A new model to determine Optimal Exposure to Tacrolimus and Mycophenolate Mofetil after renal transplantation.

BACKGROUND: Drug dosing for Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) after kidney transplantation remains challenging. Therapeutic drug monitoring (TDM) offers a means to individualize drug dosing and improve outcomes. METHODS: In this observational study, patients having mycophenolic acid (MPA) exposure assessed by limited sampling strategy (LSS) within the first 6 months were included and followed for 1 year. RESULTS: A total of 113 clinical events occurring in 110 patients were classified into 3 groups: Group 1 Stable (n = 34), Group 2 Over drug exposed (n = 64) having infections or drug toxicity and Group 3 Under drug exposed (n = 15) developing rejection or de novo donor-specific alloantibodies. Although TAC levels, MMF dose, MPA, and MPA Glucuronide (MPAG) exposure, expressed as area under curve (AUC), individually failed to predict outcomes, a scoring model incorporating all 3 drug levels TAC TDM × (MPA AUC + MPAG/10 AUC) correctly classified outcomes. A score over 1071 had a sensitivity and specificity of 0.94 (95% CI 0.56-0.83) and 0.84 (95% CI 0.69-0.89) for over exposure. A score below 625 had a sensitivity and specificity of 0.76 (95% CI 0.53-0.93) and 0.80 (95% CI 0.41-0.70) for under exposure. CONCLUSIONS: This integrated model of assessing TAC and MMF exposure may facilitate individualized therapy.

Simultaneous Pancreas and Kidney Transplantation-Is It a Treatment Option for Patients With Type 2 Diabetes Mellitus? An Analysis of the International Pancreas Transplant Registry.

PURPOSE OF REVIEW: Pancreas transplantation remains the best long-term treatment option to achieve euglycemia and freedom from insulin in patients with labile diabetes mellitus. It is an approved procedure for type 1 (T1DM), but it is still considered controversial for type 2 diabetes mellitus (T2DM). RECENT FINDINGS: This study analyzed all primary deceased donor pancreas transplants in patients with T2DM reported to IPTR/UNOS between 1995 and 2015. Characteristics, outcomes, and risk factors over time were determined using univariate and multivariate methods. The focus was on simultaneous pancreas/kidney (SPK) transplants, the most common pancreas transplant category. Patient, pancreas, and kidney graft survival rates increased significantly over time and reached 95.8, 83.3, and 91.1%, respectively, at 3 years posttransplant for transplants performed between 2009 and 2015. SPK is a safe procedure with excellent pancreas and kidney graft outcome in patients with T2DM. The procedure restores euglycemia and freedom from insulin and dialysis. Based on our results, SPK should be offered to more uremic patients with labile T2DM.

The increasing clinical importance of alloantibodies in kidney transplantation.

Historically, cellular rather than humoral immunity has gathered the most attention in kidney transplantation. As the specter of cellular acute rejection and early graft loss has faded due to the availability of highly effective immunosuppressive therapy, scientific and clinical studies now focus on improving long-term graft survival. It is increasingly appreciated that alloantibodies directed against HLA and non-HLA antigens are key factors in determining graft longevity. Significant efforts are now being made to better understand the critical impact that B cells and alloantibodies make on organ allocation and graft survival. Future therapies directed specific for the humoral alloresponse will undoubtedly lead to improved outcomes after kidney transplantation. This review will cover some of the advances in the understanding and management of the continuum of humoral immunity in renal transplantation in the pre, peri and post-transplant periods.

Inhibiting Wipf2 downregulation by transgenic expression of its 3' mRNA-untranslated region improves cytotoxicity and vaccination response.

Lymphocyte activation results in profound changes in the abundance of mRNA transcripts many of which are downregulated. The Wiskott-Aldrich syndrome (WAS) protein (WASP) family is critical for productive T-cell receptor signaling and actin reorganization. The WASP signal pathway includes the WAS/WAS-like (WASL) interacting protein family 2 (WIPF2) gene also known as WIRE/WICH. We show that both human WIPF2 and mouse Wipf2 are mice, alternatively spliced within the 3' untranslated region (3'UTR) resulting in two major transcripts of approximately 4.5 and 6 kb in size. Following T-cell activation, the level of human WIPF2 and mouse Wipf2 mRNA rapidly declines. In mice, this decline is accompanied by a marked reduction in WIPF2 protein levels. Transgenic expression of a 240-bp fragment derived from a highly conserved terminal 3'UTR found within the 6-kb transcript blocks Wipf2 downregulation. These effects may be mediated by competitive inhibition of microinhibitory RNA (miRNA) regulation since the 6-kb-derived transgene and the 4.5-kb transcript share functional binding sites for miRNA146a. Blocking Wipf2 gene and protein repression resulted in improved T-cell responses to antigen immunization in vivo as well as in vitro cytotoxic T-cell killing. Collectively, these data suggest that early downregulation of this immunologically relevant gene controls the intensity of selective lymphocyte functions.

Universal perioperative antimicrobial prophylaxis is not necessary in kidney transplantation.

Despite significant improvements in renal transplantation, certain basic issues remain unresolved such as the routine use of perioperative antimicrobial prophylaxis (AMP). To address the need for AMP, we retrospectively evaluated the clinical course of 442 consecutive renal transplant recipients (RTRs) who did not receive any AMP except for trimethoprim/sulfamethoxazole. Three hundred and forty RTRs received induction therapy with low-dose rabbit anti-thymocyte globulin, while the other 102 patients were treated with basiliximab. All RTRs received tacrolimus, mycophenolic acid, and prednisone. Nine patients (2%) developed surgical site infection (SSI). SSIs were more common in obese and older patients. All SSIs were superficial and responded well to wound drainage and outpatient antibiotic therapy. No patient or graft was lost owing to SSI. Our study shows that despite many predisposing factors, SSIs are rare following renal transplantation even in the absence of AMP. Therefore, to avoid the emergence of antibiotic-resistant pathogens, excessive costs, and antibiotic-related adverse events, we suggest that AMP should be used only in selected circumstances such as in recipients older than 65 yr or when the body mass index (BMI) is > 35.

Randomized prospective trial of early steroid withdrawal compared with low-dose steroids in renal transplant recipients using serial protocol biopsies to assess efficacy and safety.

BACKGROUND: Corticosteroid therapy after renal transplantation is associated with many adverse effects. Newer immunosuppressive agents may allow for safe and effective reductions in dose or early steroid withdrawal. METHODS: In this prospective, single-center clinical trial, 60 patients were randomized into 2 groups: control patients (n = 28), who received low doses of prednisone throughout, and study patients (n = 32), who were withdrawn from steroids 7 days posttransplant. Patients received a limited course of rabbit antilymphocyte globulin (rALG) induction therapy, tacrolimus (TAC), and mycophenolate mofetil (MMF). Patients were followed for clinical outcomes and renal function. Protocol biopsies were performed at 1, 6, and 12 months. RESULTS: Clinical rejections occurred in 11% of controls and 13% of study patients. Renal function was well maintained and equivalent in both groups. In all, 111 protocol biopsies were performed without complications. Subclinical rejection was noted in only 2 protocol biopsies, and borderline changes were seen in 12 biopsies, all of which were distributed equally between both groups. Unsuspected acute TAC toxicity was seen in 8 biopsies. Protocol biopsies led to changes in therapy in 10% of patients. In both groups, serial protocol biopsies demonstrated increased allograft fibrosis over time, which was significant at 1 year in the steroid withdrawal group. CONCLUSION: The immunosuppressive combination of rALG, TAC, and MMF prevents subclinical rejection and the need for high doses of steroids after transplantation. However, continual low-dose steroid therapy may aid in preventing chronic allograft fibrosis. Protocol biopsies help define the short-term and long-term risks of steroid withdrawal therapy.

Basiliximab plus low-dose cyclosporin vs. OKT3 for induction immunosuppression following renal transplantation.

BACKGROUND: Current immunosuppressive therapies are very effective in preventing acute rejection (AR) and graft loss following renal transplantation. Newer agents now make it possible to develop equally efficacious but better tolerated and less toxic strategies. This is especially relevant for our ageing recipients. We now compare the efficacy of basiliximab combined with early low-dose cyclosporin therapy to standard OKT3 induction therapy. METHODS: In this single-centre study, 100 consecutive recipients of cadaveric kidney transplants from November 1998 to August 2000 were treated with basiliximab combined with early low-dose cyclosporin, reduced steroids and mycophenolate mofetil (MMF). Clinical outcomes at 100 d and 1 yr were compared with a group of 26 patients transplanted from March 1995 to November 1998 who received OKT3, delayed full-dose cyclosporin, high-dose steroids and MMF. Amongst basiliximab treated patients, we compared clinical outcomes in those older and younger than 60 yr. RESULTS: Both groups were similar except for a shorter cold ischaemic time in the basiliximab group. Length of stay, number of readmissions, total hospitalization days and cytomegalovirus infections were lower in the basiliximab group. Despite a 40% reduction in steroids, basiliximab-treated patients had fewer biopsy-proven episodes of AR (basiliximab 14% vs. OKT3 35%) and required less antilymphocyte antibody therapy. Clinical outcomes including patient and graft survival were no different between groups. Long-term graft survival for patients over 60 yr was limited primarily by mortality. CONCLUSIONS: Compared with OKT3 induction therapy, the combination of early low-dose cyclosporin and basiliximab is steroid sparing, effective, well tolerated and relatively safe.