Nephrotic Syndrome

Introduction

Nephrotic syndrome is characterized by generalized edema as a result of hypoproteinemia due to excessive protein loss in the urine. Hypercholesterolemia is commonly associated with MCNS. The causes of increased permeability of glomeruli to proteins are not known in 90% of children with nephrotic syndrome hence it is called idiopathic or primary nephrotic syndrome. The Majority i.e. 80 - 85% of NS respond to steroid therapy and if biopsied will show minimal change.

Presentation

Diagnosis of nephrotic syndrome is by simple urine examination in a child who presents with edema. The edema is generalized involving eyes, abdominal wall, genitals, and ankles; ascites may be present and B.P is normal in the majority of cases.

Urine examination shows the presence of proteins- 3+ to 4+ by sulphosalicylic acid test or heat test or dipstick; RBC's absent or 10 - 12/HPF; no macrohematuria or persistent hematuria, no pyuria. Fatty or waxy casts may be present.

In the first attack, hospitalize the patient to come to a complete diagnosis and to plan the treatment. It is important to do the blood tests for serum proteins - Total proteins and albumin (serum alb <2.5 g/dl); serum cholesterol (>200 mg/dl) and BUN/S. creatinine (normal). Although steroid therapy is the backbone of therapy for nephrotic syndrome; oral prednisolone should be started after checking for infection, hypovolemia, and secondary causes.

Initial Episode Of Nephrotic Syndrome

• Urine examination for proteinuria: 3+ to 4+ urinary proteins or urinary protein (mg)/urinary creatinine (mg) ratio in a spot sample >2 or 24 hours urinary protein >40 mg/m2/hr or 50 mg/kg.

• Serum albumin <2.5 g/dl

• Serum cholesterol >200 mg/dl

• To screen for tuberculosis: X-ray chest, Mantoux Test

• To screen for urinary tract infection: Urine culture and colony count

• HbsAg test

[Steroid therapy is started after the infection is cleared (for TB, after 3-4 weeks of 2 anti TB drugs)].

Low serum C3 levels, raised BUN/Creatinine, persistent microscopic hematuria/macrohematuria, and persistent hypertension are uncommon in minimal change NS and kidney biopsy is needed if 2 or more of these are detected, prior to starting steroid therapy.

Relapse

After completion of the treatment of first-episode, weekly urine examination for proteinuria is advised for 1 month and subsequently every 2-4 weekly or whenever edema recurs. If urine shows proteinuria of 3+ to 4+ in 3-4 urine examinations in a week, a relapse is diagnosed. Many relapses occur with infections.

Treatment of relapse:
Look for the focus of infection (throat, skin, urine, etc) and treat with appropriate antibiotics e.g. Amoxycillin, Cephalexin, etc for 6-7 days.

After 1 week if urine shows 3+/4+ protein after the infection is controlled, steroid therapy should be started as oral prednisolone 2 mg/kg/day in 2 - 3 divided doses till 3 consecutive urine samples show absent or trace proteinuria, after which the dose of prednisolone is reduced to 1.5 mg/kg as a single dose on an alternate day for 4 weeks. If urine is cleared of proteins, steroid therapy is stopped.

If urine protein shows less than 2+ after control of infection, steroids should be withheld and the child should be kept under close observation to detect the presence of edema and proteinuria for the next 2-3 weeks during which either proteinuria clears or increases to 3+ to 4 requiring steroids therapy for relapse.

Each relapse should be treated as above. If more than 2 relapses occur within 6 months after initial therapy, the child is diagnosed as a frequent relapser.

The treatment of frequent relapses or steroid-dependent (relapse occurring while tapering steroids or within 2 weeks of stopping steroids) cases should be done by experienced pediatric nephrologist because this includes the need for prolonged steroid therapy which is fraught with severe side effects; use of cytotoxic drugs like cyclophosphamide or chlorambucil and newer immunomodulatory drugs like levamisole or cyclosporin A. Severe life-threatening infections like peritonitis, septicemia, meningitis, etc. occur infrequent relapses.

All through the course of steroid therapy, the primary pediatrician should advise the parents as regards diet (salt restriction in the edematous state, no need to increase protein in the diet), prevention of infections, and immunizations (Chickenpox; Hib and pneumococcal vaccine are given 4 - 6 weeks after completion of steroid therapy; DPT can be given while tapering prednisolone dose but oral polio vaccine is given after stopping steroids for 1 - 2 months).

Even when the child is in remission i.e. no proteinuria regular follow up once every 4 - 12 weeks is required for at least 1 - 5 years before a child with nephrotic syndrome is said to be well controlled.

Good response to steroids is the best marker of a good outcome and 75 - 80% nephrotic children with onset between 2 - 7 years respond to oral prednisolone therapy, do not require kidney biopsy (because minimal change N.S. is the commonest histologic diagnosis in this age group), continue to have a renal function, normal B.P. and good quality of life.

Major Therapeutic Challenges In NS

• Frequent relapses/steroid-dependent cases

• Steroid resistant cases

These 2 types of nephrotic syndrome are designated as "difficult nephrotics " because of the need to use alternative therapy, repeated and prolonged steroid therapy causing serious side effects, increased risk of life, threatening infections, thrombosis, hypertension, drug toxicity and the possibility of chronic renal failure in steroid-resistant cases. Difficult nephrotics should be managed by pediatric nephrologists, who are experienced in treating such cases.

Frequent relapsing/steroid-dependent NS requires an individualized approach. Regular examination of urine for heavy/nephrotic range proteinuria is the only method of diagnosing relapses and treatment should start when three consecutive urine samples show 2+ or more proteinuria, which is defined as a relapse. First, 2-3 relapses are treated with short courses of oral prednisolone i.e. 2 mg/kg/day till remission occurs followed by alternative days single dose for 4 weeks. Since repeated courses of high dose steroids cause more steroid toxicity than alternative day regimes given for 6-12 months after the 3rd relapse within 6 months i.e. frequent relapser or steroid-dependent case is subsequently treated with oral prednisolone used in as low dose as possible on alternate days to maintain sustained remission without major side-effects. Most children tolerate 0.5 mg/kg of prednisolone on alternate days without side-effects and maintain protein-free urine.

Along with regular urine examination, side effects of steroids should be looked for, namely cushingoid facies, obesity, striae, hirsutism, acne, hypertension, susceptibility to infections, pancreatitis, and if used for more than a year, post subcapsular cataract, growth retardation, myopathy and rarely, peptic ulceration and avascular necrosis of bone. A pubertal growth spurt may be delayed in boys.

Alternative drug therapy is indicated in a steroid-responsive NS if:

• Relapse occurs on prednisolone dose >0.5 mg/kg on alternative days with:
  
• Unacceptable side - effects.

• Boys approaching puberty or diabetes.

• Severe relapses with hypovolemia, thrombosis, sepsis, or acute renal failure.

• Relapse on prednisolone dose >1 mg/kg on alternate days.

• Drugs used for alternative therapy are introduced after inducing remission with oral prednisolone therapy whilst tapering steroids. The details for dosage, duration, and side- effects of these drugs are given in Table 1.

Table 1:Drugs used for alternative therapy in steroid-dependent or frequently relapsing NS

Check List Prior to Steroid Therapy

Presence of infection: Mantoux test, X-ray chest, CBC, urine culture, hepatitis B test. Steroids flare up the infections and in the presence of infection, steroids fail to give a good response. Treatment of infection is advised before starting steroid therapy.

Severe edema with oliguria can be associated with hypovolemia (detected clinically by poor capillary fill and raised hematocrit and BUN), which requires IV Fluids before starting steroids; otherwise, a nephrotic child can go into shock. The use of diuretics like furosemide is not advised in the presence of hypovolemia or shock.

Presence of joint involvement, skin rash, anemia, and purpura are rare but when present demand attention to rule out systemic lupus erythematosus or Henoch Schonlein Purpura, etc.