Herwig-Ulf Meier-Kriesche

Despite evidence of favorable long-term effects of mycophenolate mofetil (MMF) in renal transplantation, its introduction at different times posttransplant has not been studied in large cohorts. Single-organ renal allograft recipients (n=2217) who had MMF introduced 6 months to more than 20 years posttransplantation for various reasons were included in TranCept Switch, a multicenter, noninterventional, observational 4-year study. Changes in renal function before and after the introduction of MMF were analyzed. MMF was introduced because of renal function decline in 43% of patients and poor tolerability with previous treatment in 23% of patients. The change in slope of the calculated glomerular filtration rate (modification of diet in renal diseases formula) regression line before and after MMF initiation was +2.01 mL/min per year (P<0.001) on average. The greatest benefit was noted in patients who received MMF because of renal function decline and in whom calcineurin inhibitor treatment was subsequently reduced or withdrawn (+3.09 mL/min per year). Time from transplantation to MMF introduction influenced the glomerular filtration rate at MMF initiation (slow progressive deterioration) but not the direction of the slope change, which was positive even for late introduction. MMF introduction may be associated with improvement or stabilization of renal function even several years after transplantation.

The unfortunate fact that long-term renal allograft survival has not followed the gains made in short-term allograft survival has been documented repeatedly in the United States [1] and also worldwide [2]. Undoubtedly, large inclusive datasets are needed to document certain overarching trends. Some of the most accepted risk factors for poor outcomes after transplantation like prolonged pre-transplant dialysis time [3] and the use of expanded criteria donors [4] needed confirmatory analysis from large databases to quantify these effects. When in smaller datasets, risk factors that have been confirmed for larger populations are not evident, one of the two things might be happening. Either the local reality is different and the sampled population has different characteristics and treatments are possibly different than the overall population or there is inadequate power to adequately identify and quantify multiple risk factors at the same time. The authors of the paper and the staff of the Rogosin Institute are certainly to be congratulated for their excellent outcomes and the big progress their center has made [5]. Internal quality assessments are a key component to any program success. National trends might not be reflected in local populations and each center has to assess what works best in their local reality. Several centers have documented excellent local results despite the lack of national evidence of significant long-term progress.

Human leukocyte antigen (HLA) matching has been de-emphasized in the allocation of renal allografts and further discounting is planned in the new United Network of Organ Sharing kidney allocation model. An unforeseen consequence of poorer matching could be increased sensitization for candidates pursuing retransplantation. We examined candidates listed in the United States from 1988 to 2007 from the Scientific Renal Transplant Registry (SRTR) database that were relisted after loss of a primary kidney transplant (n=15,980). The primary outcome was change in panel reactive antibody (PRA) from prior to recipient's initial transplant to the subsequent listing. Absolute change in PRA levels were examined in general linear models and the likelihood of becoming newly sensitized in logistic models. There was no appreciable change in PRA for patients receiving a first 0 HLA-A, -B, -DR, or 0 HLA-A, -B-mismatched kidney transplant; contrariwise, there was a significant increase in PRA by increasing HLA mismatch of the first transplant. Only 10% of patients became sensitized after a 0 HLA-A, -B-mismatched transplant, whereas the proportion rose up to 37% with increasing HLA mismatches. Other factors, notably younger age and African American race, also contributed to a higher PRA at relisting. Although there might be a limited impact of HLA matching on acute rejection and graft survival, many patients might be negatively impacted from poor HLA matching of their first kidney transplant when needing a second transplant. This might be particularly important in patients with a long life expectancy because of the high likelihood of needing a second transplant during their lifetime.

There has been a notable rise of BK virus among kidney transplant recipients. Single-center reports have identified risk factors for development of BK virus. However, there has not been an assessment of risk factors and incidence of this complication at a national level. This study utilized newly collected follow-up information from the national SRTR database to investigate incidence, risk factors and outcomes for solitary kidney transplant recipients associated with treatment for BK virus (TBKV) from 2004 to 2006. Logistic and Cox models were utilized to assess risk factors and evaluate graft survival associated with TBKV. Incidence of TBKV was 1.6% at 6 months and 2.6% at 1 year following transplantation. Patients with and without TBKV at 6 months had 79% and 90% 3-year overall graft survival respectively. Risk factors included advanced donor age, pediatric, African American and male recipients, human leukocyte antigen-mismatching and tacrolimus and thymoglobulin induction as baseline immunosuppression. Acute rejection episodes were more frequent prior to and following TBKV. TBKV is a common and rising incidence, varies based on transplant characteristics and should be included as a safety endpoint in studies investigating immunosuppressive protocols. Careful monitoring and further understanding of disease etiology and treatment strategies are needed.

Exceptionally low acute rejection rates and excellent graft survival can be achieved with cyclosporine and tacrolimus (CNI)-based immunosuppressive protocols that incorporate antiproliferative immunosuppressants and corticosteroids. However, despite short-term success, long-term attrition of graft function and side effects of immunosuppressive agents continue to be significant problems, leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may contribute to long-term damage in transplant kidneys. Metabolic, cosmetic, and neuropsychiatric complications of steroids affect quality of life after transplantation. Newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs or steroids altogether. In this report we review studies that address either CNI or steroid minimization strategies and discuss their risks versus benefits. Given the accumulated experience to date, in our opinion the use of CNIs and steroids as part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI and steroid minimization strategies needs to be further validated in controlled clinical trials with adequate long-term follow-up.