A pilot study of reduced dose cyclosporine and corticosteroids to reduce new onset diabetes mellitus and acute rejection in kidney transplant recipients.

BACKGROUND: New onset diabetes mellitus (NODM) and acute rejection (AR) are important causes of morbidity and risk factors for allograft failure after kidney transplantation. METHODS: In this multi-center, open label, single-arm pilot study, 49 adult (≥18 years of age), low immunologic risk, non-diabetic recipients of a first deceased or living donor kidney transplant received early steroid reduction to 5 mg/day combined with Thymoglobulin® (Genzyme Transplant, Cambridge, MA, USA) induction, low dose cyclosporine (2-hour post-dose (C2) target of 600 to 800 ng/ml) and mycophenolic acid (MPA) therapy. RESULTS: Six months after transplantation, two patients (4%) developed NODM and one patient (2%) developed AR. Four patients had impaired fasting glucose tolerance based on 75-g oral glucose tolerance testing (OGTT). There was one patient death. There were no episodes of cytomegalovirus (CMV) infection or BK virus nephritis. In contrast, in a historical cohort of n = 27 patients treated with Thymoglobulin induction, and conventional doses of cyclosporine and corticosteroids, the incidence of NODM and AR was 18% and 15%. CONCLUSIONS: The pilot study results suggest that Thymoglobulin induction combined with early steroid reduction, reduced cyclosporine exposure and MPA, may reduce the incidence of both NODM and AR in low immunological risk patients. A future controlled study enriched for patients at high risk for NODM is under consideration. TRIAL REGISTRATION: ClinicalTrials.gov: http://NCT00706680.

Opportunities to deter transplant tourism exist before referral for transplantation and during the workup and management of transplant candidates.

Transplant tourism is a global issue, and physicians in the developed world may be in a position to actively deter this practice. To examine such opportunities, we identified 93 residents of British Columbia, Canada who had a kidney graft through tourism and determined their previous interactions with our transplant programs. These patients were mainly ethnic minorities (90%) who traveled to their country of origin for transplantation. Many tourists were transplanted early in their disease course, with 27 having a preemptive transplant. Among the 65 tourists referred for transplant, 33 failed to complete the evaluation. All tourists who completed an evaluation were placed on a waiting list in British Columbia and, after waiting a median of 2 years, pursued tourism. Most of these patients (62%) had a potential living donor, but none had an approved donor, with 13 donors found medically unsuitable, 8 ABO incompatible, and 12 who did not complete their evaluation. Thus, strategies to deter tourism should start before the development of end-stage renal disease and should be part of pretransplant workup and wait-list management, focusing on patients not progressing through their evaluation, those with a declined living donor, and those facing longer wait times, as these groups appear to be at higher risks for transplant tourism. Further studies are needed to identify individuals at risk for transplant tourism and to define effective strategies to deter these individuals.

Factors associated with progression of interstitial fibrosis in renal transplant patients receiving tacrolimus and mycophenolate mofetil.

BACKGROUND: We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed. METHODS: Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study. RESULTS: At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies. CONCLUSIONS: A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

A matched cohort pharmacoepidemiological analysis of steroid free immunosuppression in renal transplantation.

BACKGROUND: This longitudinal, sequential, matched closed-cohort design pharmacoepidemiological analysis examined the influence of maintenance steroid therapy in 380 first graft recipients after renal transplantation under conditions of normal clinical practice. METHODS: Nonexposed (steroid avoidance, n=190) and exposed (steroid treated, n=190) cohorts were matched 1:1 for key demographic factors, including donor source (living or deceased), diabetic status, panel reactive antibody level, recipient age (by decade), and sex. RESULTS: Cohorts were comparable for all variables except median human leukocyte antigen mismatch (4 vs. 3, P=0.03), use of tacrolimus (90.0% vs. 59.5%, P

A prospective 3-yr evaluation of tacrolimus-based immunosuppressive therapy in immunological high risk renal allograft recipients.

BACKGROUND: There have been no published data on use of the the newer immunosuppressants tacrolimus and mycophenolate mofetil (MMF) in high immunological risk renal transplantation. We therefore undertook a prospective study to systematically assess outcomes using these agents as part of an aggressive immunosuppressive regimen. METHODS: Fifty-nine high-risk renal allograft recipients were enrolled at 10 Canadian sites and given a regimen of: a biological induction agent, tacrolimus, MMF, and corticosteroids. Patients included 10 (17%) who had lost a previous graft to rejection <1 yr, 31 (53%) with a current panel reactive antibody (PRA) >30%, 47 (80%) with a historic PRA >50%, four (7%) who had a positive historical T-cell crossmatch with the current donor, and six (10%) with a current positive B-cell crossmatch. The mean peak PRA was 76 +/- 33%. RESULTS: The estimated 3-yr Kaplan-Meier patient and graft survival estimates were 89% and 75%, respectively. There were nine graft losses other than deaths with a functioning graft, of which six were preceded by delayed graft function (p = 0.01, chi2). Sixteen (27%) recipients experienced at least one episode of biopsy-confirmed acute rejection. Infections included cytomegalovirus in 16 patients, eight of whom had tissue-invasive disease. Only one malignancy occurred. CONCLUSIONS: The immunosuppressive strategy investigated is effective and displays a satisfactory safety profile in high immunological risk renal allograft recipients.

They talk the talk: Surveying attitudes and judging behavior about living anonymous kidney donation.

BACKGROUND: Over the past 30 years, numerous studies have reported that some individuals are willing to donate a kidney anonymously to a stranger; however, intentions are poor predictors of behavior. We surveyed individuals interested in being living anonymous donors (LADs), exposed them to an interview paralleling live-donor assessment, and measured their LAD commitment. Personality and donation decision factors were examined to corroborate cases of attitudinal and behavioral congruency. METHODS: A telephone survey of 1,002 randomly selected adults living in Vancouver, British Columbia, asked respondents how willing they were to donate a kidney, while alive, to particular individuals including a stranger. A subsample participated in a follow-up, which involved completing a mailed questionnaire and taking part in an in-depth interview. Expert raters judged respondents' commitment to being a LAD on the basis of the interviews. RESULTS: Two hundred fifty-eight (26%) of those surveyed stated they would probably or definitely be willing to donate a kidney to a stranger. Fifty-two completed the follow-up. Sixteen of the 52 (31%) were judged to be "committed LADs." No demographic differences were found between the committed LADs and the 33 remaining "noncommitted participants." The committed LADs differed significantly from the noncommitted participants on personality measures and donation decision factors. These differences underscore the latter group's anonymous donation commitment. CONCLUSIONS: This study brings into focus the potential for a significant number of individuals coming forward as potential LAD candidates if they are informed about the need and given unbiased information about the procedure. We believe there is ethical latitude in allowing the promotion of LAD donation by interested third parties such as patient advocacy groups and professional bodies. We advocate public awareness of LAD programs as a first step followed thereafter by more provocative measures to engage the public in this endeavor.

The living anonymous kidney donor: lunatic or saint?

Studies indicate that 11% to 54% of individuals surveyed would consider donating a kidney, while alive, to a stranger. The idea of 'living anonymous donors' (LADs) as a donor source, however, has not been embraced by the medical community. Reservations focus on the belief that LADs might be psychologically unstable and thus unsuitable donors. Our goal was to inform policy development by exploring the psycho-social make up and motivations of the LAD. Ninety-three unsolicited individuals contacted our center expressing interest in living anonymous donation. Of these, 43 participated in our study, completing two extensive inventories of psychopathology and personality disorder and taking part in the Comprehensive Psycho-Social Interview (CPSI). From the Personality Assessment Inventory (PAI), the revised NEO Personality Inventory (NEO PI-R), and the CPSI, coders assessed psychological health, psycho-social suitability, commitment, and motivations. Twenty-one participants passed the stringent criteria to be considered potential LADs. Content analysis of motivations showed that potential LADs were more likely than non-LADs (those who did not pass the criteria) to have a spiritual belief system and to be altruistic. Non-LADs were more likely than potential LADs to use donation to make a statement against their families. The authors conclude with a preliminary outline of eight policy recommendations.