In a 27‑year‑old patient with nephrotic‑range proteinuria (>3.5 g per 24 hours) and a close relative who previously required a kidney biopsy, what is the familial significance and what diagnostic work‑up should be undertaken?

Familial Nephrotic-Range Proteinuria: Diagnostic Approach in a 27-Year-Old with Family History

In a 27-year-old patient with nephrotic-range proteinuria and a close relative who required kidney biopsy, the most important familial glomerular diseases to consider are Alport syndrome, familial focal segmental glomerulosclerosis (FSGS), and—less commonly—hereditary membranous nephropathy. 1

Key Familial Glomerular Diseases with Nephrotic-Range Proteinuria

Alport Syndrome

• Alport syndrome is an inherited disorder of type IV collagen affecting the glomerular basement membrane, typically presenting with hematuria, progressive proteinuria (often reaching nephrotic range), and progressive kidney failure. 1
• The disease shows X-linked dominant inheritance in 80% of cases, with males more severely affected, though autosomal recessive and autosomal dominant forms exist. 1
• Genetic testing for COL4A3, COL4A4, and COL4A5 mutations can establish the diagnosis without requiring kidney biopsy in patients with a well-characterized family history. 1
• The KDIGO guideline explicitly states that treatment may proceed without kidney biopsy in Alport disease when the diagnosis is established by family history and genetic testing. 1

Familial Focal Segmental Glomerulosclerosis (FSGS)

• Familial FSGS accounts for approximately 10-20% of all FSGS cases and typically presents in young adults with nephrotic-range proteinuria. 1
• Multiple genetic mutations have been identified, including NPHS1 (nephrin), NPHS2 (podocin), ACTN4 (α-actinin-4), TRPC6, and INF2, among others. 1
• In families with well-characterized mutations causing FSGS, kidney biopsy may not be necessary before initiating treatment, according to KDIGO guidelines. 1
• However, genetic testing should be pursued in young adults (<30 years) with steroid-resistant nephrotic syndrome and a positive family history, as this can guide prognosis and treatment decisions. 1

Other Hereditary Causes

• Fabry disease (X-linked α-galactosidase A deficiency) can present with proteinuria in young adults and should be excluded, particularly if there is a maternal family history or associated symptoms (angiokeratomas, acroparesthesias, cardiac involvement). 1
• Hereditary membranous nephropathy is rare but has been described in families, though most membranous nephropathy is acquired (anti-PLA2R antibody-positive). 1

Diagnostic Work-Up Algorithm

Initial Quantitative Assessment

• Confirm nephrotic-range proteinuria with a 24-hour urine collection showing >3.5 g/day or spot urine protein-to-creatinine ratio >3,500 mg/g. 1, 2, 3
• Measure serum albumin (nephrotic syndrome defined by albumin <30 g/L) and assess for edema, hyperlipidemia, and thrombotic risk. 3
• Calculate eGFR using the CKD-EPI equation to stage kidney function and assess urgency of intervention. 2

Family History Assessment

• Obtain a detailed three-generation pedigree focusing on:
  • Relatives with kidney disease, dialysis, or transplantation 1
  • Age of onset of kidney disease in affected relatives 1
  • Pattern of inheritance (X-linked, autosomal dominant, autosomal recessive) 1
  • Associated features: hearing loss (Alport), cardiac disease (Fabry, Alport), ocular abnormalities (Alport) 1

Targeted Genetic and Serologic Testing

• Order genetic testing for COL4A3/4/5 (Alport syndrome) and podocyte genes (NPHS1, NPHS2, ACTN4, TRPC6, INF2) in young adults with nephrotic-range proteinuria and positive family history. 1
• Measure α-galactosidase A activity (males) or genetic testing for GLA mutations (females) to exclude Fabry disease. 1
• Check anti-PLA2R antibodies to exclude primary membranous nephropathy, which is typically not familial. 1
• Perform urinalysis with microscopy looking for dysmorphic red blood cells or red cell casts, which are characteristic of Alport syndrome and other glomerulonephritides. 2

Kidney Biopsy Considerations

• Kidney biopsy may be deferred if genetic testing confirms a well-characterized familial mutation (e.g., known pathogenic variant in COL4A5 or NPHS2). 1
• Kidney biopsy is indicated if:
  • Genetic testing is negative or inconclusive 1
  • Rapid progression of kidney function decline occurs 1
  • Uncertainty exists about the underlying diagnosis 1
  • The biopsy result would alter treatment decisions (e.g., distinguishing primary FSGS from genetic FSGS affects steroid responsiveness) 1

Management Implications of Familial Disease

Conservative Therapy Regardless of Etiology

• Initiate ACE inhibitor or ARB therapy immediately to reduce proteinuria and slow progression, targeting blood pressure <125/75 mmHg given nephrotic-range proteinuria. 2
• Implement sodium restriction (<2 g/day) and protein restriction (~0.8 g/kg/day) as first-line supportive measures. 2
• Monitor for thromboembolic complications given nephrotic syndrome, particularly if serum albumin <2.5 g/dL. 3

Immunosuppression Decisions

• Genetic forms of FSGS (e.g., NPHS2 mutations) are typically steroid-resistant, making genetic testing critical before exposing patients to immunosuppression risks. 1
• Alport syndrome does not respond to immunosuppression, and treatment focuses on RAAS blockade and supportive care. 1
• Primary (non-genetic) FSGS may respond to corticosteroids or calcineurin inhibitors, making biopsy and genetic testing essential to guide therapy. 1

Genetic Counseling and Family Screening

• Refer for genetic counseling to discuss inheritance patterns, recurrence risk, and implications for family planning. 1
• Screen first-degree relatives with urinalysis, urine protein-to-creatinine ratio, and serum creatinine, particularly in X-linked or autosomal dominant conditions. 1

Common Pitfalls to Avoid

• Do not assume all familial kidney disease is Alport syndrome—familial FSGS and other podocytopathies are increasingly recognized with genetic testing. 1
• Do not delay genetic testing in young adults with nephrotic syndrome and family history, as results directly impact treatment decisions and avoid unnecessary immunosuppression. 1
• Do not perform kidney biopsy reflexively—KDIGO explicitly allows treatment without biopsy in well-characterized familial genetic nephropathies. 1
• Do not overlook Fabry disease, particularly in males with proteinuria and a maternal family history, as enzyme replacement therapy is available. 1
• Do not forget to assess for extrarenal manifestations (hearing loss, ocular abnormalities, cardiac disease) that can narrow the differential diagnosis. 1