Publications by authors named "Ruth Sapir-Pichhadze"

35 Publications

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation.

Int J Immunogenet 2021 Apr 10;48(2):135-144. Epub 2021 Jan 10.

Centre for Outcomes Research and Evaluation (CORE), Research Institute of McGill University Health Centre, Montréal, QC, Canada.

The development of donor-specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post-transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor-specific antibodies post-transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet-based donor:recipient matching, including unavailability of allele-level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long-read genotyping methods, compilation of large data sets with allele-level genotypes, and standardization of methods to verify eplets as determinants of immune-mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.
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http://dx.doi.org/10.1111/iji.12525DOI Listing
April 2021

Program Report: KidneyPRO, a Web-based Training Module for Patient Engagement in Kidney Research.

Can J Kidney Health Dis 2020 21;7:2054358120979255. Epub 2020 Dec 21.

Can-SOLVE CKD Network, Vancouver, BC, Canada.

Purpose Of Report: Over the recent years, there has been increasing support and traction for patient-oriented research (POR). Such an approach ensures that health research is focused on what matters most: improving outcomes for patients. Yet the realm of health research remains enigmatic for many patients in Canada who are not familiar with research terms and practices, highlighting the need for focused capacity-building efforts, including the development of novel educational tools to support patients to meaningfully engage in the research enterprise. The need for disease-specific training in POR was identified by the network dedicated to advancing patient-oriented kidney research in Canada, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD), during the early years of the network's inception. In this report, we describe the development of KidneyPRO, an online learning module that orients patients and families to kidney research in Canada, and outlines ways to get involved. In line with the Patient Engagement framework of the Strategy for Patient Oriented Research, KidneyPRO was co-developed with the network's patient partners.

Sources Of Information: The need for KidneyPRO was identified through a review of feedback from network participants of Canadian Institutes of Health Research's (CIHR) Foundations in Patient-Oriented Research Module 2-Health Research in Canada and a network-wide survey of Can-SOLVE CKD that was conducted in June 2017 and assessed training needs of key stakeholders. This 2017 survey ranked the need for tools providing introductory knowledge on Canadian kidney research as third in the network's top 5 capacity-building priorities.

Methods: At Can-SOLVE CKD, a dedicated multi-stakeholder team was formed from the Training & Mentorship Committee (the network's core infrastructure for POR capacity building) to determine the learning objectives, content, and user interface. The team consisted of 3 patient partners, Director of Research for the Kidney Foundation of Canada, a kidney clinician-scientist, the network's Patient Partnerships & Training Lead, Can-SOLVE CKD's Indigenous People's Engagement and Research Council Coordinator, and a project coordinator. With permission, content from CIHR's Foundations in Patient-Oriented Research, along with resources from the Kidney Foundation of Canada's research arm and network project teams, was used to form the basis of the tool. The working group adapted a DoTTI (Design and develOpment, Testing early iterations, Testing for Effectiveness, Integration, and implementation) framework and iteratively identified, created, and refined the content and user interface in consultation with the Training and Mentorship Committee and the Can-SOLVE CKD Patient Governance Circle.

Key Findings: In this article, we describe the development, deployment, and evaluation of KidneyPRO, a web-based training module that helps patients understand general, patient-oriented, and kidney-specific research within Canada. KidneyPRO aims to support patient engagement in studies as partners and/or participants and empower them to take part in the research process in an active and meaningful way. It was co-designed and vetted by patients, which helps to ensure clear, useful content and a user-friendly interface. In addition, the module includes links to kidney research opportunities within the Can-SOLVE CKD Network and beyond. A literature review established that KidneyPRO fills an important gap in kidney-specific POR. Ongoing collection of website metrics and postcompletion surveys from users will be used to evaluate the effectiveness of the tool.

Limitations: As an online tool, people who do not have adequate Internet access will not be able to use KidneyPRO. Currently, the tool is not compliant with all Web Content Accessibility Guidelines. Given how the landscape of patient partnership in research is constantly evolving, the content in KidneyPRO needs to be updated on a regular basis.

Implications: Canadians with or at high risk of CKD now have access to an educational tool when seeking to engage as partners and/or participants in innovative kidney research.
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http://dx.doi.org/10.1177/2054358120979255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755936PMC
December 2020

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

Transpl Int 2021 Mar;34(3):488-498

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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http://dx.doi.org/10.1111/tri.13813DOI Listing
March 2021

Sex matters: COVID-19 in kidney transplantation.

Kidney Int 2021 03 5;99(3):555-558. Epub 2021 Jan 5.

Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada; Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada; Centre for Outcomes Research, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783460PMC
March 2021

Differences in Liver Graft Survival by Recipient Sex.

Transplant Direct 2020 Dec 10;6(12):e629. Epub 2020 Nov 10.

Faculty of Medicine, McGill University, Montreal, QC, Canada.

We aimed to characterize patterns of differences in liver graft failure rates by recipient sex, accounting for the modifying effects of donor sex and recipient age.

Methods: We evaluated 144 212 first deceased donor liver transplant recipients [1988-2019; Scientific Registry of Transplant Recipients (SRTR)]. We used multivariable time-varying Cox models, considering a recipient sex by donor sex by recipient age (0-12, 13-24, 25-44, ≥45 y) interaction.

Results: Among recipients of male donors, females <45 y had higher graft failure rates than males of the same age, but none of these differences were statistically significant [0-12 y: adjusted hazard ratio (aHR) 1.17 (0.98, 1.40); 13-24 y: aHR 1.18 (0.96, 1.46); 25-44 y: aHR 1.11 (0.96, 1.28)]; there was no material or statistically significant difference between female and male recipients ≥45 y [aHR 1.01 (0.97, 1.06)]. When the donor was female, recipients <45 y showed no statistically significant differences in graft outcomes by recipient sex [0-12 y: aHR 0.91 (0.74, 1.11); 13-24 y: aHR 0.98 (0.77, 1.25); 25-44 y: aHR 0.86 (0.73, 1.01)], whereas female recipients ≥45 y had significantly lower graft failure rates [aHR 0.85 (0.81, 0.89)] than males of the same age.

Conclusions: Among recipients of female donors, female recipients ≥45 y had significantly better outcomes than males of the same age; there were no clear differences by recipient sex in younger recipients. When the donor was male, there was no material or statistically significant difference in graft failure rates between males and females ≥45 y; among younger recipients point estimates suggested higher failure rates in females than males recipients, but confidence intervals were wide making firm conclusions impossible. Larger studies combining multiple datasets are needed.
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http://dx.doi.org/10.1097/TXD.0000000000001084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665259PMC
December 2020

Donor Age, Donor-Recipient Size Mismatch, and Kidney Graft Survival.

Clin J Am Soc Nephrol 2020 Oct 25;15(10):1455-1463. Epub 2020 Aug 25.

Immunopathology Division, Research Centre, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada

Background And Objectives: Small donor and/or kidney sizes relative to recipient size are associated with a higher risk of kidney allograft failure. Donor and recipient ages are associated with graft survival and may modulate the relationship between size mismatch and the latter. The aim of this study was to determine whether the association between donor-recipient size mismatch and graft survival differs by donor and recipient age.

Design, Setting, Participants, & Measurement: We performed a retrospective cohort study of first adult deceased donor kidney transplantations performed between 2000 and 2018 recorded in the Scientific Registry of Transplant Recipients. We used multivariable Cox proportional hazards models to assess the association between donor-recipient body surface area ratio and death-censored graft survival, defined as return to dialysis or retransplantation. We considered interactions between donor-recipient body surface area ratio and each of recipient and donor age.

Results: Among the 136,321 kidney transplant recipients included in this study, 23,614 (17%) experienced death-censored graft loss over a median follow-up of 4.3 years (interquartile range, 1.9-7.8 years). The three-way donor-recipient body surface area ratio by donor age by recipient age interaction was statistically significant (=0.04). The magnitude of the association between severe size mismatch (donor-recipient body surface area ratio <0.80 versus ≥1.00) and death-censored graft survival was stronger with older donor age and recipient age. In all recipient age categories except the youngest (18-30 years), 5- and 10-year graft survival rates were similar or better with a size-mismatched donor aged <40 years than a nonsize-mismatched donor aged 40 years or older.

Conclusions: The association of donor-recipient size mismatch on long-term graft survival is modulated by recipient and donor age. Size-mismatched kidneys yield excellent graft survival when the donor is young. Donor age was more strongly associated with graft survival than size mismatch.
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http://dx.doi.org/10.2215/CJN.02310220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536765PMC
October 2020

Predicting Clinical Outcome in Expanded Criteria Donor Kidney Transplantation: A Retrospective Cohort Study.

Can J Kidney Health Dis 2020 24;7:2054358120924305. Epub 2020 Jun 24.

Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, QC, Canada.

Background: The gaps in organ supply and demand necessitate the use of expanded criteria donor (ECD) kidneys.

Objective: To identify which pre-transplant and post-transplant predictors are most informative regarding short- and long-term ECD transplant outcomes.

Design: Retrospective cohort study.

Setting: Single center, Quebec, Canada.

Patients: The patients were 163 consecutive first-time ECD kidney only transplant recipients who underwent transplantation at McGill University Health Centre (MUHC) between January 1, 2008 and December 31, 2014 and had frozen section wedge procurement biopsies.

Measurements: Short-term graft outcomes, including delayed graft function and 1-year estimated glomerular filtration rate (eGFR), as well as long-term outcomes including all-cause graft loss (defined as return to dialysis, retransplantation, and death with function).

Methods: Pre-transplant donor, recipient, and transplant characteristics were assessed as predictors of transplant outcomes. The added value of post-transplant predictors, including longitudinal eGFR, was also assessed using time-varying Cox proportional hazards models.

Results: In univariate analyses, among the pre-transplant donor characteristics, histopathologic variables did not show evidence of association with delayed graft function, 1-year post-transplant eGFR or all cause graft loss. Recipient age was associated with all-cause graft loss (hazard ratio: 1.038 [95% confidence interval: 1.002-1.075] and the model produced only modest discrimination (C-index: 0.590; standard error [SE]: 0.045). Inclusion of time-dependent post-transplant eGFR improved the model's prediction accuracy (C-index: 0.711; SE = 0.047). Pre-transplant ECD characteristics were not associated with long-term survival, whereas post-transplant characteristics allowed better model discrimination.

Limitations: Single-center study, small sample size, and potential incomplete capture of all covariate data.

Conclusions: Incorporation of dynamic prediction models into electronic health records may enable timely mitigation of ECD graft failure risk and/or facilitate planning for renal replacement therapies. Histopathologic findings on preimplantation biopsies have a limited role in predicting long-term ECD outcomes.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1177/2054358120924305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315672PMC
June 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Hypertension Canada's 2020 Evidence Review and Guidelines for the Management of Resistant Hypertension.

Can J Cardiol 2020 05;36(5):625-634

Division of Internal Medicine, Department of Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

We present Hypertension Canada's inaugural evidence-based recommendations for the diagnosis and management of resistant hypertension. Hypertension is present in 21% of the Canadian population, and among those with hypertension, resistant hypertension has an estimated prevalence from 10% to 30%. This subgroup of hypertensive individuals is important, because resistant hypertension portends a high cardiovascular risk. Because of its importance, Hypertension Canada formed a Guidelines Committee to conduct a review of the evidence and develop recommendations for the diagnosis and management of resistant hypertension. The Hypertension Canada Guidelines Committee recommends that patients with blood pressure above target, despite use of 3 or more blood pressure-lowering drugs at optimal doses, preferably including a diuretic, be identified as those with apparent resistant hypertension. Patients identified with apparent resistant hypertension should be assessed for white coat effect, nonadherence, and therapeutic inertia, investigated for secondary hypertension, and referred to a provider with expertise in hypertension. There is no randomized controlled trial evidence for better cardiovascular outcomes with any class of antihypertensive agent at this time, so recommendations for a preferred drug class cannot be made. Furthermore, we provide a summary of the current evidence concerning the role of device therapy in the management of resistant hypertension. We will continue updating the guidelines as additional high-quality evidence with relevance to daily practice becomes available.
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http://dx.doi.org/10.1016/j.cjca.2020.02.083DOI Listing
May 2020

Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children.

Can J Cardiol 2020 05;36(5):596-624

Division of Internal Medicine, Department of Medicine, McGill University, and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.
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http://dx.doi.org/10.1016/j.cjca.2020.02.086DOI Listing
May 2020

Nonalcoholic Fatty Liver Disease and the Development of Metabolic Comorbid Conditions in Patients With Human Immunodeficiency Virus Infection.

J Infect Dis 2020 08;222(5):787-797

Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.

Background: Cardiovascular and liver disease are main causes of death in people with human immunodeficiency virus (HIV) (PWH). In HIV-uninfected patients, nonalcoholic fatty liver disease (NAFLD) is associated with incident metabolic complications. We investigated the effect of NAFLD on development of metabolic comorbid conditions in PWH.

Methods: We included PWH undergoing a screening program for NAFLD using transient elastography. NAFLD was defined as a controlled attenuation parameter ≥248 dB/m with exclusion of other liver diseases. Incident diabetes, hypertension, dyslipidemia, and chronic kidney disease were investigated using survival analysis and Cox proportional hazards.

Results: The study included 485 HIV-monoinfected patients. During a median follow-up of 40.1 months (interquartile range, 26.5-50.7 months), patients with NAFLD had higher incidences of diabetes (4.74 [95% confidence interval, 3.09-7.27] vs 0.87 [.42-1.83] per 100 person-years) and dyslipidemia (8.16 [5.42-12.27] vs 3.99 [2.67-5.95] per 100 person-years) than those without NAFLD. With multivariable analysis, NAFLD was an independent predictor of diabetes (adjusted hazard ratio, 5.13; 95% confidence interval, 2.14-12.31) and dyslipidemia (2.35; 1.34-4.14) development.

Conclusions: HIV-monoinfected patients with NAFLD are at higher risk of incident diabetes and dyslipidemia. Early referral strategies and timely management of metabolic risk may improve outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa170DOI Listing
August 2020

Policy Challenges for Organ Allocation in an Era of "Precision Medicine".

Can J Kidney Health Dis 2020 20;7:2054358120912655. Epub 2020 Mar 20.

Faculty of Medicine, The University of British Columbia, Vancouver, Canada.

There is increasing interest in the use of precision medicine tools and evidence-based outcome measures for donor-recipient matching to optimize transplant outcomes. Although the shift toward greater precision can provide health and resource benefits, it may be perceived as conflicting with both established equity-focused organ allocation norms and the legal and ethical obligations of health care providers and related institutions. With increasing evidence that various forms of human leukocyte antigen (HLA) mismatch and/or prognostic biomarkers can affect outcomes, the tension between maximizing utility and ensuring equity seems likely to intensify. In Canada, health care providers are generally required by law to put the interests of their patient, such as access to an organ, above the needs of the health care system and other patients. In addition, transplantation right of access lawsuits, which have been successful in the past, could affect the implementation of precision approaches. These legal tensions could be further heightened by media representations, which have historically favored strong rights of access. When implementing new precision technologies in organ allocation, there will be a recurrent need for policymakers to revisit the balance of equity and utility and to assess how to craft rules that reflect our society's conception of a fair allocation system.
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http://dx.doi.org/10.1177/2054358120912655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7088188PMC
March 2020

Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss.

Kidney Int 2020 04 12;97(4):778-785. Epub 2019 Nov 12.

Centre for Outcomes Research and Evaluation (CORE), McGill University Health Centre, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.
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http://dx.doi.org/10.1016/j.kint.2019.10.028DOI Listing
April 2020

Mineralocorticoid Receptor Antagonists and Renal Outcomes in Heart Failure Patients with and without Chronic Kidney Disease.

Cardiorenal Med 2020 30;10(1):32-41. Epub 2019 Oct 30.

Divisions of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Québec, Canada.

Introduction: The effect of mineralocorticoid receptor antagonists (MRAs) on chronic kidney disease (CKD) progression in patients with heart failure (HF) and with or without preexisting CKD has not been adequately studied.

Methods: We conducted a retrospective cohort study including consecutive adult patients followed at the HF clinic of a tertiary care center who had already been on an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). Exposure to MRAs was assessed at 6 months from registration. Patients who were never exposed to an MRA were the control group.

Results: A total of 314 patients who were prescribed an MRA were compared to 1,116 patients who never received an MRA. Among them, 121 and 408 patients, respectively, had CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). MRAs had to be discontinued in 36/121 patients with CKD (29.8%) and 57/165 patients without CKD (34.5%) (p = 0.39). MRA treatment was associated with a higher risk for persistent creatinine doubling among patients without CKD (hazard ratio 4.07, 95% confidence interval 1.41-11.73). A numerically lower risk was identified among CKD patients (hazard ratio 0.33, 95% confidence interval 0.04-2.78) (p for interaction = 0.009). The primary safety outcome, a composite of any doubling of serum creatinine or any episode of serious hyperkalemia (K+ >6 mmol/L), occurred more commonly in MRA users compared with nonusers in the subgroup of patients without CKD, but not in CKD patients (p for interaction = 0.02).

Conclusion: MRA treatment in addition to an ACEI or an ARB could be safely prescribed in HF patients with CKD as it is not associated with persistent renal function decline, acute kidney injury, or serious hyperkalemia, compared with ACEI/ARB monotherapy.
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http://dx.doi.org/10.1159/000503223DOI Listing
October 2019

Sex and Gender Considerations in Transplant Research: A Scoping Review.

Transplantation 2019 09;103(9):e239-e247

Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Background: In response to the promotion of sex and gender integration in health-related research, we conducted a scoping review evaluating to what extent sex and gender were considered in the transplantation literature.

Methods: We searched Medline and Embase for manuscripts published between January 1946 and October 2016. Two reviewers independently selected manuscripts describing clinical research on stem cells, tissues, or solid organ transplantation with ≥20 participants, which mentioned "sex" and/or "gender" in the title or abstract. For each eligible manuscript, 2 of 5 reviewers extracted data on study design, population (transplant candidates, recipients, donors), transplant type, and study outcomes. We evaluated whether the terms "sex" and "gender" were applied according to their correct definitions and how these variables were handled at the level of study design and analysis.

Results: Of 7565 search results, 2107 manuscripts met the inclusion criteria. Sex and gender were applied interchangeably in more than half of the studies (57.5%). Rarely were sex or gender, when applied correctly, considered in the primary study question (13.3% and 25.0%, respectively). The majority of the studies considered these variables as confounders (74.6% for sex and 68.2% for gender), and a minority considered them as effect measure modifiers (2.8% for sex and 5.0% for gender).

Conclusions: Despite a growing awareness of the need to integrate sex and gender in health research, education is required to ensure accurate and meaningful consideration of these concepts. We outline strategies for integrating sex and gender in allotransplantation and donation research during study design and analysis.
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http://dx.doi.org/10.1097/TP.0000000000002828DOI Listing
September 2019

Web-Based Self-Management Guide for Kidney Transplant Recipients (The Getting on With Your Life With a Transplanted Kidney Study): Protocol for Development and Preliminary Testing.

JMIR Res Protoc 2019 Jun 24;8(6):e13420. Epub 2019 Jun 24.

School of Physical and Occupational Therapy, McGill University, Montreal, QC, Canada.

Background: Although it is well known that compared with dialysis, kidney transplantation improves the quality of life (QoL) of patients with end-stage renal disease, posttransplant recovery of physical health and other aspects of QoL remain well below age- and sex-matched norms. In addition, most transplant recipients are not physically active even years after the transplant and face several barriers to engaging in physical activity (PA). This is of concern as low levels of PA in transplant recipients has been associated with increased risk of mortality and poor graft function. Optimization of QoL needs a team approach involving the patients and the members of the health care team. While members of the health care team are focused on optimizing the biological responses to transplant, patients may have few or no tools at their disposal to engage in behaviors that optimize QoL. To accomplish the need of supporting these patients in the self-management of their condition and to facilitate engagement with PA, new tools tailored to this population are required.

Objective: The aim of this protocol study is to develop a Web-based, patient-centered self-management intervention to promote a healthy lifestyle, increase daily PA, and improve QoL in kidney transplant recipients.

Methods: We will use the Obesity-Related Behavioral Intervention Trials model for developing behavioral treatments for chronic diseases to guide the proposed project. We will follow a modified version of the iterative 10-step process that was used to develop educational material for people with multiple sclerosis. The development of the intervention will occur in partnership with patients and a multidisciplinary team of clinicians and researchers. A comprehensive needs assessment including data from our pilot study, literature review, and focus groups will be conducted. The focus groups will be conducted with 6 to 10 participants for each type of stakeholders: patients and professional experts to identify areas of concerns of kidney transplant recipients that are appropriate to address through self-management. The areas of concern identified through the assessment needs will be included in the website.

Results: This study has received funding from the Kidney Foundation of Canada for 2 years (2018-2020) and was recently granted ethics approval. Investigators have begun conducting the needs assessment described in step 1 of the study. The study is expected to be completed by the end of 2020.

Conclusions: This will be the first comprehensive, evidence- and experience-based self-management program for kidney transplant recipients. Once the intervention is developed, we anticipate improvements in patient experience, shared decision making, daily PA, QoL, and, in future studies, improvements in health outcomes and demonstrations of cost savings in posttransplant care.

International Registered Report Identifier (irrid): PRR1-10.2196/13420.
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http://dx.doi.org/10.2196/13420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613326PMC
June 2019

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

Am J Transplant 2019 01 19;19(1):123-131. Epub 2018 Jul 19.

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.
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http://dx.doi.org/10.1111/ajt.14979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309659PMC
January 2019

Physician Practice Patterns and Barriers to Counselling on Physical Activity in Solid Organ Transplant Recipients.

Ann Transplant 2018 May 22;23:345-359. Epub 2018 May 22.

School of Physical and Occupational Therapy, McGill University, Montreal, Quebec, Canada.

BACKGROUND Many solid organ transplant (SOT) recipients fail to meet the recommended physical activity (PA) levels. "Physician recommendation" has previously been reported by SOT recipients as a key facilitator to being more physically active. The purpose of this study was to determine the proportion of Canadian SOT physicians providing PA counselling and identify barriers to including such counselling as part of the SOT recipients' routine care. MATERIAL AND METHODS We conducted a cross-sectional web-based survey study to evaluate physicians' PA counselling practices, including the prevalence and barriers to such practice. A survey link was sent to a convenience sample of transplant physicians who are members of the Canadian Society of Transplantation. RESULTS Thirty-four physicians (13.6%) participated in the survey. While 97% (n=33) of the participants reported providing PA counselling to their transplant patients, only 18% (n=6) responded they were very confident in PA counselling. Lack of time (n=19; 56%) and a lack of exercise guidelines (n=18; 53%) were identified as the main barriers to PA counselling. CONCLUSIONS Incorporating sufficient PA knowledge into physicians' educational curricula system, developing specific PA guidelines as well as establishing an easier referral system to exercise specialists might improve the frequency and quality of PA counselling post-transplant.
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http://dx.doi.org/10.12659/AOT.908629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248028PMC
May 2018

Renal resistance thresholds during hypothermic machine perfusion and transplantation outcomes - a retrospective cohort study.

Transpl Int 2018 06 25;31(6):658-669. Epub 2018 Mar 25.

Division of Nephrology and Multi-Organ Transplant Program, McGill University Health Centre, Montreal, QC, Canada.

Renal resistance (RR), of allografts undergoing hypothermic machine perfusion (HMP), is considered a measure of organ quality. We conducted a retrospective cohort study of adult deceased donor kidney transplant (KT) recipients whose grafts underwent HMP. Our aim was to evaluate whether RR is predictive of death-censored graft failure (DCGF). Of 274 KT eligible for analysis, 59% were from expanded criteria donor. RR was modeled as a categorical variable, using a previously identified terminal threshold of 0.4, and 0.2 mmHg/ml/min (median in our cohort). Hazard ratios (HR) of DCGF were 3.23 [95% confidence interval (CI): 1.12-9.34, P = 0.03] and 2.67 [95% CI: 1.14-6.31, P = 0.02] in univariable models, and 2.67 [95% CI: 0.91-7.86, P = 0.07] and 2.42 [95% CI: 1.02-5.72, P = 0.04] in multivariable models, when RR threshold was 0.4 and 0.2, respectively. Increasing risk of DCGF was observed when RR over the course of HMP was modeled using mixed linear regression models: HR of 1.31 [95% CI: 1.07-1.59, P < 0.01] and 1.25 [95% CI: 1.00-1.55, P = 0.05], in univariable and multivariable models, respectively. This suggests that RR during HMP is a predictor of long-term KT outcomes. Prospective studies are needed to assess the survival benefit of patients receiving KT with higher RR in comparison with staying wait-listed.
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http://dx.doi.org/10.1111/tri.13146DOI Listing
June 2018

Powerful diuretics: A common denominator in landmark hypertension and type 2 diabetes mellitus trials.

J Clin Hypertens (Greenwich) 2018 01 18;20(1):136-142. Epub 2017 Dec 18.

Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

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http://dx.doi.org/10.1111/jch.13151DOI Listing
January 2018

Sex and gender considerations in transplantation research: protocol for a scoping review.

Syst Rev 2017 09 8;6(1):186. Epub 2017 Sep 8.

Canadian National Transplant Research Program, Edmonton, Canada.

Background: Despite the growing appreciation of the importance of sex and gender considerations in transplantation research, there is currently no framework or good practice guidelines for the appropriate handling of sex and gender issues in human allotransplantation research.

Methods: We will conduct a scoping review to synthesize the evidence on how matters of sex and gender have been handled in human allotransplantation research. We will survey the literature discussing sex and gender in relation to transplantation, including adult and pediatric patients, hematopoietic and solid organ transplant recipients as well as organ donors. We will search MEDLINE and Embase for literature discussing sex and gender in relation to transplantation. Two reviewers will independently evaluate the eligibility of all identified titles and abstracts for inclusion in the full text review, as well as data extraction. Descriptive data and information on how sex and gender have been considered in human transplantation research will be reported.

Discussion: This scoping review will be an important stepping stone towards the development of good practice guidelines on study design and analysis considerations when handling sex and gender issues in human transplantation research. This scoping review can also help identify methodological issues that restrict the translation of transplantation research findings into clinical practice related to underestimation of sex/gender differences. This review will ultimately identify major gaps, inform donor-recipient selection, guide personalized interventions, and prioritize research recommendations in human transplantation research.
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http://dx.doi.org/10.1186/s13643-017-0578-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591534PMC
September 2017

Performance of an allele-level multi-locus HLA genotype imputation tool in hematopoietic stem cell donors from Quebec.

Immun Inflamm Dis 2017 12 25;5(4):551-559. Epub 2017 Aug 25.

Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.

Introduction: Donor-recipient HLA compatibility is an important determinant of transplant outcomes. Allele-group to allele-level imputations help assign HLA genotypes when allele-level genotypes are not available during donor selection.

Methods: We evaluated the performance of HaploStats, an allele-level multi-locus HLA genotype imputation tool from the National Marrow Donor Program, in a cross-sectional study including hematopoietic stem cell donors (HSCD) from Quebec, Canada. A total of 144 self-identified Caucasian HSCD genotyped at the allele-group and allele-level for HLA-A, -B, -C, -DRB1, and -DQB1 loci were studied. We compared allele-level genotypes imputed by HaploStats to those obtained by the reference standard, sequenced-based typing (SBT).

Results: Imputation performance, determined by allele-level genotype recall (fraction of matching imputed and sequenced genotypes) was 97%, 96%, 95%, 84%, and 81% for HLA-A, -B, -C, -DRB1, and -DQB1 loci, respectively. Our sample deviated from Hardy-Weinberg equilibrium only at the HLA-DRB1 locus. Residual ambiguity, determined by typing resolution scores (TRS), was greatest for HLA class II loci (average TRS 0.65 and 0.80 for DRB1 and DQB1, respectively). In contrast, average TRS of 0.88, 0.84, and 0.92 was observed for HLA-A, -B, and -C, respectively.

Conclusions: HLA allele imputation from ambiguous genotypes demonstrate satisfactory prediction accuracy for HLA class I but modest prediction accuracy for HLA class II loci in self-identified Caucasian HSCD from Quebec. While consideration of high-resolution allele and haplotype frequencies in the Quebec population may improve the performance of available allele-level multi-locus genotype imputation tools in Quebec, this study suggests that genotyping at the first two field level should be conducted whenever possible.
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http://dx.doi.org/10.1002/iid3.185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691302PMC
December 2017

Association of Sex with Risk of Kidney Graft Failure Differs by Age.

J Am Soc Nephrol 2017 Oct 7;28(10):3014-3023. Epub 2017 Jun 7.

Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada;

Prior studies of sex differences in kidney graft survival showed conflicting results. We hypothesized that the association between recipient sex and kidney graft failure risk differs by recipient age and donor sex. We evaluated 159,417 patients recorded in the Scientific Registry of Transplant Recipients database who received a first deceased-donor kidney transplant (1995-2013). We used time-varying Cox models to estimate the association between recipient sex and death-censored graft failure. Models, stratified on donor sex and adjusted for potential confounders, included a recipient sex by current age interaction term. Among recipients of male donors, females of all ages had significantly higher graft failure risks than males (adjusted hazard ratios 0-14 years: 1.51 [95% confidence intervals 1.19 to 1.90]; 15-24 years: 1.37 [1.18 to 1.59]; 25-44 years: 1.14 [1.03 to 1.26]; 45 years: 1.05 [1.01 to 1.09]). Among recipients of female-donor grafts, only female recipients aged 15-24 years had a significantly higher graft failure risk than their male counterparts had (1.28 [1.06 to 1.53]). Indeed, female recipients aged ≥45 years had a significantly lower graft failure risk than their male counterparts had (0.95 [0.91 to 0.99]). These observations might be explained by the combined influence of several factors, including recognition of sex-determined minor histocompatibility antigens, influence of sex hormones on immune activation, sex- and age-related differences in medication adherence, and sex-related differences in body size. Additional studies should determine whether sex- and age-specific immunosuppression strategies are warranted for kidney graft recipients.
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http://dx.doi.org/10.1681/ASN.2016121380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619967PMC
October 2017

Opportunities for Engaging Patients in Kidney Research.

Can J Kidney Health Dis 2017 12;4:2054358117703070. Epub 2017 Apr 12.

Department of Family Medicine and Emergency Medicine, Université de Montréal, Québec, Canada.

Purpose: The purpose of this review is to provide a summary of the rationale for engaging patients in research as well as to review the established and envisioned advantages and strategies for patient-researcher partnerships. The authors of this article, which include a patient and 4 researchers in kidney disease, discuss the expected benefits and opportunities for patient engagement in their respective research programs. The 4 research programs span the spectrum of kidney disease and focus on enhancing bone health, increasing living donor kidney transplants, improving medication adherence, and preventing kidney transplant rejection.

Sources Of Information: The sources of information for this review include published studies on the topics of patient engagement and the 4 research programs of the new investigators.

Key Findings: (1) Patient, health care provider, and researcher partnerships can contribute useful insights capable of enhancing research in kidney disease. (2) Regardless of the research program, there are various strategies and opportunities for engagement of patients with lived experience across the various stages of research in kidney disease. (3) Envisioned advantages of patient-researcher partnerships include: targeting patient-identified research priorities, integrating patients' experiential knowledge, improving study design and feasibility through patient-researcher input, facilitating dissemination of research findings to other patients, effectively responding to patient concerns about studies, and inspiring researchers to conduct their research.

Limitations: The limitations of the current review include the relative scarcity of literature on patient engagement within the field of kidney disease.

Implications: The findings of the current review suggest that it will be important for future studies to identify optimal strategies for patient engagement in setting research priorities, study design, participant recruitment, execution of research projects, and knowledge dissemination and translation.
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http://dx.doi.org/10.1177/2054358117703070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406191PMC
April 2017

Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine.

Can J Kidney Health Dis 2017 23;4:2054358116688227. Epub 2017 Jan 23.

Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada; Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; Multi-Organ Transplant Program, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada; Centre for Outcomes Research and Evaluation, McGill University Health Centre, Montreal, Quebec, Canada.

Purpose Of Review: P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine's relevance to the various stages of the kidney transplant cycle.

Sources Of Information: A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings.

Findings: Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients' care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence.

Limitations: For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice.

Implications: Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care.
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http://dx.doi.org/10.1177/2054358116688227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308536PMC
January 2017

Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV coinfected patients.

AIDS 2016 06;30(9):1403-311

aMcGill University, Department of Epidemiology, Biostatistics and Occupational Health, Montréal, Québec bThe Ottawa Hospital-General Campus, Ottawa, Ontario cCentre Hospitalier de l'Université de Montréal - Notre-Dame, Montréal, Québec dUniversity Health Network, University of Toronto, Toronto, Ontario eSouthern Alberta HIV Clinic, Calgary, Alberta fMcGill University, Division of Nephrology and Multi-Organ Transplant Program, Department of Medicine, Montréal, Québec gChronic Viral Illness Service, McGill University Health Centre, Montréal, Québec, Canada.

Objective: To examine the association between injection cocaine use, hepatitis C virus (HCV) infection, and chronic renal impairment (CRI).

Design: Prospective observational cohort study of HIV-HCV coinfected patients.

Methods: Data from 1129 participants in the Canadian Co-Infection Cohort with baseline and follow-up serum creatinine measurements between 2003 and 2014 were analyzed. Prevalent and incident cohorts were created to examine the association between self-reported past, current, and cumulative cocaine use and chronic HCV with CRI. CRI was defined as an estimated glomerular filtration rate below 70 ml/min per 1.73 m. Multivariate logistic regression was used to calculate odds ratios, and discrete-time proportional-hazards models were used to calculate hazard ratios for cocaine use, in the two respective cohorts, adjusted for HCV RNA and important demographic, HIV disease stage, and comorbidity confounders.

Results: Eighty-seven participants (8%) had prevalent CRI. Past injection cocaine use was associated with a two-fold greater risk of prevalent CRI [odds ratio 2.03, 95% confidence interval (CI) 0.96, 4.32]. During follow-up, 126 of 1061 participants (12%) developed incident CRI (31 per 1000 person-years). Compared to nonusers, heavy (≥ 3 days/week) and frequent injection cocaine users (≥75% of follow-up time) experienced more rapid progression to CRI (hazard ratio 2.65, 95% CI 1.35, 5.21; and hazard ratio 1.82, 95% CI 1.07, 3.07, respectively). There was no association between chronic HCV and CRI in either cohort.

Conclusion: After accounting for HCV RNA, frequent and cumulative injection cocaine abuse was associated with CRI progression and should be taken into consideration when evaluating impaired renal function in HIV-HCV coinfection.
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http://dx.doi.org/10.1097/QAD.0000000000001060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867986PMC
June 2016

Immune Sensitization and Mortality in Wait-Listed Kidney Transplant Candidates.

J Am Soc Nephrol 2016 Feb 8;27(2):570-8. Epub 2015 Jun 8.

Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Institute of Health Policy, Management, and Evaluation, and Division of Nephrology, Departments of Medicine and Division of Nephrology and the Renal Transplant Program, St. Michael's Hospital, Toronto, Ontario, Canada;

Cardiovascular mortality is the leading cause of death in ESRD. Whereas innate and adaptive immunity have established roles in cardiovascular disease, the role of humoral immunity is unknown. We conducted a retrospective cohort study in first-time adult kidney transplant candidates (N=161,308) using data from the Scientific Registry of Transplant Recipients and the Centers for Medicare and Medicaid Services to evaluate whether anti-human leukocyte antigen antibodies, measured as panel reactive antibodies (PRAs), are related to mortality in ESRD. Relationships between time-varying PRAs and all-cause or cardiovascular mortality were assessed using Cox proportional hazards models. The analysis was repeated in subcohorts of candidates at lower risk for significant comorbidities, activated on the waiting list after 2007, or unsensitized at activation. Competing risks analyses were also conducted. Fully adjusted models showed increased hazard ratios (HRs [95% confidence intervals]) for all-cause mortality (HR, 1.02 [95% CI, 0.99 to 1.06]; HR, 1.11 [95% CI,1.07 to 1.16]; and HR,1.21 [95% CI,1.15 to 1.27]) and cardiovascular mortality (HR, 1.05 [95% CI,1.00 to 1.10]; HR,1.11 [95% CI,1.05 to 1.18]; and HR,1.21 [95% CI,1.12 to 1.31]) in PRA 1%-19%, PRA 20%-79%, and PRA 80%-100% categories compared with PRA 0%, respectively. Associations between PRA and the study outcomes were accentuated in competing risks models and in lower-risk patients and persisted in other subcohorts. Our findings suggest that PRA is an independent predictor of mortality in wait-listed kidney transplant candidates. The mechanisms by which PRA confers an incremental mortality risk in sensitized patients, and the role of transplantation in modifying this risk, warrant further study.
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http://dx.doi.org/10.1681/ASN.2014090894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731107PMC
February 2016

A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection.

Kidney Int 2015 Jan 14;87(1):182-94. Epub 2014 May 14.

1] Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada [2] Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada [3] Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada [4] Division of Nephrology and the Renal Transplant Program, St Michael's Hospital, Toronto, Ontario, Canada.

In this study, we conducted a systematic review of the literature to re-evaluate the role of C4d in the diagnosis of acute antibody-mediated rejection of kidney allografts. Electronic databases were searched until September 2013. Eligible studies allowed derivation of diagnostic tables for the performance of C4d by immunofluorescence or immunohistochemistry with comparison to histopathological features of acute antibody-mediated rejection and/or donor-specific antibody (DSA) assays. Of 3492 unique abstracts, 29 studies encompassing 3485 indication and 868 surveillance biopsies were identified. Assessment of C4d by immunofluorescence and immunohistochemistry exhibited slight to moderate agreement with glomerulitis, peritubular capillaritis, solid-phase DSA assays, DSA with glomerulitis, and DSA with peritubular capillaritis. The sensitivity and specificity of C4d varied as a function of C4d and comparator test thresholds. Prognostically, the presence of C4d was associated with inferior allograft survival compared with DSA or histopathology alone. Thus, our findings support the presence of complement-dependent and -independent phenotypes of acute antibody-mediated rejection. Whether the presence of C4d in combination with histopathology or DSA should be considered for the diagnosis of acute antibody-mediated rejection warrants further study.
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http://dx.doi.org/10.1038/ki.2014.166DOI Listing
January 2015

Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure.

Kidney Int 2014 Jun 11;85(6):1404-11. Epub 2013 Dec 11.

1] Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada [2] Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada [3] Division of Nephrology and the Renal Transplant Program, St Michael's Hospital, Toronto, Ontario, Canada [4] Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.
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http://dx.doi.org/10.1038/ki.2013.465DOI Listing
June 2014