Proteinuria

19  Proteinuria Raji Sreedharan

Proteinuria can be detected by various means, and the most common is the dipstick test, a calorimetric assay that spots only albumin and not low-molecular-weight proteins. In addition, alkaline urine and the presence of contrast media in urine can lead to false dipstick positivity. Though 24-hour urine collection is the gold standard to quantify the proteinuria, spot urine protein-to-creatinine ratio can be used for initial confirmation after a positive screen with dipstick or to trend proteinuria (Table 19.1). A ratio below 0.2 protein mg/ creatinine mg is considered normal in children older than 2 years of age and a ratio less than 0.5  mg/mg is considered normal in younger children between 6 months and 2 years of age. In timed collection, protein excretion greater than 100  mg/m2 in 24 hours or 4  mg/m2/hour is considered abnormal, and over 40  mg/m2/hr is considered nephrotic range. Qualitative analysis of protein in urine by immunonephelometry helps distinguish glomerular from tubular proteinuria. Proteinuria in children can be transient, orthostatic, or persistent. Transient and orthostatic proteinuria are benign conditions and require no treatment. Several factors including fever, stress, hypovolemia, exercise, and seizures can lead to transient proteinuria (Table 19.2). Orthostatic proteinuria is defined as increased protein in urine only when upright. In this condition, absence of proteinuria when horizontal and resting can be confirmed by documenting absence of protein in a 1st morning void. Split day/night urine collection is the gold standard to diagnose orthostatic proteinuria, which is a common benign cause of proteinuria, especially in adolescents. Persistent proteinuria requires meticulous evaluation to rule out renal pathology. Evaluation of proteinuria begins with a detailed history and physical examination. Pertinent histories that help distinguish pathologic from benign proteinuria include history of respiratory symptoms concurrent with or preceding the proteinuria, presence of red urine, edema, positive family history of kidney disease, or hearing loss. Findings of edema and hypertension suggest pathologic proteinuria. Repeating urine dipstick in asymptomatic children with a negative history can eliminate unnecessary further testing for transient proteinuria. If still positive, spot urine protein-to-creatinine ratio can help confirm the presence of proteinuria. If confirmed, a 1st morning void protein-to-creatinine ratio can then identify orthostatic proteinuria. Once the benign conditions are ruled out in asymptomatic children, further testing is similar to that of symptomatic children and these children should be referred to nephrologists. This more detailed evaluation begins with 24-hour urine collection where possible, complete urinalysis, and sediment evaluation looking for glomerular or other parenchymal pathology that could be causing the proteinuria (Fig. 19.1). Positive leukocyte esterase, nitrite, and presence of pyuria or bacteriuria suggest a urinary tract infection. If not resolved with treatment of infection, proteinuria will need further evaluation. Low molecular proteins, such as β2-microglobulin, α1microglobulin, lysozyme, and retinol-binding protein are found in tubular proteinuria as is seen in Fanconi syndrome or Dent disease.

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Red blood cell (RBC) cast is pathognomonic of glomerulonephritis. Serum chemistry including creatinine, BUN, electrolytes, albumin, and cholesterol will also help separate proteinuria secondary to glomerulonephritis or nephrotic syndrome. Lupus antibody studies, streptococcal infection, and complement C3 and C4 levels along with viral studies can help delineate the various causes of glomerulonephritis and nephrotic syndrome. Renal ultrasound should be considered to rule out any gross parenchymal etiology for the proteinuria, such as dysplastic kidney and cystic kidney disease. Renal biopsy may be indicated if there is evidence for worsening of proteinuria, hypoalbuminemia, deteriorating renal function, or a poor response to the initial therapy. Differential diagnoses for proteinuria are extensive, as described in Table 19.2. The initial evaluation of a patient with proteinuria is presented in Table 19.3. Indications for a referral to a pediatric nephrologist are described in Table 19.4. If there is obvious edema with proteinuria, the diagnostic evaluation noted in Table 19.3 advances directly to the 2nd phase and, if necessary, to the 3rd phase. The combination of proteinuria, hypoalbuminemia, edema, and hyperlipidemia are the defining features of nephrotic syndrome. Nephrotic syndrome may be a result of many primary etiologic factors, with varying renal pathologic processes and long-term consequences. Proteinuria that causes edema is always clinically significant, although not all edema is secondary to proteinuria (Table 19.5). All children with nephrotic syndrome invariably have “nephrotic-range” proteinuria, necessitating detailed evaluation, and most require treatment. In rare cases, a child with asymptomatic proteinuria has nephrotic-range proteinuria. If there is concomitant hypoalbuminemia and hyperlipidemia, the work-up proceeds as if the child presented with nephrotic syndrome, despite the absence of edema. Even without hypoalbuminemia and hyperlipidemia, nephrotic-range proteinuria is less likely to be benign than is less marked asymptomatic proteinuria.

NEPHROTIC SYNDROME IN YOUNG CHILDREN Differential Diagnosis Three diseases constitute all cases of isolated nephrotic syndrome: minimal change disease (the most common); focal segmental sclerosis (also called focal glomerular sclerosis); and membranous glomerulopathy. These classifications are based on pathologic findings. Thus these presentations could be primary or secondary due to other causes. In addition, nephrotic syndrome can be present along with glomerulonephritis (GN), such as postinfectious GN, IgA GN, or membranoproliferative GN. Systemic diseases also cause childhood nephrotic syndrome, accounting for 10% of cases. The three foremost considerations include SLE, anaphylactoid purpura (Henoch-Schönlein purpura), and hemolytic uremic syndrome. These diseases have extrarenal manifestations in addition to the proteinuria and must be considered in any child who presents with systemic illness and significant

CHAPTER 19  Proteinuria (See Nelson Textbook of Pediatrics, p. 2517.) (See Nelson Textbook of Pediatrics, p. 2571.)

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TABLE 19.1  Quantification of Proteinuria in Children Method

Abnormal Proteinuria

Precautions

Urine dipstick

1+ or more in a concentrated urine specimen (specific gravity ≥1.020) 1+ or more >0.02 g/mmol or >0.2 mg/mg in children >2 yr >0.06 g/mmol or >0.6 mg/mg in children 6 mo-2 yr Nephrotic range: >0.2 g/mmol or >2 mg/mg >4 mg/m2/hr or >150 mg/1.73 m2/24 hr Nephrotic range: >40 mg/m2/hr or >3 g/1.73 m2/24 hr

False positive if urine pH >8.0 or specific gravity >1.025 or tested within 24 hr of a radiocontrast study False-positive with iodinated radiocontrast agents Protein excretion varies with child’s age

Sulfosalicylic acid test Urine protein/creatinine ratio (Up /UCr ratio) in spot urine

Timed urine protein excretion rate

In an accurately collected 24-hr urine specimen, urine creatinine should be in the range of 0.13-0.20 mmol/kg or 16-24 mg/kg ideal body weight for females, and 0.18-0.23 mmol/kg or 21-27 mg/kg ideal body weight for males

From Yap HK, Lau PYW. Hematuria and proteinuria. In: Geary DF, Schaefer F, eds. Comprehensive Pediatric Nephrology. Philadelphia: Elsevier; 2008:185, Table 10.3.

TABLE 19.2  Causes of Proteinuria Transient Proteinuria Fever Exercise Dehydration Cold exposure Congestive heart failure Seizure Stress Orthostatic (Postural) Proteinuria Glomerular Diseases Characterized by Isolated Proteinuria Idiopathic (minimal change) nephrotic syndrome Focal segmental glomerulosclerosis Mesangial proliferative glomerulonephritis Membranous nephropathy Membranoproliferative glomerulonephritis Amyloidosis Diabetic nephropathy Sickle cell nephropathy

Tubular Diseases Cystinosis Wilson disease Lowe syndrome Dent disease (X-linked recessive nephrolithiasis) Galactosemia Tubulointerstitial nephritis Acute tubular necrosis Renal dysplasia Polycystic kidney disease Reflux nephropathy Drugs (e.g., penicillamine, lithium, NSAID) Heavy metals (e.g., lead, gold, mercury)

Glomerular Diseases with Proteinuria as a Prominent Feature Acute postinfectious glomerulonephritis (e.g., streptococcal, endocarditis, hepatitis B or C virus, and HIV) Immunoglobulin A nephropathy Henoch-Schönlein purpura nephritis Lupus nephritis Serum sickness Alport syndrome Vasculitic disorders Reflux nephropathy NSAID, nonsteroidal antiinflammatory drug. From Pais P, Avner ED. Fixed proteinuria. In: Kliegman RM, Stanton BF, St. Geme JW III, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016:2520, Table 526.1.

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Section 4  Genitourinary Disorders Trace

Urine dipstick protein ≥1+

Repeat urine dipstick protein

≥1+

Negative or trace

Obtain 1st morning urine for protein/creatinine ratio and urinalysis with microscopic examination

Repeat urine dipstick 6 mo to 1 yr later Consider discharge if urine dipstick protein negative or trace

Urine protein/creatinine ratio ≤0.02 g/mmol (0.2 mg/mg) and no microscopic hematuria

Urine protein/creatinine ratio >0.02 g/mmol (0.2 mg/mg) ± microscopic hematuria

FIGURE 19.1  Algorithm for investigating proteinuria. ANA, antinuclear antibody; ANCA, antinuclear cytoplasmic antibody; anti-dsDNA, anti– double-stranded DNA; BP, blood pressure; IgA, immunoglobulin A. (From Yap HK, Lau PYW. Hematuria and proteinuria. In: Geary DF, Scharfer F, eds. Comprehensive Pediatric Nephrology. Philadelphia: Elsevier; 2008:190.)

Possibilities 1. Urine dipstick false positive 24-hr urinary total protein

2.

≤0.3 g/1.73 m2/day >0.3 g/1.73 m

Repeat urine tests 6 mo later

2/day

Further evaluation History (drugs, family history) Physical examination (including BP) Investigations: • Serum urea, creatinine, electrolytes • Serum total cholesterol • Serum albumin • Serum complements C3 and C4 • Serum IgA • ANA or anti-dsDNA antibodies, ANCA (if indicated) • Hepatitis B and C, HIV serology (if indicated) • Renal ultrasound • Consider renal biopsy (see section on indications for renal biopsy)

proteinuria. Hereditary forms of nephrotic syndrome are a genetically heterogeneous group of disorders representing a spectrum of hereditary renal diseases. There are 13 subtypes of hereditary nephrotic syndrome associated with 35 genes. Several of the more common disorders along with other causes of nephrotic syndrome are noted in Tables 19.6 and 19.7.

MINIMAL CHANGE DISEASE Most cases of nephrotic syndrome in children are caused by minimal change nephrotic syndrome, defined as normal histologic features of the kidney by light microscopy and immune stains. Preschool-aged children constitute the age group in which minimal change nephrotic syndrome is most common. Patients often present with asymptomatic edema, which may manifest as swollen or puffy eyes upon awakening in the morning; increasing abdominal girth (increased waist or belt size) from ascites; pedal or leg edema, which causes difficulty in putting on their regular-sized shoes, especially after being upright during the

Transient proteinuria

3. Postural/orthostatic proteinuria Consider: • 24-hr urinary total protein • Renal Doppler ultrasound (if nutcracker syndrome is suspected)

daytime; or swelling in other sites, such as the scrotum, penis, vulva, and scalp. Tense edema or ascites is occasionally painful. Minimal change nephrotic syndrome is slightly more common in boys than in girls. The hallmark of this disease is total clearing of the proteinuria with oral prednisone therapy. A common misconception is that neither hematuria nor hypertension is present in children with minimal change disease. Microscopic hematuria and hypertension are present in up to 20% of children who have minimal change disease. The blood urea nitrogen (BUN) or serum creatinine level may also be elevated in up to 30% of the cases, usually from prerenal causes. Serum complement studies, specifically C3, are invariably normal. Older age, hematuria, hypertension, and azotemia may occur with minimal change nephrotic syndrome, but the combination suggests another disease.

Diagnosis Studies that would help confirm that a patient with nephrotic syndrome has minimal change disease include urinalysis, serum chemistry

CHAPTER 19  Proteinuria TABLE 19.3  Work-up of a Child

TABLE 19.5  Causes of Edema

Pediatrician’s Work-up: Phase I Early morning urinalysis to include examination of the sediment Ambulatory and recumbent urinalyses for dipstick protein testing

Kidney Diseases Acute glomerulonephritis Nephrotic syndrome Acute renal failure Chronic renal failure

with Proteinuria

Pediatrician’s Work-up: Phase II Blood electrolytes, BUN, creatinine, serum proteins, cholesterol ASLO titer, C3 complement, ANA Timed 12-hr urine collections, recumbent and ambulatory Renal ultrasonography, IVP, voiding cystourethrography Pediatric Nephrologist’s Work-up: Phase III Renal biopsy Management of established renal disease ANA, antinuclear antibody; ASLO, antistreptolysin O; BUN, blood urea nitrogen; IVP, intravenous pyelography. Modified from Norman ME. An office approach to hematuria and proteinuria. Pediatr Clin North Am. 1987;34:545-562.

TABLE 19.4  When to Refer the Child with

Proteinuria to a Nephrologist

Persistent nonorthostatic proteinuria A family history of glomerulonephritis, chronic renal failure, or kidney transplantation Systemic complaints such as fever, arthritis or arthralgias, and rash Hypertension, edema, cutaneous vasculitis, or purpura Coexistent hematuria with or without cellular casts in the spun sediment Elevated blood urea nitrogen (BUN) and creatinine levels or unexplained electrolyte abnormalities Increased parental anxiety Modified from Norman ME. An office approach to hematuria and proteinuria. Pediatr Clin North Am. 1987;34:545-561, Table 24.9.

including BUN, creatinine, albumin, and cholesterol levels, along with complements and lupus antibody titers. The urinalysis would be expected to show 3+ to 4+ protein, which is correlated with a urine concentration of 300-2000 mg/dL. The urine may also occasionally yield positive results for blood. Microscopic examination of the urine sediment often shows oval fat bodies and/or refractile granular casts, which are seen when there is significant lipiduria. Red blood cells might also be present, but it is unusual to see red blood cell casts. Their presence would suggest a diagnosis of poststreptococcal glomerulonephritis or other causes of nephritis (see Chapter 20). The complement C3 and C4 levels are normal in minimal change disease and are depressed in some other causes of nephritis (see Chapter 20). The serum cholesterol values are elevated in minimal change nephrotic syndrome and are usually higher than 250 mg/dL; levels in the range of 500-600 mg/dL may occur. The serum albumin concentration is invariably less than 2.5 and often less than 2.0 g/dL. A renal biopsy is not immediately indicated because most patients (>90%) with minimal change disease respond to prednisone, a response that is considered diagnostic.

Treatment With a presumptive diagnosis of minimal change nephrotic syndrome, it is recommended in the Kidney Disease: Improving Global Outcomes

315

Heart Failure Liver Failure Nutritional and Gastrointestinal Disorders Protein-calorie malnutrition Protein-losing enteropathy Nutritional edema (especially on refeeding) Endocrine Disorders Hypothyroidism Mineralocorticoid excess Miscellaneous Hydrops fetalis Venocaval obstruction Capillary leak syndrome (systemic inflammatory response syndrome) Turner syndrome (lymphedema) Allergic reaction (periorbital edema)

(KDIGO) guidelines that patients be placed on a therapeutic course of prednisone, 60 mg/m2/day or 2 mg/kg/day, up to a maximum of 60 mg for 4-6 weeks, followed by a dose of 40 mg/m2 or 1.5 mg/kg (maximum 40 mg) given every other day for another 6 weeks. In most patients, there is total resolution of proteinuria within 10-21 days of initiating therapy. Patients who do not respond to prednisone therapy should be considered candidates for a renal biopsy to guide further therapy. Total clearing of proteinuria in response to prednisone is an excellent prognostic sign. Very few patients progress to renal failure, although many patients (~80%) who initially respond to prednisone therapy with total clearing of proteinuria may have relapses and require intermittent prednisone therapy for many years. Approximately 18% of patients treated with prednisone for minimal change nephrotic syndrome respond to therapy and never experience a relapse. Patients with recurrent nephrotic syndrome are subgrouped into those who experience frequent and infrequent relapses. A patient with infrequent relapse has fewer than 2 relapses in any 6-month period; a person with frequent relapse has 2 or more relapses within 6 months. Prednisone should be reinitiated at a dose of 60 mg/m2/day or 2 mg/ kg/day until a maximum of 60 mg/day and continued until the urine test results are negative for protein for 3 consecutive days. After that, alternate-day prednisone is given at a dose of 40 mg/m2 or 1.5 mg/kg (maximum 40 mg) in the morning for another 4 weeks and then discontinued altogether. Relapses are frequent during the influenza virus seasons; any minor upper respiratory infection may trigger a relapse of nephrotic syndrome. Patients who suffer infrequent relapses may be treated with prednisone alone. Patients with frequently relapsing nephrotic syndrome may be steroid dependent and require constant daily prednisone therapy to maintain a remission. Because constant daily prednisone has significant untoward side effects (growth failure, cushingoid facies, osteoporosis, cataracts, opportunistic infections, hypertension, and glucose intolerance), other therapies need to be considered. A renal biopsy is recommended prior to initiating alternative agents to confirm the

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TABLE 19.6  Causes of Childhood Nephrotic Syndrome Idiopathic Nephrotic Syndrome Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Glomerulonephritis associated with nephrotic syndrome–membranoproliferative glomerulonephritis, crescentic glomerulonephritis, immunoglobulin A nephropathy Genetic Disorders Associated with Proteinuria or Nephrotic Syndrome Over 100 genetic syndromic disorders are associated with proteinuria, the more common disorders are listed below. Nephrotic Syndrome (Typical) Finnish-type congenital nephrotic syndrome (absence of nephrin) Focal segmental glomerulosclerosis (mutations in nephrin, podocin, MYO1E, α-actinin-4, TRPC6) Diffuse mesangial sclerosis (mutations in laminin β2 chain) Denys-Drash syndrome (mutations in WT1 transcription factor) Congenital nephrotic syndrome with lung and skin involvement (integrin α3 mutation) Mitochondrial disorders (rare association, steroid resistance, MELAS) Proteinuria With or Without Nephrotic Syndrome Nail-patella syndrome (mutation in LMX1B transcription factor) Alport syndrome (mutation in collagen 4 biosynthesis genes) Multisystem Syndromes With or Without Nephrotic Syndrome Galloway-Mowat syndrome Charcot-Marie-Tooth disease Jeune syndrome Cockayne syndrome Bardet Biedl syndrome Metabolic Disorders With or Without Nephrotic Syndrome Alagille syndrome α1-Antitrypsin deficiency Fabry disease Glutaric acidemia Glycogen storage disease Hurler syndrome Partial lipodystrophy Mitochondrial cytopathies Sickle cell disease

Secondary Causes of Nephrotic Syndrome Infections Endocarditis Hepatitis B, C HIV-1 Infectious mononucleosis Malaria Syphilis (congenital and secondary) Toxoplasmosis Schistosomiasis Filariasis Drugs Captopril Penicillamine Gold Nonsteroidal antiinflammatory drugs Pamidronate Interferon Mercury Heroin Lithium Immunologic or Allergic Disorders Vasculitis syndromes Castleman disease Kimura disease Bee sting Food allergens Serum sickness Associated with Malignant Disease Lymphoma Leukemia Solid tumors Glomerular Hyperfiltration Oligomeganephronia Morbid obesity Adaptation to nephron reduction

Modified from Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629-638; From Pais P, Avner ED. Fixed proteinuria. In: Kliegman RM, Stanton BF, St. Geme JW III, eds. Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016:2522, Table 527.1.

diagnosis of minimal change nephrotic syndrome. Treatment strategies with corticosteroid-sparing agents for patients with frequent relapse who develop steroid-related adverse effects include, alkylating agents; cyclophosphamide or chlorambucil. It is not recommended that second courses of alkylating agents be given.

Complications of Nephrotic Syndrome Even in patients with the frequent relapse variant of minimal change disease, the incidence of renal failure is only 1%. The reported mortality rate remains higher, at approximately 5%. Infection.  The major cause of death in nephrotic syndrome is overwhelming infection, usually secondary to spontaneous bacterial

peritonitis, which develops in as many as 10% of patients with nephrotic syndrome at some point in the course of illness. Such infection is most frequent in patients who are edematous with significant ascites. Peritoneal fluid interferes with macrophage function, whereas ascitic fluid may dilute local complement or immunoglobulin levels, altering host defense mechanisms in the peritoneum. The most common pathogen is Streptococcus pneumoniae. Escherichia coli and Staphylococcus aureus are other etiologic agents that may cause spontaneous peritonitis in patients with minimal change disease. With the use of appropriate antibiotics, mortality from peritonitis is ~10%. Any child with nephrotic syndrome in relapse with evidence of ascites needs to be evaluated quickly if either abdominal pain or fever

CHAPTER 19  Proteinuria TABLE 19.7  Causes of Nephrotic

Syndrome in Infants Younger Than 1 Year Secondary Causes Infections Syphilis Cytomegalovirus Toxoplasmosis Rubella Hepatitis B HIV Malaria Drug reactions Toxins Mercury Systemic lupus erythematosus Syndromes with associated renal disease Nail-patella syndrome Lowe syndrome Nephropathy associated with congenital brain malformation Denys-Drash syndrome: Wilms tumor Hemolytic uremic syndrome Primary Causes Congenital nephrotic syndrome Diffuse mesangial sclerosis Minimal change disease Focal segmental sclerosis Membranous nephropathy From Kliegman RM, Greenbaum LA, Lye PS. Practical strategies in pediatric diagnosis and therapy. 2nd ed. Philadelphia: Saunders; 2004:418.

develops. A blood specimen and paracentesis (e.g., Gram stain, culture, neutrophil count, measurement of glucose and protein levels) should be obtained, and the patient should be started on intravenous cefotaxime (or ceftriaxone) and an aminoglycoside without further delay. Thrombosis.  A second serious complication of nephrotic syndrome is spontaneous thrombosis, pulmonary embolus, or both. The blood of patients with nephrotic syndrome is hypercoagulable, and there is an increased incidence of thrombotic phenomena in these children. Children can have arterial thrombosis, as well as venous thrombosis with resultant pulmonary emboli. The renal vein and dural sinus veins are other possible sites of thrombosis. Use of injectable and oral antithrombolytic agents, in addition to heparin, have allowed for more effective treatment of thrombotic complications. Hyperlipidemia.  Hyperlipidemia is treated by some authorities with statins to lower the serum cholesterol levels and theoretically reduce vascular pathologic processes.

OTHER FORMS OF NEPHROTIC SYNDROME Focal Segmental Sclerosis Diagnosis Clinical criteria do not always allow clinicians to differentiate minimal change disease from focal segmental sclerosis before completion of a course of prednisone therapy. Inability to clear proteinuria completely during prednisone therapy may be the first indication of focal segmental sclerosis. Patients who respond to prednisone initially with clearing of proteinuria but do not respond to a subsequent course of steroids

317

should also be considered to have focal segmental sclerosis. Such patients represent about 7% of those who have an initial response to prednisone therapy. A patient who does not respond to prednisone with total clearing of proteinuria should undergo renal biopsy. Focal segmental sclerosis may be primary (idiopathic) or secondary to severe obesity, reflux nephropathy, sickle cell nephropathy, reduced renal mass (single kidney), opiate or analgesic abuse, chronic bacteremia (endocarditis), renal transplant rejection, or nephropathy resulting from human immunodeficiency virus infection. Genetic variants in several genes result in focal segmental glomerulosclerosis. The genetic basis of these hereditary focal segmental glomerulosclerotic disorders is genetically heterogeneous. Nine hereditary subtypes have been described. FSGS1 : ACTN4; FSGS2 : TRPC6; FSGS3 : CD2AP; FSGS4 : APOL1; FSGS5 : INF2; FSGS6 : MYO1E; FSGS7 : PAX2; FSGS8 : ANLN; FSGS9 : CRB2. Many of these genes code for proteins which are involved in the structure and function of the podocyte foot process.

Treatment Results of treatment of focal segmental sclerosis have been poor. Patients have severe and unremitting proteinuria despite treatment with prednisone, chlorambucil, or cyclophosphamide. The long-term outcome has been poor; 33% are in renal failure ~10 years after diagnosis, and nearly 100% are in renal failure 20 years after diagnosis. The incidence of focal segmental sclerosis appears to be increasing, particularly in the African American population, possibly related to obesity and genetic predisposition. Patients with focal segmental sclerosis present 2 difficult problems. First, renal function may be maintained reasonably well for years, but massive proteinuria persists. Hence, patients are often edematous for months or years, and stigmata of protein malnutrition may develop as a result of large protein losses. Symptomatic therapy with a low-sodium diet and judicious use of diuretics is sometimes effective. Dietary manipulation of protein intake is ineffective; increasing dietary protein intake is accompanied by a concomitant increase in urinary protein excretion. There is no evidence that protein restriction either modifies serum proteins or prevents progression to renal insufficiency. The second problem occurs when affected patients progress to endstage renal failure. Recurrence of the disease in transplanted kidneys occurs in 25-30% of recipients. Therefore, many patients undergo a long period of dialysis before receiving a kidney transplant in an effort to diminish the frequency of recurrent disease. Some patients respond to calcineurin inhibitors, cyclosporine, or tacrolimus, with total clearing of their proteinuria. There may be no progression to renal insufficiency. It is unknown what percentage of patients with focal segmental sclerosis respond to cyclosporine; it is estimated that 25-60% have an initial response.

Membranous Nephropathy Membranous nephropathy is a pathologic diagnosis made following renal biopsy and may be primary or secondary to other diseases (e.g., hepatitis, systemic lupus erythematosus [SLE] or malignancy) or toxins and drugs such as nonsteroidal antiinflammatory, gold, mercury, bismuth, silver, D-penicillamine, trimethadione, probenecid, and captopril. All the secondary causes must be considered and should be addressed and treated before the condition is considered primary. Antibodies against the phospholipase A2 receptor (PLA2R) in the serum or a renal biopsy by immune staining have been identified in 70% of patients with primary or idiopathic membranous nephropathy. Circulating antibodies against thrombospondin type-1 domaincontaining 7A (THSD7A) are found in another 5-10% of the remaining patients with primary membranous nephropathy. The changes in

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the antibody titers correspond to remission or relapse of proteinuria and can be used to monitor the disease.

Treatment Addressing the triggers of secondary membranous nephropathy in itself may result in resolution of proteinuria in the majority of cases. Membranous nephropathy secondary to SLE is more difficult to treat. In addition, the increased incidence of spontaneous resolution of the proteinuria makes selecting the patients who should be treated very complicated. Close monitoring of primary membranous nephropathy to determine the need for treatment is recommended for 6 months prior to initiating treatment. Sodium restriction, diuretics, and angiotensin-converting enzyme (ACE) inhibitors can be used for control of proteinuria and symptoms. In patients with no decrease of proteinuria, or with severe, life-threatening symptoms related to the nephrotic syndrome, immunosuppression with steroids and cyclophosphamide can be tried.

NEPHROTIC SYNDROME IN INFANTS YOUNGER THAN 1 YEAR Nephrotic syndrome that manifests very early in life is a much more serious entity, and the prognosis is guarded (see Table 19.7). The outlook is poorest in younger infants (<6 months of age) and improves as the age at presentation approaches 1 year. Minimal change disease is rarely seen in infants younger than 6 months of age. It is more common in infants who present at 6-8 months. By 1 year, it is the most common cause of nephrotic syndrome. The conditions that result in nephrotic syndrome in infants differ markedly from those seen in older children. Secondary causes are more prominent and need to be considered, particularly in newborns or very young infants. It is especially important to test for syphilis because the early institution of penicillin therapy may lead to the resolution of the renal disease and may mitigate the involvement of other organ systems as well. Congenital toxoplasmosis is also treatable with the combination of steroids and pyrimethamine–sulfadiazine–folinic acid. Other congenital infections offer less opportunity for treatment to influence the outcome; extrarenal manifestations of these infections are much more serious than kidney disease. Primary renal disease causing nephrotic syndrome in early infancy is most often caused by either congenital nephrotic syndrome or diffuse mesangial sclerosis (Table 19.8). In both diseases, the prognosis for survival is poor unless aggressive supportive therapy and kidney transplantation are undertaken.

Congenital Nephrotic Syndrome Congenital nephrotic syndrome is an autosomal recessive disorder resulting from mutations in the gene encoding the protein, nephrin (see Table 19.8). Infants with congenital nephrotic syndrome are often premature, with a low birthweight, placentomegaly, increased amniotic fluid α-fetoprotein levels, and hypogammaglobinemia (decreased immunoglobulin G levels). Ascites and edema, caused by massive proteinuria, are usually present in affected infants during the first few weeks after birth. Patients do not respond to steroids or cytotoxic therapy. Infections and thrombosis are the two major complications; they cause considerable morbidity and mortality. Because of the massive proteinuria, patients fail to thrive; they require nasogastric feeding with a high-calorie, highprotein formula. Nephrectomy and peritoneal dialysis are often necessary to control protein losses and allow for adequate growth and control of uremia so that the infant can reach a size and nutritional state sufficient for renal transplantation.

Diffuse Mesangial Sclerosis Diffuse mesangial sclerosis is the other diagnostic entity seen in infants (see Table 19.8). This disease is similar to congenital nephrotic syndrome, but it often results in less severe protein losses. Patients are often full term and of a normal birthweight. The amniotic fluid α-fetoprotein is normal, and the onset of edema (1 week-33 months) is later than in congenital nephrotic syndrome (birth-3 months). The patients have hypertension, hematuria, and renal insufficiency at presentation. When diffuse mesangial sclerosis is seen in association with a female phenotype, chromosome typing is recommended to look for patients with Drash syndrome (XY gonadal dysgenesis, nephropathy, and Wilms tumor). When this syndrome is present, bilateral nephrectomy and gonadectomy are recommended because the potential for malignancy is very high. Treatment is similar to patients with congenital nephrotic syndrome and eventually requires renal transplantation. The major goal is to help these infants achieve the growth and good nutrition necessary for successful renal transplantation. Nephrotic syndrome occasionally occurs after transplantation for congenital nephrotic syndrome, probably secondarily to an autoimmune reaction to nephrin.

ASYMPTOMATIC PROTEINURIA DISORDERS Many patients have proteinuria, but there is no edema, the blood pressure is normal, and serum protein levels are normal. The extent of the work-up must be tailored to the seriousness of the problem. Whether an evaluation should be performed depends on whether the proteinuria is both persistent and nonorthostatic (see Fig. 19.2). For a child younger than 7 or 8 years of age who has persistent proteinuria, normal total protein and serum albumin levels, normal complement, and no other signs of renal disease, there are two options. One option is to observe the patient carefully with repeated urinalyses every 3-6 months and to counsel the parents with regard to swelling and/or ascites, which may develop in association with influenza or an upper respiratory infection. If there is evidence of overt nephrotic syndrome with edema, a decrease in serum albumin and an increase in serum cholesterol, a trial of daily prednisone therapy is indicated. It is good practice to give the pneumococcal vaccine to patients who have persistent proteinuria but no evidence of edema or nephrotic syndrome, because of the risk of pneumococcal peritonitis if nephrotic syndrome develops. The other option involves instituting prednisone therapy to document that proteinuria has disappeared; this confirms the suspicion that the patient has steroid-responsive nephrotic syndrome. The rationale for withholding prednisone unless symptoms develop is that the natural history of minimal change disease is to remit; this may occur with or without prednisone administration. If the patient has a more serious lesion, symptoms will develop, at which time evaluation and therapy may be undertaken. In a patient older than 8 or 9 years, once the presence of persistent and nonorthostatic proteinuria is established, the next step is to quantify the amount of protein in a 24-hour specimen. If urinary protein excretion is greater than 8 mg/kg/day, a renal biopsy may be considered. Alternatively, these patients can also be treated with steroids and the response assessed. If proteinuria does not clear after 6-8 weeks of therapy, renal biopsy is then indicated. The choice of 8 mg/kg/day of proteinuria is arbitrary; the International Study of Kidney Disease in Children (ISKDC) definition of proteinuria is 8 mg/m2/hour, and nephrotic syndrome is defined as 40 mg/m2/hour. Hence, for an average 8-year-old patient who weighs 30 kg and is 1 m2 tall, proteinuria by these definitions is a level of 96 mg/day, and nephrotic syndrome is at a level of 960 mg/day. Renal biopsy can be considered at a

CHAPTER 19  Proteinuria

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TABLE 19.8 Nephrotic Syndrome in Children Caused by Genetic Disorders of Podocytes Gene

Name

Location

Inheritance

Renal Disease

NPHN

NEPHRIN

PDCN

PODOCIN

19q13.12

AR

FINNISH CONGENITAL NEPHROSIS

1q25.2

AR

PLCE1

PHOSPHOLIPASE C, EPSILON-1

NEPHROTIC SYNDROME, STEROID-RESISTANT

10q23.33

AR

NEPHROTIC SYNDROME, EARLY-ONSET, TYPE 3

WT1

Wilms tumor supressor gene

11p13

AD

NEPHROTIC SYNDROME, TYPE 4 / Denys-Drash with diffuse mesangial sclerosis / Frasier syndrome

LAMB2

LAMININ, BETA-2

3p21.31

AR

NEPHROTIC SYNDROME, TYPE 5, WITH OR WITHOUT OCULAR ABNORMALITIES

PTPRO

GLOMERULAR EPITHELIAL PROTEIN 1

12p12.3

AR

NEPHROTIC SYNDROME, TYPE 6

DGKE

DIACYLGLYCEROL KINASE, EPSILON

17q22

AR

NEPHROTIC SYNDROME, TYPE 7, WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

ARHGDIA

RHO GDP-DISSOCIATION INHIBITOR ALPHA

17q25.3

AR

NEPHROTIC SYNDROME, TYPE 8

ADCK4

AARF DOMAIN-CONTAINING KINASE 4

10q13.2

AR

NEPHROTIC SYNDROME, TYPE 9

EMP2

EPITHELIAL MEMBRANE PROTEIN 2

16p13.3

AR

NEPHROTIC SYNDROME, TYPE 10

NUP107

NUCLEOPORIN KD107

12q15

AR

NEPHROTIC SYNDROME, TYPE 11

NUP93

NUCLEOPORIN, 93-KD

16q13

AR

NEPHROTIC SYNDROME, TYPE 12

NUP205

NUCLEOPORIN

7q33

AR

NEPHROTIC SYNDROME, TYPE 13

LMX1B

LIM-homeodomain protein

9q34

AD

Nail-Patella Syndrome

SMARCAL1

SW1/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1

2q35

AR

Schimke immunoosseous dysplasia with FSGS*

*Podocyte expression of SMARCAL1 is presumptive but not yet established. Mutations in another protein, CD2-AP or NEPH1 (a novel protein structurally related to nephrin), is the cause of congenital nephrotic syndrome in mice. A mutational variant in the CD2AP gene has been identified in some patients with steroid-resistant nephrotic syndrome. AD, autosomal dominant; AR, autosomal recessive; FSGS, focal segmental glomerulosclerosis. Modified from Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629-638.

Proteinuria Both positive for protein

Repeat ×2 (one in a.m.)

One negative

No significant proteinuria at night

Routine pediatric follow-up

Day/Night split 24-hr urine

Nonorthostatic Proteinuria >8 years

<8 years OR

<8 mg/kg/day

>8 mg/kg/day

Prednisone

Follow in 3 mo

OR Follow & repeat in 3 mo

Renal biopsy

Proteinuria persists

Proteinuria clears

FIGURE 19.2  Algorithm for age-based management of proteinuria.

Prednisone for symptoms

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Section 4  Genitourinary Disorders

level of 240 mg/day of proteinuria. This guideline helps avoid a biopsy for the patient with minimal proteinuria but does not require fullblown nephrotic syndrome to develop before a definitive work-up is initiated. Because the patient has isolated proteinuria, membranoproliferative glomerulonephritis (MPGN) or SLE is an unlikely possibility. However, the incidence of focal segmental sclerosis is much higher in adolescents than in younger children. With the possibility of treatment with cyclosporine and/or ACE inhibitors preventing future renal failure, aggressive evaluation is warranted to identify patients who might benefit from these therapies. Low molecular protein, such as β2-microblobulin, α1microglobulin, lysozyme, and retinol-binding protein can be seen in urine in tubular disorders, such as Fanconi syndrome or Dent disease. If associated with acidosis, hypokalemia, and hypophosphatemia, Fanconi syndrome should be considered. In males, if proteinuria is associated with hypercalciuria and nephrocalcinosis, Dent disease, an X-linked proximal tubulopathy that eventually leads to end-stage renal disease, should be considered, and the urine should be tested for β2microblobulin. Gene testing can confirm the diagnosis.

The presence of protein in the urine increases the risk of renal insufficiency, regardless of its cause. This has led to therapies that reduce proteinuria, thereby decreasing the risk of a progressive loss of renal function. The traffic of protein across the glomerular capillary membrane appears to stimulate a cascade of inflammatory events that cause interstitial fibrosis. ACE inhibitors result in efferent arteriolar vasodilatation, leading to a decrease in intraglomerular pressure, which in turn leads to a decreased transport of protein across the glomerular filter. Patients who are treated with ACE inhibitors are less likely to increase their level of proteinuria and are less likely to lose their renal function than are patients who are not treated with these agents. This was first apparent in the treatment of diabetic nephropathy, but there is evidence that ACE inhibitors offer advantages to patients with other nephropathies as well. Angiotensin II blockers offer another avenue for accomplishing a decrease in intraglomerular pressures, and these also decrease proteinuria when used alone or in conjunction with an ACE inhibitor. ACE inhibitors and angiotensin II blockers may be useful for patients with proteinuria either as a 1st step or as adjunctive therapy for those who fail to respond to other medications.

SUMMARY AND RED FLAGS Asymptomatic proteinuria may be associated with nonspecific febrile benign illnesses, postural mechanisms, and glomerular or tubular dysfunction. Significant proteinuria with edema suggests nephrotic syndrome, which in most children suggests minimal change nephrotic syndrome. An age younger than 1 year or older than 10 years plus significant hematuria, azotemia, and hypertension are red flags that

REFERENCES A bibliography is available at ExpertConsult.com.

suggests a cause of nephrosis other than the more benign minimal change disease. Additional red flags include a poor response to prednisone therapy and signs of multiple organ system involvement by a primary systemic disease, such as SLE. Fever and abdominal pain in a patient with nephrotic syndrome should suggest spontaneous primary bacterial peritonitis.

CHAPTER 19  Proteinuria

REFERENCES The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on Glomerulonephritis (GN), Chapters 3 and 4. Bergstein JM. A practical approach to proteinuria. Pediatr Nephrol. 1999;13:697-700. Bonilla-Felix M, Parra C, Dajani T, et al. Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int. 1999;55:1885-1890. Chesney RW. The idiopathic nephrotic syndrome. Curr Opin Pediatr. 1999;11:158-161. Durkan A, Hodson E, Willis N, et al. Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database Syst Rev. 2001;(4):CD002290. Gorensek MJ, Lebel MH, Nelson JD. Peritonitis in children with nephrotic syndrome. Pediatrics. 1988;81:849. Greenstein SM, Delrio M, Ong E, et al. Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts. Pediatr Nephrol. 2000;14:1061-1065. Hodson EM, Knight JF, Willis NS, et al. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2001;(1):CD001533. Hogg RJ, Portman RJ, Milliner D, et al. Evaluation and management of proteinuria and nephrotic syndrome in children: Recommendations from a pediatric nephrology panel established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE). Pediatrics. 2000;105:1242-1249. Homberg C, Jalanko H, Tryggvason K, et al. Congenital nephrotic syndrome. In: Barratt TM, Avner ED, Harmon WE, eds. Pediatric Nephrology. Baltimore: Lippincott Williams & Wilkins; 1999:765-777. Korbet SM. Clinical picture and outcome of primary focal segmental glomerulosclerosis. Nephrol Dial Transplant. 1999;14:68-73. Leung AK, Robson WL. Evaluating the child with proteinuria. J R Soc Health. 2000;120:16-22. Lin CY, Sheng CC, Chen CH, et al. The prevalence of heavy proteinuria and progression risk factors in children undergoing urinary screening. Pediatr Nephrol. 2000;14:953-959.

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McBryde KD, Kershaw DB, Smoyer WE. Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr Adolesc Health Care. 2001;31:280-307. Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int. 1978;13:159-165. The primary nephrotic syndrome in children: Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr. 1981;98:561-564. Remuzzi G, Ruggenenti P, Benigni A. Understanding the nature of renal disease progression. Perspective in Clinical Nephrology. Kidney Int. 1997;51:2-15. Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care. Lancet. 2015;385:1983-1992. Rood I, Deegens J, Wetzels J. Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice. Nephrol Dial Transplant. 2012;27:882-890. Roth KS, Amaker BH, Chan JC. Nephrotic syndrome: Pathogenesis and management. Pediatr Rev. 2002;23:237-248. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;53:359-364. Rytand DA, Spreiter S. Prognosis in postural (orthostatic) proteinuria. N Engl J Med. 1981;305:618. Trompeter RS, Lloyd BW, Hicko J, et al. Long-term outcome for children with minimal change nephrotic syndrome. Lancet. 1985;1:368. Vehaskari VM, Rapola J. Isolated proteinuria: Analysis of a school-age population. J Pediatr. 1982;101:661. Yashikawa N, Kitagawa K, Ohta K, et al. Asymptomatic constant isolated proteinuria in children. J Pediatr. 1991;119:375.