A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients.

AJT A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients.

• Lim WH, Eris J, Kanellis J, et al. 
• A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients. [JOURNAL ARTICLE]
• Am J Transplant 2014 Aug 1.

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2)  = 68%, p < 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2)  = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2)  = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.

http://www.unboundmedicine.com/medline/citation/25088685/A_Systematic_Review_of_Conversion_From_Calcineurin_Inhibitor_to_Mammalian_Target_of_Rapamycin_Inhibitors_for_Maintenance_Immunosuppression_in_Kidney_Transplant_Recipients_

Sent with Reeder

Enviado desde mi iPad

Adenosine Triphosphate-Competitive mTOR Inhibitors: A New Class of Immunosuppressive Agents That Inhibit Allograft Rejection

AJT - Early Adenosine Triphosphate-Competitive mTOR Inhibitors: A New Class of Immunosuppressive Agents That Inhibit Allograft Rejection

The mechanistic/mammalian target of rapamycin (mTOR) is inhibited clinically to suppress T cell function and prevent allograft rejection. mTOR is the kinase subunit of two mTOR-containing complexes, mTOR complex (mTORC) 1 and 2. Although mTORC1 is inhibited by the macrolide immunosuppressant rapamycin (RAPA), its efficacy may be limited by its inability to block mTORC1 completely and its limited effect on mTORC2. Adenosine triphosphate (ATP)-competitive mTOR inhibitors are an emerging class of mTOR inhibitors that compete with ATP at the mTOR active site and inhibit any mTOR-containing complex. Since this class of compounds has not been investigated for their immunosuppressive potential, our goal was to determine the influence of a prototypic ATP-competitive mTOR inhibitor on allograft survival. AZD8055 proved to be a potent suppressor of T cell proliferation. Moreover, a short, 10-day course of the agent successfully prolonged murine MHC-mismatched, vascularized heart transplant survival. This therapeutic effect was associated with increased graft-infiltrating regulatory T cells and reduced CD4⁺ and CD8⁺ T cell interferon-γ production. These studies establish for the first time, that ATP-competitive mTOR inhibition can prolong organ allograft survival and warrant further investigation of this next generation mTOR inhibitors.

http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fajt.12799

Sent with Reeder

Enviado desde mi iPad

Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients

Clinical Transplantation Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients

Abstract

Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000-2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. CMV immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were non-specific colitis (31.3%), IBD-like colitis (25%), normal/near normal (18.8%), graft-vs-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18. 75%). No graft loss occurred. Four patients died during the study period. Late onset MPA was more frequent, and no correlation with MPA dose or formulation was found.

This article is protected by copyright. All rights reserved.

http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fctr.12452

Sent with Reeder

Enviado desde mi iPad

Cardiovascular morbidity and mortality after kidney transplantation

Transplant International Cardiovascular morbidity and mortality after kidney transplantation

Abstract

Kidney transplantation is the optimal treatment for patients with end stage renal disease (ESRD) who would otherwise require dialysis. Patients with ESRD are at dramatically increased cardiovascular (CV) risk compared to the general population. As well as improving quality of life, successful transplantation accords major benefits by reducing cardiovascular risk in these patients. Worldwide, cardiovascular disease remains the leading cause of death with a functioning graft and therefore is a leading cause of graft failure. This review focuses on the mechanisms underpinning excess cardiovascular morbidity and mortality and current evidence for improving cardiovascular risk in kidney transplant recipients. Conventional cardiovascular risk factors such as hypertension, diabetes mellitus, dyslipidaemia, and pre-existing ischaemic heart disease are all highly prevalent in this group. In addition, kidney transplant recipients exhibit a number of risk factors associated with pre-existing renal disease. Furthermore, complications specific to transplantation may ensue including reduced graft function, side effects of immunosuppression and post transplantation diabetes mellitus. Strategies to improve cardiovascular outcomes post transplantation may include pharmacological intervention including lipid lowering or antihypertensive therapy, optimisation of graft function, lifestyle intervention and personalising immunosuppression to the individual patients risk profile.

This article is protected by copyright. All rights reserved.

http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Ftri.12413

Sent with Reeder

Enviado desde mi iPad

Benefits of Rituximab Combined With Intravenous Immunoglobulin for Desensitization in Kidney Transplant Recipients

Transplantation - Current Issue Benefits of Rituximab Combined With Intravenous Immunoglobulin for Desensitization in Kidney Transplant Recipients

BackgroundHighly HLA-sensitized (HS) patients have difficulty accessing compatible donors, especially deceased donor (DD) transplants. Desensitization protocols (DES) have evolved, but rigorous evaluation is lacking. Here, we examined the efficacy of rituximab as a DES agent in a placebo-controlled trial. MethodsCandidates were randomized to IVIG+placebo versus IVIG+rituximab. End points included rates of transplantation, antibody-mediated rejection (ABMR), and renal function. Protocol biopsies were performed at 1 year and analysis of patient and graft survival and donor-specific HLA antibodies (DSA) were performed. ResultsInitially, 15 HS DDs were randomized with 13 receiving transplants. However, we discontinued study entry after five serious adverse events were observed. The study was un-blinded and attribution of patients was noted (IVIG+placebo N=7, IVIG+rituximab N=6). No significant differences were seen in DSA levels at transplant. All ABMR episodes occurred in the IVIG+placebo arm and required intense therapy (P=0.06). The two graft losses were in the placebo group. DSA rebound associated with severe ABMR was seen in three patients in the IVIG+placebo group. No rebound was seen in the IVIG+rituximab group. Renal function at 6 and 12 months showed a significant benefit for IVIG+rituximab (P=0.04). ConclusionsBased on limited assessment with acknowledged limitations, both protocols appear effective in achieving levels of DSA allowable for transplantation. However, IVIG+rituximab appeared more effective in preventing DSA rebound and, more importantly, preventing ABMR and development of transplant glomerulopathy.


http://journals.lww.com/transplantjournal/Fulltext/2014/08150/Benefits_of_Rituximab_Combined_With_Intravenous.15.aspx

Sent with Reeder

Enviado desde mi iPad

Diarrhea After Kidney Transplantation: A New Look at a Frequent Symptom.

Transplantation - Published Ahead-of-Print Diarrhea After Kidney Transplantation: A New Look at a Frequent Symptom.

Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often considered by patients and clinicians an unavoidable side effect of immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies. (C) 2014 by Lippincott Williams & Wilkins


http://pdfs.journals.lww.com/transplantjournal/9000/00000/Diarrhea_After_Kidney_Transplantation___A_New_Look.98094.pdf

Sent with Reeder

Enviado desde mi iPad