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• W2000909923 abstract "Related Article, p. 1127 Related Article, p. 1127 Diabetes mellitus (DM) is a major contributor to cardiovascular, cerebrovascular, and peripheral vascular disease, with significant associated morbidity and mortality. Unfortunately, the incidence is increasing in the general and transplant populations. Recognizing the poorer prognosis in diabetic recipients, DM used to be a contraindication for transplant and still is a relative contraindication in Europe. Many immunosuppressive agents, the calcineurin inhibitors, steroids, and even the mammalian target of rapamycin (mTOR) inhibitors, are diabetogenic and can cause posttransplant DM, now termed “new-onset diabetes after transplant” (NODAT). NODAT affects up to 34% of nondiabetic recipients in the first year after transplant.1Cole E.H. Johnston O. Rose C.L. Gill J.S. Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival.Clin J Am Soc Nephrol. 2008; 3: 814-821Crossref PubMed Scopus (192) Google Scholar, 2Matas A.J. Gillingham K.J. Humar A. et al.Posttransplant diabetes mellitus and acute rejection: impact on kidney transplant outcome.Transplantation. 2008; 85: 338-343Crossref PubMed Scopus (46) Google Scholar, 3Vincenti F. Friman S. Scheuermann E. et al.Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.Am J Transplant. 2007; 7: 1506-1514Crossref PubMed Scopus (479) Google Scholar, 4Woodward R.S. Schnitzler M.A. Baty J. et al.Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients.Am J Transplant. 2003; 3: 590-598Crossref PubMed Scopus (329) Google Scholar The separate impact of pretransplant DM and NODAT on transplant outcomes and economics is only beginning to be understood.4Woodward R.S. Schnitzler M.A. Baty J. et al.Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients.Am J Transplant. 2003; 3: 590-598Crossref PubMed Scopus (329) Google Scholar, 5Cosio F.G. Pesavento T.E. Kim S. Osei K. Henry M. Ferguson R.M. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Crossref PubMed Google Scholar, 6Hjelmesaeth J. Hartmann A. Leivestad T. et al.The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events.Kidney Int. 2006; 69: 588-595Crossref PubMed Scopus (261) Google Scholar Acute rejection consistently has been identified as a key factor associated with inferior long-term transplant success, even in the present era of transplant.7McDonald S. Russ G. Campbell S. Chadban S. Kidney transplant rejection in Australia and New Zealand: relationships between rejection and graft outcome.Am J Transplant. 2007; 7: 1201-1208Crossref PubMed Scopus (104) Google Scholar Although acute rejection rates have been decreased successfully, a corresponding improvement in long-term outcomes has not been observed. A major contributor to long-term graft loss is recipient death with a functioning graft, with most deaths caused by cardiovascular events. Certainly, the changing recipient demographics (eg, increasing age and more individuals with diabetes) contributes to the significant mortality observed. Posttransplant complications such as NODAT increasingly are recognized as potentially modifiable risk factors. In this issue of the American Journal of Kidney Diseases, Kuo et al8Kuo H.-T. Sampaio M.S. Vincenti F. Bunnapradist S. Associations of pretransplant diabetes mellitus, new-onset diabetes after transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) Database.Am J Kidney Dis. 2010; 56: 1127-1139Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar examine the impact of DM and acute rejection on outcomes of kidney transplants using data from the United Network of Organ Sharing/Organ Transplant Procurement Network (UNOS/OPTN). Single-center studies previously have shown that NODAT has a negative impact on patient survival similar to pretransplant DM.5Cosio F.G. Pesavento T.E. Kim S. Osei K. Henry M. Ferguson R.M. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Crossref PubMed Google Scholar, 6Hjelmesaeth J. Hartmann A. Leivestad T. et al.The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events.Kidney Int. 2006; 69: 588-595Crossref PubMed Scopus (261) Google Scholar The detrimental effect begins within the first 2 years after transplant, although the duration of DM is 10-20 years shorter with NODAT compared with pretransplant DM. In a previous USRDS registry analysis from 1995-2002, patients who developed acute rejection or NODAT had a similar risk of transplant failure from any cause.1Cole E.H. Johnston O. Rose C.L. Gill J.S. Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival.Clin J Am Soc Nephrol. 2008; 3: 814-821Crossref PubMed Scopus (192) Google Scholar However, the mechanisms of graft loss were different: acute rejection was associated with death-censored graft loss, while NODAT was associated with death with a functioning transplant. In an attempt to maintain low acute rejection rates and maximize long-term patient and transplant outcomes, the transplant community seems to have taken a somewhat inconsistent and even schizophrenic approach to immunosuppressive protocols. In the United States, transplant physicians and surgeons have overwhelmingly embraced the use of tacrolimus over cyclosporine9OPTN/SRTROPTN/SRTR annual report: immunosuppression use for maintenance prior to discharge, 1998 to 2007 recipients with kidney transplants.http://www.ustransplant.org/annual_reports/current/506e_ki.htmGoogle Scholar despite an incidence of NODAT that is 2-fold higher with tacrolimus.4Woodward R.S. Schnitzler M.A. Baty J. et al.Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients.Am J Transplant. 2003; 3: 590-598Crossref PubMed Scopus (329) Google Scholar, 10Ekberg H. Tedesco-Silva H. Demirbas A. et al.Reduced exposure to calcineurin inhibitors in renal transplantation.N Engl J Med. 2007; 357: 2562-2575Crossref PubMed Scopus (1392) Google Scholar This may occur because the acute rejection rate with tacrolimus is half that observed with cyclosporine.10Ekberg H. Tedesco-Silva H. Demirbas A. et al.Reduced exposure to calcineurin inhibitors in renal transplantation.N Engl J Med. 2007; 357: 2562-2575Crossref PubMed Scopus (1392) Google Scholar Meanwhile, almost 35% of the community has adopted steroid avoidance to decrease NODAT,9OPTN/SRTROPTN/SRTR annual report: immunosuppression use for maintenance prior to discharge, 1998 to 2007 recipients with kidney transplants.http://www.ustransplant.org/annual_reports/current/506e_ki.htmGoogle Scholar although a randomized double-blinded placebo-controlled trial of steroid avoidance versus standard steroids showed no difference in the incidence of NODAT at 1 through 5 years and almost twice the rate of biopsy-proven acute rejection in the steroid-avoidance arm.11Woodle E.S. First M.R. Pirsch J. Shihab F. Gaber A.O. Van Veldhuisen P. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy.Ann Surg. 2008; 248: 564-577PubMed Google Scholar The transplant community's conflicting approaches might reflect that we really do not know what the differential impact of pretransplant DM, NODAT, and acute rejection are on transplant outcomes. The US Food and Drug Administration (FDA) appears to support the concept that acute rejection remains the most important surrogate measure for long-term outcomes with the recent approval of the combination of tacrolimus, mycophenolate, and prednisone, although it leads to a 2-fold increase in the risk of NODAT. Belatacept, which is associated with less NODAT and better glomerular filtration rate, but more acute rejection and posttransplant lymphoproliferative disease,12Durrbach A. Pestana J.M. Pearson T. et al.A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study).Am J Transplant. 2010; 10: 547-557Crossref PubMed Scopus (421) Google Scholar is requiring additional safety data to determine whether it will be approved by the FDA. Given the tradeoff between risks of acute rejection and NODAT, enhanced understanding of how each influences transplant outcomes is crucial to guide immunosuppression decisions. The study by Kuo et al8Kuo H.-T. Sampaio M.S. Vincenti F. Bunnapradist S. Associations of pretransplant diabetes mellitus, new-onset diabetes after transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) Database.Am J Kidney Dis. 2010; 56: 1127-1139Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar examines the impact of pretransplant DM, as well as NODAT and acute rejection developing within the first year after kidney transplant, on graft failure, death-censored graft failure, and all-cause and cardiovascular mortality. Including patients who underwent transplant in 2004-2007, this analysis elucidates the relative contribution of pretransplant DM, acute rejection, and NODAT to transplant outcomes in the most current era of kidney transplants. From the original group of 45,989 patients, 37,448 with transplant survival and follow-up longer than 1 year were identified as the study group. Using univariate and multivariate analyses of more than 20 of the common transplant variables associated with transplant and patient outcomes, patient and transplant survival were reported in 6 mutually exclusive groups: 1, no DM and no acute rejection; 2, NODAT only; 3, pretransplant DM only; 4, acute rejection only; 5, NODAT and acute rejection; and 6, pretransplant DM and acute rejection. In the original group, 32% of patients had DM at the time of transplant. The incidence of NODAT at 1 year was 14.3% within the original group, but 9.7% for the study group (>1 year transplant survival and follow-up). Additionally, within the study group, the acute rejection rate at 12 months was higher in those also developing NODAT compared with those who did not (14.7% vs 9.6%, respectively). These findings suggest an association between NODAT, acute rejection, and early transplant failure. As previously suggested by others, NODAT may be a consequence of augmented immunosuppression (eg, steroids) used to treat acute rejection, or conversely, acute rejection may occur as a consequence of immunosuppression decrease to avoid or treat NODAT. In the study group, the rate of NODAT was 16.4% at 3 years. A sobering finding is that when those with pretransplant DM are included, approximately half of all kidney transplant recipients will have DM by 3 years after transplant. Using univariate and multivariate analyses, both acute rejection and pretransplant DM had significant and distinct effects on transplant and patient survival. In adjusted multivariate analyses, acute rejection (but not DM) was associated significantly with death-censored graft failure, nearly doubling the risk of graft loss (Fig 1A ). Pretransplant DM (but not NODAT) was associated significantly with both all-cause and cardiovascular mortality. To a lesser degree, increased all-cause mortality also was observed in patients with acute rejection; patients with both pretransplant DM and acute rejection had the highest mortality (Fig 1B). NODAT alone was not associated significantly with death-censored graft failure, all-cause mortality, or cardiovascular mortality. These findings parallel those of earlier reports1Cole E.H. Johnston O. Rose C.L. Gill J.S. Impact of acute rejection and new-onset diabetes on long-term transplant graft and patient survival.Clin J Am Soc Nephrol. 2008; 3: 814-821Crossref PubMed Scopus (192) Google Scholar, 2Matas A.J. Gillingham K.J. Humar A. et al.Posttransplant diabetes mellitus and acute rejection: impact on kidney transplant outcome.Transplantation. 2008; 85: 338-343Crossref PubMed Scopus (46) Google Scholar showing different mechanisms contributing to long-term transplant failure; acute rejection is associated with death-censored graft loss, whereas DM contributes to patient mortality. However, in this study, only pretransplant DM, not NODAT, was associated significantly with increased all-cause and cardiovascular mortality. There are limitations to the study. Steroid use was reported in >90% at discharge, which does not reflect that probably 30% in this era would have had steroid therapy withdrawn by 4 weeks. Even in centers that do not use steroid avoidance, most are tapering steroid dosages to 5 mg/d by 1 month, and this might contribute to the lower incidence of NODAT observed. Additionally, the definition and capture of NODAT and acute rejection remain significant challenges in registry data. Although single-center studies have shown an early impact of NODAT on survival, the median duration of follow-up in this study is only 1.5 years, which may be insufficient to show the adverse effect of NODAT. The investigators also did not provide hazard ratios for the other variables in the model. Therefore, given the tradeoff between risks of acute rejection and NODAT with our present immunosuppressants, how do we best maximize transplant and patient outcomes? This study helps answer these questions. Our interpretation is that acute rejection, even in the present era, remains the most significant potentially modifiable factor of a list of more than 20 variables and certainly is more important than NODAT. One should be careful not to discard calcineurin inhibitors and steroids prematurely in favor of any alternative agent that might be associated with less NODAT, but more acute rejection. Financial Disclosure: The authors declare that they have no relevant financial interests. Associations of Pretransplant Diabetes Mellitus, New-Onset Diabetes After Transplant, and Acute Rejection With Transplant Outcomes: An Analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) DatabaseAmerican Journal of Kidney DiseasesVol. 56Issue 6PreviewDiabetes and acute rejection are major contributors to morbidity and mortality in kidney transplant recipients. Immunosuppressive medications decrease acute rejection, but increase the frequency of new-onset diabetes after transplant. Our objective was to investigate the joint associations of diabetes (pretransplant diabetes and new-onset diabetes after transplant) and acute rejection with transplant outcomes in a recent transplant cohort. Full-Text PDF" @default.
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• W2000909923 title "The Tradeoff Between the Risks of Acute Rejection and New-Onset Diabetes After Kidney Transplant" @default.
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