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Background: Chronic kidney disease (CKD) is highly prevalent in Central America, and genetic factors may contribute to CKD risk. To understand the influences of genetic admixture on CKD susceptibility, we conducted an admixture mapping screening of CKD traits and risk factors in US Hispanic and Latino individuals from Central America country of origin., Methods: We analyzed 1023 participants of HCHS/SOL (Hispanic Community Health Study/Study of Latinos) who reported 4 grandparents originating from the same Central America country. Ancestry admixture findings were validated on 8191 African Americans from WHI (Women's Health Initiative), 3141 American Indians from SHS (Strong Heart Study), and over 1.1 million European individuals from a multistudy meta-analysis., Results: We identified 3 novel genomic regions for albuminuria (chromosome 14q24.2), CKD (chromosome 6q25.3), and type 2 diabetes (chromosome 3q22.2). The 14q24.2 locus driven by a Native American ancestry had a protective effect on albuminuria and consisted of 2 nearby regions spanning the RGS6 gene. Variants at this locus were validated in American Indians. The 6q25.3 African ancestry-derived locus, encompassing the ARID1B gene, was associated with increased risk for CKD and replicated in African Americans through admixture mapping. The European ancestry type 2 diabetes locus at 3q22.2, encompassing the EPHB1 and KY genes, was validated in European individuals through variant association., Conclusions: US Hispanic/Latino populations are culturally and genetically diverse. This study focusing on Central America grandparent country of origin provides new loci discovery and insights into the ancestry-of-origin influences on CKD and risk factors in US Hispanic and Latino individuals., Competing Interests: None.

Abstract: Although the number of deaths due to coronavirus disease 2019 (COVID-19) is higher in men than women, prior studies have provided limited sex-stratified clinical data.We evaluated sex-related differences in clinical outcomes among critically ill adults with COVID-19.Multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units at 67 U.S. hospitals from March 4 to May 9, 2020. Multilevel logistic regression was used to evaluate 28-day in-hospital mortality, severe acute kidney injury (AKI requiring kidney replacement therapy), and respiratory failure occurring within 14 days of intensive care unit admission.A total of 4407 patients were included (median age, 62 years; 2793 [63.4%] men; 1159 [26.3%] non-Hispanic White; 1220 [27.7%] non-Hispanic Black; 994 [22.6%] Hispanic). Compared with women, men were younger (median age, 61 vs 64 years, less likely to be non-Hispanic Black (684 [24.5%] vs 536 [33.2%]), and more likely to smoke (877 [31.4%] vs 422 [26.2%]). During median follow-up of 14 days, 1072 men (38.4%) and 553 women (34.3%) died. Severe AKI occurred in 590 men (21.8%), and 239 women (15.5%), while respiratory failure occurred in 2255 men (80.7%) and 1234 women (76.5%). After adjusting for age, race/ethnicity and clinical variables, compared with women, men had a higher risk of death (OR, 1.50, 95% CI, 1.26-1.77), severe AKI (OR, 1.92; 95% CI 1.57-2.36), and respiratory failure (OR, 1.42; 95% CI, 1.11-1.80).In this multicenter cohort of critically ill adults with COVID-19, men were more likely to have adverse outcomes compared with women., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Viral infections, including hepatitis C, can cause secondary glomerular nephropathies. Studies suggest that hepatitis C virus infection (HCV+) is a risk factor for chronic kidney disease (CKD) but evidence of this relationship is lacking among Hispanics/Latinos. We examined the association between HCV+ and incident CKD in a prospective cohort of Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos. HCV+ was defined by detectable HCV antibodies with additional confirmation through HCV RNA or recombinant immunoblot assay testing. Incident CKD was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or sex-specific threshold for albuminuria measured during follow-up. We used Poisson regression to estimate incidence rate ratios (IRR) of CKD and changes in eGFR- or albuminuria-based risk stages, separately. We used linear regression to estimate associations with continuous, annualized changes in eGFR and albuminuria.Over a follow-up period of 5.9 years, 712 incident CKD events occurred among 10,430 participants. After adjustment for demographic characteristics and comorbidities, HCV+ was not associated with incident CKD, defined by eGFR and albuminuria thresholds (IRR 1.29, 95% Confidence Interval 0.61, 2.73). HCV+ was significantly associated with higher eGFR risk stages (IRR 2.39, 95% CI 1.47, 3.61) with most participants transitioning from stage G1 to G2. HCV+ was associated with a continuous, annualized eGFR decline of -0.69 mL/min/m2/year (95% CI -1.23, -0.16). This large, cohort study did not find evidence of a strong association between HCV+ and new-onset CKD among Hispanics/Latinos. HCV infection may not be associated with risk of CKD among Hispanics/Latinos, although treatment with direct-acting antivirals is recommended for all HCV+ individuals, including those with established CKD or end-stage kidney disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants., Methods: This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in the Women's Health Initiative and the UK Biobank when variants were available., Results: Two low-frequency intronic variants were associated with estimated glomerular filtration rate (rs58720902 at AQR , minor allele frequency=0.01, P =1.6×10 -8 ) or urine albumin-to-creatinine ratio (rs527493184 at ZBTB16 , minor allele frequency=0.002, P =1.1×10 -8 ). An additional variant at PRNT (rs2422935, minor allele frequency=0.54, P =2.89×10 -8 ) was significantly associated with estimated glomerular filtration rate in meta-analysis with replication samples. We also identified 2 known loci for urine albumin-to-creatinine ratio ( BCL2L11 rs116907128, P =5.6×10 -8 and HBB rs344, P =9.3×10 -11 ) and validated 8 loci for urine albumin-to-creatinine ratio previously identified in the UK Biobank., Conclusions: Our study shows gains in gene discovery when using dense imputation from multi-ethnic whole-genome sequencing data in admixed Hispanics/Latinos. It also highlights limitations in genetic research of kidney traits, including the lack of suitable replication samples for variants that are more common in non-European ancestry and those at low frequency in populations.

Patients with chronic kidney disease (CKD) experience significantly greater morbidity than the general population. The hospitalization rate for patients with CKD is significantly higher than the general population. The extent to which neighborhood-level socioeconomic status (SES) is associated with hospitalization has been less explored, both in the general population and among those with CKD.We evaluated the relationship between neighborhood SES and hospitalizations for adults with CKD participating in the Chronic Renal Insufficiency Cohort Study. Neighborhood SES quartiles were created utilizing a validated neighborhood-level SES summary measure expressed as z-scores for 6 census-derived variables. The relationship between neighborhood SES and hospitalizations was examined using Poisson regression models after adjusting for demographic characteristics, individual SES, lifestyle, and clinical factors while taking into account clustering within clinical centers and census block groups.Among 3291 participants with neighborhood SES data, mean age was 58 years, 55% were male, 41% non-Hispanic white, 49% had diabetes, and mean estimated glomerular filtration rate (eGFR) was 44 ml/min/1.73 m. In the fully adjusted model, compared to individuals in the highest SES neighborhood quartile, individuals in the lowest SES neighborhood quartile had higher risk for all-cause hospitalization (rate ratio [RR], 1.28, 95% CI, 1.09-1.51) and non-cardiovascular hospitalization (RR 1.30, 95% CI, 1.10-1.55). The association with cardiovascular hospitalization was in the same direction but not statistically significant (RR 1.21, 95% CI, 0.97-1.52).Neighborhood SES is associated with risk for hospitalization in individuals with CKD even after adjusting for individual SES, lifestyle, and clinical factors.

Objective: To investigate the effect of LPA gene variants and renal function on lipoprotein(a) [Lp(a)] levels in people with chronic kidney disease and determine the association between elevated Lp(a) and myocardial infarction and death in this setting., Approach and Results: The CRIC Study (Chronic Renal Insufficiency Cohort) is an ongoing prospective study of 3939 participants with chronic kidney disease. In 3635 CRIC participants with genotype data, carriers of the rs10455872 or rs6930542 variants had a higher median Lp(a) level (mg/dL) compared with noncarriers (73 versus 23; P <0.001 and 56 versus 22; P <0.001, respectively). The 3744 participants (55% male and 41% non-Hispanic White) with available baseline Lp(a) levels were stratified into quartiles of baseline Lp(a) (mg/dL): <9.8, 9.8 to 26.0, 26.1 to 61.3, and >61.3. There were 315 myocardial infarctions and 822 deaths during a median follow-up of 7.5 years. The second quartile had the lowest event rate. After adjusting for potential confounders and using a Cox proportional hazards model, the highest quartile of Lp(a) was associated with increased risk of myocardial infarction (hazard ratio, 1.49; 95% confidence interval, 1.05-2.11), death (hazard ratio, 1.28; 95% confidence interval, 1.05-1.57), and the composite outcome (hazard ratio, 1.29; 95% confidence interval, 1.07-1.56) compared with the second quartile of Lp(a)., Conclusions: Among adults with chronic kidney disease, elevated Lp(a) is independently associated with myocardial infarction and death. Future studies exploring pharmacological Lp(a) reduction in this population are warranted., (© 2017 American Heart Association, Inc.)

Background: Chronic kidney disease is associated with an increased risk of heart failure (HF). We aimed to evaluate the role of large artery stiffness, brachial, and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multiethnic, multicenter prospective observational study of patients with chronic kidney disease., Methods and Results: We studied 2602 participants who were free of HF at baseline. Carotid-femoral pulse wave velocity (CF-PWV; the gold standard index of large artery stiffness), brachial, and central pressures (estimated via radial tonometry and a generalized transfer function) were assessed at baseline. Participants were prospectively followed up to assess the development of new-onset hospitalized HF. During 3.5 years of follow-up, 154 participants had a first hospital admission for HF. CF-PWV was a significant independent predictor of incident hospitalized HF. When compared with the lowest tertile, the hazard ratios among subjects in the middle and top CF-PWV tertiles were 2.33 (95% confidence interval, 1.37-3.97; P=0.002) and 5.24 (95% confidence interval, 3.22-8.53; P<0.0001), respectively. After adjustment for multiple confounders, the hazard ratios for the middle and top CF-PWV tertiles were 1.95 (95% confidence interval, 0.92-4.13; P=0.079) and 3.01 (95% confidence interval, 1.45-6.26; P=0.003), respectively. Brachial systolic and pulse pressure were also independently associated with incident hospitalized HF, whereas central pressures were less consistently associated with this end point. The association between CF-PWV and incident HF persisted after adjustment for systolic blood pressure., Conclusions: Large artery stiffness is an independent predictor of incident HF in chronic kidney disease, an association with strong biological plausibility given the known effects of large artery stiffening of left ventricular pulsatile load., (© 2014 American Heart Association, Inc.)

The aging kidney is associated with a number of structural and functional changes. As a result of these changes the aging kidney is more susceptible to nephrotoxic and ischemic injury. We will review the structural and functional changes that occur with aging and then review the salient features of acute renal failure in the elderly population.