Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).

BACKGROUND: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. RESULTS: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. CONCLUSIONS: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Infrequent dialysis: a new paradigm for hemodialysis initiation.

Nearly a half-century ago, the thrice-weekly hemodialysis schedule was empirically established as a means to provide an adequate dialysis dose while also treating the greatest number of end-stage renal disease (ESRD) patients using limited resources. Landmark trials of hemodialysis adequacy have historically been anchored to thrice-weekly regimens, but a recent randomized controlled trial demonstrated that frequent hemodialysis (six times per week) confers cardiovascular and survival benefits. Based on these collective data and experience, clinical practice guidelines advise against a less than thrice-weekly treatment schedule in patients without residual renal function, yet provide limited guidance on the optimal treatment frequency when substantial native kidney function is present. Thus, during the transition from Stage 5 chronic kidney disease to ESRD, the current paradigm is to initiate hemodialysis on a "full-dose" thrice-weekly regimen even among patients with substantial residual renal function. However, emerging data suggest that frequent hemodialysis accelerates residual renal function decline, and infrequent regimens may provide better preservation of native kidney function. Given the high mortality rates during the first 6 months of hemodialysis and the survival benefits of preserved native kidney function, initiation with twice-weekly treatment schedules ("infrequent hemodialysis") with an incremental increase in frequency over time may provide an opportunity to optimize patient survival. This review outlines the clinical benefits of post-hemodialysis residual renal function, studies of twice-weekly treatment regimens, and the potential risks and benefits of infrequent hemodialysis.

Major Outcomes With Personalized Dialysate TEMPerature (MyTEMP): Rationale and Design of a Pragmatic, Registry-Based, Cluster Randomized Controlled Trial.

BACKGROUND: Small randomized trials demonstrated that a lower compared with higher dialysate temperature reduced the average drop in intradialytic blood pressure. Some observational studies demonstrated that a lower compared with higher dialysate temperature was associated with a lower risk of all-cause mortality and cardiovascular mortality. There is now the need for a large randomized trial that compares the effect of a low vs high dialysate temperature on major cardiovascular outcomes. OBJECTIVE: The purpose of this study is to test the effect of outpatient hemodialysis centers randomized to (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol for 4 years on cardiovascular-related death and hospitalizations. DESIGN: The design of the study is a pragmatic, registry-based, open-label, cluster randomized controlled trial. SETTING: Hemodialysis centers in Ontario, Canada, were randomized on February 1, 2017, for a trial start date of April 3, 2017, and end date of March 31, 2021. PARTICIPANTS: In total, 84 hemodialysis centers will care for approximately 15 500 patients and provide over 4 million dialysis sessions over a 4-year follow-up. INTERVENTION: Hemodialysis centers were randomized (1:1) to provide (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol of 36.5°C. For the personalized protocol, nurses set the dialysate temperature between 0.5°C and 0.9°C below the patient's predialysis body temperature for each dialysis session, to a minimum dialysate temperature of 35.5°C. PRIMARY OUTCOME: A composite of cardiovascular-related death or major cardiovascular-related hospitalization (a hospital admission with myocardial infarction, congestive heart failure, or ischemic stroke) captured in Ontario health care administrative databases. PLANNED PRIMARY ANALYSIS: The primary analysis will follow an intent-to-treat approach. The hazard ratio of time-to-first event will be estimated from a Cox model. Within-center correlation will be considered using a robust sandwich estimator. Observation time will be censored on the trial end date or when patients die from a noncardiovascular event. TRIAL REGISTRATION: www.clinicaltrials.gov; identifier: NCT02628366.

CONTEXTE: De petits essais à répartition aléatoire ont montré que l'utilisation d'un dialysat à basse température réduisait le risque d'hypotension intra-dialytique. De même, certaines études observationnelles ont démontré qu'un dialysat à basse température était associé à un plus faible risque de mortalité toute cause ou d'origine cardiovasculaire. Le temps est venu de procéder à un vaste essai à répartition aléatoire comparant les effets d'un dialysat à basse température et à température standard sur les principaux résultats cardiovasculaires. OBJECTIF: Répartir aléatoirement des centres d'hémodialyse ambulatoire pour qu'ils suivent pendant quatre ans (i) un protocole personnalisé de dialysat à basse température ou (ii) un protocole de dialysat à température standard, et tester l'effet sur les hospitalisations et la mortalité attribuables à des événements cardiovasculaires. TYPE D'ÉTUDE: Un essai clinique à répartition aléatoire en grappes. CADRE: Le 1er février 2017, des centres d'hémodialyse de l'Ontario (Canada) ont été répartis aléatoirement en vue d'un essai qui a débuté le 3 avril 2017 et qui se poursuivra jusqu'au 31 mars 2021. PARTICIPANTS: Quatre-vingt-quatre centres d'hémodialyse qui prendront en charge environ 15 500 patients pendant les quatre ans de suivi. INTERVENTION: Les centres d'hémodialyse ont été répartis aléatoirement (1:1) pour offrir (i) un protocole personnalisé de dialysat à température réduite ou (ii) un protocole de dialysat à 36,5°C. Pour le protocole personnalisé, les infirmières règlent la température du dialysat entre 0,5 et 0,9°C sous la température corporelle du patient mesurée avant la dialyse, jusqu'à une température minimale de 35,5°C. PRINCIPAUX RÉSULTATS: Un ensemble d'hospitalisations attribuables à un événement cardiovasculaire majeur (accident ischémique cérébral non fatal, infarctus du myocarde ou insuffisance cardiaque congestive) et de décès d'origine cardiovasculaire consignés dans les bases de données de santé de l'Ontario. PRINCIPALE ANALYSE ENVISAGÉE: L'analyse primaire adoptera une approche fondée sur l'intention de traiter. Un modèle de Cox servira à estimer le rapport de risque du temps écoulé jusqu'au premier événement. La corrélation intra-centre sera prise en compte à l'aide d'un estimateur sandwich robuste. Le temps d'observation sera censuré à la date de fin de l'essai ou au moment d'un décès non lié à un événement cardiovasculaire.

Prevalence of CKD, Diabetes, and Hypertension in Rural Tanzania.

INTRODUCTION: Chronic kidney disease (CKD), diabetes, and hypertension play a disproportionate role in the growing public health challenge posed by noncommunicable diseases (NCDs) in East Africa. The impact of these NCDs may pose the greatest challenge in rural areas with limited screening and treatment facilities, although precise prevalence estimates of these conditions in rural Tanzania are lacking. METHODS: The prevalence of CKD, diabetes, and hypertension, were estimated from a probability sample of adults (n = 739) residing in 2 communities within Kisarawe, a rural district of Tanzania. Following consent, participants were studied in their homes. Random point-of-care (POC) measures of glycosylated hemoglobin and blood pressure, were obtained. Serum creatinine, drawn at the POC and measured at Muhimbili National University, was used to calculate estimated glomerular filtration rate with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: The median age was 35 years (interquartile range 25-45 years). Overall the pooled prevalence for CKD stages III, IV, and V was 12.4% (95% confidence interval [CI] = 10.2-14.8). Surprisingly, the prevalence of CKD stage V (3.0%; 95% CI = 2.1-4.4) was high among the youngest age group (18-36 years). The prevalence estimates for prehypertension and hypertension were 38.0% (95% CI = 34.6-41.5) and 19.9% (95% CI = 17.1-22.9), respectively. The prevalence estimates for prediabetes and diabetes were 25.7% (95% CI = 22.6-29.1) and 14.8% (95% CI = 12.4-17.6), respectively. CONCLUSION: Although this pilot study had a relatively small sample size, the prevalence estimates for CKD, diabetes, and hypertension were higher than we expected based on previous estimates from Tanzania. CKD was not significantly associated with diabetes or hypertension, suggesting the possibility of an alternative causality.

Relationships of clinic size, geographic region, and race/ethnicity to the frequency of missed/shortened dialysis treatments.

BACKGROUND: Significant international differences abound in the adherence of hemodialysis (HD) patients to prescribed treatments. Unfortunately, factors influencing adherence within the United States (US) are not well understood. This study explores the hypothesis that race/ethnicity, geographic region and clinic size are associated with differences in the frequency of missed/shortened treatments. METHODS: A retrospective analysis on all prevalent chronic HD patients treated at Dialysis Clinics Inc. facilities between January 2007 and June 2008. Logistic regression models were computed in which the outcome measures were the odds for missing or shortening treatments. RESULTS: The cohort consisted of 15,340 HD patients of whom 48% were non-Hispanic whites (NHW), 41% African Americans (AA), 6% Hispanics, 2% Native Americans, 2% Asians, and 1% unknown. Patients were older in the Northeast than in the South (p < 0.001) or West (p = 0.0052). The frequency of missed and shortened treatments was lower in the Northeast than other regions, p < 0.0001. Hospitalization rates were lower in the West than the Northeast (p < 0.01) but mortality rates were similar across all regions. The odds ratio and 95% confidence interval for missed [1.31 (1.14-1.52)] and shortened treatments [1.86 (1.73-2.0)] were greater in clinics with >100 patients than in those with <50 patients. Compared to NHW, the frequencies of missed and shortened treatments were higher in AA, Hispanics and Native Americans (p < 0.001) but lower among Asians (p < 0.001). CONCLUSION: The frequency of missed and shortened HD varies significantly by race/ethnicity, geographic region and clinic size. The relationship of clinic size to missed/shortened treatments may warrant consideration when planning new HD facilities.

Relationship of missed and shortened hemodialysis treatments to hospitalization and mortality: observations from a US dialysis network.

BACKGROUND: The relationship of missed and shortened hemodialysis (HD) to clinical outcomes has not been well characterized in HD patients in the USA. Here we explored the frequency of missed and shortened treatments and their impact on mortality and hospitalization. METHODS: A retrospective review of data from a cohort of 15 340 HD patients treated in facilities operated by Dialysis Clinics, Inc. We compared the frequency of missed and shortened treatments by gender, race, age and treatment schedules [Mondays, Wednesdays, Fridays (MWF) versus Tuesdays, Thursdays, Saturdays (TTS)]. RESULTS: Of the 15 340 patients, 48% were non-Hispanic whites (NHWs), 41% African Americans (AAs), 6% Hispanics, 2% Native American (NA), 2% Asians and 1% other races. The median number of years on HD was 1.8 years and the median follow-up was 12.4 months. The odds of missing at least one treatment in a month were higher in: patients aged <55 years, odds ratio (OR) 1.33 (P<0.0001); in AAs, OR 1.51 (P < 0.0001); in NAs, OR 1.50 (P = 0.0003); and in Hispanics, OR 1.33 (P = 0.0003) compared with NHWs and in patients who dialyzed on TTS compared with MWF, OR 1.33 (P < 0.0001). Similar findings were observed for treatments shortened by at least 10 min per month. Missed and shortened treatments were most prevalent on Saturdays and were also associated with progressive increases in hospitalization and mortality. CONCLUSION: Missed and shortened HD treatments pose a challenge to providers. Improved adherence to prescribed dialysis may decrease the morbidity and mortality.