Late intra‐patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report

The natural history for patients with de novo donor-specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation with serologic data is limited. We studied 315 consecutive renal transplants without pretransplant DSA, with a mean follow-up of 6.2 ± 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA posttransplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 ± 3.0 years posttransplant. Independent predictors of dnDSA were HLA-DRβ1 MM > 0 (OR 5.66, p < 0.006); and nonadherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p = 0.061). The median 10-year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody-mediated injury can occur and progress in patients with dnDSA in the absence of graft dysfunction and furthermore, nonadherence and cellular rejection contribute to dnDSA development and progression to graft loss. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons. Show more

We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation. From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used. In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure. This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure. Show more

Lack of adherence to immunosuppressive drugs is a risk factor for development of de novo donor-specific antibodies (dnDSA) and can contribute to antibody-mediated rejection and graft loss. Moreover, nonadherence is the main determinant of immunosuppressive drug level variability. High intrapatient variability of tacrolimus relates to a worse outcome in transplant recipients through unknown mechanisms. We hypothesized that a high within-patient variability of tacrolimus could increase the rate of dnDSA development and contribute to further death-censored graft loss (DCGL). Show more