Having demonstrated an association between C2 and acute rejection (AR) in a retrospective study of patients in whom CsA dose adjustment was based solely on trough blood CsA levels (C0) [4], we introduced a target-driven protocol for CsA dose adjustment that was based primarily on C2 but also C0 and various clinical factors (see below). The protocol was applied to 60 consecutive renal transplant recipients (36 male, 55 Caucasian, age 45.9±13.6 years, four with diabetes mellitus, time on renal replacement therapy 59.3±49.4 months, 51 first grafts). The donor profile was as follows: 28 male, age 47.7±16 years, 10 living/50 cadaveric. The mean number of human leukocyte antigen (HLA) mismatches was A 0.79±0.53, B 0.89±0.54 and DR 0.19±0.44. The standard immunosuppressive regimen comprised Neoral®, prednisolone and azathioprine (AZA), but 10 patients at high immunological risk received basiliximab and 11 were treated with mycophenolate mofetil (MMF) in place of AZA. Neoral® was commenced at 10 mg/kg/day in divided doses and then adjusted according to C2 values (for doses 4/5 and then every fourth dose until hospital discharge, target range 13501650 ng/ml). Neoral® dose increases for patients with suboptimal C2 values were waived if paired C0 values exceeded 500 ng/ml or there was delayed graft function and/or clinical evidence of CsA nephrotoxicity.
The incidence of acute allograft rejection (biopsy-proven or suspected on clinical grounds with a good response to increased immunosuppression) within the first 20 days post-transplant was 10%. Delayed graft function occurred in 33.3% of cases. The incidence of adverse events was as follows: hepatitis [alanine aminotransferase (ALT) >50 IU/l] 27%, hyperbilirubinaemia (serum bilirubin >30 µmol/l) 27%, haemolytic uraemic syndrome 3.3%, CsA nephrotoxicity (with improvement in serum creatinine following CsA dose reduction) 8.3%. Target range C2 values were achieved in 42, 67 and 67% of patients by days 3, 5 and 7, respectively. There was a non-significant trend towards a lower incidence of AR in patients who achieved target range C2 values by days 3 (8 vs 11.4%), 5 (7.9 vs 13.6%) and 7 (7.5 vs 15%) post-transplant. The C2:C0 ratio changed considerably during the first week post-transplant: median values on days 3, 5 and 7 were 2.55, 2.82 and 3.46, respectively, with corresponding values of 2.45, 3.12 and 3.55 for patients who had data for all three time points (Figure 1, n = 40, P<0.01). The observed trend may be attributable to a progressive improvement in CsA absorption from the gastrointestinal tract (and therefore a more rapid attainment of peak CsA concentrations in the blood) and/or a progressive increase in CsA metabolism.
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Conflict of interest statement. None declared.
Department of Renal Medicine St James's University Hospital Beckett Street Leeds LS9 7TF UK Email: John.Stoves{at}bradfordhospitals.nhs.uk
References
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