Alport Syndrome: Diagnosis and Management in a 27-Year-Old with Nephrotic-Range Proteinuria
In a 27-year-old adult with nephrotic-range proteinuria and a family history of kidney disease requiring biopsy, Alport syndrome should be strongly considered, and genetic testing for COL4A3, COL4A4, and COL4A5 genes should be pursued immediately—ideally before kidney biopsy—as this will definitively establish the diagnosis, guide treatment decisions, and spare the patient from unnecessary immunosuppression. 1, 2, 3
Why Alport Syndrome Should Be High on the Differential
Alport syndrome is now recognized as the most common genetic kidney disease and the second most common cause of genetic kidney failure, making it a critical consideration in any young adult with unexplained proteinuria and family history. 2, 4
The presence of a close relative requiring kidney biopsy strongly suggests familial kidney disease, which is a specific indication for genetic testing according to current KDIGO guidelines. 1
In adults with steroid-resistant nephrotic syndrome and FSGS on biopsy, 11-24% will have disease-causing variants primarily in type IV collagen genes (which cause Alport syndrome) or podocyte genes. 1, 5
Alport syndrome results from mutations in COL4A3, COL4A4, or COL4A5 genes that disrupt the α3-α4-α5 collagen IV network in basement membranes of the kidney, cochlea, and eye. 2, 3, 6
Immediate Diagnostic Workup
Genetic Testing (Priority #1)
Order genetic testing for COL4A3, COL4A4, and COL4A5 genes immediately, as this represents a paradigm shift from the 2012 guidelines that discouraged genetic testing in adults. 1
Genetic testing should be performed before initiating any immunosuppressive therapy, as identification of a causative variant will spare the patient from potentially toxic therapies that are ineffective in genetic kidney disease. 1
Next-generation sequencing panels are now readily available and can identify the specific mutation, inheritance pattern (X-linked, autosomal recessive, autosomal dominant, or digenic), and inform prognosis. 2, 3
Clinical Assessment for Syndromic Features
Evaluate for sensorineural hearing loss by obtaining a detailed history of hearing difficulties and referring for formal audiometry, as hearing loss is a hallmark extrarenal manifestation of Alport syndrome. 7, 2, 3
Perform ophthalmologic examination to assess for anterior lenticonus (pathognomonic for Alport syndrome), retinal flecks, or corneal abnormalities. 7, 2, 3
Document any history of microscopic hematuria, which is the earliest and most consistent finding in Alport syndrome, often preceding proteinuria by years. 3
Laboratory Evaluation
Quantify proteinuria with 24-hour urine collection or spot urine protein-to-creatinine ratio to confirm nephrotic-range proteinuria (>3.5 g/day). 8
Measure serum albumin, creatinine, and calculate eGFR to assess disease severity and baseline kidney function. 8
Obtain urinalysis with microscopy to document hematuria and assess for dysmorphic red blood cells or red cell casts. 8
Role of Kidney Biopsy
Kidney biopsy should be deferred until genetic testing results are available, as a positive genetic test for Alport syndrome eliminates the need for biopsy in most cases. 1
If biopsy is performed, electron microscopy is essential to identify the characteristic findings of Alport syndrome: irregular thickening and thinning of the glomerular basement membrane with a "basket-weave" appearance. 8, 3
Immunofluorescence staining for α3, α4, and α5 chains of type IV collagen on skin or kidney biopsy can demonstrate absence or abnormal distribution of these chains, supporting the diagnosis. 3
Treatment Strategy Based on Genetic Diagnosis
If Alport Syndrome is Confirmed
Initiate an ACE inhibitor (or ARB if ACE inhibitor is not tolerated) immediately, as early treatment can delay progression to kidney failure by years. 4, 6
Target blood pressure ≤125/80 mmHg using maximally tolerated doses of ACE inhibitor/ARB, adding additional antihypertensive agents as needed. 9
Do NOT use immunosuppressive therapy, as patients with genetic causes of FSGS/Alport syndrome are much less likely to respond and will only experience toxicity without benefit. 1, 5
Consider enrollment in clinical trials investigating SGLT2 inhibitors, endothelin receptor antagonists, or other novel therapies specifically for Alport syndrome. 6
Genotype-Phenotype Considerations
Autosomal recessive Alport syndrome and males with X-linked Alport syndrome typically have more severe disease with earlier onset of kidney failure and extrarenal manifestations. 6
Autosomal dominant Alport syndrome and females with X-linked Alport syndrome show more variability, with some individuals having protracted kidney involvement and preserved kidney function into adulthood. 6
Protein-truncating variants are associated with severe symptoms, kidney failure, and absence of the α3-α4-α5(IV) network, while missense variants may present with milder disease and detectable α3-α4-α5(IV) in the glomerular basement membrane. 6
Family Screening and Genetic Counseling
Identify and screen all first-degree relatives for hematuria, proteinuria, and kidney function, as early identification allows for timely intervention. 1, 4
Offer genetic testing to at-risk family members once the proband's causative variant is identified, enabling predictive testing and early treatment. 1
Provide genetic counseling regarding inheritance patterns, reproductive risks, and implications for future generations. 2
Common Pitfalls to Avoid
Do not assume FSGS on biopsy is "primary" and initiate corticosteroids without first excluding genetic causes through testing, as this exposes patients to unnecessary toxicity. 1, 5
Do not delay genetic testing until after steroid failure, as early diagnosis improves outcomes and allows for appropriate counseling. 1, 3
Do not overlook the family history—a relative requiring kidney biopsy is a red flag for hereditary nephritis and mandates genetic evaluation. 1
Do not forget to assess for extrarenal manifestations (hearing loss, ocular abnormalities), as their presence strengthens the diagnosis and has implications for monitoring. 2, 3
Prognosis and Long-Term Management
The clinical course is highly variable and influenced by gender, mode of inheritance, affected gene, and variant type. 2, 6
Males with X-linked Alport syndrome typically progress to kidney failure by age 20-30 years without treatment, while early ACE inhibitor therapy can delay this by a decade or more. 6
Patients with Alport syndrome have a much lower risk of disease recurrence after kidney transplantation compared to primary FSGS, making transplantation an excellent option when kidney failure occurs. 1
Regular monitoring of kidney function, proteinuria, blood pressure, hearing, and vision is essential throughout life. 2, 3