New-onset diabetes after renal transplantation: diagnosis, incidence, risk factors, impact on outcomes, and novel implications.

OBJECTIVE: New-onset diabetes after transplantation (NODAT) is a multifactorial, complex metabolic disorder associated with impaired long-term graft function, reduced recipient survival, and increased risks of cardiovascular disease and infectious complications. The impact of NODAT is generally underestimated partly due to the inconsistent criteria that have been previously used for its diagnosis and to the generally short observation periods. The aim of this article was to review the recent literature on NODAT and to highlight the novel implications. FINDINGS: The 2010 American Diabetes Association guidelines provide useful, simplified criteria to unify the diagnosis including application of hemoglobin A1C levels. We sought to establish the impact of various modifiable and nonmodifiable risk factors. A vast number of papers have examined the effects of immunosuppressive medications on the development of NODAT: Neither calcineurin inhibitor nor sirolimus (SRL) or steroids seems to be innocent of contributing to it. Immunosuppressants account for 74% of the occurrence of NODAT. Among modifiable risk factors, obesity is independent and significant, with great prevalence in the population. In additional to lifestyle modifications, the role of bariatric surgery (BS) either before or after transplantation is highlighted herein as a strategy to reduce disease in the view of the results among overweight, nontransplanted patients. SUMMARY: Because of the strong association between high glucose values in the early posttransplant period and the development of NODAT, the condition must be recognized early after (or even before) transplantation by intensive screening. Patients at risk for NODAT must modify appropriate risk factors and particularly undergo pretransplant planning and/or posttransplant adjustment individualizing immunosuppressive therapy to mitigate the risk of this serious complication.

Sirolimus therapy predisposes to new-onset diabetes mellitus after renal transplantation: a long-term analysis of various treatment regimens.

PURPOSE: This retrospective analysis evaluated the impacts of sirolimus (SRL), cyclosporine (CsA), and steroids (S) on the occurrence, treatment, and complications of new-onset diabetes after transplantation (NODAT). METHODS: We compared 4 groups: group 1, SRL plus full-exposure CsA/S (n = 118); group 2, full-exposure CsA/S/no SRL ± antiproliferative drug (n = 141); group 3, SRL plus reduced CsA exposure/S (n = 212); and group 4, no SRL/full-exposure CsA/S ± antiproliferative drug (n = 43). RESULTS: NODAT rates reflected the level of CsA exposure; at 10 years 54% versus 30% for groups 1 versus 2 (P = .0001); at 5 years 30% versus 21% for Groups 3 versus 4 (P = .3); 81% of cases were detected within 1 year. The lower NODAT rate in group 3 reflected a benefit of reduced CsA exposure (P = .02; hazard ratio (HR), 1.006). Group 1 showed higher CsA (P = .0001) and lower SRL concentrations (P = .016) versus group 3. CsA exposure closely correlating with NODAT among group 1 (P = .0001) was the major difference between groups 1 and 3 (P = .04; HR, 0.97). Differences in steroid treatment did not play a significant role in NODAT. Comparing groups 1 and 2, SRL was an independent risk factor for NODAT (P = .004; HR, 3.5). CONCLUSIONS: Our 10-year experience revealed SRL to be an etiologic agent for NODAT, displaying interactive, possibly pharmacokinetic, and pharmacodynamic effects with concomitant CsA in combination treatment.

Bortezomib successfully reverses early recurrence of light-chain deposition disease in a renal allograft: a case report.

Light-Chain Deposition Disease (LCDD) frequently recurs after renal transplantation, displaying a pernicious course. Herein we have described a 39-year-old Caucasian man with a history of immunoglobulin G-kappa multiple myeloma who failed two chemotherapy regimens, but ultimately responded to the combination of thalidomide, bortezomib, and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation 3 years prior to transplantation, during which time he showed no evidence of persistent or recurrent disease. At 3 days following spousal living related renal transplantation, he displayed a rapid deterioration of renal function requiring dialysis therapy. This episode failed to respond to empiric antirejection therapy including anti-thymocyte globulin, plasmapheresis, and anti-CD20 monoclonal antibody. Increasing evidence suggested recurrence of LCDD, including positive immunofluorescence staining of basement membranes and vessels for kappa light chains as well as free kappa light chains in his urine and serum. Following suspension of sirolimus, he was initiated on and responded to bortezomib (1.3 mg/m(2)) with discontinuation of dialysis within 3 weeks and progressively improving renal function. His maintenance therapy, in addition to six 2-week-long cycles of bortezomib separated by 1-week rest periods, includes cyclosporine (50 mg twice daily), prednisone (10 mg daily), and curcumin (9 g daily). In sum, bortezomib rescue therapy salvaged a spousal renal transplant afflicted with recurrent LCDD.

Impact of rituximab therapy for treatment of acute humoral rejection.

INTRODUCTION: Antibody mediated rejection (AMR) is associated with a greater incidence of allograft loss because traditional approaches - pulse steroid or anti-lymphocyte antibodies are usually ineffective. This retrospective analysis documented the benefit of rituximab administration in addition to plasmapheresis (PP). METHODS: We retrospectively reviewed the data from 54 kidney transplant patients treated for AMR between 2001 and 2006, including 26 patients who received PP plus rituximab (Group A), versus 28 subjects who underwent PP without rituximab (Group B). Only patients whose serum IgG levels were below normal values received intravenous gamma globulin (IVIG). In addition to clinical and demographic variables we evaluated graft/patient survivals at two years post-diagnosis, Banff classification of rejections, serum creatinine and calculated GFR values at baseline, rejection, resolution as well as three, six, 12 and 24 months thereafter. RESULTS: The demographic features of the cohorts showed no significant differences. The two-year graft survival for patients treated with rituximab plus PP was 90%, significantly better than 60% in the PP cohort (p = 0.005). Upon multivariate analysis administration of rituximab was the most significant factor (>or= 0.009); whereas, IVIG also produced a useful effect (p = 0.05). Neither the mean (>or= 0.42) nor the slope (p = 0.25) of GFR values showed a significant difference among salvaged kidneys over 24 months after completion of AMR treatment. The rates and types of infectious complications at three and six months did not show significant differences or impact on graft survival. CONCLUSION: Addition of rituximab improved the outcomes of PP treatment of antibody mediated rejection episodes.

Case report: successful treatment of posttransplant lymphoproliferative disorder and quiescence of dermatomyositis with rituximab and sirolimus.

Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab-SRL combination to treat PTLD while maintaining dermatomyositis in remission.