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Lihua Li,1– 3 Meaghan S Cuerden,4 Bian Liu,1,3,5 Salimah Shariff,6 Arsh K Jain,4,6 Madhu Mazumdar1– 3 1Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 4London Health Sciences Centre, London, Ontario, Canada; 5Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Institute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaCorrespondence: Madhu MazumdarDepartment of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, 1425 Madison Avenue, New York, NY, USATel +1 212-659-1470Email Madhu.Mazumdar@mountsinai.orgIntroduction: Statistical methods to assess the impact of an intervention are increasingly used in clinical research settings. However, a comprehensive review of the methods geared toward practitioners is not yet available.Methods and Materials: We provide a comprehensive review of three methods to assess the impact of an intervention: difference-in-differences (DID), segmented regression of interrupted time series (ITS), and interventional autoregressive integrated moving average (ARIMA). We also compare the methods, and provide illustration of their use through three important healthcare-related applications.Results: In the first example, the DID estimate of the difference in health insurance coverage rates between expanded states and unexpanded states in the post-Medicaid expansion period compared to the pre-expansion period was 5.93 (95% CI, 3.99 to 7.89) percentage points. In the second example, a comparative segmented regression of ITS analysis showed that the mean imaging order appropriateness score in the emergency department at a tertiary care hospital exceeded that of the inpatient setting with a level change difference of 0.63 (95% CI, 0.53 to 0.73) and a trend change difference of 0.02 (95% CI, 0.01 to 0.03) after the introduction of a clinical decision support tool. In the third example, the results from an interventional ARIMA analysis show that numbers of creatinine clearance tests decreased significantly within months of the start of eGFR reporting, with a magnitude of drop equal to − 0.93 (95% CI, − 1.22 to − 0.64) tests per 100,000 adults and a rate of drop equal to 0.97 (95% CI, 0.95 to 0.99) tests per 100,000 per adults per month.Discussion: When choosing the appropriate method to model the intervention effect, it is necessary to consider the structure of the data, the study design, availability of an appropriate comparison group, sample size requirements, whether other interventions occur during the study window, and patterns in the data.Keywords: difference-in-difference, interrupted time series, segmented regression, autoregressive integrated moving average

Importance: Recent guidelines call for better evidence on health outcomes after living kidney donation., Objective: To determine the risk of hypertension in normotensive adults who donated a kidney compared with nondonors of similar baseline health. Their rates of estimated glomerular filtration rate (eGFR) decline and risk of albuminuria were also compared., Design, Setting, and Participants: Prospective cohort study of 924 standard-criteria living kidney donors enrolled before surgery and a concurrent sample of 396 nondonors. Recruitment occurred from 2004 to 2014 from 17 transplant centers (12 in Canada and 5 in Australia); follow-up occurred until November 2021. Donors and nondonors had the same annual schedule of follow-up assessments. Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics., Exposure: Living kidney donation., Main Outcomes and Measures: Hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure [DBP] ≥90 mm Hg, or antihypertensive medication), annualized change in eGFR (starting 12 months after donation/simulated donation date in nondonors), and albuminuria (albumin to creatinine ratio ≥3 mg/mmol [≥30 mg/g])., Results: Among the 924 donors, 66% were female; they had a mean age of 47 years and a mean eGFR of 100 mL/min/1.73 m2. Donors were more likely than nondonors to have a family history of kidney failure (464/922 [50%] vs 89/394 [23%], respectively). After statistical weighting, the sample of nondonors increased to 928 and baseline characteristics were similar between the 2 groups. During a median follow-up of 7.3 years (IQR, 6.0-9.0), in weighted analysis, hypertension occurred in 161 of 924 donors (17%) and 158 of 928 nondonors (17%) (weighted hazard ratio, 1.11 [95% CI, 0.75-1.66]). The longitudinal change in mean blood pressure was similar in donors and nondonors. After the initial drop in donors' eGFR after nephrectomy (mean, 32 mL/min/1.73 m2), donors had a 1.4-mL/min/1.73 m2 (95% CI, 1.2-1.5) per year lesser decline in eGFR than nondonors. However, more donors than nondonors had an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up (438/924 [47%] vs 49/928 [5%]). Albuminuria occurred in 132 of 905 donors (15%) and 95 of 904 nondonors (11%) (weighted hazard ratio, 1.46 [95% CI, 0.97-2.21]); the weighted between-group difference in the albumin to creatinine ratio was 1.02 (95% CI, 0.88-1.19)., Conclusions and Relevance: In this cohort study of living kidney donors and nondonors with the same follow-up schedule, the risks of hypertension and albuminuria were not significantly different. After the initial drop in eGFR from nephrectomy, donors had a slower mean rate of eGFR decline than nondonors but were more likely to have an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up., Trial Registration: ClinicalTrials.gov Identifier: NCT00936078.

Background: Curcumin is a commonly used herbal supplement with anti-inflammatory and anti-fibrotic properties. Animal studies and small human trials suggest that curcumin reduces albuminuria in patients with chronic kidney disease (CKD). Micro-particle curcumin is a new, more bioavailable formulation of curcumin., Methods: To determine whether micro-particle curcumin versus placebo slows the progression of albuminuric CKD we conducted a randomized, double-blind, placebo-controlled trial with 6-month follow-up. We included adults with albuminuria [a random urine albumin-to-creatinine ratio >30 mg/mmol (265 mg/g) or a 24-h urine collection with more than 300 mg of protein] and an estimated glomerular filtration rate (eGFR) between 15 and 60 mL/min/1.73 m2 within the 3 months before randomization. We randomly allocated participants 1:1 to receive micro-particle curcumin capsules (90 mg/day) or matching placebo for 6 months. After randomization, the co-primary outcomes were the changes in albuminuria and the eGFR., Results: We enrolled 533 participants, but 4/265 participants in the curcumin group and 15/268 in the placebo group withdrew consent or became ineligible. The 6-month change in albuminuria did not differ significantly between the curcumin and placebo groups [geometric mean ratio 0.94, 97.5% confidence interval (CI) 0.82 to 1.08, P = .32]. Similarly, the 6-month change in eGFR did not differ between groups (mean between-group difference -0.22 mL/min/1.73 m2, 97.5% CI -1.38 to 0.95, P = .68)., Conclusions: Ninety milligrams of micro-particle curcumin daily did not slow the progression of albuminuric CKD over 6 months., Trial Registration: ClinicalTrials.gov Identifier: NCT02369549., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Although living kidney donation is safe, some donors experience perioperative complications., Objective: This study explored how perioperative complications affected donor-reported health-related quality of life, depression, and anxiety., Design: This research was a conducted as a prospective cohort study., Setting: Twelve transplant centers across Canada., Patients: A total of 912 living kidney donors were included in this study., Measurements: Short Form 36 health survey, Beck Depression Inventory and Beck Anxiety Inventory., Methods: Living kidney donors were prospectively enrolled predonation between 2009 to 2014. Donor perioperative complications were graded using the Clavien-Dindo classification system. Mental and physical health-related quality of life was assessed with the 3 measurements; measurements were taken predonation and at 3- and 12-months postdonation., Results: Seventy-four donors (8%) experienced a perioperative complication; most were minor (n = 67 [91%]), and all minor complications resolved before hospital discharge. The presence (versus absence) of a perioperative complication was associated with lower mental health-related quality of life and higher depression symptoms 3-month postdonation; neither of these differences persisted at 12-month. Perioperative complications were not associated with any changes in physical health-related quality of life or anxiety 3-month postdonation., Limitations: Minor complications may have been missed and information on complications postdischarge were not collected. No minimal clinically significant change has been defined for kidney donors across the 3 measurements., Conclusions: These findings highlight a potential opportunity to better support the psychosocial needs of donors who experience perioperative complications in the months following donation., Trial Registration: NCT00319579 and NCT00936078., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.X.G. received operating grant support from the CIHR, which included partnership funding from Astellas for data collection. L.S.F. received investigator-initiated research grants from Merck and Johnson & Johnson and an educational grant from Medtronic., (© The Author(s) 2021.)

Background: Living kidney donors incur donation-related expenses, but how these expenses impact postdonation mental health is unknown., Methods: In this prospective cohort study, the association between mental health and donor-incurred expenses (both out-of-pocket costs and lost wages) was examined in 821 people who donated a kidney at one of the 12 transplant centers in Canada between 2009 and 2014. Mental health was measured by the RAND Short Form-36 Health Survey along with Beck Anxiety Inventory and Beck Depression Inventory., Results: A total of 209 donors (25%) reported expenses of >5500 Canadian dollars. Compared with donors who incurred lower expenses, those who incurred higher expenses demonstrated significantly worse mental health-related quality of life 3 months after donation, with a trend towards worse anxiety and depression, after controlling for predonation mental health-related quality of life and other risk factors for psychological distress. Between-group differences for donors with lower and higher expenses on these measures were no longer significant 12 months after donation., Conclusions: Living kidney donor transplant programs should ensure that adequate psychosocial support is available to all donors who need it, based on known and unknown risk factors. Efforts to minimize donor-incurred expenses and to better support the mental well-being of donors need to continue. Further research is needed to investigate the effect of donor reimbursement programs, which mitigate donor expenses, on postdonation mental health., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Safely reducing red blood cell transfusions can prevent transfusion-related adverse effects, conserve the blood supply, and reduce health care costs. Both anemia and red blood cell transfusion are independently associated with AKI, but observational data are insufficient to determine whether a restrictive approach to transfusion can be used without increasing AKI risk., Methods: In a prespecified kidney substudy of a randomized noninferiority trial, we compared a restrictive threshold for red blood cell transfusion (transfuse if hemoglobin<7.5 g/dl, intraoperatively and postoperatively) with a liberal threshold (transfuse if hemoglobin<9.5 g/dl in the operating room or intensive care unit, or if hemoglobin<8.5 g/dl on the nonintensive care ward). We studied 4531 patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high risk of perioperative death. The substudy's primary outcome was AKI, defined as a postoperative increase in serum creatinine of ≥0.3 mg/dl within 48 hours of surgery, or ≥50% within 7 days of surgery., Results: Patients in the restrictive-threshold group received significantly fewer transfusions than patients in the liberal-threshold group (1.8 versus 2.9 on average, or 38% fewer transfusions in the restricted-threshold group compared with the liberal-threshold group; P <0.001). AKI occurred in 27.7% of patients in the restrictive-threshold group (624 of 2251) and in 27.9% of patients in the liberal-threshold group (636 of 2280). Similarly, among patients with preoperative CKD, AKI occurred in 33.6% of patients in the restrictive-threshold group (258 of 767) and in 32.5% of patients in the liberal-threshold group (252 of 775)., Conclusions: Among patients undergoing cardiac surgery, a restrictive transfusion approach resulted in fewer red blood cell transfusions without increasing the risk of AKI., (Copyright © 2019 by the American Society of Nephrology.)

Background: Perioperative corticosteroid use may reduce acute kidney injury. We sought to test whether methylprednisolone reduces the risk of acute kidney injury after cardiac surgery., Methods: We conducted a prespecified substudy of a randomized controlled trial involving patients undergoing cardiac surgery with cardiopulmonary bypass (2007-2014); patients were recruited from 79 centres in 18 countries. Eligibility criteria included a moderate-to-high risk of perioperative death based on a preoperative score of 6 or greater on the European System for Cardiac Operative Risk Evaluation I. Patients ( n = 7286) were randomly assigned (1:1) to receive intravenous methylprednisolone (250 mg at anesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients, caregivers, data collectors and outcome adjudicators were unaware of the assigned intervention. The primary outcome was postoperative acute kidney injury, defined as an increase in the serum creatinine concentration (from the preoperative value) of 0.3 mg/dL or greater (≥ 26.5 μmol/L) or 50% or greater in the 14-day period after surgery, or use of dialysis within 30 days after surgery., Results: Acute kidney injury occurred in 1479/3647 patients (40.6%) in the methylprednisolone group and in 1426/3639 patients (39.2%) in the placebo group (adjusted relative risk 1.04, 95% confidence interval 0.96 to 1.11). Results were consistent across several definitions of acute kidney injury and in patients with preoperative chronic kidney disease., Interpretation: Intraoperative corticosteroid use did not reduce the risk of acute kidney injury in patients with a moderate-to-high risk of perioperative death who had cardiac surgery with cardiopulmonary bypass. Our results do not support the prophylactic use of steroids during cardiopulmonary bypass surgery. Trial registration: ClinicalTrials.gov, no. NCT00427388., Competing Interests: Competing interests: P.J. Devereaux has received grants from Abbott Diagnostics, Boehringer Ingelheim, Covidien, Octapharma, Philips Healthcare, Roche Diagnostics and Stryker for projects outside the work reported here. Chirag Parikh reports personal fees from AbbVie Pharmaceutical Research and Development and GENFIT Biopharmaceutical Company; funding from Renalytix AI; and grants from the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart, Lung and Blood Institute. Vlado Perkovic reports receiving personal fees for advisory boards or scientific presentations from Retrophin, Janssen, Merck and Servier. Vlado Perkovic was a member of the SONAR Steering Committee; has served on steering committees for trials funded by AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novo Nordisk, Retrophin and Tricida; and has participated in scientific presentations and advisory boards with AbbVie, Astellas, Astra-Zeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Retrophin, Sanofi, Servier, Vifor and Tricida. Richard Whitlock reports grants and personal fees from Boehringer Ingelheim. No other competing interests were declared., (© 2019 Joule Inc. or its licensors.)

Background: The progression to end-stage renal disease (ESRD) is the most important complication of chronic kidney disease (CKD). Patients with ESRD require dialysis or transplantation to survive, incur numerous complications, and have high mortality rates. Slowing the progression of CKD is an important goal. Unfortunately, even when current treatments are appropriately applied, patients with CKD still progress to ESRD. Current treatments do not address the inflammation and fibrosis that mediate progression to ESRD, but micro-particle curcumin, a natural health product, has both anti-inflammatory and anti-fibrotic properties and may be an effective treatment for patients with CKD., Objective: Micro-particle curcumin for the treatment of CKD-1 (MPAC-CKD-1) will measure the effect of micro-particle curcumin on 2 important markers of CKD progression: albuminuria and estimated glomerular filtration rate (eGFR). Efficacy in either of these markers will justify a larger, international trial to investigate micro-particle curcumin's ability to lower the risk of ESRD in patients with CKD., Design: MPAC-CKD-1 is a multicenter, double-blind prospective randomized controlled trial., Setting: Four kidney disease clinics in Ontario, Canada (3 in London and 1 in Hamilton)., Patients: We will enroll patients with CKD, defined by an eGFR between 15 and 60 mL/min/1.73 m 2 and a daily albumin excretion of more than 300 mg (or a random urine sample albumin-to-creatinine ratio more than 30 mg/mmol)., Measurements: We will measure changes in the co-primary outcomes of urinary albumin-to-creatinine ratio and eGFR at 3 months and 6 months. We will also measure compliance, safety parameters, and changes in health-related quality of life., Methods: Participants will be randomly assigned to receive micro-particle curcumin 90 mg once daily or matching placebo for 6 months. We will enroll at least 500 patients to exclude clinically meaningful 6-month changes in these 2 co-primary outcomes (16% difference in albuminuria, and a 2.3 mL/min/1.73 m 2 between-group difference in the 6-month change in eGFR, at a two-tailed alpha of 0.025, power of 0.80)., Results: Patient enrollment began on October 1, 2015, with 414 participants randomized as of July 2018. We expect to report the results in 2020., Limitations: MPAC-CKD-1 is not powered to assess outcomes such as the need for renal replacement therapy or death., Conclusions: MPAC-CKD-1 is a multicenter, double-blind prospective randomized controlled trial designed to test whether micro-particle curcumin reduces albuminuria and slows eGFR decline in patients with albuminuric CKD. MPAC-CKD-1 will also test the feasibility of this intervention and inform the need for a future larger scale trial (MPAC-CKD-2)., Trial Registration: MPAC-CKD-1 is registered with U.S. National Institutes of Health at clinicaltrials.gov (NCT02369549). Protocol version 2.0, December 6, 2014., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: No investigator or research personnel has a financial or other competing interest in MPAC-CKD-1. The study design and collection, management, analysis, and interpretation of the study data have not and will not involve the funders. The trial funders will have no role in the reporting of the results.

Background: Approximately 40% of the kidneys for transplant worldwide come from living donors. Despite advantages of living donor transplants, rates have stagnated in recent years. One possible barrier may be costs related to the transplant process that potential willing donors may incur for travel, parking, accommodation, and lost productivity., Methods: To better understand and quantify the financial costs incurred by living kidney donors, we conducted a prospective cohort study, recruiting 912 living kidney donors from 12 transplant centers across Canada between 2009 and 2014; 821 of them completed all or a portion of the costing survey. We report microcosted total, out-of-pocket, and lost productivity costs (in 2016 Canadian dollars) for living kidney donors from donor evaluation start to 3 months after donation. We examined costs according to ( 1 ) the donor's relationship with their recipient, including spousal (donation to a partner), emotionally related nonspousal (friend, step-parent, in law), or genetically related; and ( 2 ) donation type (directed, paired kidney, or nondirected)., Results: Living kidney donors incurred a median (75th percentile) of $1254 ($2589) in out-of-pocket costs and $0 ($1908) in lost productivity costs. On average, total costs were $2226 higher in spousal compared with emotionally related nonspousal donors ( P =0.02) and $1664 higher in directed donors compared with nondirected donors ( P <0.001). Total costs (out-of-pocket and lost productivity) exceeded $5500 for 205 (25%) donors., Conclusions: Our results can be used to inform strategies to minimize the financial burden of living donation, which may help improve the donation experience and increase the number of living donor kidney transplants., (Copyright © 2018 by the American Society of Nephrology.)

Importance: In observational studies, increased water intake is associated with better kidney function., Objective: To determine the effect of coaching to increase water intake on kidney function in adults with chronic kidney disease., Design, Setting, and Participants: The CKD WIT (Chronic Kidney Disease Water Intake Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until 2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m2 and microalbuminuria or macroalbuminuria) and a 24-hour urine volume of less than 3.0 L., Interventions: Patients in the hydration group (n = 316) were coached to drink more water, and those in the control group (n = 315) were coached to maintain usual intake., Main Outcomes and Measures: The primary outcome was change in kidney function (eGFR from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall quality of health (0 [worst possible] to 10 [best possible])., Results: Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR, 43 mL/min/1.73 m2; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5]; control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of 619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was -2.2 mL/min/1.73 m2 in the hydration group and -1.9 mL/min/1.73 m2 in the control group (adjusted between-group difference, -0.3 mL/min/1.73 m2 [95% CI, -1.8 to 1.2; P = .74]). The mean between-group differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, -2.2 pmol/L (95% CI, -3.9 to -0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m2 (95% CI, 0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, -4 to 51; P = .11); and quality of health, 0.2 points (95% CI, -0.3 to 0.3; P = .22)., Conclusions and Relevance: Among adults with chronic kidney disease, coaching to increase water intake compared with coaching to maintain the same water intake did not significantly slow the decline in kidney function after 1 year. However, the study may have been underpowered to detect a clinically important difference., Trial Registration: clinicaltrials.gov Identifier: NCT01766687.

Background: When safe to do so, avoiding blood transfusions in cardiac surgery can avoid the risk of transfusion-related infections and other complications while protecting a scarce resource and reducing costs. This protocol describes a kidney substudy of the Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial, a multinational noninferiority randomized controlled trial to determine whether the risk of major clinical outcomes in patients undergoing planned cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion., Objective: The objective of this substudy is to determine whether the risk of acute kidney injury is no greater with a restrictive versus liberal approach to red blood cell transfusion, and whether this holds true in patients with and without preexisting chronic kidney disease., Design and Setting: Multinational noninferiority randomized controlled trial conducted in 73 centers in 19 countries (2014-2017)., Patients: Patients (~4800) undergoing planned cardiac surgery with cardiopulmonary bypass., Measurements: The primary outcome of this substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative value (obtained in the 30-day period before surgery), where an acute rise is defined as ≥26.5 μmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery., Methods: We will report the absolute risk difference in acute kidney injury and the 95% confidence interval. We will repeat the primary analysis using alternative definitions of acute kidney injury, including staging definitions, and will examine effect modification by preexisting chronic kidney disease (defined as a preoperative estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m 2 )., Limitations: It is not possible to blind patients or providers to the intervention; however, objective measures will be used to assess outcomes, and outcome assessors will be blinded to the intervention assignment., Results: Substudy results will be reported by the year 2018., Conclusions: This substudy will provide generalizable estimates of the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass., Trial Registration: www.clinicaltrials.gov; clinical trial registration number NCT 02042898., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To evaluate habitual physical activity in a cohort of adolescents with type 1 diabetes in relation to similarly aged control subjects., Methods: A cross-sectional case control study of 54 healthy adolescents and 66 patients with type 1 diabetes, 14 to 18 years of age, was conducted. Subjects were surveyed using the Habitual Activity Estimation Scale, a validated self-report instrument to assess activity levels in teens. Subjects' time was classified into categories ranging from inactive (lying down, resting) to very active (increased heart rate and diaphoresis). Active time, described in relative (%) and absolute hours per day was determined for each individual. Age, sex, weight, height and body mass index were recorded for all participants, and the charts of subjects with type 1 diabetes were reviewed for most recent levels of glycated hemoglobin, low-density lipoproteins, high-density lipoproteins, total cholesterol, triglycerides and blood pressure. A regression analysis was performed to determine factors associated with hours spent being active., Results: Subjects with type 1 diabetes spent similar hours being very active (3.4 hours vs. 3.5 hours, p=0.49) but reported more time being inactive than controls (2.0 hours vs. 1.3 hours, p=0.002). In both groups, female gender was associated with more hours spent being active. Metabolic control as assessed by glycated hemoglobin worsened with activity. In the group with type 1 diabetes, more hours spent being active were associated with lower systolic blood pressure, lower serum triglyceride levels, lower total cholesterol and higher high-density lipoproteins, whereas inactivity correlated with higher low-density lipoproteins and total cholesterol., Conclusions: Adolescents with type 1 diabetes reported significantly more time being inactive than did healthy controls. In patients with type 1 diabetes, activity was associated with improved cardiovascular risk profile., (Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Importance: Most acute kidney injury observed in the hospital is defined by sudden mild or moderate increases in the serum creatinine concentration, which may persist for several days. Such acute kidney injury is associated with lower long-term kidney function. However, it has not been demonstrated that an intervention that reduces the risk of such acute kidney injury better preserves long-term kidney function., Objectives: To characterize the risk of acute kidney injury with an intervention in a randomized clinical trial and to determine if there is a difference between the 2 treatment groups in kidney function 1 year later., Design, Setting, and Participants: The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) enrolled 4752 patients undergoing first isolated coronary artery bypass graft (CABG) surgery at 79 sites in 19 countries. Patients were randomized to receive CABG surgery either with a beating-heart technique (off-pump) or with cardiopulmonary bypass (on-pump). From January 2010 to November 2011, 2932 patients (from 63 sites in 16 countries) from CORONARY were enrolled into a kidney function substudy to record serum creatinine concentrations during the postoperative period and at 1 year. The last 1-year serum creatinine concentration was recorded on January 18, 2013., Main Outcomes and Measures: Acute kidney injury within 30 days of surgery (≥50% increase in serum creatinine concentration from prerandomization concentration) and loss of kidney function at 1 year (≥20% loss in estimated glomerular filtration rate from prerandomization level)., Results: Off-pump (n = 1472) vs on-pump (n = 1460) CABG surgery reduced the risk of acute kidney injury (17.5% vs 20.8%, respectively; relative risk, 0.83 [95% CI, 0.72-0.97], P = .01); however, there was no significant difference between the 2 groups in the loss of kidney function at 1 year (17.1% vs 15.3%, respectively; relative risk, 1.10 [95% CI, 0.95-1.29], P = .23). Results were consistent with multiple alternate continuous and categorical definitions of acute kidney injury or kidney function loss, and in the subgroup with baseline chronic kidney disease., Conclusions and Relevance: Use of off-pump compared with on-pump CABG surgery reduced the risk of postoperative acute kidney injury, without evidence of better preserved kidney function with off-pump CABG surgery at 1 year. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function., Trial Registration: clinicaltrials.gov Identifier: NCT00463294.

BACKGROUND: When searching for renal literature, nephrologists must choose between several different bibliographic databases. We compared the availability of renal clinical studies in six major bibliographic databases. METHODS: We gathered 151 renal systematic reviews, which collectively contained 2195 unique citations referencing primary studies in the form of journal articles, meeting articles or meeting abstracts published between 1963 and 2008. We searched for each citation in three subscription-free bibliographic databases (PubMed, Google Scholar and Scirus) and three subscription-based databases (EMBASE, Ovid-MEDLINE and ISI Web of Knowledge). For the subscription-free databases, we determined which full-text journal articles were available free of charge via links to the article source. RESULTS: The proportion of journal articles contained within each of the six databases ranged from 96 to 97%; results were similar for meeting articles. Availability of meeting abstracts was poor, ranging from 0 to 37% (P < 0.01) with ISI Web of Knowledge containing the largest proportion [37%, 95% confidence interval (95% CI) 32-43%]. Among the subscription-free databases, free access to full-text articles was highest in Google Scholar (38% free, 95% CI 36-41%), and was only marginally higher (39%) when all subscription-free databases were searched. After 2000, free access to full-text articles increased to 49%. CONCLUSIONS: Over 99% of renal clinical journal articles are available in at least one major bibliographic database. Subscription-free databases provide free full-text access to almost half of the articles published after the year 2000, which may be of particular interest to clinicians in settings with limited access to subscription-based resources.

Many guidelines suggest that angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists (collectively referred to as renin, angiotensin, aldosterone system blockers (RAAS blockers)) are the preferred treatment for hypertension in most patients with chronic kidney disease (CKD). Improving the recognition of CKD with the introduction of eGFR reporting was intended to have more patients recognized with and treated for this disease. To quantify this, we examined trends in RAAS-blocker use over an 88-month period before and after routine eGFR reporting in southwestern Ontario, Canada. An intervention analysis with seasonal time-series modeling on linked health administrative data for 45,361 ambulatory residents with CKD (eGFR stages 3-5) older than 65 years was performed with a primary outcome of RAAS-blocker usage. The reporting of eGFR was associated with a significant increase in the use of RAAS blockers, as the prescription rate was 571 per 1000 patients with CKD prior to reporting but improved to 607 per 1000 after reporting. There was a significant increase in RAAS-blocker use attributable to eGFR reporting of 19 per 1000 CKD patients. Since about 8% of the adult population has CKD, this equates to about 15,200 new patients receiving RAAS-blocker treatment by 1 year after the introduction of eGFR reporting in community laboratories. Thus, eGFR reporting contributes to improved, guideline-appropriate care of older patients with CKD.

Purpose: To characterize the effects of formulary changes and governmental safety warnings on use of erythropoiesis-stimulating agents (ESAs) in patients with cancer., Patients and Methods: We conducted a cross-sectional time-series analysis using health administrative data from Ontario, Canada. From January 1997 to December 2009 we identified all ESA initiations among patients diagnosed with cancer. We explored the effects of two formulary changes that progressively liberalized coverage for ESAs, first by rescinding the requirement for blood transfusion in 2003 and then by removing all restrictions in 2007. We also explored the effect of US Food and Drug Administration and Health Canada warnings issued in the second quarter of 2007. To assess regional variability in ESA use, we determined prescription rates for each of Ontario's 14 regional cancer centers., Results: After the first formulary change, the ESA initiation rate increased to 1.66 new users per 1,000 patients with cancer, 374% more than predicted (P < .001). After the second formulary change, the initiation rate increased to 3.97 new users per 1,000 patients with cancer, 73% more than predicted (P < .001). After the safety warnings, this rate declined 81% by study end (P < .001). We found significant regional variation in ESA use., Conclusion: Formulary access and safety warnings had significant impacts on the new use of ESA drugs in patients with cancer. This suggests that both are effective means of influencing the use of these drugs. Variable ESA prescription rates across our region may reflect a lack of consensus regarding their utility.

Introduction: CORONARY is a large international randomised controlled trial comparing coronary artery bypass graft (CABG) surgery done with and without a bypass pump. Compared with on-pump, off-pump surgery may prevent acute kidney injury (AKI) in the short term and may better preserve kidney function 1 year following surgery. Secondary analyses may also clarify whether effects are similar in patients with and without pre-operative chronic kidney disease and whether AKI avoidance mediates preserved 1-year kidney function., Methods and Analysis: With respect to the study schedule, the last of 4752 patients from 79 sites in 19 countries were randomised in November 2011 to cardiac surgery performed with an on-pump or off-pump procedure. The authors will use regression models to compare the groups in the outcome of peri-operative AKI (per cent change in serum creatinine, ≥50% increase in serum creatinine) and 1-year kidney function (per cent change in estimated glomerular filtration rate (eGFR), ≥20% eGFR loss 1 year after surgery). The authors will use interaction terms in regression models to determine if there is a differential impact of the intervention in those with and without pre-existing chronic kidney disease. The authors will use regression-based tests to determine the proportion of the total effect of surgery type (off-pump vs on-pump CABG) on 1-year eGFR that is mediated by peri-operative AKI., Ethics and Dissemination: In the year 2009, the authors were competitively awarded a grant from the Canadian Institutes of Health Research to answer these kidney questions in CORONARY. Ethics approval was obtained for additional renal data collection in centres that agreed to study participation (>90% of participating centres). This collection began for patients enrolled after 1 January 2010. Remaining 1-year renal outcome data will be collected throughout 2012. Results will be reported in 2013., Clinical Trial Registration Number: NCT 00463294.

Patients undergoing conventional maintenance hemodialysis typically receive three sessions per week, each lasting 2.5-5.5 hours. Recently, the use of more intensive hemodialysis (>5.5 hours, three to seven times per week) has increased, but the effects of these regimens on survival are uncertain. We conducted a retrospective cohort study to examine whether intensive hemodialysis associates with better survival than conventional hemodialysis. We identified 420 patients in the International Quotidian Dialysis Registry who received intensive home hemodialysis in France, the United States, and Canada between January 2000 and August 2010. We matched 338 of these patients to 1388 patients in the Dialysis Outcomes and Practice Patterns Study who received in-center conventional hemodialysis during the same time period by country, ESRD duration, and propensity score. The intensive hemodialysis group received a mean (SD) 4.8 (1.1) sessions per week with a mean treatment time of 7.4 (0.87) hours per session; the conventional group received three sessions per week with a mean treatment time of 3.9 (0.32) hours per session. During 3008 patient-years of follow-up, 45 (13%) of 338 patients receiving intensive hemodialysis died compared with 293 (21%) of 1388 patients receiving conventional hemodialysis (6.1 versus 10.5 deaths per 100 person-years; hazard ratio, 0.55 [95% confidence interval, 0.34-0.87]). The strength and direction of the observed association between intensive hemodialysis and improved survival were consistent across all prespecified subgroups and sensitivity analyses. In conclusion, there is a strong association between intensive home hemodialysis and improved survival, but whether this relationship is causal remains unknown.

Background: Information in health administrative databases increasingly guides renal care and policy., Study Design: Systematic review of observational studies., Setting & Population: Studies describing the validity of codes for acute kidney injury (AKI) and chronic kidney disease (CKD) in administrative databases operating in any jurisdiction., Selection Criteria: After searching 13 medical databases, we included observational studies published from database inception though June 2009 that validated renal diagnostic and procedural codes for AKI or CKD against a reference standard., Index Tests: Renal diagnostic or procedural administrative data codes., Reference Tests: Patient chart review, laboratory values, or data from a high-quality patient registry., Results: 25 studies of 13 databases in 4 countries were included. Validation of diagnostic and procedural codes for AKI was present in 9 studies, and validation for CKD was present in 19 studies. Sensitivity varied across studies and generally was poor (AKI median, 29%; range, 15%-81%; CKD median, 41%; range, 3%-88%). Positive predictive values often were reasonable, but results also were variable (AKI median, 67%; range, 15%-96%; CKD median, 78%; range, 29%-100%). Defining AKI and CKD by only the use of dialysis generally resulted in better code validity. The study characteristic associated with sensitivity in multivariable meta-regression was whether the reference standard used laboratory values (P < 0.001); sensitivity was 39% lower when laboratory values were used (95% CI, 23%-56%)., Limitations: Missing data in primary studies limited some of the analyses that could be done., Conclusions: Administrative database analyses have utility, but must be conducted and interpreted judiciously to avoid bias arising from poor code validity., (Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The kidney is the most common transplanted organ, accounting for almost all living donor transplantations and most deceased donor organ transplantations. The organ shortage has caused policymakers in many nations to debate the merits of adopting presumed consent legislation as a way to increase donor organ donation from deceased donors., Objective: To compare characteristics and kidney transplantation rates for countries with presumed consent for deceased organ donation with countries with explicit consent., Design: A longitudinal study of international kidney transplantation from 1997 to 2007., Setting: 44 nations performing kidney transplantation., Patients: Recipients of deceased and living kidney donor transplants., Measurements: Rates of transplantation of kidneys from deceased and living donors., Results: National characteristics, such as population size, proportion of the population self-identified as Catholic, per capita gross domestic product, health expenditures, and physician density, varied widely for the 22 nations with presumed consent and the 22 nations with explicit consent. Deceased donor kidney transplantation rates were higher in nations with presumed consent (median, 22.6 transplantations per million population [pmp]; interquartile range [IQR], 9.3 to 33.8) versus nations with explicit consent (median, 13.9 transplantations pmp; IQR, 3.6 to 23.1). Living donor kidney transplantation rates were lower in nations with presumed consent (median, 2.4 transplantations pmp; IQR, 1.7 to 4.3) versus nations with explicit consent (median, 5.9 transplantations pmp; IQR, 2.3 to 12.2). The findings were consistent when nations were classified according to per capita gross domestic product, health expenditures, and physician density., Limitation: As with any observational study, associations may not be causal., Conclusion: Nations with presumed consent have higher rates of deceased donor kidney transplantation than nations with explicit consent. Any nation deciding to adopt presumed consent should carefully consider and reduce any negative effect on rates of living donation., Primary Funding Source: Canadian Institutes of Health Research and Lawson Health Research Institute.

Background: Rather than searching the entire MEDLINE database, clinicians can perform searches on a filtered set of articles where relevant information is more likely to be found. Members of our team previously developed two types of MEDLINE filters. The 'methods' filters help identify clinical research of high methodological merit. The 'content' filters help identify articles in the discipline of renal medicine. We will now test the utility of these filters for physician MEDLINE searching., Hypothesis: When a physician searches MEDLINE, we hypothesize the use of filters will increase the number of relevant articles retrieved (increase 'recall,' also called sensitivity) and decrease the number of non-relevant articles retrieved (increase 'precision,' also called positive predictive value), compared to the performance of a physician's search unaided by filters., Methods: We will survey a random sample of 100 nephrologists in Canada to obtain the MEDLINE search that they would first perform themselves for a focused clinical question. Each question we provide to a nephrologist will be based on the topic of a recently published, well-conducted systematic review. We will examine the performance of a physician's unaided MEDLINE search. We will then apply a total of eight filter combinations to the search (filters used in isolation or in combination). We will calculate the recall and precision of each search. The filter combinations that most improve on unaided physician searches will be identified and characterized., Discussion: If these filters improve search performance, physicians will be able to search MEDLINE for renal evidence more effectively, in less time, and with less frustration. Additionally, our methodology can be used as a proof of concept for the evaluation of search filters in other disciplines.

Methods to reimburse living organ donors for the non-medical expenses they incur have been implemented in some jurisdictions and are being considered in others. A global understanding of existing legislation and programs would help decision makers implement and optimize policies and programs. We searched for and collected data from countries that practice living organ donation. We examined legislation and programs that facilitate reimbursement, focusing on policy mechanisms, eligibility criteria, program duration and types of expenses reimbursed. Of 40 countries, reimbursement is expressly legal in 16, unclear in 18, unspecified in 6 and expressly prohibited in 1. Donor reimbursement programs exist in 21 countries; 6 have been enacted in the last 5 years. Lost income is reimbursed in 17 countries, while travel, accommodation, meal and childcare costs are reimbursed in 12 to 19 countries. Ten countries have comprehensive programs, where all major cost categories are reimbursed to some extent. Out-of-country donors are reimbursed in 10 jurisdictions. Reimbursement is conditional on donor income in 7 countries, and recipient income in 2 countries. Many nations have programs that help living donors with their financial costs. These programs differ in operation and scope. Donors in other regions of the world are without support.

Randomized trials provide high-quality evidence for patient care. The Der Deutsche Diabetes Dialyse Studie (4D), a randomized study which demonstrated no benefit of statins among diabetic patients receiving hemodialysis, was published in July 2005. To determine effects of this study we conducted a retrospective, population-based, time series analysis with change-point regression to see if the rate of statin prescription to dialysis patients had been modified. We linked health administrative data for all diabetic hemodialysis patients living in Ontario, Canada, with similar characteristics to the 4D patient cohort. During the nearly 11-year period prior to study publication, the rate of statin use increased almost 14-fold, from 43 to 597 per 1000 patients. For 2.5 years after study publication, rather than diminish, statin use continued to rise to an absolute rate of 676 per 1000 patients. These temporal patterns in statin use closely mimicked trends in the diabetic population not receiving dialysis. The 4D trial had no impact on statin use when we restricted the analysis to incident statin prescriptions or expanded the characteristics of the dialysis patients considered for study. Thus, we found that publication of a large, expensive, randomized controlled trial in patients receiving hemodialysis had no immediate impact on clinical practice. The use of a common cardiovascular medication in this patient population appears to be influenced by other factors.

Objective: To evaluate endothelial function (EF) in a cohort of obese adolescents with impaired insulin sensitivity., Study Design: Cardiovascular risk factors and adipocytokines, along with digital hyperemia, were evaluated by peripheral arterial tonometry (PAT) in adolescents with obesity and insulin resistance (IR) in relation to healthy, nonobese controls., Results: The obese and control subjects were of similar age (13.4+/-1.7 years vs 14.0+/-1.4 years) and sex. The obese subjects had IR (mean homeostasis model of assessment [HOMA] score=5.4; 95% confidence interval=3.3-7.5) and significantly greater body mass index (BMI) (BMI z-score 2.4+/-0.2 kg/m(2) vs 0.0+/-0.8 kg/m(2)) and waist circumference (WC) measures (109.6+/-11.1cm vs 70.5+/-9.4 cm) with elevated low-density lipoprotein cholesterol (LDL-C), triglyceride, and high-sensitivity C-reactive protein levels. The mean PAT ratio was significantly lower in obese adolescents compared with controls (1.51+/-0.4 vs 2.06+/-0.4; P=.002), indicative of impaired EF. Linear regression demonstrated associations between PAT ratio and BMI, WC, age, and LDL-C but not between PAT and leptin, resistin, or adiponectin levels or IR., Conclusions: Obese adolescents with IR exhibited significantly worse EF as assessed by PAT compared with healthy, nonobese controls, and EF showed a significant association with measures of adiposity and other cardiovascular risk factors.

Serum creatinine alone can be difficult to interpret as a measure of kidney function such that chronic kidney disease might be under-recognized in the general population. In the province of Ontario, Canada, all outpatient laboratories now report estimated glomerular filtration rate (eGFR) in addition to serum creatinine. To determine the impact of this reporting on clinical practice, we linked health administrative data for more than 8 million adults of age 25 years or older over an almost 10-year period and conducted a population-based intervention analysis with seasonal time-series modeling to determine overall trends in the number and type of patients seen by nephrologists. Compared to the period when only serum creatinines were reported, the number of patients seen in consultation by nephrologists increased after eGFR reporting by an average of 24% (an absolute increase of 2.9 consults per 100,000 adults), an increase of about 23 consults per nephrologist per year. The greatest increases were seen in women (39% increase) and those 80 years of age and older (58% increase). Our study found that eGFR reporting was associated with a sudden increase in the number of nephrology consults. However, it remains to be seen whether the routine reporting of eGFR results in improved treatment and outcomes for those with chronic kidney disease.

Older individuals or those with medical complexities are undergoing living donor nephrectomy more than ever before. Transplant outcomes for recipients of kidneys from these living expanded criteria donors are largely uncertain. We systematically reviewed studies from 1980 to June 2008 that described transplant outcomes for recipients of kidneys from expanded criteria living donors. Results were organized by the following criteria: older age, obesity, hypertension, reduced glomerular filtration rate (GFR), proteinuria and hematuria. Pairs of reviewers independently evaluated each citation and abstracted data on study and donor characteristics, recipient survival, graft survival, serum creatinine and GFR. Transplant outcomes for recipients of kidneys from older donors (> or =60 years) were described in 31 studies. Recipients of kidneys from older donors had poorer 5-year patient and graft survival than recipients of kidneys from younger donors [meta-analysis of 12 studies, 72% vs. 80%, unadjusted relative risk (RR) of survival 0.89, 95% confidence interval (CI) 0.83-0.95]. In meta-regression, this association diminished over time (1980s RR 0.79, 95% CI 0.65-0.96 vs. 1990s RR 0.91, 95% CI 0.85-0.99). Few transplant outcomes were described for other expanded criteria. This disconnect between donor selection and a lack of knowledge of recipient outcomes should give transplant decision-makers pause and sets an agenda for future research.

When evaluating a living kidney donor and recipient with a father-child relationship, it may be discovered that the two are not biologically related. We analyzed data from the United Network for Organ Sharing and the Canadian Organ Replacement Registry to determine how frequently this occurs. We surveyed 102 potential donors, recipients, and transplant professionals for their opinion on whether such information should be disclosed to the donor-recipient pair. We communicated with transplant professionals from 13 Canadian centers on current practices for handling this information. In the United States and Canada, the prevalence of father-child living kidney donor-recipient pairs with less than a one-haplotype human leukocyte antigen match (i.e., misattributed paternity) is between 1% and 3%, or approximately 0.25% to 0.5% of all living kidney donations. Opinions about revealing this information were variable: 23% strongly favored disclosure; whereas, 24% were strongly opposed to it. Current practices are variable; some centers disclose this information, whereas others do not. Discovering misattributed paternity in living donation is uncommon but can occur. Opinions on how to deal with this sensitive information are variable. Discussion among transplant professionals will facilitate best practices and policies. Strategies adopted by some centers can be considered.

Background and Objectives: Patients receiving dialysis have a high burden of cardiovascular disease. Some receive coronary artery revascularization but the optimal method is controversial., Design, Setting, Participants, & Measurements: The authors reviewed any randomized controlled trial or cohort study of 10 or more patients receiving maintenance dialysis which compared coronary artery bypass graft (CABG) to percutaneous intervention (PCI) for revascularization of the coronary arteries. The primary outcomes were short-term (30 d or in-hospital) and long-term (at least 1 year) mortality., Results: Seventeen studies were found. There were no randomized trials: all were retrospective cohort studies from years 1977 to 2002. There were some baseline differences between the groups receiving CABG compared with those receiving PCI, and most studies did not consider results adjusted for such characteristics. Given the variability among studies and their methodological limitations, few definitive conclusions about the optimal method of revascularization could be drawn. In an exploratory meta-analysis, short-term mortality was higher after CABG compared to PCI. A substantial number of patients died over a subsequent 1 to 5 yr, with no difference in mortality after CABG compared to PCI., Conclusions: Although decisions about the optimal method of coronary artery revascularization in dialysis patients are undertaken routinely, it was surprising to see how few data has been published in this regard. Additional research will help inform physician and patient decisions about coronary artery revascularization.

Individuals with isolated medical abnormalities (IMAs) are undergoing living donor nephrectomy more frequently. Knowledge of health risks for these living donors is important for donor selection, informed consent and follow-up. We systematically reviewed studies with > or = 3 living kidney donors with preexisting IMAs, including older age, obesity, hypertension, reduced glomerular filtration rate (GFR), proteinuria, microscopic hematuria and nephrolithiasis. We abstracted data on study and donor characteristics, perioperative outcomes, longer term renal and blood pressure outcomes and mortality and compared them to those of non-IMA donors. We found 22 studies on older donors (n = 987), 10 on obese donors (n = 484), 6 on hypertensive donors (n = 125), 4 on donors with nephrolithiasis (n = 32), 2 on donors with microscopic hematuria and one study each on donors with proteinuria or reduced GFR. Perioperative outcomes for donors with and without IMAs were similar. Few studies reported longer term (> or = 1 year) rates of hypertension, proteinuria or renal function. Studies were frequently retrospective and without a comparison group. Given the variability among studies and their methodological limitations, uncertainties remain regarding long-term medical outcomes for IMA donors. As transplant centers continue to cautiously screen and counsel potential IMA donors, rigorously conducted, longer term prospective cohort studies are needed.