Congenital Nephrotic Syndrome

Congenital nephrotic syndrome is nephrotic syndrome presenting at birth or in the first 3 months of life. Infantile nephrotic syndrome presents between 3 and 12 months. Most cases are genetic and do not respond to steroids.

The Finnish type, due to NPHS1 (nephrin) mutations, is the classic form, with an incidence of about 1 in 8200 births in Finland and rare in other populations. Other genes include NPHS2 (podocin), WT1, LAMB2 (Pierson syndrome), PLCE1 and LAMA5. Secondary causes are congenital infections (syphilis, cytomegalovirus, toxoplasmosis, hepatitis B and HIV).

The prognosis without treatment is poor, because of infection, thrombosis, malnutrition and growth failure. With intensive care, children can reach kidney transplantation.

Pathophysiology.

Absent or abnormal slit diaphragm proteins allow massive loss of protein into the urine from foetal life. Loss of albumin, immunoglobulins, thyroid binding globulin and clotting regulators leads to oedema, infection, hypothyroidism and thrombosis.

• Antenatal: raised alpha fetoprotein in amniotic fluid and maternal serum, large placenta (over 25% of birth weight), prematurity and low birth weight.
• Early: generalised oedema, ascites, abdominal distension, wide sutures and fontanelles, and poor feeding.
• Complications: severe infection (sepsis, peritonitis), thrombosis (renal vein, sagittal sinus), hypothyroidism, rickets, malnutrition and hypotension.
• Syndromic: eye anomalies and neurological problems (LAMB2), genital anomalies and Wilms tumour (WT1).

Red flags.

• Sepsis, hypovolaemia, anuria or collapse.
• Thrombosis, seizures or neurological signs.
• Evidence of congenital infection.

• Urinalysis and protein to creatinine ratio showing massive proteinuria, serum albumin under 10 g/L in the Finnish type, and raised cholesterol.
• Urea, creatinine and electrolytes, thyroid function, immunoglobulins, coagulation and antithrombin, and calcium and vitamin D.
• Infection screen: syphilis, cytomegalovirus, toxoplasmosis, hepatitis B, HIV and rubella.
• Genetic testing of NPHS1, NPHS2, WT1, LAMB2 and other genes, which are diagnostic. Biopsy is not usually needed.
• Renal and abdominal ultrasound, and echocardiography.

Differential diagnosis. Congenital infection, diffuse mesangial sclerosis, hypoalbuminaemia from other causes (protein losing enteropathy, liver disease), steroid sensitive disease with early onset and neonatal oedema from other causes (hydrops, heart failure).

Supportive care (the mainstay).

• Albumin infusions: 20% albumin 1 g/kg IV once or twice daily to maintain albumin over 15 to 20 g/L, with furosemide 1 mg/kg if overloaded. Home infusions are used in some centres.
• Nutrition: high energy (130 to 150 kcal/kg/day) and protein (3 to 4 g/kg/day) via nasogastric or gastrostomy feeding, with vitamins and minerals.
• Prophylaxis against infection: penicillin or cephalosporin prophylaxis, and immunoglobulin replacement 0.4 to 0.5 g/kg for low IgG. Early IV antibiotics for fever.
• Thromboprophylaxis: aspirin 3 to 5 mg/kg daily or low-molecular-weight heparin or warfarin for children with a high risk or after thrombosis, with specialist direction.
• Levothyroxine for hypothyroidism, vitamin D and calcium.

Reducing proteinuria. An angiotensin converting enzyme inhibitor (enalapril 0.1 mg/kg/day, increased to 0.5 mg/kg/day, maximum 40 mg) with indometacin 1 to 3 mg/kg/day may be used, with careful monitoring of kidney function and potassium.

Definitive treatment.

• Unilateral then bilateral nephrectomy for refractory protein loss, followed by dialysis (peritoneal) until a weight of about 8 to 10 kg, when transplantation is feasible.
• Kidney transplantation. Recurrence is uncommon in the Finnish type but anti-nephrin antibodies can occur.

Monitoring. Albumin, protein loss, growth, thyroid function, infection and thrombosis. Frequent review.

Referral and escalation. Refer urgently to a paediatric nephrology centre with dialysis and transplant capability. Offer genetic counselling and prenatal testing in affected families.