Alisporivir as a Treatment Option for Alport Syndrome
Alisporivir (a cyclophilin inhibitor) shows promise as a treatment option for Alport syndrome by increasing mutant type IV collagen secretion, potentially offering a safer alternative to cyclosporin A with fewer nephrotoxic effects. 1
Background on Alport Syndrome
Alport syndrome is a hereditary disorder of type IV collagen characterized by progressive hematuric nephritis and sensorineural hearing loss. It's the second most common monogenic cause of renal failure after autosomal dominant polycystic kidney disease. About 80% of patients have X-linked disease caused by mutations in the COL4A5 gene, resulting in the replacement of the collagen IV α3α4α5 network with the α1α1α2 heterotrimer 2.
Current Treatment Approaches
Standard Treatment
The current standard treatment for Alport syndrome focuses on:
Angiotensin-converting enzyme (ACE) inhibitors, which delay renal failure progression by reducing:
- Intraglomerular hypertension
- Proteinuria
- Fibrosis 2
Early initiation of treatment is now recommended:
- At time of diagnosis in males with X-linked Alport syndrome
- At time of diagnosis in males and females with autosomal recessive Alport syndrome
- At onset of microalbuminuria in females with X-linked Alport syndrome and in patients with autosomal dominant Alport syndrome 3
Previous Experience with Cyclosporin A
Cyclosporin A (CsA) has been previously used in Alport syndrome:
- It can effectively reduce proteinuria in most patients 4
- However, long-term use is problematic due to significant nephrotoxicity:
- In a study of nine Alport syndrome patients, mean proteinuria decreased from 2±1.06 to 0.65±0.73 g/day after 6 months
- However, mean inulin clearance decreased from 102±29 to 74±16.3 ml/min/1.73 m²
- Control renal biopsies revealed significant lesions of cyclosporin nephrotoxicity in three patients with extended treatment 4
Alisporivir as a Novel Therapeutic Option
Recent research has identified alisporivir (ALV) as a promising treatment candidate for Alport syndrome:
Mechanism of action:
Advantages over cyclosporin A:
- ALV could potentially provide the beneficial effects of increasing mutant collagen IV secretion
- Without the nephrotoxic effects associated with CsA's calcineurin inhibition 1
Other Potential Therapeutic Approaches
Additional treatment options that have shown some benefit in Alport syndrome include:
- Aldosterone blockade with spironolactone:
- When added to ACE inhibitors or ACE inhibitors plus angiotensin receptor blockers (triple blockade)
- Significantly reduced urinary protein/creatinine ratio at 3,6,12, and 18 months
- Did not affect estimated glomerular filtration rate
- Caused only mild elevation in serum potassium levels 5
Conclusion and Recommendations
Based on the available evidence:
Alisporivir represents a promising novel therapeutic approach for Alport syndrome by addressing the underlying pathophysiology through increased mutant type IV collagen secretion.
Unlike cyclosporin A, which has demonstrated nephrotoxicity with long-term use despite its ability to reduce proteinuria, alisporivir may offer similar benefits with a potentially better safety profile.
While awaiting further clinical trials of alisporivir, the current standard of care should include early initiation of ACE inhibitors according to the updated 2020 clinical practice recommendations.
For patients with persistent proteinuria despite ACE inhibitor therapy, adding an aldosterone receptor blocker like spironolactone may provide additional renoprotective benefits.
Monitoring Recommendations
For patients who might receive alisporivir in the future:
- Regular assessment of renal function
- Monitoring of proteinuria levels
- Evaluation for potential side effects
- Assessment of collagen IV biomarkers if available
The development of alisporivir represents an important advance in potential targeted therapy for Alport syndrome, moving beyond symptomatic management to address the underlying molecular pathology of the disease.