Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusions: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD. Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Positive Psychological Intervention Delivered Using Virtual Reality in Patients on Hemodialysis With Comorbid Depression: Protocol and Design for the Joviality Randomized Controlled Trial.

BACKGROUND: Depression is highly prevalent in individuals on hemodialysis, but it is infrequently identified and remains undertreated. In this paper, we present details of the methodology of a randomized controlled trial (RCT) aimed at testing the feasibility and preliminary efficacy of a 5-week positive psychological intervention in individuals on hemodialysis with comorbid depression delivered using immersive virtual reality (VR) technology. OBJECTIVE: We aim to describe the protocol and design of the Joviality trial whose main objectives are 2-fold: determine the feasibility of the Joviality VR software through metrics capturing rates of recruitment, refusal, retention, noncompliance, and adherence, as well as end-user feedback; and assess preliminary efficacy for outcomes measures of depressive symptoms, psychological well-being and distress, quality of life, treatment adherence, clinical biomarkers, and all-cause hospitalizations. METHODS: This 2-arm RCT is scheduled to enroll 84 individuals on hemodialysis with comorbid depression from multiple outpatient centers in Chicago, Illinois, United States. Enrollees will be randomized to the following groups: VR-based Joviality positive psychological intervention or sham VR (2D wildlife footage and nature-based settings with inert music presented using a head-mounted display). To be eligible, individuals must be on hemodialysis for at least 3 months, have Beck Depression Inventory-II scores of ≥11 (ie, indicative of mild-to-severe depressive symptoms), be aged ≥21 years, and be fluent in English or Spanish. The Joviality VR software was built using agile design principles and incorporates fully immersive content, digital avatars, and multiplex features of interactability. Targeted skills of the intervention include noticing positive events, positive reappraisal, gratitude, acts of kindness, and mindful or nonjudgmental awareness. The primary outcomes include metrics of feasibility and acceptability, along with preliminary efficacy focused on decreasing symptoms of depression. The secondary and tertiary outcomes include quality of life, treatment adherence, clinical biomarkers, and all-cause hospitalization rates. There are 4 assessment time points: baseline, immediately after the intervention, 3 months after the intervention, and 6 months after the intervention. We hypothesize that depressive symptoms and hemodialysis-related markers of disease will substantially improve in participants randomized to the VR-based Joviality positive psychology treatment arm compared with those in the attention control condition. RESULTS: This RCT is funded by the National Institute of Diabetes and Digestive and Kidney Diseases and is scheduled to commence participant recruitment in June 2023. CONCLUSIONS: This trial will be the first to test custom-built VR software to deliver a positive psychological intervention, chairside, in individuals on hemodialysis to reduce symptoms of depression. Within the context of an RCT using an active control arm, if proven effective, VR technology may become a potent tool to deliver mental health programming in clinical populations during their outpatient treatment sessions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05642364; https://clinicaltrials.gov/ct2/show/NCT05642364. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45100.

Immune response to the mRNA COVID-19 vaccine in hemodialysis patients: cohort study.

Background: End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines. Methods: A transcriptomic analysis of the immune response to the Covid-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells (PBMCs) was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and seven days after the second dose (V2D7) using anti-Spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified six months after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response. Results: Transcriptomic analyses demonstrated differing time courses of immune responses, with predominant T cell activity in controls one week after the first vaccination dose, compared to predominant myeloid cell activity in HD at this time point. HD demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p < 0.05). Anti-spike IgG remained elevated above baseline at six months in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development. Conclusion: Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance hemodialysis subjects (HD) comparable to healthy controls (HC) and identify transcriptomic and clinical predictors of anti-Spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of end stage renal disease (ESRD). Funding: F30HD102093, F30HL151182, T32HL144909, R01HL138628This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.

Aspirin for Primary and Secondary Prevention of Mortality, Cardiovascular Disease, and Kidney Failure in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale and Objective: Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study. Study Design: Prospective observational cohort. Setting & Participants: 3,664 Chronic Renal Insufficiency Cohort participants. Exposure: Aspirin use in patients with and without preexisting CVD. Outcomes: Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding. Analytical Approach: Intention-to-treat analysis and multivariable Cox proportional hazards model to examine associations of time varying aspirin use. Results: The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57 ± 11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45 mL/min/1.73 m2. Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P = 0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P = 0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P = 0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin. Limitations: This is not a randomized controlled trial, and therefore, causality cannot be determined. Conclusions: Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding.

Emergency Department/Urgent Care as Usual Source of Care and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort Study.

Rationale & Objective: Having a usual source of care increases use of preventive services and is associated with improved survival in the general population. We evaluated this association in adults with chronic kidney disease (CKD). Study Design: Prospective, observational cohort study. Setting & Participants: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictor: Usual source of care was self-reported as: 1) clinic, 2) emergency department (ED)/urgent care, 3) other. Outcomes: Primary outcomes included incident end-stage kidney disease (ESKD), atherosclerotic events (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, hospitalization events, and all-cause death. Analytical Approach: Multivariable regression analyses to evaluate the association between usual source of care (ED/urgent care vs clinic) and primary outcomes. Results: Among 3,140 participants, mean age was 65 years, 44% female, 45% non-Hispanic White, 43% non-Hispanic Black, and 9% Hispanic, mean estimated glomerular filtration rate 50 mL/min/1.73 m2. Approximately 90% identified clinic as usual source of care, 9% ED/urgent care, and 1% other. ED/urgent care reflected a more vulnerable population given lower baseline socioeconomic status, higher comorbid condition burden, and poorer blood pressure and glycemic control. Over a median follow-up time of 3.6 years, there were 181 incident end-stage kidney disease events, 264 atherosclerotic events, 263 incident heart failure events, 288 deaths, and 7,957 hospitalizations. Compared to clinic as usual source of care, ED/urgent care was associated with higher risk for all-cause death (HR, 1.53; 95% CI, 1.05-2.23) and hospitalizations (RR, 1.41; 95% CI, 1.32-1.51). Limitations: Cannot be generalized to all patients with CKD. Causal relationships cannot be established. Conclusions: In this large, diverse cohort of adults with moderate-to-severe CKD, those identifying ED/urgent care as usual source of care were at increased risk for death and hospitalizations. These findings highlight the need to develop strategies to improve health care access for this high-risk population.

Atherosclerotic Cardiovascular Disease Events in Adults With CKD Taking a Moderate- or High-Intensity Statin: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guideline uses risk stratification to guide the decision to initiate nonstatin lipid-lowering medication among adults with atherosclerotic cardiovascular disease (CVD). We determined atherosclerotic CVD (ASCVD) event rates among adults with chronic kidney disease (CKD) taking statin therapy within 2018 AHA/ACC cholesterol guideline risk categories. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adults with CKD not on dialysis in the Chronic Renal Insufficiency Cohort (CRIC) study who were taking a moderate/high-intensity statin 1 year after enrollment (baseline for the current analysis, n = 1,753). EXPOSURE: 2018 AHA/ACC cholesterol guideline risk categories: without a history of ASCVD, a history of 1 major ASCVD event and multiple high-risk conditions, and a history of ≥2 major ASCVD events. OUTCOME: Adjudicated ASCVD events after the year 1 study visit. ANALYTICAL APPROACH: We calculated age-sex standardized rates for ASCVD events and age-sex adjusted hazard ratios for ASCVD events accounting for the competing risk of death. RESULTS: There were 394 ASCVD events over a median follow-up period of 8 years. The ASCVD event rates (with 95% CI) per 1,000 person-years among participants without a history of ASCVD, with a history of 1 major ASCVD event and multiple high-risk conditions, and with a history of ≥2 major ASCVD events were 21.7 (18.4-25.1), 45.0 (37.8-52.3), and 73.3 (53.3-93.4), respectively. Compared with participants without a history of ASCVD, the HR (95% CI) rates for ASCVD events among those with a history of 1 major ASCVD event and multiple high-risk conditions, and with a history of ≥2 major ASCVD events were 1.89 (1.52-2.36) and 2.50 (1.85-3.39), respectively. LIMITATIONS: Data on whether participants were taking a maximally tolerated statin dosage were unavailable. CONCLUSIONS: The 2018 AHA/ACC cholesterol guideline identifies adults with CKD who have very high ASCVD risk despite taking a moderate/high-intensity statin.

Mobile Health (mHealth) Technology: Assessment of Availability, Acceptability, and Use in CKD.

RATIONALE & OBJECTIVE: Digital and mobile health (mHealth) technologies improve patient-provider communication and increase information accessibility. We assessed the use of technology, attitudes toward using mHealth technologies, and proficiency in using mHealth technologies among individuals with chronic kidney disease (CKD). STUDY DESIGN: Cross-sectional survey with open text responses. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC) Study participants who completed current use and interest in using mHealth technologies questionnaires and the eHealth literacy Survey (eHEALS). EXPOSURE: Participant characteristics. OUTCOMES: Use of technology (ie, internet, email, smartphone, and mHealth applications [apps]), interest in future mHealth use, and proficiency in using digital and mHealth technologies, or eHealth literacy, determined by eHEALS score. ANALYTICAL APPROACH: Poisson regression and a qualitative content analysis of open-ended responses. RESULTS: Study participants (n = 932) had a mean age of 68 years old and an estimated glomerular filtration rate (eGFR) of 54 mL/min/1.73 m2, and 59% were male. Approximately 70% reported current use of internet, email, and smartphones, and 35% used mHealth apps; only 27% had adequate eHealth literacy (eHEALS score ≥ 32). Participants <65 years of age (vs. ≥65), with more education, higher income, better cognition, and adequate health literacy reported more use of technology, and greater interest in using technologies. Participants of White (vs. non-White) race reported more use of internet and email but less interest in future use of mHealth. Younger age, higher annual income, and greater disease self-efficacy were associated with adequate eHealth literacy. Three themes regarding interest in using digital and mHealth technologies emerged: willingness, concerns, and barriers. LIMITATIONS: Residual confounding, ascertainment bias. CONCLUSIONS: Many individuals with CKD currently use the internet and smartphones and are interested in using mHealth in the future, but few use mHealth apps or have adequate eHealth literacy. mHealth technologies present an opportunity to engage individuals with CKD, especially members of racial or ethnic minority groups because those groups reported greater interest in using mHealth technology than the nonminority population. Further research is needed to identify strategies to overcome inadequate eHealth literacy.

Prevalence, Awareness, and Treatment of Hypertension in Hispanics/Latinos With CKD in the Hispanic Community Health Study/Study of Latinos.

RATIONALE & OBJECTIVE: Lower rates of hypertension awareness, treatment, and control have been observed in Hispanics/Latinos compared with non-Hispanic whites. These factors have not been studied in Hispanics/Latinos with chronic kidney disease (CKD). We sought to describe the prevalence, awareness, treatment, and control of hypertension in Hispanic/Latino adults with CKD. STUDY DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: US.Hispanics/Latinos aged 18 to 74 years enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) with CKD. Comparisons were made with the National Health and Nutrition Examination Survey (NHANES) 2007 to 2010. EXPOSURE: CKD was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urinry albumin-creatinine ratio ≥ 30 mg/g creatinine. OUTCOMES: Hypertension was defined as systolic blood pressure (BP) ≥ 140 or diastolic BP ≥ 90 mm Hg or use of antihypertensives. For hypertension control, 2 thresholds were examined: <140/90 and <130/80 mm Hg. RESULTS: The prevalence of hypertension was 51.5%; among those with hypertension, hypertension awareness and treatment were present in 78.1% and 70.4%, respectively. A low prevalence of BP control was observed (32.6% with BP < 140/90 mm Hg; 17.9% with BP < 130/80 mm Hg). Health insurance coverage was associated with higher odds of BP < 140/90 mm Hg (OR, 1.98; 95% CI, 1.15-3.43). Compared with non-Hispanic whites with CKD in NHANES, HCHS/SOL participants with CKD had a lower prevalence of hypertension but a lower rate of BP control (32.6% vs 48.6% for BP < 140/90 mm Hg). LIMITATIONS: Use of a single measurement of creatinine, cystatin C, and urinary albumin excretion to define CKD. Single-visit measurement of BP. CONCLUSIONS: Hispanics/Latinos with CKD residing in the United States have very low rates of BP control. The association of health insurance coverage with hypertension control suggests that improved access to health care may improve outcomes for this growing population.

Incident Chronic Kidney Disease Risk among Hispanics/Latinos in the United States: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BACKGROUND: Although Hispanics/Latinos in the United States are often considered a single ethnic group, they represent a heterogenous mixture of ancestries who can self-identify as any race defined by the U.S. Census. They have higher ESKD incidence compared with non-Hispanics, but little is known about the CKD incidence in this population. METHODS: We examined rates and risk factors of new-onset CKD using data from 8774 adults in the Hispanic Community Health Study/Study of Latinos. Incident CKD was defined as eGFR <60 ml/min per 1.73 m2 with eGFR decline ≥1 ml/min per 1.73 m2 per year, or urine albumin/creatinine ratio ≥30 mg/g. Rates and incidence rate ratios were estimated using Poisson regression with robust variance while accounting for the study's complex design. RESULTS: Mean age was 40.3 years at baseline and 51.6% were women. In 5.9 years of follow-up, 648 participants developed CKD (10.6 per 1000 person-years). The age- and sex-adjusted incidence rates ranged from 6.6 (other Hispanic/mixed background) to 15.0 (Puerto Ricans) per 1000 person-years. Compared with Mexican background, Puerto Rican background was associated with 79% increased risk for incident CKD (incidence rate ratios, 1.79; 95% confidence interval, 1.33 to 2.40), which was accounted for by differences in sociodemographics, acculturation, and clinical characteristics. In multivariable regression analysis, predictors of incident CKD included BP >140/90 mm Hg, higher glycated hemoglobin, lower baseline eGFR, and higher baseline urine albumin/creatinine ratio. CONCLUSIONS: CKD incidence varies by Hispanic/Latino heritage and this disparity may be in part attributed to differences in sociodemographic characteristics. Culturally tailored public heath interventions focusing on the prevention and control of risk factors might ameliorate the CKD burden in this population.

CKD and ESRD in US Hispanics.

Hispanics are the largest racial/ethnic minority group in the United States, and they experience a substantial burden of kidney disease. Although the prevalence of chronic kidney disease (CKD) is similar or slightly lower in Hispanics than non-Hispanic whites, the age- and sex-adjusted prevalence rate of end-stage renal disease is almost 50% higher in Hispanics compared with non-Hispanic whites. This has been attributed in part to faster CKD progression among Hispanics. Furthermore, Hispanic ethnicity has been associated with a greater prevalence of cardiovascular disease risk factors, including obesity and diabetes, as well as CKD-related complications. Despite their less favorable socioeconomic status, which often leads to limited access to quality health care, and their high comorbid condition burden, the risk for mortality among Hispanics appears to be lower than for non-Hispanic whites. This survival paradox has been attributed to a complex interplay between sociocultural and psychosocial factors, as well as other factors. Future research should focus on evaluating the long-term impact of these factors on patient-centered and clinical outcomes. National policies are needed to improve access to and quality of health care among Hispanics with CKD.

Acculturation and chronic kidney disease in the Hispanic community health study/study of Latinos (HCHS/SOL).

Hispanics/Latinos are burdened by chronic kidney disease (CKD). The role of acculturation in this population has not been explored. We studied the association of acculturation with CKD and cardiovascular risk factor control. We performed cross-sectional analyses of 13,164 U.S. Hispanics/Latinos enrolled in the HCHS/SOL Study between 2008 and 2011. Acculturation was measured using the language and ethnic social relations subscales of the Short Acculturation Scale for Hispanics, and proxies of acculturation (language preference, place of birth and duration of residence in U.S.). CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or urine albumin-to-creatinine ratio ≥ 30 mg/g. On multivariable analyses stratified by age, lower language subscale score was associated with higher odds of CKD among those older than 65 (OR 1.29, 95% CI, 1.03, 1.63). No significant association was found between proxies of acculturation and CKD in this age strata. Among individuals aged 18-44, a lower language subscale score was associated with lower eGFR (ß = -0.77 ml/min/1.73 m2, 95% CI -1.43, -0.10 per 1 SD increase) and a similar pattern was observed for ethnic social relations. Among those older than 65, lower language subscale score was associated with higher log-albuminuria (ß = 0.12, 95% CI 0.03, 0.22). Among individuals with CKD, acculturation measures were not associated with control of cardiovascular risk factors. In conclusion, lower language acculturation was associated with a higher prevalence of CKD in individuals older than 65. These findings suggest that older individuals with lower language acculturation represent a high risk group for CKD.

Blood Pressure and Risk of Cardiovascular Events in Patients on Chronic Hemodialysis: The CRIC Study (Chronic Renal Insufficiency Cohort).

We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34; P<0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of cardiovascular events, with the nadir risk between 140 and 170 mm Hg. In contrast, there was a linear stepwise association between out-of-dialysis-unit-SBP with risk of cardiovascular events. Participants with out-of-dialysis-unit-SBP ≥128 mm Hg (top 2 quartiles) had >2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP ≤112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12-3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42-5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target.

Urine biomarkers of tubular injury do not improve on the clinical model predicting chronic kidney disease progression.

Few investigations have evaluated the incremental usefulness of tubular injury biomarkers for improved prediction of chronic kidney disease (CKD) progression. As such, we measured urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-ß-D-glucosaminidase and liver fatty acid binding protein under highly standardized conditions among 2466 enrollees of the prospective Chronic Renal Insufficiency Cohort Study. During 9433 person-years of follow-up, there were 581 cases of CKD progression defined as incident end-stage renal disease or halving of the estimated glomerular filtration rate. Levels of the urine injury biomarkers, normalized for urine creatinine, were strongly associated with CKD progression in unadjusted Cox proportional hazard models with hazard ratios in the range of 7 to 15 comparing the highest with the lowest quintiles. However, after controlling for the serum creatinine-based estimated glomerular filtration rate and urinary albumin/creatinine ratio, none of the normalized biomarkers was independently associated with CKD progression. None of the biomarkers improved on the high (0.89) C-statistic for the base clinical model. Thus, among patients with CKD, risk prediction with a clinical model that includes the serum creatinine-based estimated glomerular filtration rate and the urinary albumin/creatinine ratio is not improved on with the addition of renal tubular injury biomarkers.

Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study.

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P<1×10-6 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery P=5.42×10-7; replication P=0.039; combined P=7.42×10-9). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P=4.90×10-6). Similarly, rs931891 in LINC00923 associated with eGFR decline (P=1.44×10-4) in white patients without diabetes. In summary, SNPs in LINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted.

Different components of blood pressure are associated with increased risk of atherosclerotic cardiovascular disease versus heart failure in advanced chronic kidney disease.

Blood pressure is a modifiable risk for cardiovascular disease (CVD). Among hemodialysis patients, there is a U-shaped association between blood pressure and risk of death. However, few studies have examined the association between blood pressure and CVD in patients with stage 4 and 5 chronic kidney disease. Here we studied 1795 Chronic Renal Insufficiency Cohort (CRIC) Study participants with estimated glomerular filtration rate <30 ml/min per 1.73 m2 and not on dialysis. The association of systolic (SBP), diastolic (DBP), and pulse pressure with the risk of physician-adjudicated atherosclerotic CVD (stroke, myocardial infarction, or peripheral arterial disease) and heart failure was tested using Cox regression adjusted for demographics, comorbidity and medications. There was a significant association with higher SBP (adjusted hazard ratio 2.04 [95% confidence interval: 1.46-2.84]) for SBP over 140 vs under 120 mmHg, higher DBP (2.52 [1.54-4.11]) for DBP >90 mm Hg versus <80 mm Hg and higher pulse pressure (2.67 [1.82-3.92]) for pulse pressure >68 mm Hg versus <51 mm Hg with atherosclerotic CVD. For heart failure, there was a significant association with higher pulse pressure only (1.42 [1.05-1.92]) for pulse pressure >68 mm Hg versus <51 mmHg, but not for SBP or DBP. Thus, among participants with stage 4 and 5 chronic kidney disease, there was an independent association between higher SBP, DBP, and pulse pressure with the risk of atherosclerotic CVD, whereas only higher pulse pressure was independently associated with a greater risk of heart failure. Further trials are needed to determine whether aggressive reduction of blood pressure decreases the risk of CVD events in patients with stage 4 and 5 chronic kidney disease.

Predictors and Outcomes of Health-Related Quality of Life in Adults with CKD.

BACKGROUND AND OBJECTIVES: Low health-related quality of life is associated with increased mortality in patients with ESRD. However, little is known about demographic and clinical factors associated with health-related quality of life or its effect on outcomes in adults with CKD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Data from 3837 adult participants with mild to severe CKD enrolled in the prospective observational Chronic Renal Insufficiency Cohort and Hispanic Chronic Renal Insufficiency Cohort Studies were analyzed. Health-related quality of life was assessed at baseline with the Kidney Disease Quality of Life-36 and its five subscales: mental component summary, physical component summary, burden of kidney disease (burden), effects of kidney disease (effects), and symptoms and problems of kidney disease (symptoms). Low health-related quality of life was defined as baseline score >1 SD below the mean. Using Cox proportional hazards analysis, the relationships between low health-related quality of life and the following outcomes were examined: (1) CKD progression (50% eGFR loss or incident ESRD), (2) incident cardiovascular events, and (3) all-cause death. RESULTS: Younger age, women, low education, diabetes, vascular disease, congestive heart failure, obesity, and lower eGFR were associated with low baseline health-related quality of life (P<0.05). During a median follow-up of 6.2 years, there were 1055 CKD progression events, 841 cardiovascular events, and 694 deaths. Significantly higher crude rates of CKD progression, incident cardiovascular events, and all-cause death were observed among participants with low health-related quality of life in all subscales (P<0.05). In fully adjusted models, low physical component summary, effects, and symptoms subscales were independently associated with a higher risk of incident cardiovascular events and death, whereas low mental component summary was independently associated with a higher risk of death (P<0.05). Low health-related quality of life was not associated with CKD progression. CONCLUSIONS: Low health-related quality of life across several subscales was independently associated with a higher risk of incident cardiovascular events and death but not associated with CKD progression.

CKD Progression and Mortality among Hispanics and Non-Hispanics.

Although recommended approaches to CKD management are achieved less often in Hispanics than in non-Hispanics, whether long-term outcomes differ between these groups is unclear. In a prospective longitudinal analysis of participants enrolled into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies, we used Cox proportional hazards models to determine the association between race/ethnicity, CKD progression (50% eGFR loss or incident ESRD), incident ESRD, and all-cause mortality, and linear mixed-effects models to assess differences in eGFR slope. Among 3785 participants, 13% were Hispanic, 43% were non-Hispanic white (NHW), and 44% were non-Hispanic black (NHB). Over a median follow-up of 5.1 years for Hispanics and 6.8 years for non-Hispanics, 27.6% of all participants had CKD progression, 21.3% reached incident ESRD, and 18.3% died. Hispanics had significantly higher rates of CKD progression, incident ESRD, and mean annual decline in eGFR than did NHW (P<0.05) but not NHB. Hispanics had a mortality rate similar to that of NHW but lower than that of NHB (P<0.05). In adjusted analyses, the risk of CKD progression did not differ between Hispanics and NHW or NHB. However, among nondiabetic participants, compared with NHB, Hispanics had a lower risk of CKD progression (hazard ratio, 0.61; 95% confidence interval, 0.39 to 0.95) and incident ESRD (hazard ratio, 0.50; 95% confidence interval, 0.30 to 0.84). At higher levels of urine protein, Hispanics had a significantly lower risk of mortality than did non-Hispanics (P<0.05). Thus, important differences in CKD progression and mortality exist between Hispanics and non-Hispanics and may be affected by proteinuria and diabetes.

Atrial Fibrillation and Risk of ESRD in Adults with CKD.

BACKGROUND AND OBJECTIVES: Atrial fibrillation frequently complicates CKD and is associated with adverse outcomes. Progression to ESRD is a major complication of CKD, but the link with atrial fibrillation has not been fully delineated. In this study, we examined the association of incident atrial fibrillation with the risk of ESRD in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied participants in the prospective Chronic Renal Insufficiency Cohort Study without atrial fibrillation at entry. Incident atrial fibrillation was identified by study visit ECGs, self-report, and hospital discharge diagnostic codes, with confirmation by physician adjudication. ESRD through 2012 was ascertained by participant self-report, medical records, and linkage to the US Renal Data System. Data on potential confounders were obtained from self-report, study visits, and laboratory tests. Marginal structural models were used to study the potential association of incident atrial fibrillation with risk of ESRD after adjustment for time-dependent confounding. RESULTS: Among 3091 participants, 172 (5.6%) developed incident atrial fibrillation during follow-up. During mean follow-up of 5.9 years, 43 patients had ESRD that occurred after development of incident atrial fibrillation (11.8/100 person-years) compared with 581 patients without incident atrial fibrillation (3.4/100 person-years). In marginal structural models with inverse probability weighting, incident atrial fibrillation was associated with a substantially higher rate of ESRD (hazard ratio, 3.2; 95% confidence interval, 1.9 to 5.2). This association was consistent across important subgroups by age, sex, race, diabetes status, and baseline eGFR. CONCLUSIONS: Incident atrial fibrillation was associated with higher risk of developing ESRD in CKD. Additional study is needed to identify potentially modifiable pathways through which atrial fibrillation was associated with a higher risk of progression to ESRD. More aggressive monitoring and treatment of patients with CKD and atrial fibrillation may improve outcomes in this high-risk population.

Relationship Between Medication Adherence and Distance to Dispensing Pharmacies and Prescribers Among an Urban Medicaid Population with Diabetes Mellitus.

STUDY OBJECTIVE: To determine whether a relationship exists between medication adherence to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) and distance to dispensing pharmacies and prescribers among an urban public aid population with diabetes mellitus. DESIGN: Retrospective cohort study using claims data. DATA SOURCE: Illinois Department of Healthcare and Family Services database. PATIENTS: A total of 6532 patients aged 18-64 years with diabetes who had at least one prescription fill for an ACEI or ARB and had continuous Medicaid coverage in the greater Chicago area in 2009. MEASUREMENTS AND MAIN RESULTS: We assessed medication adherence, defined as proportion of days covered (PDC) of 0.8 or higher, to ACEIs and ARBs and its association with distances between patients and their pharmacies and prescribers. Of the 6532 patients included in the analyses, 2930 (45%) had PDC levels of 0.8 or higher. No significant differences were observed between patients who were adherent versus those who were nonadherent in distance to pharmacy (median 1.39 vs 1.35 miles, p=0.15) or distance to prescriber (median 4.39 vs 4.48 miles, p=0.80). In a multivariate regression model including age, sex, race/ethnicity, number of pharmacies, number of prescribers, distance to pharmacy, and distance to prescriber, a greater number of prescribers was associated with higher adherence (two prescribers vs one prescriber: odds ratio [OR] 1.396, 95% confidence interval [CI] 1.233-1.580; three or more prescribers vs one prescriber: OR 2.208, 95% CI 1.787-2.727). CONCLUSION: ACEI or ARB adherence was not associated with distances to pharmacies and prescribers.