Polypharmacy and mortality association by chronic kidney disease status: The REasons for Geographic And Racial Differences in Stroke Study.

Many Americans take multiple medications simultaneously (polypharmacy). Polypharmacy's effects on mortality are uncertain. We endeavored to assess the association between polypharmacy and mortality in a large U.S. cohort and examine potential effect modification by chronic kidney disease (CKD) status. The REasons for Geographic And Racial Differences in Stroke cohort data (n = 29 627, comprised of U.S. black and white adults) were used. During a baseline home visit, pill bottle inspections ascertained medications used in the previous 2 weeks. Polypharmacy status (major [≥8 ingredients], minor [6-7 ingredients], and none [0-5 ingredients]) was determined by counting the total number of generic ingredients. Cox models (time-on-study and age-time-scale methods) assessed the association between polypharmacy and mortality. Alternative models examined confounding by indication and possible effect modification by CKD. Over 4.9 years median follow-up, 2538 deaths were observed. Major polypharmacy was associated with increased mortality in all models, with hazard ratios and 95% confidence intervals ranging from 1.22 (1.07-1.40) to 2.35 (2.15-2.56), with weaker associations in more adjusted models. Minor polypharmacy was associated with mortality in some, but not all, models. The polypharmacy-mortality association did not differ by CKD status. While residual confounding by indication cannot be excluded, in this large American cohort, major polypharmacy was consistently associated with mortality.

Discovery of a Potent and Selective Covalent p300/CBP Inhibitor.

Aberrant gene activation driven by the histone acetyltransferases p300 and CREB binding protein (CBP) has been linked to several diseases, including cancers. Because of this, many efforts have been aimed toward the targeting of the closely related paralogues, p300 and CBP, but these endeavors have been exclusively directed toward noncovalent inhibitors. X-ray crystallography of A-485 revealed that both p300 and CBP possess a cysteine (C1450) near the active site, thus rendering covalent inhibition an attractive chemical approach. Herein we report the development of compound 2, an acrylamide-based inhibitor of p300/CBP that forms a covalent adduct with C1450. We demonstrated using mass spectrometry that compound 2 selectively targets C1450, and we also validated covalent binding using kinetics experiments and cellular washout studies. The discovery of covalent inhibitor 2 gives us a unique tool for the study of p300/CBP biology.

Outcomes in Hepatocellular Carcinoma Liver Transplantation before and after the Mandated Six-Month Wait Time.

The United Network for Organ Sharing (UNOS) implemented a policy that requires patients with hepatocellular carcinoma seeking liver transplantation to wait six months before being granted Model for End-Stage Liver Disease exception points. We investigated the difference in resource utilization between patients who underwent liver transplantation before and after the present policy. We conducted a retrospective cohort study of adult liver transplants from 2013 to 2018. Patients were classified into prepolicy or postpolicy groups based on 964 days before or after the wait-time policy. We also retrieved national survival outcome data from United Network for Organ Sharing. Differences across compared groups for continuous variables were assessed using the independent sample t test, and the chi-squared test was used for binary variables. We found statistical differences in recipient age (P = 0.005), days on wait-list (P = 0.001), sustained virological response (P < 0.001), and hepatocellular carcinoma recurrence one year posttransplant (P = 0.04). There were statistically significant differences in the number of treatment days pretransplant and length of transplant admission stay, indicating an increase in resource utilization in the postpolicy group. No statistically significant differences were found between groups in one-year graft or patient survival despite an observed increase in resource utilization by the hepatocellular carcinoma postpolicy group.

Differences in Risk of Sudden Cardiac Death Between Blacks and Whites.

BACKGROUND: Prior studies have consistently demonstrated that blacks have an approximate 2-fold higher incidence of sudden cardiac death (SCD) than whites; however, these analyses have lacked individual-level sociodemographic, medical comorbidity, and behavioral health data. OBJECTIVES: The purpose of this study was to evaluate whether racial differences in SCD incidence are attributable to differences in the prevalence of risk factors or rather to underlying susceptibility to fatal arrhythmias. METHODS: The Reasons for Geographic and Racial Differences in Stroke study is a prospective, population-based cohort of adults from across the United States. Associations between race and SCD defined per National Heart, Lung, and Blood Institute criteria were assessed. RESULTS: Among 22,507 participants (9,416 blacks and 13,091 whites) without a history of clinical cardiovascular disease, there were 174 SCD events (67 whites and 107 blacks) over a median follow-up of 6.1 years (interquartile range: 4.6 to 7.3 years). The age-adjusted SCD incidence rate (per 1,000 person-years) was higher in blacks (1.8; 95% confidence interval [CI]: 1.4 to 2.2) compared with whites (0.7; 95% CI: 0.6 to 0.9), with an unadjusted hazard ratio of 2.35; 95% CI: 1.74 to 3.20. The association of black race with SCD risk remained significant after adjustment for sociodemographics, comorbidities, behavioral measures of health, intervening cardiovascular events, and competing risks of non-SCD mortality (hazard ratio: 1.97; 95% CI: 1.39 to 2.77). CONCLUSIONS: In a large biracial population of adults without a history of cardiovascular disease, SCD rates were significantly higher in blacks as compared with whites. These racial differences were not fully explained by demographics, adverse socioeconomic measures, cardiovascular risk factors, and behavioral measures of health.

Dietary Oxidative Balance Scores and Biomarkers of Inflammation among Individuals with and without Chronic Kidney Disease.

BACKGROUND: Oxidative stress and inflammation are proposed mechanisms of nonspecific kidney injury and progressive kidney failure. Higher dietary oxidative balance scores (OBS) are associated with lower prevalence of chronic kidney disease (CKD). METHODS: We investigated the association between OBS and biomarkers of inflammation using data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Nutrient estimates from the Block Food Frequency Questionnaires were used to define tertiles of 11 pro- and antioxidant factors. Points for each OBS component were summed, with a higher score indicating predominance of antioxidant exposures. Multivariable linear regression models were used to estimate the association between OBS and biomarkers of inflammation (interleukin-6 [IL-6], interleukin-8 [IL-8], interleukin-10 [IL-10], fibrinogen, C-reactive protein [CRP], white blood cell count, and cystatin C). An interaction term was included to determine if associations between OBS and inflammatory markers differed between individuals with and without CKD. RESULTS: Of 682 participants, 22.4% had CKD. In adjusted models, OBS was associated with CRP and IL-6. For every 5-unit increase in OBS, the CRP concentration was -15.3% lower (95% CI: -25.6, -3.6). The association of OBS with IL-6 differed by CKD status; for every 5-unit increase in OBS, IL-6 was -10.7% lower (95% CI: -16.3, -4.7) among those without CKD, but there was no association among those with CKD (p = 0.03). CONCLUSION: This study suggests that a higher OBS is associated with more favorable levels of IL-6 and CRP, and that the association of OBS and IL-6 may be modified by CKD status.

County-level air quality and the prevalence of diagnosed chronic kidney disease in the US Medicare population.

BACKGROUND: Considerable geographic variation exists in the prevalence of chronic kidney disease across the United States. While some of this variability can be explained by differences in patient-level risk factors, substantial variability still exists. We hypothesize this may be due to understudied environmental exposures such as air pollution. METHODS: Using data on 1.1 million persons from the 2010 5% Medicare sample and Environmental Protection Agency air-quality measures, we examined the association between county-level particulate matter ≤2.5 µm (PM2.5) and the prevalence of diagnosed CKD, based on claims. Modified Poisson regression was used to estimate associations (prevalence ratios [PR]) between county PM2.5 concentration and individual-level diagnosis of CKD, adjusting for age, sex, race/ethnicity, hypertension, diabetes, and urban/rural status. RESULTS: Prevalence of diagnosed CKD ranged from 0% to 60% by county (median = 16%). As a continuous variable, PM2.5 concentration shows adjusted PR of diagnosed CKD = 1.03 (95% CI: 1.02-1.05; p<0.001) for an increase of 4 µg/m3 in PM2.5. Investigation by quartiles shows an elevated prevalence of diagnosed CKD for mean PM2.5 levels ≥14 µg/m3 (highest quartile: PR = 1.05, 95% CI: 1.03-1.07), which is consistent with current ambient air quality standard of 12 µg/m3, but much lower than the level typically considered healthy for sensitive groups (~40 µg/m3). CONCLUSION: A positive association was observed between county-level PM2.5 concentration and diagnosed CKD. The reliance on CKD diagnostic codes likely identified associations with the most severe CKD cases. These results can be strengthened by exploring laboratory-based diagnosis of CKD, individual measures of exposure to multiple pollutants, and more control of confounding.

Pre-ESRD Care and Mortality in Incident ESRD Patients With Multiple Myeloma.

OBJECTIVES: The relationship between mortality and pre-ESRD (end-stage renal disease) nephrology care in incident ESRD patients with multiple myeloma (MM) as the primary cause of renal failure has not been examined. MATERIALS AND METHODS: Among 439,206 incident US hemodialysis patients with MM as the primary cause of ESRD (June 1, 2005 to May 31, 2009) identified using the US Renal Data System, adjusted odds ratios (OR) for reported pre-ESRD nephrology care for ESRD due to MM (n=4561) versus other causes (n=434,645) were calculated. The association of pre-ESRD nephrology care with subsequent mortality in MM-ESRD patients was examined. RESULTS: MM-ESRD patients were less likely to have any predialysis nephrology care in the year before initiation of dialysis (34.8% vs. 58.5%; OR=0.38; 95% confidence interval [CI], 0.34-0.43) compared with patients with ESRD due to other causes. MM-ESRD patients compared with others were more likely to have catheters on first dialysis (91.8% vs. 75.6%; OR=4.15; 95% CI, 3.54-4.86). Incident MM-ESRD patients receiving predialysis care for ≥6 months had significantly lower 1-year mortality (hazard ratio 0.89; 95% CI, 0.82-0.97 and 0.88; 95% CI, 0.80-0.96, respectively), relative to those without this care. A catheter for dialysis access was associated with a 1.6-fold increase in 1-year mortality in incident MM-ESRD (hazard ratio 1.55; 95% CI, 1.32-1.83). CONCLUSIONS: MM-ESRD patients were less likely to have predialysis nephrology care and more likely to use catheters on first dialysis. However, predialysis care is independently associated with lower mortality in MM-ESRD patients. Predialysis care should be prioritized in MM patients approaching ESRD.

Serum albumin concentration and risk of end-stage renal disease: the REGARDS study.

Background: Serum albumin concentration is a commonly available biomarker with prognostic value in many disease states. It is uncertain whether serum albumin concentrations are associated with incident end-stage renal disease (ESRD) independently of urine albumin-to-creatinine ratio (ACR). Methods: A longitudinal evaluation was performed of a population-based community-living cohort from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Participants were ≥45 years of age at study entry and had serum albumin, creatinine, cystatin C and spot urine ACR measured at the baseline visit (n = 19 633). Estimated glomerular filtration rate (eGFR) was from the Chronic Kidney Disease Epidemiology Collaboration combined creatinine-cystatin C equation. Baseline serum albumin concentration was the predictor variable, and hazard ratios (HRs) for incident ESRD (from US Renal Data System linkage) were calculated in sequentially adjusted models. Results: Age at study entry was 63.9 ± 9.7 years, 62% of the participants were female and 40% were black. Mean eGFR at baseline was 83.3 ± 20.8 mL/min/1.73 m2. Over a median 8-year follow-up, 1.2% (n = 236) developed ESRD. In models adjusted for baseline eGFR, ACR and other ESRD risk factors, the HR for incident ESRD was 1.16 [95% confidence interval (CI) 1.01-1.33] for each standard deviation (0.33 g/dL) lower serum albumin concentration. The HR comparing the lowest (<4 g/dL) and highest quartiles (≥4.4 g/dL) of serum albumin was 1.61 (95% CI 0.98-2.63). Results were qualitatively similar among participants with eGFR <60 and ≥60 mL/min/1.73 m2, and those with and without diabetes. Conclusions: In community-dwelling US adults, lower serum albumin concentration is associated with higher risk of incident ESRD independently of baseline urine ACR, eGFR and other ESRD risk factors.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 µM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

Older Patients' Perspectives on Managing Complexity in CKD Self-Management.

BACKGROUND AND OBJECTIVES: Patients with CKD are asked to perform self-management tasks including dietary changes, adhering to medications, avoiding nephrotoxic drugs, and self-monitoring hypertension and diabetes. Given the effect of aging on functional capacity, self-management may be especially challenging for older patients. However, little is known about the specific challenges older adults face maintaining CKD self-management regimens. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an exploratory qualitative study designed to understand the relationship among factors facilitating or impeding CKD self-management in older adults. Six focus groups (n=30) were held in August and September of 2014 with veterans≥70 years old with moderate-to-severe CKD receiving nephrology care at the Atlanta Veterans Affairs Medical Center. Grounded theory with a constant comparative method was used to collect, code, and analyze data. RESULTS: Participants had a mean age (range) of 75.1 (70.1-90.7) years, 60% were black, and 96.7% were men. The central organizing concept that emerged from these data were managing complexity. Participants typically did not have just one chronic condition, CKD, but a number of commonly co-occurring conditions. Recommendations for CKD self-management therefore occurred within a complex regimen of recommendations for managing other diseases. Participants identified overtly discordant treatment recommendations across chronic conditions (e.g., arthritis and CKD). Prioritization emerged as one effective strategy for managing complexity (e.g., focusing on BP control). Some patients arrived at the conclusion that they could group concordant recommendations to simplify their regimens (e.g., protein restriction for both gout and CKD). CONCLUSIONS: Among older veterans with moderate-to-severe CKD, multimorbidity presents a major challenge for CKD self-management. Because virtually all older adults with CKD have multimorbidity, an integrated treatment approach that supports self-management across commonly occurring conditions may be necessary to meet the needs of these patients.

Evaluating Risk Factors for Clostridium difficile Infection In Stem Cell Transplant Recipients: A National Study.

OBJECTIVE Large-scale studies evaluating risk factors for Clostridium difficile infection (CDI), a leading cause of infectious diarrhea among patients undergoing stem cell transplantation (SCT), are lacking. We have evaluated risk factors for CDI among both autologous SCT (auto-SCT), and allogeneic SCT (allo-SCT) recipients using the National Inpatient Sample (NIS) database provided by the Healthcare Cost and Utilization Project (HCUP). METHODS We used patient data obtained from the NIS database for all adult patients admitted for auto- and allo-SCTs from January 2001 to December 2010. We performed multivariate logistic regression analyses to evaluate risk factors of CDI in auto- and allo-SCT patients. RESULTS Auto-SCTs constituted 61.5% of all SCTs performed during the study period. Of the 53,072 auto-SCT patients, 5.8% had CDI, whereas 8.5% of 33,189 allo-SCT patients had CDI. Univariate analyses identified age, gender, indication for SCT, radiation as part of the conditioning regimen, respiratory failure, septicemia, lengthy hospital stay, and multiple comorbidities as risk factors for CDI in both subsets. On multivariate analyses for auto-SCT, there was significant correlation between age and the indication for transplant (P=.003), but the indication for either auto- or allo-SCT was not associated with CDI on multivariate analyses. The following factors were found to be associated with CDI: septicemia (auto-SCT odds ratio [OR],=1.64; 95% confidence interval [CI], 1.35-2; and allo-SCT OR, 1.69; 95% CI, 1.36-2.1), male gender (auto-SCT OR, 1.29; 95% CI, 1.09-1.53; and allo-SCT OR, 1.36; 95% CI, 1.18-1.57), lengthy hospital stay (auto-SCT OR, 2.81; 95% CI, 2.29-3.45; and allo-SCT OR, 2.63; 95% CI, 2.15-3.22), and presence of multiple comorbidities (auto-SCT OR, 1.32; 95% CI, 1.11-1.57; and allo-SCT OR, 1.18; 95% CI, 1.0-1.4). CONCLUSIONS The prevalence of CDI was higher among patients undergoing allo-SCT. CDI was significantly associated with longer hospital stay, septicemia, and male gender for auto- and allo-SCT recipients. While this analysis did not permit us to directly ascribe the associations to be causative for CDI, it identifies the more vulnerable population for CDI and provides a rationale for the development of more effective approaches to preventing CDI. Infect Control Hosp Epidemiol 2017;38:651-657.

Sickle Cell Trait and the Risk of ESRD in Blacks.

Blacks, compared with whites, have an increased risk of progression to end-stage renal disease (ESRD). Emerging evidence suggests that, in addition to APOL1 high-risk genotypes, hemoglobin variants, including sickle cell trait (SCT) and hemoglobin C trait, have a role in kidney disease in blacks. However, the association between these hemoglobin traits and ESRD remains unknown. In a large population-based cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we evaluated 9909 self-reported blacks (739 with SCT and 243 with hemoglobin C trait). Incident ESRD occurred in 40 of 739 (5.4%) individuals with SCT, six of 243 (2.5%) individuals with hemoglobin C trait, and 234 of 8927 (2.6%) noncarriers. The incidence rate for ESRD was 8.5 per 1000 person-years for participants with SCT and 4.0 per 1000 person-years for noncarriers. Compared with individuals without SCT, individuals with SCT had a hazard ratio for ESRD of 2.03 (95% confidence interval, 1.44 to 2.84). Hemoglobin C trait did not associate with prevalent CKD or ESRD. The incidence rate for ESRD among participants with APOL1 high-risk genotypes was 6.6 per 1000 person-years, with a hazard ratio for ESRD of 1.77 (95% confidence interval, 1.31 to 2.38) for participants with, compared with those without, APOL1 high-risk genotypes. In this cohort, SCT strongly associated with risk of progression to ESRD in blacks, and this degree of risk for ESRD was similar to that conferred by APOL1 high-risk genotypes. These results may have important public policy implications for genetic counseling of SCT carriers.

Oxidative Balance Score and the Risk of End-Stage Renal Disease and Cardiovascular Disease.

BACKGROUND: Oxidative balance score (OBS) is a composite measure of oxidative stress-related exposures. The aim of this study was to investigate the association between OBS, end-stage renal disease (ESRD), and cardiovascular disease (CVD). METHODS: Using data from the Chronic Renal Insufficiency Cohort, we calculated the main exposure OBS by summing up 12 apriori-defined pro- and antioxidant factors obtained from the diet history questionnaire and lifestyle assessment. We divided OBS into quartiles (Q1-Q4), with Q1 (predominance of pro-oxidants) as the reference. We analyzed OBS quartiles as an ordinal variable. Crude and adjusted hazards ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models for time to ESRD and CVD. RESULTS: Compared to Q1, Q4 (high antioxidant) was associated with ESRD in the crude model (HR 1.35, 95% CI 1.08-1.69) and adjusting for age, sex, and race (HR 1.36, 95% CI 1.09-1.71) but not in the fully adjusted model (HR 1.12, 95% CI 0.84-1.51). HR of ESRD increased as the OBS quartiles increased in the crude model (ptrend < 0.05) but not in the fully adjusted model (ptrend = 0.30). Compared to Q1, Q4 was associated with CVD in the crude (HR 1.33, 95% CI 1.06-1.68) but not adjusted models. The HR of CVD increased with an increase in OBS quartiles in the crude model (ptrend < 0.05). CONCLUSION: The reverse association between OBS and progression to ESRD suggests that perhaps the effect of oxidative balance-related exposure is different in the setting of established chronic kidney disease.

The association between cytomegalovirus infection, obesity, and metabolic syndrome in U.S. adult females.

OBJECTIVE: The purpose of this analysis was to determine whether cytomegalovirus (CMV) infection is associated with the prevalence of metabolic syndrome (MetS) and whether this relationship differs by BMI. METHODS: Data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) were pooled (N = 2,532). Logistic regression was used for assessing the association between CMV and MetS, stratified by gender and BMI, categorized as normal weight, overweight, obesity, and extreme obesity, and adjusted for age, race/ethnicity, and poverty level. RESULTS: In unadjusted analyses, CMV infection was significantly associated with MetS in females (OR: 1.50; 95% CI: 1.1-2.1) but not males. After adjusting for confounders, the odds of MetS were higher in CMV+ normal-weight females (aOR: 65.31; 95% CI: 6.8-625.6) but lower in CMV+ females with extreme obesity (aOR: 0.25; 95% CI: 0.1-0.9). CMV infection was associated with higher high-density lipoprotein cholesterol (HDL-C) and lower triglycerides in females with extreme obesity but lower HDL-C in normal-weight females. CONCLUSIONS: CMV infection was found to be associated with unique MetS phenotypes that differ between BMI categories and gender. Seropositive normal-weight females had a higher prevalence of MetS and dyslipidemia, while infection in females with extreme obesity was associated with a more metabolically benign profile.

ESRD Databases, Public Policy, and Quality of Care: Translational Medicine and Nephrology.

Efforts to improve care of patients with ESRD and the policies that guide those activities depend on evidence-based best practices derived from clinical trials and carefully conducted observational studies. Our review describes this process in the context of the translational research model (bench to bedside to populations), with a particular emphasis on bedside care. We illustrate some of its accomplishments and describe the limitations of the data and evidence supporting policy and practice.

Albuminuria, kidney function, and sudden cardiac death: Findings from The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

BACKGROUND: Moderate-to-severe kidney disease increases risk for sudden cardiac death (SCD). Limited studies have evaluated how mild degrees of kidney dysfunction impact SCD risk. OBJECTIVE: The purpose of this study was to evaluate the association of albuminuria, which is one of the earliest biomarkers of kidney injury, and SCD. METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a prospective, population-based cohort of U.S. adults. Associations between albuminuria, which is categorized using urinary albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and SCD were assessed independently and in combination. RESULTS: After median follow-up of 6.1 years, we identified 335 SCD events. Compared to participants with ACR <15 mg/g, those with higher levels had an elevated adjusted risk of SCD (ACR 15-30 mg/g, hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.11-2.11; ACR >30 mg/g, HR 1.56, 95% CI 1.17-2.11). In contrast, compared to the group with eGFR >90 mL/min/1.73 m2, the adjusted risk of SCD was significantly elevated only among those with eGFR <45 mL/min/1.73 m2 (HR 1.66, 95% CI 1.06-2.58). The subgroup with eGFR <45 mL/min/1.73 m2 (n = 1003) comprised 3.7% of REGARDS, whereas ACR 15-30 mg/g (n = 3089 [11.3%]) and ACR >30 mg/g (n = 4040 [14.8%] were far more common. In the analysis that combined ACR and eGFR categories, albuminuria consistently identified individuals with eGFR ≥60 mLmin/1.73 m2 who were at significantly increased SCD risk. CONCLUSION: Low levels of kidney injury as measured by ACR predict an increase in SCD risk.

A Randomized Trial to Reduce Disparities in Referral for Transplant Evaluation.

Georgia has the lowest kidney transplant rates in the United States and substantial racial disparities in transplantation. We determined the effectiveness of a multicomponent intervention to increase referral of patients on dialysis for transplant evaluation in the Reducing Disparities in Access to kidNey Transplantation Community Study (RaDIANT), a randomized, dialysis facility-based, controlled trial involving >9000 patients receiving dialysis from 134 dialysis facilities in Georgia. In December of 2013, we selected dialysis facilities with either low transplant referral or racial disparity in referral. The intervention consisted of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients conducted from January to December of 2014. We examined the proportion of patients with prevalent ESRD in each facility referred for transplant within 1 year as the primary outcome, and disparity in the referral of black and white patients as a secondary outcome. Compared with control facilities, intervention facilities referred a higher proportion of patients for transplant at 12 months (adjusted mean difference [aMD], 7.3%; 95% confidence interval [95% CI], 5.5% to 9.2%; odds ratio, 1.75; 95% CI, 1.36 to 2.26). The difference between intervention and control facilities in the proportion of patients referred for transplant was higher among black patients (aMD, 6.4%; 95% CI, 4.3% to 8.6%) than white patients (aMD, 3.7%; 95% CI, 1.6% to 5.9%; P<0.05). In conclusion, this intervention increased referral and improved equity in kidney transplant referral for patients on dialysis in Georgia; long-term follow-up is needed to determine whether these effects led to more transplants.

Association of Multimorbidity with Mortality and Healthcare Utilization in Chronic Kidney Disease.

OBJECTIVES: Chronic kidney disease (CKD) almost universally occurs in individuals with other medical problems. However, few studies have described CKD-related multimorbidity using a framework that identifies chronic conditions as concordant (having overlap in treatment goals) versus discordant (having opposing treatment recommendations) and unrelated (having no overlap, but contributing to complexity via different resource requirements). DESIGN: Retrospective cohort. SETTING: Veterans Affairs (VA) Medical Centers. PARTICIPANTS: VA patients (n = 821,334) ages 18-100 years with at least one outpatient visit and incident CKD defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 for at least 3 months between January 1, 2005 and December 31, 2008 after excluding prevalent CKD. MEASUREMENTS: We determined the associations of number of chronic conditions (1, 2, 3, 4, 5, 6 or more) stratified by the presence of one or more discordant/unrelated conditions with mortality, hospitalizations and emergency department (ED) visits. RESULTS: There were 381,187 deaths over 6.8 median years of follow-up. Higher risks of death, hospitalization and ED visits were associated with higher number of chronic conditions, among those with and without discordant/unrelated conditions. However, the magnitudes of the associations were consistently larger when at least one discordant/unrelated condition was present. For example, compared to patients with one concordant condition, patients with six or more concordant conditions had an age-, race- and sex-adjusted hazard ratio (HR) for mortality of 1.72 (95% CI 1.64-1.80) whereas those with six or more conditions, at least one of which was discordant/unrelated, had a HR of 2.05 (2.01-2.09) (P-interaction <0.001). CONCLUSIONS: The presence of one or more discordant/unrelated conditions was associated with increased risk for adverse health outcomes, beyond the effect of multimorbidity.

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

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.

Flavanone Intake Is Inversely Associated with Risk of Incident Ischemic Stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

BACKGROUND: Flavonoids may have beneficial cerebrovascular effects, but evidence from racially and geographically representative cohorts in comprehensive flavonoid databases is lacking. Given racial and geographic disparities in stroke incidence, representative cohort studies are needed. OBJECTIVES: We evaluated the association between flavonoid intake and incident ischemic stroke in a biracial, national cohort using updated flavonoid composition tables and assessed differences in flavonoid intake by sex, race, and region of residence. METHODS: We evaluated 20,024 participants in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a biracial prospective study. Participants with stroke history or missing dietary data were excluded. Flavonoid intake was estimated by using a Block98 food frequency questionnaire and the USDA's Provisional Flavonoid Addendum and Proanthocyanidin Database. Associations between quintiles of flavonoid intake and incident ischemic stroke were evaluated by using Cox proportional hazards models, adjusting for confounders. RESULTS: Over 6.5 y, 524 acute ischemic strokes occurred. Flavanone intake was lower in the Southeastern United States but higher in blacks than in whites. After multivariable adjustment, flavanone intake was inversely associated with incident ischemic stroke (HR: 0.72; 95% CI: 0.55, 0.95; P-trend = 0.03). Consumption of citrus fruits and juices was inversely associated with incident ischemic stroke (HR: 0.69; 95% CI: 0.53, 0.91; P-trend = 0.02). Total flavonoids and other flavonoid subclasses were not associated with incident ischemic stroke. There was no statistical interaction with sex, race, or region for any flavonoid measure. CONCLUSIONS: Greater consumption of flavanones, but not total or other flavonoid subclasses, was inversely associated with incident ischemic stroke. Associations did not differ by sex, race, or region for the association; however, regional differences in flavanone intake may contribute to regional disparities in ischemic stroke incidence. Higher flavanone intake in blacks suggests that flavanone intake is not implicated in racial disparities in ischemic stroke incidence.