Demographic Factors

The clinical and histopathologic distribution of nephrotic syndrome varies by age at onset and race. MCNS typically presents between 2 and 8 years of age (peak, 3 years). About 20% to 30% percent of nephrotic syndrome in adolescence is MCNS. FSGS occurs at a median of 6 years of age and is more common in adolescents than in younger children. MCNS is twofold more common in boys than girls until adolescence when both sexes are equally affected, and its incidence is higher in white and East Asian relative to black children. Steroid-resistant nephrotic syndrome is more common in black and Hispanic children. Genetic syndromes and congenital infections are considerably more common causes of nephrotic syndrome in infancy.

Edema

Edema is the main presenting feature, and its onset may be rapid or insidious. Edema is detectable when fluid accumulation is greater than 3% to 5% of body weight. Edema often presents in the periorbital region, is more pronounced in the morning, and is often misdiagnosed and treated as an allergic reaction or seasonal allergies. Edema may fluctuate with positional changes and activity, with lower extremity swelling being more noticeable over the course of the day. Edema develops in other dependent areas such as the sacral region and genitalia. Pleural effusions are generally asymptomatic but if large may cause respiratory compromise. Ascites may lead to umbilical or inguinal hernias as well as to more serious complications, such as spontaneous bacterial peritonitis (SBP). Bowel wall edema may produce diminished appetite; abdominal colic; and diarrhea, which, if chronic, can lead to a protein-losing enteropathy. Skin breakdown and infection can occur in the setting of severe edema (Figure 63-2).

Figure 63-2 Clinical and laboratory findings that may be present in nephrotic syndrome.

Blood Pressure and Volume Status

Children with MCNS may have mild elevations in blood pressure, but significant hypertension is suggestive of another underlying pathology, such as FSGS or glomerulonephritis with or without renal failure.

Careful assessment of volume status is critical. The child with anasarca may be profoundly intravascularly volume depleted. Tachycardia, orthostatic blood pressure changes, and hemoconcentration are indicative of hypovolemia. Children with nephrotic syndrome are at increased risk of cardiovascular collapse in the setting of ongoing volume loss (e.g., vomiting and diarrhea), particularly if compounded by adrenal insufficiency caused by long-term steroid administration. The acute management of hypovolemia in these patients consists of standard resuscitation with intravenous (IV) saline.

Urine

Nephrotic patients are often oliguric, and the urine appears concentrated and foamy. Nephrotic-range proteinuria is characterized by urine protein excretion greater than 40 mg/m²/h on a 24-hour collection or a random urinary protein-to-creatinine ratio greater than 2. The specific gravity may be artificially high secondary to the proteinuria. Microscopic hematuria may be noted, but gross hematuria is rare.

Laboratory Findings

The laboratory abnormalities associated with nephrotic syndrome are listed in Box 63-1. Serum albumin is typically below 2.4 g/dL. Chronic hypoproteinemia produces transverse white bands in the nail beds, dull hair, and softening of ear cartilage. Hyperlipidemia, particularly hypercholesterolemia but also hypertriglyceridemia, results from increased lipoprotein synthesis in the liver, attributed to low portal vein oncotic pressure and urinary loss of high-density lipoprotein and an unidentified regulatory substance. The associated hyponatremia (serum sodium, 120s-130 mEq/L) is typically not associated with central nervous system symptoms and is most likely caused by antidiuretic hormone–mediated free water retention but less commonly may be a sign of adrenal insufficiency. Blood urea nitrogen, serum creatinine, and hematocrit may be elevated secondary to intravascular volume depletion. Pseudohypocalcemia is caused by hypoalbuminemia. However, true hypocalcemia may result from loss of 25-hydroxyvitamin D–binding protein in the urine.

Complications

The two most important acute complications of nephrotic syndrome contributing to morbidity and mortality are infections and thromboembolic events. Common serious infections include pneumonia, SBP, and cellulitis. Several factors contribute to impaired immunity and infection: (1) defective opsonization through complement loss, (2) changes in T-cell function and IgG concentrations, (3) edema, and (4) immunosuppressive treatment. Children with nephrotic syndrome are at higher risk for infection with encapsulated organisms, especially Streptococcus pneumoniae, as well as with gram-negative organisms, measles, and varicella.

The prothrombotic state of nephrotic syndrome is also multifactorial, resulting from a combination of disproportionate urinary loss of anticoagulant factors, increased production of clotting factors, thrombocytosis, increased platelet adhesion and aggregability, increased viscosity, and hyperlipidemia. This state may be exacerbated by diuretic and steroid therapy, venous catheters, and immobilization. Arterial sticks and catheters should be avoided because of the potential for arterial thrombosis and consequent ischemic injury to the extremity. Pulmonary embolus should be considered in a nephrotic patient with respiratory distress or pleuritic chest pain. Renal vein thrombosis should be suspected in the setting of acute azotemia, hypertension, flank pain, or gross hematuria.

Acute renal failure may develop in the setting of intravascular volume depletion, pyelonephritis, bilateral renal vein thrombosis, or medications associated with decreased renal perfusion (e.g., renin–angiotensin blockade and diuretics). Urinary loss of vitamin D–binding protein may lead to vitamin D deficiency and even secondary hyperparathyroidism. Hypothyroidism may result from loss of thyroid-binding globulin and thyroxine in the urine. Anemia may result from transferrin loss. Finally, trace metal deficiencies (copper and zinc) may occur secondary to ceruloplasmin and albumin losses, respectively.

Supportive Therapy

Dietary restriction of sodium to less than 2 g/d decreases edema as well as the risk of steroid-induced hypertension. Dietary protein should neither be restricted nor enhanced. Children with nephrotic syndrome should consume the recommended daily allowance of protein. Administration of diuretics, such as furosemide and metolazone, with or without 25% IV albumin, may be used to treat symptomatic edema but should be used with caution to avoid acute volume overload or intravascular depletion. Empiric antibiotic coverage should be administered for suspected serious bacterial infections and peritoneal fluid sampled for cell count and culture to identify a causative organism.

Glucocorticoids

The standard treatment regimen at initial presentation is 4 to 6 weeks of prednisone 60 mg/m²/d or 2 mg/kg of ideal body weight (maximum, 80 mg/d) followed by 4 to 6 weeks of 40 to 60 mg/m² on alternating days, after which the dose is gradually tapered. If there is concern about enteral absorption because of bowel wall edema, IV methylprednisolone may be used. Patients should have a PPD placed before starting therapy. The first morning urine sample should be monitored daily by urine dip. Remission is defined as at least 3 consecutive days of negative to trace urine protein. Approximately 95% of children with MCNS compared with 20% to 25% of those with FSGS go into remission after 8 weeks of prednisone. About 75% of children with MCNS are in remission by 2 weeks. Relapse is defined by 3 consecutive days of 2+ or greater urine protein. Approximately 80% of patients have at least one relapse, and 50% become frequent relapsers (i.e., two relapses in 6 months or three in 1 year). Steroid dependence is defined by a relapse while weaning or within 2 weeks of stopping steroid therapy. Steroid resistance is defined as lack of remission by 8 weeks of standard steroid therapy. Pulse IV methylprednisolone may produce remission in some steroid-resistant patients.

Other

Adjunctive therapies for steroid resistance (or steroid dependence with serious steroid side effects) include alkylating agents (e.g., cyclophosphamide), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), and renin-angiotensin blockade (angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists). Children and adolescents with progressive renal failure may require renal replacement therapy and a renal transplant. FSGS may recur after transplant in 30% to 50% of cases.