Karen L. Hardinger

Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure.

Background. Mycophenolate mofetil (MMF) use in renal transplantation has steadily increased since 1995 because of its ability to lower the risks of rejection and chronic allograft nephropathy. However, significant gastrointestinal (GI) complications may lead to MMF dose reductions and discontinuations. Little is known of the association between MMF dose reductions and discontinuations following GI complications and graft survival. Methods. Using the United States Renal Data System, we identified 3,675 adult recipients (age ≥18) with a diagnosed GI complication who were prescribed MMF at the time of first GI diagnosis and had Medicare as their primary insurer. MMF doses were ascertained from Medicare payment records. We estimated risk of graft loss associated with MMF dose adjustments after GI diagnosis: dosage unchanged (reference), reduced <50%, reduced ≥50%, and MMF discontinued. Patients were followed until graft loss, death, last recorded immunosuppression prescription, or 3 years posttransplant. Results. Compared to those with no MMF dose reductions or discontinuations, the risk of graft failure increased with MMF doses reduction ≥50% (HR=2.36, 95% CI 1.23–4.54) and those with MMF discontinuation (2.72, CI 1.60–4.64). Conclusion. Renal transplant recipients who underwent MMF dose reduction or withdrawal following GI diagnosis are associated with increased risk of graft failure.

A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy: 10-year results.

Background. Use of induction for renal transplantation is controversial because of the concerns about long-term safety and efficacy. Methods. We compared the safety and efficacy at 10 years among patients randomized to thymoglobulin or Atgam induction in a single center, randomized, double-blinded trial. Quality-adjusted life years (QALYs) were calculated using utility weights. Results. The primary composite endpoint of freedom from death, graft loss, or rejection, “event-free survival,” was higher with thymoglobulin compared with Atgam (48% vs. 29%; P=0.011). At 10 years, patient survival (75% vs. 67%) and graft survival (48% vs. 50%) were similar, whereas acute rejection remained lower (11% vs. 42%, P=0.004) in the thymoglobulin group. The incidence of all types of cancer was numerically lower with thymoglobulin compared with Atgam (8% vs. 21%, P=NS). There were no posttransplant lymphoproliferative disorder in the thymoglobulin group and there were two cases in the Atgam group. There were no new cases of cytomegalovirus disease in either group. Mean serum creatinine levels were higher (1.7±0.5 mg/dL vs. 1.2±0.3 mg/dL; P=0.003) and estimated glomerular filtration rates tended to be lower (49±22 mL/min vs. 65±19 mL/min; P=0.065) in the thymoglobulin group. There were 0.53 QALYs gained (3.68 thymoglobulin vs. 3.15 Atgam; 16.7% improvement) from thymoglobulin compared with Atgam. Conclusions. This long-term follow-up showed that thymoglobulin was associated with higher event-free survival and improved QALYs, without increased posttransplant lymphoproliferative disorder or cytomegalovirus disease, compared with Atgam at 10 years.

Cytomegalovirus Disease after Prophylaxis with Oral Ganciclovir in Renal Transplantation: The Importance of HLA-DR Matching

This study assessed the incidence of cytomegalovirus (CMV) disease and associated outcomes after oral ganciclovir prophylaxis in renal transplantation. A retrospective analysis was performed of all adult renal transplant recipients at a single transplant center transplanted between August 16, 1996, and December 31, 2000. CMV disease prophylaxis included ganciclovir 1000 mg orally thrice daily prescribed for 90 d in D-/R+ cases and 180 d in D+/R- and D+/R+ cases. Forty (9.1%) of 470 patients studied were diagnosed with CMV disease, which varied significantly by CMV serostatus and number of HLA-DR matches. The highest incidence of disease, 26.2%, was in D+/R- patients with zero HLA-DR matches. Five-year graft survival was 56.8% with CMV disease compared with 79.1% without (P < 0.001). Five-year graft survival with CMV disease was 75.9% with one or two HLA-DR matches versus 16.2% with zero HLA-DR matches (P < 0.001). CMV remains an important factor in long-term graft survival after oral ganciclovir prophylaxis. However, we have observed that the adverse impact of CMV disease on graft survival is apparent only in patients with zero HLA-DR matches. These results call for the development of new CMV disease prophylaxis and treatment strategies in patients with zero HLA-DR matches. In addition, organ allocation policies discouraging combining CMV-seropositive donors and zero HLA-DR matches may be worth consideration.

A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients.

Background. To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen. Methods. The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66). Results. At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3±0.3 vs. 1.6±0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (

Novel immunosuppressive agents in kidney transplantation

17,723±11,647 TAC vs.

Inhibitory Interactions between BK and JC Virus among Kidney Transplant Recipients

16,515±10,189 CsA). Conclusions. When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.

Evolving experience of hepatitis B virus prophylaxis in liver transplantation

Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents, efalizumab and alefacept, and maintenance agents, sotrastaurin and tofacitinib. The purpose of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.

Influence of Early Posttransplantation Prednisone and Calcineurin Inhibitor Dosages on the Incidence of New-Onset Diabetes

BK and JC polyomaviruses can reactivate after transplantation, causing renal dysfunction and graft loss. The incidence of JC reactivation after renal transplant is not well understood. Here, we characterized JC reactivation using samples collected during the first year after transplantation from 200 kidney recipients. We detected BK and JC viruses in the urine of 35 and 16% of transplant recipients, respectively. The median viral load in the urine was 400 times higher for BK virus than JC virus. The presence of BK viruria made concurrent JC viruria less likely: JC viruria was detected in 22% of non-BK viruric recipients compared with 4% of BK viruric recipients (P=0.001). The co-detection rate was 1.5%, which is less than the expected 5.6% if reactivation of each virus was independent (P=0.001). We did not observe JC viremia, JC nephropathy, or progressive multifocal leukoencephalopathy. The onset of JC viruria was associated with donor, but not recipient, JC-specific antibody in a titer-dependent fashion and inversely associated with donor and recipient BK-specific antibody. Donor and recipient JC seropositivity did not predict BK viruria or viremia. In conclusion, among renal transplant recipients, infection with one polyomavirus inversely associates with infection with the other.

Rabbit Antithymocyte Globulin Is More Beneficial in Standard Kidney Than In Extended Donor Recipients

Abstract: Passive immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is important to prevent recurrence of hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) for chronic HBV cirrhosis. With availability of lamivudine (3TC), the use of combination prophylaxis with long‐term HBIG/3TC has been shown to prevent short‐term HBV recurrence. This report compares HBV recurrence rates between groups receiving no/short‐term HBIG, long‐term HBIG alone, or HBIG/3TC prophylaxis, and describes HBIG requirements during the first 6 and 12 months in the latter two groups. This study involved patients undergoing OLT at the University of Tennessee‐Memphis between May 1990 and July 2001. During this period, 388 liver transplants were performed at our center. All hepatitis B surface antigen (HBsAg)‐positive recipients (n = 27) were included in this retrospective analysis. The groups were similar with regard to pre‐transplant demographic characteristics such as age, gender, weight, and pre‐transplant diagnosis. Owing to the retrospective study design, median follow‐up was longer for the no‐prophylaxis (5.6 years) and the HBIG‐alone (6.0 years) groups compared to the HBIG/3TC group (4.2 years). Patient survival was 50% in the no‐prophylaxis and 71% in the HBIG‐alone groups compared to 100% in the HBIG/3TC group (P = 0.09). When censored for death with a functioning graft, graft survival was 50% in the no‐prophylaxis and 86% in the HBIG‐alone group compared to 100% in the HBIG/3TC group (P = 0.07). The overall incidence of HBV recurrence in the no‐prophylaxis era was 100% and 21% in the HBIG‐alone era compared to 0% in the HBIG/3TC era (P < 0.001), despite similar mean and median HBIG trough titers in the HBIG‐alone and HBIG/3TC groups. The incidence of HBV recurrence in HBV DNA‐positive recipients was 100% in the no‐prophylaxis era, 30% in the HBIG‐alone era, and 0% in the HBIG/3TC era (P < 0.001). Recipients in the HBIG‐alone group had a nearly two‐fold increase in HBIG requirement at 6 and 12 months in order to maintain similar HBIG trough titers post‐transplant compared to recipients in the HBIG/3TC group despite similar pre‐transplant HBV serology. This increased HBIG requirement in the HBIG‐alone group resulted in a marked increase in the mean overall cost of HBV prophylaxis in this group (

Impact of hepatitis C virus status in pancreas transplantation: a case controlled study

47,367 at 6 months;