Prevention Of Kidney Allograft Rejection Research Articles

Corticosteroids and methotrexate as adjuvants to costimulation blockade in non-human primate renal transplantation.

Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.

Safety and efficacy of Rapamune\xae (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea

BackgroundFew post-marketing surveillance studies have examined the safety and efficacy of Rapamune® (Sirolimus) in Asian countries. This study aimed to better understand safety and efficacy of Rapamune for kidney transplant recipients in the routine clinical practice setting in Korea.MethodsThis was an open-label, non-comparative, observational, prospective, multi-center, post-marketing surveillance study conducted at 15 Korean transplant centers between 31 August 2009 and 24 September 2015. The subjects were administered Rapamune as part of routine practice. The safety was monitored based on reporting of adverse events (AEs). Efficacy endpoints included acute rejection, graft function, graft survival, and patient survival.ResultsRapamune was most commonly used for late conversion therapy after post-transplant 1 year and was substituted for anti-metabolites (63.6%) or calcineurin inhibitors (28.7%). The median treatment duration of Rapamune was 182 days. Among 209 subjects enrolled, AEs and adverse drug reactions (ADRs) were reported in 54.07% and 43.06% of subjects, respectively, in the safety analysis set. Most of the AEs were expected (96.21%), mild (75.83%), did not result in any action taken with regard to the study drug (72.99%), and resolved by the end of the study (75.36%). The most frequently reported AEs/ADRs were pharyngitis and diarrhea. Most of the serious AEs/ADRs occurred in one or two subjects. Unexpected ADRs of renal artery occlusion and cholangitis were reported by one subject each. The incidence of biopsy-proven acute rejection was 2.87%. At the end of the study, 99.51% of the subjects and their grafts had survived. The mean eGFR was 64.72 ± 19.56 mL/min.ConclusionsRapamune had an acceptable safety profile in prevention of kidney allograft rejection in Korea.

The influence of comedication on tacrolimus blood concentration in patients subjected to kidney transplantation: a retrospective study

Tacrolimus is an immunosuppressant used for the prevention of kidney allograft rejection. The effects of comedication on tacrolimus trough concentrations (TTC) in kidney transplant recipients, subjected to basic immunosuppressant regime consisting of tacrolimus, corticosteroids and mycophenolate mofetil were investigated. This retrospective case series study involved 208 of these patients, with the outpatient examination recorded in the database of patients, at the unit of monitoring, with a total of 5,011 such examinations. Binary logistic regression analysis has shown that calcium channel blockers, diuretics and proton pump inhibitors (PPIs) significantly affected TTC (p < 0.001). PPIs significantly increased the number of examinations in which the TTC were in the recommended therapeutic range (from 5 to 15 ng/ml), as well as over the therapeutic range (p < 0.0001). When calcium channel blockers were added to PPIs, even more pronounced effect was obtained in comparison to triple-drug therapy only (p < 0.0001). In case a diuretic was given with a PPI, a significantly increased number of examinations with subtherapeutic TTC was observed when compared with PPI only (p = 0.0203). The combination of calcium channel blockers, diuretics and PPIs resulted in the number of examinations with TTC in the recommended therapeutic range not being different from the number of examinations with TTC in the triple-drug therapy only (p = 0.3829). β-adrenergic antagonists can be administered without fear of affecting the tacrolimus optimal therapeutic concentrations. This was confirmed with all combinations of the examined drugs used in patients subjected to kidney transplantation concomitantly with β blockers.

Belatacept utilization recommendations: an expert position

Introduction: There is a continuing need for an immunosuppressive therapy that offers a high benefit–risk profile for renal transplant recipients, supporting long-term patient and graft survival while minimizing cumulative nephrotoxicity and other side effects. Belatacept, the first biological agent developed for primary maintenance immunosuppression, was recently approved for use in Europe. Belatacept combined with corticosteroids and a mycophenolic acid is indicated for prophylaxis of graft rejection in adults receiving renal transplant. Its use is contraindicated in Epstein–Barr virus seronegative or serostatus unknown patients due to increased risk of developing posttransplant lymphoproliferative disorder.Areas covered: This review provides practical recommendations for the use of belatacept, based on safety and efficacy data from Phase II and Phase III clinical trials in de novo kidney transplant recipients.Expert opinion: Treatment with belatacept is associated with improved long-term graft function, making belatacept an important option for prevention of kidney allograft rejection. Furthermore, efficacy and safety data over several years of therapy suggest that belatacept is particularly suitable for long-term immunosuppression, and the selective targeting offered by belatacept may help avoid some of the non-specific chronic safety risks associated with calcineurin inhibitors and steroids. Future studies will clarify the optimal regimen for belatacept usage.

An evaluation of sirolimus in renal transplantation

Introduction: Sirolimus is a powerful antiproliferative immunosuppressive drug approved for the prevention of kidney allograft rejection. By its unique mechanism of action, sirolimus provides a multitude of clinical potential and has been used effectively in different drug combinations. Extensive experience has been gained regarding the best timing of its application, side effect profile and potential benefits and limitations compared with other immunosuppressive drugs.Areas covered: The authors evaluate the recent experience with sirolimus in kidney transplantation. Pivotal randomized controlled trials were used to provide an overview with special attention to pharmacokinetic and dynamic aspects of sirolimus, its current clinical use as well as perspectives for its future role.Expert opinion: Sirolimus enriches the possibilities of immunosuppressive therapies after renal transplantation. Beneficial effects toward kidney function by allowing CNI sparing, lower incidence of malignancies and less viral infections have been suggested. Sirolimus should be used cautiously in de novo patients for reasons of wound healing. An early conversion to a sirolimus-based CNI-free regimen has shown promising results, whereas late conversion is more challenging. Finally, sirolimus-associated side effects are causing tolerability concerns and frequent discontinuations. Future research should aim to better define the therapeutic window and those patients most likely to benefit.

Blockade of T-Lymphocyte KCa3.1 and Kv1.3 Channels as Novel Immunosuppression Strategy to Prevent Kidney Allograft Rejection

Currently, there is an unmet clinical need for novel immunosuppressive agents for long-term prevention of kidney transplant rejection as alternatives to the nephrotoxic calcineurin inhibitor cyclosporine (CsA). Recent studies have shown that K(+) channels have a crucial role in T-lymphocyte activity. We investigated whether combined blockade of the T-cell K(+) channels K(Ca)3.1 and K(v)1.3, both of which regulate calcium signaling during lymphocyte activation, is effective in prevention of rejection of kidney allografts from Fisher rats to Lewis rats. All recipients were initially treated with CsA (5 mg/kg d) for 7 days. In rats with intact allograft function, treatment was continued for 10 days with either CsA (5 mg/kg d), or a combination of TRAM-34 (K(Ca)3.1 inhibitor; 120 mg/kg d) plus Stichodactyla helianthus toxin (ShK, K(v)1.3 inhibitor; 80 microg/kg 3 times daily), or vehicle alone. Kidney sections were stained with periodic acid-Schiff or hematoxylin-eosin and histochemically for markers of macrophages (CD68), T-lymphocytes (CD43), or cytotoxic T-cells (CD8). Our results showed that treatment with TRAM-34 and ShK reduced total interstitial mononuclear cell infiltration (-42%) and the number of CD43+ T-cells (-32%), cytotoxic CD8+ T-cells (-32%), and CD68+ macrophages (-26%) in allografts when compared to vehicle treatment alone. Efficacy of TRAM-34/ShK treatment was comparable with that of CsA. In addition, no visible organ damage or other discernible adverse effects were observed with this treatment. Thus, selective blockade of T-lymphocyte K(Ca)3.1 and K(v)1.3 channels may represent a novel alternative therapy for prevention of kidney allograft rejection.

Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primates.

Costimulation blockade has been proposed to induce allograft tolerance. We combined an antagonist anti-CD40 monoclonal antibody (mAb) with an antagonist anti-CD86 mAb in a rhesus monkey kidney allograft model. We chose this combination because it leaves CD80-CD152 signaling unimpaired, allowing for the down-regulatory effect of CD152 signaling to take place through this pathway. Rhesus monkeys underwent transplantation with a major histocompatibility complex-mismatched kidney. One group of animals received anti-CD40 alone, and a second group received the combination of anti-CD40 and anti-CD86, twice weekly for 56 days. Three animals with low levels of anti-CD40 rejected the transplanted kidney while still receiving treatment. Three animals with high levels of anti-CD40 rejected at days 91, 134, and 217 with signs of chronic rejection. Animals treated with the combination of anti-CD40 and anti-CD86 mAbs rejected their kidneys at days 61, 75, and 78, shortly after cessation of treatment. Two animals were killed on days 71 and 116 with a blocked ureter. These animals developed virtually no signs of tubulitis or infiltration during treatment and no donor-specific alloantibodies. Both treatment protocols prevented rejection for the duration of the treatment in most animals. Blocking costimulation by anti-CD40 or by anti-CD40 plus anti-CD86 may be an effective method to prevent graft rejection and may obviate the need for other immunosuppressive drugs, especially in the immediate posttransplantation period.

Synergistic effect of rapamycin and cyclosporine in prevention of acute kidney allograft rejection in the mouse.

The effect of rapamycin (RAPA) and cyclosporine A (CsA) monotherapy and combination therapy was examined in prevention of kidney allograft rejection in the mouse. Both drugs were administered orally for up to 14 days in BALB/c (H-2(d)) to C57BL/6 (H-2(b)) mice strong combination. Six groups were treated with RAPA and/or CsA. This study shows that concomitant therapy of RAPA and CsA produces strong synergistic interaction in prolonging renal allograft survival in mice when compared with monotherapy of RAPA or CsA.