a) Non-transplant indications of CNI (Calcineurin Inhibitors). [4] b) Alisporivir in Alport's syndrome. [3] c) Aquapheresis in acute decompensated heart failure (ADHF). [3]
Definition
Calcineurin inhibitors (CNIs) are immunosuppressive drugs primarily used to prevent rejection in organ transplantation by inhibiting T-cell activation. Non-transplant indications refer to their use in various immune-mediated diseases outside the transplant setting (Harrison's 21e, Ch. 265).
Etiopathogenesis
CNIs (cyclosporine, tacrolimus) inhibit calcineurin phosphatase, blocking IL-2 transcription and T-cell activation. Their immunosuppressive effect is leveraged in autoimmune and inflammatory diseases to reduce pathogenic immune responses (Harrison's 21e, Ch. 265).
| Disease Category | Indications | Mechanism of Benefit |
|---|---|---|
| Glomerular diseases | Steroid-resistant nephrotic syndrome (SRNS) (minimal change disease, FSGS) | Reduces T-cell mediated podocyte injury |
| Autoimmune disorders | Psoriasis, rheumatoid arthritis | Inhibition of T-cell mediated inflammation |
| Dermatological disorders | Atopic dermatitis, severe eczema | Decreases skin inflammation |
| Other | Autoimmune hepatitis, uveitis | Suppression of aberrant immune activation |
Clinical Features
- Depends on underlying disease, e.g., proteinuria and edema in SRNS, joint pain and swelling in RA, skin lesions in psoriasis (Harrison's 21e).
Diagnosis
- Confirm diagnosis of underlying disease by appropriate clinical evaluation, biopsy (for nephrotic syndrome), and lab tests.
- Indication for CNI therapy based on steroid resistance or autoimmune refractory disease (Brenner & Rector's The Kidney).
Management
- CNI dosing individualized; monitor blood levels to avoid nephrotoxicity and neurotoxicity.
- Adjunct immunosuppressants may be added based on disease (e.g., steroids, mycophenolate).
- Monitor renal function and electrolytes regularly.
Recent Advances
- Use of tacrolimus over cyclosporine in nephrotic syndrome due to better side effect profile.
- Development of topical CNIs (e.g., tacrolimus ointment) for dermatological use with fewer systemic side effects (Harrison's 21e).
Key Points for Exam
- CNIs inhibit calcineurin → IL-2 suppression → T-cell inactivation.
- Non-transplant uses mainly include steroid-resistant nephrotic syndrome and autoimmune diseases.
- Monitor drug levels and renal function vigilantly.
- Tacrolimus preferred in many non-transplant settings due to potency and tolerability.
Definition
Alisporivir is a non-immunosuppressive cyclophilin inhibitor investigated as a potential treatment for Alport's syndrome, a hereditary disease characterized by defective type IV collagen in the glomerular basement membrane causing progressive nephropathy (Brenner & Rector's The Kidney).
Etiopathogenesis
- Alport's syndrome is caused by mutations in COL4A3, COL4A4, or COL4A5 genes, leading to defective GBM structure and progressive glomerulosclerosis.
- Cyclophilins contribute to mitochondrial dysfunction and fibrosis progression; alisporivir inhibits cyclophilin D, modulating mitochondrial permeability transition and reducing fibrosis (Recent trials).
Clinical Features
- Persistent hematuria, progressive proteinuria, sensorineural hearing loss, and ocular abnormalities.
- Progression to ESRD typically in adolescence or early adulthood.
Diagnosis
- Clinical features + family history.
- Confirmed by renal biopsy showing GBM thinning, splitting.
- Genetic testing for COL4 gene mutations.
Management
- No definitive cure; supportive therapy includes ACE inhibitors or ARBs to delay progression.
- Alisporivir under clinical investigation aims to reduce fibrosis by mitochondrial protection (Phase II trials ongoing).
- Renal replacement therapy in ESRD.
Recent Advances
- Alisporivir demonstrated reduction in mitochondrial dysfunction and slowed disease progression in animal models.
- Phase II clinical trials are evaluating efficacy and safety in human Alport's syndrome (Brenner & Rector's The Kidney).
Key Points for Exam
- Alisporivir is a cyclophilin inhibitor targeting mitochondrial dysfunction in Alport's.
- Potential to slow progression by reducing fibrosis beyond ACEi effects.
- Currently investigational; not yet standard of care.