of blood pressure. Overall mortality (about 3%–5%) is most likely in the early phase, primarily resulting from CNS or cardiac complications. As with most renal conditions, chronic proteinuria, hypertension, or abnormal renal function are associated with worse long-term renal prognosis and require follow-up.

ACUTE KIDNEY INJURY

The term “acute kidney injury (AKI)” denotes 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, AGN), 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 24–1 lists prerenal, renal, and postrenal causes of AKI.

Clinical Findings

The hallmark of early AKI 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 AKI as outlined in Table 24–1 is helpful in determining if an immediately reversible cause is present.

Entities that can be quickly addressed and corrected, for example, intravascular volume depletion or urinary tract obstruction, 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, a diagnosis of acute tubular necrosis 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 true intravascular volume depletion or a decrease in effective circulating volume, as may be seen in cardiac failure, cirrhosis, or nephrotic syndrome. Table 24–2 lists the urinary indices helpful in distinguishing these “prerenal” conditions from true renal parenchymal insult, such as acute tubular necrosis.

B. Renal Causes

Causes of AKI intrinsic to the kidneys include acute glomerulonephritides, HUS, acute interstitial nephritis, and nephrotoxic injury. The diagnosis of acute tubular necrosis, 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 AKI, especially in the setting of anuria of acute onset. Whatever the cause, ensuring urine drainage is the first step toward reversibility of oliguria.

Complications

The severity of the complications of AKI 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) uremia.

Treatment

Prerenal and/or postrenal factors should be excluded and rectified. Normal circulating volume should be maintained and normal blood pressure and cardiac performance established with appropriate fluid or pressor support. 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 the 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. Routine assessment of weight is helpful to assess fluid balance in children in whom this is possible. Increasing urine output with diuretics, such as furosemide (1–2 mg/kg per dose, intravenously, maximum of 200 mg every 6 hours), can be attempted. The effective dose will depend on the amount of functional compromise. If a response does not occur within 1 hour and the urine output remains low (< 0.5 mL/kg/h), the furosemide dose should be maximized and a continuous infusion may be considered. 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 and fluid intake should be restricted accordingly. The child should be monitored closely for indications for acute dialysis.

All medication dosages should be adjusted as appropriate for the degree of renal clearance.

A. Acute Dialysis: Indications

Immediate indications for dialysis are: (1) hyperkalemia refractory to medical management; (2) unrelenting metabolic acidosis (usually in a situation where fluid overload or hypernatremia prevent repeated sodium bicarbonate administration); (3) fluid overload (which may be manifest as significant hypertension, congestive heart failure, pulmonary edema, or simply inability to provide appropriate medication and nutritional support due to fluid restriction); (4) symptoms of uremia, usually manifested in children by CNS depression (rare); and (5) ingestions of drugs/substances removed by hemodialysis. 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 BUN which contributes to platelet dysfunction in renal failure. Accumulation of metabolic end products that contribute to bleeding correlates better with the degree 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 often 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 hemodynamic status will tolerate the intermittent solute and fluid removal, or (3) if impediments to efficient peritoneal dialysis are present (eg, postoperative abdomen, adhesions). If vascular access and potential usage of anticoagulation are not impediments, a slow, continuous hemodialytic process, continuous renal replacement therapy (CRRT), may be applied in hemodynamically unstable, critically ill patients, including those on extracorporeal membrane oxygenation. Typically, either systemic or regional anticoagulation is provided to maintain the extracorporeal circuit. Nutritional support and medication doses should be reviewed and adjusted accordingly for patients receiving dialytic therapies.

C. Dialysis Management and Complications

Intravascular volume depletion can be observed in any dialytic therapy; thus, close attention to the patient’s hemodynamic status with adjustment in dialytic fluid removal is indicated. Significant intravascular volume depletion can contribute to acute tubular nephropathy and limit the timely recovery of intrinsic renal function. Complications specific to peritoneal dialysis include peritonitis and technical complications such as dialysate leakage or respiratory compromise from intra-abdominal dialysate fluid. Peritonitis risk can be diminished by strict aseptic technique. Peritoneal fluid cultures should be 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 and phosphate, absent from standard dialysate solutions, can be added to the dialysate as clinically required. Several antibiotics can be added to the dialysate for intraperitoneal administration with associated systemic absorption. This scenario is usually reserved for treatment of peritonitis or with limited vascular access for drug administration. Correction of fluid overload is accomplished with 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. Because fluid removal is dependent on many factors (osmolar load of dialysate, individual peritoneal membrane transport characteristics, peritoneal membrane perfusion, etc), it is not possible to exactly control the hourly rate of fluid removal during peritoneal dialysis.

Even in small infants, hemodialysis can rapidly correct major metabolic and electrolyte disturbances as well as volume overload. The process is highly efficient. Systemic anticoagulation, usually with heparin, is typically 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 yet have been achieved. Appropriate vascular access must be maintained. Hemodialysis is generally intermittent, daily to three times per week. If need be, CRRT may be used to maintain more minute-to-minute, continuous metabolic and fluid control especially in the hemodynamically unstable or septic patient. The choice of anticoagulation is typically based upon institutional preference and the clinical situation. Appropriately trained staffs are needed to administer any dialytic therapy to children.

Course & Prognosis

The course and prognosis of AKI vary with the etiology. If severe oliguria occurs in acute tubular necrosis, it usually lasts about 10 days. Anuria or oliguria lasting longer than 6 weeks is concerning for progression to cortical necrosis and associated limited renal recovery. The diuretic phase of recovery from AKI begins with an increase in urinary output to large volumes of isosthenuric urine containing sodium levels of 80–150 mEq/L. The associated polyuria may persist for several days or weeks, and the care provider must ensure appropriate hydration to prevent prerenal azotemia or acute tubular necrosis. Urinary abnormalities usually disappear completely within a few months. If renal recovery does not ensue within about 6 weeks of oligoanuria, arrangements should be made for chronic dialysis and possible eventual renal transplantation. Some children requiring prolonged (> 1 month) dialysis support will demonstrate recovery to varying degrees of CKD but are obviously at high risk for eventual progression to ESRD. Children who have experienced significant AKI require long-term follow-up with a nephrologist.

CHRONIC RENAL FAILURE

Chronic renal failure in children most commonly results from congenital abnormalities of the kidneys or urinary tract (CAKUT). Renal hypoplasia/dysplasia, obstructive uropathy, or severe VUR without (or despite) surgical intervention is often associated with progressive renal insufficiency in children. In older children, the chronic glomerulonephritides and nephroses, irreversible nephrotoxic injury, or HUS may also cause chronic renal failure. Early evaluation and close follow-up by a pediatric nephrology team in these situations is advised.

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 this compensatory ability is overwhelmed. In children who have structural kidney lesions associated with impaired urinary concentration, polyuria and dehydration are more likely to be problems than fluid overload until very late in the course of renal insufficiency. Some such children can continue to produce generous volumes of poor quality urine 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 with associated hypertension and eventual loss of urine output.

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 normal serum calcium and phosphate levels early in the course, but at the expense of the skeleton. 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 < 30% renal function). These symptoms can be minimized if chronic renal failure has been detected early and associated complications treated, but refractory symptoms remain indications for renal replacement therapy. CNS abnormalities such as confusion and lethargy are very late symptoms, followed even later by stupor and coma. Such findings are unusual as children usually seek medical attention before deteriorating to this point, and the rise in BUN is typically gradual. Other late complications of untreated renal failure are platelet dysfunction and bleeding tendencies, pericarditis, and chronic fluid overload leading to congestive heart failure, pulmonary edema, and worsening hypertension.

Treatment

A. Management of Complications

Treatment of chronic renal failure is primarily aimed at controlling the associated complications. Acidosis may be treated with sodium citrate or bicarbonate solutions, as long as the added sodium does not aggravate hypertension. Sodium restriction is advisable when hypertension is present. Hyperphosphatemia is controlled by dietary restriction and dietary phosphate binders (eg, calcium carbonate, sevelamer). Supplementation with vitamin D (cholecalciferol or ergocalciferol) and calcitriol is typically required. These measures target the prevention of renal osteodystrophy or rickets. Dietary potassium restriction will be necessary as the GFR falls. Diet must be maintained to provide the child’s daily requirements for optimal growth. Routine input from a renal dietitian is helpful in this regard. Protein restriction in children is not recommended; rather, appropriate quantities of protein required for age and growth are targeted as part of dietary plans.

Renal function must be monitored regularly (creatinine and BUN), and serum electrolytes, calcium, phosphorus, intact PTH, 25-OH-vitamin D, iron and ferritin, 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 supplements, blood pressure medications, iron supplements, and epoetin alfa. Linear growth failure may be treated with daily subcutaneous human recombinant growth hormone; an adult height in the low-normal range is targeted. 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. The multidisciplinary nephrology team works with each child/family to determine appropriate timing for chronic dialysis and/or kidney transplantation.

B. Dialysis and Transplantation

Chronic peritoneal dialysis (home-based) and hemodialysis provide lifesaving treatment for children prior to kidney 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. The goal for all children with chronic or end-stage kidney disease is to achieve kidney transplantation, using dialysis as a life-saving bridge, when necessary. Pre-emptive kidney transplantation in a child with known progressing CKD should be considered if possible, given improved long-term graft and patient survival, as compared to peers transplanted after receiving dialysis.

At present, the graft survival rate for living donor kidney transplants is 96.4% at 1 year, 93.4% at 3 years, and 86.4% at 5 years. With deceased donor transplantation, graft survivals are 95%, 90%, and 79%, respectively. Five-year patient survival remains well above 95% at 5 years after transplant. Adequate growth and well-being are directly related to acceptance of the graft, the degree of normal function, and the side effects of medications.

Hypertension in children is commonly of renal origin, although the prevalence of obesity-related hypertension is rapidly rising in the pediatric population. Systemic hypertension is anticipated as a complication of known renal parenchymal disease, but it may be found on routine physical examination in an otherwise healthy-appearing 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 paradoxical elevations of blood pressure have been reported in clinical situations in which chronic diuretic therapy is used, such as bronchopulmonary dysplasia. Chronic hypoxia may have a role in vascular alterations, similar to what is seen with hypertension in older children with obstructive sleep apnea. Umbilical artery catheterization continues to be an important contributor to hypertension in infants and young children.

Infants and children with hypertension require careful evaluation to exclude a secondary cause of hypertension. These can include renal parenchymal or renovascular disease (renal arterial or venous thrombosis, congenital vascular stenosis), other vascular diseases (vasculitis, aortic coarctation), endocrine disorders (thyroid disease, cortisol excess, pheochromocytoma, congenital adrenal hyperplasia), monogenic hypertension (glucocorticoid remediable aldosteronism, Liddle syndrome, etc), and primary hyperaldosteronism. The family history of hypertension and cardiovascular disease should be reviewed with particular attention to early-onset hypertension. Primary or essential hypertension is becoming increasingly common with a Western diet and limited routine exercise.

Clinical Findings

A child is normotensive if the average recorded systolic and diastolic blood pressures are lower than the 90th percentile for age, sex, and height. 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 100–120/65–80 mm Hg in the late teens. A blood pressure between the 90–95th percentile or exceeding 120/80 in adolescents is consistent with elevated blood pressure. 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. Ideally the child should be sitting quietly for 5 minutes with feet flat on the floor before blood pressure is measured in the right arm, upon which norms are based. 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. Manual blood pressure measurement should be pursued when automated readings are concerning. In cases where more detailed assessment is needed, 24-hour ambulatory blood pressure monitoring can be very valuable, for example, in aiding with the diagnosis of white coat hypertension or loss of normal 24-hour variation in blood pressures.

Routine laboratory studies include serum BUN, creatinine, and electrolytes and urinalysis. Abnormal BUN and creatinine would support underlying renal disease as the cause, and serum electrolytes demonstrating hypokalemic alkalosis suggest excess mineralocorticoid effect. Depending on the age of the child, routine assessment of serum lipids, glucose, A_1C hemoglobin, thyroid function tests, renin, and aldosterone is indicated. Screening of plasma/urine catecholamines and metanephrines and/or serum cortisol should be obtained as clinically indicated. Pheochromocytoma is unusual in the setting of increasing obesity. Echocardiogram has been recommended for routine assessment of hypertension in children. Careful assessment of distal pulses is necessary to exclude aortic coarctation clinically, and echocardiogram may be of value in select patients to exclude left ventricular hypertrophy. 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. However, the sensitivity and specificity of Doppler ultrasound for renal artery stenosis vary widely between institutions. Renal MRA or CTA is indicated when there is high suspicion for renal artery stenosis. 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.

Treatment

A. Acute Hypertensive Emergencies

A hypertensive emergency exists when CNS signs of hypertension appear, such as papilledema, encephalopathy, or seizures. Retinal hemorrhages or exudates also indicate a need for prompt and effective control. Such children require appropriate management in the intensive care setting with consideration of continuous arterial BP monitoring and intravenous antihypertensive therapy. 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. The primary classes of useful antihypertensive drugs are: (1) ACE inhibitors and angiotensin receptor blockers (the latter used less frequently in children based on less clinical experience and limitations in accurate dosing for smaller children), (2) calcium channel blockers, (3) α- and β-adrenergic blockers, (4) diuretics, and (5) vasodilators. Acute elevations of blood pressure not exceeding the 99th percentile in the asymptomatic patient may be treated with oral antihypertensives, aiming for progressive improvement and control within 48 hours.

Sublingual nifedipine is a rapid-acting calcium channel blocker that can be administered to acutely decrease severe hypertension. However, its use has fallen out of favor for acute management of hypertension in adults in whom an abrupt decline in blood pressure can significantly diminish perfusion of the coronary and cerebral arteries in the setting of underlying atherosclerosis. Alternatively, nicardipine is a very effective and generally well-tolerated antihypertensive that is administered via continuous intravenous infusion for control of systemic hypertension in children. Sodium nitroprusside is a very effective infusion to gain control of malignant hypertension, but long-term usage is limited by concern for rare thiocyanate toxicity, of particular concern when renal failure is present. Hydralazine is a vasodilator that can be administered intermittently by the intravenous route. Any vasodilator can induce reflex tachycardia and sodium retention, so concomitant administration of a β-blocker or diuretic may be indicated. Intravenous forms of β-blockers such as esmolol or labetalol (both available as continuous infusions) are useful when there are no cardiac or respiratory contraindications to their use.

Diuretics such as furosemide can be useful in the acute setting when there is evidence of intravascular volume overload.

B. Sustained Hypertension

For children with sustained hypertension, rate of correction of blood pressure needs to be taken into account. Too rapid reduction in blood pressure in children with chronic hypertension places them at risk for loss of adequate cerebral and renal perfusion pressure. Therefore, reductions in blood pressure to goal measurements based on age, gender, and height by no more than 25% for each 24–48-hour period are recommended. Several choices are available for treatment (Table 24–3). A single drug such as an ACE inhibitor or a β-blocker (unless contraindicated, eg, with underlying asthma) may be adequate to treat mild hypertension. ACE inhibitors are often the preferred choice of pediatric nephrologists given the frequent renal etiology of hypertension. Diuretics are useful to treat renal insufficiency that is often associated with sodium and fluid retention, but the disadvantages of possible electrolyte imbalance must be considered. Calcium channel blockers are increasingly useful and appear well tolerated in children. Direct vasodilators such as hydralazine and minoxidil often require diuretics and/or β-blockers to combat associated sodium and fluid retention and reflex tachycardia. Although minoxidil is extremely effective in control of hypertension of a variety of etiologies, hirsutism is a significant side effect. The advice of a pediatric nephrologist should be sought in the management of acute and chronic hypertension in children.

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 24–4 lists some of the major entities.

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, which is associated with hyporeninemic hypoaldosteronism or inherited in an autosomal manner. Types I and II and their variants are encountered most frequently in children. Type III is described historically as a combination of types I and II. Other primary tubular disorders in childhood, such as glycinuria, hyperuricosuria, or renal glycosuria, may result from a defect in a single tubular transport pathway (see Table 24–4).

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. Concomitant hypercalciuria may lead to nephrocalcinosis, nephrolithiasis, and renal failure. Other situations that may be responsible for distal RTA are found in some of the entities listed in Table 24–4.

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. Historically the diagnosis could be established with an acid loading test, but this is rarely pursued currently. Instead, the findings of RTA with persistent elevation in urine pH despite acidosis, hypercalciuria or nephrocalcinosis, and relatively low requirement of alkali to normalize serum pH and bicarbonate concentration (1–3 mEq/kg/day) support a distal defect. Some forms of genetic distal RTA are associated with hearing loss. Correction of acidosis with citrate or less commonly bicarbonate reduces complications and improves growth. Distal RTA is often permanent. However, if renal damage from calcinosis is prevented, the prognosis with treatment is good.

Proximal Renal Tubular Acidosis (Type II)

Proximal RTA, the most common form of RTA in childhood, is characterized by failure to reabsorb bicarbonate appropriately in the proximal tubule with associated reduced serum bicarbonate concentration and normal anion gap hyperchloremic metabolic acidosis. Once a steady state is reached, the intact distal nephron appropriately excretes hydrogen ion, leading to a low urine pH.

Proximal RTA is often an isolated defect, and in the newborn can be considered an aspect of renal immaturity which improves with increasing gestational age. Proximal RTA in infants is accompanied by failure to thrive and sometimes hypokalemia. Secondary forms result from reflux or obstructive uropathy or occur in association with other tubular disorders (see Table 24–4). Due to bicarbonate wasting, children with proximal RTA typically require 5–20 mEq/kg/day citrate/bicarbonate to achieve normal serum pH and bicarbonate concentration.

Evaluation & Treatment

The diagnosis of RTA is made with the finding of normal anion gap, hyperchloremic metabolic acidosis in the absence of diarrhea, or intravascular volume depletion. A concomitant urine pH is helpful in many cases, as it is elevated in distal RTA despite the metabolic acidosis. The finding of hypophosphatemia or glycosuria should lead to further investigation of proximal tubular function (eg, Fanconi syndrome). A renal ultrasound should be obtained to exclude urinary tract obstruction (which can be seen with either proximal or distal RTA) and nephrocalcinosis (seen in distal RTA). A urine calcium to creatinine ratio may be helpful in the latter condition. In either proximal or distal RTA, citrate or bicarbonate supplementation is provided to target a serum bicarbonate level of 20–24 mEq/L, as an index of normal serum pH. Citrate solutions are more effective and often better tolerated than sodium bicarbonate. Sodium citrate contains 1 mEq/mL of Na⁺ and citrate. Potassium citrate contains 2 mEq/mL of citrate and 1 mEq/mL each of Na⁺ and K⁺. The medication is administered two to three times per day, targeting a trough serum bicarbonate at goal. Potassium supplementation may be required (and can often be accomplished simply with a change from sodium citrate to potassium citrate) because the added sodium load presented to the distal tubule may exaggerate potassium losses.

The prognosis is excellent in cases of isolated proximal RTA, especially when the problem is related to renal immaturity. Alkali therapy can usually be discontinued after several months to a few years. Growth should be normal, and the gradual increase in the serum bicarbonate level to greater than 24 mEq/L heralds the normalization of the threshold for proximal tubular bicarbonate reabsorption. If the defect is part of Fanconi syndrome or distal RTA, the prognosis depends on the underlying disorder or syndrome.

CYSTINOSIS

Cystinosis, most often transmitted via autosomal recessive inheritance, is the most common cause of Fanconi syndrome in children and results from mutations in the CTNS gene, which encodes the cystine transporter. There are three types of cystinosis: adult, adolescent, and infantile. The adult form is characterized by ocular cystinosis without renal involvement. In the adolescent and infantile types, cystine accumulation in lysosomes causes cell death in numerous organs, including the kidneys. Treatment with oral cysteamine aids in the metabolic conversion of cystine (unable to exit cells) to cysteine (able to exit cells) and delays intracellular accumulation and associated complications, which include Fanconi syndrome with salt-wasting and functional nephrogenic diabetes insipidus (NDI), proximal RTA, hypophosphatemic rickets, eventual progression to ESRD, hypothyroidism, ocular cystinosis with eventual blindness, and neurologic deterioration. The infantile type is most common and the most severe. Characteristically, children present in the first or early second year of life with Fanconi syndrome, polyuria and polydipsia, and failure to thrive. If left untreated, ESRD is reached by 7–10 years of age 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 blood cell cystine levels are diagnostic. The condition does not recur in transplanted kidneys, but ongoing cysteamine therapy is required to prevent complications in other organs.

OCULOCEREBRORENAL SYNDROME (LOWE SYNDROME)

Lowe syndrome results from various mutations in the OCRL1 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 tubular and include hypophosphatemic rickets with low serum phosphorus levels, low to normal serum calcium levels, elevated serum alkaline phosphatase levels, proximal RTA, and aminoaciduria. Renal treatment includes alkali therapy, phosphate replacement, and vitamin D support. Progressive glomerulosclerosis likely results from progressive renal tubular injury and may lead to chronic renal failure and end-stage renal disease between the second and fourth decades of life.

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

There are a number of genetic tubular disorders which result in hypokalemic metabolic alkalosis. Bartter syndrome is characterized by severe hypokalemic, hypochloremic metabolic alkalosis, extremely high levels of circulating renin and aldosterone, and a paradoxical absence of hypertension. On renal biopsy (rarely pursued in the current era), a striking juxtaglomerular hyperplasia is seen. A neonatal form of Bartter syndrome is thought to result from mutations in two genes (NKCC2, ROMK) affecting nephron Na⁺-K⁺ or K⁺ transport. These patients typically have a history of polyhydramnios and following birth have recurrent life-threatening episodes of fever and dehydration with the aforementioned electrolyte and acid–base disturbances, 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 and tetany associated with severe hypokalemia, and hypomagnesemia. These children have hypocalciuria. Treatment with prostaglandin inhibitors and potassium-conserving diuretics (eg, amiloride) and potassium and magnesium supplements where indicated is beneficial in Bartter or Gitelman syndrome. These are lifelong conditions which require ongoing electrolyte supplementation.

Liddle syndrome is associated with constitutive activation of the epithelial sodium channel with associated salt and water retention. Thus, the initial presenting abnormality is often hypertension associated with hypokalemia and metabolic alkalosis. Serum renin and aldosterone are suppressed due to the sodium and fluid retention. Treatment in Liddle syndrome is with a low-sodium diet and blockade of the epithelial sodium channel with amiloride or triamterene. Spironolactone is ineffective in this condition as aldosterone is typically suppressed.

NEPHROGENIC DIABETES INSIPIDUS

Hereditary nephrogenic (vasopressin-resistant) diabetes insipidus is most often caused by X-linked mutations in the AVPR2 gene that encodes the vasopressin V₂ receptor. Autosomal (recessive and dominant) forms of NDI occur less commonly due to mutations of the AQP2 gene that codes for the collecting tubule water channel protein, aquaporin-2. Affected children often have a profound impairment in maximal urinary concentrating capacity, which rarely exceeds 100 mOsm/kg H₂O. Genetic counseling and mutation testing are available.

Acquired NDI is observed in numerous conditions including sickle cell anemia, chronic pyelonephritis, hypokalemia, hypercalcemia, Fanconi syndrome, obstructive uropathy, chronic renal insufficiency, and lithium treatment.

The symptoms of NDI include polyuria and polydipsia. In severe cases, water intake is preferred to formula, leading to failure to thrive. In some children, particularly if the solute intake is unrestricted, adjustment to an elevated serum osmolality may develop. Children with genetic NDI are particularly susceptible to episodes of dehydration, fever, vomiting, and hypernatremia when access to free water is limited.

The diagnosis can be suspected on the basis of a history of polydipsia and polyuria. The family history may be informative in hereditary cases while a review of the patient’s medical history, medications, and serum chemistries can help identify a source of acquired NDI. The diagnosis is confirmed by performing a water deprivation test, during which time serum and urine osmolality are assessed and either arginine vasopressin or desmopressin administered to assess tubular response. When hereditary NDI is suspected, it is imperative that a water deprivation test be performed in the hospital in a controlled setting. Due to the severe concentrating defect, restricting water intake overnight at home in such children can lead to severe intravascular volume depletion and hyperosmolality. In addition to hyperglycemia, the differential diagnosis of polydipsia and polyuria includes primary polydipsia, which occurs in children as young as infancy.

In infants with NDI, it is usually best to allow water as demanded and to restrict salt intake. Caregivers must be aware of the risks of dehydration and hypernatremia if fluid intake is restricted either due to lack of provision by the caregiver or inability to keep fluids down (eg, vomiting). A low-salt diet limits the amount of urine that must be produced for daily solute excretion. Due to the need for high-volume free-water intake, caloric intake may be limited and affected children often benefit from routine follow-up with a renal dietitian. Treatment with hydrochlorothiazide decreases urine volume by limiting the amount of free water delivered to the distal nephron for excretion. Prostaglandin inhibitors such as indomethacin are efficacious by decreasing renal blood flow, thereby diminishing GFR, and by preventing reclamation of the AQP2 water channel from the apical membrane of the collecting duct cell. Prostaglandin inhibitors, however, are associated with risk of gastritis/ulceration.

NEPHROLITHIASIS

Renal calculi in children may result from products of hereditary errors of metabolism, such as cystine in cystinuria, glycine in hyperglycinuria, urates in Lesch-Nyhan syndrome, and oxalates in primary hyperoxaluria. Stones in children are most often calcium oxalate and calcium phosphate in composition, resulting most commonly from hypercalciuria or hypocitraturia. These diagnoses are best established via 24-hour urine collection to assess for common biochemical risk factors for stone formation. Large stones are quite often seen in children with spina bifida who have paralyzed lower limbs or in any situation where immobilization promotes calcium mobilization from the bones or there is recurrent UTI with urease-producing organisms (struvite calculi). Treatment is focused on the primary condition, if possible. Most cases are initially addressed with attention toward maintaining optimal hydration and targeting the inciting cause of stone formation with appropriate medical therapy. Surgical removal of stones or lithotripsy should be considered for obstruction, intractable severe pain, and chronic infection.

Cystinuria

Cystinuria 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 is recommended.

Primary Hyperoxaluria

Oxalate in humans is derived from the oxidative deamination of glycine to glyoxylate, 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. Recently a type III primary hyperoxaluria has been described in association with increased mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity; this type appears to be milder than types I or II.

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.

A low-oxalate diet with normal calcium intake and high fluid intake is recommended. High-dose pyridoxine can be administered in type I primary hyperoxaluria as it is a cofactor for the defective pathway, but the overall prognosis is poor, with half of patients developing ESRD by 15 years of age. Renal transplantation is not very successful because of destruction of the transplant kidney with continued oxalate overproduction. However, encouraging results have been obtained with concomitant liver transplantation that corrects the metabolic defect. Types II and III primary hyperoxaluria appear to have better long-term renal outcomes.

Secondary hyperoxaluria with associated urolithiasis can be a consequence of severe ileal disease or ileal resection due to excessive absorption of dietary oxalate.

It is estimated that 8% of girls and 2% of boys will acquire urinary tract infections (UTIs) in childhood. Girls older than 6 months have UTIs far more commonly than boys, whereas uncircumcised boys younger than 3 months 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 frequently E coli (> 85%), Klebsiella, Proteus, other gram-negative bacteria, and, less frequently, Enterococcus or coagulase-negative staphylococci.

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, VUR, 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.

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 infection, or other genitourinary infections may be apparent on examination.

B. Laboratory Findings

Screening urinalysis indicates pyuria (> 5 WBCs/hpf) 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 white cells 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 usually 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 younger 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 10⁵ cfu/mL or greater 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. The finding of significant hydronephrosis or other concerning urinary tract abnormalities on screening ultrasound warrants further imaging. A voiding cystourethrogram is no longer routinely recommended following first UTI in childhood, although the sensitivity of the renal ultrasound for detection of significant VUR varies widely in medical literature. VUR, a congenital abnormality present in about 1% of the population beyond infancy, 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. Significant debate exists in the literature regarding appropriate radiographic imaging for UTI and best management of VUR, including indications for and value of surgical intervention and/or prophylactic antibiotics.

Treatment

A. Antibiotic Therapy

Management of UTI is influenced by clinical assessment. Very young children (age < 3 months) and children with dehydration, toxicity, or sepsis continue to 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 presumed location of the infection in the urinary tract.

Most 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 is significant variation in 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 less commonly 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 appropriate agent 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. 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. Some 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 may benefit from prophylactic antimicrobials; however, addressing the underlying dysfunctional voiding is most important.

The North American Pediatric Renal Trials & Collaborative Study (NAPRTCS) (www.naprtcs.org) has collected clinical information on children undergoing kidney transplant since 1987 and expanded the registry in 1994 to include patients with CKD and dialysis. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcomes after kidney transplantation in addition to identifying factors associated with both favorable and poor outcomes. Since 2009, NAPRTCS data have been used as a source of benchmarking for pediatric nephrology centers, providing center-specific outcomes for CKD, dialysis, and transplant patients for comparison with national statistics.

The Standardized Care to Improve Outcomes in Pediatric ESRD (SCOPE) Collaborative helps pediatric dialysis centers minimize dialysis-related infections in peritoneal dialysis and hemodialysis patients through encouragement of multicenter adherence to recommended best practices. As of 2018, SCOPE has demonstrated a 41% reduction in peritonitis rates and 47.5% reduction in hemodialysis-associated bloodstream infections.

Since 1997, the National Kidney Foundation (NKF) (https://www.kidney.org) has published clinical practice guidelines in nephrology known as KDOQI—Kidney Disease Outcomes Quality Initiative. There are numerous guidelines addressing the best practice care of patients with CKD.