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Cyclosporine-induced chronic nephropathy: an obliterative microvascular renal injury
Insights
Cyclosporine treatment in cardiac transplant recipients significantly impairs kidney function, causing reduced glomerular filtration rate and increased renal vascular resistance. Long-term use leads to persistent kidney damage and a 10% incidence of end-stage renal failure.
Area of Science:
- Nephrology
- Immunology
- Cardiology
Background:
- Cyclosporine is a key immunosuppressant in organ transplantation.
- Cardiac transplant recipients are at risk for kidney complications.
Purpose of the Study:
- To investigate the long-term effects of cyclosporine on kidney function and morphology in cardiac transplant recipients.
Main Methods:
- Physiologic and morphologic studies on 200 cardiac transplant recipients treated with varying cyclosporine doses.
- Renovascular pressure and flow measurements, dextran sieving.
- Renal biopsies and long-term follow-up (up to 9 years).
Main Results:
- Cyclosporine (low and high dose) reduced glomerular filtration rate by 40-47%.
- Renal vascular resistance doubled, primarily due to preglomerular resistance increase.
- Morphologic changes included afferent arteriolopathy, glomerular collapse/sclerosis, and interstitial fibrosis.
- Persistent azotemia observed; 10% cumulative incidence of end-stage renal failure.
Conclusions:
- Cyclosporine therapy significantly compromises kidney function and structure in cardiac transplant recipients.
- Long-term immunosuppression with cyclosporine is associated with progressive nephropathy and end-stage renal disease.
Abstract:
Physiologic and morphologic techniques have been used to study kidneys of 200 cardiac transplant recipients treated with either low- or high-dose cyclosporine. After 12 months, both low- (4.6 +/- 0.4) and high-dose cyclosporine (6.3 +/- 0.3 mg/kg/24 h; P less than 0.01) were associated with depression of glomerular filtration rate below values in a third group of 100 recipients never exposed to cyclosporine by 40 to 47%. Determination of renovascular pressures and flows as well as analysis of transglomerular sieving of dextrans revealed renal vascular resistance in cyclosporine-treated recipients to be elevated greater than twofold, due largely to an increase in preglomerular resistance. Morphologic changes in renal tissue of both cyclosporine groups included an occlusive afferent arteriolopathy with downstream collapse or sclerosis of glomeruli. Ischemic nephrons were associated with patchy fibrosis of the surrounding interstitium. Follow-up for up to 9 yr reveals persistent but stable azotemia, on average. Longitudinal physiologic studies over a 48-month period (N = 15) during which cyclosporine was reduced in dosage (to 3.1 +/- 0.3 mg/kg) or withdrawn revealed a persistently reduced but constant level of glomerular filtration rate. Increasing ischemic glomerular collapse and sclerosis were observed at repeat renal biopsy. Remnant (spared) glomeruli exhibited hypertrophy; presumably elevated single nephron glomerular filtration rate maintained two-kidney glomerular filtration rate constant despite the declining fraction of functional glomeruli. By actuarial analysis, the cumulative incidence of end-stage renal failure in cardiac transplant recipients treated at this institution from 1980 onwards with continuous cyclosporine therapy has reached 10%.(ABSTRACT TRUNCATED AT 250 WORDS)