Sex Differences in Hypertension and Its Management Throughout Life.

BACKGROUND: The prevalence of hypertension and uncontrolled hypertension may differ by age and sex. METHODS: We included participants in the Atherosclerosis Risk in Communities study at seven study visits over 33 years (visit 1: 15 636 participants; mean age, 54 years; 55% women), estimating sex differences in prevalence of hypertension (systolic blood pressure ≥130 mm Hg; diastolic blood pressure ≥80 mm Hg; or self-reported antihypertension medication use) and uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) using unadjusted and comorbidity-adjusted models. RESULTS: The prevalence of hypertension increased from 40% (ages, 43-46 years) to 93% (ages, 91-94 years). Within hypertensive individuals, the prevalence of uncontrolled hypertension was higher in men (33%) than women (23%) at ages 43 to 46 years but became higher in women than men starting at ages 61 to 64, with 56% of women and 40% men having uncontrolled hypertension at ages 91 to 94. This sex difference was not explained by differences in coronary heart disease, diabetes, body mass index, estimated glomerular filtration rate, number of antihypertension medications, classes of medications, or adherence to medications. In both sexes, uncontrolled hypertension was associated with a higher risk for chronic kidney disease progression (hazard ratio, 1.5 [1.2-1.9]; P=4.5×10-4), heart failure (hazard ratio, 1.6 [1.4-2.0]; P=8.1×10-7), stroke (hazard ratio, 2.1 [1.6-2.8]; P=1.8×10-8), and mortality (hazard ratio, 1.5 [1.3-1.6]; P=6.2×10-19). CONCLUSIONS: Sex differences in the prevalence of hypertension and uncontrolled hypertension vary by age, with the latter having implications for health throughout the life course.

Peripheral artery disease and risk of kidney outcomes: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: The potential impact of peripheral artery disease (PAD) on kidney outcomes is not well understood. The aim of this study was to explore the association between PAD and end-stage kidney disease (ESKD) and chronic kidney disease (CKD). METHODS: Among 14,051 participants (mean age 54 [SD 6 years]) from the Atherosclerosis Risk in Communities study, we categorized PAD status as symptomatic PAD (intermittent claudication or leg revascularization), asymptomatic PAD (ankle-brachial index [ABI] ≤0.90 without clinical history of symptoms), and ABI 0.91-1.00, 1.01-1.10, 1.11-1.20 (reference), 1.21-1.30, and >1.30. We evaluated their associations with two kidney outcomes: ESKD (the need of renal replacement therapy or death due to kidney disease) and CKD (ESKD cases or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 with a ≥25 % decline from the baseline) using multivariable Cox proportional hazards models. RESULTS: Over ∼30 years of follow-up, there were 598 cases of incident ESKD and 4686 cases of incident CKD. After adjusting for potential confounders, both symptomatic PAD and asymptomatic PAD conferred a significantly elevated risk of ESKD (hazard ratio 2.28 [95 % confidence interval 1.23-4.22] and 1.75 [1.19-2.57], respectively). Corresponding estimates for CKD were 1.54 (1.14-2.09) and 1.63 (1.38-1.93). Borderline low ABI 0.91-1.00 also showed elevated risk of adverse kidney outcomes after adjustment for demographic variables. Largely consistent results were observed across demographic and clinical subgroups. CONCLUSIONS: Symptomatic PAD and asymptomatic PAD were independently associated with an elevated risk of ESKD and CKD. These results highlight the importance of monitoring kidney function in persons with PAD, even when symptoms are absent.

Sacubitril-Valsartan in Patients Requiring Hemodialysis.

Importance: Randomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but patients with kidney failure requiring dialysis were excluded. Objective: To investigate the comparative effectiveness of sacubitril-valsartan vs angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs or ARBs) in patients with HFrEF requiring hemodialysis. Design, Setting, and Participants: This retrospective, 1:1 propensity score-matched comparative effectiveness study included patients who were 18 years or older with HFrEF, enrolled in Medicare Parts A, B, and D, and survived at least 90 days receiving in-center hemodialysis from July 8, 2015, to December 31, 2020. Patients were excluded for less than 180 days of continuous Medicare Parts A, B, and D primary payer coverage or prior dispensing of sacubitril-valsartan. Data analysis was conducted from September 23, 2023, to June 25, 2024. Exposures: New use of sacubitril-valsartan vs new or continued use of ACEIs or ARBs. Main Outcomes and Measures: The associations between initiation of sacubitril-valsartan therapy and all-cause mortality, cardiovascular mortality, all-cause hospitalization, and HF hospitalization were assessed using Cox proportional hazards regression models in a propensity score-matched sample. Results: Participants included 1:1 matched pairs of 1434 sacubitril-valsartan users and 1434 ACEI or ARB users (mean [SD] age, 64 [13] years). Of the 2868 matched participants, 996 (65%) were male; 987 (34%) were Black or African American and 1677 (58%) were White; and median dialysis vintage was 3.8 (IQR, 1.8-6.3) years. The median follow-up was 0.9 (IQR, 0.4-1.7) years. Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]). There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]). Only 195 participants (14%) ever received the maximum combination dose of sacubitril (97 mg twice daily) and valsartan (103 mg twice daily). Conclusions and Relevance: In this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.

Risk of Major Bleeding, Stroke/Systemic Embolism, and Death Associated With Different Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.

BACKGROUND: Patients with atrial fibrillation and severe chronic kidney disease have higher risks of bleeding, thromboembolism, and mortality. However, optimal anticoagulant choice in these high-risk patients remains unclear. METHODS AND RESULTS: Using deidentified electronic health records from the Optum Labs Data Warehouse, adults with atrial fibrillation and severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min per 1.73 m2) initiating warfarin, apixaban, or rivaroxaban between 2011 and 2021 were included. Using inverse probability of treatment weighting, adjusted risks of major bleeding, stroke/systemic embolism, and death were compared among agents. A total of 6794 patients were included (mean age, 78.5 years; mean estimated glomerular filtration rate, 24.7 mL/min per 1.73 m2; 51% women). Apixaban versus warfarin was associated with a lower risk of major bleeding (incidence rate, 1.5 versus 2.9 per 100 person-years; subdistribution hazard ratio [sub-HR], 0.53 [95% CI, 0.39-0.70]), and similar risks for stroke/systemic embolism (incidence rate, 1.9 versus 2.4 per 100 person-years; sub-HR, 0.80 [95% CI, 0.59-1.09]) and death (incidence rate, 4.6 versus 4.5 per 100 person-years; HR, 1.03 [95% CI, 0.82-1.29]). Rivaroxaban versus warfarin was associated with a higher risk of major bleeding (incidence rate, 4.9 versus 2.9 per 100 person-years; sub-HR, 1.65 [95% CI, 1.10-2.48]), with no difference in risks for stroke/systemic embolism and death. Apixaban versus rivaroxaban was associated with a lower risk of major bleeding (sub-HR, 0.53 [95% CI, 0.36-0.78]). CONCLUSIONS: These real-world findings are consistent with potential safety advantages of apixaban over warfarin and rivaroxaban for patients with atrial fibrillation and severe chronic kidney disease. Further randomized trials comparing individual oral anticoagulants are warranted.

GLP-1RA vs DPP-4i Use and Rates of Hyperkalemia and RAS Blockade Discontinuation in Type 2 Diabetes.

Importance: Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk. Objective: To compare rates of hyperkalemia and RASi persistence among new users of GLP-1RAs vs dipeptidyl peptidase-4 inhibitors (DPP-4is). Design, Setting, and Participants: This cohort study included all adults with T2D in the region of Stockholm, Sweden, who initiated GLP-1RA or DPP-4i treatment between January 1, 2008, and December 31, 2021. Analyses were conducted between October 1, 2023, and April 29, 2024. Exposures: GLP-1RAs or DPP-4is. Main Outcomes and Measures: The primary study outcome was time to any hyperkalemia (potassium level >5.0 mEq/L) and moderate to severe (potassium level >5.5 mEq/L) hyperkalemia. Time to discontinuation of RASi use among individuals using RASis at baseline was assessed. Inverse probability of treatment weights served to balance more than 70 identified confounders. Marginal structure models were used to estimate per-protocol hazard ratios (HRs). Results: A total of 33 280 individuals (13 633 using GLP-1RAs and 19 647 using DPP-4is; mean [SD] age, 63.7 [12.6] years; 19 853 [59.7%] male) were included. The median (IQR) time receiving treatment was 3.9 (1.0-10.9) months. Compared with DPP-4i use, GLP-1RA use was associated with a lower rate of any hyperkalemia (HR, 0.61; 95% CI, 0.50-0.76) and moderate to severe (HR, 0.52; 95% CI, 0.28-0.84) hyperkalemia. Of 21 751 participants who were using RASis, 1381 discontinued this therapy. The use of GLP-1RAs vs DPP-4is was associated with a lower rate of RASi discontinuation (HR, 0.89; 95% CI, 0.82-0.97). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. Conclusions: In this study of patients with T2D managed in routine clinical care, the use of GLP-1RAs was associated with lower rates of hyperkalemia and sustained RASi use compared with DPP-4i use. These findings suggest that GLP-1RA treatment may enable wider use of guideline-recommended medications and contribute to clinical outcomes in this population.

Prescription Patterns for Sodium-Glucose Cotransporter 2 Inhibitors in U.S. Health Systems.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure (HF) hospitalizations, recurrent cardiovascular events, and chronic kidney disease (CKD) progression, and thus constitute a Class 1a recommendation in people with diabetes and atherosclerotic cardiovascular disease, HF, or CKD and in people with severe albuminuria or HF, regardless of diabetes status. OBJECTIVES: The purpose of this study was to comprehensibly characterize the rate of SGLT2 inhibitor prescriptions among people with a Class 1a recommendation for SGLT2 inhibitor use. METHODS: Among 3,189,827 adults from 28 U.S. health systems within Optum Labs Data Warehouse between April 1, 2022, and March 31, 2023, we assessed SGLT2 inhibitor prescription rates, stratified by presence of diabetes and Class 1a recommendation. RESULTS: Among 716,387 adults with diabetes, 63.4% had a Class 1a recommendation for SGLT2 inhibitor therapy. There was little difference by Class 1a recommendation status (present: 11.9%; 95% CI: 11.9%-12.0% vs absent: 11.4%; 95% CI: 11.3%-11.6%; standardized mean difference: 1.3%). Among 2,473,440 adults without diabetes, 6.2% had a Class 1a recommendation for SGLT2 inhibitor therapy, and 3.1% (3.0%-3.2%) of those received a prescription. Internists/family practitioners initiated SGLT2 inhibitor prescriptions most commonly among people with diabetes, whereas specialists initiated SGLT2 inhibitor prescriptions most commonly among people without diabetes. No health system had >25% SGLT2 inhibitor prescription rate among people with a Class 1a recommendation. Health systems with higher proportions of patients with commercial insurance and lower proportions with Medicare had higher SGLT2 inhibitor prescription rates. CONCLUSIONS: In this analysis of U.S. data from 2022 to 2023, SGLT2 inhibitor prescription among people with a Class 1a recommendation is low. Interventions are needed to increase uptake of guideline-recommended SGLT2 inhibitor use.

Plasma proteomics of acute tubular injury.

The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ's metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development. Using the SomaScan proteomics platform on 434 patients with biopsy-confirmed kidney disease, we here identify plasma biomarkers associated with ATI severity. We employ regional transcriptomics and proteomics, single-cell RNA sequencing, and pathway analysis to explore biomarker protein and gene expression and enriched biological pathways. Additionally, we examine ATI biomarker associations with acute kidney injury (AKI) in the Kidney Precision Medicine Project (KPMP) (n = 44), the Atherosclerosis Risk in Communities (ARIC) study (n = 4610), and the COVID-19 Host Response and Clinical Outcomes (CHROME) study (n = 268). Our findings indicate 156 plasma proteins significantly linked to ATI with osteopontin, macrophage mannose receptor 1, and tenascin C showing the strongest associations. Pathway analysis highlight immune regulation and organelle stress responses in ATI pathogenesis.

Plasma proteins associated with plant-based diets: Results from the Atherosclerosis Risk in Communities (ARIC) study and Framingham Heart Study (FHS).

BACKGROUND & AIMS: Plant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. METHODS: ARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n = 7690) and replication (n = 2543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n = 1358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. RESULTS: In ARIC discovery, a total of 837 diet-protein associations (PDI = 233; provegetarian = 182; hPDI = 406; uPDI = 16) were observed at false discovery rate (FDR) < 0.05. Of these, 453 diet-protein associations (PDI = 132; provegetarian = 104; hPDI = 208; uPDI = 9) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI = 1; provegetarian = 0; hPDI = 8; uPDI = 0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests). CONCLUSIONS: Using large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions.

Plasma proteomic comparisons change as coverage expands for SomaLogic and Olink.

The number of assays on highly-multiplexed proteomic platforms has grown tenfold over the past 15 years from less than 1,000 to >11,000. The leading aptamer-based and antibody-based platforms have different strengths. For example, Eldjarn et al1 demonstrated that the aptamer-based SomaScan 5k (4,907 assays, assessed in the Icelandic 36K) and the antibody-based Olink Explore 3072 (2,931 assays, assessed in the UK BioBank) had a similar number of cis-pQTLs among all targets (2,120 vs. 2,101) but Olink had a greater number of cis-pQTLs among the overlapping targets (1,164 vs. 1,467). Analysis of split plasma measures showed the SomaScan assays to be more precise: median coefficient of variation (CV) of 9.9% vs. 16.5% for Olink.1 Precision of the newest versions of the platforms-SomaScan 11k (>11,000 assays, released in December 2023) and Olink Explore HT (>5,400 assays, released in July 2023)-has not yet been established. We assessed the reproducibility of the SomaScan 11k and Olink Explore HT using split plasma samples from 102 Atherosclerosis Risk in Communities (ARIC) Study participants. We found that the SomaScan 11k assays had a median CV of 6.8% (vs 6.6% for the subset of assays available on the SomaScan 5k) and the Olink Explore HT assays had a median CV of 35.7% (vs 19.8% for the subset of assays available on the Olink Explore 3072). Across Olink assays, the CVs were strongly negatively correlated with protein detectability, i.e., percent of samples above the limit of detection (LOD). For the 4,443 overlapping assays, the distribution of between-platform correlations was bimodal with a peak at r~0 and with another smaller peak at r~0.8. These findings on precision are consistent with the updated results by Eldjarn et al1 but indicate that precision of these two leading platforms in human plasma has diverged as the number of included proteins has increased.

Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis.

Physical frailty is a syndrome that typically manifests in later life, although the pathogenic process causing physical frailty likely begins decades earlier. To date, few studies have examined the biological signatures in mid-life associated with physical frailty later in life. Among 4,189 middle-aged participants (57.8 ± 5.0 years, 55.8% women) from the Atherosclerosis Risk in Community (ARIC) study, we evaluated the associations of 4,955 plasma proteins (log 2-transformed and standardized) measured using the SomaScan platform with their frailty status approximately 20 years later. Using multinomial logistic regression models adjusting for demographics, health behaviors, kidney function, total cholesterol, and comorbidities, 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Top frailty-associated proteins included neurocan core protein (NCAN, OR = 0.66), fatty acid-binding protein heart (FABP3, OR = 1.62) and adipocyte (FABP4, OR = 1.65), as well proteins involved in the contactin-1 (CNTN1), toll-like receptor 5 (TLR5), and neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway relevant to skeletal muscle regeneration, myelination, and inflammation. Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. After further adjusting for midlife body mass index (BMI) - an established frailty risk factor - only CNTN1 (OR = 0.75) remained significantly associated with frailty. Post-hoc analyses demonstrated that the top 41 midlife frailty-associated proteins mediate 32% of the association between mid-life BMI and late-life frailty. Our findings provide new insights into frailty etiology earlier in the life course, enhancing the potential for prevention.

Extreme Humid-Heat Exposure and Mortality Among Patients Receiving Dialysis.

RATIONALE & OBJECTIVE: Exposure to extreme heat events has been linked to increased morbidity and mortality in the general population. Patients receiving maintenance dialysis may be vulnerable to greater risks from these events, but this is not well understood. We characterized the association of extreme heat events and the risk of death among patients receiving dialysis in the United States. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Data from the US Renal Data System were used to identify adults living in US urban settlements prone to extreme heat who initiated maintenance dialysis between 1997 and 2016. EXPOSURE: An extreme heat event, defined as a time-updated heat index (a humid-heat metric) exceeding 40.6°C for≥2 days or 46.1°C for≥1day. OUTCOME: Death. ANALYTICAL APPROACH: Cox proportional hazards regression to estimate the elevation in risk of death during a humid-heat event adjusted for age, sex, year of dialysis initiation, dialysis modality, poverty level, and climate region. Interactions between humid-heat and these same factors were explored. RESULTS: Among 945,251 adults in 245 urban settlements, the mean age was 63 years, and 44% were female. During a median follow-up period of 3.6 years, 498,049 adults were exposed to at least 1 of 7,154 extreme humid-heat events, and 500,025 deaths occurred. In adjusted models, there was an increased risk of death (hazard ratio 1.18 [95% CI, 1.15-1.20]) during extreme humid-heat exposure. The relative mortality risk was higher among patients living in the Southeast (P<0.001) compared with the Southwest. LIMITATIONS: Possibility of exposure misclassification, did not account for land use and air pollution co-exposures. CONCLUSIONS: This study suggests that patients receiving dialysis face an increased risk of death during extreme humid-heat exposure. PLAIN-LANGUAGE SUMMARY: Patients who receive dialysis are vulnerable to extreme weather events, and rising global temperatures may bring more frequent extreme heat events. We sought to determine whether extreme heat exposure was associated with an increased risk of death in urban-dwelling patients receiving dialysis across the United States. We found that people receiving dialysis were more likely to die during extreme humid-heat events, defined by a heat index exceeding 40.6°C (105°F) for≥2 days or 46.1°C (115°F) for≥1day. These findings inform the nephrology community about the potential importance of protecting patients receiving maintenance dialysis from the risks associated with extreme heat.

Pneumococcal vaccination effectiveness (PCV13 and PPSV23) in individuals with and without reduced kidney function: a test-negative design study.

Background: Streptococcus pneumoniae vaccination effectiveness (VE) in individuals with reduced kidney function is unknown. We estimated pneumococcal conjugate vaccine (PCV13), pneumococcal polysaccharide vaccine (PPSV23), and combined PCV13 and PPSV23 effectiveness against pneumococcal disease in individuals with and without reduced estimated glomerular filtration rate (eGFR). Methods: All eligible individuals (case and controls) were adults (aged ≥18 years) hospitalized within the Geisinger Health System and required to have S. pneumoniae urinary antigen testing (i.e. test-negative design). Vaccination records were obtained from the electronic health record and statewide vaccination registry. After controlling for the probability of receiving a pneumococcal vaccine, we used multivariable logistic regression models to estimate the odds ratios (ORs) of vaccination between those who did and did not meet the S. pneumoniae case definition. VE was calculated as (1 - OR) × 100%. Results: There were 180 cases and 3889 controls (mean age 69 years, female 48%, white 97%, mean eGFR 71 mL/min/1.73 m2). The adjusted population PCV13 VE was 39% (95% CI 13%-58%), and combination PCV13 and PPSV23 was 39% (95% CI 12%-58%). PPSV23 VE was -3.7% (95% CI -57% to 32%). Stratified by eGFR, adjusted PCV13 VE was consistent in eGFR ≥60 [VE 38% (95% CI 2.9%-61%)] and 30-59 [VE 61% (95% CI 24%-80%)] without significant interaction. VE was not calculable for eGFR <30 due to small sample size. Conclusion: PCV13 vaccination was associated with reduced risk of S. pneumoniae hospitalization in individuals with a reduced eGFR (30-59 mL/min/1.73 m2).

Consistency of metabolite associations with measured glomerular filtration rate in children and adults.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.

Associations of Urine and Plasma Metabolites With Kidney Failure and Death in a Chronic Kidney Disease Cohort.

RATIONALE & OBJECTIVE: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. STUDY DESIGN: Prospective metabolome-wide association study. SETTING & PARTICIPANTS: Persons with CKD enrolled in the GCKD (German CKD) study with metabolite measurements, with external validation within the ARIC (Atherosclerosis Risk in Communities) Study. EXPOSURES: 1,513 urine and 1,416 plasma metabolites (Metabolon Inc) measured at study entry using untargeted mass spectrometry. OUTCOMES: Main end points were kidney failure (KF) and a composite kidney end point (CKE) of KF, estimated glomerular filtration rate<15mL/min/1.73m2, or a 40% decrease in estimated glomerular filtration rate. Death from any cause was a secondary end point. After a median of 6.5 years of follow-up, 500 persons had experienced KF, 1,083 had experienced the CKE, and 680 had died. ANALYTICAL APPROACH: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design with external validation. RESULTS: 5,088 GCKD study participants were included in analyses of urine metabolites, and 5,144 were included in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with the CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (HR, 1.95; 95% CI, 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, the CKE, and death. External validation of the identified associations of metabolites with KF or the CKE revealed directional consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LIMITATIONS: Use of observational data and semiquantitative metabolite measurements at a single time point. CONCLUSIONS: The observed associations between metabolites and KF, the CKE, or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts. PLAIN-LANGUAGE SUMMARY: Incomplete understanding of the variability of chronic kidney disease (CKD) progression motivated the search for new biomarkers that would help identify people at increased risk. We explored metabolites in plasma and urine for their association with unfavorable kidney outcomes or death in persons with CKD. Metabolomic analyses revealed 182 metabolites significantly associated with CKD progression or death. Many of these associations confirmed previously reported findings or were validated by analysis in an external study population. Our comprehensive screen of the metabolome serves as a valuable foundation for future investigations into biomarkers associated with CKD progression.

Dihydropyridine Calcium Channel Blockers and Kidney Outcomes.

BACKGROUND: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. OBJECTIVE: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. DESIGN: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. PARTICIPANTS: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. MAIN MEASURES: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. KEY RESULTS: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). CONCLUSIONS: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.