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6(September 15, 2010)

Proteinuria in Children ALEXANDER K.C. LEUNG, MBBS, and ALEX H.C. WONG, MD, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada Am Fam Physician. 2010 Sep 15;82(6):645-651. Patient Information Handout Proteinuria is common in children and may represent a benign condition or a serious underlying renal disease or systemic disorder. Proteinuria may occur secondary to glomerular or tubular dysfunction. Although a 24-hour urine protein excretion test is usually recommended, it may be impractical in children. A spot, first-morning urine test for protein/creatinine ratio can be useful in this situation. Proteinuria is usually benign, in the form of transient or orthostatic proteinuria. Persistent proteinuria may be associated with more serious renal diseases. Clinical features from the history, physical examination, and laboratory tests help determine the cause of proteinuria. Treatment should be directed at the underlying cause. Patients with active urinary sediments, persistent and gross hematuria, hypertension, hypocomplementemia, renal insufficiency with depressed glomerular filtration rate, or signs and symptoms suggestive of vasculitic disease may require a renal biopsy and referral to a pediatric nephrologist. The presence of protein in urine is a common laboratory finding in children. Although proteinuria is usually benign, the condition can be a marker for a serious underlying renal disease or systemic disorder.1,2 When proteinuria coexists with hematuria, the likelihood of clinically significant renal disease is higher.2,3 The challenge for the primary care physician is to separate benign forms of proteinuria from those with clinical significance. SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence rating Clinical recommendations References A 24-hour urine protein excretion test is often difficult in children. Spot, C 2,1819

Clinical recommendations first-morning urine testing for UPr/Cr is more useful and correlates well with the 24-hour urine collection. Spot, first- morning urine testing should be used in children if the urine dipstick test result is 1+ or more. When a child's UPr/Cr is greater than 0.2 (greater than 0.5 for children six C to 24 months of age) or urinalysis results are abnormal, further investigation with history, physical examination, and blood work is recommended to rule out significant renal disease. Referral to a pediatric nephrologist should be considered if a definitive C diagnosis is required or a renal biopsy is considered.

Evidence rating References

UPr/Cr = urine protein/creatinine ratio. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml. Epidemiology Proteinuria is present at routine urine testing in up to 10 percent of school-aged children, although this decreases to 0.1 percent at repeated testing.4 A study including mass screening of school-aged children in Asia revealed similar findings.57 The prevalence increases with age, peaks during adolescence, and is higher in girls.8 Mechanism of Proteinuria The glomerular barrier has three layers (the fenestrated endothelium, the basement membrane, and the podocytes), forming both a size-selective and electrostatic filter. 1,9,10 The electrostatic barrier consists of negatively charged sialoproteins and proteoglycans. Most proteins, such as immunoglobulins G and M, are too large (greater than 100 kDa) to pass through the glomerular barrier. Some have a charge or conformation that prevents them from traversing the filter. At least one half of the proteins in normal urine are Tamm-Horsfall proteins, which are localized to the thick ascending limbs of the loop of Henle.11 The remaining proteins are filtered plasma proteins of different molecular sizes, including mostly low-molecular-weight proteins (less than 40 kDa), such as transferrin, microglobulins, and intermediate-sized albumin.1,2,12,13 Most filtered proteins at the glomerulus are reabsorbed in the proximal tubule. Slit diaphragms between podocytes have recently been discovered. These slit diaphragms contribute to the barrier effect. Mutations of the slit diaphragms can disrupt normal function and lead to proteinuria.9 Mechanisms of proteinuria can be categorized as glomerular, tubular, secretory, or overflow; glomerular and tubular are the primary mechanisms in children.10,12,14 Proteinuria may result

from increased glomerular permeability due to damage to the integrity of the glomerular filter.10 Proteinuria can also occur when a reduced number of functioning nephrons leads to increased diffusion of protein across the remaining glomeruli. Tubular proteinuria occurs when there is an increased excretion of normally filtered low-molecular weight proteins due to impaired reabsorption by the proximal tubules.10,14 Secretory proteinuria results from oversecretion of certain proteins in the tubules, most notably the oversecretion of Tamm-Horsfall proteins in interstitial nephritis. Overflow proteinuria occurs when the plasma concentrations of lowmolecular-weight proteins exceed the capacity of the tubules to reabsorb the filtered protein. Examples include hemoglobinuria in intravascular hemolysis and myoglobinuria in rhabdomyolysis. Measurement of Proteinuria OFFICE TESTING The urine dipstick test uses the tetrabromophenol blue colorimetric method, which is the most widely used screening method. The intensity of color changes from yellow to blue and correlates with the amount of protein in the urine: trace (10 mg per dL), 1+ (30 mg per dL), 2+ (100 mg per dL), 3+ (300 mg per dL), and 4+ (1,000 mg per dL or greater).15 A reading of 1+ or more is considered abnormal. The dipstick test primarily detects albuminuria, with a specificity and sensitivity of more than 99 percent,16 but is not sensitive for other proteins. The dipstick test may yield false-positive results for proteinuria with alkaline urine (pH greater than 8), concentrated urine (specific gravity greater than 1.030), gross hematuria, pyuria, bacteriuria, prolonged immersion of reagent strip in the urine, placement of reagent strip directly in the urine stream, and presence of phenazopyridine or quaternary ammonium compounds in the urine.12 False-negative results may occur with acidic urine (pH less than 4.5), dilute urine (specific gravity less than 1.010), and presence of proteins other than albumin in the urine.12 The sulfosalicylic acid method, or turbidimetry, detects all forms of protein and is generally used as a supplementary test when the presence of a low-molecular-weight or other protein is suspected but not detected by the dipstick test. In the sulfosalicylic acid method, three drops of a sulfosalicylic acid 20% solution are added to 5 mL of urine. Depending on the amount of protein precipitated, various grades of turbidity from minimal (trace) to heavy flocculation (4+) are noted.2,3 QUANTITATIVE LABORATORY TESTING The first-line test is 24-hour quantitative urine protein excretion. In children, the amount of urinary protein excretion varies by age and body size. The normal amount is less than 4 mg per m2 per hour or 100 mg per m2 per day.2 However, this quantitative measurement is not practical in children, particularly if they are incontinent.2 Also, it has an inherent time delay, is often difficult to obtain in an outpatient setting, and is subject to collection errors. The single-void urine protein/creatinine ratio (UPr/Cr) calculated in milligrams of protein per milligrams of creatinine is a convenient method for estimating urine protein excretion without a 24-hour urine collection.2,17 Multiple studies have found that the 24-hour urine protein test

correlates well with UPr/Cr.1820 Multiplying UPr/Cr by 0.63 can give an estimate of the total amount of protein (g per m2 per day) in the urine. Tubular secretion of creatinine increases in the presence of a significant reduction in the glomerular filtration rate, and this might lead to an artificially low UPr/Cr.18 Nevertheless, the UPr/Cr is useful for following trends in proteinuria. A spot, first-morning urine sampling is optimal for determining UPr/Cr because it excludes any postural effect on the protein component. Etiology The etiology of proteinuria in children is diverse (Table 12,19,21,22), but a classification scheme based on the clinical timing and frequency of the problem can help narrow the differential diagnosis. The orthostatic and transient forms are benign and more common. Persistent proteinuria may be associated with underlying renal diseases and requires further investigation. Table 1. Causes of Proteinuria in Children Transient (functional) proteinuria Idiopathic Related to medical condition (e.g., fever, seizure) Unrelated to medical condition (e.g., exercise, stress, dehydration, cold exposure) Orthostatic proteinuria Persistent proteinuria Glomerular Adaptation (hyperfiltration) due to nephron loss (e.g., reflux nephropathy secondary to vesicoureteric reflux) Alport syndrome Collagen vascular disease or vasculitis: Henoch-Schnlein purpura, systemic lupus erythematosus Diabetes mellitus Glomerulopathy: minimal change glomerulopathy,* focal segmental glomerulosclerosis, mesangial proliferative glomerulonephritis, congenital nephrotic syndrome, immunoglobulin A nephropathy, membranoproliferative glomerulonephritis Infection: group A beta-hemolytic streptococcus infection, viral infection (hepatitis B, hepatitis C, human immunodeficiency virus, infectious mononucleosis), other infection (malaria, syphilis) Malignancies (lymphoma, solid tumors) Toxin (mercury) Tubulointerstitial Acute tubular necrosis: aminoglycosides, cisplatin, amphotericin B, NSAIDs, radiocontrast media Acute tubulointerstitial nephritis (NSAIDs, penicillin, cephalosporins, quinolones, sulfonamides, cimetidine [Tagamet], allopurinol [Zyloprim]) Polycystic kidney disease Proximal renal tubular acidosis: Fanconi syndrome (global proximal tubule dysfunction), cystinosis, Lowe syndrome, galactosemia, Wilson disease Pyelonephritis

Toxins (lead, copper, mercury)

NSAID = nonsteroidal anti-inflammatory drug. *Most common form of nephrotic syndrome. Information from references 2,19,21, and 22. TRANSIENT PROTEINURIA Transient (functional) proteinuria is temporary and clears when the inciting factor remits or is removed. Transient proteinuria can occur with fever, exercise, stress, or cold exposure.17,23,24 It may also be caused by hemodynamic alterations in glomerular blood flow. ORTHOSTATIC PROTEINURIA Orthostatic proteinuria is not uncommon in children, particularly during adolescence. The diagnosis is suggested with normal protein excretion (i.e., negative dipstick test result or UPr/Cr of 0.2 or less) in a spot, first-morning urine sample after the child has been supine for the entire night, but increased protein excretion (i.e., positive dipstick test result or UPr/Cr greater than 0.2) at least four to six hours after the child has been upright.25 The cause of orthostatic proteinuria is not clear; however, the anatomic compression of the left renal vein has been suggested.26 Longterm studies with follow-up ranging from 20 to 50 years have demonstrated a benign course.27,28 PERSISTENT PROTEINURIA Persistent proteinuria can be glomerular or tubulointerstitial in origin. In both categories, the causes can be primary, stemming intrinsically from the renal tissue; or secondary, mainly caused by systemic diseases. When proteinuria is associated with hematuria, renal dysfunction, and hypertension, significant renal disease may be present.2 Glomerular diseases are more common than tubulointerstitial diseases.2,29,30 Albumin and immunoglobulin G in the urine are the usual indicators for glomerular diseases. Glomerular diseases can have nephrotic and/or nephritic features, and making a distinction between these features can help narrow the differential diagnosis. Nephrotic syndrome is characterized by heavy proteinuria (greater than 1 g per m2 per day or UPr/Cr greater than 2.0), edema, hypoalbuminemia (less than 25 g per L), and hyperlipidemia.18,3032 Nephritic features include hematuria; hypertension; oliguria; and active urinary sediments, such as red blood cells, white blood cells, and cellular casts. Tubulointerstitial diseases are less common causes of proteinuria and usually involve low molecular-weight proteins. Proteinuria associated with renal tubular disorders is generally mild. Tubular proteinuria rarely presents a diagnostic dilemma because the underlying disease is usually detected before the proteinuria.14,29

Interstitial nephritis includes a variety of pathologic processes involved in the progression of most renal diseases, and is a final common pathway for all forms of endstage renal disease.14 Diagnostic Evaluation Proteinuria is often an incidental finding on urine dipstick testing or urinalysis. Asymptomatic children with proteinuria usually have the transient or orthostatic type. If a urine dipstick test shows trace amounts of protein, the test should be repeated with first-morning urine. If the firstmorning test shows trace or negative amount of protein, a repeat first-morning test performed in one year should also be considered.2 In children with a urine dipstick test result of 1+ or greater, a spot, first-morning urine test for UPr/Cr and a urinalysis with microscopic examination should be performed. If the UPr/Cr is 0.2 or less (0.5 or less for children six to 24 months of age) and urinalysis results are normal, a diagnosis of transient or orthostatic proteinuria should be considered. A repeat first-morning dipstick test in one year should be considered. If the UPr/Cr is greater than 0.2 (greater than 0.5 for children six to 24 months of age), or if urinalysis results are abnormal (e.g., hematuria, leukocyturia, active urinary sediments), persistent proteinuria or proteinuria of clinical significance is more likely. A UPr/Cr greater than 2.0 is associated with nephrotic syndrome, and further evaluation with history, physical examination, and additional blood work is essential.2,29 History and Physical Examination Because of the wide differential diagnosis of proteinuria in children, the symptoms and signs may vary. Common features of renal disease include growth failure, hypertension, and edema (i.e., periorbital, presacral, genital, or ankle). Associated deafness or visual impairment suggests hereditary nephritis. Table 2 lists clinical features that can provide clues to the underlying cause of persistent proteinuria.2,19,21,22 Table 2. Clinical Clues to the Cause of Persistent Proteinuria in Children Cause of proteinuria Glomerular Adaptation (hyperfiltration) due to nephron loss Alport syndrome Clinical features History of vesicoureteric reflux or recurrent urinary tract infection Laboratory findings* Elevated serum creatinine or blood urea nitrogen level RBCs on urinalysis

Hearing abnormality, decreased vision, gross hematuria, family history of the condition Collagen vascular disease or vasculitis Henoch-Schnlein Nonblanchable, palpable purpura in purpura gravity-dependent areas; arthritis; abdominal pain; hematuria Systemic lupus Recurrent fever, butterfly rash, arthritis, erythematosus hematuria, growth failure, multisystem involvement

WBCs, RBCs, cellular casts on urinalysis Positive antinuclear antibody, pancytopenia, decreased complement C3 and C4 levels

Cause of proteinuria Diabetes mellitus Glomerulopathy Congenital nephrotic syndrome

Clinical features Laboratory findings* Polyuria, polydipsia, polyphagia, weight Elevated fasting blood glucose loss and A1C levels, glycosuria Younger than three months, prematurity, low birth weight, placentomegaly, edema at birth or during first week of life

Elevated alpha-fetoprotein level in amniotic fluid, nephrotic-range proteinuria, hypoalbuminemia, hyperlipidemia Focal segmental Nephrotic or nephritic features, history Proteinuria of varying degrees, glomerulosclerosis of HIV including nephrotic-range proteinuria; hypoalbuminemia; hyperlipidemia; thrombocytosis; normal complement levels; HIV serology IgA nephropathy Usually older than 10 years, nephritic Hematuria, elevated serum features, recent upper respiratory tract IgA, normal complement C3 infection, microscopic hematuria and C4 levels interspersed with episodes of macroscopic hematuria Membranoproliferative Nephrotic and/or nephritic features; Hematuria, decreased glomerulonephritis history of chronic hepatitis B or C; may complement C3 level, usually be associated with infections, normal complement C4 level, rheumatologic disease, and positive hepatitis serology malignancies results, possibly nephrotic laboratory findings Mesangial proliferative Nephrotic features, hematuria Nephrotic-range proteinuria, glomerulonephritis hypoalbuminemia, hyperlipidemia, thrombocytosis, normal complement levels Minimal change Most common form of nephrotic Nephrotic-range proteinuria, glomerulopathy syndrome, facial or generalized edema, hypoalbuminemia, younger than six years, may be hyperlipidemia, associated with recent viral infection or thrombocytosis, normal allergy complement levels Infection Poststreptococcal Recent pharyngitis or skin infection, Positive throat swab results; glomerulonephritis nephritic features elevated antistreptolysin O titer; decreased complement C3 and C4 levels; dysmorphic RBCs or RBC casts on urinalysis Malignancies Weight loss, cachexia Abnormal laboratory findings depend on the underlying

Cause of proteinuria Tubulointerstitial Acute tubular necrosis

Clinical features

Laboratory findings* cause

Elevated serum creatinine or blood urea nitrogen levels; granular casts, epithelial cell casts, renal tubular epithelial cell casts on urinalysis Acute tubulointerstitial Medication history: NSAIDs, penicillin, Acute rise in serum creatinine nephritis cephalosporins, quinolones, level, eosinophilia, WBC casts sulfonamides, cimetidine (Tagamet), on urinalysis allopurinol (Zyloprim); nonspecific malaise, fever, rash Polycystic kidney Hematuria, hypertension, renal RBCs on urinalysis, elevated disease insufficiency, nephromegaly, family serum creatinine or blood urea history of the condition nitrogen levels Proximalrenal tubular Cystinosis: visual impairment, Fanconi Cystinosis:elevated leukocyte acidosis syndrome, thyroid disorder, cystine level Fanconi hepatosplenomegaly, delayed puberty syndrome and Lowe Fanconi syndrome: growth failure, syndrome: acidic urine, polyuria, polydipsia Lowe syndrome: glycosuria, aminoaciduria cataracts, Fanconi syndrome, hypotonia Wilson disease: decreased Wilson disease: Kayser-Fleischer rings serum ceruloplasmin level, on slit lamp examination, liver elevated liver enzymes dysfunction or cirrhosis Pyelonephritis Fever, chills, flank and costovertebral Leukocytes on urinalysis, tenderness, hematuria, irritative urinary positive urine culture results symptoms Toxins Copper: history of exposure (e.g., food Elevated level of the toxin containers) Lead: history of exposure, constipation, lead line along gum margin, cognitive or behavioral impairment Mercury: history of exposure (e.g., dental amalgam filling, seafood), may have cognitive impairment or nephrotictype syndrome

Medication history: aminoglycosides, cisplatin, amphotericin B, NSAIDs; history of radiocontrast media

HIV = human immunodeficiency virus; IgA = immunoglobulin A; NSAID = nonsteroidal antiinflammatory drug; RBC = red blood cell; WBC = white blood cell. *Basic laboratory work-up for suspected renal disease includes a complete blood count and measurement of serum electrolyte, blood urea nitrogen, and serum creatinine levels. Additional laboratory tests listed in this table can help evaluate for specific conditions.

Distinguishing among the different types of glomerulopathy is difficult clinically; therefore, they are generally diagnosed histologically. Nephrotic features: heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia; nephritic features: hematuria, hypertension, oliguria, and active urinary sediments. Also a rare cause in glomerular proteinuria. Information from references 2,19,21, and 22. LABORATORY TESTS A complete blood count and serum electrolyte, blood urea nitrogen, and serum creatinine measurements should be considered when appropriate if renal disease is suspected. An elevation in blood urea nitrogen or serum creatinine suggests impaired renal function. Additional blood work should be ordered when indicated by history, physical examination, or initial laboratory results (Table 2).2,19,21,22 Hematuria may be secondary to simple urinary tract infections, but may also be caused by more serious renal diseases. IMAGING STUDIES Ultrasonography of the urinary tract is an appropriate, noninvasive screening test for anatomic abnormalities and should be considered in patients with chronic kidney disease.2 A dimercaptosuccinic acid scan is the preferred study to detect renal scars. RENAL BIOPSY Renal biopsy is not routinely indicated in the proteinuria work-up.33 A biopsy should be considered when proteinuria is accompanied by active urinary sediments, persistent and gross hematuria, hypertension, hypocomplementemia, renal insufficiency with depressed glomerular filtration rate (less than 60 mL per minute per 1.73 m2 for more than three months), or signs and symptoms suggestive of vasculitic disease.34 A renal biopsy should also be considered in selected patients with nephrotic syndrome associated with a later age of onset or unresponsiveness to corticosteroid treatment. Management The family can be reassured if the proteinuria is transient or orthostatic, and the child is asymptomatic, has no associated hematuria, and has normal blood pressure and glomerular filtration rate. Regular follow-up is important, however, as long as significant proteinuria persists. Although there are no formal guidelines for monitoring, a child with persistent proteinuria should initially receive a physical examination, blood pressure measurement, urinalysis, and blood tests for creatinine and urea nitrogen levels every six to 12 months.29 There is no specific limitation on diet or physical activity. Once the child is stable, follow-up can be annual.

The treatment of persistent proteinuria should be directed at the underlying cause.2,29 Patients with idiopathic nephrotic syndrome should receive a trial of prednisone (2 mg per kg per day, or 60 mg per m2 per day to a maximum of 80 mg per day) in up to three divided doses for four to six weeks, followed by treatment on alternate days for another four to six weeks.35 If steroid therapy fails or adverse effects are intolerable, second-line therapy (e.g., cyclophosphamide, chlorambucil [Leukeran], cyclosporine [Sandimmune]) may be required.36 In patients with renal dysfunction, an adjunctive angiotensin-converting enzyme inhibitor and/or angiotensin-II receptor blocker can be used to decrease proteinuria and slow progression of renal disease.3740 Referral to a pediatric nephrologist may be needed for a definitive diagnosis or consideration of renal biopsy.2

editor's note: This article is based on content that Dr. Leung is preparing for a chapter in a book titled Common Problems in Ambulatory Pediatrics. The book will be published by Nova Science Publishers, Inc., Hauppauge, NY.

Arch Dis Child 2005;90:766-767

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How significant are asymptomatic gross and microscopic hematuria?

Asymptomatic hematuria (gross or microscopic) is relatively common in children. The estimated prevalence of asymptomatic microscopic hematuria in children is 0.5% to 2.0%; the incidence of asymptomatic gross hematuria is not known. Because the clinical significance of asymptomatic hematuria is uncertain, the traditional approach is to pursue a thorough clinical investigation. To evaluate its clinical significance and determine when diagnostic evaluation is necessary, investigators at Indiana University prospectively evaluated 570 children who were referred for evaluation of asymptomatic hematuria. Microscopic hematuria (defined as >5 red blood cells/high-powered field) was detected at routine exams. Diagnostic evaluation consisted of personal history (to exclude symptoms), physical exam, blood pressure measurement, and laboratory studies (including complete blood count, urinalysis, serum creatinine and C3 levels, creatinine clearance, protein and calcium excretion, and ultrasonography or intravenous pyelography). Streptozyme titers were measured when hematuria was of less than 6 months duration, antinuclear antibody assays were conducted in teenagers, and

black children underwent hemoglobin electrophoresis. Urine cultures and renal biopsies were performed selectively (e.g., for persistent hematuria, hypertension, proteinuria, and decreased renal function). Of 342 children with microscopic hematuria, no cause was discovered in 80%. The most common cause was hypercalciuria (16% of all patients). Four children had poststreptococcal glomerulonephritis, and 4 had structural abnormalities of the urinary tract. Gross hematuria was a different story: Of 228 children, a cause was detected in 62%, including one Wilms tumor. Hypercalciuria without a history of stone disease was the most common cause (22% of patients), followed by IgA nephropathy (16%) and poststreptococcal nephritis (9%). Twelve patients were hypertensive, and 10 had structural abnormalities.

Comment
Because of the low incidence of significant findings in children with asymptomatic microscopic hematuria (without proteinuria), it seems rational and safe to simply follow such children and to evaluate them further only if hypertension, proteinuria, or other symptoms emerge. Gross hematuria, on the other hand, should always prompt a thorough investigation. Harlan R. Gephart, MD Published in Journal Watch Pediatrics and Adolescent Medicine May 6, 2005 Bergstein J et al. The clinical significance of asymptomatic gross and microscopic hematuria in children. Arch Pediatr Adolesc Med2005;159:3535. [Abstract/FREE Full text]
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Community-acquired MRSA: unraveling its disease

spectrum
How widespread are community-acquired infections due to emerging methicillin-resistant Staphylococcus aureus (MRSA) strains, and are these strains responsible for changes in the clinical spectrum of staphylococcal disease? Two reports now begin to supply some answers. Fridkin and colleagues studied infections identified by a specialized MRSA surveillance project in Atlanta, Baltimore, and several regions of Minnesota. During 2001 and 2002, 2107 MRSA isolates (8%20% of all MRSA isolates collected) were classified as community-acquired; 1647 of them were associated with clinical illness. Annual incidence of community-associated MRSA disease varied by site, ranging from 18.0 to 25.7 cases per 100,000 population. Rates were significantly higher among children <2 years old than among individuals 2 and, in Atlanta, among blacks than whites. Of the 1647 disease episodes, 77% were infections of skin and soft tissue, and 6% were invasive infections (e.g., bacteremia, septic arthritis, osteomyelitis). Twenty-three percent of patients required hospitalization for MRSA disease; of these, 10% required intensive care. Only one patient died as a result of MRSA infection. Antimicrobial therapy (typically, a -lactam) inactive against the infecting strain was given to 73% of patients, with no discernible adverse effects on outcomes among patients interviewed (all of whom had skin or soft-

tissue infections). Although patients with community-acquired MRSA infections, by definition, lacked established risk factors for MRSA infection, 45% had underlying conditions or circumstances associated with skin infections (see Journal Watch Infectious Diseases Feb 28, 2005) or suggesting contact with the healthcare system. Miller and colleagues described 14 cases of surgically confirmed necrotizing fasciitis due to community-acquired MRSA, occurring in Los Angeles from January 15, 2003, through April 15, 2004. Necrotizing fasciitis, typically caused by group A streptococcus, Clostridium perfringens, or a mixture of aerobic and anaerobic organisms, had been attributed to a monomicrobial MRSA infection before in only one patient, following surgery. Of the 14 patients (median age, 46 years), all underwent at least one surgical procedure, 10 required intensive care, and 3 had reconstructive plastic surgery; all survived. In most patients, disease onset seemed less acute than in classic necrotizing fasciitis, with symptoms present an average of 6 days before hospitalization. Blood cultures were positive in 4 of 10 patients. All but 4 patients had coexisting conditions or risk factors, including current or past injection-drug use (6 patients), hospitalization within the previous year (6), homelessness (4), a seizure disorder (3), diabetes (3), chronic hepatitis C (3), or earlier MRSA infection (3). Wound cultures from 12 of the 14 patients grew only MRSA. All MRSA isolates were susceptible to clindamycin, trimethoprim-sulfamethoxazole, vancomycin, gentamicin, and rifampin. The five isolates available for analysis belonged to the same genotype and carried Panton-Valentine leukocidin, lukD, and lukE toxin genes.

Comment
Community-acquired MRSA infections are increasing. Although these reports do not address the proportion of community-associated staphylococcal infections that are caused by MRSA strains not originating in hospitals, an editorialist suggests that in Atlanta this figure may exceed 5%. Community-acquired MRSA must be added to the monomicrobial etiologies of necrotizing fasciitis, and clinicians must be alert to the need for antimicrobial therapy directed against these strains, as well as to the necessity for surgical intervention. Although the development of necrotizing fasciitis due to community-acquired MRSA is disturbing, it should be noted that 9 of the 14 reported patients either had been hospitalized within the previous year or had a history of MRSA infection. Neil R. Blacklow, MD Published in Journal Watch Infectious Diseases April 22, 2005 Fridkin SK et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med2005;352:143644. [CrossRef][Medline][Web of Science] Miller LG et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med2005;352:144553. [CrossRef][Medline][Web of Science] Chambers HF. Community-acquired MRSAResistance and virulence converge. N Engl J Med2005;352:14857. [CrossRef][Medline][Web of Science]
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M. Susan Jay, MD Published in Journal Watch Pediatrics and Adolescent Medicine May 6, 2005

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(Pediatrics in Review. 2008;29:342-348. doi:10.1542/pir.29-10-342) 2008 American Academy of Pediatrics

Hematuria
Susan F. Massengill, MD*
*

Director, Pediatric Nephrology, Levine Children's Hospital at Carolinas Medical Center, Charlotte, NC

Objectives
After completing this article, readers should be able to:
1. Define hematuria. 2. List the common conditions associated with hematuria. 3. Identify the important elements of the history and physical examination that suggest serious renal disease. 4. Plan a practical and systematic approach to the evaluation of hematuria. 5. Appreciate when consultation with a pediatric nephrologist is necessary.

Case Study
An 8-year-old white girl is referred for evaluation of hematuria, proteinuria, and hypertension. She has had recurrent episodes of gross hematuria. The first was at 3 years of age and was attributed to a urinary tract infection, but a urine culture was negative. She was treated with 10 days of antibiotics, and the symptoms resolved. The second episode, at age 5 years, was attributed to acute poststreptococcal glomerulonephritis, although an antistreptolysin O (ASO) titer was normal, and complement studies were not ordered. Blood pressure at that time was 120/80 mm Hg (normal for age and height is 94/54 mm Hg). The girl was lost to follow-up and presents 3 years later with blood pressure at the 95th percentile, gross hematuria, and

generalized edema. Urinalysis of tea-colored urine shows too-numerous-to-count dysmorphic red blood cells (RBCs), white blood cells, proteinuria, and RBC casts. The differential diagnosis includes immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, and hereditary nephritis, although the latter condition is unusual in a female. She is admitted for additional evaluation.

Introduction
Hematuria is a common finding in children and often comes to the attention of the pediatrician as a result of a routine screening urinalysis, as an incidental finding when evaluating urinary tract symptoms, or when a child has gross hematuria. Although the differential diagnosis for hematuria is extensive, most cases are isolated and benign. Generally, hematuria is a medical rather than a urologic issue. Only the rare child or adolescent who has hematuria needs initial screening radiographic imaging or invasive urologic procedures such as cystoscopy.

Definition
Hematuria is defined as the presence of five or more RBCs per high-power (40x) field in three consecutive fresh, centrifuged specimens obtained over the span of several weeks. (1) Confirmation of hematuria is critical. A positive urine dipstick test may result from myoglobinuria or hemoglobinuria, in which the urine often is discolored, but no RBCs are noted on microscopic evaluation. In addition, certain drugs (sulfonamides, nitrofurantoin, salicylates, phenazopyridine, phenolphthalein), toxins (lead, benzene), and foods (food coloring, beets, blackberries, rhubarb, paprika) may falsely discolor urine, in which case the urine dipstick test is negative for heme. In newborns, a red or pink discoloration in the diaper can be seen when urate crystals precipitate in the urine. Hallmarks of glomerular bleeding are discolored urine, RBC casts, and distorted RBC morphology (Figs. 1 and 2). Evaluation of RBC morphology is helpful in distinguishing glomerular from extraglomerular sources (Table 1). The appearance of variable RBC shapes,

such as budding or blebs, is more suggestive of glomerular sources. Phase-contrast microscopy is not readily available to most general practitioners, and if available, is limited by the experience of the observer. However, dysmorphic RBCs can be differentiated from eumorphic RBCs by using standard bright-field microscopy. The presence of blood clots is indicative of extraglomerular bleeding.

Figure 1. Urine sediment showing a red blood cell cast that is tightly packed with red blood cells. Red blood cell casts are virtually diagnostic of glomerulonephritis or vasculitis. Courtesy of Bruder Stapelton, MD.

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Figure 2. Phase-contrast microscopy showing dysmorphic red blood cells and red blood cell cast in a patient who has glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions. Courtesy of Bruder Stapelton, MD.

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Table 1. Glomerular Versus Extraglomerular Hematuria

Factor Glomerular Extraglomerular

Color RBC Morphology Casts Clots Proteinuria

Smoky, tea- or cola-colored, red Dysmorphic RBC, WBC Absent 2+

Red or pink Normal None Present (+/ ) <2+

RBC=red blood cell, WBC=white blood cell

Prevalence
Large population studies in Galveston, Texas, and Helsinki, Finland, evaluating the presence of asymptomatic microscopic hematuria in school-age children, have shown a prevalence of 3% to 6% when a single urine specimen is evaluated. (1)(2) However, with repeat urinary screenings, the prevalence declines to 0.5% to 1%. The prevalence of hematuria does not differ by ethnicity or socioeconomic level, but opinions differ as to whether the prevalence is slightly higher in females. In a study of 8,954 school-age children, persistent asymptomatic hematuria led to a kidney biopsy in 28 children, with only 5 having identifiable renal pathology. The lack of serious disease identified in this and other studies has led to the recommendation that a kidney biopsy is not warranted for asymptomatic microscopic hematuria alone.

Causes
Because annual screening urinalyses no longer are recommended by the American Academy of Pediatrics, hematuria comes to the attention of the practitioner either incidentally or when evaluating a child who has urinary tract symptoms or gross hematuria. Hematuria may be either microscopic or macroscopic (gross hematuria). Microscopic hematuria may be either persistent or transient. The diagnostic evaluation of hematuria depends on the category: gross hematuria, symptomatic microscopic hematuria, asymptomatic microscopic hematuria with proteinuria, or isolated asymptomatic microscopic hematuria (Fig. 3).

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Figure 3. Algorithm for evaluation of hematuria. ANA=antinuclear antibody, ANCA= antineutrophil cytoplasmic antibody, Abs=antibodies, BUN=blood urea nitrogen, C=complement, Ca=calcium, CBC=complete blood count, Cr=creatinine, CT=computed tomography scan, HSP=HenochSchnlein purpura, Hb=hemoglobin, KUB=kidney-ureterbladder radiograph, RBC=red blood cell, R/O=rule out, RUS=renal ultrasonography

Gross Hematuria
Gross hematuria is suspected when urine is discolored, usually red or tea-colored. In contrast to

microscopic hematuria, underlying causes of gross hematuria are identified in 56% of cases (Table 2). (3)(4) In evaluating gross hematuria, it is important to confirm the presence of RBCs by microscopy. Following centrifugation of the urine, the finding of red urinary sediment with a positive dipstick test for hemoglobin is indicative of hematuria, whereas red supernatant with negative dipstick testing for hemoglobin is indicative of myoglobinuria, hemoglobinuria, or other causes of discolored urine. Aside from renal disease, common causes of gross hematuria include urinary tract infection, trauma, coagulopathy, crystalluria, and nephrolithiasis.

Table 2. Clues to Diagnosing Causes of Gross Hematuria

History Lower tract symptoms (dysuria, urgency, frequency, suprapubic pain) Recent illness (pharyngitis, impetigo, viral illness) Abdominal pain Concurrent illness Extreme exertion, influenza Arthralgias Diarrhea ( bloody) Cough, hemoptysis Hearing loss Nail or patellar abnormalities Sickle cell disease Drugs (diuretics, cyclophosphamide) Birth asphyxia Possible Diagnosis UTI

Postinfectious glomerulonephritis UTI, HSP, crystalluria/stone IgAN Rhabdomyolysis HSP, SLE HUS Vasculitis Alport disease Nail patella syndrome Glomerulonephritis, papillary necrosis Stones, hemorrhagic cystitis Renal vein thrombosis

Physical Findings Suprapubic pain Flank pain

Possible Diagnosis UTI IgAN, stones, renal vein thrombosis, pyelonephritis HSP, SLE, HUS, bleeding dyscrasia, abuse Glomerulonephritis, nephrotic syndrome Wilms tumor, hydronephrosis, cystic kidney disease Adenovirus (hemorrhagic cystitis) Infection, trauma Nail patella syndrome Possible Diagnosis Benign familial hematuria, thin basement membrane disease Alport syndrome

Rash (purpura, petechiae) Edema Abdominal mass

Conjunctivitis, pharyngitis Meatal stenosis Nail or patellar abnormalities Family History Hematuria

Hearing loss or prominent history of renal failure in males Cystic kidney disease

Autosomal dominant polycystic kidney disease Nail patella syndrome

Nail/patellar abnormalities Sickle cell disease or trait

HSP=Henoch-Schnlein purpura, HUS=hemolytic-uremic syndrome, IgAN= immunoglobulin A nephropathy, SLE=systemic lupus erythematosus, UTI=urinary tract infection

Suspicion of postinfectious acute glomerulonephritis (PIAGN) increases when gross hematuria is accompanied by a history of an antecedent illness, particularly streptococcal pharyngitis or impetigo. Other common features include edema (85%) and hypertension (85%). Confirmatory laboratory evidence includes a positive throat culture for group A Streptococcus, elevated streptococcal antibody titers, hypocomplementemia (depressed C3 value), and urinary RBC casts. PIAGN typically is a self-limited condition, and recurrence is rare. Complement values should normalize within 6 to 8 weeks. However, microscopic hematuria may persist for 6 to 12 months. Persistence of hematuria longer than 12 months or recurrent gross hematuria should lead to a reconsideration of the diagnosis of PIAGN. Membranoproliferative glomerulonephritis commonly presents in older children and young adults, with a female predominance. Nephrotic syndrome is present in 50% of affected children; another 25% have a nephritic picture with edema, hypertension, and renal insufficiency. When it occurs in this condition, gross hematuria is more common in children than in adults and is infrequent after the first year of diagnosis. Hypocomplementemia is common in nearly all forms of this disease. Gross hematuria in the presence of abdominal pain with or without bloody stools, arthralgias, and a purpuric rash suggests Henoch-Schnlein purpura nephritis. Pathologic proteinuria often is an accompanying finding if gross hematuria is present. The onset of renal findings may be delayed for 3 to 4 months after the initial presentation. Therefore, it is important to monitor urinalyses routinely in affected children. Recurrent episodes of gross hematuria in children occur less commonly. When the hematuria coincides with acute illnesses or strenuous exercise, immunoglobulin A (IgA) nephropathy should be considered. In the adolescent population, IgA nephropathy is the most frequent cause of gross hematuria. (5) It is important to realize that although gross hematuria may resolve, patients may have persistent microscopic hematuria between episodes. Evaluation of the family history for chronic kidney disease (end-stage renal disease, renal transplantation) may uncover conditions such as hereditary nephritis. Inherited mutations in type IV collagen of the glomerular basement membrane are responsible for X-linked, autosomal recessive, and autosomal dominant forms of Alport syndrome (AS) as well as for benign familial hematuria. (6)(7) The predominant form of AS is X-linked (85%), and as expected, males are affected more severely, with virtually all male patients developing kidney failure by the second or third decade of life, along with accompanying high-frequency sensorineural hearing loss and anterior lenticonus. Females who have X-linked AS may have only microhematuria. For the minority of females afflicted with the more progressive disease, the risk of developing kidney failure occurs in fewer than 10% to 15% and much later in life. Most patients who have the autosomal recessive form of AS develop significant proteinuria in late childhood or early adolescence and kidney failure before 30 years of age. Tissue diagnosis now is available for both kidney and skin biopsy specimens. Immunostaining shows abnormal staining for alpha-3, -4, and -5 chains of type IV collagen. In contrast to AS, benign familial hematuria is characterized by microscopic hematuria with occasional episodic gross hematuria (<10%), but proteinuria and hypertension are unusual features. Benign familial hematuria has an autosomal dominant pattern of transmission, although many family members are unaware that they have hematuria.

The most common hematologic disorders causing gross hematuria are sickle cell disease and sickle cell trait. Occlusion of the vasa recta capillaries can result in renal papillary infarcts. Hematuria occurs more commonly in males and frequently is unilateral, with the left kidney more likely to be affected. Recurrence occurs in 40% of cases. Contributing factors include hypoxia, acidosis, high osmolality, and stasis. Painless gross hematuria following minor trauma can occur in conjunction with ureteropelvic junction obstruction, which can be diagnosed easily by renal ultrasonography or nuclear renography. Finding this condition should prompt referral to a pediatric urologist. Idiopathic urethrorrhagia may present with either asymptomatic terminal hematuria or spotting of blood on underpants. This disorder is benign and self-limited.

Symptomatic Microscopic Hematuria

Patients who have symptomatic microscopic hematuria often require the greatest attention and a methodical approach toward categorizing the disease process. When accompanied by elevated proteinuria on a "first" morning urine sample (protein-to-creatinine ratio >0.2), the likelihood of underlying renal disease is higher. Clinical manifestations in patients who have symptomatic microscopic hematuria may be nonspecific (fever, malaise, weight change), extrarenal (malar rash, purpura, arthralgia/arthritis, headaches), or localized, with urinary tract symptoms (dysuria, suprapubic pain, flank pain, edema, oliguria). Clearly, the history and physical findings direct the extent of the evaluation. For example, a patient who has malar rash, arthritis, pericardial rub, edema, and hypertension likely has systemic lupus erythematosus. Fever, flank pain, nausea, and vomiting suggest upper urinary tract involvement. Dysuria, frequency, urgency, and incontinence suggest crystalluria or urinary tract infection. It is believed that microcrystallization is irritating to the uroepithelium and leads to the symptom complex and hematuria.

Asymptomatic (Isolated) Hematuria

Those who have asymptomatic hematuria rarely are found to have significant renal disease and,

therefore, do not warrant an extensive evaluation. As many as 25% of patients have normalization of their urinalysis findings if followed for 5 years. Family history is particularly important to assess for benign familial hematuria, also known as thin basement membrane disorder, in which biopsy specimens are characterized ultrastructurally by diffuse thinning of the glomerular basement membrane. Often, multiple family members have a history of hematuria but are free of the long-term complications of progressive renal insufficiency, hearing, or ocular abnormalities seen in those who have AS. Rarely is gross hematuria seen in this group of patients (<10%). Patients should have regular monitoring for the development of hypertension and proteinuria. Hypercalciuria frequently is associated with asymptomatic hematuria. Some affected patients are at risk for developing symptomatic urolithiasis. Hypercalciuria is defined as a urinary calcium-to-creatinine ratio of more than 0.2 (<6 months of age, >0.86; 7 to 18 months of age, >0.6) or 24-hour urinary calcium excretion exceeding 4 mg/kg per day. Hypercalciuria in most cases is idiopathic, but other considerations include immobilization, diuretics, vitamin D intoxication, hyperparathyroidism, and sarcoidosis.

Asymptomatic Hematuria and Proteinuria

The combination of hematuria and proteinuria is worrisome because it might be due to serious renal disease. However, finding both abnormalities is not uncommon; in most cases, serial urinalyses show resolution of one or both features. When evaluating this combination, it is important to determine initially if the proteinuria is orthostatic by evaluating a first morning urine protein (normal protein-to-creatinine ratio is <0.2). The persistence of pathologic proteinuria is more indicative of a glomerular process. This population deserves special attention and a thorough evaluation by a pediatric nephrologist.

Diagnostic Evaluation
Figure 3 provides an algorithm for evaluating a patient who has hematuria. The first step

involves measurement of blood pressure. A dipstick urinalysis evaluates for pyuria, proteinuria, heme positivity, and urinary concentrating defects; microscopy evaluates for white blood cells and clumps, RBC morphology, crystals, and casts. Crystalluria can be caused by calcium oxalate, calcium phosphate, uric acid, or cystine crystals. Hypercalciuria is, by far, the most common cause of crystalluria. Urine culture should be reserved for those who have clinical symptoms or laboratory evidence (pyuria, hematuria, bacteriuria, positive nitrites) of a urinary tract infection. Radiographic studies should be delayed unless the symptom complex is highly suggestive of conditions such as nephrolithiasis. The second stage of evaluation involves a more thorough search for underlying renal disease, particularly when edema, hypertension, alterations in urine output, or systemic symptoms are present. Serum chemistries (electrolytes, blood urea nitrogen, and creatinine) evaluate for renal insufficiency. Suspicion of acute PIAGN should prompt ordering of ASO and other streptococcal antibody titers and a C3 measurement. Secondary causes of renal disease, such as systemic lupus erythematosus, small vessel vasculitis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) disease, warrant checking an antinuclear antibody titer, complement levels (C3, C4), antineutrophil cytoplasmic antibodies, hepatitis serologies, or HIV serology, respectively. A complete blood count is helpful in the setting of petechiae, bruising, fatigue, abdominal masses, or suspicion of chronic disease. Evaluation for sickle cell disease or trait by hemoglobin electrophoresis is indicated if the family is unaware of the patient's status. Renal ultrasonography can identify structural abnormalities, asymmetry, echogenicity, renal masses, and renal vein thrombosis. Abdominal radiographs may identify radiopaque stones comprised of calcium, struvite, and cystine. Radiolucent stones such as uric acid calculi are not detected. Spiral helical computed tomography scan is the most sensitive imaging modality for detecting nephrolithiasis but delivers a high radiation dose and is expensive. Radiocontrast should be used with caution in the patient who has renal insufficiency and rarely when evaluating for stone disease. Renal biopsy is reserved for the patients who have recurrent episodes of gross hematuria, coexisting nephrotic syndrome, coexisting hypertension with nephritic component, renal insufficiency, family history suggesting hereditary nephritis, and coexisting systemic symptoms (arthritis, purpura, malar rash, hemoptysis, anemia), as well as in those in whom nonglomerular causes have been excluded. At times, parental anxiety or the need for a definite diagnosis may prompt a renal biopsy. Cystoscopy, an invasive and costly procedure, almost never is indicated for asymptomatic microscopic hematuria; it rarely discerns any underlying disease. Rhabdomyosarcoma typically causes gross hematuria and voiding dysfunction. Wilms tumor is identified best by radiographic imaging with ultrasonography.

When to Refer to a Pediatric Nephrologist

Unless the cause of gross hematuria is clear (urinary tract infection, PIAGN), referral to pediatric nephrology for a detailed evaluation is indicated. Early referral often is necessary for those experiencing symptomatic microscopic hematuria because many of the associated conditions necessitate a targeted evaluation and management. The patient who has asymptomatic hematuria needs periodic evaluation every 1 to 2 years to re-evaluate for coexisting symptoms or proteinuria and to revisit the family history with respect to other family members having hematuria or hearing deficits. The child who has persistent asymptomatic hematuria and concomitant proteinuria needs additional evaluation, often including a renal biopsy, by a pediatric nephrologist.

Continuation of Case Study

Laboratory studies revealed moderate kidney failure, hypocomplementemia, negative ASO titer, and negative antinuclear antibody titer. Kidney biopsy was performed due to the chronicity and nephritic nature of the presentation and showed membranoproliferative glomerulonephritis. Following a prolonged clinical course of steroid therapy, the child's blood pressure, kidney function, and urinalysis normalized. This case emphasizes the acute and relapsing aspects of a chronic disease and the importance of systematically evaluating the child who has hematuria with appropriate laboratory studies and referrals.

Summary
Hematuria is a common finding in children and adolescents presenting to a pediatrician in a busy practice. More often than not, parents, and sometimes the child, are anxious and demand an immediate diagnosis, particularly when there is gross hematuria. Critical to the evaluation is distinguishing the difference between the child who has asymptomatic microscopic hematuria that often is benign and requires conservative management and the child who has hematuria and accompanying proteinuria, edema, hypertension, or other symptoms suggestive of underlying renal disease. A simple and practical approach to the child who has hematuria should result in

fewer invasive studies, a less costly evaluation, and appropriate referral. A stepwise approach makes failure to identify the patient who has serious renal disease unlikely.

Footnotes

Author Disclosure Dr Massengill has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/ device.

(Pediatrics in Review. 2009;30:94-105.) 2009 American Academy of Pediatrics

The Nephrotic Syndrome

Roberto Gordillo, MD* Adrian Spitzer, MD
Postdoctoral Fellow Professor of Pediatrics, Albert Einstein College of Medicine/Children's Hospital at Montefiore, Division of Pediatric Nephrology, Bronx, NY
*

Abbreviations: ACE: angiotensin-converting enzyme BSA: body surface area CNF: congenital nephrotic syndrome of the Finnish type CNS: congenital nephrotic syndrome FSGS: focal segmental glomerulosclerosis HDL: high-density lipoprotein Ig: immunoglobulin IL: interleukin ISKDC: International Study of Kidney Disease in Children LDL: lowdensity lipoprotein MCNS: minimal-change nephrotic syndrome MN: membranous nephropathy MPGN: mesangioproliferative glomerulonephritis RAA: renin-angiotensinaldosterone SLE: systemic lupus erythematosus UPr/Cr: urine protein/creatinine ratio VLDL: very low-density lipoprotein

Objectives

After completing this article, readers should be able to:

1. 2. 3. 4. 5. 6. 7. Explain the mechanism and the consequences of proteinuria. Make a presumptive diagnosis of minimal-change nephrotic syndrome. Interpret the signs associated with steroid resistance. Ascertain the timing and the indications for a kidney biopsy. Gauge the indications for referral to a pediatric nephrologist. Determine the adequacy of the therapy. Predict the disease course.

Introduction
The word "nephrosis" was introduced in the medical literature at the beginning of the 20th century in an attempt to distinguish diseases of the kidney characterized by exudation and proliferation from those characterized by inflammation (nephritis). As it became apparent that this is not a single disease, not even a group of related diseases, the term "nephrosis" was supplanted by "nephrotic syndrome." The clinical features that characterize the nephrotic syndrome result from alterations of the glomerular capillary wall and consist of heavy proteinuria and hypoalbuminemia, often associated with edema and generalized hyperlipidemia.

Pathophysiology
Proteinuria and Hypoalbuminemia
Proteinuria is the result of alterations in the integrity of the glomerular filtration barrier. This barrier is composed of three layers in series: the fenestrated endothelium, the glomerular basement membrane, and the visceral glomerular epithelium, comprised of podocytes and their

slit diaphragms. Podocyte is the name of the epithelial cell, and foot process is the segment of the cell that extends into the urinary space. (In the nephrotic syndrome, there is effacement of the foot process, but the rest of the cell usually is preserved.) Endothelial cells have numerous openings that are 70 to 100 nm in diameter, called fenestrae, which form a physical barrier for passage of macromolecules from plasma into the renal tubule. Electron microscopic studies led to the identification of negatively charged particles (heparan sulfate proteoglycans) in the glomerular basement membrane, which preclude the passage of anionic macromolecules, such as albumin. Removal of these charges in animals by in situ perfusion of heparitinase resulted in proteinuria. Until recently, the podocytes were considered to play a passive role in the process of glomerular filtration. This concept changed dramatically with the discovery that mutation of a protein located at the slit diaphragm, named nephrin, is the cause of the congenital nephrotic syndrome of the Finnish type (CNF). (1) The slit diaphragm is a thin membrane that bridges the filtration pores between adjacent podocytes and is anchored to the cell cytoskeleton by adaptor proteins such as podocin and CD2AP. Podocytes have been found to affect the structure and function of the glomerular basement membrane and to regulate the integrity and survival of glomerular endothelial cells. A number of acquired and inherited diseases now are attributed to defects of the slit diaphragm protein complex (Table 1).

Table 1. Genetic Forms of Nephrotic Syndrome

Gene/Protein Location Phenotype Inheritance

NPHS/nephrin NPHS2/podocin CD2AP/CD2AP TRPC6/TRPC6 WT1 ACTIN4 tRNALeu

Slit diaphragm Slit diaphragm Near slit diaphragm Podocyte Podocyte Foot process Podocyte

CNF FSGS FSGS FSGS FSGS FSGS FSGS

AR AR

AD AR AD

COQ2

Podocyte

FSGS

AD=autosomal dominant, AR=autosomal recessive, CNF=congenital nephrotic syndrome of the Finnish type, FSGS=focal segmental glomerulosclerosis

Edema
The classic theory is that edema formation results from a decrease in plasma oncotic pressure due to loss of serum albumin, causing water to extravasate into the interstitial space. Such movement reduces the intravascular volume, leading to renal hypoperfusion and stimulation of the reninangiotensin-aldosterone (RAA) system. Aldosterone increases reabsorption of sodium, particularly at the level of the distal segments of the nephron. This hypothesis, although attractive, is not supported fully by clinical findings. Plasma volume has been shown to be decreased only in some children who have minimal-change nephrotic syndrome (MCNS), particularly during the initial phase of a relapse. The decrease is absent in others and almost always absent in adults who have nephrotic syndrome. In addition, studies have failed to demonstrate elevation of RAA hormones, and increased sodium reabsorption was found to continue when albumin was infused or angiotensin-converting enzyme (ACE) inhibitors were administered to suppress renin production. An intrinsic renal abnormality leading to retention of sodium is postulated. Vasopressin excess also contributes to the retention of water.

Hyperlipidemia
Increased concentrations of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) result in elevated serum cholesterol and triglycerides concentrations. The high-density lipoprotein (HDL) fraction is normal. Consequently, the LDL/HDL cholesterol ratio is increased. Several mechanisms allegedly contribute to nephrotic syndrome dyslipidemia: overproduction due to low plasma albumin concentration and low oncotic pressure and impaired catabolism of apolipoprotein B and VLDL chylomicrons.

Epidemiology
The incidence of idiopathic nephrotic syndrome in the United States has been reported to be 2.7 new cases per 100,000 children per year, and the cumulative prevalence rate is 16 per 100,000 children. The ratio of males to females is approximately 2:1 during childhood, but the sex difference wanes by adolescence. There is an increased familial incidence, particularly among siblings. The mean age at onset has been reported to be 3.4 years in Asians and 4.2 years in

Europeans. Compared with other populations, African American and Hispanic children have a greater incidence of nephrotic syndrome, a more severe form of disease, and a poorer prognosis. (2)

Classification
Nephrotic syndrome can be primary (idiopathic) or secondary. Among children, 90% of cases are primary and the rest are secondary (Table 2). The advent of percutaneous renal biopsy in the 1950s and 1960s led to the identification of three histologic types of idiopathic nephrotic syndrome: MCNS, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). Whereas the incidence of nephrotic syndrome has remained stable for decades, the distribution of histologic types apparently has changed due to an increase in the incidence of FSGS.

Table 2. Secondary Causes of Nephrotic Syndrome

Infections

y y y y y

Hepatitis B, C Human immunodeficiency virus Malaria Toxoplasmosis Syphilis

Drugs

y y y y y

Gold Non-steroidal anti-inflammatory drugs Pamidronate Interferon Heroin

Lithium

Malignancies

y y

Lymphoma Leukemia

Miscellaneous

y y y y

Systemic lupus erythematosus Mesangioproliferative glomerulonephritis Immunoglobulin A nephropathy Diabetes mellitus

MCNS is the most common form of disease in children, accounting for approximately 85% of cases. On light microscopy, the glomeruli appear normal; electron microscopy allows detection of fusion of the epithelial foot processes, a finding common to all proteinuric states. FSGS accounts for 10% to 15% of all cases of nephrotic syndrome. Scar tissue develops initially in segments of some glomeruli, leading eventually to global, extensive glomerular sclerosis and tubular atrophy. MN is characterized histologically by diffuse thickening of the glomerular capillary walls and accounts for approximately 4% of nephrotic syndrome cases in children. Other glomerulopathies that can be associated with nephrotic syndrome are mesangioproliferative glomerulonephritis (MPGN), lupus nephritis, and immunoglobulin A (IgA) nephropathy. In the first two conditions, nephritic findings (hematuria, hypertension, decreased renal function) predominate; in the third, microscopic hematuria is interspersed with episodes of macroscopic hematuria (Table 3). In all of these diseases, the occurrence of nephrotic syndrome is associated with a guarded-to-poor prognosis.

Table 3. Differential Diagnosis of Nephrotic Syndrome

Physical Findings Renal Function Serum Albumin C3 Complement

Diagnosis

UPr/Cr

Other

MCNS FSGS

Edema Edema

Normal Normal or low Normal or low Normal or low Normal or low Low

Low Low

Normal Normal

>3.0 1.0 to 3.0 >3.0

Hyperlipidemia Hyperlipidemia Hematuria? Hyperlipidemia

CNS

Anasarca

Very low

Normal

MN

Edema

Very low

Normal

>3.0

Hematuria?

MPGN

Edema?

Low

Low

>3.0

Hematuria Hypertension Hematuria Hypertension Hematuria Hypertension? Hematuria Hypertension Hematuria

PSGN

Edema

Normal

Low

<1.0

HSP

Purpuric rash Arthritis Butterfly rash Arthritis Edema?

Low

Normal or low Normal or low Normal or low

Normal

1.0 to 3.0 1.0 to 3.0 1.0 to 3.0

LN

Low

Low

IgA

Normal or low

Normal

CNS=congenital nephrotic syndrome, Cr=creatinine, FSGS=focal-segmental glomerular sclerosis, HSP=Henoch-Schnlein purpura, LN=lupus nephritis, IgA=immunoglobulin A nephropathy, MCNS=minimal-change nephrotic syndrome, MN=membranous nephropathy, MPGN=membranoproliferative glomerulonephritis, PSGN=poststreptococcal glomerulonephritis, UPr=urine protein

Steroid-sensitive Nephrotic Syndrome

In the 1970s, a series of prospective, controlled, multicenter studies performed under the aegis of the International Study of Kidney Disease in Children (ISKDC) resulted in a better understanding of the relationships between the clinical course and histologic characteristics of various forms of nephrotic syndrome. Definitions of terms (Table 4), such as nephrotic level albuminuria and hypoalbuminemia, response to therapy, and indications for renal biopsy, were established. Various therapeutic regimens were tested, and prevention of relapse became the primary goal of therapy for patients who had MCNS. Care shifted from the hospital to the home, with emphasis on daily monitoring of the urine to detect proteinuria and initiate prednisone therapy early. Today, hospitalization should be necessary only when there is incapacitating edema (which is preventable) or infection.

Table 4. Definition of Terms

Responder: Protein-free urine for >3 days during initial treatment Infrequent relapser: Fewer than three relapses within 6 months of the initial response or fewer than four relapses within any 12-month period Frequent relapser: Three or more relapses within 6 months following initial response or four relapses within any 12-month period Steroid-dependent: Recurrence of proteinuria on alternate-day steroid therapy or within 2 weeks after cessation of treatment Steroid-resistant: Failure to respond to initial prednisone therapy or to 4 weeks of daily prednisone for relapse

A major conclusion of these studies was that the best prognostic indicator in children who have nephrotic syndrome is steroid responsiveness. Ninety-five percent of children who eventually respond to steroids do so within the first 4 weeks of treatment (Fig. 1). (3) As a result of this observation, children who fulfill the clinical criteria of MCNS (heavy proteinuria, hypoalbuminemia, and hyperlipidemia) are started on prednisone therapy without undergoing a renal biopsy. A renal biopsy at the time of diagnosis is indicated for patients who have macroscopic hematuria, severe hypertension, persistent renal insufficiency, or a low serum C3 complement value (Table 5). These signs may be indicative of MPGN, systemic lupus erythematosus (SLE), or postinfectious glomerulonephritis. A biopsy also should be performed if proteinuria persists at the end of 4 weeks of daily steroid therapy, when the chance of subsequent response is approximately 5%. It is worth noting that microscopic hematuria is present during the first few weeks of illness in as many as one third of children who have MCNS. Persistence or recurrence of hematuria often is a sign of impending steroid resistance.

Figure 1. Cumulative distribution of time to response for initial responders. Note that approximately 95% of the children who eventually respond do so by 4 weeks of daily prednisone therapy. Reprinted with permission from J Pediatr. 1981;98:561 564.

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Table 5. Indications for Renal Biopsy in Nephrotic Syndrome

At Time of Diagnosis:

Two or more of the following:

y y y y y

Age >10 years Persistent or gross hematuria Hypertension Renal insufficiency Low C3 complement values

Subsequently:

Persistent proteinuria (at the end of 4 weeks of daily prednisone therapy)

Clinical Features
The hallmark of nephrotic syndrome is heavy proteinuria, and the most common presenting sign is edema that becomes visible when fluid retention exceeds 3% to 5% of body weight.

Usually, edema appears initially in areas of low tissue resistance (ie, periorbital, scrotal, and labial regions). Ultimately, it becomes generalized and can be massive (anasarca). Edema is characteristically dependent. In the morning, it is periorbital, frequently misinterpreted as being caused by an allergy, and later in the day is localized primarily to the lower extremities. Anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common symptoms. A respiratory tract infection preceding the onset of the disease by a few days often is reported, but its pathogenetic role is doubtful. A history of allergy is reported by as many as 50% of children who have MCNS.

Laboratory Findings
Plasma protein concentration is reduced markedly, due primarily to the loss of albumin in the urine; the serum albumin concentration usually is below 2.5 g/dL (25 g/L). The low concentration of albumin stimulates synthesis of lipids by the liver, resulting in high concentrations of cholesterol, triglycerides, and lipoproteins. Serum sodium may be decreased, due, in part, to hyperlipidemia and, in part, to the retention of water caused by hypovolemia and increased secretion of antidiuretic hormone. The total calcium value may be low because of hypoalbuminemia, but the ionized calcium concentration is normal. The concentration of protein in the urine can be estimated by the dipstick method. The strips are impregnated with tetrabromophenol blue, which reacts preferentially to albumin. The color change allows the reader to distinguish between a protein concentration of approximately 30 mg/dL (300 g/L) (1+), 100 mg/dL (1,000 g/L) (2+), 300 mg/dL (3,000 g/L) (3+), and 1,000 mg/dL (10,000 g/L) (4+). False-positive results may occur when the urine is alkaline (pH >7) or contains blood, pus, mucus, semen, or vaginal secretions. By this method, severity of proteinuria may be underestimated when the urine is diluted or overestimated when the urine is concentrated. Patients who have a positive dipstick result should have a quantitative measurement of urinary protein excretion. Conventionally, this evaluation is performed on a 12- or 24-hour timed urine sample. An excretion of more than 50 mg/kg per day or 40 mg/m2 per hour is considered indicative of nephrotic syndrome. Accurate collections of urine are cumbersome, particularly in children, which explains the wide acceptance of the urine protein/creatinine ratio (UPr/Cr) as a reliable substitute. A strong correlation has been found between the UPr/Cr obtained in random specimens of urine and the 24-hour excretion of protein, corrected for body surface area (BSA). For children older than 2 years of age, a UPr/Cr of less than 0.2 is considered to be normal, a value of less than 0.5 is accepted as normal for children between 6 months and 2 years of age, and a value of more than 3.0 is consistent with nephrotic syndrome. Actual protein excretion (g/m2 per day) can be calculated by the formula: 0.63 x (UPr/Cr). Due to circadian variations, the accuracy of the measurements can be increased by using a first-voided morning specimen.

Cause
The cause of MCNS remains unknown. A decrease in immune responsiveness or disorders affecting T-lymphocyte number or function has been postulated. (4) Also, there are reports of increased expression of interleukin-2 (IL-2) receptors on T-lymphocytes; increases in IL-8, IL13, insulin-like growth factor-1, transforming growth factor-beta, and interferon-gamma;

abnormalities in nephrin expression or distribution; and the presence of a circulating "vascular permeability factor." One such factor may be an active isoform of hemopexin, a plasma protein that can increase glomerular permeability by enhancing protease activity. Recently, a group of investigators developed a humanized animal model of idiopathic nephrotic syndrome by injecting CD34+ stem cells or CD34 peripheral blood mononuclear cells from patients afflicted with MCNS or FSGS into immunocompromised mice. (5) Only the injection of CD34+ stem cells induced albuminuria and effacement of the podocyte foot processes. This finding suggests that the cells responsible for the pathogenesis of MCNS, as well as FSGS, are likely immature cells undergoing differentiation into T cells.

Treatment and Course of MCNS

Prednisone is the drug of choice and should be started as soon as a presumptive diagnosis of primary nephrotic syndrome has been made, and infection, including tuberculosis, has been ruled out (Fig. 2). The treatment proposed by the ISKDC consisted of 60 mg/m2 BSA per day, calculated on the basis of ideal weight for height (not to exceed 80 mg/day), divided in three doses. Daily administration was continued for 4 weeks, followed by 40 mg/m2 BSA per day, given as a single dose in the morning, on alternate days, for an additional 4 weeks. Of the patients afflicted with MCNS, about 90% responded to steroids, and of those, about 60% relapsed. Subsequent studies of small numbers of children have revealed that similar rates of initial response can be achieved with twice-daily or even once-daily administration of prednisone. There are exceptions to this rule, however. A minority of children who fail to respond to a twice-daily regimen respond when given the daily prednisone in three divided doses.

Figure 2. Treatment of minimal-change nephrotic syndrome.

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In a retrospective analysis of 389 children included in the ISKDC studies who had MCNS, 80% were in remission at 8 years. Seventy-five percent of initial responders who remained in remission during the first 6 months after initial response either continued to be in remission or relapsed rarely. In contrast, initial "relapsers," both frequent and infrequent, achieved a

nonrelapsing course only after an average of 3 years. (6) Absence of hematuria at presentation, remission within 7 to 9 days from the start of treatment, and age older than 4 years have been reported to be predictive of few relapses. (7) A prolonged initial treatment with prednisone (6 weeks of daily followed by 6 weeks of alternate-day administration) has been found to decrease the frequency of relapses. (8) In a Cochrane Review of the subject, the authors concluded that the higher the relapse rate with 2 months of initial treatment, the greater the effect of subsequent prolonged administration of prednisone. (9) Beginning with a relapse rate of 68% in children treated for 2 months, the relapse rate fell by an average of 7.5% with every 1-month increase in the length of treatment (approximately 30% at 6 months). The treatment regimen used currently by most nephrologists consists of 6 weeks of daily prednisone, given in two divided doses, followed by 6 weeks of alternate-day prednisone given as a single dose in the morning. A relapse is treated with prednisone, 60 mg/m2 BSA per day, given in two divided doses until the urine is protein-free for 3 consecutive days, followed by 40 mg/m2 BSA per day, on alternate days, given as a single dose in the morning for 6 additional weeks, when the first relapse occurs more than 3 months after the initial response and for 12 additional weeks when the first relapse occurs within 3 months after the initial response. Children who are frequent relapsers may benefit from an alkylating agent, such as cyclophosphamide (2 mg/kg per day), generally given for 8 to 12 weeks (Fig. 3). (10) A metaanalysis revealed that the relative risk of relapse in children who received this treatment is reduced by 60%. (11) The cumulative dose of cyclophosphamide should not exceed 200 mg/kg because of gonadal toxicity. Levamisole, chlorambucil, cyclosporine, and mycophenolate-mofetil also have been found to reduce the frequency of relapses. In a number of uncontrolled studies, cyclosporine has been reported to reduce the incidence of relapses in 75% to 90% of patients who have steroid-dependent nephrotic syndrome. The drug has serious adverse effects (hypertension, hyperkalemia, hypertrichosis, gingival hyperplasia). Renal insufficiency, initially transitory, can become permanent due to interstitial fibrosis. Often, proteinuria recurs when the treatment is discontinued. (12) Cyclosporine administration requires careful monitoring of serum concentrations and should be undertaken only by experienced physicians. The frequency of relapses usually decreases with time, becoming rare at or after puberty. Nonetheless, as many as 52% of patients have been reported to have at least one relapse during adulthood. Pregnancy apparently is a predisposing factor. As long as the patient responds to steroid therapy, the risk of progression toward renal insufficiency remains negligible.

Figure 3. Actuarial remission rate after treatment with cyclophosphamide in steroid-dependent nephrotic syndrome. Reprinted with permission from Arch Dis Child. 1987;62:1102 1106.

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Steroid-resistant Nephrotic Syndrome

Steroid-resistant nephrotic syndrome may occur at birth or during the first postnatal year, but is more common after the age of 2 years. This group of patients represents no more than 10% of the entire population of children who have nephrotic syndrome, but their prognosis usually is bleak. Their renal function deteriorates, and eventually they become candidates for dialysis or renal transplantation.

Congenital Nephrotic Syndrome (CNS)

The name implies the presence of proteinuria at birth, leading to clinical symptoms shortly thereafter. Yet, an arbitrary limit of 3 months after birth is being used to separate the congenital from the infantile form of nephrotic syndrome. The most common type of CNS is the Finnish type. CNF is an autosomal recessive disease, its incidence in Finland being 1 per 8,200 live births. However, patients who have CNF have been reported all over the world. In a subgroup of Mennonites from Lancaster, Pennsylvania, the incidence is 1 in 500, almost 20 times that encountered in Finland. In 1998, a gene (NPHS1) that codes for a protein (nephrin) located on podocytes was found to be mutated in CNF. (1) Soon thereafter, it became apparent that CNF also can be caused by mutations in NPHS2, which codes for another podocyte protein (podocin), and that mutations in NPHS1 sometimes may cause mild, rather than severe, nephrotic syndrome.

The "typical" form of CNF is characterized by massive proteinuria that starts during fetal life. Elevated concentrations of alpha-fetoprotein in the amniotic fluid and normal fetal ultrasonographic findings serve to make a presumptive diagnosis of CNF. A definitive diagnosis requires genetic analysis of placental tissue or amniotic cells. Most affected children are born preterm, weighing a mean of 2,500 g. The amniotic fluid often is meconium stained, and the placenta is large. Edema and abdominal distention become evident soon after birth. The serum albumin concentration usually is below 1.0 g/dL (10 g/L). Albuminuria is massive and related directly to the concentration of albumin in the blood. Many other proteins, such as IgG, transferrin, antithrombin III, lipoprotein lipase, vitamin D-binding protein, and thyroid-binding protein, also are lost in the urine. These losses lead to metabolic disturbances, including lipid abnormalities that can produce atherosclerotic changes as early as the first postnatal year. During the first months of extrauterine life, renal pathology is limited to slight-to-moderate mesangial cell proliferation by light microscopy and effacement of foot processes and thin glomerular basement membranes by electron microscopy. During the ensuing months, the renal tubules become dilated, mesangial hypercellularity increases, the Bowman capsule thickens, the interstitium becomes fibrotic, and glomeruli sclerose. Electron microscopy reveals the disappearance of the slit diaphragms. Initial treatment aims to sustain a good nutritional state, control edema, and prevent complications such as infections and vascular thrombosis. Unilateral or bilateral nephrectomy (followed by peritoneal dialysis) often is required to curtail the massive loss of protein. Successful treatment results in satisfactory growth and development and the chance for eventual kidney transplantation. In some patients, the nephrotic syndrome recurs, due to the development of antinephrin antibodies against the foreign antigens in the graft. Rare forms of CNS are those associated with diffuse mesangial sclerosis, specifically, the Denys-Drash, Galloway-Mowat, and Pierson syndromes. CNS also can be associated with infections such as syphilis, toxoplasmosis, cytomegalovirus, congenital rubella, and hepatitis B.

Focal-Segmental Glomerular Sclerosis

FSGS was identified half a century ago as a postmortem finding in 20 children who had nephrotic syndrome. The significance of this observation became apparent years later when the advent of renal biopsy allowed investigators to associate FSGS with steroid resistance. Initially, the disease consists of hyalinization or sclerosis of some glomeruli (focal) that involves only part of the glomerular tuft (segmental). The lesion appears in the juxtamedullary nephrons and extends to the cortex, resulting in progressive loss of renal function. The location of the lesion within the glomerulus may have prognostic significance. Peripheral lesions opposite the origin of the proximal tubule ("tip lesions") appear to have a better prognosis than do hilar lesions, particularly those characterized by capillary collapse (collapsing glomerulopathy) that occur in immunocompromised patients. FSGS is fourfold more common and more aggressive in African Americans than in Caucasians or Asians. (2) As in MCNS, the major signs of disease are edema and albuminuria. Hematuria is more frequent in FSGS than in MCNS, but the overlap diminishes its value as an element of diagnosis. Results of blood chemistries are indistinguishable from those in MCNS. The age at onset also is similar in the two conditions. Because of these similarities, FSGS cannot be diagnosed at presentation,

and children commonly are started on standard prednisone therapy. Lack of response at 4 weeks prompts a renal biopsy, which often reveals the specific histologic lesion of FSGS. The lesion may be missed, however, if the tissue sample contains a small number of glomeruli or does not include juxtamedullary glomeruli, which are affected first. In addition, about 20% of children who have FSGS respond to steroid therapy and do not undergo a renal biopsy. The relationship between MCNS and FSGS remains controversial. Some believe that these are two distinct entities; others believe that FSGS is a severe form of MCNS. The latter opinion is supported by the observation that some children who initially respond to steroids become steroid-resistant, with a renal biopsy revealing focal-segmental lesions. FSGS is a heterogeneous condition, the histologic expression of a variety of diseases, including heroin-associated nephropathy, acquired immunodeficiency syndrome, multiple myeloma, Alport syndrome, reflux nephropathy, diabetic nephropathy, and obesity. Heterogeneity also applies to "idiopathic" FSGS. Some patients respond to steroid therapy; most do not. In some patients, disease progression is slow, reaching end stage in about 10 years; in others, it reaches that point in about 2 years. Moreover, in this latter group, the disease has a high likelihood of recurring in the transplanted kidney, probably due to the presence of a blood-circulating factor. Despite sustained efforts, no factor has been isolated. The heterogeneity of FSGS has been amplified by the recognition that some cases of FSGS are due to genetic abnormalities. GENETIC FORMS OF FSGS. In recent years, impressive progress has been made in describing the molecular structure of the podocytes and the slit diaphragms that link them. Specifically, a number of proteins have been identified that work in concert to control the permeability of the glomerular membrane. Mutations in the genes that encode these proteins are associated with nephrotic syndrome and focal-segmental glomerular lesions. The impetus for this exploding field of research has been the discovery that lack of nephrin, a protein located at the slit-diaphragm, accounts for CNF. Table 1 summarizes the current state of knowledge. Genetic forms account for only a small percentage of FSGS. Genetic diagnosis, although commercially available, is expensive, is performed in only a few laboratories, and is justified only in isolated circumstances. Despite the impressive progress made in identifying genetic types of FSGS, the cause of the disease still has not been identified in most patients. It has been proposed that genetic variants in two or more podocyte genes that alone do not produce disease may interact to cause FSGS. This concept, although enticing, is yet to be proved. TREATMENT. The therapy for FSGS, regardless of variety, has been and continues to be a frustrating endeavor. It is reasonable to assert that no agent that could conceivably be of benefit to these patients has escaped clinical experimentation. Alas, no definitive evidence has emerged that any of these drugs is effective, although a few facts have been learned from these trials. Pulse methylprednisolone, hailed as being salutary for most children who have steroid-resistant nephrotic syndrome, has proven to be of minimal benefit. Alkylating agents such as cyclophosphamide also have been shown to have little therapeutic effect, but they continue to be used. In uncontrolled trials, cyclosporine has been reported to induce remission in 25% to 50% of patients who have steroid-resistant FSGS, but patients relapse promptly when the drug is

discontinued and develop serious adverse effects if the treatment is sustained for long periods. A multicenter, prospective, controlled, randomized trial, sponsored by the National Institutes of Health, is in progress. Patients younger than 40 years of age who have biopsy-proven FSGS are assigned to treatment with either pulse steroids plus mycophenolate-mofetil or to cyclosporine. The results of this therapeutic trial will not be known for several years. Recurrence of disease in transplanted kidneys is a major problem; it has been reported to occur in as many as 50% of children who have FSGS. Being older than 6 years of age at onset and progression to end-stage renal disease in fewer than 3 years are considered risk factors. For most affected children, proteinuria develops within hours after transplantation, although it may start as late as 3 months later. High-dose cyclosporine, plasmapheresis, or a combination of both is associated with partial or total remission in a minority of cases. The outcome of the treatment is unpredictable.

Membranous Nephropathy
MN was identified initially postmortem as a diffuse, irregular thickening of the glomerular basement membranes in the absence of any inflammatory changes. With the introduction of acidsilver-methenamine stain and electron microscopy, it became evident that the distortion of the basement membranes is due to the presence of blobs of silver-negative, electron-dense deposits. The deposits are located exclusively in the subepithelial area and are flanked by silver-positive tissue, giving the appearance of spikes. MN is very rare in children and can manifest at any age. It presents as either asymptomatic proteinuria or nephrotic syndrome. Microscopic hematuria and hypertension are rare. No clinical or laboratory findings allow a positive identification; the diagnosis rests ultimately on the specific histologic findings. The disease can be either primary or due to a variety of conditions, including infections (hepatitis B, malaria, syphilis), autoimmune diseases (SLE, Crohn disease), drugs (penicillamine), tumors (Wilms, neuroblastoma), and other disorders. The pathogenesis of MN has not been determined precisely, although evidence points toward binding of an antibody to an in situ glomerular basement membrane antigen. In several cases of neonatal MN, a podocyte antigen, neutralendopeptidase, (13) served as the pathogen. Antibodies to this protein originated in pregnant women who lacked the neutral endopeptidase epitop due to a mutational deletion. No similar findings have been reported in older patients. The course of the disease is variable. Spontaneous remissions occur in 25% to 50% of children, whereas 25% to 30% develop renal insufficiency. Treatment with steroids and immunosuppressive drugs is common, although the results have been discouraging.

Complications of Nephrotic Syndrome

Some patients exhibit signs of acute renal failure (ie, reduction in glomerular filtration rate and oliguria). These signs usually are reversed when the intravascular volume is expanded by infusion of salt-poor human albumin and diuresis is induced by furosemide or other diuretic drugs. Rarely, acute renal failure can be caused by bilateral renal vein thrombosis. The diagnosis is made by ultrasonography. Thromboembolic complications also can affect the lungs, the brain, and the peripheral vessels. The overall incidence of thromboembolic events is about 3%. Such events are caused by loss of antithrombin III and protein S in the urine as well as an increase in fibrinogen concentration, leading to a hypercoagulable state. The antiphospholipid syndrome also has been incriminated as a cause of thromboembolic complications in some patients who have nephrotic syndrome. This disorder is characterized by persistently elevated concentrations of antibodies directed against membrane anionic phospholipids (eg, anticardiolipin antibody, antiphosphatidylserine) or their associated plasma proteins, predominantly beta-2 glycoprotein I (apolipoprotein H). A circulating anticoagulant also may be present. The mechanism of thrombosis in this syndrome has not yet been defined. Emerging evidence from murine models suggests that antiphospholipid-mediated complement activation may be the primary event. Irrespective of cause or pathogenesis, the first line of treatment is low-molecular weight heparin. If the thrombosis extends, thrombolytic drugs, such as tissue plasminogen activator, followed by warfarin should be considered. Warfarin should be discontinued as soon as the nephrotic syndrome resolves. Infections are frequent and serious complications of nephrotic syndrome. Urine loss of factor B (which contributes to opsonization of bacteria), a decrease in IgG synthesis, and impaired T-cell function contribute to the susceptibility to infection. The most common infection is peritonitis, which used to be due primarily to Streptococcus pneumoniae. Vaccination has reduced infections with S pneumoniae substantially and increased the relative frequency of gram-negative organisms. There also has been an increase in penicillin-resistant S pneumoniae. A high degree of suspicion must be maintained when caring for patients who have ascites. Fever and chills occur in as many as 80% of patients who have peritonitis. Abdominal pain or discomfort is found in as many as 70% of patients and often is accompanied by ileus or diarrhea. Peritoneal fluid must be analyzed for any patient in whom peritonitis is considered. An ascitic fluid neutrophil count of more than 500 cells/mcL is the single best predictor of infection, with a sensitivity of 86% and specificity of 98%. Lowering the ascitic fluid neutrophil count to more than 250 cells/mcL results in an increased sensitivity (93%) but a lower specificity (94%). Notably, steroids do not mask the signs and symptoms of peritonitis. (14) A combination of an aminoglycoside and ampicillin provides empiric coverage of more than 90% of cases of peritonitis caused by gram-negative aerobes or gram-positive cocci. The thirdgeneration cephalosporin cefotaxime is as efficacious and is not nephrotoxic but does not treat enterococci. Subsequently, antibiotic therapy should be guided by the results of ascitic fluid cultures and sensitivities. Cellulitis, meningitis, and pneumonitis also may occur in patients who have nephrotic syndrome. Anasarca and pulmonary edema are preventable complications of nephrotic

syndrome and reflect massive retention of sodium and water, consequent to the loss of albumin in the urine and its leakage into the extravascular compartment. Diuretic drugs and salt-poor albumin infusions are only partially effective. The primary goal of therapy should be diminution of protein loss. Stunting of growth, a complication of prolonged steroid administration, is well recognized. Thirty-four patients who had a frequently relapsing course and a mean age of 8.0 years at onset were found to have a mean height 2.5 cm below the target height, when evaluated 13 years later. (15) Growth rate should be monitored closely in frequent relapsers or steroiddependent children, and an alternative therapy (cyclophosphamide, mycophenolate-mofetil, cyclosporine) should be considered as soon as the growth curve plateaus. Reduced mineral bone density, a recently recognized complication of MCNS, is due to the prolonged administration of steroids and, possibly, to vitamin D deficiency. In a randomized, controlled study of 40 children who had MCNS, daily administration of 400 IU of vitamin D and 1 g of calcium diminished, but did not end, the decrease in bone mineral density.

Ancillary Therapy of Nephrotic Syndrome

Edema in nephrotic syndrome requires treatment only when it is associated with severe ascites, peritonitis, respiratory distress, or heart failure. The first line of therapy is diuretic drugs. Commonly used are loop diuretics (furosemide, ethacrynic acid), which block reabsorption of sodium in the loop of Henle, and thiazide diuretics (hydrochlorothiazide), which block reabsorption of sodium in the distal tubule. For patients who fail to respond to diuretics, concomitant administration of salt-poor albumin (0.5 to 1 g/kg body weight up to 25 g, in a 25% solution administered intravenously over 30 to 60 minutes) may induce diuresis. This treatment appears to be particularly effective in children who have very low serum albumin concentrations (<1.5 g/dL [15 g/L]) and in those who have clinical signs of intravascular volume contraction. Aggressive administration of diuretic drugs may induce hypovolemia and secondary renal failure, thromboembolism, or electrolyte disturbances. Hypovolemia can be prevented or treated by administration of salt-poor albumin. Approximately 20 years ago, it was noticed that angiotensin II inhibitors diminished proteinuria, independently of their effect on blood pressure and glomerular filtration rate. As a result, ACE inhibitors and angiotensin receptor blockers, given alone or in combination, have become important components of the antiproteinuric therapy. Twelve weeks of treatment were reported to reduce proteinuria by about 1 g/24 hours. Recently, it has been found that ACE inhibitors prevent loss of podocytes and preserve nephrin expression; they also may slow progression of renal disease. A protective effect on renal function also was seen with angiotensin receptor blockers.

Hyperlipidemia is one of the primary features of the nephrotic syndrome that may persist well beyond remission. Several studies have revealed premature coronary atherosclerosis and increased incidence of myocardial infarction in patients who have nephrotic syndrome. Hyperlipidemia also may contribute to progression of renal disease. These observations have prompted many physicians to use statins in patients who have had persistent hyperlipidemia. Statins also have been found to slow the progression of chronic renal disease, albeit to a trivial extent. These effects may be due to improvement of endothelial function, systemic or intrarenal anti-inflammatory actions, amelioration of oxidative stress, and inhibition of macrophage recruitment and function. Vaccination of children who have nephrotic syndrome has been found to be generally effective. Antibody responses to pneumococcal, influenza, varicella, and hepatitis vaccines have been adequate, and the adverse effects have not been found to be different from those reported in the general population. However, pneumococcal and hepatitis antibody concentrations were reported to decline faster in children who had nephrotic syndrome than in the general population. The Committee on Infectious Diseases of the American Academy of Pediatrics recommends vaccination with the conjugated pneumococcal vaccine. The state of immunity to varicella should be assessed for patients who have not been vaccinated, and treatment with acyclovir should be started as soon as an at-risk patient is exposed to the virus. Retention of sodium is paramount to water retention and the development of edema. Thus, a lowsodium diet is warranted, although fluid intake does not need to be restricted as long as sodium intake is limited. Prolonged loss of proteins in the urine may compromise the nutritional status of the children and must be prevented by an adequate diet and, when necessary, the addition of high-protein products. Vitamin D and calcium supplementation also are advisable.

Summary and Conclusions

Nephrotic syndrome encompasses a diverse group of conditions that share the common denominator of massive loss of protein in the urine. Progress in identifying the cause and pathogenesis of each of these conditions has been slow. The current identification of various forms of nephrotic syndrome is based primarily on histologic findings, which are not always pathognomonic. Treatment has and still depends on drugs that lack specificity and have numerous, often serious, adverse effects. The following conclusions are worth remembering:

y y y y

y y

Most children who have nephrotic syndrome have MCNS, which is responsive to prednisone therapy. Response to steroid therapy is the best prognostic indicator. Most ( 60%) of children who have MCNS relapse, some of them frequently. Cyclophosphamide and cyclosporine decrease the incidence of relapses. Compelling evidence suggests that renal biopsy should be performed at onset only in children who, in addition to proteinuria, have macroscopic hematuria, hypertension, persistent renal insufficiency, or low C3 complement values. Another indication is failure to respond to steroid therapy (proteinuria still present at the end of 4 weeks of daily prednisone therapy). Most children who have nephrotic syndrome and fail to respond to steroids have FSGS. Most alkylating agents are ineffective. Cyclosporine has been reported, in uncontrolled studies, to induce remission in 20% to 50% of patients who failed to respond to steroids. The drug requires monitoring of serum values and has serious adverse effects. Proteinuria recurs in most patients as soon as the treatment is discontinued. Several genetic forms of FSGS, due to mutations that encode proteins at the level of the podocytes, have been identified. They account for a small minority of patients who have nephrotic syndrome, and none responds to treatment. Dialysis and transplantation have improved the long-term prognosis of patients who reach endstage renal disease, even infants who have CNS. Some glomerulopathies, such as FSGS, MPGN, and possibly CNS, may recur in renal transplants. Treatment with immunosuppressive agents and plasmapheresis is effective in about 30% of such patients.

Footnotes

Author Disclosure Drs Gordillo and Spitzer have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.