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Mechanism of Hyperkalemia-Induced Metabolic Acidosis.
Harris AN, Grimm PR, Lee HW, Delpire E, Fang L, Verlander JW, Welling PA, Weiner ID
(2018) J Am Soc Nephrol :
Show Abstract · Added April 3, 2018
Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs.We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK).DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion.Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.
Copyright © 2018 by the American Society of Nephrology.
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Diabetes and CKD in the United States Population, 2009-2014.
Zelnick LR, Weiss NS, Kestenbaum BR, Robinson-Cohen C, Heagerty PJ, Tuttle K, Hall YN, Hirsch IB, de Boer IH
(2017) Clin J Am Soc Nephrol 12: 1984-1990
Show Abstract · Added October 24, 2017
BACKGROUND AND OBJECTIVES - Diabetes is an important cause of CKD. However, among people with diabetes, it is unclear to what extent CKD is attributable to diabetes itself versus comorbid conditions, such as advanced age and hypertension. We examined associations of diabetes with clinical manifestations of CKD independent of age and BP and the extent to which diabetes contributes to the overall prevalence of CKD in the United States.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We performed a cross-sectional study of 15,675 participants in the National Health and Nutrition Examination Surveys from 2009 to 2014. Diabetes was defined by use of glucose-lowering medications or hemoglobin A≥6.5%. eGFR was calculated using the CKD Epidemiology Collaboration formula, and albumin-to-creatinine ratio was measured in single-void urine samples. We calculated the prevalence of CKD manifestations by diabetes status as well as prevalence ratios, differences in prevalence, and prevalence attributable to diabetes using binomial and linear regression, incorporating data from repeat eGFR and urine albumin-to-creatinine ratio measurements to estimate persistent disease.
RESULTS - For participants with diabetes (=2279) versus those without diabetes (=13,396), the estimated prevalence of any CKD (eGFR<60 ml/min per 1.73 m; albumin-to-creatinine ratio ≥30 mg/g, or both) was 25% versus 5.3%, respectively; albumin-to-creatinine ratio ≥30 mg/g was 16% versus 3.0%, respectively; albumin-to-creatinine ratio ≥300 mg/g was 4.6% versus 0.3%, respectively; eGFR<60 ml/min per 1.73 mwas 12% versus 2.5%, respectively; and eGFR<30 ml/min per 1.73 mwas 2.4% versus 0.4%, respectively (each<0.001). Adjusting for demographics and several aspects of BP, prevalence differences were 14.6% (<0.001), 10.8% (<0.001), 4.5% (<0.001), 6.5% (<0.001), and 1.8% (=0.004), respectively. Approximately 24% (95% confidence interval, 19% to 29%) of CKD among all United States adults was attributable to diabetes after adjusting for demographics.
CONCLUSIONS - Diabetes is strongly associated with both albuminuria and reduced GFR independent of demographics and hypertension, contributing substantially to the burden of CKD in the United States.
Copyright © 2017 by the American Society of Nephrology.
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Metabolic Effects of Diet and Exercise in Patients with Moderate to Severe CKD: A Randomized Clinical Trial.
Ikizler TA, Robinson-Cohen C, Ellis C, Headley SAE, Tuttle K, Wood RJ, Evans EE, Milch CM, Moody KA, Germain M, Limkunakul C, Bian A, Stewart TG, Himmelfarb J
(2018) J Am Soc Nephrol 29: 250-259
Show Abstract · Added October 24, 2017
CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F-isoprostane concentrations, and peak oxygen uptake (VO). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.
Copyright © 2018 by the American Society of Nephrology.
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Nephrology Provider Prognostic Perceptions and Care Delivered to Older Adults with Advanced Kidney Disease.
Salat H, Javier A, Siew ED, Figueroa R, Lipworth L, Kabagambe E, Bian A, Stewart TG, El-Sourady MH, Karlekar M, Cardona CY, Ikizler TA, Abdel-Kader K
(2017) Clin J Am Soc Nephrol 12: 1762-1770
Show Abstract · Added September 20, 2017
BACKGROUND AND OBJECTIVES - Prognostic uncertainty is one barrier that impedes providers in engaging patients with CKD in shared decision making and advance care planning. The surprise question has been shown to identify patients at increased risk of dying.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - In our prospective observational study, 488 patients ≥60 years of age with CKD stage 4 or 5 were enrolled. Binary surprise question (, "Would you be surprised if this patient died in the next 12 months?") responses were recorded, and dialysis planning preferences, presence of advance care planning documentation, and care preceding death were abstracted.
RESULTS - The median patient age was 71 (65-77) years old. Providers responded no and yes to the surprise question for 171 (35%) and 317 (65%) patients, respectively. Median follow-up was 1.9 (1.5-2.1) years, during which 18% of patients died (33% of surprise question no, 10% of surprise question yes;<0.001). In patients with a known RRT preference (58%), 13% of surprise question no participants had a preference for conservative management (versus 2% of yes counterparts;<0.001). A medical order (, physician order for life-sustaining treatment) was documented in 13% of surprise question no patients versus 5% of yes patients (=0.004). Among surprise question no decedents, 41% died at home or hospice, 38% used hospice services, and 54% were hospitalized in the month before death. In surprise question yes decedents, 39% died at home or hospice (=0.90 versus no), 26% used hospice services (=0.50 versus no), and 67% were hospitalized in the month before death (=0.40 versus surprise question no).
CONCLUSIONS - Nephrologists' prognostic perceptions were associated with modest changes in care, highlighting a critical gap in conservative management discussions, advance care planning, and end of life care among older adults with CKD stages 4 and 5 and high-risk clinical characteristics.
PODCAST - This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_09_18_CJASNPodcast_17_11.mp3.
Copyright © 2017 by the American Society of Nephrology.
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eGFR and Albuminuria in Relation to Risk of Incident Atrial Fibrillation: A Meta-Analysis of the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study.
Bansal N, Zelnick LR, Alonso A, Benjamin EJ, de Boer IH, Deo R, Katz R, Kestenbaum B, Mathew J, Robinson-Cohen C, Sarnak MJ, Shlipak MG, Sotoodehnia N, Young B, Heckbert SR
(2017) Clin J Am Soc Nephrol 12: 1386-1398
Show Abstract · Added September 19, 2017
BACKGROUND AND OBJECTIVES - The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.
RESULTS - In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.
CONCLUSIONS - In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.
Copyright © 2017 by the American Society of Nephrology.
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Effects of Vitamin DSupplementation on Vitamin DMetabolism in Health and CKD.
Batacchi Z, Robinson-Cohen C, Hoofnagle AN, Isakova T, Kestenbaum B, Martin KJ, Wolf MS, de Boer IH
(2017) Clin J Am Soc Nephrol 12: 1498-1506
Show Abstract · Added September 19, 2017
BACKGROUND AND OBJECTIVES - Vitamin D supplements are prescribed to correct low circulating concentrations of 25-hydroxyvitamin D. In CKD, vitamin D metabolism is complicated by decreased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by CYP27B1 and possibly decreased conversion of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D by CYP24A1. The aim of this study was to determine the effects of vitamin Dsupplementation on vitamin D metabolism in health and CKD.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We conducted a treatment-only intervention study of 25 individuals with CKD (eGFR<60 ml/min per 1.73 m) and 44 individuals without CKD from three academic centers, all with screening 25-hydroxyvitamin D <30 ng/ml. Each participant was prescribed vitamin D(ergocalciferol) 50,000 IU orally twice weekly for 5 weeks. We tested whether changes in plasma concentrations of vitamin D metabolites and vitamin D metabolic ratios differed by CKD status. Plasma 1,25-dihydroxyvitamin D-to-25-hydroxyvitamin Dratio and 24,25-dihydroxyvitamin D-to-25-hydroxyvitamin Dratio were calculated as estimates of CYP27B1 and CYP24A1 function, respectively.
RESULTS - With treatment, plasma 25-hydroxyvitamin Dand total 25-hydroxyvitamin D concentrations increased similarly for participants with and without CKD. For participants without CKD, 1,25-dihydroxyvitamin Dincreased (2.8±1.3-32.9±1.4 pg/ml), whereas 1,25-dihydroxyvitamin Ddecreased (45.6±1.9-14.6±1.9 pg/ml), resulting in no significant change in total 1,25-dihydroxyvitamin D; 1,25-dihydroxyvitamin D-to-25-hydroxyvitamin Dratio decreased (3.0±0.2-1.7±0.2 pg/ng), and 24,25-dihydroxyvitamin D-to-25-hydroxyvitamin Dratio increased (115.7±7.8-195.2±7.9 pg/ng). Individuals with CKD had lower baseline levels and smaller changes in magnitude for 1,25-dihydroxyvitamin D(2.1±1.6-24.4±1.6 pg/ml;interaction =0.01), 1,25-dihydroxyvitamin D-to-25-hydroxyvitamin Dratio (1.8±0.2-1.1±0.2 pg/ng;interaction =0.05), and 24,25-dihydroxyvitamin D-to-25-hydroxyvitamin Dratio (72.0±9.1-110.3±9.3 pg/ng;interaction <0.001). Fibroblast growth factor-23 and parathyroid hormone were not significantly changed in either group.
CONCLUSIONS - Vitamin Dsupplementation decreases conversion of 25-hydroxyvitamin Dto 1,25-dihydroxyvitamin Dand induces vitamin Dcatabolism as evidenced by changes in Dmetabolites and vitamin D metabolic ratios. These effects occur without significant changes in fibroblast growth factor-23 or parathyroid hormone and are blunted in CKD.
PODCAST - This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_02_CJASNPodcast_17_09.mp3.
Copyright © 2017 by the American Society of Nephrology.
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Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model.
Zhang MZ, Wang X, Yang H, Fogo AB, Murphy BJ, Kaltenbach R, Cheng P, Zinker B, Harris RC
(2017) J Am Soc Nephrol 28: 3300-3311
MeSH Terms: Animals, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Disease Models, Animal, Mice, Receptors, Lysophosphatidic Acid
Show Abstract · Added May 29, 2018
Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, -smooth muscle actin, connective tissue growth factor, collagen I, and TGF-; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, =4; at 20 weeks: 364±18 with vehicle, =7, and 536±12 with LPAR inhibition, =7; <0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.
Copyright © 2017 by the American Society of Nephrology.
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MeSH Terms
Blocking TGF-and-Catenin Epithelial Crosstalk Exacerbates CKD.
Nlandu-Khodo S, Neelisetty S, Phillips M, Manolopoulou M, Bhave G, May L, Clark PE, Yang H, Fogo AB, Harris RC, Taketo MM, Lee E, Gewin LS
(2017) J Am Soc Nephrol 28: 3490-3503
MeSH Terms: Animals, Aristolochic Acids, Cell Nucleus, Collagen, Crosses, Genetic, Epithelium, Female, Gene Deletion, Kidney Failure, Chronic, Kidney Tubules, Proximal, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Signal Transduction, Transforming Growth Factor beta1, Wnt Proteins, beta Catenin
Show Abstract · Added July 18, 2017
The TGF-and Wnt/-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF-has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF-signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF-type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF-receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF-receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF-receptor impaired-catenin activityandGenetically restoring-catenin activity in proximal tubules lacking the TGF-receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF-receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of-catenin activity or an indirect effect of-catenin interacting with other growth factors. In conclusion, blocking TGF-and-catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.
Copyright © 2017 by the American Society of Nephrology.
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21 MeSH Terms
Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules.
Grimm PR, Coleman R, Delpire E, Welling PA
(2017) J Am Soc Nephrol 28: 2597-2606
MeSH Terms: Aldosterone, Animals, Blood Pressure, Epithelial Sodium Channels, Hydrochlorothiazide, Kidney Tubules, Distal, Mice, Natriuresis, Phosphorylation, Potassium, Potassium Channels, Inwardly Rectifying, Protein-Serine-Threonine Kinases, Pseudohypoaldosteronism, Signal Transduction, Sodium Chloride Symporter Inhibitors, Solute Carrier Family 12, Member 3
Show Abstract · Added May 3, 2017
Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mousegene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK). Renal expression of the constitutively active (CA)-SPAK mutant was specifically targeted to the early DCT using a DCT-driven Cre recombinase. CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia, concurrent with NCC hyperphosphorylation. However, thiazide-mediated inhibition of NCC and consequent restoration of sodium excretion did not immediately restore urinary potassium excretion in CA-SPAK mice. Notably, CA-SPAK mice exhibited ASDN remodeling, involving a reduction in connecting tubule mass and attenuation of epithelial sodium channel (ENaC) and ROMK expression and apical localization. Blocking hyperactive NCC in the DCT gradually restored ASDN structure and ENaC and ROMK expression, concurrent with the restoration of urinary potassium excretion. These findings verify that NCC hyperactivity underlies FHHt but also reveal that NCC-dependent changes in the driving force for potassium secretion are not sufficient to explain hyperkalemia. Instead, a DCT-ASDN coupling process controls potassium balance in health and becomes aberrantly activated in FHHt.
Copyright © 2017 by the American Society of Nephrology.
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16 MeSH Terms
andLoci Associate with Plasma Osmolality.
Böger CA, Gorski M, McMahon GM, Xu H, Chang YC, van der Most PJ, Navis G, Nolte IM, de Borst MH, Zhang W, Lehne B, Loh M, Tan ST, Boerwinkle E, Grams ME, Sekula P, Li M, Wilmot B, Moon JG, Scheet P, Cucca F, Xiao X, Lyytikäinen LP, Delgado G, Grammer TB, Kleber ME, Sedaghat S, Rivadeneira F, Corre T, Kutalik Z, Bergmann S, Nielson CM, Srikanth P, Teumer A, Müller-Nurasyid M, Brockhaus AC, Pfeufer A, Rathmann W, Peters A, Matsumoto M, de Andrade M, Atkinson EJ, Robinson-Cohen C, de Boer IH, Hwang SJ, Heid IM, Gögele M, Concas MP, Tanaka T, Bandinelli S, Nalls MA, Singleton A, Tajuddin SM, Adeyemo A, Zhou J, Doumatey A, McWeeney S, Murabito J, Franceschini N, Flessner M, Shlipak M, Wilson JG, Chen G, Rotimi CN, Zonderman AB, Evans MK, Ferrucci L, Devuyst O, Pirastu M, Shuldiner A, Hicks AA, Pramstaller PP, Kestenbaum B, Kardia SLR, Turner ST, Study LC, Briske TE, Gieger C, Strauch K, Meisinger C, Meitinger T, Völker U, Nauck M, Völzke H, Vollenweider P, Bochud M, Waeber G, Kähönen M, Lehtimäki T, März W, Dehghan A, Franco OH, Uitterlinden AG, Hofman A, Taylor HA, Chambers JC, Kooner JS, Fox CS, Hitzemann R, Orwoll ES, Pattaro C, Schlessinger D, Köttgen A, Snieder H, Parsa A, Cohen DM
(2017) J Am Soc Nephrol 28: 2311-2321
MeSH Terms: Aged, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Osmolar Concentration, Plasma, Sodium, Sodium-Bicarbonate Symporters, Transcription Factors, Water-Electrolyte Imbalance
Show Abstract · Added September 19, 2017
Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at<5.0 × 10Of these, rs9980 atreplicated in stage 2 meta-analysis (=3.1 × 10), with combined stages 1 and 2 genome-wide significance of=5.6 × 10Transethnic meta-analysis further supported the association at rs9980 (=5.9 × 10). Additionally, rs16846053 atshowed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (=6.7 × 10).encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance.encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants forandareexpression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation inandexpression and function in the central nervous system may affect the regulation of systemic water balance.
Copyright © 2017 by the American Society of Nephrology.
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14 MeSH Terms