Variable cyclosporine exposure: a risk factor for chronic allograft nephropathy and graft loss?
BACKGROUND
Following the introduction of ciclosporine (CsA), the 2-year survival of transplanted kidneys improved from less than 60% to over 80%. Though the introduction of this drug resulted in a marked improvement in graft survival, its use was not without problems. Variable absorption and a narrow therapeutic index resulted in the need for measurements of CsA blood concentrations to tailor the drug dose to maximize therapeutic efficacy while minimizing toxicity.


METHODS
Data were available from the LOTESS study of 4948 transplant patients receiving Neoral with at least 5 years' follow-up. Potential risk factors associated with outcome in renal transplant recipients treated with CsA were explored: the primary outcome variable was graft loss. A stepwise binary logistic regression analysis was used to identify donor, recipient, and treatment variables related to outcome.


RESULTS
In the initial analysis, chronic rejection was the only significant predictor of graft loss. The relative risk (RR) of graft loss was 16.9 (95% CI = 13.9-20.4). Further analysis identified four independent risk factors for chronic rejection cadaveric donor (RR, 1.50; 95% CI = 1.05-2.15), older donor (RR, 1.02; 95% CI = 1.01-1.02), younger recipient (RR, 1.02; 95% CI = 1.02-1.03), and variable predose CsA concentration (RR, 1.25; 95% CI = 1.06-1.48).


CONCLUSIONS
With the UK kidney transplant waiting list at about 5000 patients and only 1658 transplants performed during 2002, it is important maximize graft survival. For example, perhaps marginal donors (age > 55) can be matched to older recipients without increasing the risk of chronic allograft nephropathy and therefore graft loss. Variable predose CsA concentrations may arise from at least three different sources: adherence to treatment, drug formulation, and individual variation in absorption. Therefore, it is important to emphaze to patients that erratic compliance may increase their risk of graft loss. Second, although only one CsA formulation is marketed in the UK, when generic forms of CsA are introduced it will be important to demonstrate consistent delivery of CsA from these new formulations. Third, improved monitoring of CsA using a C2 rather than a predose blood concentration measurement may be used to reduce intra-individual variations in drug exposure.
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Department of Clinical Pharmacology, St Bartholomew's and the Royal London Hospital, School of Medicine and Dentistry, London, United Kingdom. s.he@qmul.ac.uk
Johnston
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D000328:Adult; D002102:Cadaver; D016572:Cyclosporine / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D012044:Regression Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D012449:Safety; D014019:Tissue Donors; D017211:Treatment Failure
D007166:Immunosuppressive Agents; D016572:Cyclosporine