What is the management of Congenital Nephrotic Syndrome (CNS) of the Finnish type in infants and children?

Management of Finnish Type Congenital Nephrotic Syndrome

Children with Finnish type congenital nephrotic syndrome (CNS) require immediate referral to a specialized pediatric nephrology center for intensive supportive management focused on albumin replacement, aggressive nutrition, complication prevention, and eventual bilateral nephrectomy followed by kidney transplantation—this comprehensive approach has reduced mortality from 100% to approximately 30% over the past decades. 1, 2

Initial Diagnostic Confirmation

Genetic testing should be performed as first-line diagnostic measure, preferably using whole-exome sequencing to identify NPHS1 mutations (particularly the Fin-major variant p.Leu41Aspfs) that characterize Finnish type CNS 1, 2, 3. The diagnosis is supported by:

• Massive proteinuria and generalized edema in the neonatal period (typically first weeks of life) 4, 5
• Placental weight >25% of birth weight 1, 4
• Elevated amniotic fluid alpha-fetoprotein and prenatal findings of enlarged nuchal translucency or fetal edema 1
• Normal glomerular filtration rate during first 6 months despite massive proteinuria 4

Kidney biopsy is not routinely recommended unless genetic diagnosis cannot be established or there is substantial reduction in eGFR to <30 ml/min/1.73 m² 1

Immediate Management Priorities

Vascular Access Preservation

Preserve all central and peripheral vessels from the outset—avoid peripherally inserted catheters and unnecessary venepunctures, as these children will require dialysis access and eventual transplantation 1, 2. When central venous access is required, implement prophylactic anticoagulation 2, 3.

Albumin Replacement Therapy

Administer intravenous albumin infusions only when clinically indicated for intravascular hypovolemia, severe edema with respiratory compromise, or as part of regular protocols 2, 4. The purpose is to support intravascular volume and reduce life-threatening edema, not to normalize serum albumin levels 2.

• Home administration by trained parents/caregivers should be implemented to improve quality of life and reduce hospitalizations 2, 3
• Administer furosemide (0.5-2 mg/kg) at the end of albumin infusions unless marked hypovolemia or hyponatremia is present 2, 6
• Daily albumin infusions have been the cornerstone of improved survival in multiple cohorts 4, 7, 8

Fluid and Edema Management

• Restrict dietary sodium as first-line intervention for edema control 2, 6
• Restrict fluid intake when feasible, especially with hyponatremia and severe edema 2, 6
• Use furosemide 0.5-2 mg/kg per dose (up to six times daily) for intravascular volume overload with preserved kidney function 2, 6
• Critical caveat: Avoid diuretics with evidence of intravascular hypovolemia 2, 6
• Never exceed furosemide doses >6 mg/kg per day for periods longer than 1 week 2

Antiproteinuric Therapy

ACE inhibitors (66.7% usage in cohorts) and indomethacin (58.3% usage) improve clinical control and delay progression to dialysis, though they do not cure the disease 4. These medications reduce proteinuria burden and may extend the conservative management phase.

Aggressive Nutritional Support

Optimize protein and caloric intake to prevent growth failure and malnutrition, which are major determinants of quality of life and transplant outcomes 1, 2. Patients require:

• High protein intake to compensate for urinary losses 8
• Adequate caloric supplementation, often requiring enteral feeding 8
• Iron supplementation for urinary iron losses causing anemia 1, 6
• Vitamin B12 and copper supplementation as needed for deficiencies 1
• Vitamin D (colecalciferol or calcifediol) and calcium (250-500 mg/day) for low 25-OH-D3, low ionized calcium, or elevated PTH 6
• Thyroid hormone replacement if hypothyroidism develops 1

Complication Prevention and Monitoring

Primary Outcome Measures to Monitor

Target normal growth, nutritional status, cognitive and motor development; absence of thrombotic complications, severe infections, edema, and anemia; normal blood pressure; euthyroidism; and minimized hospitalizations 1. These should be regularly assessed as primary outcomes rather than laboratory values alone.

Infection Prevention

• Implement infection prophylaxis measures given hypogammaglobulinemia from urinary IgG losses 2, 3
• Monitor serum IgG levels regularly 1, 6
• Ambulatory management when possible reduces nosocomial infection risk 2, 3

Thrombosis Prevention

• Monitor for thromboembolism, particularly with severe hypoalbuminemia 6, 3
• Prophylactic anticoagulation when central venous catheters are placed 2, 3

Anemia Management

Treat iron deficiency anemia with iron supplementation; administer erythropoietin if anemia persists despite iron repletion 1, 6. Anemia results from urinary losses of erythropoietin, iron, transcobalamin, and transferrin 1.

Surgical Management: Nephrectomy Timing

A stepwise approach with prolonged conservative management is appropriate—routine early nephrectomies should be avoided 2, 3. However, nephrectomy should be considered when:

• Persistent intravascular hypovolemia despite optimal albumin replacement 2
• Recurrent thromboses 2
• Failure to thrive despite aggressive nutritional support 2
• Preparation for kidney transplantation (elective bilateral nephrectomy) 4, 7, 8

Historical data show that introduction of elective bilateral nephrectomy combined with albumin infusions and nutritional support reduced mortality from 100% to 30% 7, 8.

Kidney Replacement Therapy

Dialysis

Peritoneal dialysis is the modality of choice because it preserves central venous access for future transplantation 1. Dialysis typically begins at median age 3-4 years when conservative management fails 4.

• Major complication: Acute peritonitis occurs in 85.7% of patients on peritoneal dialysis 4
• Haemodialysis is an alternative with comparable outcomes if peritoneal dialysis is not feasible 1
• Follow general guidelines for kidney replacement therapy in infants and children 1

Kidney Transplantation

Early referral to transplant center is recommended to minimize time on dialysis 3. In autosomal recessive disease, parental kidney donation is usually accepted 1.

Critical post-transplant complication: 25-35% of Finnish type CNS patients (Fin-major homozygotes) develop post-transplant de novo glomerulopathy due to anti-nephrin antibodies from alloimmunization against the nephrin molecule in the graft 1. This occurs because:

• The Fin-major variant (p.Leu41Aspfs) causes total absence of nephrin in native kidneys 1
• At least 70% of those with post-transplant glomerulopathy have detectable anti-nephrin antibodies 1
• Recurrence can occur at any time after transplantation 1
• Kidney function is initially normal despite heavy proteinuria 1

When post-transplant proteinuria develops, consider antibody-mediated disease and implement antibody reduction strategies: plasmapheresis, methylprednisolone pulses, and cyclophosphamide or rituximab 1. Successful treatment outcomes have been reported with daily plasma exchanges combined with immunosuppression 1.

Despite this risk, 71.4% of transplanted patients maintain normal kidney function after median follow-up of 3.73 years, with significant improvements in cholesterol, triglycerides, and achievement of adequate height and weight in 50% of patients 4.

Multidisciplinary Team Approach

Management requires a specialized team including pediatric nephrologists, neonatologists, nurses, dieticians, surgeons, psychologists, and social workers 2, 3. Decisions about intensive versus palliative treatments in neonates with severe disease should be made through family-centered shared decision-making 1.

Common Pitfalls to Avoid

• Never use immunosuppressive agents for genetic CNS—they are ineffective and expose patients to unnecessary toxicity 2
• Do not perform routine early nephrectomies—prolonged conservative management is now standard 2, 3
• Avoid aggressive diuresis in hypovolemic patients—this worsens intravascular depletion 2, 6
• Do not rely on transferrin saturation and ferritin levels for iron status assessment in CNS—they are unreliable 1
• Do not overlook mitochondrial disease screening—if symptoms suggest mitochondrial disease (nystagmus, retinitis pigmentosa, developmental delay, cardiomyopathy), initiate CoQ10 trial even before genetic results 1