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Haemodialysis centres have conventionally provided maintenance haemodialysis using a standard dialysate temperature (eg, 36·5°C) for all patients. Many centres now use cooler dialysate (eg, 36·0°C or lower) for potential cardiovascular benefits. We aimed to assess whether personalised cooler dialysate, implemented as centre-wide policy, reduced the risk of cardiovascular-related death or hospital admission compared with standard temperature dialysate. MyTEMP was a pragmatic, two-arm, parallel-group, registry-based, open-label, cluster-randomised, superiority trial done at haemodialysis centres in Ontario, Canada. Eligible centres provided maintenance haemodialysis to at least 15 patients a week, and the medical director of each centre had to confirm that their centre would deliver the assigned intervention. Using covariate-constrained randomisation, we allocated 84 centres (1:1) to use either personalised cooler dialysate (nurses set the dialysate temperature 0·5–0·9°C below each patient's measured pre-dialysis body temperature, with a lowest recommended dialysate temperature of 35·5°C), or standard temperature dialysate (36·5°C for all patients and treatments). Patients and health-care providers were not masked to the group assignment; however, the primary outcome was recorded in provincial databases by medical coders who were unaware of the trial or the centres’ group assignment. The primary composite outcome was cardiovascular-related death or hospital admission with myocardial infarction, ischaemic stroke, or congestive heart failure during the 4-year trial period. Analysis was by intention to treat. The study is registered at ClinicalTrials.gov, NCT02628366. We assessed all of Ontario's 97 centres for inclusion into the study. Nine centres had less than 15 patients and one director requested that four of their seven centres not participate. 84 centres were recruited and on Feb 1, 2017, these centres were randomly assigned to administer personalised cooler dialysate (42 centres) or standard temperature dialysate (42 centres). The intervention period was from April 3, 2017, to March 31, 2021, and during this time the trial centres provided outpatient maintenance haemodialysis to 15 413 patients (about 4·3 million haemodialysis treatments). The mean dialysate temperature was 35·8°C in the cooler dialysate group and 36·4°C in the standard temperature group. The primary outcome occurred in 1711 (21·4%) of 8000 patients in the cooler dialysate group versus 1658 (22·4%) of 7413 patients in the standard temperature group (adjusted hazard ratio 1·00, 96% CI 0·89 to 1·11; p=0·93). The mean drop in intradialytic systolic blood pressure was 26·6 mm Hg in the cooler dialysate group and 27·1 mm Hg in the standard temperature group (mean difference –0·5 mm Hg, 99% CI –1·4 to 0·4; p=0·14). Centre-wide delivery of personalised cooler dialysate did not significantly reduce the risk of major cardiovascular events compared with standard temperature dialysate. The rising popularity of cooler dialysate is called into question by this study, and the risks and benefits of cooler dialysate in some patient populations should be clarified in future trials. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Renal Network, Ontario Strategy for Patient-Oriented Research Support Unit, Dialysis Clinic, Inc., ICES (formerly known as the Institute for Clinical Evaluative Sciences), Lawson Health Research Institute, and Western University.

Renin-angiotensin polymorphisms and QTc interval prolongation in end- stage renal disease. Polymorphisms of renin-angiotensin system (RAS) genes in patients with end-stage renal disease (ESRD) on chronic hemodialysis may be associated with QTc interval prolongation, leading to fatal arrhythmias. The objective of this study was to determine (1) the prevalence of QTc prolongation in hemodialysis patients, and (2) the association of a prolonged QTc in these patients with RAS polymorphisms [angiotensin-converting enzyme-insertion/deletion (ACE-I/D), angiotensin type 1 receptor-A1166C (AT1R-A1166C), and angiotensinogen-M235T (AGT-M235T)]. Twelve-lead electrocardiograms (ECGs), serum electrolytes (sodium, potassium, and calcium), and ACE and angiotensin II levels were obtained 10 to 12 hours after a hemodialysis session in 43 patients with ESRD on chronic hemodialysis [mean age (±SD), 55 ± 14 years]. Using polymerase chain reaction (PCR), the presence of polymorphisms of the ACE-I/D, AT1R-A1166C, and AGT-M235T genes was determined from the buccal cells. A maximum QT interval in patients with sinus rhythm and normal QRS duration was corrected for heart rate using Hodges' formula. Fifty-eight percent of the patients had QTc interval prolongation (>440 msec). The ACE-DD genotype (P = 0.002) and the C allele of the AT1R-A1166C gene (P = 0.004), but not the AGT-M235T gene, contributed to QTc prolongation. Polymorphisms of ACE and AT1R genes additively contribute to QTc prolongation found in a great majority of ESRD patients. Therefore, ESRD patients with both or one of these polymorphisms may be at a higher risk for sudden cardiac death.

Renal injury evokes tubular cholesterol accumulation, mediated in part by increased HMG CoA reductase (HMGCR) levels. The present study was undertaken to define potential molecular determinants of these changes and to ascertain the relative importance of increased cholesterol production versus mevalonate pathway-driven protein prenylation, on the emergence of the so-called postrenal injury \"cytoresistant state.\" Cultured proximal tubule (HK-2) cells were subjected to Fe or ATP depletion injury, followed 1 to 24 hours later by assessments of: 1) sterol transcription factor expression (SREBP)-1 and -2); 2) HMGCR mRNA levels; and 3) Ras/Rho prenylation. HMGCR mRNA and Ras/Rho prenylation were also assessed after in vivo ischemic and Fe-mediated renal damage. Using specific inhibitors, the relative importance of protein prenylation versus terminal cholesterol synthesis on HK-2 cell susceptibility to injury was also assessed. Acute injury induced HK-2 cell SREBP disruption and reductions in HMGCR mRNA. Renal cortical HMGCR mRNA also fell in response to either in vivo ischemic or Fe-mediated oxidant damage. At 24 hours after in vitro/in vivo injury, a time of cholesterol buildup, no increase in Ras/Rho prenylation was observed. Prenylation inhibitors did not sensitize HK-2 cells to injury. Conversely, squalene synthase (terminal cholesterol synthesis) blockade sensitized HK-2 cells to both Fe and ATP depletion attack. We concluded that: 1) acute tubular cell injury can destroy SREBPs and lower HMGCR mRNA. This suggests that posttranscriptional/translational events are responsible for HMGCR enzyme and cholesterol accumulation after renal damage. 2) Injury-induced cholesterol accumulation appears dissociated from increased protein prenylation. 3) Cholesterol accumulation, per se, seems to be the dominant mechanism by which the mevalonate pathway contributes to the postrenal injury cytoresistant state.

OBJECTIVE: To explore the hypothesis that CD36, a scavenger receptor and fatty acid translocase, is upregulated in peripheral blood mononuclear cells (PBMCs) among patients with type 2 diabetes and is a biomarker of PBMC activation and inflammation. RESEARCH DESIGN AND METHODS: We used a cross-sectional observational design to study a multi-racial/ethnic population sample consisting of Caucasians, Hispanics, and Native Americans with type 2 diabetes (n = 33) and nondiabetic control subjects (n = 27). PBMC CD36 mRNA/protein and plasma high sensitivity (hs) C-reactive protein (hsCRP), hs-interleukin-6 (hsIL-6), and adiponectin were measured. RESULTS: Unadjusted PBMC CD36 mRNA and protein were 1.56- and 1.63-fold higher, respectively, among type 2 diabetic subjects versus control subjects. PBMC CD36 protein was directly associated with CD36 mRNA, plasma hsCRP, and hsIL-6 and inversely associated with plasma adiponectin in both groups. CONCLUSIONS: Increased CD36 expression is a biomarker of PBMC activation and inflammation and may become a useful tool in cardiovascular disease risk stratification.

Diabetic nephropathy, the most common cause of end-stage renal disease, aggregates in families and specific ethnic groups. Deconstructing diabetic nephropathy into intermediate, quantitative phenotypes may increase feasibility of detecting susceptibility loci by genetic screens. Glomerular filtration rate (GFR), which characterizes diabetic nephropathy, was employed as a quantitative trait in a preliminary whole-genome scan. Estimated GFR (eGFR) was calculated for 882 diabetic sibpairs (mean age 57 years) of African-American (25.6% of total), American Indian (8.6%), European-American (14.2%), and Mexican-American (51.6%) descent enrolled in the initial phase of the Family Investigation of Nephropathy and Diabetes (FIND). A whole-genome scan was performed using 404 microsatellite markers (average spacing 9 cM) and model-free linkage analysis. For all ethnicities combined, strong evidence for linkage was observed on chromosomes 1q43 (P = 3.6 x 10(-3)), 7q36.1 (P = 2.1 x 10(-4)), 8q13.3 (P = 4.6 x 10(-4)), and 18q23.3 (P = 2.7 x 10(-3)). Mexican-American families, who comprised the major ethnic subpopulation in FIND, contributed to linkage on chromosomes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, whereas African-American and American-Indian families displayed linkage peaks on chromosomes 11p15.1 and 15q22.3, respectively. We have demonstrated multiple chromosomal regions linked to eGFR in a multi-ethnic collection of families ascertained by a proband with diabetic nephropathy. Identification of genetic variants within these loci that are responsible for the linkage signals could lead to predictive tests or novel therapies for subsets of patients at risk for diabetic nephropathy.

Prevalence of Diabetes Is Higher Among Female than Male Zuni Indians Marina Scavini , MD 1 2 , Christine A. Stidley , PHD 1 3 , Vallabh O. Shah , PHD 4 , Andrew S. Narva , MD 5 , Francesca Tentori , MD 4 6 , David S. Kessler , MD 7 , Arlene Bobelu , BS 1 , Carleton P. Albert , BS 4 , Jeanette Bobelu , BSN 4 , Eunice Jamon , LPN 4 , Kathy Natachu 4 , Donica Neha , BSN 4 , Mildred Waikaniwa 4 , Thomas K. Welty , MD 4 , Jean W. MacCluer , PHD 8 and Philip G. Zager , MD 4 1 Dialysis Clinic, Inc., Albuquerque, New Mexico 2 H. San Raffaele Scientific Institute, Milan, Italy 3 Department of Family and Community Medicine, University of New Mexico, Albuquerque, New Mexico 4 Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 5 Kidney Disease Program, Indian Health Service, Albuquerque, New Mexico 6 Universita’ degli Studi di Milano, Scuola di Specializzazione in Nefrologia, Milan, Italy 7 Zuni Indian Hospital, Zuni Pueblo, New Mexico 8 Southwest Foundation for Biomedical Research, San Antonio, Texas Abstract OBJECTIVE —Test the hypothesis that diabetes and related risk factors are more common among female than male Zuni Indians. RESEARCH DESIGN AND METHODS —We conducted a population-based, cross-sectional survey of the Zuni Indians aged ≥5 years. We used households within neighborhood clusters as the sampling frame. We administered a questionnaire, collected blood and urine, and measured height and weight. Self-reported diabetes was used to assess previously diagnosed diabetes. Participants without a prior history of diabetes were classified as having newly diagnosed diabetes if they had HbA 1c >7.0% or random glucose ≥11.1 mmol/l during the survey. RESULTS —The prevalence of previously diagnosed diabetes among Zuni Indians aged ≥5 years ( n = 1,503) was higher among female Zuni Indians (16.7% [95% CI 14.1–19.3]) than male Zuni Indians (9.7% [7.4–12.1]) ( P < 0.001). The prevalence of newly diagnosed diabetes was similar among female Zuni Indians (2.4% [1.4–3.4]) and male Zuni Indians (2.4% [1.2–3.6]). The prevalence of previously and newly diagnosed diabetes was higher among female Zuni Indians (19.1% [16.4–21.9]) than male Zuni Indians (12.2% [9.5–14.8]) ( P < 0.001). The prevalence of obesity was higher among female Zuni Indians (34.3% [30.9–37.7]) than male Zuni Indians (21.5% [18.4–24.7]) ( P < 0.001). Obesity was associated with diabetes among female and male Zuni Indians. Physical inactivity was more common among female Zuni Indians (44.2% [40.7–47.8]) than male Zuni Indians (35.1% [31.5–38.7]) ( P < 0.001). However, physical inactivity was not associated with diabetes among either female or male Zuni Indians. Gestational diabetes was a risk factor among female Zuni Indians. CONCLUSIONS —Among the Zuni Indians, the prevalence of diabetes was 57% higher among female than male members of the population. Culture, tradition, and lifestyle differences may contribute to the higher prevalence of diabetes and obesity among female Zuni Indians. GDM, gestational diabetes mellitus IQR, interquartile range OR, odds ratio PBCSS, population-based cross-sectional survey SHS, Strong Heart Study ZTC, Zuni Tribal Census Footnotes Address correspondence and reprint requests to Philip G. Zager, MD, UNM Nephrology ACC5, Albuquerque, NM 87131-5271. E-mail: pzag{at}unm.edu . Received for publication 3 March 2002 and accepted in revised form 7 October 2002. Opinions expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. DIABETES CARE

Genome-Wide Scan for Estimated Glomerular Filtration Rate in Multi-Ethnic Diabetic Populations The Family Investigation of Nephropathy and Diabetes (FIND) Jeffrey R. Schelling , Hanna E. Abboud , Susanne B. Nicholas , Madeleine V. Pahl , John R. Sedor , Sharon G. Adler , Nedal H. Arar , Donald W. Bowden , Robert C. Elston , Barry I. Freedman , Katrina A.B. Goddard , Xiuqing Guo , Robert L. Hanson , Eli Ipp , Sudha K. Iyengar , Gyungah Jun , W.H. Linda Kao , Balakuntalam S. Kasinath , Paul L. Kimmel , Michael J. Klag , William C. Knowler , Robert G. Nelson , Rulan S. Parekh , Shannon R. Quade , Stephen S. Rich , Mohammed F. Saad , Marina Scavini , Michael W. Smith , Kent Taylor , Cheryl A. Winkler , Philip G. Zager , Vallabh O. Shah and on behalf of the Family Investigation of Nephropathy and Diabetes Research Group * Address correspondence and reprint requests to Dr. Sudha Iyengar, Department of Epidemiology and Biostatistics, Case Western Reserve University, Wolstein Research Building, Rm. 1300, 10900 Euclid Ave., Cleveland, OH 44106-7281. E-mail: ski{at}case.edu Abstract OBJECTIVE— Diabetic nephropathy, the most common cause of end-stage renal disease, aggregates in families and specific ethnic groups. Deconstructing diabetic nephropathy into intermediate, quantitative phenotypes may increase feasibility of detecting susceptibility loci by genetic screens. Glomerular filtration rate (GFR), which characterizes diabetic nephropathy, was employed as a quantitative trait in a preliminary whole-genome scan. RESEARCH DESIGN AND METHODS— Estimated GFR (eGFR) was calculated for 882 diabetic sibpairs (mean age 57 years) of African-American (25.6% of total), American Indian (8.6%), European-American (14.2%), and Mexican-American (51.6%) descent enrolled in the initial phase of the Family Investigation of Nephropathy and Diabetes (FIND). A whole-genome scan was performed using 404 microsatellite markers (average spacing 9 cM) and model-free linkage analysis. RESULTS— For all ethnicities combined, strong evidence for linkage was observed on chromosomes 1q43 ( P = 3.6 × 10 −3 ), 7q36.1 ( P = 2.1 × 10 −4 ), 8q13.3 ( P = 4.6 × 10 −4 ), and 18q23.3 ( P = 2.7 × 10 −3 ). Mexican-American families, who comprised the major ethnic subpopulation in FIND, contributed to linkage on chromosomes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, whereas African-American and American-Indian families displayed linkage peaks on chromosomes 11p15.1 and 15q22.3, respectively. CONCLUSIONS— We have demonstrated multiple chromosomal regions linked to eGFR in a multi-ethnic collection of families ascertained by a proband with diabetic nephropathy. Identification of genetic variants within these loci that are responsible for the linkage signals could lead to predictive tests or novel therapies for subsets of patients at risk for diabetic nephropathy. ARB, angiotensin receptor blocker CKD, chronic kidney diseases eGFR, estimated glomerular filtration rate ESRD, end-stage renal disease FIND, Family Investigation of Nephropathy and Diabetes GFR, glomerular filtration rate IBD, identity by descent LOD, logarithm of odds MDRD, Modification of Diet in Renal Disease Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on. DOI: 10.2337/db07-0313. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0313 . * * A complete list of members of the Family Investigation of Nephropathy and Diabetes Research Group and their respective affiliations can be found in the appendix . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 8, 2007. Received March 14, 2007. DIABETES

Background: Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. Methods: A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. Results: Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10 –5 , LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. Conclusion: These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.

Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR. Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula. The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4x10.sup.-5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5x10.sup.-4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5x10.sup.-4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.

BackgroundPrevious studies have shown that the assessment of Doppler mitral flow velocity (DMFV) curves can be used to predict prognosis owing to left ventricular (LV) diastolic dysfunction in certain specific diseases. Our aim was to study whether the prognostic value of DMFV curves is affected by the many end-stage renal disease factors, such as chronic uremia and long-term hemodialysis (HD), which cause LV diastolic dysfunction and death.MethodsRetrospective echo Doppler studies obtained 10 to 12 hours after HD in 90 patients (52 males; mean age, 56 years) were analyzed to determine changes in deceleration time (DT) of the early mitral filling wave (E) and the ratio of E to the atrial velocity (A). The study findings (n = 83) showed 2 groups of DT: long DT (DT > 240 milliseconds) and normal/short DT (DT ≤ 240 milliseconds). Continuous variables of LV size using internal dimensions, systolic function using ejection fraction, hypertrophy using wall thickness and mass, and pulmonary hypertension and E/A were compared between the 2 groups.ResultsPatients with long DT versus normal/short DT had lower absolute and indexed LV mass (P = 0.03 and P = 0.02, respectively) and pulmonary hypertension (P ≤ 0.001), without a significant difference in LV systolic function or E/A. The mortality rate, adjusted for age and sex, was lower with long DT versus normal/short DT, with a hazard ratio of death, 0.44 (95% confidence interval, 0.23-0.86, P = 0.02).ConclusionsOur study identified characteristics of DMFV curves in patients on long-term HD, which are clearly of value in predicting outcomes and survival in these patients.