Role of Cyclosporin in Treatment
Cyclosporin is an effective immunosuppressive agent for treating idiopathic glomerular diseases associated with nephrotic syndrome, including minimal change disease (MCD), membranous nephropathy (MGN), and focal segmental glomerulosclerosis (FSGS), with Grade A evidence supporting its use after failed cytotoxic therapy in MCD and as first-line therapy in MGN and FSGS. 1
Mechanism of Action
- Cyclosporin works through specific and reversible inhibition of immunocompetent lymphocytes in the G0 or G1 phase of the cell cycle, preferentially inhibiting T-helper cells 2
- It inhibits lymphokine production and release, including interleukin-2 (T-cell growth factor), without causing bone marrow suppression 2
Dosing Guidelines
- Initial dose should be 3-4 mg/kg/day given in divided doses (twice daily) for at least 6 months 1
- Target trough levels (C0) should be maintained between 125-175 ng/ml and 2-hour post-dose levels (C2) between 400-600 ng/ml 1
- Progressive reduction to the smallest effective dose should be implemented after initial response 1
- If proteinuria is not reduced by 50% after 6 months, cyclosporin should be discontinued and alternative therapy considered 1
Treatment Algorithm by Disease Type
For Membranous Nephropathy (MGN):
Risk Assessment:
- Low risk: Normal renal function despite maximum conservative therapy
- Medium risk: Proteinuria 4-8 g/day observed for up to 6 months
- High risk: Deteriorating renal function over 2-3 months ± proteinuria >8 g/day 1
Treatment Based on Risk:
Response Management:
For Minimal Change Disease (MCD) and FSGS:
- Cyclosporin is recommended after failure of a 12-week course of cytotoxic therapy in MCD 1
- For steroid-resistant cases, cyclosporin at 3-5 mg/kg/day in divided doses is recommended 3
- In FSGS, cyclosporin can be used as first-line therapy either as monotherapy or combined with corticosteroids 1
Monitoring Parameters
- Regular monitoring of renal function, blood pressure, and cyclosporin levels is essential 1
- Treatment targets include:
- Complete or partial remission of proteinuria
- Maintenance of stable GFR (≥70% of pretreatment level)
- Avoiding hypertension
- Maintaining non-toxic cyclosporin levels 1
Adverse Effects
- Renal: Nephrotoxicity is a major concern but risk is low if dosing guidelines are followed 1
- Cardiovascular: Hypertension is common and requires monitoring 1, 4
- Dermatologic: Hypertrichosis (excessive hair growth) 1, 5
- Oral: Gingival hyperplasia 1, 5
- Gastrointestinal: Nausea, vomiting (up to 10% of patients), abdominal pain 6
- Neurological: Tremor, paresthesias, and rarely seizures or delirium 1
Duration of Treatment
- For complete remission: Taper cyclosporin over 3-4 months 1
- For partial remission: Continue full dose for additional 1-2 years, then either:
- Maintain at non-toxic level indefinitely if renal function is stable and partial remission was difficult to achieve
- Slowly taper over 1-3 years, adjusting if proteinuria worsens 1
Special Considerations
- Cyclosporin is metabolized through the hepatic cytochrome P450 system (CYP3A4); drug interactions are common and can affect blood levels 1
- FDA-approved indications include prevention of organ rejection in kidney, liver, and heart transplants, but use in glomerular diseases is off-label 2
- Long-term use (>55 months) has been associated with renal impairment in 71% of patients in one study, requiring discontinuation in 25% of cases 4
- Pregnancy: Categorized as FDA category C; not recommended unless maternal benefit justifies potential risk 1
Pitfalls and Caveats
- Failure to monitor drug levels can lead to toxicity or subtherapeutic dosing 1
- Concomitant medications that affect P450 system can cause unpredictable cyclosporin levels 1, 6
- Targeting complete remission rather than partial remission may lead to unnecessary toxicity 1
- Abrupt discontinuation can lead to disease flare; always taper slowly 1