American Journal of Kidney Diseases

Predictors of Net Acid Excretion in the Chronic Renal Insufficiency Cohort (CRIC) Study

Published:March 22, 2019DOI:

      Rationale & Objective

      Higher urine net acid excretion (NAE) is associated with slower chronic kidney disease progression, particularly in patients with diabetes mellitus. To better understand potential mechanisms and assess modifiable components, we explored independent predictors of NAE in the CRIC (Chronic Renal Insufficiency Cohort) Study.

      Study Design


      Setting & Participants

      A randomly selected subcohort of adults with chronic kidney disease enrolled in the CRIC Study with NAE measurements.


      A comprehensive set of variables across prespecified domains including demographics, comorbid conditions, medications, laboratory values, diet, physical activity, and body composition.


      24-hour urine NAE.

      Analytical Approach

      NAE was defined as the sum of urine ammonium and calculated titratable acidity in a subset of CRIC participants. 22 individuals were excluded for urine pH < 4 (n = 1) or ≥7.4 (n = 19) or extreme outliers of NAE values (n = 2). From an analytic sample of 978, we identified the association of individual variables with NAE in the selected domains using linear regression. We estimated the percent variance explained by each domain using the adjusted R2 from a domain-specific model.


      Mean NAE was 33.2 ± 17.4 (SD) mEq/d. Multiple variables were associated with NAE in models adjusted for age, sex, estimated glomerular filtration rate (eGFR), race/ethnicity, and body surface area, including insulin resistance, dietary potential renal acid load, and a variety of metabolically active medications (eg, metformin, allopurinol, and nonstatin lipid agents). Body size, as indicated by body surface area, body mass index, or fat-free mass; race/ethnicity; and eGFR also were independently associated with NAE. By domains, more variance was explained by demographics, body composition, and laboratory values, which included eGFR and serum bicarbonate level.


      Cross-sectional; use of stored biological samples.


      NAE relates to several clinical domains including body composition, kidney function, and diet, but also to metabolic factors such as insulin resistance and the use of metabolically active medications.

      Graphical abstract

      Index Words

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        • Dobre M.
        • Yang W.
        • Chen J.
        • et al.
        Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.
        Am J Kidney Dis. 2013; 62: 670-678
        • de Brito-Ashurst I.
        • Varagunam M.
        • Raftery M.J.
        • Yaqoob M.M.
        Bicarbonate supplementation slows progression of CKD and improves nutritional status.
        J Am Soc Nephrol. 2009; 20: 2075-2084
        • Scialla J.
        • Anderson C.
        Dietary acid load: a novel nutritional target in chronic kidney disease?.
        Adv Chronic Kidney Dis. 2013; 20: 141-149
        • Scialla J.J.
        • Appel L.J.
        • Astor B.C.
        • et al.
        Net endogenous acid production is associated with a faster decline in GFR in African Americans.
        Kidney Int. 2012; 82: 106-112
        • Banerjee T.
        • Crews D.C.
        • Wesson D.E.
        • et al.
        High dietary acid load predicts ESRD among adults with CKD.
        J Am Soc Nephrol. 2015; 26: 1693-1700
        • Rebholz C.M.
        • Coresh J.
        • Grams M.E.
        • et al.
        Dietary acid load and incident chronic kidney disease: results from the ARIC Study.
        Am J Nephrol. 2015; 42: 427-435
        • Scialla J.J.
        • Asplin J.
        • Dobre M.
        • et al.
        Higher net acid excretion is associated with a lower risk of kidney disease progression in patients with diabetes.
        Kidney Int. 2017; 91: 204-215
        • Vallet M.
        • Metzger M.
        • Haymann J.P.
        • et al.
        Urinary ammonia and long-term outcomes in chronic kidney disease.
        Kidney Int. 2015; 88: 137-145
        • Raphael K.L.
        • Carroll D.J.
        • Murray J.
        • Greene T.
        • Beddhu S.
        Urine ammonium predicts clinical outcomes in hypertensive kidney disease.
        J Am Soc Nephrol. 2017; 28: 2483-2490
        • Khairallah P.
        • Scialla J.J.
        Role of acid-base homeostasis in diabetic kidney disease.
        Curr Diab Rep. 2017; 17: 28
        • Abate N.
        • Chandalia M.
        • Cabo-Chan A.
        • Moe O.W.
        • Sakhaee K.
        The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestations of insulin resistance.
        Kidney Int. 2004; 65: 386-392
        • Lennon E.J.
        • Lemann Jr., J.
        • Litzow J.R.
        The effects of diet and stool composition on the net external acid balance of normal subjects.
        J Clin Invest. 1966; 45: 1601-1607
        • Ricardo A.C.
        • Anderson C.A.
        • Yang W.
        • et al.
        Healthy lifestyle and risk of kidney disease progression, atherosclerotic events, and death in CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.
        Am J Kidney Dis. 2015; 65: 412-424
        • Gutierrez O.M.
        • Parsa A.
        • Isakova T.
        • et al.
        Genetic African ancestry and markers of mineral metabolism in CKD.
        Clin J Am Soc Nephrol. 2016; 11: 653-662
        • Wilson F.P.
        • Xie D.
        • Anderson A.H.
        • et al.
        Urinary creatinine excretion, bioelectrical impedance analysis, and clinical outcomes in patients with CKD: the CRIC Study.
        Clin J Am Soc Nephrol. 2014; 9: 2095-2103
        • Chumlea W.C.
        • Guo S.S.
        • Kuczmarski R.J.
        • et al.
        Body composition estimates from NHANES III bioelectrical impedance data.
        Int J Obes Relat Metab Disord. 2002; 26: 1596-1609
        • Remer T.
        • Manz F.
        Potential renal acid load of foods and its influence on urine pH.
        J Am Diet Assoc. 1995; 95: 791-797
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • Naylor B.A.
        • Treacher D.F.
        • Turner R.C.
        Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Cameron M.A.
        • Maalouf N.M.
        • Adams-Huet B.
        • Moe O.W.
        • Sakhaee K.
        Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis.
        J Am Soc Nephrol. 2006; 17: 1422-1428
        • Maalouf N.M.
        • Cameron M.A.
        • Moe O.W.
        • Adams-Huet B.
        • Sakhaee K.
        Low urine pH: a novel feature of the metabolic syndrome.
        Clin J Am Soc Nephrol. 2007; 2: 883-888
        • Maalouf N.M.
        • Cameron M.A.
        • Moe O.W.
        • Sakhaee K.
        Metabolic basis for low urine pH in type 2 diabetes.
        Clin J Am Soc Nephrol. 2010; 5: 1277-1281
        • Pelantova H.
        • Buganova M.
        • Holubova M.
        • et al.
        Urinary metabolomic profiling in mice with diet-induced obesity and type 2 diabetes mellitus after treatment with metformin, vildagliptin and their combination.
        Mol Cell Endocrinol. 2016; 431: 88-100
        • Frassetto L.A.
        • Lanham-New S.A.
        • Macdonald H.M.
        • et al.
        Standardizing terminology for estimating the diet-dependent net acid load to the metabolic system.
        J Nutr. 2007; 137: 1491-1492
        • Scialla J.J.
        The balance of the evidence on acid-base homeostasis and progression of chronic kidney disease.
        Kidney Int. 2015; 88: 9-11
        • Frassetto L.A.
        • Shi L.
        • Schloetter M.
        • Sebastian A.
        • Remer T.
        Established dietary estimates of net acid production do not predict measured net acid excretion in patients with type 2 diabetes on paleolithic-hunter-gatherer-type diets.
        Eur J Clin Nutr. 2013; 67: 899-903
        • Taylor E.N.
        • Curhan G.C.
        Differences in 24-hour urine composition between black and white women.
        J Am Soc Nephrol. 2007; 18: 654-659
        • Canales B.K.
        • Smith J.A.
        • Weiner I.D.
        • et al.
        Polymorphisms in renal ammonia metabolism genes correlate with 24-hour urine pH.
        Kidney Int Rep. 2017; 2: 1111-1121
        • Ring T.
        • Nielsen S.
        Whole body acid-base modeling revisited.
        Am J Physiol Renal Physiol. 2017; 312: F647-F653
        • Crowley M.J.
        • Diamantidis C.J.
        • McDuffie J.R.
        • et al.
        Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review.
        Ann Intern Med. 2017; 166: 191-200
        • Stang M.
        • Wysowski D.K.
        • Butler-Jones D.
        Incidence of lactic acidosis in metformin users.
        Diabetes Care. 1999; 22: 925-927
        • Daniele G.
        • Xiong J.
        • Solis-Herrera C.
        • et al.
        Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes.
        Diabetes Care. 2016; 39: 2036-2041
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334
        • Hood V.L.
        • Tannen R.L.
        Protection of acid-base balance by pH regulation of acid production.
        N Engl J Med. 1998; 339: 819-826