Measurement of cyclosporin exposure in renal transplant recipients during the early post-operative period: is C2 alone sufficient?

We note the association between achievement of target C2 [the 2 h post-dose blood cyclosporin (CsA) concentration] values and a lower incidence of acute renal transplant rejection reported by di Paolo et al. [1]. This is supported by other studies [2,3]. The authors also state that target C2 was not achieved during the early post-operative period in a significant proportion of patients, despite using high doses of Neoral®. The experience with C2 monitoring in our unit has been very similar, but our data also suggest that C2 is not a reliable measure of CsA exposure in the first week post-transplantation.

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 1350–1650 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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Fig. 1. C2:C0 ratio during the first week post-renal transplantation. The box indicates the upper and lower quartiles and the central line is the median. The points at the end of the ‘whiskers’ are the 2.5 and 95% values.

 
In summary, we have observed that although achievement of target C2 values is associated with a lower incidence of acute renal allograft rejection, changes in Neoral® dose that are based solely on C2 data may be misguided because C2 is an unreliable measure of CsA exposure in the first week post-transplantation. It would seem prudent to take account of both C2 and C0 as well as clinical factors when making early adjustments to Neoral® dose.

Conflict of interest statement. None declared.

John Stoves, Richard Baker and Charles G. Newstead

Department of Renal Medicine St James's University Hospital Beckett Street Leeds LS9 7TF UK Email: John.Stoves{at}bradfordhospitals.nhs.uk

References

  1. di Paolo S, Teutonico A, Stallone G et al. Cyclosporin exposure correlates with 1 year graft function and histological damage in renal transplanted patients. Nephrol Dial Transplant 2004; 19: 2107–2112[Abstract/Free Full Text]
  2. Keown PA for The International Neoral Renal Transplantation Study Group. Neoral C2 absorption profiling: a simple, accurate and precise predictor of rejection risk in renal transplantation. Am J Transplant 2001; 1[Suppl 1]: 990A
  3. Clase CM, Mahalati K, Kiberd BA et al. Adequate early cyclosporine exposure is critical to prevent allograft rejection: patients monitored by absorption profiling. Am J Transplant 2002; 2: 789–795[CrossRef][ISI][Medline]
  4. Stoves J, Newstead CG, Will EJ. Trough (C0) and 2 h post-dose (C2) cyclosporine blood levels and the development of early acute renal allograft rejection: a Bayesian analysis. Nephrol Dial Transplant 2002; 17[Suppl 1]: 174A




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