title: Higher net acid excretion is associated with a lower risk of kidney disease progression in patients with diabetes.
abstract: Higher diet-dependent nonvolatile acid load is associated with faster chronic kidney disease (CKD) progression, but most studies have used estimated acid load or measured only components of the gold standard, net acid excretion (NAE). Here we measured NAE as the sum of urine ammonium and titratable acidity in 24-hour urines from a random subset of 980 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. In multivariable models accounting for demographics, comorbidity and kidney function, higher NAE was significantly associated with lower serum bicarbonate (0.17 mEq/l lower serum bicarbonate per 10 mEq/day higher NAE), consistent with a larger acid load. Over a median of 6 years of follow-up, higher NAE was independently associated with a significantly lower risk of the composite of end-stage renal disease or halving of estimated glomerular filtration rate among diabetics (hazard ratio 0.88 per 10 mEq/day higher NAE), but not those without diabetes (hazard ratio 1.04 per 10 mEq/day higher NAE). For comparison, we estimated the nonvolatile acid load as net endogenous acid production using self-reported food frequency questionnaires from 2848 patients and dietary urine biomarkers from 3385 patients. Higher net endogenous acid production based on biomarkers (urea nitrogen and potassium) was modestly associated with faster CKD progression consistent with prior reports, but only among those without diabetes. Results from the food frequency questionnaires were not associated with CKD progression in any group. Thus, disparate results obtained from analyses of nonvolatile acid load directly measured as NAE and estimated from diet suggest a novel hypothesis that the risk of CKD progression related to low NAE or acid load may be due to diet-independent changes in acid production in diabetes.
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA; Department of Medicine, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA. Electronic address: Julia.scialla@duke.edu.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Scialla
authors.affiliation: Litholink Corp, Laboratory Corporation of America Holdings, Chicago, Illinois, USA.
authors.forename: John
authors.initials: J
authors.lastname: Asplin
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Mirela
authors.initials: M
authors.lastname: Dobre
authors.affiliation: Kidney Health Research Institute, Geisinger Health System, Danville, Pennsylvania, USA.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Chang
authors.affiliation: Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lash
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA; Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Department of Biostatistics and Epidemiology and the Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Radhakrishna R
authors.initials: RR
authors.lastname: Kallem
authors.affiliation: Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors.forename: L Lee
authors.initials: LL
authors.lastname: Hamm
authors.affiliation: Department of Biostatistics and Epidemiology and the Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Harold I
authors.initials: HI
authors.lastname: Feldman
authors.affiliation: Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine and The Welch Center for Prevention, Epidemiology and Clinical Research, Baltimore, Maryland, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Appel
authors.affiliation: Department of Family Medicine and Public Health, University of California San Diego, San Diego, California, USA.
authors.forename: Cheryl A M
authors.initials: CA
authors.lastname: Anderson
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000652:urine*; D000143:Acids / Q000378:metabolism*; D000368:Aged; D064751:Ammonium Compounds / Q000652:urine; D001639:Bicarbonates / Q000097:blood; D015415:Biomarkers / Q000652:urine; D001806:Blood Urea Nitrogen; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000652:urine; D018450:Disease Progression; D005247:Feeding Behavior; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood; D016016:Proportional Hazards Models; D065667:Renal Elimination; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D000143:Acids; D064751:Ammonium Compounds; D001639:Bicarbonates; D015415:Biomarkers; D011188:Potassium
keywords: chronic kidney disease; diabetic nephropathy; nutrition