Proteasome inhibitor-based therapy for antibody-mediated rejection

The development of donor-specific anti-human leukocyte antigen antibodies (DSAs) following renal transplantation significantly reduces long-term renal graft function and survival. The traditional therapies for antibody-mediated rejection (AMR) have provided inconsistent results and transient effects that may be due to a failure to deplete mature antibody-producing plasma cells. Proteasome inhibition (PI) is a novel AMR therapy that deletes plasma cells. Initial reports of PI-based AMR treatment in refractory rejection demonstrated the ability of bortezomib to deplete plasma cells producing DSA, reduce DSA levels, provide histological improvement or resolution, and improve renal allograft function. These results have subsequently been confirmed in a multicenter collaborative study. PI has also been shown to provide effective primary AMR therapy in case reports. Recent studies have demonstrated that PI therapy results in differential responses in early and late post-transplant AMR. Additional randomized studies are evaluating the role of PI in transplant induction, acute AMR, and chronic rejection in renal transplantation. An important theoretical advantage of PI-based regimens is derived from several potential strategies for achievement of synergy

Contrast-Induced Nephropathy in Renal Transplant Recipients: A Single Center Experience

BACKGROUND: Contrast-induced nephropathy (CIN) in native kidneys is associated with a significant increase in mortality and morbidity. Data regarding CIN in renal allografts are limited, however. We retrospectively studied CIN in renal allografts at our institution: its incidence, risk factors, and effect on long-term outcomes including allograft loss and death. METHODS: One hundred thirty-five renal transplant recipients undergoing 161 contrast-enhanced computed tomography (CT) scans or coronary angiograms (Cath) between years 2000 and 2014 were identified. Contrast agents were iso- or low osmolar. CIN was defined as a rise in serum creatinine (SCr) by \u3e0.3 mg/dl or 25% from baseline within 4 days of contrast exposure. After excluding 85 contrast exposures where patients had no SCr within 4 days of contrast administration, 76 exposures (CT: RESULTS: Incidence of CIN was 13% following both, CT (6 out of 45) and Cath (4 out of 31). Significant bivariate predictors of CIN were IV fluid administration ( CONCLUSION: CIN is common in kidney transplant recipients, and there is room for quality improvement with regards to careful renal function monitoring post-contrast exposure. In our study

Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies

This study assessed the long-term effects of prolonged-release tacrolimus (Advagraf(®) [Tacrolimus QD]), which has been developed to provide similar efficacy and safety to twice-daily tacrolimus (Prograf(®) [Tacrolimus BID]) with the added benefit of once-daily dosing

LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups

African-American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post-transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once-daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak-trough fluctuations vs. tacrolimus twice-daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy-proven acute rejection (BPAR), or lost to follow-up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [-1.48% (-5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [-1.29% (-5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [-13.82% (-27.22%, -0.31%)] and KTR ≥65 [-13.46% (-25.27%, -0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high-risk subgroups, in particular black KTR and KTR ≥65 years old

A call for transplant stewardship: The need for expanded evidence‐based evaluation of induction and biologic‐based cost‐saving strategies in kidney transplantation and beyond

Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost‐containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher‐quality evidence for high single‐dose rATG, and dose‐rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target‐attainment or on ideal‐body‐weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost‐saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high‐cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost‐burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient‐specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost‐saving initiatives in the transplant population.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170795/1/ctr14372_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170795/2/ctr14372.pd