Darshika Chhabra

Impact of Anemia after Renal Transplantation on Patient and Graft Survival and on Rate of Acute Rejection

BACKGROUND AND OBJECTIVES The impact of posttransplantation anemia on patient survival, renal allograft survival, and rate of acute rejection is not known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 1023 patients who underwent kidney transplantation at one center from January 1992 through June 2003 were retrospectively analyzed. Posttransplantation anemia was defined as mean hemoglobin <11 g/dl after 3 mo after transplantation. Data on demographics, pretransplantation dialysis, previous transplant history, pretransplantation hemoglobin, degree of HLA mismatch, and donor characteristics were collected. Some of the posttransplantation data that were collected in addition to the hemoglobin included delayed graft function; diabetes; hypertension; induction and maintenance of immunosuppressive regimen; posttransplantation infections; and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, statins, aspirin, and beta blockers. Cox regression models were used to assess the effects of posttransplantation anemia on each outcome: Mortality, graft survival, and rate of acute rejection. Median follow-up time was 4 yr. RESULTS During the entire follow-up period, there were 89 (9%) deaths, 143 (14%) acute rejection episodes, and 235 (23%) kidney losses. In multivariate Cox regression models, being anemic after transplantation, after the first 90 d, was associated with increased overall mortality and increased renal allograft loss. Posttransplantation anemia was also associated with increased acute rejection rates. CONCLUSIONS This study shows that posttransplantation anemia is associated with worse patient and graft survival and higher rates of acute rejection when compared with nonanemic renal transplant recipients.

Long-term renal transplant function in recipient of simultaneous kidney and pancreas transplant maintained with two prednisone-free maintenance immunosuppressive combinations: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus.

Background. It is not known how different steroid-free immunosuppressive combinations affect long-term kidney transplant function in recipients of simultaneous kidney and pancreas transplant (SPK). Here, we sought to evaluate, in SPK recipients, the impact on long-term renal allograft function of two Tac-based prednisone-free maintenance immunosuppressive protocols: tacrolimus (Tac)/mycophonelate mofetil (MMF) versus Tac/ sirolimus (SRL). Methods. In this single-center, retrospective, sequential study, we analyzed 59 SPK transplant patients with at median follow up of 5 years. All patients received induction therapy with thymoglobulin and maintenance immunosuppression with Tac/MMF (n=22) or Tac/SRL (n=37). There were no differences between the two groups in regards to age, gender, race, panel reactive antibodies, degree of mismatch, donor age, incidence of delay graft function, and Tac trough levels at different time points after transplantation. Results. Kaplan−Meier patient survival at 6 years after transplantation was not statistically different between the two groups. Rate of ACR was similar. Kidney survival, even if not statistically significant, was better in the Tac/MMF group than in the Tac/SRL (90.7% vs. 70.7%, P=0.09). The slope of glomerular filtration rate decline per month at 5 years after transplantation was not statistically different between the two groups. Both groups had the same decline over time in glomerular filtration rate of 0.40±0.06 mL/min/1.732/month. Pancreas survival at 6 years after transplantation was 100% in both treatment groups. Conclusions. Our data suggest that, in SPK recipients, long-term kidney allograft survival and function are not statistically different. A trend toward an increased rate of renal allograft loss was found in the Tac/SRL-treated group.

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens: Tacrolimus/Mycophenolate Mofetil versus Tacrolimus/Sirolimus

BACKGROUND AND OBJECTIVES The optimal maintenance immunosuppressive regimen to improve long-term renal allograft function and graft survival is yet to be determined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This observational study prospectively compared tacrolimus/sirolimus with tacrolimus/mycophenolate mofetil in renal transplant recipients using a prednisone-free regimen with over 8.5 years of follow-up. Patients received methylprednisonlone and anti-IL2 receptor antagonist (Basiliximab) induction and were blindly randomized to either the tacrolimus/mycophenolate mofetil (n=45) or tacrolimus/sirolimus (n=37) groups. Outcome measures included patient and renal allograft survival, incidence of acute rejection, and estimated GFR. RESULTS The tacrolimus/mycophenolate mofetil group compared with the tacrolimus/sirolimus group had overall better renal allograft survival (91% versus 70%, P=0.02); 13 patients (35.1%) in the tacrolimus/sirolimus group and 8 patients (17.8%) in the tacrolimus/mycophenolate mofetil group experienced biopsy-proven acute cellular rejection (P=0.07). By 3 months post-transplant, estimated GFR was significantly lower in the tacrolimus/sirolimus group compared with the tacrolimus/mycophenolate mofetil group (47.7 versus 59.6 ml/min per 1.73 m(2), P=0.0002), and this trend persisted throughout the follow-up period. Also, the slope of decline in the tacrolimus/sirolimus group was significantly steeper than in the tacrolimus/mycophenolate mofetil group. CONCLUSIONS This study shows that, in a prednisone-free immunosuppressive regimen, long-term renal graft survival and function are significantly worse in the tacrolimus/sirolimus group than the tacrolimus/mycophenolate mofetil group. The synergistic nephrotoxic effect and higher acute rejection rates in the tacrolimus/sirolimus compared with the tacrolimus/mycophenolate mofetil group adversely affect graft survival.

Impact of calcineurin-inhibitor conversion to mTOR inhibitor on renal allograft function in a prednisone-free regimen.

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone‐free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow‐up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy‐proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone‐free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.

Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus

Tacrolimus and Sirolimus are commonly used maintenance immunesuppressants in kidney transplantation. Since their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of Tacrolimus to Sirolimus conversion on frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late Sirolimus conversion and 12 on Tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12 and 24-months post-randomization with T cell subpopulations analyzed by flow cytometry and T cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24-months post-randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4+25+++Foxp3+ regulatory T cells. While Tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post-transplant, Sirolimus conversion increased indirect alloreactive T cell frequencies compared to Tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in Sirolimus-converted patients. Thus, chronic immune alterations are induced after Sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). It preferentially inhibits denovo pathway of guanosine nucleotide synthesis in T and B-lymphocytes and prevents their proliferation, thereby suppresses both cell mediated and humoral immune responses. Clinical trials in kidney transplant recipients have shown the efficacy of MMF in reducing the incidence and severity of acute rejection episodes. It also improves long term graft function as well as graft and patient survival in kidney transplant recipients. MMF is useful as a component of toxicity sparing regimens to reduce or avoid exposure of steroids or calcineurin inhibitor (CNI). Enteric-coated mycophenolate sodium (EC-MPS) can be used as an alternative immunosuppressive agent in kidney transplant recipients with efficacy and safety profile similar to MMF.

Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients.

Introduction: Several new medications are now available for immunosuppression in the kidney transplant field. Tacrolimus and mycophenolate mofetil were first introduced for immunosuppression in renal transplantation in the mid 1990s. Since then, the combination of tacrolimus and mycophenolate mofetil has been evaluated in numerous clinical trials. The outcomes of these trials have varied due to differences in induction and/or maintenance therapy, drug dosing and monitoring protocols, and study design. The aim of this review is to analyze the literature critically and to provide an overview of tacrolimus and mycophenolate mofetil combination therapy in renal transplantation.

Late conversion of tacrolimus to sirolimus in a prednisone-free immunosuppression regimen in renal transplant patients.

Chhabra D, Grafals M, Cabral B, Leventhal J, Parker M, Gallon L. Late conversion of tacrolimus to sirolimus in a prednisone‐free immunosuppression regimen in renal transplant patients.
Clin Transplant 2009: DOI: 10.1111/j.1399‐0012.2009.01047.x
© 2009 John Wiley & Sons A/S.