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Abstract In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple organs. However, our knowledge regarding regulatory mechanisms governing the parathyroids has remained limited. Here, we present the comprehensive maps of the chromatin landscape of the human parathyroid glands, identifying active regulatory elements and chromatin interactions. These data allow us to define regulatory circuits and previously unidentified genes that play crucial roles in parathyroid biology. We experimentally validate candidate parathyroid-specific enhancers and demonstrate their integration with GWAS SNPs for parathyroid-related diseases and traits. For instance, we observe reduced activity of a parathyroid-specific enhancer of the Calcium Sensing Receptor gene, which contains a risk allele associated with higher PTH levels compared to the wildtype allele. Our datasets provide a valuable resource for unraveling the mechanisms governing parathyroid gland regulation in health and disease.

Abstract Background and Aims High tissue sodium accumulation and intermuscular adipose tissue (IMAT) are associated with aging, type 2 diabetes, and chronic kidney disease. In this study, we aim to investigate whether high lower‐extremity tissue sodium accumulation relates to IMAT quantity and whether systemic inflammatory mediators and adipocytokines contribute to such association. Methods Tissue sodium content and IMAT accumulation (percentage of IMAT area to muscle area) were measured in 83 healthy individuals using sodium imaging (23Na‐MRI) and proton (1H‐MRI) imaging of the calf. Insulin sensitivity was assessed by glucose disposal rate (GDR) measured with the hyperinsulinemic‐euglycemic clamp. Results Median (interquartile range) muscle and skin sodium contents were 16.6 (14.9, 19.0) and 12.6 (10.9, 16.7) mmol/L, respectively. Median IMAT was 3.69 (2.80, 5.37) %. In models adjusted for age, sex, BMI, GDR, adiponectin, and high‐sensitivity C‐reactive protein, increasing tissue sodium content was significantly associated with higher IMAT quantity (p = 0.018 and 0.032 for muscle and skin tissue sodium, respectively). In subgroup analysis stratified by sex, skin sodium was significantly associated with IMAT only among men. In interaction analysis, the association between skin sodium and IMAT was greater with increasing levels of high‐sensitivity C‐reactive protein and interleukin‐6 (p for interaction = 0.022 and 0.006, respectively). Conclusions Leg muscle and skin sodium are associated with IMAT quantity among healthy individuals. The relationship between skin sodium and IMAT may be mediated by systemic inflammation.

Rationale & Objective: Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles that lack cardioprotective properties; altered lipid composition may be associated with these changes. To investigate HDL lipids as potential cardiovascular risk factors in CKD, we tested the associations of HDL ceramides, sphingomyelins, and phosphatidylcholines with mortality. Study Design: We leveraged data from a longitudinal prospective cohort of participants with CKD. Setting & Participants: We included participants aged greater than 21 years with CKD, excluding those on maintenance dialysis or with prior kidney transplant. Exposure: HDL particles were isolated using density gradient ultracentrifugation. We quantified the relative abundance of HDL ceramides, sphingomyelins, and phosphatidylcholines via liquid chromatography tandem mass spectrometry (LC-MS/MS). Outcomes: Our primary outcome was all-cause mortality. Analytical Approach: We tested associations using Cox regressions adjusted for demographics, comorbid conditions, laboratory values, medication use, and highly correlated lipids with opposed effects, controlling for multiple comparisons with false discovery rates (FDR). Results: There were 168 deaths over a median follow-up of 6.12 years (interquartile range, 3.71-9.32). After adjustment, relative abundance of HDL ceramides (HR, 1.22 per standard deviation; 95% CI, 1.06-1.39), sphingomyelins with long fatty acids (HR, 1.44; 95% CI, 1.05-1.98), and saturated and monounsaturated phosphatidylcholines (HR, 1.22; 95% CI, 1.06-1.41) were significantly associated with increased risk of all-cause mortality (FDR

Summary: Background: Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. Methods: Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). Findings: Three independent lead single nucleotide polymorphisms (SNPs) (P-value 99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. Interpretation: Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. Funding: Wellcome (220740/Z/20/Z).

Abstract Background Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery. Methods We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center (“Vanderbilt” cohort) or Michigan Medicine, the academic medical center of the University of Michigan (“Michigan” cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants. Results The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971–1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability. Conclusion The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.

Background The ratio of 24,25‐dihydroxyvitamin D3/25‐hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25‐hydroxyvitamin D (25[OH]D), and 1,25‐dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross‐sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25‐dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography–tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression‐calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross‐sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non‐Hispanic White race and ethnicity, 42% non‐Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow‐up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95–1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0–1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Abstract Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

Background Genetics, along with lifestyle and behavioral characteristics, play an important role in hypertension in adults. Our aim was to identify genetic variants associated with blood pressure in childhood and adolescence. Methods and Results We conducted a candidate single‐nucleotide polymorphism (SNP) analysis and genome‐wide association study among 9778 participants aged

Abstract Background Acute kidney injury (AKI) and obesity are independent risk factors for chronic kidney disease (CKD). This study aimed to determine if obesity modifies risk for CKD outcomes after AKI. Methods This prospective multisite cohort study followed adult survivors after hospitalization, with or without AKI. The primary outcome was a combined CKD event of incident CKD, progression of CKD and kidney failure, examined using time-to-event Cox proportional hazards models, adjusted for diabetes status, age, pre-existing CKD, cardiovascular disease status and intensive care unit admission, and stratified by study center. Body mass index (BMI) was added as an interaction term to examine effect modification by body size. Results The cohort included 769 participants with AKI and 769 matched controls. After median follow-up of 4.3 years, among AKI survivors, the rate of the combined CKD outcome was 84.7 per1000-person-years with BMI ≥30 kg/m2, 56.4 per 1000-person-years with BMI 25–29.9 kg/m2, and 72.6 per 1000-person-years with BMI 20–24.9 kg/m2. AKI was associated with a higher risk of combined CKD outcomes; adjusted-HR 2.43 (95%CI 1.87–3.16), with no evidence that this was modified by BMI (p for interaction = 0.3). After adjustment for competing risk of death, AKI remained associated with a higher risk of the combined CKD outcome (subdistribution-HR 2.27, 95%CI 1.76–2.92) and similarly, there was no detectable effect of BMI modifying this risk. Conclusions In this post-hospitalization cohort, we found no evidence for obesity modifying the association between AKI and development or progression of CKD.

Acute and chronic kidney injuries induce increased cell cycle progression in renal tubules. While increased cell cycle progression promotes repair after acute injury, the role of ongoing tubular cell cycle progression in chronic kidney disease is unknown. Two weeks after initiation of chronic kidney disease, we blocked cell cycle progression at G1/S phase by using an FDA-approved, selective inhibitor of CDK4/6. Blocking CDK4/6 improved renal function and reduced tubular injury and fibrosis in 2 murine models of chronic kidney disease. However, selective deletion of cyclin D1, which complexes with CDK4/6 to promote cell cycle progression, paradoxically increased tubular injury. Expression quantitative trait loci (eQTLs) for CCND1 (cyclin D1) and the CDK4/6 inhibitor CDKN2B were associated with eGFR in genome-wide association studies. Consistent with the preclinical studies, reduced expression of CDKN2B correlated with lower eGFR values, and higher levels of CCND1 correlated with higher eGFR values. CDK4/6 inhibition promoted tubular cell survival, in part, through a STAT3/IL-1β pathway and was dependent upon on its effects on the cell cycle. Our data challenge the paradigm that tubular cell cycle progression is beneficial in the context of chronic kidney injury. Unlike the reparative role of cell cycle progression following acute kidney injury, these data suggest that blocking cell cycle progression by inhibiting CDK4/6, but not cyclin D1, protects against chronic kidney injury.

Background Sodium (Na+) stored in skin and muscle tissue is associated with essential hypertension. Sodium magnetic resonance imaging is a validated method of quantifying tissue stores of Na+. In this study, we evaluated tissue Na+ in patients with elevated blood pressure or stage I hypertension in response to diuretic therapy or low Na+ diet. Methods and Results In a double‐blinded, placebo‐controlled trial, patients with systolic blood pressure 120 to 139 mm Hg were randomized to low sodium diet (

Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30-46) vs 38 (31-47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.

Introduction: Assessment of impaired vitamin D metabolism is limited by lack of functional measures. CYP24A1-mediated vitamin D clearance, calculated as the ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (the vitamin D metabolic ratio, VDMR), is induced by 1,25-dihydroxyvitamin D and may assess tissue-level activity. We tested associations of the VDMR with risks of death and progression to end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD). Methods: We studied participants from the Chronic Renal Insufficiency Cohort (CRIC), which included a random subset of 1080 CRIC participants plus additional participants who experienced ESRD or died (case cohort study design). Serum 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 was measured 1 year after enrollment. The primary outcomes included death and progression to ESRD. Using inverse probability weighting, we tested associations of VDMR (24,25[OH]2D3/25[OH]D3) with risks of death and ESRD, adjusting for demographics, comorbidity, and kidney function (estimated glomerular filtration rate [eGFR] and urine protein-to-creatinine ratio [PCR]). Results: There were a total of 708 ESRD events and 650 deaths events over mean (SD) follow-up periods of 4.9 (2.9) years and 6.5 (2.5) years, respectively. Lower VDMR was associated with increased risk of ESRD prior to adjusting for kidney function (hazard ratio [HR], 1.80 per 20 pg/ng lower VDMR; 95% confidence interval [CI], 1.56–2.08), but not with adjustment for kidney function (HR, 0.94 per 20 pg/ng; 95% CI, 0.81–1.10). Lower VDMR was associated with modestly increased mortality risk, including adjustment for kidney function (HR, 1.18 per 20 pg/ng; 95% CI, 1.02–1.36). Conclusion: Lower VDMR, a measure of CYP24A1-mediated vitamin D clearance, was significantly associated with all-cause mortality but not with progression to ESRD in patients with CKD. Keywords: kidney, mortality, vitamin D

Abstract Introduction The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. Methods We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). Results Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. Conclusion In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function.

Persistently low levels of estimated glomerular filtration rate (eGFR) are a biomarker of chronic kidney disease. Here, the authors reinterpret the genetic architecture of kidney function across ancestries, to identify not only genes, but the tissue and anatomical contexts of renal homeostasis.

Introduction: High dietary acid load and metabolic acidosis are associated with an accelerated decline in kidney function and may contribute to the observed heterogeneity in end-stage renal disease (ESRD) risk according to APOL1 genotype. Our objective was to examine the associations of metabolic acidosis and dietary acid load with kidney disease progression, according to APOL1 genotype, among individuals with chronic kidney disease (CKD). Methods: We studied 1048 African American participants in the Chronic Renal Insufficiency Cohort. Metabolic acidosis was defined as blood levels of serum bicarbonate less than 22 mEq/L, and dietary acid load was quantified by potential renal acid load (PRAL) using data from the Diet Health Questionnaire. APOL1 status was defined as having 2 risk variants, consisting of either possible combination of the G1 and G2 risk alleles. We tested associations of APOL1 and dietary and metabolic acidosis with CKD progression, defined as time to ESRD or 50% decline in eGFR. Results: During a median follow-up period of 7 years, 379 participants had an incident CKD progression event (6.4 events per 100 person-years). After full adjustment, among participants with 2 APOL1 variants, the analysis failed to detect an association between metabolic acidosis or dietary acid load and CKD progression (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.96–1.11 per 1 mEq/L higher serum bicarbonate and an HR, 1.03; 95% CI, 0.92–1.15 per 10 mEq/L higher PRAL). Similar associations were noted among participants without the APOL1 high-risk genotype. Conclusion: In a population at high risk of developing ESRD, metabolic acidosis and dietary acid load were not associated with CKD progression. Keywords: acidosis, APOL1, chronic kidney disease, dietary acid load, end-stage renal disease

Introduction: Cardiac biomarkers soluble ST2 (sST2) and galectin-3 may reflect cardiac inflammation and fibrosis. It is plausible that these mechanisms may also contribute to the progression of kidney disease. We examined associations of sST2 and galectin-3 with kidney function decline in participants with chronic kidney disease (CKD). Methods: This was a pooled analysis of 2 longitudinal cohorts of participants with CKD: the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS). We measured circulating concentrations of sST2 and galectin-3 at baseline. Our primary outcome was progression to estimated glomerular filtration rate (eGFR)

Elevated serum urate levels are a risk factor for gout. Here, Tin et al. perform whole-exome sequencing in 19,517 individuals and detect low-frequency genetic variants in urate transporter genes, SLC22A12 and SLC2A9, associated with serum urate levels and confirm their damaging nature in vitro and in silico.

ABSTRACT IMPACT: This study establishes the association between childhood hypertension and health outcomes in early adulthood, identifying the need to understand blood pressure during early life for primary prevention of hypertension and cardiovascular disease. OBJECTIVES/GOALS: There is evidence that blood pressure level in early life can influence hypertension and other cardiovascular risk factors later in life. We examined whether hypertension before the age of 18 is associated with higher odds of obesity and hypertension after the age of 18. METHODS/STUDY POPULATION: We studied 19,367 children and adolescents from the Vanderbilt University Medical Center’s Synthetic Derivative, a de-identified version of the electronic medical record. Childhood hypertension was defined as systolic blood pressure (SBP) ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg at three or more outpatient visits before the age of 18. Obesity and hypertension in early adulthood were the primary outcomes. Obesity was defined as being above normal weight for adulthood height at age 30 based on the NIH’s body mass index tables. Hypertension was defined as SBP ≥130 mmHg or DBP ≥80 mmHg at three or more outpatient visits after the age of 18. Odds ratios and 95% confidence intervals (CIs) were computed from logistic regression models adjusted for demographics, medication use, and childhood weight. RESULTS/ANTICIPATED RESULTS: Most subjects were female (63%) and white (80%). During childhood, 17% of participants had hypertension. Approximately 58% of this group were obese at age 30, and 38% had hypertension as adults. Compared to females with no childhood hypertension, females with childhood hypertension had 1.35 times higher odds of being obese at age 30 (95% CI: 1.15, 1.58) and 3.56 times higher odds of having hypertension over the age of 18 (95% CI: 3.09, 4.09). Males with childhood hypertension, compared to males without, had 1.28 times higher odds of being obese at age 30 (95% CI: 1.08, 1.52) and 2.74 times higher odds of having hypertension over the age of 18 (95% CI: 2.35, 3.20). Associations between childhood hypertension, early adulthood obesity, and hypertension significantly differed by gender (p-for-interaction for both:

Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

Abstract Background Critically ill patients with acute kidney injury (AKI) can be divided into two subphenotypes, resolving or nonresolving, on the basis of the trajectory of serum creatinine. It is unknown if the biology underlying these two AKI recovery patterns is different. Methods We measured eight circulating biomarkers in plasma obtained from a cohort of patients admitted to an intensive care unit (ICU) (n = 1241) with systemic inflammatory response syndrome. The biomarkers were representative of several biologic processes: apoptosis (soluble Fas), inflammation (soluble tumor necrosis factor receptor 1, interleukin 6, interleukin 8) and endothelial dysfunction, (angiopoietin 1, angiopoietin 2, and soluble vascular cell adhesion molecule 1). We tested for associations between biomarker levels and AKI subphenotypes using relative risk regression accounting for multiple hypotheses with the Bonferroni correction. Results During the first 3 days of ICU admission, 868 (70%) subjects developed AKI; 502 (40%) had a resolving subphenotype, and 366 (29%) had a nonresolving subphenotype. Hospital mortality was 12% in the resolving subphenotype and 21% in the nonresolving subphenotype. Soluble Fas was the only biomarker associated with a nonresolving subphenotype after adjustment for age, body mass index, diabetes, and Acute Physiology and Chronic Health Evaluation III score (p = 0.005). Conclusions Identifying modifiable targets in the Fas-mediated pathway may lead to strategies for prevention and treatment of a clinically important form of AKI.

Objective To examine whether lifestyle factors, including sedentary time and physical activity, could independently contribute to risk of end-stage renal disease (ESRD).Study design Case-cohort study.Setting South-eastern USA.Participants The Southern Community Cohort Study recruited ~86 000 black and white participants from 2002 to 2009. We assembled a case cohort of 692 incident ESRD cases and a probability sample of 4113 participants.Predictors Sedentary time was calculated as hours/day from daily sitting activities. Physical activity was calculated as metabolic equivalent (MET)-hours/day from engagement in light, moderate and vigorous activities.Outcomes Incident ESRD.Results At baseline, among the subcohort, mean (SD) age was 52 (8.6) years, and median (25th, 75th centile) estimated glomerular filtration rate (eGFR) was 102.8 (85.9–117.9) mL/min/1.73 m2. Medians (25th–75th centile) for sedentary time and physical activity were 8.0 (5.5–12.0) hours/day and 17.2 (8.7–31.9) MET-hours/day, respectively. Median follow-up was 9.4 years. We observed significant interactions between eGFR and both physical activity and sedentary behaviour (p27 MET-hours/day. High levels of sitting time were associated with increased ESRD risk only among those with reduced kidney function (eGFR ≤30 mL/min/1.73 m2); this association was attenuated after excluding the first 2 years of follow-up.Conclusions In a population with a high prevalence of chronic kidney disease risk factors such as hypertension and diabetes, physical activity appears to be associated with reduced risk of ESRD among those with preserved kidney function. A positive association between sitting time and ESRD observed among those with advanced kidney disease is likely due to reverse causation.

OBJECTIVES/GOALS: Early age at menopause has been linked to increased risk of cardiovascular disease; however, there is limited evidence for a relationship between early menopause and heart failure (HF). We examined whether early menopause is associated with incident HF among women in the southeastern United States. METHODS/STUDY POPULATION: The Southern Community Cohort Study enrolled ~86,000 low-income black and white adults from 2002 to 2009. Participants for this analysis were 11,948 women who were postmenopausal at enrollment, had no history of HF, and were on Medicaid or Medicare. HF events were ascertained using ICD-9 codes 428.x via linkage of the cohort with CMS Research Identifiable Files through December 31, 2010. Early menopause was defined as self-reported age at menopause less than 45 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed from multivariable Cox regression models, overall and by race, adjusting for demographic, lifestyle, and reproductive factors, including reason for menopause. RESULTS/ANTICIPATED RESULTS: At baseline, mean age was 58±9 years, and 65% of participants were black. Among women with early menopause, 76% (n = 4,836) had menopause due to hysterectomy or oophorectomy. In women with later menopause, 74% (n = 4,102) reported natural menopause. During a median follow-up of 5.0 years (range 3.1-6.7), 2,157 incident HF events occurred. Compared with women with later onset of menopause, those with early menopause had increased HF risk (HR: 1.27, 95% CI: 1.10–1.47). Risk of HF associated with early menopause was similar in white and black women (p-value for interaction: 0.13). DISCUSSION/SIGNIFICANCE OF IMPACT: In this largely low-income population, early menopause was associated with an increased risk of developing HF. Women with early menopause represent a potential target population for future interventions to decrease risk of HF and cardiovascular risk factors.

OBJECTIVES/SPECIFIC AIMS: The Life’s Simple 7 (LS7) metric was created by the American Heart Association with the goal of educating the public on seven modifiable factors that contribute to heart health. While it is well documented that these ideal health behaviors lower risk of cardiovascular disease (CVD) in the general population, the association between the LS7 ideal health metrics and end stage renal disease (ESRD) risk has not been examined in a lower socioeconomic population at high risk for both ESRD and CVD. Our objective is to examine the association between the LS7 score and incident ESRD in a cohort of white and black men and women in the southeastern US, where rates of CVD and ESRD are high. METHODS/STUDY POPULATION: The Southern Community Cohort Study recruited ~86,000 low-income blacks and whites in the southeastern US (2002-2009). Utilizing a nested case-control design, our analysis included 1628 incident cases of ESRD identified via linkage of the cohort with the United States Renal Data System (USRDS) from January 1, 2002 to March 31, 2015. Controls (n = 4884) were individually matched 3:1 with ESRD cases based on age, sex, and race. Demographic, medical, and lifestyle information were obtained via baseline questionnaire. The AHA definitions for ideal health were used for non-smoking (never or quit >12 months), body mass index (BMI75 min/week of vigorous physical activity or >150min/week of moderate/vigorous activity). Modified definitions were used for consuming a healthy diet [Healthy Eating Index (HEI10) score>70] and for blood pressure, fasting plasma glucose, and total cholesterol, based on self-reported no history of diagnosis of hypertension, diabetes, and hypercholesterolemia, respectively. The number of ideal health parameters were summed to generate the LS7 score, which ranged from 0-7 with higher scores indicating more ideal health. Adjusted odds ratios (95% confidence intervals) for incident ESRD associated with LS7 score were calculated using conditional logistic regression models, adjusting for income and education. The SCCS ESRD case-cohort dataset will be available by TS 2019 and analyses will be completed to adjust for baseline estimated glomerular filtration rate (eGFR) as a marker of kidney function and to examine whether eGFR modifies the relationship between LS7 and incident ESRD. RESULTS/ANTICIPATED RESULTS: At baseline, mean age was 54 years, 55% (3600) of participants were women, and 87% (5656) were black. A total of 58% (943) of ESRD cases were non-smokers compared to 54% (2633) of controls. ESRD cases had higher prevalence of BMI>25 kg/m2 (81% vs. 74%), hypertension (84% vs. 59%), hypercholesterolemia (48% vs. 34%), and diabetes (66% vs. 22%) compared to controls. A total of 18% (839) of controls and 12% (194) of ESRD cases met ideal exercise recommendations, and 20% of either cases (302) or controls (916) had a HEI10 score above 70. The median LS7 score for controls and ESRD cases was 3 and 2, respectively, and 17% (983) of participants had a low score (0-1) while 2% (105) met 6 or 7 ideal health metrics. Higher LS7 score was associated with lower odds of ESRD (P-trend3 (above median) had 75% reduced odds of ESRD (OR 0.25; 95% CI 0.22, 0.29) compared to those with a score of 2 or less. DISCUSSION/SIGNIFICANCE OF IMPACT: In the SCCS population, the presence of any 3 or more ideal health behaviors is associated with reduced odds of developing ESRD. The components of the LS7 represent important modifiable risk factors that may be targets for future interventions driven by the patient. The attributable risk due to each factor is needed to dissect which ideal behaviors are the most beneficial.

Elevated levels of circulating pro-atherogenic uremic solutes, particularly trimethylamine N-oxide (TMAO), have been implicated in cardiovascular disease development in patients with chronic kidney disease (CKD). TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). We determined the functional effects of three common FMO3 variants at amino acids 158, 308, and 257 on TMAO concentrations in a prospective cohort study and evaluated associations of polymorphisms with CKD progression and mortality. Each additional minor allele at amino acid 158 was associated with a 0.38 μg/mL higher circulating TMAO (p = 0.01) and with faster rates of annualized relative eGFR decline. Participants with 0, 1 and 2 variant alleles averaged an eGFR loss of 8%, 12%, and 14% per year, respectively (p-for trend = 0.05). Compared to participants with the homozygous reference allele, heterozygous and homozygous variant participants had a 2.0-fold (95% CI: 0.85, 4.6) and 2.2-fold (95% CI: 0.89, 5.48) higher risk of mortality, respectively (p-for-trend = 0.04). No associations with clinical outcomes were observed for allelic variants at amino acids 257 or 308. Understanding the contribution of genetic variation of FMO3 to disease progression and all-cause mortality can guide recommendations for diet modification or pharmacotherapy in CKD patients at increased risk of adverse outcomes.

To date, there are no known estimates of the prevalence of chronic kidney disease within Cambodia, the vast majority of whose citizens live in rural areas with limited access to renal replacement therapy.Observational analysis of patients from the Takeo province in Cambodia who presented to MoPoTsyo, a non-governmental organization, for screening and management of diabetes mellitus between 2010 and 2012 (n = 402; 75% females). Estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi equation.On average, women were younger, with a higher percentage of hypercholesterolemia but also high-density lipoprotein level. Men had a higher serum creatinine level (1.31 mg/dl) than that of women (1.13 mg/dl) at 95% CI. More than half of all screened patients had a reduced eGFR; 60% (95% CI 55%, 65%) had an eGFR