Publications by authors named "Manish M Sood"

194 Publications

Comparison of Clinical Outcomes and Safety Associated With Chlorthalidone vs Hydrochlorothiazide in Older Adults With Varying Levels of Kidney Function.

JAMA Netw Open 2021 Sep 1;4(9):e2123365. Epub 2021 Sep 1.

Ottawa Hospital Research Institute, Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Canada.

Importance: Thiazide diuretics are commonly prescribed for the treatment of hypertension, a disease highly prevalent among older individuals and in those with chronic kidney disease. How specific thiazide diuretics compare in regard to safety and clinical outcomes in these populations remains unknown.

Objective: To compare safety and clinical outcomes associated with chlorthalidone or hydrochlorothiazide use among older adults with varying levels of kidney function.

Design, Setting, And Participants: This population-based retrospective cohort study was conducted in Ontario, Canada, from 2007 to 2015. Participants included adults aged 66 years or older who initiated chlorthalidone or hydrochlorothiazide during this period. Data were analyzed from December 2019 through September 2020.

Exposures: New chlorthalidone users were matched 1:4 with new hydrochlorothiazide users by a high-dimensional propensity score. Time-to-event models accounting for competing risks examined the associations between chlorthalidone vs hydrochlorothiazide use and the outcomes of interest overall and within estimated glomerular filtration rate (eGFR) categories (≥60, 45-59, and <45 mL/min/1.73 m2).

Main Outcomes And Measures: The outcomes of interest were adverse kidney events (ie, eGFR decline ≥30%, dialysis, or kidney transplantation), cardiovascular events (composite of myocardial infarction, coronary revascularization, heart failure, or atrial fibrillation), all-cause mortality, and electrolyte anomalies (ie, sodium or potassium levels outside reference ranges).

Results: After propensity score matching, the study cohort included 12 722 adults (mean [SD] age, 74 [7] years; 7063 [56%] women; 5659 [44%] men; mean [SD] eGFR, 69 [19] mL/min/1.73 m2), including 2936 who received chlorthalidone and 9786 who received hydrochlorothiazide. Chlorthalidone use was associated with a higher risk of eGFR decline of 30% or greater (hazard ratio [HR], 1.24 [95% CI, 1.13-1.36]) and cardiovascular events (HR, 1.12 [95% CI, 1.04-1.22]) across all eGFR categories compared with hydrochlorothiazide use. Chlorthalidone use was also associated with a higher risk of hypokalemia compared with hydrochlorothiazide use, which was more pronounced among those with higher eGFR (eGFR ≥60 mL/min/1.73 m2: HR, 1.86 [95% CI, 1.67-2.08]; eGFR 45-59 mL/min/1.73 m2: HR, 1.57 [95% CI, 1.25-1.96]; eGFR <45 mL/min/1.73 m2: HR, 1.10 [95% CI, 0.84-1.45]; P for interaction = .001). No significant differences were observed between chlorthalidone and hydrochlorothiazide for dialysis or kidney transplantation (HR, 1.44 [95% CI, 0.88-2.36]), all-cause mortality (HR, 1.10 [95% CI, 0.93-1.29]), hyperkalemia (HR, 1.05 [95% CI, 0.79-1.39]), or hyponatremia (HR, 1.14 [95% CI, CI 0.98-1.32]).

Conclusions And Relevance: This cohort study found that among older adults, chlorthalidone use was associated with a higher risk of eGFR decline, cardiovascular events, and hypokalemia compared with hydrochlorothiazide use. The excess risk of hypokalemia with chlorthalidone was attenuated in participants with reduced kidney function. Placed in context with prior observational studies comparing the safety and clinical outcomes associated with thiazide diuretics, these results suggest that there is no evidence to prefer chlorthalidone over hydrochlorothiazide.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.23365DOI Listing
September 2021

MyTEMP: Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial.

Can J Kidney Health Dis 2021 27;8:20543581211041182. Epub 2021 Aug 27.

ICES, London, ON, Canada.

Background: Major Outcomes with Personalized Dialysate TEMPerature (MyTEMP) is a 4-year cluster-randomized clinical trial comparing the effect of using a personalized, temperature-reduced dialysate protocol versus a dialysate temperature of 36.5°C on cardiovascular-related death and hospitalization. Randomization was performed at the level of the dialysis center ("the cluster").

Objective: The objective is to outline the statistical analysis plan for the MyTEMP trial.

Design: MyTEMP is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized trial.

Setting: A total of 84 dialysis centers in Ontario, Canada.

Patients: Approximately 13 500 patients will have received in-center hemodialysis at the 84 participating dialysis centers during the trial period (April 3, 2017, to March 1, 2021, with a maximum follow-up to March 31, 2021).

Methods: Patient identification, baseline characteristics, and study outcomes will be obtained primarily through Ontario administrative health care databases held at ICES. Covariate-constrained randomization was used to allocate the 84 dialysis centers (1:1) to the intervention group or the control group. Centers in the intervention group used a personalized, temperature-reduced dialysate protocol, and centers in the control group used a fixed dialysate temperature of 36.5°C.

Outcomes: The primary outcome is a composite of cardiovascular-related death or major cardiovascular-related hospitalization (defined as a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) recorded in administrative health care databases. The key secondary outcome is the mean drop in intradialytic systolic blood pressure, defined as the patients' predialysis systolic blood pressure minus their nadir systolic blood pressure during the dialysis treatment. Anonymized data on patients' predialysis and intradialytic systolic blood pressure were collected at monthly intervals from each dialysis center.

Analysis Plan: The primary analysis will follow an intent-to-treat approach. The primary outcome will be analyzed at the patient level as the hazard ratio of time-to-first event, estimated from a subdistribution hazards model. Within-center correlation will be accounted for using a robust sandwich estimator. In the primary analysis, patients' observation time will end if they experience the primary outcome, emigrate from Ontario, or die of a noncardiovascular cause (which will be treated as a competing risk event). The between-group difference in the mean drop in intradialytic systolic blood pressure obtained during the dialysis sessions throughout the trial period will be analyzed at the center level using an unadjusted random-effects linear mixed model.

Trial Status: The MyTEMP trial period is April 3, 2017, to March 31, 2021. We expect to analyze and report results by 2023 once the updated data are available at ICES.

Trial Registration: MyTEMP is registered with the US National Institutes of Health at clincaltrials.gov (NCT02628366).

Statistical Analytic Plan: Version 1.1 June 15, 2021.
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http://dx.doi.org/10.1177/20543581211041182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404662PMC
August 2021

Hyperkalemia with RAAS inhibition: Mechanism, clinical significance, and management.

Pharmacol Res 2021 Oct 23;172:105835. Epub 2021 Aug 23.

Department of Medicine (Division of Nephrology) and The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada; Institute for Clinical Evaluative Sciences, Ottawa, Canada.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based treatments for a number of conditions including hypertension, diabetes mellitus, chronic kidney disease, and congestive heart failure. Among the most common adverse effects of RAAS inhibitors is hyperkalemia which results from either reduced secretion of aldosterone or increased resistance to aldosterone. Many of the conditions for which RAAS inhibitors are recommended further amplify the risk for hyperkalemia in and of themselves. RAAS inhibitor-related hyperkalemia is associated with an increased risk for cardiovascular events, hospitalizations, and death. Yet discontinuation of RAAS inhibitors for patients with chronic kidney disease and congestive heart failure is also associated with an increased risk for cardiovascular events, hospitalizations, and death. Therefore, clinicians are often left to struggle with the dilemma of the best management approach to RAAS inhibitor-related hyperkalemia. The ideal solution involves pharmacotherapies that are safe and effective in mitigating hyperkalemia and allow patients to continue to receive the beneficial effects from RAAS inhibitors. In this regard, modern pharmacologic agents such as patiromer and zirconium cyclosilicate are providing a mechanism whereby physicians are better equipped to maintain their patients on RAAS inhibitors.
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http://dx.doi.org/10.1016/j.phrs.2021.105835DOI Listing
October 2021

Stroke and Chronic Kidney Disease.

Contrib Nephrol 2021 Aug 3;199:1-11. Epub 2021 Aug 3.

Ottawa Hospital Research Institute, The Ottawa Hospital, Civic Campus, Ottawa, Ontario, Canada.

Chronic kidney disease (CKD) is strongly associated with the full spectrum of cerebrovascular disease including ischaemic and haemorrhagic stroke, small vessel disease, and vascular cognitive impairment. Shared conventional vascular risk factors such as age, hypertension, and diabetes mellitus may account for many of these associations, but novel renal-specific risk factors such as uraemia-related coagulopathy or endothelial dysfunction have also been proposed. In this chapter, we will explore the impact of CKD on stroke risk, mechanisms, and outcomes. We will also outline potential challenges and inequities in stroke care delivery and research for these patients along with some strategies to help improve stroke prevention and management for this high-risk group.
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http://dx.doi.org/10.1159/000517698DOI Listing
August 2021

The impact of measuring split kidney function on post-donation kidney function: A retrospective cohort study.

PLoS One 2021 2;16(7):e0253609. Epub 2021 Jul 2.

Division of Nephrology, Department of Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Background: Studies have reported agreement between computed tomography (CT) and renography for the determination of split kidney function. However, their correlation with post-donation kidney function remains unclear. We compared CT measurements with renography in assessment of split kidney function (SKF) and their correlations with post-donation kidney function.

Methods: A single-centre, retrospective cohort study of 248 donors from January 1, 2009-July 31, 2019 were assessed. Pearson correlations were used to assess post-donation kidney function with renography and CT-based measurements. Furthermore, we examined high risk groups with SKF difference greater than 10% on renography and donors with post-donation eGFR less than 60 mL/min/1.73m2.

Results: 62% of donors were women with a mean (standard deviation) pre-donation eGFR 99 (20) and post-donation eGFR 67 (22) mL/min/1.73m2 at 31 months of follow-up. Post-donation kidney function was poorly correlated with both CT-based measurements and renography, including the subgroup of donors with post-donation eGFR less than 60 mL/min/1.73m2 (r less than 0.4 for all). There was agreement between CT-based measurements and renography for SKF determination (Bland-Altman agreement [bias, 95% limits of agreement] for renography vs: CT volume, 0.76%, -7.60-9.15%; modified ellipsoid,1.01%, -8.38-10.42%; CC dimension, 0.44%, -7.06-7.94); however, CT missed SKF greater than 10% found by renography in 20 out 26 (77%) of donors.

Conclusions: In a single centre study of 248 living donors, we found no correlation between CT or renography and post-donation eGFR. Further research is needed to determine optimal ways to predict remaining kidney function after donation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253609PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253423PMC
July 2021

Short- and Long-term Health Care Resource Utilization and Costs Following Intracerebral Hemorrhage.

Neurology 2021 08 9;97(6):e608-e618. Epub 2021 Jun 9.

From the Division of Critical Care (S.M.F., S.W.E., K.K.), Department of Medicine, and Department of Emergency Medicine (S.M.F.), University of Ottawa; ICES (D.Q., R.T., M.M.S., D.C.S., P.T.), Toronto; Clinical Epidemiology Program (D.Q., R.T., D.D., M.M.S., S.W.E., P.T., K.K.), Ottawa Hospital Research Institute; School of Epidemiology and Public Health (D.Q., D.D., M.M.S., S.W.E., P.T.), University of Ottawa; Bruyère Research Institute (D.Q., P.T.); Division of Palliative Care (D.Q., P.T., K.K.), Department of Medicine, Division of Neurology (D.D.), Department of Medicine, and Division of Nephrology (M.M.S.), Department of Medicine, University of Ottawa, Ontario; Calgary Stroke Program (E.E.S., M.D.H.), Hotchkiss Brain Institute, and Department of Clinical Neurosciences (E.E.S., M.D.H.), Cumming School of Medicine, University of Calgary, Alberta; Interdepartmental Division of Critical Care Medicine (V.A.M., D.C.S.), University of Toronto; Krembil Research Institute (V.A.M.), Toronto Western Hospital, University Health Network; Department of Critical Care Medicine (V.A.M., D.C.S.), Sunnybrook Health Sciences Centre; Li Ka Shing Knowledge Institute (D.C.S.), St. Michael's Hospital, Toronto; Department of Medicine (B.R.), Division of Critical Care and Department of Health Research Methods, Evidence, and Impact (B.R.), McMaster University, Hamilton; and Institut du Savoir Montfort (K.K.), Ottawa, Ontario, Canada.

Objective: We sought to evaluate the short- and long-term resource use and costs associated with intracerebral hemorrhage (ICH) taken from an entire population. We in addition sought to evaluate the association of oral anticoagulation (OAC) and health care costs.

Methods: This was a retrospective cohort study of adult patients (≥18 years) with ICH in the entire population of Ontario, Canada (2009-2017). We captured outcomes through linkage to health administrative databases. We used generalized linear models to identify factors associated with total cost. Analysis of OAC use was limited to patients ≥66 years of age. The primary outcome was total 1-year direct health care costs in 2020 US dollars.

Results: Among 16,248 individuals with ICH (mean age 71.2 years, male 52.3%), 1-year mortality was 46.0%, and 24.2% required mechanical ventilation. The median total 1-year cost was $26,886 (interquartile range [IQR] $9,641-$62,907) with costs for those who died in hospital of $7,268 (IQR $4,031-$14,966) vs $44,969 (IQR $20,264-$82,414, < 0.001) for survivors to discharge. OAC use (analysis limited to individuals ≥66 years old) was associated with higher total 1-year costs (cost ratio 1.06 [95% confidence interval 1.01-1.11]). Total 1-year costs for the entire cohort exceeded $120 million per year over the study period.

Conclusions: ICH is associated with significant health care costs, and the median cost of a patient with ICH is roughly 10 times the median inpatient cost in Ontario. Costs were higher among survivors than deceased patients. OAC use is independently associated with increased costs. To maximize cost-effectiveness, future therapies for ICH must aim to reduce disability, not only improve mortality.
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http://dx.doi.org/10.1212/WNL.0000000000012355DOI Listing
August 2021

Initial and Recurrent Hyperkalemia Events in Patients With CKD in Older Adults: A Population-Based Cohort Study.

Can J Kidney Health Dis 2021 27;8:20543581211017408. Epub 2021 May 27.

Department of Medicine, University of Ottawa, ON, Canada.

Background: The risk of hyperkalemia is elevated in chronic kidney disease (CKD); however, the initial and recurrent risk among older individuals is less clear.

Objectives: We set out to examine the initial and 1-year recurrent risk of hyperkalemia by level of kidney function (estimated glomerular filtration rate, eGFR) in older adults (≥66 years old).

Design: Population-based, retrospective cohort study.

Settings: Ontario, Canada.

Participants: 905 167 individuals (≥66 years old) from 2008 to 2015.

Measurements: Serum potassium values.

Methods: Individuals were stratified by eGFR (≥90, 60-89, 30-59, 15-29 mL/min/1.73 m) and examined for the risk of incident hyperkalemia (K ≥ 5.5 mEq/L) using adjusted Cox proportional hazards models. The 1-year risk of recurrent hyperkalemia was examined using multivariable Andersen-Gill models.

Results: Among a population of 905 167 individuals (15% eGFR ≥ 90, 58% eGFR 60-89, 25% eGFR 30-59, 3% eGFR 15-29) with a potassium measurement, there were a total of 18 979 (2.1%) individuals with hyperkalemia identified. The event rate (per 1000 person-years) and adjusted hazard ratio (HR) of hyperkalemia was inversely associated with eGFR (mL/min; eGFR >90 mL/min: 8.8, referent, 60-89 mL/min: 11.8 HR 1.41; eGFR 30-59: 39.8, HR 4.37; eGFR 15-29: 133.6, 13.65) and with an increasing urine albumin-to-creatinine ratio (ACR, mg/mmol; ACR< 3: 14, referent, ACR 3-30: 35.1, HR 1.98; ACR >30: 93.7, 4.71). The 1-year event rate and adjusted risk of recurrent hyperkalemia was similarly inversely associated with eGFR (eGFR ≥ 90: 10.1, referent, eGFR 60-89: 14.4, HR 1.47; eGFR 30-59: 54.8, HR 4.90; eGFR 15-29: 208.0, HR 12.98). Among individuals with a baseline eGFR of 30 to 59 and 15 to 29, 0.9 and 3.8% had greater than 2 hyperkalemia events. The relative risk of initial and recurrent hyperkalemia was marginally higher with RAAS blockade. Roughly 1 in 4 individuals with hyperkalemia required hospitalization the day of or within 30 days after their hyperkalemia event.

Limitations: Limited to individuals aged 66 years and above.

Conclusions: Patients with low eGFR are at a high risk of initial and recurrent hyperkalemia.

Trial Registration: .
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http://dx.doi.org/10.1177/20543581211017408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165829PMC
May 2021

Progression and Regression of Chronic Kidney Disease by Age Among Adults in a Population-Based Cohort in Alberta, Canada.

JAMA Netw Open 2021 Jun 1;4(6):e2112828. Epub 2021 Jun 1.

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Importance: The burden of chronic kidney disease (CKD) is expected to increase worldwide as the global population ages, potentially increasing the demand for nephrology services. Understanding whether CKD inevitably progresses or may regress can inform clinical decision-making and health policy.

Objective: To study CKD progression and regression by age in adults with CKD.

Design, Setting, And Participants: This population-based cohort study used linked administrative and laboratory data to assess adults in the province of Alberta, Canada, with incident mild, moderate, or severe CKD, defined by estimated glomerular filtration rate (eGFR) of 45 to 59, 30 to 44, or 15 to 29 mL/min/1.73 m2 for longer than 3 months, from April 1, 2009, to March 31, 2015. Data were analyzed from July 20 to November 30, 2020.

Exposures: Age.

Main Outcomes And Measures: Time to the earliest of CKD regression or progression (defined as sustained increase or drop in eGFR category for >3 months, respectively, and a ≥25% increase or decrease in eGFR from baseline, respectively), kidney failure (the earlier of kidney replacement initiation or eGFR <15 mL/min/1.73 m2 for >3 months), death, or censoring (outmigration, 5 years of follow-up, or end of study on March 31, 2017).

Results: Study participants with CKD (55.2% women and 44.8% men) included 81 320 with mild CKD (mean [SD] age, 72.4 [11.3] years), 35 929 with moderate CKD (mean [SD] age, 77.1 [11.5] years), and 12 237 with severe CKD (mean [SD] age, 76.6 [13.8] years). The annual incidence of CKD increased with advancing age, from 180 per 100 000 population younger than 65 years to 7250 per 100 000 in those 85 years or older. After cohort entry, the 5-year probability of regression was similar to that of progression or kidney failure in mild (14.3% vs 14.6%), moderate (18.9% vs 16.5%), and severe (19.3% vs 20.4%) CKD. As mortality at 5 years increased with advancing age in moderate (from 9.6% for age <65 years to 48.4% for age ≥85 years) and severe (from 10.8% for age <65 years to 60.2% for age ≥85 years) CKD, the risk of progression or kidney failure decreased substantially (for moderate CKD, from 32.3% for <65 years to 9.4% for ≥85 years; for severe CKD, from 55.2% for <65 years to 4.7% for ≥85 years), whereas the probabilities of regression varied to a lesser extent (for moderate CKD, from 22.5% for <65 years to 15.4% for ≥85 years; for severe CKD, from 13.9% for <65 years to 18.7% for ≥85 years).

Conclusions And Relevance: This cohort study found that with advancing age, CKD regression and death were more likely than CKD progression or kidney failure. These findings have important implications for patient care and for assessing the potential effect of population aging on the burden of CKD.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.12828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188272PMC
June 2021

Epidemiology, thrombolytic management, and outcomes of acute stroke among patients with chronic kidney disease: a systematic review and meta-analysis.

Nephrol Dial Transplant 2021 Jun 8. Epub 2021 Jun 8.

Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Background: The relative frequency of ischemic versus hemorrhagic stroke among patients with chronic kidney disease (CKD) has not been clearly described. Moreover, no recent meta-analysis has investigated the outcomes of patients with CKD treated with thrombolysis for acute ischemic stroke. We conducted a systematic review and meta-analysis to estimate the proportion of stroke subtypes and the outcomes of thrombolysis in CKD.

Methods: A PubMed, EMBASE and Cochrane literature research was conducted. The primary outcome was the proportion and incidence of ischemic versus hemorrhagic strokes among patients with CKD. In addition, we assessed the impact of CKD on disability, mortality, and bleeding among patients with acute ischemic stroke treated with thrombolysis. The pooled proportion and the risk ratio (RR) were estimated using a random-effects model.

Results: Thirty-nine observational studies were included: 22 on the epidemiology of stroke types and 17 on the outcomes of thrombolysis in this population. In the main analysis (> 99,281 patients), ischemic stroke was more frequent than hemorrhagic among patients with CKD (78.3%, 95% confidence interval 73.3%-82.5%). However, among patients with kidney failure, the proportion of ischemic stroke decreased and was closer to that of hemorrhagic stroke: 59.8% (95% confidence interval 49.4%-69.4%). CKD was associated with worse clinical outcomes in patients with acute ischemic stroke compared with patients with preserved kidney function.

Conclusions: The relative frequency of hemorrhagic stroke seems to increase as kidney function declines. Among patients with acute ischemic stroke treated with thrombolysis, presence of CKD is associated with higher disability, mortality, and bleeding, compared with patients with preserved kidney function.
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http://dx.doi.org/10.1093/ndt/gfab197DOI Listing
June 2021

Chronic Kidney Disease and Cerebrovascular Disease: Consensus and Guidance From a KDIGO Controversies Conference.

Stroke 2021 Jul 3;52(7):e328-e346. Epub 2021 Jun 3.

Ottawa Hospital Research Institute, Department of Medicine, The Ottawa Hospital, Civic Campus, ON, Canada (M.M.S.).

The global health burden of chronic kidney disease is rapidly rising, and chronic kidney disease is an important risk factor for cerebrovascular disease. Proposed underlying mechanisms for this relationship include shared traditional risk factors such as hypertension and diabetes, uremia-related nontraditional risk factors, such as oxidative stress and abnormal calcium-phosphorus metabolism, and dialysis-specific factors such as cerebral hypoperfusion and changes in cardiac structure. Chronic kidney disease frequently complicates routine stroke risk prediction, diagnosis, management, and prevention. It is also associated with worse stroke severity, outcomes and a high burden of silent cerebrovascular disease, and vascular cognitive impairment. Here, we present a summary of the epidemiology, pathophysiology, diagnosis, and treatment of cerebrovascular disease in chronic kidney disease from the Kidney Disease: Improving Global Outcomes Controversies Conference on central and peripheral arterial disease with a focus on knowledge gaps, areas of controversy, and priorities for research.
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http://dx.doi.org/10.1161/STROKEAHA.120.029680DOI Listing
July 2021

Is Warfarin Being Relegated to the Pharmaceutical Dustbin?

Am J Kidney Dis 2021 08 28;78(2):174-176. Epub 2021 May 28.

Department of Medicine, The Ottawa Hospital, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1053/j.ajkd.2021.02.329DOI Listing
August 2021

Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2021 07 5;100(1):35-48. Epub 2021 May 5.

Department of Cardiology I: Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Münster, Germany. Electronic address:

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, vascular biology, epidemiology, and health economics attended. The objective was to identify key issues related to the optimal detection, management, and treatment of cerebrovascular diseases, central aortic disease, renovascular disease, and peripheral artery disease in the setting of CKD. This report outlines the common pathophysiology of these vascular processes in the setting of CKD, describes best practices for their diagnosis and management, summarizes areas of uncertainty, addresses ongoing controversial issues, and proposes a research agenda to address key gaps in knowledge that, when addressed, could improve patient care and outcomes.
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http://dx.doi.org/10.1016/j.kint.2021.04.029DOI Listing
July 2021

Central and peripheral arterial diseases in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2021 07 5;100(1):35-48. Epub 2021 May 5.

Department of Cardiology I: Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Münster, Germany. Electronic address:

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, vascular biology, epidemiology, and health economics attended. The objective was to identify key issues related to the optimal detection, management, and treatment of cerebrovascular diseases, central aortic disease, renovascular disease, and peripheral artery disease in the setting of CKD. This report outlines the common pathophysiology of these vascular processes in the setting of CKD, describes best practices for their diagnosis and management, summarizes areas of uncertainty, addresses ongoing controversial issues, and proposes a research agenda to address key gaps in knowledge that, when addressed, could improve patient care and outcomes.
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http://dx.doi.org/10.1016/j.kint.2021.04.029DOI Listing
July 2021

Blood Transfusion and Adverse Graft-related Events in Kidney Transplant Patients.

Kidney Int Rep 2021 Apr 2;6(4):1041-1049. Epub 2021 Feb 2.

Division of Nephrology, Kidney Research Center, Department of Medicine, University of Ottawa, Ontario, Canada.

Background: The impact of posttransplant red blood cell transfusion (RBCT) and their potential immunomodulatory effects on kidney transplant recipients are unclear. We examined the risks for adverse graft outcomes associated with post-kidney transplant RBCT.

Methods: We conducted a retrospective cohort study of all adult kidney transplant recipients at The Ottawa Hospital from 2002 to 2018. The exposure of interest was receipt of an RBCT after transplant categorized as 1, 2, 3 to 5, and >5 RBC. Outcomes of interest were rejection and death-censored graft loss (DCGL). Cox proportional hazards models were used to calculate hazard ratios (HR) with RBCT as a time-varying, cumulative exposure.

Results: Among 1258 kidney transplant recipients, 468 (37.2%) received 2373 total RBCTs, 197 (15.7%) had rejection and 114 (9.1%) DCGL. For the receipt of 1, 2, 3 to 5, and >5 RBCT, compared with individuals never transfused, the adjusted HRs (95% confidence interval [CI]) for rejection were 2.47 (1.62-3.77), 1.27 (0.77-2.11), 1.74 (1.00-3.05), and 2.23 (1.13-4.40), respectively; DCGL 2.32 (1.02-5.27), 3.03 (1.62-5.64), 7.50 (4.19-13.43), and 14.63 (8.32-25.72), respectively. Considering a time-lag for an RBCT to be considered an exposure before an outcome to limit reverse causation, RBCT was not associated with rejection; the HRs for DCGL attenuated but remained similar. RBCT was also associated with a negative control outcome, demonstrating possible unmeasured confounding.

Conclusion: RBCT after kidney transplant is not associated with rejection, but may carry an increased risk for DCGL.
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http://dx.doi.org/10.1016/j.ekir.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071620PMC
April 2021

Effects of a Knowledge-Translation Intervention on Early Dialysis Initiation: A Cluster Randomized Trial.

J Am Soc Nephrol 2021 Apr 15. Epub 2021 Apr 15.

Department of Medicine and Community Health Sciences, Libin Cardiovascular Institute, Calgary, Canada.

Background: The Initiating Dialysis Early and Late (IDEAL) trial, published in 2009, found no clinically measurable benefit with respect to risk of mortality or early complications with early dialysis initiation versus deferred dialysis start. After these findings, guidelines recommended an intent-to-defer approach to dialysis initiation, with the goal of deferring it until clinical symptoms arise.

Methods: To evaluate a four-component knowledge translation intervention aimed at promoting an intent-to-defer strategy for dialysis initiation, we conducted a cluster randomized trial in Canada between October 2014 and November 2015. We randomized 55 clinics, 27 to the intervention group and 28 to the control group. The educational intervention, using knowledge-translation tools, included telephone surveys from a knowledge-translation broker, a 1-year center-specific audit with feedback, delivery of a guidelines package, and an academic detailing visit. Participants included adults who had at least 3 months of predialysis care and who started dialysis in the first year after the intervention. The primary efficacy outcome was the proportion of patients who initiated dialysis early (at eGFR >10.5 ml/min per 1.73 m). The secondary outcome was the proportion of patients who initiated in the acute inpatient setting.

Results: The analysis included 3424 patients initiating dialysis in the 1-year follow-up period. Of these, 509 of 1592 (32.0%) in the intervention arm and 605 of 1832 (33.0%) in the control arm started dialysis early. There was no difference in the proportion of individuals initiating dialysis early or in the proportion of individuals initiating dialysis as an acute inpatient.

Conclusions: A multifaceted knowledge translation intervention failed to reduce the proportion of early dialysis starts in patients with CKD followed in multidisciplinary clinics.

Clinical Trial Registry Name And Registration Number: ClinicalTrials.gov, NCT02183987. Available at: https://clinicaltrials.gov/ct2/show/NCT02183987.
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http://dx.doi.org/10.1681/ASN.2020091254DOI Listing
April 2021

β-blockers in hemodialysis: simple questions, complicated answers.

Clin Kidney J 2021 Mar 22;14(3):731-734. Epub 2020 Dec 22.

Department of Medicine, Division of Nephrology, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada.

In this issue of the , Wu present the results of a nationwide population-based study using Taiwanese administrative data to compare safety and efficacy outcomes with initiation of bisoprolol versus carvedilol among patients receiving maintenance hemodialysis for >90 days. The primary outcomes were all-cause mortality and major adverse cardiovascular events over 2 years of follow-up. The study found that bisoprolol was associated with a lower risk for both major adverse cardiovascular events and all-cause mortality compared with carvedilol. While the bulk of the existing evidence favors a cardioprotective and survival benefit with β-blockers as a medication class among dialysis patients, there is wide heterogeneity among specific β-blockers in regard to pharmacologic properties and dialyzability. While acknowledging the constraints of observational data, these findings may serve to inform clinicians about the preferred β-blocker agent for dialysis patients to help mitigate cardiovascular risk and improve long-term survival for this high-risk population.
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http://dx.doi.org/10.1093/ckj/sfaa249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986367PMC
March 2021

Reducing the risk of atrial fibrillation in ESKD: Is the devil in the dialysis?

Nephrol Dial Transplant 2021 Mar 5. Epub 2021 Mar 5.

Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1093/ndt/gfab063DOI Listing
March 2021

Cannabis and Cigarette Use Before and After Living Kidney Donation.

Can J Kidney Health Dis 2021 27;8:2054358121997243. Epub 2021 Feb 27.

Division of Nephrology, Department of Medicine, Kidney Research Centre, University of Ottawa and The Ottawa Hospital Research Institute, ON, Canada.

Background: It is unclear whether kidney donation leads to lifestyle changes in terms of cannabis and cigarette use.

Objective: To describe cigarette and cannabis use before and after kidney donation and to determine their associations with lifestyle and clinical factors.

Design: Retrospective cohort study.

Setting: The Living Kidney Donor program in the Champlain Local Health Integration Network at The Ottawa Hospital in Ottawa, Canada.

Patients: The study included 178 living kidney donors who donated between January 2009 and December 2018.

Measurements: Donors were screened for cannabis and cigarette use by telephone interview. Their clinical characteristics and changes in kidney function before and after donation were recorded.

Methods: Cannabis and cigarette use before and after kidney donation were compared using chi-square test. Risk factors associated with their use was examined by univariate and multivariate logistic regression. Wilcoxon rank sum test was used to examine the association of cannabis and Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) estimated glomerular filtration rate (eGFR) at donation and at last follow-up. -test was used to examine the association of cigarette smoking and CKD-EPI eGFR at donation and at last follow-up.

Results: Among 305 donors, 262 met inclusion criteria and 178 participated (mean of 4.7 ± 2.9 years from kidney donation). Cannabis and cigarette use were reported by 5% (9 of 178) and 13% (23 of 178) at donation. After donation, 8% (14 of 178) and 5% (9 of 178) started cannabis and cigarettes, respectively; 74% (17 of 23) of smokers remained smokers after donation and 88% (53 of 60) who quit smoking before donation did not restart after donation. In multivariate analysis, non-married/common-in-law status was associated with cannabis use (odds ratio, 2.73; 95% confidence interval, 1.05-7.11; = .04). There was no difference in eGFR pre- or post-donation among cannabis or cigarette users.

Limitations: The single-center study design limits generalizability. Social desirability bias may have affected survey responses and cigarette smoking was not quantified.

Conclusions: Cannabis and cigarette use was uncommon in the studied population and was not associated with remaining kidney function. Cannabis use increased post-donation. Most smokers remained smokers after donation and most donors who quit smoking before donation did not restart after donation. This warrants education and support for potential donors who smoke, to quit smoking prior to donation to reduce risks of cardiovascular and end-stage kidney disease.

Trial Registration: Not applicable as this is not a clinical trial.
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http://dx.doi.org/10.1177/2054358121997243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923981PMC
February 2021

Intracerebral Hemorrhage Incidence, Mortality, and Association With Oral Anticoagulation Use: A Population Study.

Stroke 2021 May 9;52(5):1673-1681. Epub 2021 Mar 9.

Division of Critical Care, Department of Medicine (S.M.F., S.W.E., K.K.), University of Ottawa, ON, Canada.

Background And Purpose: Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke associated with significant morbidity and mortality. Recent epidemiological data on incidence, mortality, and association with oral anticoagulation are needed.

Methods: Retrospective cohort study of adult patients (≥18 years) with ICH in the entire population of Ontario, Canada (April 1, 2009-March 30, 2019). We captured outcome data using linked health administrative databases. The primary outcome was mortality during hospitalization, as well as at 1 year following ICH.

Results: We included 20 738 patients with ICH. Mean (SD) age was 71.3 (15.1) years, and 52.6% of patients were male. Overall incidence of ICH throughout the study period was 19.1/100 000 person-years and did not markedly change over the study period. In-hospital and 1-year mortality were high (32.4% and 45.4%, respectively). Mortality at 2 years was 49.5%. Only 14.5% of patients were discharged home independently. Over the study period, both in-hospital and 1-year mortality reduced by 10.4% (37.5% to 27.1%, <0.001) and 7.6% (50.0% to 42.4%, <0.001), respectively. Use of oral anticoagulation was associated with both in-hospital mortality (adjusted odds ratio 1.37 [95% CI, 1.26-1.49]) and 1-year mortality (hazard ratio, 1.18 [95% CI, 1.12-1.25]) following ICH.

Conclusions: Both short- and long-term mortality have decreased in the past decade. Most survivors from ICH are likely to be discharged to long-term care. Oral anticoagulation is associated with both short- and long-term mortality following ICH. These findings highlight the devastating nature of ICH, but also identify significant improvement in outcomes over time.
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http://dx.doi.org/10.1161/STROKEAHA.120.032550DOI Listing
May 2021

Ambulatory Treatments for RAAS Inhibitor-Related Hyperkalemia and the 1-Year Risk of Recurrence.

Clin J Am Soc Nephrol 2021 03 19;16(3):365-373. Epub 2021 Feb 19.

Division of Nephrology, Department of Medicine and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Background And Objective: The optimal ambulatory management of renin-angiotensin-aldosterone system inhibitor (RAASi)-related hyperkalemia to reduce the risk of recurrence is unknown. We examined the risk of hyperkalemia recurrence on the basis of outpatient pharmacologic changes following an episode of RAASi-related hyperkalemia.

Design: We performed a population-based, retrospective cohort study of older adults (=49,571; mean age 79 years) who developed hyperkalemia (potassium ≥5.3 mEq/L) while on a RAASi and were grouped as follows: no intervention, RAASi discontinuation, RAASi dose decrease, new diuretic, diuretic dose increase, or sodium polystyrene sulfonate within 30 days. The primary outcome was hyperkalemia recurrence, with secondary outcomes of cardiovascular events and all-cause mortality within 1 year.

Results: Among patients who received a pharmacologic intervention (23% of the cohort), RAASi discontinuation was the most commonly prescribed strategy (74%), followed by RAASi decrease (15%), diuretic increase (7%), new diuretic (3%), and sodium polystyrene sulfonate (1%). A total of 16,977 (34%) recurrent hyperkalemia events occurred within 1 year. Compared with no intervention (35%, referent), the cumulative incidence of recurrent hyperkalemia was lower with RAASi discontinuation (29%; hazard ratio, 0.82; 95% confidence interval, 0.78 to 0.85), whereas there was no difference with RAASi dose decrease (36%; hazard ratio, 0.94; 95% confidence interval, 0.86 to 1.02), new diuretic (32%; hazard ratio, 0.95; 95% confidence interval, 0.78 to 1.17), or diuretic increase (38%; hazard ratio, 0.99; 95% confidence interval, 0.87 to 1.12) and a higher incidence with sodium polystyrene sulfonate (55%; hazard ratio, 1.30; 95% confidence interval, 1.04 to 1.63). RAASi discontinuation was not associated with a higher risk of 1-year cardiovascular events (hazard ratio, 0.96; 95% confidence interval, 0.91 to 1.02) or all-cause mortality (hazard ratio, 1.05; 95% confidence interval, 0.96 to 1.15) compared with no intervention.

Conclusions: Among older adults with RAASi-related hyperkalemia, RAASi discontinuation is associated with the lowest risk of recurrent hyperkalemia, with no apparent increase in short-term risks for cardiovascular events or all-cause mortality.
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http://dx.doi.org/10.2215/CJN.12990820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011018PMC
March 2021

Validation of the International Classification of Disease 10th Revision Codes for Kidney Transplant Rejection and Failure.

Can J Kidney Health Dis 2020 16;7:2054358120977390. Epub 2020 Dec 16.

Division of Nephrology, Kidney Research Center, Department of Medicine, University of Ottawa, ON, Canada.

Background: Clinical research requires that diagnostic codes captured from routinely collected health administrative data accurately identify individuals with a disease.

Objective: In this study, we validated the International Classification of Disease 10th Revision (ICD-10) definition for kidney transplant rejection (T86.100) and for kidney transplant failure (T86.101).

Design: Retrospective cohort study.

Setting: A large, regional transplantation center in Ontario, Canada.

Patients: All adult kidney transplant recipients from 2002 to 2018.

Measurements: Chart review was undertaken to identify the first occurrence of biopsy-confirmed rejection and graft loss for all participants. For each observation, we determined the first date a single ICD-10 code T86.100 or T86.101 was recorded as a hospital encounter discharge diagnosis.

Methods: Using chart review as the gold standard, we determined the sensitivity, specificity, and positive predictive value (PPV) for the ICD-10 codes T86.100 and T86.101.

Results: Our study population comprised of 1,258 kidney transplant recipients. The prevalence of rejection and death-censored graft loss were 15.6 and 9.1%, respectively. For the ICD-10 rejection code (T86.100), sensitivity was 72.9% (95% confidence interval [CI], 66.6-79.2), specificity 97.5% (96.5-98.4), and PPV 83.8% (78.3-89.4). For the ICD-10 graft loss code (T86.101), sensitivity was 21.2% (95% CI, 13.2-29.3), specificity 86.3% (84.3-88.3), and PPV 11.7% (7.0-16.4).

Limitations: Single-center study which may limit generalizability of our findings.

Conclusions: A single ICD-10 code for kidney transplant rejection (T86.100) was present in 84% of true kidney transplant rejections and is an accurate way of identifying kidney transplant recipients with rejection using administrative health data. The ICD-10 code for graft failure (T86.101) performed poorly and should not be used for administrative health research.
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http://dx.doi.org/10.1177/2054358120977390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747098PMC
December 2020

Patient, Caregiver, and Provider Perspectives on Challenges and Solutions to Individualization of Care in Hemodialysis: A Qualitative Study.

Can J Kidney Health Dis 2020 12;7:2054358120970715. Epub 2020 Nov 12.

Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.

Background: Clinical settings often make it challenging for patients with kidney failure to receive individualized hemodialysis (HD) care. Individualization refers to care that reflects an individual's specific circumstances, values, and preferences.

Objective: This study aimed to describe patient, caregiver, and health care professional perspectives regarding challenges and solutions to individualization of care in people receiving in-center HD.

Design: In this multicentre qualitative study, we conducted focus groups with individuals receiving in-center HD and their caregivers and semi-structured interviews with health care providers from May 2017 to August 2018.

Setting: Hemodialysis programs in 5 cities: Calgary, Edmonton, Winnipeg, Ottawa, and Halifax.

Participants: Individuals receiving in-center HD for more than 6 months, aged 18 years or older, and able to communicate in English were eligible to participate, as well as their caregivers. Health care providers with HD experience were recruited using a purposive approach and snowball sampling.

Methods: Two sequential methods of qualitative data collection were undertaken: (1) focus groups and interviews with HD patients and caregivers, which informed (2) individual interviews with health care providers. A qualitative descriptive methodology guided focus groups and interviews. Data from all focus groups and interviews were analyzed using conventional content analysis.

Results: Among 82 patients/caregivers and 31 health care providers, we identified 4 main themes: session set-up, transportation and parking, socioeconomic and emotional well-being, and HD treatment location and scheduling. Particular challenges faced were as follows: (1) session set-up: lack of preferred supplies, machine and HD access set-up, call buttons, bed/chair discomfort, needling options, privacy in the unit, and self-care; (2) transportation and parking: lack of reliable/punctual service, and high costs; (3) socioeconomic and emotional well-being: employment aid, finances, nutrition, lack of support programs, and individualization of treatment goals; and (4) HD treatment location and scheduling: patient displacement from their usual spot, short notice of changes to dialysis time and location, lack of flexibility, and shortages of HD spots.

Limitations: Uncertain applicability to non-English speaking individuals, those receiving HD outside large urban centers, and those residing outside of Canada.

Conclusions: Participants identified challenges to individualization of in-center HD care, primarily regarding patient comfort and safety during HD sessions, affordable and reliable transportation to and from HD sessions, increased financial burden as a result of changes in functional and employment status with HD, individualization of treatment goals, and flexibility in treatment schedule and self-care. These findings will inform future studies aimed at improving patient-centered HD care.
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http://dx.doi.org/10.1177/2054358120970715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672734PMC
November 2020

Higher-Dose Sitagliptin and the Risk of Congestive Heart Failure in Older Adults with CKD.

Clin J Am Soc Nephrol 2020 12 25;15(12):1728-1739. Epub 2020 Nov 25.

ICES, Kidney, Dialysis and Transplantation Research Program, Ontario, Canada.

Background And Objectives: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d.

Design, Setting, Participants, & Measurements: This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95% confidence intervals were obtained using bootstrap variance estimators.

Results: Of 9215 patients, 6518 started sitagliptin at >50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at >50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, -0.12%; 95% confidence interval, -0.19 to -0.06) and a lower risk of all-cause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98).

Conclusions: The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at >50 versus ≤50 mg/d.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_25_CJN08310520_final.mp3.
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http://dx.doi.org/10.2215/CJN.08310520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769019PMC
December 2020

Dialysis Modality and Mortality in Heart Failure: A Retrospective Study of Incident Dialysis Patients.

Cardiorenal Med 2020 25;10(6):452-461. Epub 2020 Nov 25.

ICES, Toronto, Ontario, Canada.

Introduction: Prior studies reported lower mortality with hemodialysis (HD) compared to peritoneal dialysis (PD) in patients with heart failure (HF). We examined mortality rate by initial dialysis modality in incident dialysis patients with a history of HF using contemporary data and methods that ensure comparable HD and PD groups.

Methods: Retrospective cohort study using administrative databases in Ontario, Canada. Adults (age 50-80) with a history of HF who initiated maintenance dialysis between April 1, 2007 and March 31, 2016 were included. We excluded patients typically ineligible for PD as an initial modality (dialysis start in hospital, dementia, long-term care facility residency). We determined the cause-specific hazard ratio (transplant as a competing event) between initial dialysis modality (HD vs. PD) and all-cause mortality using an intention-to-treat approach.

Results: We included 2,199 patients with HF who initiated maintenance dialysis (77% HD and 23% PD). There were 1,152 (67.8%) and 340 (68.1%) mortality events over a median follow-up of 2.4 and 2.5 years in the HD and PD groups, respectively. Patients initiating HD versus PD was not associated with the mortality rate (adjusted hazard ratio 1.0, 95% CI 0.9-1.1). Similar results were seen in analyses censoring at modality switches and treating modality as time-varying.

Conclusions: We found no difference in mortality by initial dialysis modality. Our data support the current practice of selecting dialysis modality based on patient preference for patients with pre-existing HF.
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http://dx.doi.org/10.1159/000511168DOI Listing
August 2021

Ethical Issues in the Design and Conduct of Pragmatic Cluster Randomized Trials in Hemodialysis Care: An Interview Study With Key Stakeholders.

Can J Kidney Health Dis 2020 26;7:2054358120964119. Epub 2020 Oct 26.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.

Background: Pragmatic cluster randomized trials (CRTs) offer an opportunity to improve health care by answering important questions about the comparative effectiveness of treatments using a trial design that can be embedded in routine care. There is a lack of empirical research that addresses ethical issues generated by pragmatic CRTs in hemodialysis.

Objective: To identify stakeholder perceptions of ethical issues in pragmatic CRTs conducted in hemodialysis.

Design: Qualitative study using semi-structured interviews.

Setting: In-person or telephone interviews with an international group of stakeholders.

Participants: Stakeholders (clinical investigators, methodologists, ethicists and research ethics committee members, and other knowledge users) who had been involved in the design or conduct of a pragmatic individual patient or cluster randomized trial in hemodialysis, or their role would require them to review and evaluate pragmatic CRTs in hemodialysis.

Methods: Interviews were conducted in-person or over the telephone and were audio-recorded with consent. Recorded interviews were transcribed verbatim prior to analysis. Transcripts and field notes were analyzed using a thematic analysis approach.

Results: Sixteen interviews were conducted with 19 individuals. Interviewees were largely drawn from North America (84%) and were predominantly clinical investigators (42%). Six themes were identified in which pragmatic CRTs in hemodialysis raise ethical issues: (1) patients treated with hemodialysis as a vulnerable population, (2) appropriate approaches to informed consent, (3) research burdens, (4) roles and responsibilities of gatekeepers, (5) inequities in access to research, and (6) advocacy for patient-centered research and outcomes.

Limitations: Participants were largely from North America and did not include research staff, who may have differing perspectives.

Conclusions: The six themes reflect concerns relating to individual rights, but also the need to consider population-level issues. To date, concerns regarding inequity of access to research and the need for patient-centered research have received less coverage than other, well-known, issues such as consent. Pragmatic CRTs offer a potential approach to address equity concerns and we suggest future ethical analyses and guidance for pragmatic CRTs in hemodialysis embed equity considerations within them. We further note the potential for the co-creation of health data infrastructure with patients which would aid care but also facilitate patient-centered research. These present results will inform planned future guidance in relation to the ethical design and conduct of pragmatic CRTs in hemodialysis.

Trial Registration: Registration is not applicable as this is a qualitative study.
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http://dx.doi.org/10.1177/2054358120964119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597560PMC
October 2020

A Higher Concentration of Dialysate Magnesium to Reduce the Frequency of Muscle Cramps: A Narrative Review.

Can J Kidney Health Dis 2020 22;7:2054358120964078. Epub 2020 Oct 22.

Division of Nephrology, Department of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada.

Purpose Of Review: Strategies to mitigate muscle cramps are a top research priority for patients receiving hemodialysis. As hypomagnesemia is a possible risk factor for cramping, we reviewed the literature to better understand the physiology of cramping as well as the epidemiology of hypomagnesemia and muscle cramps. We also sought to review the evidence from interventional studies on the effect of oral and dialysate magnesium-based therapies on muscle cramps.

Sources Of Information: Peer-reviewed articles.

Methods: We searched for relevant articles in major bibliographic databases including MEDLINE and EMBASE. The methodological quality of interventional studies was assessed using a modified version of the Downs and Blacks criteria checklist.

Key Findings: The etiology of muscle cramps in patients receiving hemodialysis is poorly understood and there are no clear evidence-based prevention or treatment strategies. Several factors may play a role including a low concentration of serum magnesium. The prevalence of hypomagnesemia (concentration of <0.7 mmol/L) in patients receiving hemodialysis ranges from 10% to 20%. Causes of hypomagnesemia include a low dietary intake of magnesium, use of medications that inhibit magnesium absorption (eg, proton pump inhibitors), increased magnesium excretion (eg, high-dose loop diuretics), and a low concentration of dialysate magnesium. Dialysate magnesium concentrations of ≤0.5 mmol/L may be associated with a decrease in serum magnesium concentration over time. Preliminary evidence from observational and interventional studies suggests a higher dialysate magnesium concentration will raise serum magnesium concentrations and may reduce the frequency and severity of muscle cramps. However, the quality of evidence supporting this benefit is limited, and larger, multicenter clinical trials are needed to further determine if magnesium-based therapy can reduce muscle cramps in patients receiving hemodialysis. In studies conducted to date, increasing the concentration of dialysate magnesium appears to be well-tolerated and is associated with a low risk of symptomatic hypermagnesemia.

Limitations: Few interventional studies have examined the effect of magnesium-based therapy on muscle cramps in patients receiving hemodialysis and most were nonrandomized, pre-post study designs.
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http://dx.doi.org/10.1177/2054358120964078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585892PMC
October 2020

A Comparison of Patient-Reported Outcome Measures of Quality of Life By Dialysis Modality in the Treatment of Kidney Failure: A Systematic Review.

Can J Kidney Health Dis 2020 19;7:2054358120957431. Epub 2020 Oct 19.

The Ottawa Hospital Research Institute, The Ottawa Hospital, ON, Canada.

Background: There is an increasing demand to incorporate patient-reported outcome measures (PROMs) such as quality of life (QOL) in decision-making when selecting a chronic dialysis modality.

Objective: To compare the change in QOL over time among similar patients on different dialysis modalities to provide unique and novel insights on the impact of dialysis modality on PROMs.

Design: Systematic reviews, randomized controlled trials, and nonrandomized controlled trials were examined via a comprehensive search strategy incorporating multiple bibliographic databases.

Setting: Data were extracted from relevant studies from January 1, 2000 to December 31, 2019 without limitations on country of study conduction.

Patients: Eligible studies included adults (≥18 years) with end-stage kidney disease of any cause who were prescribed dialysis treatment (either as lifetime treatment or bridge to transplant).

Measurements: The 5 comparisons were peritoneal dialysis (PD) vs in-center hemodialysis (ICHD), home hemodialysis (HHD) vs ICHD, HHD modalities compared with one another, HHD vs PD, and self-care ICHD vs traditional nurse-based ICHD.

Methods: Included studies compared adults on different dialysis modalities with repeat measures within individuals to determine changes in QOL between dialysis modalities (in-center or home dialysis). Methodological quality was assessed by the Scottish Intercollegiate Guidelines Network (SIGN 50) checklist. A narrative synthesis was conducted, synthesizing the direction and size of any observed effects across studies.

Results: Two randomized controlled trials and 9 prospective cohort studies involving a combined total of 3711 participants were included. Comparing PD and ICHD, 5 out of 9 studies found significant differences ( < .05) favoring PD in the change of multiple QOL domains, including "physical component score," "role of social component score," "cognitive status," "role limitation due to emotional function," "role limitation due to physical function," "bodily pain," "burden of kidney disease," "effects of kidney disease on daily life," "symptoms/problems," "sexual function," "finance," and "patient satisfaction." Conversely, 3 of these studies demonstrated statistically significant differences ( < .05) favoring ICHD in the domains of "role limitation due to physical function," "general health," "support from staff," "sleep quality," "social support," "health status," "social interaction," "body image," and "overall health." Comparing HHD and ICHD, significant differences ( < .05) favoring HHD for the QOL domains of "general health," "burden of kidney disease," and the visual analogue scale were reported.

Limitations: Our study is constrained by the small sample sizes of included studies, as well as heterogeneity among both study populations and validated QOL scales, limiting inter-study comparison.

Conclusions: We identified differences in specific QOL domains between dialysis modalities that may aid in patient decision-making based on individual priorities.

Trial Registration: PROSPERO Registration Number: CRD42016046980.

Primary Funding Source: The original research for this study was derived from the Canadian Agency for Drugs and Technologies in Health (CADTH) 2017 optimal use report, titled "Dialysis Modalities for the Treatment of End-Stage Kidney Disease: A Health Technology Assessment." The CADTH receives funding from Canada's federal, provincial, and territorial governments, with the exception of Quebec.
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http://dx.doi.org/10.1177/2054358120957431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580133PMC
October 2020

A Mixed Method Investigation to Determine Priorities for Improving Information, Interaction, and Individualization of Care Among Individuals on In-center Hemodialysis: The Triple I Study.

Can J Kidney Health Dis 2020 19;7:2054358120953284. Epub 2020 Oct 19.

Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.

Background: Current health systems do not effectively address all aspects of chronic care. For better self-management of disease, kidney patients have identified the need for improved health care information, interaction with health care providers, and individualization of care.

Objective: The Triple I study examined challenges to exchange of between patients and health care providers and of care in in-center hemodialysis with the aim of identifying the top 10 challenges that individuals on in-center hemodialysis face in these 3 areas.

Design: We employed a sequential mixed methods approach with 3 phases:1. A qualitative study with focus groups and interviews (Apr 2017 to Aug 2018);2. A cross-sectional national ranking survey (Jan 2019 to May 2019);3. A prioritization workshop using a modified James Lind Alliance process (June 2019).

Setting: In-center hemodialysis units in 7 academic centers across Canada: Vancouver, Calgary, Edmonton, Winnipeg, Ottawa, Montreal, and Halifax.

Participants: Individuals receiving in-center hemodialysis, their caregivers, and health care providers working in in-center hemodialysis participated in each of the 3 phases.

Methods: In Phase 1, we collected qualitative data through (1) focus groups and interviews with hemodialysis patients and their caregivers and (2) individual interviews with health care providers and decision makers. Participants identified challenges to in-center hemodialysis care and potential solutions to these challenges. In Phase 2, we administered a pan-Canadian cross-sectional ranking survey. The survey asked respondents to prioritize the challenges to in-center hemodialysis care identified in Phase 1 by ranking their top 5 topics/challenges in each of the 3 "I" categories. In Phase 3, we undertook a face-to-face priority setting workshop which followed a modified version of the James Lind Alliance priority setting workshop process. The workshop employed an iterative process incorporating small and large group sessions during which participants identified, ranked, and voted on the top challenges and innovations to hemodialysis care. Four patient partners contributed to study design, implementation, analysis, and interpretation.

Results: Across the 5 participating centers, we conducted 8 focus groups and 44 interviews, in which 113 participants identified 45 distinct challenges to in-center hemodialysis care. Subsequently, completion of a national ranking survey (n = 323) of these challenges resulted in a short-list of the top 30 challenges. Finally, using small and large group sessions to develop consensus during the prioritizing workshop, 38 stakeholders used this short-list to identify the top 10 challenges to in-center hemodialysis care. These included individualization of dialysis-related education; improved information in specific topic areas (transplant status, dialysis modalities, dialysis-related complications, and other health risks); more flexibility in hemodialysis scheduling; better communication and continuity of care within the health care team; and increased availability of transportation, financial, and social support programs.

Limitations: Participants were from urban centers and were predominately English-speaking. Survey response rate of 31.5% in Phase 2 may have led to selection bias. We collected limited information on social determinants of health, which could confound our results.

Conclusion: Overall, the challenges we identified demonstrate that individualized care and information that improves interaction with health care providers is important to patients receiving in-center hemodialysis. In future stages of this project, we will aim to address these challenges by trialing innovative patient-centered solutions.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1177/2054358120953284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580147PMC
October 2020

Graft Function, Albuminuria, and the Risk of Hemorrhage and Thrombosis After Kidney Transplantation.

Can J Kidney Health Dis 2020 8;7:2054358120952198. Epub 2020 Oct 8.

Division of Nephrology, Cumming School of Medicine and the Department of Community Health Sciences, University of Calgary, AB, Canada.

Background: Compared to the general population, kidney transplant recipients are at increased risk of hemorrhage and thrombosis. Whether this risk is affected by graft function and albuminuria is unknown.

Objective: To determine the association between graft function and albuminuria and the risk of post-transplant hemorrhage and thrombosis.

Design: Retrospective cohort study.

Setting: We used linked health care databases in Alberta, Canada.

Patients/sample/participants: We included adult kidney transplant recipients from 2002 to 2015 with a functioning graft at 1 year.

Measurements: Estimated glomerular filtration rate (eGFR) and albuminuria measurements at 1 year post-transplant were used to categorize recipients (eGFR: ≥45 vs. <45 mL/min/1.73 m; albuminuria: absence vs. presence). We determined the rates of post-transplant hemorrhage and venous thrombosis based on validated diagnostic and procedural codes.

Methods: We determined the association between categories of eGFR and albuminuria and post-transplant hemorrhage and venous thrombosis using Poisson regression with log link.

Results: Of 1284 kidney transplant recipients, 21% had an eGFR <45 mL/min/1.73 m and 40% had presence of albuminuria at 1 year post-transplant. Over a median follow-up of 6 years, there were 100 hemorrhages (12.6 events per 1000 person-years) and 57 venous thrombosis events (7.1 events per 1000 person-years). The age- and sex-adjusted rate of hemorrhage and thrombosis was over 2-fold higher in recipients with lower eGFR and presence of albuminuria compared to higher eGFR and no albuminuria (hemorrhage: incidence rate ratio, IRR, 2.6, 95% confidence interval [CI]: 1.5-4.4, = .001; thrombosis: IRR, 2.3, 95% CI: 1.1-5.0, = .046).

Limitations: Complete relevant medication information, such as anticoagulants, were not available in our datasets. Due to sample size, this study was underpowered to conduct a fully adjusted analysis.

Conclusion: Among kidney transplant recipients, lower eGFR and presence of albuminuria at 1 year post-transplant were associated with an over 2-fold higher risk of hemorrhage and venous thrombosis. Graft function and albuminuria at 1 year post-transplant are important prognostic factors in determining risk of post-transplant hemorrhage and venous thrombosis. Further research, including medication data, are needed to further delineate outcomes and safety.

Trial Registration: Not applicable (cohort study).
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http://dx.doi.org/10.1177/2054358120952198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549159PMC
October 2020

Performance of the Kidney Failure Risk Equation by Disease Etiology in Advanced CKD.

Clin J Am Soc Nephrol 2020 10 14;15(10):1424-1432. Epub 2020 Sep 14.

Division of Nephrology, Department of Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.

Background And Objectives: The kidney failure risk equation is a clinical tool commonly used for prediction of progression from CKD to kidney failure. The kidney failure risk equation's accuracy in advanced CKD and whether this varies by CKD etiology remains unknown. This study examined the kidney failure risk equation's discrimination and calibration at 2 and 5 years among a large tertiary care population with advanced CKD from heterogeneous etiologies.

Design, Setting, Participants, & Measurements: This retrospective cohort study included 1293 patients with advanced CKD (median eGFR 15 ml/min per 1.73 m) referred to the Ottawa Hospital Multi-Care Kidney Clinic between 2010 and 2016, with follow-up clinical data available through 2018. Four-variable kidney failure risk equation scores for 2- and 5-year risks of progression to kidney failure (defined as dialysis or kidney transplantation) were calculated upon initial referral and correlated with the subsequent observed kidney failure incidence within these time frames. Receiver operating characteristic curves and calibration plots were used to measure the discrimination and calibration of the kidney failure risk equation both in the overall advanced CKD population and by CKD etiology: diabetic kidney disease, hypertensive nephrosclerosis, GN, polycystic kidney disease, and other. Pairwise comparisons of the receiver operating characteristic curves by CKD etiology were performed to compare kidney failure risk equation discrimination.

Results: The kidney failure risk equation provided adequate to excellent discrimination in identifying patients with CKD likely to progress to kidney failure at the 2- and 5-year time points both overall (2-year area under the curve, 0.83; 95% confidence interval, 0.81 to 0.85; 5-year area under the curve, 0.81; 95% confidence interval, 0.77 to 0.84) and across CKD etiologies. The kidney failure risk equation displayed adequate calibration at the 2- and 5-year time points both overall and across CKD etiologies (Hosmer-Lemeshow 0.05); however, the predicted risks of kidney failure were higher than the observed risks across CKD etiologies with the exception of polycystic kidney disease.

Conclusions: The kidney failure risk equation provides adequate discrimination and calibration in advanced CKD and across CKD etiologies.
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http://dx.doi.org/10.2215/CJN.03940320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536763PMC
October 2020
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