Proteinuria and Nephrotic Syndrome Overview

Proteinuria and Nephrotic Syndrome

• Proteinuria is defined as the presence of protein in the urine.
• Proteinuria can be physiological (caused by fever, exercise, stress, or seizures) or pathological (caused by glomerular or tubular disease).
• Orthostatic proteinuria is an exaggerated form of physiological proteinuria.
• Pathological proteinuria is further categorized into non-nephrotic range and nephrotic range proteinuria based on spot urine protein/creatinine ratio and 24-hour urine protein excretion.
• Diagnostic tests for proteinuria include urine dipstick test (detects albumin only), spot urine protein/creatinine ratio, and 24-hour urine protein collection.

Pathological Causes of Proteinuria

• Glomerular proteinuria: Increased permeability of glomerular capillaries allows large molecules like albumin to pass into the urine. Causes may include nephrotic syndrome, glomerulonephritis, and reflux nephropathy.
• Tubular proteinuria: Defective tubular reabsorption of low-molecular weight proteins like B2 microglobulin. Causes include Fanconi syndrome, tubulointerstitial nephritis, and acute tubular necrosis.

Evaluation of Proteinuria

• Renal function tests (RFTs)
• Albumin levels
• Total serum protein
• Renal ultrasound
• Urinary protein electrophoresis
• Serology for glomerular diseases (ANA, hepatitis serology, complement levels C3, C4)
• DMSA scan
• Renal biopsy

Management of Proteinuria

• Treatment depends on the cause (etiology).
• Angiotensin-converting enzyme inhibitors (ACEIs) are recommended.
• 30-40% reduction in proteinuria and control of hypertension are treatment goals.
• Vitamin D analogs (like calcitriol) can reduce proteinuria in adults with chronic kidney disease (CKD) by 15-20%.

Nephrotic Syndrome

Epidemiology

• Nephrotic syndrome (NS) is a common renal disorder in developed countries, with rates of 20-40 per million people.
• In India, the estimated rate is 90-100 per million population.

Definition

• NS is a clinical syndrome characterized by heavy proteinuria (greater than 40 mg/m²/hr or >1g/m²/24hr).
• Hypoalbuminemia, generalized edema, and hyperlipidemia are also characteristic features.
• Hematuria (typically microscopic), hypertension, and elevated urea levels may be seen.

Important Terms

• Idiopathic NS: The underlying disease mechanism is unclear.
• Secondary NS: Secondary to other systemic diseases (e.g., lupus, HSP, hepatitis B).
• Urinary remission: Urinary albumin is undetectable or low for a few days.
• Relapse: Recovery from initial symptoms is followed by a return to previous symptoms and heavy proteinuria.
• Frequent relapse: Multiple relapse in a year or 6 months.
• Steroid dependent NS: Relapse despite steroid therapy.
• Steroid resistance NS: Persistent proteinuria despite high-dose steroid therapy.
• Congenital NS: NS presenting in the first three months of life.

Pathogenesis of Nephrotic Syndrome

• Genetic abnormalities,
• Immune dysfunctions.
• Circulating factors
• Podocytes and anti-proteinuric agents.

Clinical Features of Nephrotic Syndrome

• Onset is usually between 2 and 6 years of age.
• More common in boys (60-70%).
• Typically insidious and presents with swelling around the eyes (periorbital edema) that is worse in the morning but resolves during the day.
• Swelling may spread to involve other parts of the body, including the face, extremities, and abdomen.
• Could be associated with upper respiratory tract infections (URTIs).
• Some symptoms include: Abdominal pain, fever, vomiting, rash, organomegally, lymphadenopathy are less common.

Evaluation for Nephrotic Syndrome

• Examination to detect associated infection, physical findings.
• Assessment of systemic disease features (fever, rash, joint pain, organomegally, lymphadenopathy) is important, as is monitoring of blood pressure.
• Patients with massive edema may occasionally have elevated blood pressure. Blood pressure often normalizes when edema subsides.
• Urine analysis: 3-4+ proteinuria, protein/creatinine ratio.
• Complete blood count with microscopy and urine culture.
• Blood tests: Measurement of urea, creatinine, electrolytes, proteins, and cholesterol, serum albumin, and C3 complement levels are vital.
• Ultrasound of abdomen and chest imaging.
• Other blood tests like Monteux test for tuberculosis should be considered.
• Renal biopsy is typically not needed for minimal change nephrotic syndrome (MCNS).

Treatment of Initial Episode of Nephrotic Syndrome

• Prednisone: 2 mg/kg/day or 60 mg/m²/day in divided doses for 6 weeks.
• Prednisone dosage can be tapered by reducing the dose over the course of 6 weeks.
• More concentrated doses are given during alternative days for more 6 weeks..
• Monitor blood pressure.
• Adjust dietary sodium and fat intake.
• Provide psychosocial support to the family.

Subsequent Course

• Majority of patients with MCNS (minimal change NS) will have frequent relapses, which may be precipitated by URTIs.
• Patients may be classified as having infrequent relapses, frequent relapses, or steroid-dependent relapses.
• Relapses can be treated with a course of prednisone until proteinuria resolves, followed by tapering over 4 weeks.
• Repeated steroid treatment for frequent relapses can lead to unacceptable side effects.

Treatment of frequent relapses and steroid dependence

• Patients often develop serious steroid toxicity.
• Side effects include features like obesity, hirsutism, striae, hypertension, impaired glucose tolerance, cataracts, and growth retardation.
• Alternate long-term prednisone therapy might be considered in severe cases.

Steroid Sparing Agents

• Levamisole, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, and rituximab are commonly used steroid-sparing agents.

Steroid Resistant Nephrotic Syndrome Management

• 3-6 doses of pulse methylprednisolone (20-30 mg)
• IV cyclophosphamide (500-750 mg/m² monthly)
• Calcineurin inhibitors (for two to three years)
• Rituximab (375 mg/m²)

General Care

• Dietary management to control edema.
• Prevention and treatment of infections.
• Psychological support for the patient and family.
• Avoid non-traditional or hazardous medications.

Complications

• Infections, Hypovolemia, acute kidney injury, Thromboembolism, hyperlipidemia, urinary loss of low-molecular weight proteins, hypoproteinemia, and malnutrition.
• TB flare-ups may occur in patients on immunosuppressive therapies.

1- Infection

• Children with nephrotic syndrome are more susceptible to bacterial infections, especially if they are on immunosuppressive therapy.
• Common infections include peritonitis, cellulitis, empyema, bone/joint infections, sepsis, and tuberculosis.
• Usual pathogens include Streptococcus pneumoniae and staphylococci.

Causes of Infection in NS

• Steroid and immunosuppressant use
• Edema as a site for bacterial growth
• Urinary loss of immunoglobulins, factor B, and transferrin

Peritonitis

• Mostly seen in patients who have relapses with ascites.
• Symptoms include; abdominal pain, fever, vomiting.
• Diagnosis is made through peritoneal fluid analysis. Confirmation is done by presence of neutrophils (75-100/mm³).
• Treatment includes Parenteral antibiotics such as third-generation cephalosporins for 7–10 days.

Stress Dose Corticosteroids

• In patients who have received >1 mg/kg/day of prednisolone for more than two weeks within the past six to twelve months.
• Patients undergoing surgery and serious illnesses may need a dose of corticosteroids.
• Hydrocortisone is given at 30–100 mg/m²/day in divided doses and then tapered as the condition improves.

Outcome of Nephrotic Syndrome

• Patients with steroid-sensitive NS typically have an excellent prognosis with complete resolution of symptoms and no residual renal dysfunction within 14-20 years of onset.
• Steroid-resistant NS patients have a higher risk of developing progressive kidney disease.