Progression of Kidney Disease in Kidney Transplant Recipients With a Failing Graft: A Matched Cohort Study.

Background: Few studies have assessed outcomes in transplant recipients with failing grafts as most studies have focused on outcomes after graft loss.

Objective: To determine whether renal function declines faster in kidney transplant recipients with a failing graft than in people with chronic kidney disease of their native kidneys.

Design: Retrospective cohort study.

Premortem anticoagulation timing and dose in donation after circulatory death: multicentre study of associations with graft function.

Background: In controlled donation after circulatory determination of death (DCD), it is common to administer premortem heparin to potential donors. This practice remains controversial because there is limited evidence for it and there is the possibility of inducing hemorrhage. To our knowledge, no previous studies have assessed the effects of heparin timing and dose on graft function.

Immunosuppressant Medication Use in Patients with Kidney Allograft Failure: A Prospective Multicenter Canadian Cohort Study.

Background: Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely.

Methods: This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers.

Acute Kidney Allograft Rejection Following Coronavirus mRNA Vaccination: A Case Report.

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Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients.

Background: We aimed to identify care processes and structures that were independently associated with higher medication adherence among young transplant recipients.

Methods: We conducted a prospective, observational cohort study of 270 prevalent kidney, liver, and heart transplant recipients 14-25 years old. Patients were ≥3 months post-transplant, ≥2 months post-discharge, and followed in one of 14 pediatric or 14 adult transplant programs in Canada.

Successful Treatment of a Reinfected Liver Graft Because of Receipt of a HCV-Positive Kidney.

Transplantation of hepatitis C virus (HCV)-positive organs has undergone a paradigm shift because of the advent of direct-acting antivirals. We present the case of a 57-year-old man successfully treated initially with pegylated interferon and ribavirin after HCV recurrence postliver transplantation. He subsequently developed end-stage renal disease and received a genotype 1a HCV-positive kidney transplant.

Mortality and Morbidity in Kidney Transplant Recipients With a Failing Graft: A Matched Cohort Study.

Background: Due to their history of renal disease and exposure to immunosuppression, kidney transplant recipients with a failing graft may be at higher risk of adverse outcomes compared to nontransplant controls. Understanding the burden of disease in transplant recipients may inform treatment decisions of people whose native kidneys are failing and may be eligible for a transplant.

Objective: To compare mortality and morbidity in kidney transplant recipients with a failing graft to matched nontransplant controls.

Donation after circulatory determination of death in western Canada: a multicentre study of donor characteristics and critical care practices.

Purpose: Donation after circulatory determination of death (DCD) has been performed in Canada since 2006. Numerous aspects of donor management remain controversial.

Methods: We performed a multicentre cohort study involving potential DCD donors in western Canada (2008-2017), as well as recipients of their organs, to describe donor characteristics and critical care practices, and their relation to one-year recipient and graft survival.

Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results.

Background: Empagliflozin, an SGLT2 inhibitor, has shown remarkable reductions in cardiovascular mortality and heart failure admissions (EMPA-REG OUTCOME). However, the mechanism underlying the heart failure protective effects of empagliflozin remains largely unknown. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodelling and heart failure, in part, by regulating extracellular matrix (ECM) homeostasis.

BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches.

BK polyomavirus is ubiquitous, with a seropositivity rate of over 75% in the adult population. Primary infection is thought to occur in the respiratory tract, but asymptomatic BK virus latency is established in the urothelium. In immunocompromised host, the virus can reactivate but rarely compromises kidney function except in renal grafts, where it causes a tubulointerstitial inflammatory response similar to acute rejection.

Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial.

Background: Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria.

Methods: In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1·73m(2) or greater and proteinuria 0·2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years.

Sirolimus: a therapeutic advance for dermatologic disease.

Sirolimus, also known as rapamycin (SRL, Rapamune®), was approved in 1999 by the US Food and Drug Administration to prevent graft rejection in renal transplantation. As a member of the mammalian target of rapamycin (mTOR) inhibitor class, its potent immunosuppressant, anti-angiogenic and anti-proliferative properties are well recognized. When compared to other immunosuppressants, SRL has a lower risk of renal, neurologic and lymphoproliferative complications.

Risk of death following kidney allograft failure: a systematic review and meta-analysis of cohort studies.

Background: People with kidney allograft failure represent an increasing fraction of all those starting dialysis therapy. We sought to summarize prognosis following kidney allograft failure and identify potentially beneficial interventions or modifiable risk factors.

Methods: We searched MEDLINE and EMBASE (inception to 1 October 2013) and article reference lists without language restriction and selected cohort studies of all-cause mortality and fatal infection-related and cardiovascular events in people starting dialysis following kidney allograft failure.

Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection.

Background: Human BK polyomavirus is the causative agent of BK nephropathy which is now the leading cause of early renal graft loss. Although no randomized clinical trials have supported this therapy, reduction of immunosuppressive drugs is the current BK nephropathy treatment. We hypothesized that inhibition of the intracellular protein kinase pathways activated by BK virus may be a more effective therapeutic strategy than reduction of immunosuppression.

MAP kinase activation increases BK polyomavirus replication and facilitates viral propagation in vitro.

BK polyomavirus causes disease in immunosuppressed patients. BK virus replication was augmented in HEL-299 cells cultured in conditions that activated the MAP kinase, ERK1/2. To determine if MAP kinase activation increased BK virus replication, cells were treated with serum and phorbol 12-myristate 13-acetate (PMA).

Reducing the risk of viral infection in renal transplantation.

Viruses are under constant surveillance by the immune system. With the introduction of more potent immunosuppressive regimens in transplantation, the increased risk of infectious diseases accompanies the decreased risk of acute rejection. Is the overall burden of immunosuppression the prime consideration or do the various immunosuppressive agents contribute individual risks? Do some immunosuppressive agents actually protect against viral disease? Cytomegalovirus (CMV) was initially a significant complication of transplantation, but the incidence of severe CMV disease has decreased with the identification of high-risk groups and the introduction of screening and prophylactic strategies to control reactivation and de novo infection.

Blockade of K(ATP) channels reduces endothelial hyperpolarization and leukocyte recruitment upon reperfusion after hypoxia.

Ischemia/reperfusion injury in renal transplantation leads to slow or initial nonfunction, and predisposes to acute and chronic rejection. In fact, severe ischemia reperfusion injury can significantly reduce graft survival, even with modern immunosuppressive agents. One of the mechanisms by which ischemia/reperfusion causes injury is activation of endothelial cells resulting in inflammation.

Mechanisms of human complement factor B induction in sepsis and inhibition by activated protein C.

To investigate the potential role of the local expression of alternative complement factor B (hBf) in human sepsis, we examined the induction of Bf gene expression in human peripheral blood monocytes (PBMCs) from patients with septic shock and the mechanisms of hBf gene regulation by tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and lipopolysaccharide (LPS) in human monocytes. PBMCs from septic shock patients showed increased hBf mRNA expression when compared with control patients. Costimulation with TNF-alpha and IFN-gamma or stimulation with LPS demonstrated a time- and dose-dependent induction of hBf mRNA expression in human PBMCs.

The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation--study design.

Background: In non-transplant patients with chronic kidney disease and proteinuria, inhibition of the renin-angiotensin system with an ACE-inhibitor or an angiotensin receptor blocker has been shown to delay the progression of renal disease. Observational studies in the kidney transplant population have produced conflicting results with some studies showing benefit and others no benefit of renin-angiotensin system blockade.

Methods: This report describes the design and methodological issues of a randomized controlled trial evaluating the effect of ramipril in a renal transplant population.

Autoantibodies in lupus nephritis patients requiring renal transplantation.

The goal of this nested case-control study was to compare autoantibody profiles in systemic lupus erythematosus (SLE) patients with lupus nephritis (LN), lupus nephritis patients requiring renal transplantation (LNTP) and a SLE control group without nephritis (CON). Sera were assayed for a variety of autoantibodies by addressable laser bead immunoassay (ALBIA) and enzyme-linked immunoassay (ELISA) and to dsDNA by Crithidia luciliae assay. The frequency of nucleosome autoantibodies was significantly greater in the LNTP group (79%) compared to the LN (18%) and CON (9%) groups (P < 0.

ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment.

Reactive oxygen species (ROS)-induced injury has been shown to occur during the reperfusion phase of ischemia-reperfusion and ROS are known to induce signaling events. We hypothesized that oxygen sensing in endothelial cells is also dependent on internal redox changes during hypoxia and that endothelial cells respond to changing oxygen environments via signaling, switching to an inflammatory phenotype. Endothelial cells exposed to relative hypoxia or the mitochondrial inhibitors rotenone, antimycin A, or FCCP show loss of mitochondrial membrane potential.