Publications by authors named "Adriana M Hung"

91 Publications

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Nat Commun 2021 07 16;12(1):4350. Epub 2021 Jul 16.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.
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http://dx.doi.org/10.1038/s41467-021-24491-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285412PMC
July 2021

Comparison of COVID-19 versus influenza on the incidence, features, and recovery from acute kidney injury in hospitalized United States Veterans.

Kidney Int 2021 Jun 7. Epub 2021 Jun 7.

Vanderbilt University Medical Center, Division of Nephrology and Hypertension, Vanderbilt Center for Kidney Disease and Integrated Program for Acute Kidney Injury Research, Nashville, Tennessee, USA; VA Tennessee Valley, Health Services Research and Development; VA Geriatrics Research Education and Clinical Center, Tennessee Valley Health System, Veteran's Health Administration, Nashville, Tennessee, USA. Electronic address:

Acute kidney injury is a common complication in patients hospitalized with SARSCoV-2 (COVID-19), with prior studies implicating multiple potential mechanisms of injury. Although COVID-19 is often compared to other respiratory viral illnesses, few formal comparisons of these viruses on kidney health exist. In this retrospective cohort study, we compared the incidence, features, and outcomes of acute kidney injury among Veterans hospitalized with COVID-19 or influenza and adjusted for baseline conditions using weighted comparisons. A total of 3402 hospitalizations for COVID-19 and 3680 hospitalizations for influenza admitted between October 1, 2019 and May 31, 2020 across 127 Veterans Administration hospitals nationally were studied using the electronic medical record. Acute kidney injury occurred more frequently among those with COVID-19 compared to those with influenza (40.9% versus 29.4%, weighted analysis) and was more severe. Patients with COVID-19 were more likely to require mechanical ventilation and vasopressors and experienced higher mortality. Proteinuria and hematuria were frequent in both groups but more common in COVID-19. Recovery of kidney function was less common in patients with COVID-19 and acute kidney injury but was similar among survivors. Thus, findings from this study confirm that acute kidney injury is more common and severe among patients hospitalized with COVID-19 compared to influenza, a finding that may be driven largely by illness severity. Hence, the combined impact of these two illnesses on kidney health may be significant and have important implications for resource allocation.
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http://dx.doi.org/10.1016/j.kint.2021.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183091PMC
June 2021

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Nat Med 2021 04 9;27(4):668-676. Epub 2021 Apr 9.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10; IFNAR2, P = 9.8 × 10 and IL-10RB, P = 2.3 × 10) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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http://dx.doi.org/10.1038/s41591-021-01310-zDOI Listing
April 2021

Hospitalization for Heart Failure Among Patients With Diabetes Mellitus and Reduced Kidney Function Treated With Metformin Versus Sulfonylureas: A Retrospective Cohort Study.

J Am Heart Assoc 2021 Apr 6:e019211. Epub 2021 Apr 6.

Veteran Administration Tennessee Valley VA Health Care System Geriatric Research Education Clinical Center (GRECC) Nashville TN.

Background Metformin and sulfonylurea are commonly prescribed oral medications for type 2 diabetes mellitus. The association of metformin and sulfonylureas on heart failure outcomes in patients with reduced estimated glomerular filtration rate remains poorly understood. Methods and Results This retrospective cohort combined data from National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylurea who reached an estimated glomerular filtration rate of 60 mL/min per 1.73 m or serum creatinine of 1.5 mg/dL and continued metformin or sulfonylurea were included. The primary outcome was hospitalization for heart failure. Echocardiogram reports were obtained to determine each patient's ejection fraction (EF) (reduced EF <40%; midrange EF 40%-49%; ≥50%). The primary analysis estimated the cause-specific hazard ratios for metformin versus sulfonylurea and estimated the cumulative incidence functions for heart failure hospitalization and competing events. The weighted cohort included 24 685 metformin users and 24 805 sulfonylurea users with reduced kidney function (median age 70 years, estimated glomerular filtration rate 55.8 mL/min per 1.73 m). The prevalence of underlying heart failure (12.1%) and cardiovascular disease (31.7%) was similar between groups. There were 16.9 (95% CI, 15.8-18.1) versus 20.7 (95% CI, 19.5-22.0) heart failure hospitalizations per 1000 person-years for metformin and sulfonylurea users, respectively, yielding a cause-specific hazard of 0.85 (95% CI, 0.78-0.93). Among heart failure hospitalizations, 44.5% did not have echocardiogram information available; 29.3% were categorized as reduced EF, 8.9% as midrange EF, and 17.2% as preserved EF. Heart failure hospitalization with reduced EF (hazard ratio, 0.79; 95% CI, 0.67-0.93) and unknown EF (hazard ratio, 0.84; 95% CI 0.74-96) were significantly lower in metformin versus sulfonylurea users. Conclusions Among patients with type 2 diabetes mellitus who developed worsening kidney function, persistent metformin compared with sulfonylurea use was associated with reduced heart failure hospitalization.
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http://dx.doi.org/10.1161/JAHA.120.019211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174186PMC
April 2021

Associations of biogeographic ancestry with hypertension traits.

J Hypertens 2021 Apr;39(4):633-642

Vanderbilt Genetics Institute, Vanderbilt University.

Objectives: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits.

Methods: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples.

Results: Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion).

Conclusion: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.
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http://dx.doi.org/10.1097/HJH.0000000000002701DOI Listing
April 2021

Kidney disease genetic risk variants alter lysosomal beta-mannosidase () expression and disease severity.

Sci Transl Med 2021 01;13(576)

Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney-specific expression quantitative trait analysis and identified that the expression of beta-mannosidase () was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in using phenome-wide association analysis of 40,963 subjects with exome sequencing data. is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. loss altered multiple pathways, including endocytosis and autophagy. In the absence of toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.
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http://dx.doi.org/10.1126/scitranslmed.aaz1458DOI Listing
January 2021

Variants, N-Acetylated Amino Acids, and Progression of CKD.

Clin J Am Soc Nephrol 2020 12;16(1):37-47

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

Background And Objectives: Genetic variants in , a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two -associated metabolites, N--acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in , N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts.

Design, Setting, Participants, & Measurements: We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; =962), the Atherosclerosis Risk in Communities (ARIC) study (=1050), and Bio, an electronic health record-linked biorepository (=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (=1624).

Results: Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N--acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study.

Conclusions: We demonstrate significant associations between an gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.
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http://dx.doi.org/10.2215/CJN.08600520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792648PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Renin-angiotensin aldosterone inhibitor use at hospital discharge among patients with moderate to severe acute kidney injury and its association with recurrent acute kidney injury and mortality.

Kidney Int 2021 05 8;99(5):1202-1212. Epub 2020 Sep 8.

VA Tennessee Valley, Health Services Research and Development, Nashville, Tennessee, USA; VA Geriatrics Research Education and Clinical Center (GRECC), Tennessee Valley Health System (THVS), Veteran's Health Administration, Nashville, Tennessee, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Recurrent episodes of acute kidney injury (AKI) are common among AKI survivors. Renin-angiotensin aldosterone inhibitors (RAASi) are often indicated for these patients but may increase the risk for recurrent AKI. Here, we examined whether RAASi associates with a higher risk for recurrent AKI and mortality among survivors of moderate to severe AKI in a retrospective cohort of Veterans who survived Stage II or III AKI. The primary exposure was RAASi at hospital discharge and the primary endpoint was recurrent AKI within 12 months. Cox proportional hazards models were fit on a propensity score-weighted cohort to compare time to recurrent AKI and mortality by RAASi exposure. Among 96,983 patients, 40% were on RAASi at discharge. Compared to patients who continued RAASi use, those discontinuing use experienced no difference in risk for recurrent AKI but had a significantly higher risk of mortality [hazard ratio 1.33 (95% confidence interval1.26-1.41)]. No differences in recurrent AKI risk was observed for non-users started or not on RAASi compared to prevalent users who continued RAASi. Subgroup analyses among those with diabetes, chronic kidney disease, heart failure, and malignancy were similar with exception of a modest reduction in recurrent AKI risk among RAASi discontinuers with chronic kidney disease. Thus, RAASi use among survivors of moderate to severe AKI was associated with little to no difference in risk for recurrent AKI but was associated with improved survival. Reinitiating or starting RAASi among patients with strong indications is warranted but should be balanced with individual overall risk for recurrent AKI and with adequate monitoring.
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http://dx.doi.org/10.1016/j.kint.2020.08.022DOI Listing
May 2021

A Description of Risk Factors for Non-alcoholic Fatty Liver Disease in the Southern Community Cohort Study: A Nested Case-Control Study.

Front Nutr 2020 21;7:71. Epub 2020 May 21.

Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, TN, United States.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and hypercholesterolemia. In addition, total fat and folate intake have been associated with NAFLD. We investigated risk factors for NAFLD among individuals of largely low socioeconomic status, and whether these associations differed by race. A nested case-control study was conducted within the Southern Community Cohort Study. Through linkage of the cohort with Centers for Medicare and Medicaid Services, International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify incident NAFLD cases. Controls were matched 4:1 to cases on enrollment age, sex, and race. A logistic regression was used to estimate odds ratios for the associations of NAFLD with covariates of interest. Neither total fat nor folate intake was significantly associated with NAFLD. Hypercholesterolemia (odds ratio 1.21) and body mass index (75th vs. 25th percentile) for blacks (odds ratio 1.96) and whites (odds ratio 2.33) were associated with an increased risk of non-alcoholic fatty liver disease. No significant interaction with race for any of the studied variables was noted. Both hypercholesterolemia and increasing body mass index, but not total fat and folate intake, were risk factors for NAFLD in the Southern Community Cohort Study.
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http://dx.doi.org/10.3389/fnut.2020.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326146PMC
May 2020

Pro-inflammatory HDL in women with obesity and nonalcoholic steatohepatitis.

Obes Res Clin Pract 2020 Jul - Aug;14(4):333-338. Epub 2020 Jun 25.

Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Background: Individuals with non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), are at increased risk for cardiovascular events, independent of traditional risk factors. Limited data on pro-inflammatory high density lipoprotein (HDL) in NASH exists in the literature. We hypothesized that HDL from individuals with NASH would be more pro-inflammatory than HDL from individuals without NASH.

Methods: Study participants were individuals with obesity who had undergone bariatric surgery with wedge liver biopsy. Using HDL isolated from serum obtained from study participants at the time of surgery, HDL-elicited macrophage cytokine expression (TNF-α, IL-1β, and IL-6) from THP-1 macrophages, HDL-associated receptor expression (ABCA1 and ABCG1) from apolipoprotein E deficient (apo E) mouse peritoneal macrophages, and isolevuglandin (isoLG) modified HDL were measured.

Results: 11 women with NASH and 15 women without NASH were included in the study. Both TNF-α (P = 0.032) and IL-1β (P = 0.029) were significantly more expressed by THP-1 macrophages exposed to HDL from women with NASH compared to women without NASH. ABCA1 and ABCG1 expression by apo E mouse peritoneal macrophages was not significantly different when exposed to HDL from either women with NASH or women without NASH. IsoLG-modified HDL isolated from the serum of women with NASH trended higher than women without NASH.

Conclusion: Our study suggests a more pro-inflammatory HDL in women with obesity and NASH compared to women with obesity and without NASH.
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http://dx.doi.org/10.1016/j.orcp.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507596PMC
June 2020

The polygenic architecture of left ventricular mass mirrors the clinical epidemiology.

Sci Rep 2020 05 5;10(1):7561. Epub 2020 May 5.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.
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http://dx.doi.org/10.1038/s41598-020-64525-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200691PMC
May 2020

Hospitalization for Lactic Acidosis Among Patients With Reduced Kidney Function Treated With Metformin or Sulfonylureas.

Diabetes Care 2020 07 23;43(7):1462-1470. Epub 2020 Apr 23.

Geriatric Research Education Clinical Center, Tennessee Valley Healthcare System, Veterans Health Administration, Nashville, TN

Objective: To compare the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function.

Research Design And Methods: This retrospective cohort combined data from the National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylureas were followed from development of reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m or serum creatinine ≥1.4 mg/dL [female] or 1.5 mg/dL [male]) through hospitalization for lactic acidosis, death, loss to follow-up, or study end. Lactic acidosis hospitalization was defined as a composite of primary discharge diagnosis or laboratory-confirmed lactic acidosis (lactic acid ≥2.5 mmol/L and either arterial blood pH <7.35 or serum bicarbonate ≤19 mmol/L within 24 h of admission). We report the cause-specific hazard of lactic acidosis hospitalization between metformin and sulfonylureas from a propensity score-matched weighted cohort and conduct an additional competing risks analysis to account for treatment change and death.

Results: The weighted cohort included 24,542 metformin users and 24,662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8 mL/min/1.73 m). There were 4.18 (95% CI 3.63, 4.81) vs. 3.69 (3.19, 4.27) lactic acidosis hospitalizations per 1,000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio [aHR] 1.21 [95% CI 0.99, 1.50]). Results were consistent for both primary discharge diagnosis (aHR 1.11 [0.87, 1.44]) and laboratory-confirmed lactic acidosis (1.25 [0.92, 1.70]).

Conclusions: Among veterans with diabetes who developed reduced kidney function, occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those patients who continued sulfonylureas.
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http://dx.doi.org/10.2337/dc19-2391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305006PMC
July 2020

Blood Pressure Control and the Association With Diabetes Mellitus Incidence: Results From SPRINT Randomized Trial.

Hypertension 2020 02 23;75(2):331-338. Epub 2019 Dec 23.

Memphis Veterans Affairs Medical Center and University of Tennessee Health Science Center, Memphis (W.C.C.).

The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reduced cardiovascular outcomes. We evaluated diabetes mellitus incidence in this randomized trial that compared intensive blood pressure strategy (systolic blood pressure <120 mm Hg) versus standard strategy (<140 mm Hg). Participants were ≥50 years of age, with systolic 130 to 180 mm Hg and increased cardiovascular risk. Participants were excluded if they had diabetes mellitus, polycystic kidney disease, proteinuria >1 g/d, heart failure, dementia, or stroke. Postrandomization exclusions included participants missing blood glucose or ≥126 mg/dL (6.99 mmol/L) or on hypoglycemics. The outcome was incident diabetes mellitus: fasting blood glucose ≥126 mg/dL (6.99 mmol/L), diabetes mellitus self-report, or new use of hypoglycemics. The secondary outcome was impaired fasting glucose (100-125 mg/dL [5.55-6.94 mmol/L]) among those with normoglycemia (<100 mg/dL [5.55 mmol/L]). There were 9361 participants randomized and 981 excluded, yielding 4187 and 4193 participants assigned to intensive and standard strategies. There were 299 incident diabetes mellitus events (2.3% per year) for intensive and 251 events (1.9% per year) for standard, rates of 22.6 (20.2-25.3) versus 19.0 (16.8-21.5) events per 1000 person-years of treatment, respectively (adjusted hazard ratio, 1.19 [95% CI, 0.95-1.49]). Impaired fasting glucose rates were 26.4 (24.9-28.0) and 22.5 (21.1-24.1) per 100 person-years for intensive and standard strategies (adjusted hazard ratio, 1.17 [1.06-1.30]). Intensive treatment strategy was not associated with increased diabetes mellitus but was associated with more impaired fasting glucose. The risks and benefits of intensive blood pressure targets should be factored into individualized patient treatment goals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015147PMC
February 2020

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.

Am J Hypertens 2019 11;32(12):1146-1153

Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.

Background: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

Methods: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

Results: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

Conclusion: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
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http://dx.doi.org/10.1093/ajh/hpz150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856621PMC
November 2019

Timing of Recovery From Moderate to Severe AKI and the Risk for Future Loss of Kidney Function.

Am J Kidney Dis 2020 02 16;75(2):204-213. Epub 2019 Sep 16.

VA Tennessee Valley Health System, Health Services Research and Development, Nashville, TN; VA Geriatrics Research Education and Clinical Center, Tennessee Valley Health System, Veteran's Health Administration, Nashville, TN; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.

Rationale & Objective: The extent of recovery of kidney function following acute kidney injury (AKI) is known to be associated with future chronic kidney disease. Less is known about how the timing of recovery affects the rate of future loss of kidney function.

Study Design: We performed a retrospective cohort study examining the independent association between the timing of recovery from moderate to severe AKI and future loss of kidney function.

Setting & Participants: 47,903 adult US veterans with stage 2 or 3 AKI who recovered to within 120% of baseline creatinine level within 90 days of peak injury.

Exposure: The timing of recovery of kidney function from peak inpatient serum creatinine level grouped into 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days.

Outcome: A sustained 40% decline in estimated glomerular filtration rate below that calculated from the last serum creatinine level available during the 90-day recovery period or kidney failure (2 outpatient estimated glomerular filtration rates<15mL/min/1.73m, dialysis procedures > 90 days apart, kidney transplantation, or registry within the US Renal Data System).

Analytical Approach: Time to the primary outcome was examined using multivariable Cox proportional hazards regression.

Results: Among 47,903 patients, 29,316 (61%), 10,360 (22%), 4,520 (9%), and 3,707 (8%) recovered within 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days, respectively. With a median follow-up of 42 months, unadjusted incidence rates for the kidney outcome were 2.01, 3.55, 3.86, and 3.68 events/100 person-years, respectively. Compared with 1 to 4 days, recovery within 5 to 10, 11 to 30, and 31 to 90 days was associated with increased rates of the primary outcome: adjusted HRs were 1.33 (95% CI, 1.24-1.43), 1.41 (95% CI, 1.28-1.54), and 1.58 (95% CI, 1.43-1.75), respectively.

Limitations: Predominately male population, residual confounding, and inability to make causal inferences because of the retrospective observational study design.

Conclusions: The timing of recovery provides an added dimension to AKI phenotyping and prognostic information regarding the future occurrence of loss of kidney function. Studies to identify effective interventions on the timing of recovery from AKI are warranted.
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http://dx.doi.org/10.1053/j.ajkd.2019.05.031DOI Listing
February 2020

Association of Treatment With Metformin vs Sulfonylurea With Major Adverse Cardiovascular Events Among Patients With Diabetes and Reduced Kidney Function.

JAMA 2019 Sep;322(12):1167-1177

Veteran Administration Tennessee Valley VA Health Care System Geriatric Research Education Clinical Center, Nashville.

Importance: Before 2016, safety concerns limited metformin use in patients with kidney disease; however, the effectiveness of metformin on clinical outcomes in patients with reduced kidney function remains unknown.

Objective: To compare major adverse cardiovascular events (MACE) among patients with diabetes and reduced kidney function who continued treatment with metformin or a sulfonylurea.

Design, Setting, And Participants: Retrospective cohort study of US veterans receiving care within the national Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016. There were 174 882 persistent new users of metformin and sulfonylureas who reached a reduced kidney function threshold (estimated glomerular filtration rate <60 mL/min/1.73 m2 or creatinine ≥1.4 mg/dL for women or ≥1.5 mg/dL for men). Patients were followed up from reduced kidney function threshold until MACE, treatment change, loss to follow-up, death, or study end (December 2016).

Exposures: New users of metformin or sulfonylurea monotherapy who continued treatment with their glucose-lowering medication after reaching reduced kidney function.

Main Outcomes And Measures: MACE included hospitalization for acute myocardial infarction, stroke, transient ischemic attack, or cardiovascular death. The analyses used propensity score weighting to compare the cause-specific hazard of MACE between treatments and estimate cumulative risk accounting for the competing risks of changing therapy or noncardiovascular death.

Results: There were 67 749 metformin and 28 976 sulfonylurea persistent monotherapy users; the weighted cohort included 24 679 metformin and 24 799 sulfonylurea users (median age, 70 years [interquartile range {IQR}, 62.8-77.8]; 48 497 men [98%]; and 40 476 white individuals [82%], with median estimated glomerular filtration rate of 55.8 mL/min/1.73 m2 [IQR, 51.6-58.2] and hemoglobin A1c level of 6.6% [IQR, 6.1%-7.2%] at cohort entry). During follow-up (median, 1.0 year for metformin vs 1.2 years for sulfonylurea), there were 1048 MACE outcomes (23.0 per 1000 person-years) among metformin users and 1394 events (29.2 per 1000 person-years) among sulfonylurea users. The cause-specific adjusted hazard ratio of MACE for metformin was 0.80 (95% CI, 0.75-0.86) compared with sulfonylureas, yielding an adjusted rate difference of 5.8 (95% CI, 4.1-7.3) fewer events per 1000 person-years of metformin use compared with sulfonylurea use.

Conclusions And Relevance: Among patients with diabetes and reduced kidney function persisting with monotherapy, treatment with metformin, compared with a sulfonylurea, was associated with a lower risk of MACE.
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http://dx.doi.org/10.1001/jama.2019.13206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753652PMC
September 2019

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Nat Commun 2019 09 11;10(1):4130. Epub 2019 Sep 11.

Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.

Nat Commun 2019 08 26;10(1):3842. Epub 2019 Aug 26.

Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.
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http://dx.doi.org/10.1038/s41467-019-11704-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710266PMC
August 2019

Racial disparities in end-stage renal disease in a high-risk population: the Southern Community Cohort Study.

BMC Nephrol 2019 08 7;20(1):308. Epub 2019 Aug 7.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Ave, Ste 600, Nashville, TN, 37203, USA.

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/1.73m 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.
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http://dx.doi.org/10.1186/s12882-019-1502-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686512PMC
August 2019

Evaluation of weight change and hypoglycaemia as mediators in the association between insulin use and death.

Diabetes Obes Metab 2019 12 29;21(12):2626-2634. Epub 2019 Aug 29.

GRECC, Veterans Health Administration (VHA) Tennessee Valley Healthcare System, Geriatric Research and Education Clinical Center (GRECC), HSR&D Center, Nashville, Tennessee.

Aim: To evaluate whether weight change or hypoglycaemia mediates the association between insulin use and death.

Materials And Methods: In a retrospective cohort of veterans who filled a new prescription for metformin and added insulin or sulphonylurea (2001-2012), we assessed change in body mass index (BMI) and hypoglycaemia during the first 12 months of treatment intensification. Cox proportional hazards models compared the risk of death between treatment groups. Using the difference method, we estimated the indirect effect and proportion mediated through each mediator. A sensitivity analysis assessed mediators in the first 6 months of intensified therapy.

Results: Among 28 892 patients surviving 12 months, deaths per 1000 person-years were 15.4 for insulin users and 12.9 for sulphonylurea users (HR 1.20, 95% CI 0.87, 1.64). Change in BMI and hypoglycaemia mediated 13% (-98, 98) and -1% (-37, 71) of this association, respectively. Among 30 214 patients surviving 6 months, deaths per 1000 person-years were 34.8 for insulin users and 21.3 for sulphonylurea users (HR 1.66, 95% CI 1.28, 2.15). Change in BMI and hypoglycaemia mediated 9% (1, 23) and 0% (-9, 4) of this association, respectively.

Conclusions: We observed an increased risk of death among metformin users intensifying treatment with insulin versus sulphonylurea and surviving 6 months of intensified therapy, but not among those surviving 12 months. This association was mediated in part by weight change.
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http://dx.doi.org/10.1111/dom.13846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055153PMC
December 2019

Association of Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

Circulation 2019 09 24;140(12):1031-1040. Epub 2019 Jul 24.

Massachusetts General Hospital, Boston (A.G.B., D.K., P.N., S.K.).

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 () risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between risk alleles and cardiovascular disease (CVD) that is independent of the effects of on kidney disease. We sought to test the association of G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program.

Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association.

Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; =0.031). When both cardiovascular and renal outcomes were modeled, was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets.

Conclusions: risk variants display a modest association with CVD, and this association is likely mediated by the known association with chronic kidney disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754626PMC
September 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD.

Clin J Am Soc Nephrol 2019 05 23;14(5):702-711. Epub 2019 Apr 23.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; and

Background And Objectives: Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting of CKD. Whether interventions that modify systemic inflammation can improve HDL function in CKD is unknown.

Design, Setting, Participants, & Measurements: We conducted a analysis of two randomized, clinical trials, IL-1 trap in participants with GFR 15-59 ml/min per 1.73 m (study A) and IL-1 receptor antagonist in participants on maintenance hemodialysis (study B), to evaluate if IL-1 blockade had improved the anti-inflammatory activity (IL-6, TNF-, and Nod-like receptor protein 3), antioxidant function (superoxide production), and net cholesterol efflux capacity of HDL. HDL function was measured using LPS-stimulated THP-1 macrophages or peritoneal macrophages of apoE-deficient mice exposed to the apoB-depleted, HDL-containing fraction obtained from the plasma of the study participants, collected before and after the interventions to block IL-1 effects. Analysis of covariance was used for between group comparisons.

Results: The mean age of the participants was 60±13 years, 72% (=33) were men, and 39% (=18) were black. There were 32 CKD (16 IL-1 trap and 16 placebo) and 14 maintenance hemodialysis (7 IL-1 receptor antagonist and 7 placebo) participants. Compared with placebo, IL-1 inhibition, in study A and B reduced cellular expression of TNF- by 15% (=0.05) and 64% (=0.02), IL-6 by 38% (=0.004) and 56% (=0.08), and Nod-like receptor protein 3 by 16% (=0.01) and 25% (=0.02), respectively. The intervention blunted superoxide production in the treated arm compared with placebo, with the values being higher by 17% in the placebo arm in study A (<0.001) and 12% in the placebo arm in study B (=0.004). Net cholesterol efflux capacity was not affected by either intervention.

Conclusions: IL-1 blockade improves the anti-inflammatory and antioxidative properties of the HDL-containing fraction of plasma in patients with stages 3-5 CKD, including those on maintenance hemodialysis.
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http://dx.doi.org/10.2215/CJN.04360418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500942PMC
May 2019

Accuracy of a composite event definition for hypoglycemia.

Pharmacoepidemiol Drug Saf 2019 05 6;28(5):625-631. Epub 2019 Mar 6.

Veterans Health Administration Tennessee Valley Healthcare System, Geriatric Research and Education Clinical Center (GRECC), HSR&D Center, Nashville, TN, USA.

Purpose: To evaluate the accuracy of a composite definition for the identification of hypoglycemia events that used both administrative claims and laboratory data in a cohort of patients.

Methods: We reviewed medical records in a sample of presumed hypoglycemia events among patients who received care at the Veterans Health Administration Tennessee Valley Healthcare System in 2001 to 2012. A hypoglycemia event was defined as a hospitalization or emergency department visit judged by the treating clinician to be due to hypoglycemia, or an outpatient laboratory or point-of-care blood glucose measurement <60 mg/dL. Based on medical record review, each event was classified as true positive (severe, documented symptomatic, documented asymptomatic) or false positive (probable symptomatic, not hypoglycemia). The positive predictive values (PPV) of the individual event types (hospitalization, emergency department, and outpatient) were estimated.

Results: Of 2250 events identified through the composite definition, 321 events (15 hospitalizations, 103 emergency department visits, and 203 outpatient events) were reviewed. The PPVs were 80% for hospitalization events, 48% for emergency department events, and 96% for outpatient events. The emergency department definition included a nonspecific diagnosis code for diabetic complications which captured many false positive events. Excluding this code from the definition improved the PPV for emergency department events to 70% and missed one true event.

Conclusions: Our composite definition for hypoglycemia performed moderately well in a cohort of Veterans. Further evaluation of the emergency department events may be needed.
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http://dx.doi.org/10.1002/pds.4712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497537PMC
May 2019
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