Publications by authors named "Keith McCullough"

60 Publications

Routinely measured cardiac troponin I and N-terminal pro-B-type natriuretic peptide as predictors of mortality in haemodialysis patients.

ESC Heart Fail 2022 Jan 13. Epub 2022 Jan 13.

Fukuoka Renal Clinic, Fukuoka, Japan.

Aims: Cardiac troponin (cTn) and B-type natriuretic peptide (BNP) are elevated in haemodialysis (HD) patients, and this elevation is associated with HD-induced myocardial stunning/myocardial strain. However, studies using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS) have shown that these cardiac biomarkers are measured in <2% of HD patients in real-world practice. This study aimed to examine whether routinely measured N-terminal pro-BNP (NT-proBNP) and cTnI (contemporary assay) are more appropriate than clinical models for reclassifying the risk of HD patients who have the highest risk of death.

Methods And Results: Pre-dialysis levels of cTnI and NT-proBNP at study enrolment were measured in 1152 HD patients (Japan DOPPS Phase 5). The patients were prospectively followed for 3 years. Cox regression was used to test the associations of cardiac biomarkers with all-cause mortality, adjusting for potential confounders. Subgroup analyses were performed to assess potential effect modification of clinical characteristics, such as age, systolic blood pressure, HD vintage, diabetes mellitus, coronary artery disease, and a history of congestive heart failure. At baseline, 337 (29%) patients had elevated cTnI (99th percentile of a healthy population: >0.04 ng/mL) with a median (inter-quartile range) level of 0.020 (0.005-0.041) ng/mL, and 1140 (99%) patients had elevated NT-proBNP (cut-off for heart failure: >125 pg/mL) with a median level of 3658 (1689-9356) pg/mL. There were 167 deaths during a median follow-up of 2.8 (2.2-2.8) years. Higher levels of both cardiac biomarkers were incrementally associated with mortality after adjustment for potential confounders. Even after adjustment for alternative cardiac biomarkers, the overall P value for the association was <0.01 for both biomarkers. However, the prognostic significance of NT-proBNP was moderately diminished when cTnI was added to the model. The hazard ratios of mortality for cTnI > 0.04 ng/mL (vs. cTnI < 0.006 ng/mL) and NT-proBNP > 8000 pg/mL (vs. NT-proBNP < 2000 pg/mL) were 2.56 (95% confidence interval: 1.37-4.81) and 1.90 (95% confidence interval: 0.95-3.79), respectively. Subgroup analyses showed that the associations of both cardiac biomarkers with mortality were generally consistent between stratified groups.

Conclusions: Routinely measured NT-proBNP and cTnI levels are strongly associated with mortality among prevalent HD patients. These associations remain robust, even after adjustment for alternative biomarkers, suggesting that cTnI and NT-proBNP have identical prognostic significance and may reflect different pathological aspects of cardiac abnormalities.
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January 2022

Thrombocytopenia predicts mortality in Chinese hemodialysis patients- an analysis of the China DOPPS.

BMC Nephrol 2022 Jan 3;23(1):11. Epub 2022 Jan 3.

Department of Nephrology, Peking University People's Hospital, Unit 10C in Ward Building; 11 Xizhimennan Street, Xicheng District, Beijing, 100044, China.

Background: Hemodialysis (HD) patients have a higher mortality rate compared with general population. Our previous study revealed that platelet counts might be a potential risk factor. The role of platelets in HD patients has rarely been studied. The aim of this study is to examine if there is an association of thrombocytopenia (TP) with elevated risk of all-cause mortality and cardiovascular (CV) death in Chinese HD patients.

Methods: Data from a prospective cohort study, China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5, were analyzed. Demographic data, comorbidities, platelet counts and other lab data, and death records which extracted from the medical record were analyzed. TP was defined as the platelet count below the lower normal limit (< 100*10/L). Associations between platelet counts and all-cause and CV mortality were evaluated using Cox regression models. Stepwise multivariate logistic regression was used to identify the independent associated factors, and subgroup analyses were also carried out.

Results: Of 1369 patients, 11.2% (154) had TP at enrollment. The all-cause mortality rates were 26.0% vs. 13.3% (p < 0.001) in patients with and without TP. TP was associated with higher all-cause mortality after adjusted for covariates (HR:1.73,95%CI:1.11,2.71), but was not associated with CV death after fully adjusted (HR:1.71,95%CI:0.88,3.33). Multivariate logistic regression showed that urine output < 200 ml/day, cerebrovascular disease, hepatitis (B or C), and white blood cells were independent impact factors (P < 0.05). Subgroup analysis found that the effect of TP on all-cause mortality was more prominent in patients with diabetes or hypertension, who on dialysis thrice a week, with lower ALB (< 4 g/dl) or higher hemoglobin, and patients without congestive heart failure, cerebrovascular disease, or hepatitis (P < 0.05).

Conclusion: In Chinese HD patients, TP is associated with higher risk of all-cause mortality, but not cardiovascular mortality. Platelet counts may be a useful prognostic marker for clinical outcomes among HD patients, though additional study is needed.
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January 2022

Representativeness of the PDOPPS cohort compared to the Australian PD population.

Perit Dial Int 2021 Nov 10:8968608211056242. Epub 2021 Nov 10.

Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia.

Background: The Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) is an international, prospective study following persons treated by peritoneal dialysis (PD) to identify modifiable practices associated with improvements in PD technique and person survival. The aim of this study was to assess the representativeness of the Australian cohort included in PDOPPS compared to the complete Australian PD population, as reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry.

Methods: Adults with at least one PD treatment reported to ANZDATA Registry during the census period of PDOPPS Phase I (November 2014 to April 2018) were compared to the Australian PDOPPS cohort. The primary outcomes were the representativeness of centres and persons. Secondary outcomes explored the association of person characteristics with consent to study participation.

Results: After data linkage, 511 PDOPPS participants were compared to 5616 Australians treated with PD. Within centres eligible for PDOPPS, selected centres were similar to other Australian centres. The PDOPPS participants' cohort tended to include older persons, more males, a higher proportion of Caucasians and more persons with higher socioeconomic advantage compared to the Australian PD population. Differences in distribution across sex and ethnicities between the PDOPPS cohort and the overall PD population were in part due to the selection and consent processes, during which females and non-Caucasians were more likely to not consent to PDOPPS participation.

Conclusion: Sampling methods used in PDOPPS allowed for good national representativeness of the included centres. However, representativeness of the unweighted PDOPPS sample was suboptimal in regard to some participant characteristics.
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November 2021

International peritoneal dialysis training practices and the risk of peritonitis.

Nephrol Dial Transplant 2021 Oct 11. Epub 2021 Oct 11.

Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.

Background: The effects of training practices on outcomes of patients receiving peritoneal dialysis (PD) are poorly understood and there is a lack of evidence informing best training practices. This prospective cohort study aims to describe and compare international PD training practices and their association with peritonitis.

Methods: Adult patients on PD < 3 months participating in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) were included. Training characteristics (including duration, location, nurse affiliation, modality, training of family members, use of individual/group training, and use of written/oral competency assessments) were reported at patient and facility levels. Hazard ratio for time to first peritonitis was estimated using Cox models, adjusted for selected patient and facility case-mix variables.

Results: 1376 PD patients from 120 facilities across 7 countries were included. Training was most commonly performed at the facility (81%), by facility-affiliated nurses (87%) in a 1:1 setting (79%). In the UK, being trained by both facility and third-party nurses was associated with reduced peritonitis risk (aHR 0.31, 95% CI 0.15-0.62, vs facility nurses only). However, this training practice was utilized in only 5 of 14 UK facilities. No other training characteristics were convincingly associated with peritonitis risk.

Conclusions: There was no evidence to support that peritonitis risk was associated with when, where, how, or how long PD patients are trained.
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October 2021

Blood flow rate: An independent risk factor of mortality in Chinese hemodialysis patients.

Semin Dial 2021 Sep 22. Epub 2021 Sep 22.

Department of Nephrology, Peking University People's Hospital, Beijing, China.

Background: Studies suggested the association between blood flow rate (BFR) and mortality might be beyond dialysis adequacy. This study aimed to explore if BFR is an independent predictor of clinical outcomes in Chinese hemodialysis (HD) patients.

Methods: This study included data from patients in China Dialysis Outcomes and Practice Patterns Study (DOPPS) Phase 5. Patients with a record of BFR were included, and demographic data, comorbidities, hospitalization, and death records were collected. Associations between BFR and all-cause mortality and hospitalization were analyzed using Cox regression models.

Results: One thousand four hundred twelve (98.9%) patients were included. Most patients were with BFR < 300 ml/min. After full adjustment, each 10-ml/min increase of BFR was associated with a 6.4% decrease in all-cause mortality risk (HR: 0.936, 95% CI: 0.880-0.996) but not first hospitalization (HR: 0.987, 95% CI: 0.949-1.027). The impact of BFR on mortality may be more prominent in patients who were male gender, nondiabetic, albumin < 4.0 g/dl, and hemoglobin ≥ 9.0 g/dl.

Conclusion: Increased BFR is independently associated with a lower risk of all-cause mortality within the range of BFR 200-300 ml/min. And this effect is more pronounced in patients who were male gender, nondiabetic, albumin < 4.0 g/dl, and hemoglobin ≥ 9.0 g/dl.
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September 2021

European hemodialysis patient satisfaction with phosphate binders is associated with serum phosphorus levels: the Dialysis Outcomes and Practice Patterns Study.

Clin Kidney J 2021 Aug 11;14(8):1886-1893. Epub 2021 Jun 11.

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: Hemodialysis (HD) patients are commonly prescribed phosphate binders (PBs) to manage serum phosphorus levels, as hyperphosphatemia is strongly associated with poorer survival. Nonadherence with the PB prescription is associated with elevated serum phosphorus levels. We studied associations between patient satisfaction with their PB and serum phosphorus levels and mortality rates.

Methods: Adult HD patients in Germany, Italy, Spain and the UK in the Dialysis Outcomes and Practice Patterns Study were administered a survey instrument in late 2017. Patients were asked about their satisfaction with their PBs, as measured through three questions (difficulty, inconvenience and dissatisfaction) on a 5-point Likert scale, with each dichotomized into average worst versus good responses. These were used as predictors in linear regression models of continuous serum phosphorus levels and in Cox proportional hazards models of mortality, with adjustments for demographics, comorbidities and laboratory values.

Results: Patients having greater difficulty, inconvenience and dissatisfaction with their PB had higher serum phosphorus levels in adjusted models {+0.21 mg/dL [95% confidence interval (CI) ±0.23], +0.30 (±0.21) and 0.36 (±0.22), respectively}, and higher odds of having serum phosphorus levels ≥6.0 mg/dL. Measures of dissatisfaction were also associated with an elevated risk of mortality, with adjusted hazard ratios of 2.2 (95% CI 1.3-3.6), 1.6 (1.0-2.6) and 1.7 (1.1-2.7), respectively; this association was not strongly affected by adjustment for baseline serum phosphorous level.

Conclusions: Self-reported difficulty, inconvenience and dissatisfaction in taking one's prescribed PBs were associated with elevated serum phosphorus levels and serum phosphorus levels above clinically meaningful thresholds. While the mechanism for the association with mortality is unclear, patient-reported satisfaction should be considered when attempting to manage patient serum phosphorus levels.
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August 2021

Secondary hyperparathyroidism, weight loss, and longer term mortality in haemodialysis patients: results from the DOPPS.

J Cachexia Sarcopenia Muscle 2021 08 1;12(4):855-865. Epub 2021 Jun 1.

Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan.

Background: Wasting is a common complication of kidney failure that leads to weight loss and poor outcomes. Recent experimental data identified parathyroid hormone (PTH) as a driver of adipose tissue browning and wasting, but little is known about the relations among secondary hyperparathyroidism, weight loss, and risk of mortality in dialysis patients.

Methods: We included 42,319 chronic in-centre haemodialysis patients from the Dialysis Outcomes and Practice Patterns Study phases 2-6 (2002-2018). Linear mixed models were used to estimate the association between baseline PTH and percent weight change over 12 months, adjusting for country, demographics, comorbidities, and labs. Accelerated failure time models were used to assess 12 month weight loss as a mediator between baseline high PTH and mortality after 12 months.

Results: Baseline PTH was inversely associated with 12 month weight change: 12 month weight loss >5% was observed in 21%, 18%, 18%, 17%, 15%, and 14% of patients for PTH ≥600 pg/mL, 450-600, 300-450, 150-300, 50-150, and <50 pg/mL, respectively. In adjusted analyses, 12 month weight change compared with PTH 150-299 pg/mL was -0.60%, -0.12%, -0.10%, +0.15%, and +0.35% for PTH ≥600, 450-600, 300-450, 50-150, and <50 pg/mL, respectively. This relationship was robust regardless of recent hospitalization and was more pronounced in persons with preserved appetite. During follow-up after the 12 month weight measure [median, 1.0 (interquartile range, 0.6-1.7) years; 6125 deaths], patients with baseline PTH ≥600 pg/mL had 11% [95% confidence interval (CI), 9-13%] shorter lifespan, and 18% (95% CI, 14-23%) of this effect was mediated through weight loss ≥2.5%.

Conclusions: Secondary hyperparathyroidism may be a novel mechanism of wasting, corroborating experimental data, and, among chronic dialysis patients, this pathway may be a mediator between elevated PTH levels and mortality. Future research should determine whether PTH-lowering therapy can limit weight loss and improve longer term dialysis outcomes.
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August 2021

Variation in Peritoneal Dialysis-Related Peritonitis Outcomes in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS).

Am J Kidney Dis 2022 Jan 28;79(1):45-55.e1. Epub 2021 May 28.

Division of Nephrology, St. Michael's Hospital and the Keenan Research Center in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. Electronic address:

Rationale & Objective: Peritoneal dialysis (PD)-associated peritonitis is a significant PD-related complication. We describe the likelihood of cure after a peritonitis episode, exploring its association with various patient, peritonitis, and treatment characteristics.

Study Design: Observational prospective cohort study.

Setting & Participants: 1,631 peritonitis episodes (1,190 patients, 126 facilities) in Australia, New Zealand, Canada, Japan, Thailand, the United Kingdom, and the United States.

Exposure: Patient characteristics (demographics, patient history, laboratory values), peritonitis characteristics (organism category, concomitant exit-site infection), dialysis center characteristics (use of icodextrin and low glucose degradation product solutions, policies regarding antibiotic self-administration), and peritonitis treatment characteristics (antibiotic used).

Outcome: Cure, defined as absence of death, transfer to hemodialysis (HD), PD catheter removal, relapse, or recurrent peritonitis within 50 days of a peritonitis episode.

Analytical Approach: Mixed-effects logistic models.

Results: Overall, 65% of episodes resulted in a cure. Adjusted odds ratios (AOR) for cure were similar across countries (range, 54%-68%), by age, sex, dialysis vintage, and diabetes status. Compared with Gram-positive peritonitis, the odds of cure were lower for Gram-negative (AOR, 0.41 [95% CI, 0.30-0.57]), polymicrobial (AOR, 0.30 [95% CI, 0.20-0.47]), and fungal (AOR, 0.01 [95% CI, 0.00-0.07]) peritonitis. Odds of cure were higher with automated PD versus continuous ambulatory PD (AOR, 1.36 [95% CI, 1.02-1.82]), facility icodextrin use (AOR per 10% greater icodextrin use, 1.06 [95% CI, 1.01-1.12]), empirical aminoglycoside use (AOR, 3.95 [95% CI, 1.23-12.68]), and ciprofloxacin use versus ceftazidime use for Gram-negative peritonitis (AOR, 5.73 [95% CI, 1.07-30.61]). Prior peritonitis episodes (AOR, 0.85 [95% CI, 0.74-0.99]) and concomitant exit-site infection (AOR, 0.41 [95% CI, 0.26-0.64]) were associated with a lower odds of cure.

Limitations: Sample selection may be biased and generalizability may be limited. Residual confounding and confounding by indication limit inferences. Use of facility-level treatment variables may not capture patient-level treatments.

Conclusions: Outcomes after peritonitis vary by patient characteristics, peritonitis characteristics, and modifiable peritonitis treatment practices. Differences in the odds of cure across infecting organisms and antibiotic regimens suggest that organism-specific treatment considerations warrant further investigation.
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January 2022

Mortality, hospitalization and transfer to haemodialysis and hybrid therapy, in Japanese peritoneal dialysis patients.

Perit Dial Int 2021 May 18:8968608211016127. Epub 2021 May 18.

Kawashima Hospital, Tokushima, Japan.

Background And Objectives: Survival of peritoneal dialysis (PD) patients in Japan is high, but few reports exist on cause-specific mortality, transfer to haemodialysis (HD) or hybrid dialysis and hospitalisation risks. We aimed to identify reasons for transfer to HD, hybrid dialysis and hospitalisation in the Japan Peritoneal Dialysis and Outcomes Practice Patterns Study.

Methods: This observational study included 808 adult PD patients across 31 facilities in Japan in 2014-2017. Information on all-cause and cause-specific mortality and hospitalisation and permanent transfer to HD and PD/HD hybrid therapy were prospectively collected and rates calculated.

Results: Median follow-up time was 1.66 years where 162 patients transferred to HD, 79 transferred to hybrid dialysis and 74 patients died. All-cause and cardiovascular disease (CVD)-related mortality rates were 5.1 and 1.7 deaths/100 patient-years, respectively. Rates of transfer to HD and hybrid therapy were 11.2 and 5.5 transfers/100 patient-years, respectively. Among HD transfers, 40% were due to infection (including peritonitis), while 20% were due to inadequate solute/water clearance. Eighty-one percent of hybrid dialysis transfers were due to inadequate solute/water clearance. All--cause, peritonitis-related and CVD-related hospitalisation rates were 120.4, 21.1 and 15.6/100 patient-years, respectively. Median hospital length of stay was 19 days.

Conclusions: Mortality, hospitalisation and transfer to HD/hybrid dialysis rates are relatively low in Japan compared to many other countries with hybrid transfers, accounting for one-third of dialysis transfers from PD. Further study is needed to explain the high inter-facility variation in hospitalisation rates and how to further reduce hospitalisation rates for Japanese PD patients.
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May 2021

Burden of Kidney Disease, Health-Related Quality of Life, and Employment Among Patients Receiving Peritoneal Dialysis and In-Center Hemodialysis: Findings From the DOPPS Program.

Am J Kidney Dis 2021 10 16;78(4):489-500.e1. Epub 2021 Apr 16.

St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. Electronic address:

Rationale & Objective: Individuals faced with decisions regarding kidney replacement therapy options need information on how dialysis treatments might affect daily activities and quality of life, and what factors might influence the evolution over time of the impact of dialysis on daily activities and quality of life.

Study Design: Observational cohort study.

Setting & Participants: 7,771 hemodialysis (HD) and peritoneal dialysis (PD) participants from 6 countries participating in the Peritoneal and Dialysis Outcomes and Practice Patterns Studies (PDOPPS/DOPPS).

Predictors: Patient-reported functional status (based on daily living activities), country, demographic and clinical characteristics, and comorbidities.

Outcome: Employment status and patient-reported outcomes (PROs) including Kidney Disease Quality of Life (KDQOL) instrument physical and mental component summary scores (PCS, MCS), kidney disease burden score, and depression symptoms (Center for Epidemiologic Studies Depression Scale [CES-D] score > 10).

Analytical Approach: Linear regression (PCS, MCS, kidney disease burden score), logistic regression (depression symptoms), adjusted for predictors plus 12 additional comorbidities.

Results: In both dialysis modalities, patients in Japan had the highest PCS and employment (55% for HD and 68% for PD), whereas those in the United States had the highest MCS score, lowest kidney disease burden, and lowest employment (20% in HD and 42% in PD). After covariate adjustment, the association of age, sex, dialysis vintage, diabetes, and functional status with PROs was similar in both modalities, with women having lower PCS and kidney disease burden scores. Lower functional status (score <11) was strongly associated with lower PCS and MCS scores, a much greater burden of kidney disease, and greater likelihood of depression symptoms (CES-D, >10). The median change in KDQOL-based PROs was negligible over 1 year in participants who completed at least 2 annual questionnaires.

Limitations: Selection bias due to incomplete survey responses. Generalizability was limited to the dialysis populations of the included countries.

Conclusions: Variation exists in quality of life, burden of kidney disease, and depression across countries but did not appreciably change over time. Functional status remained one of the strongest predictors of all PROs. Routine assessment of functional status may provide valuable insights for patients and providers in anticipating outcomes and support needs for patients receiving either PD or HD.
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October 2021

Survival Among Incident Peritoneal Dialysis Versus Hemodialysis Patients Who Initiate With an Arteriovenous Fistula.

Kidney Med 2020 Nov-Dec;2(6):732-741.e1. Epub 2020 Oct 22.

Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

Rationale & Objective: Comparisons of outcomes between in-center hemodialysis (HD) and peritoneal dialysis (PD) are confounded by selection bias because PD patients are typically younger and healthier and may have received longer predialysis care. We compared first-year survival between what we hypothesized were clinically equivalent groups; namely, patients who initiate maintenance HD using an arteriovenous fistula (AVF) and those selecting PD as their initial modality.

Study Design: Observational, registry-based, retrospective cohort study.

Setting & Participants: US Renal Data System data for 5 annual cohorts (2010-2014; n = 130,324) of incident HD with an AVF and incident PD patients.

Exposures And Predictors: Exposure was more than 1 day receiving PD or more than 1 day receiving HD with an AVF. Time at risk for both cohorts was determined for 12 consecutive 30-day segments, censoring for transplantation, loss to follow-up, or end of time. Predictors included patient-level characteristics obtained from Centers for Medicare & Medicaid Services 2728 Form and other data sources.

Outcomes: Patient survival.

Analytical Approach: Unadjusted and multivariable risk-adjusted HRs for death of HD versus PD patients, averaged over 2010 to 2014, were calculated.

Results: The HD cohort's average unadjusted mortality rate was consistently higher than for the PD cohort. The HR of HD versus PD was 1.25 (95% CI, 1.20-1.30) in the unadjusted model and 0.84 (95% CI, 0.80-0.87) in the adjusted model. However, multivariable risk-adjusted analyses showed the HR of HD versus PD for the first 90 days was 1.06 (95% CI, 0.98-1.14), decreasing to 0.74 (95% CI, 0.68-0.80) in the 270- to 360-day period.

Limitations: Residual confounding due to selection bias inherent in dialysis modality choice and the observational study design. Form 2728 provides baseline data at dialysis incidence alone, but not over time.

Conclusions: US patients receiving HD with an AVF appear to have a survival advantage over PD patients after 90 days of dialysis initiation after accounting for patient characteristics. These findings have implications in the choice of initial dialysis modality and vascular access for patients.
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October 2020

International variation in dialysis discontinuation in patients with advanced kidney disease.

CMAJ 2020 Aug;192(35):E995-E1002

University Health Network (Jassal), Toronto, Ont.; Arbor Research Collaborative for Health (Larkina, Port, McCullough, Pisoni), Ann Arbor, Mich.; ERA-EDTA Registry (Jager), Department of Medical Informatics, Academic Medical Centre, Amsterdam Public Health Research Institute, University of Amsterdam, Amsterdam, Netherlands; Wolfson Palliative Care Research Centre (Murtagh), Hull York Medical School, University of Hull, Hull, UK; VA Puget Sound Health Care System (O'Hare), Seattle, Wash.; Department of Blood Purification (Hanafusa), Tokyo Women's Medical University, Tokyo, Japan; Departments of Epidemiology (Morgenstern) and Environmental Health Sciences (Morgenstern), School of Public Health, and Department of Urology (Morgenstern), Medical School, University of Michigan, Ann Arbor, Mich.; DaVita Outcomes Research and Patient Empowerment (Tentori), Denver, Colo.; Divisions of Nephrology (Perlman, Swartz) and Palliative Care (Swartz), Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Mich.

Background: Decisions about dialysis for advanced kidney disease are often strongly shaped by sociocultural and system-level factors rather than the priorities and values of individual patients. We examined international variation in the uptake of conservative approaches to the care of patients with advanced kidney disease, in particular discontinuation of dialysis.

Methods: We employed an observational cohort study design using data collected from patients maintained on long-term hemodialysis between 1996 and 2015 in facilities across 12 developed countries participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS). The main outcome was discontinuation of dialysis therapy. We analyzed the association between several patient characteristics and time to dialysis discontinuation by country and phase of study entry.

Results: A total of 259 343 DOPPS patients contributed data to the study, of whom 48 519 (18.7%) died during the study period. Of the decedents, 5808 (12.0%) discontinued dialysis before death. Rates of discontinuation were higher within the first few months after initiation of dialysis, among older adults, among those with a greater number of comorbidities and among those living in an institution. After adjustment for age, sex, dialysis duration, diabetes and dialysis era, rates of discontinuation were highest in Canada, the United States and Australia/New Zealand (33.8, 31.4 and 21.5 per 1000/yr, respectively) and lowest in Japan and Italy (< 0.1 per 1000/yr). Crude discontinuation rates were highest in dialysis facilities that were more likely to offer comprehensive conservative renal care to older adults.

Interpretation: We found persistent international variation in average rates of dialysis discontinuation not explained by differences in patient case-mix. These differences may reflect physician-, facility- and society-level differences in clinical practice. There may be opportunities for international cross-collaboration to improve support for patients with end-stage renal disease who prefer a more conservative approach.
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August 2020

International variation in the management of mineral bone disorder in patients with chronic kidney disease: Results from CKDopps.

Bone 2019 12 4;129:115058. Epub 2019 Sep 4.

Centre for Research in Epidemiology and Population Health (CESP), UMRS 1018, UVSQ, University Paris-Saclay, Villejuif, France; Department of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne Billancourt/Paris, France. Electronic address:

Background And Objectives: Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3-5 CKD patients.

Design, Setting, Participants, And Measurements: Prospective cohort study of 7658 adult patients with eGFR <60mL/min/1.73m, excluding dialysis or transplant patients, participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, Germany, and the US. CKD-MBD laboratory markers included serum levels of phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25-D). MBD treatment data included phosphate binders and vitamin D (nutritional and active). Nephrologist survey data were collected on target MBD marker levels.

Results: Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60-20mL/min/1.73m and more sharply for eGFR<20. 25-D showed no relation to eGFR. Nephrologist survey data indicated marked variation in upper target P and iPTH levels. Among patients with P>5.5mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%-51%, and use of any (active or nutritional) vitamin D was 60%-87%.

Conclusions: Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study.
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December 2019

Update to the study protocol, including statistical analysis plan, for the multicentre, randomised controlled OuTSMART trial: a combined screening/treatment programme to prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies.

Trials 2019 Aug 5;20(1):476. Epub 2019 Aug 5.

MRC Centre for Transplantation, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

Background: Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates.

Methods: OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants.

Discussion: Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report.

Trial Registration: ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012-004308-36 . Registered on 10 December 2012.
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August 2019

Epithelial tissue cut-out following needle insertion into a joint: a potential complication during arthroscopy.

ANZ J Surg 2019 05 9;89(5):557-561. Epub 2019 Apr 9.

Bendigo Health, Bendigo, Victoria, Australia.

Background: Knee arthroscopy is a common orthopaedic procedure and often involves insertion of a needle through skin into a joint. This needle insertion can create epithelial tissue cut-outs possibly containing commensal bacteria that can be flushed into the joint, and potentially lead to post-arthroscopy septic arthritis. This study aims to assess the frequency of epithelial tissue cut-out creation on insertion of different needle sizes at different angles to the skin.

Methods: Using an ex-vivo porcine limb tissue model, needles of various gauge (14-23G) were inserted at angles of 90, 60, 45 and 30° to the skin surface. Ten passes were undertaken at each angle. Needle lumen contents were then examined for solid tissue cut-out.

Results: Two hundred and eighty needle passes were performed resulting in 70 tissue cut-outs (25%) containing solid material. This was more common amongst lower gauge needles. 8 of the 70 (11.4%) tissue cut-outs contained macroscopic evidence of epithelium. The overall rate of epithelial tissue cut-out was 2.9%. The 23G needle had the lowest rate of tissue cut-out creation, occurring twice out of 40 passes (P = 0.002). Neither of these contained macroscopic epithelial tissue.

Conclusion: Hypodermic needle insertion through skin into a joint can create epithelial tissue cut-out. Epithelial tissue cut-out occurs more frequently with use of lower gauge needles. This study suggests use of a 23G needle during arthroscopy, inserted either at 60 or 90° to the skin, to reduce epithelial tissue cut-out and any potential contribution to post-arthroscopy septic arthritis.
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May 2019

Guideline attainment and morbidity/mortality rates in a large cohort of European haemodialysis patients (EURODOPPS).

Nephrol Dial Transplant 2019 12;34(12):2105-2110

ERA-EDTA Registry, Department of Medical Informatics, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health research institute, Amsterdam, The Netherlands.

Background: Haemodialysis patients experience a wide variety of intermediate complications, such as anaemia, hypertension and mineral bone disease (MBD). We aimed to assess the risk of death and hospital admissions as a function of the simultaneous attainment of different guideline targets (for hypertension, anaemia and MBD) in a large European cohort of dialysis patients.

Methods: EURODOPPS is part of the Dialysis Outcomes and Practice Patterns Study (DOPPS) international, prospective cohort study of adult, in-centre haemodialysis patients for whom clinical data are extracted from medical records. In the present analysis, 6317 patients from seven European countries were included between 2009 and 2011. The percentages of patients treated according to the international guidelines on anaemia, hypertension and MBD were determined. The overall degree of guideline attainment was considered to be high if four or all five of the evaluated targets were attained, moderate if two or three targets were attained, and low if fewer than two targets were attained. Fully adjusted multivariate Cox models were used to investigate the relationship of target attainment with mortality and first hospital admission.

Results: At baseline, the degree of target attainment was low in 1751 patients (28%), moderate in 3803 (60%) and high in 763 (12%). In the fully adjusted model using time-dependent covariates, low attainment was associated with higher all-cause mortality [hazard ratio (95% confidence interval) = 1.19 (1.05-1.34)] and high attainment was associated with lower all-cause mortality [0.82 (0.68-0.99)]. In a similar model that additionally accounted for death as a competing risk, low and high attainments were not associated with hospital admission.

Conclusion: In a large international cohort of dialysis patients, we have shown that more stringent application of guidelines is associated with lower mortality.
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December 2019

The association between longer haemodialysis treatment times and hospitalization and mortality after the two-day break in individuals receiving three times a week haemodialysis.

Nephrol Dial Transplant 2019 09;34(9):1577-1584

European Renal Association-European Dialysis and Transplant Association Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.

Background: On the first haemodialysis (HD) day after the 2-day break in three times a week (3×W) in-centre HD, mortality and hospitalization are higher. If longer HD sessions prescribed 3×W is associated with a reduction in these events is unknown.

Methods: HD session length in 19 557 prevalent European in-centre 3×W HD patients participating in the Dialysis Outcomes and Practice Patterns Study (1998-2011) were categorized into <200, 200-225, 226-250 or >250 min. Standardized event rates on the first (HD1) versus the second (HD2) HD day after the 2-day break, with supporting Cox proportional hazards models adjusted for patient and dialysis characteristics, were generated for all-cause mortality, all-cause hospitalization, out-of-hospital death and fluid overload hospitalization.

Results: By comparing HD1 with HD2, increased rates of all endpoints were observed (all P < 0.002). As HD session lengthened across the four groups, all-cause mortality per 100 patient-years on the HD1 (23.0, 20.4, 16.4 and 14.6) and HD2 (26.1, 13.3, 13.4 and 12.1) reduced. Similar improvements were observed for out-of-hospital death but were less marked for hospitalization endpoints. However, even patients dialysing >250 min were at significantly greater risk on HD1 when compared with their HD2 for out-of-hospital death [hazard ratio (HR) = 2.1, 95% CI 1.0-4.3], all-cause hospitalization (HR = 1.3, 95% CI 1.2-1.4) and fluid overload hospitalization (HR = 3.2, 95% CI 1.8-6.0).

Conclusions: Despite the association between reduced mortality across all dialysis days in patients performing longer sessions, elevated risk on the first dialysis day relative to the second persists even in patients dialysing 4.5 h 3×W.
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September 2019

Projecting ESRD Incidence and Prevalence in the United States through 2030.

J Am Soc Nephrol 2019 01 17;30(1):127-135. Epub 2018 Dec 17.

Arbor Research Collaborative for Health, Ann Arbor, Michigan; and Departments of.

Background: Population rates of obesity, hypertension, diabetes, age, and race can be used in simulation models to develop projections of ESRD incidence and prevalence. Such projections can inform long-range planning for ESRD resources needs.

Methods: We used an open compartmental simulation model to estimate the incidence and prevalence of ESRD in the United States through 2030 on the basis of wide-ranging projections of population obesity and ESRD death rates. Population trends in age, race, hypertension, and diabetes were on the basis of data from the Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey and the US Census.

Results: The increase in ESRD incidence rates within age and race groups has leveled off and/or declined in recent years, but our model indicates that population changes in age and race distribution, obesity and diabetes prevalence, and ESRD survival will result in a 11%-18% increase in the crude incidence rate from 2015 to 2030. This incidence trend along with reductions in ESRD mortality will increase the number of patients with ESRD by 29%-68% during the same period to between 971,000 and 1,259,000 in 2030.

Conclusions: The burden of ESRD will increase in the United States population through 2030 due to demographic, clinical, and lifestyle shifts in the population and improvements in RRT. Planning for ESRD resource allocation should allow for substantial continued growth in the population of patients with ESRD. Future interventions should be directed to preventing the progression of CKD to kidney failure.
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January 2019

Evaluating the effectiveness of IV iron dosing for anemia management in common clinical practice: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BMC Nephrol 2017 Nov 9;18(1):330. Epub 2017 Nov 9.

Arbor Research Collaborative for Health, 340 E. Huron, Suite 300, Ann Arbor, MI, 48104, USA.

Background: Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice.

Methods: 9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3-month average, categorized as 0, <300, ≥300 mg/month) with 3-month change in Hgb, TSAT, ferritin, and ESA dose were evaluated using adjusted GEE models.

Results: Relative change: Monotonically positive associations between IV iron dose and Hgb, TSAT, and ferritin change, and inverse associations with ESA dose change, were observed across multiple strata of prior Hgb, TSAT, and ferritin levels. Absolute change: TSAT, ferritin, and ESA dose changes were nearest zero with IV iron <300 mg/month, rather than 0 mg/month or ≥300 mg/month by maintenance or replacement dosing. Findings were robust to numerous sensitivity analyses.

Conclusions: Though residual confounding cannot be ruled out in this observational study, findings suggest that IV iron dosing <300 mg/month, as commonly seen with maintenance dosing of 100-200 mg/month, may be a more effective approach to support Hgb than the higher IV iron doses (300-400 mg/month) often given in many European and North American hemodialysis clinics. Alongside studies supporting the safety of IV iron in 100-200 mg/month dose range, these findings help guide the rational dosing of IV iron in anemia management protocols for everyday hemodialysis practice.
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November 2017

A C-index for recurrent event data: Application to hospitalizations among dialysis patients.

Biometrics 2018 06 3;74(2):734-743. Epub 2017 Aug 3.

Arbor Research Collaborative for Health, Ann Arbor, Michigan 48104, U.S.A.

We propose a C-index (index of concordance) applicable to recurrent event data. The present work addresses the dearth of measures for quantifying a regression model's ability to discriminate with respect to recurrent event risk. The data which motivated the methods arise from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a long-running prospective international study of end-stage renal disease patients on hemodialysis. We derive the theoretical properties of the measure under the proportional rates model (Lin et al., 2000), and propose computationally convenient inference procedures based on perturbed influence functions. The methods are shown through simulations to perform well in moderate samples. Analysis of hospitalizations among a cohort of DOPPS patients reveals substantial improvement in discrimination upon adding country indicators to a model already containing basic clinical and demographic covariates, and further improvement upon adding a relatively large set of comorbidity indicators.
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June 2018

HLA Amino Acid Polymorphisms and Kidney Allograft Survival.

Transplantation 2017 05;101(5):e170-e177

1 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA. 2 Arbor Research Collaborative for Health, Ann Arbor, MI. 3 National Marrow Donor Program, Minneapolis, MN. 4 Department of Pathology, Stanford University, Palo Alto, CA. 5 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA.

Background: The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid (AA) mismatches (MMs) at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those MMs assessed at the antigenic (2-digit) specificity.

Methods: Data on 240 024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding AA polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen MMs.

Results: We show that estimated AA MMs at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen MMs with graft survival. A statistically significant linear relationship between the estimated number of AA MMs and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months after transplantation (hazard ratio, 1.30 per 15 DRB1 AA MM; P < 0.0001).

Conclusions: This study shows that independent of the well-known association of HLA antigen (2-digit specificity) MMs with kidney graft survival, estimated AA MMs at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of GF.
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May 2017

Predialysis blood pressure on survival in hemodialysis patients.

Kidney Int 2017 03;91(3):755-756

Departments of Epidemiology and Environmental Health Sciences, School of Public Health, and Department of Urology, Medical School, University of Michigan, Ann Arbor, Michigan, USA.

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March 2017

Interdialytic Weight Gain: Trends, Predictors, and Associated Outcomes in the International Dialysis Outcomes and Practice Patterns Study (DOPPS).

Am J Kidney Dis 2017 Mar 17;69(3):367-379. Epub 2016 Nov 17.

Arbor Research Collaborative for Health, Ann Arbor, MI; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

Background: High interdialytic weight gain (IDWG) is associated with adverse outcomes in hemodialysis (HD) patients. We identified temporal and regional trends in IDWG, predictors of IDWG, and associations of IDWG with clinical outcomes.

Study Design: Analysis 1: sequential cross-sections to identify facility- and patient-level predictors of IDWG and their temporal trends. Analysis 2: prospective cohort study to assess associations between IDWG and mortality and hospitalization risk.

Setting & Participants: 21,919 participants on HD therapy for 1 year or longer in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 2 to 5 (2002-2014).

Predictors: Analysis 1: study phase, patient demographics and comorbid conditions, HD facility practices. Analysis 2: relative IDWG, expressed as percentage of post-HD weight (<0%, 0%-0.99%, 1%-2.49%, 2.5%-3.99% [reference], 4%-5.69%, and ≥5.7%).

Outcomes: Analysis 1: relative IDWG as a continuous variable using linear mixed models; analysis 2: mortality; all-cause and cause-specific hospitalization using Cox regression, adjusting for potential confounders.

Results: From phase 2 to 5, IDWG declined in the United States (-0.29kg; -0.5% of post-HD weight), Canada (-0.25kg; -0.8%), and Europe (-0.22kg; -0.5%), with more modest declines in Japan and Australia/New Zealand. Among modifiable factors associated with IDWG, the most notable was facility mean dialysate sodium concentration: every 1-mEq/L greater dialysate sodium concentration was associated with 0.13 (95% CI, 0.11-0.16) greater relative IDWG. Compared to relative IDWG of 2.5% to 3.99%, there was elevated risk for mortality with relative IDWG≥5.7% (adjusted HR, 1.23; 95% CI, 1.08-1.40) and elevated risk for fluid-overload hospitalization with relative IDWG≥4% (HRs of 1.28 [95% CI, 1.09-1.49] and 1.64 [95% CI, 1.27-2.13] for relative IDWGs of 4%-5.69% and ≥5.7%, respectively).

Limitations: Possible residual confounding. No dietary salt intake data.

Conclusions: Reductions in IDWG during the past decade were partially explained by reductions in dialysate sodium concentration. Focusing quality improvement strategies on reducing occurrences of high IDWG may improve outcomes in HD patients.
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March 2017