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.

Keywords: chronic kidney disease; diabetic nephropathy; nutrition.

Figure 1. Median levels of acid excretion and markers of acid production by categories of eGFRand diabetes

Estimated GFR is grouped according to Kidney Disease: Improving Global Outcomes (KDIGO) categorizations as G2 (eGFR 60-90 ml/min/1.73m²); G3a (eGFR 45-59 ml/min/1.73m²); G3b (eGFR 30-44 ml/min/1.73m²) and G4/5 (eGFR<30 ml/min/1.73m²). A) Median net acid excretion is depicted in mEq/day with the median percentage as ammonium depicted by dark gray bars. Urine ammonium was directly measured. Titratable acidity was calculated from urine pH, urinary phosphate and creatinine using the Henderson Hasselbalch equation. Median urine pH in each group is reported in text above the bars. P-values for difference in net acid excretion by diabetes status and kidney function are depicted above each set of bars. P-value for comparisons by diabetes are adjusted for eGFR. Overall, percentage of acid excretion as ammonium and urine pH each were lower at lower eGFR (each p value for trend<0.001 using a continuous linear model) and among patients with diabetes compared to those without (p=0.04 and 0.002, respectively). B) Biomarkers of acid production are depicted in mEq/day. Urine sulfate (dark gray bars) represents equimolar amounts of acid produced during metabolism of organic sulfur. Urine citrate represents total urine citrate in mEq based on each participants' urine pH (light gray bars). Thus this represents amount of acid produced from intermediate metabolism with losses of citrate salts in the urine. Citrate represents only one potential organic anion in the urine, whereas total organic anion excretion is estimated at 0.5mEq/kg/day; therefore, total acid production is not depicted. Median serum bicarbonate concentration (HCO₃^-) in each group is reported above the bars. P-values for difference in net acid excretion by diabetes status and kidney function are depicted above each set of bars. P-value for comparisons by diabetes are adjusted for eGFR. Overall, serum bicarbonate, urine citrate and urine sulfate were lower at lower eGFR (p value for trend<0.01 for each using a continuous linear model).

Figure 1. Median levels of acid excretion and markers of acid production by categories of eGFRand diabetes

Estimated GFR is grouped according to Kidney Disease: Improving Global Outcomes (KDIGO) categorizations as G2 (eGFR 60-90 ml/min/1.73m²); G3a (eGFR 45-59 ml/min/1.73m²); G3b (eGFR 30-44 ml/min/1.73m²) and G4/5 (eGFR<30 ml/min/1.73m²). A) Median net acid excretion is depicted in mEq/day with the median percentage as ammonium depicted by dark gray bars. Urine ammonium was directly measured. Titratable acidity was calculated from urine pH, urinary phosphate and creatinine using the Henderson Hasselbalch equation. Median urine pH in each group is reported in text above the bars. P-values for difference in net acid excretion by diabetes status and kidney function are depicted above each set of bars. P-value for comparisons by diabetes are adjusted for eGFR. Overall, percentage of acid excretion as ammonium and urine pH each were lower at lower eGFR (each p value for trend<0.001 using a continuous linear model) and among patients with diabetes compared to those without (p=0.04 and 0.002, respectively). B) Biomarkers of acid production are depicted in mEq/day. Urine sulfate (dark gray bars) represents equimolar amounts of acid produced during metabolism of organic sulfur. Urine citrate represents total urine citrate in mEq based on each participants' urine pH (light gray bars). Thus this represents amount of acid produced from intermediate metabolism with losses of citrate salts in the urine. Citrate represents only one potential organic anion in the urine, whereas total organic anion excretion is estimated at 0.5mEq/kg/day; therefore, total acid production is not depicted. Median serum bicarbonate concentration (HCO₃^-) in each group is reported above the bars. P-values for difference in net acid excretion by diabetes status and kidney function are depicted above each set of bars. P-value for comparisons by diabetes are adjusted for eGFR. Overall, serum bicarbonate, urine citrate and urine sulfate were lower at lower eGFR (p value for trend<0.01 for each using a continuous linear model).

Figure 2. Relative hazard of End-Stage Renal Disease or 50% decline in estimated glomerular filtration rate by metrics of acid excretion in participants A) without diabetes, and B) with diabetes

Hazard ratios are adjusted for age, sex, race, cardiovascular disease, estimated glomerular filtration rate, log (24-hour urine albumin), 24-hour urine creatinine, body mass index and stratified by diabetes. Point estimates are indicated by black circles and 95% confidence interval are indicated by error bars. P-values are for linear trend derived from a continuous linear model of acidification parameter and outcome. The p-value for interaction between net acid excretion (continuous model) and diabetes was 0.06. P-values are for linear trend derived from a continuous linear model of net acid excretion and outcome. The p-value for interaction between urine pH (continuous model) and diabetes was 0.02; between urine ammonium (continuous model) and diabetes was 0.38; and between urine titratable acidity (continuous model) and diabetes was 0.01.

Figure 2. Relative hazard of End-Stage Renal Disease or 50% decline in estimated glomerular filtration rate by metrics of acid excretion in participants A) without diabetes, and B) with diabetes

Hazard ratios are adjusted for age, sex, race, cardiovascular disease, estimated glomerular filtration rate, log (24-hour urine albumin), 24-hour urine creatinine, body mass index and stratified by diabetes. Point estimates are indicated by black circles and 95% confidence interval are indicated by error bars. P-values are for linear trend derived from a continuous linear model of acidification parameter and outcome. The p-value for interaction between net acid excretion (continuous model) and diabetes was 0.06. P-values are for linear trend derived from a continuous linear model of net acid excretion and outcome. The p-value for interaction between urine pH (continuous model) and diabetes was 0.02; between urine ammonium (continuous model) and diabetes was 0.38; and between urine titratable acidity (continuous model) and diabetes was 0.01.

Figure 3. Relative hazard of End-Stage Renal Disease or 50% decline in estimated glomerular filtration rate per 10 mEq/d higher net acid excretion among diabetic participants and within strata

Hazard ratios are adjusted for age, sex, race, cardiovascular disease, estimated glomerular filtration rate, log (24-hour urine albumin), 24-hour urine creatinine, body mass index and stratified by diabetes. Point estimates are indicated by black circles and 95% confidence interval are indicated by error bars.

Figure 4. Proposed relationship between diet-dependent acid load (DAL), net acid excretion (NAE), organic anion production rate (OAP) and systemic acid base status

High diet (DAL) and diet-independent (OAP) components of acid load impact NAE and affect steady-state serum bicarbonate concentration. Worsened systemic acid-base status may feedback to inhibit diet-independent components of acid load, contributing to falling NAE in CKD. Adverse associations between low NAE and outcomes may related to diet-independent components of acid load which reflect greater metabolic compensation for acid-base derangements or impaired tubular functions in CKD.