Sodium Bicarbonate Supplementation and Urinary TGF-ß1 in Nonacidotic Diabetic Kidney Disease: A Randomized, Controlled Trial.

BACKGROUND AND OBJECTIVES: In early-phase studies of individuals with hypertensive CKD and normal serum total CO2, sodium bicarbonate reduced urinary TGF-ß1 levels and preserved kidney function. The effect of sodium bicarbonate on kidney fibrosis and injury markers in individuals with diabetic kidney disease and normal serum total CO2 is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a randomized, double-blinded, placebo-controlled study in 74 United States veterans with type 1 or 2 diabetes mellitus, eGFR of 15-89 ml/min per 1.73 m2, urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and serum total CO2 of 22-28 meq/L. Participants received oral sodium bicarbonate (0.5 meq/kg lean body wt per day; n=35) or placebo (n=39) for 6 months. The primary outcome was change in urinary TGF-ß1-to-creatinine from baseline to months 3 and 6. Secondary outcomes included changes in urinary kidney injury molecule-1 (KIM-1)-to-creatinine, fibronectin-to-creatinine, neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine, and UACR from baseline to months 3 and 6. RESULTS: Key baseline characteristics were age 72±8 years, eGFR of 51±18 ml/min per 1.73 m2, and serum total CO2 of 24±2 meq/L. Sodium bicarbonate treatment increased mean total CO2 by 1.2 (95% confidence interval [95% CI], 0.3 to 2.1) meq/L, increased urinary pH by 0.6 (95% CI, 0.5 to 0.8), and decreased urinary ammonium excretion by 5 (95% CI, 0 to 11) meq/d and urinary titratable acid excretion by 11 (95% CI, 5 to 18) meq/d. Sodium bicarbonate did not significantly change urinary TGF-ß1/creatinine (difference in change, 13%, 95% CI, -10% to 40%; change within the sodium bicarbonate group, 8%, 95% CI, -10% to 28%; change within the placebo group, -4%, 95% CI, -19% to 13%). Similarly, no significant effect on KIM-1-to-creatinine (difference in change, -10%, 95% CI, -38% to 31%), fibronectin-to-creatinine (8%, 95% CI, -15% to 37%), NGAL-to-creatinine (-33%, 95% CI, -56% to 4%), or UACR (1%, 95% CI, -25% to 36%) was observed. CONCLUSIONS: In nonacidotic diabetic kidney disease, sodium bicarbonate did not significantly reduce urinary TGF-ß1, KIM-1, fibronectin, NGAL, or UACR over 6 months.

Influence of Medications Containing Acid Salts on Serum Bicarbonate in CKD.

Background: Many medications are formulated with acid salts. Their effect on acid-base balance in CKD is unclear. Methods: We calculated the acid load (meq/d) from medications prescribed to 74 United States veterans with diabetes and CKD to identify agents with high potential acid load. We also determined cross-sectional associations between the acid load from medications and acid-base parameters after adjusting for demographics, eGFR, protein intake, and other confounders. Results: Of the 125 medications prescribed, 31 (25%) contained an acid salt. Metformin hydrochloride (15.4 meq/d at 2550 mg/d) and gabapentin hydrochloride (13.0 meq/d at 2700 mg/d) were identified as agents with a high potential acid load. Mean daily acid load from medications was 6.6 meq/d in the overall cohort, 14.2 meq/d in the high medication acid load group (≥7.7 meq/d, n=29), and 1.6 meq/d in the low medication acid load group (<7.7 meq/d, n=45). After adjusting for potential confounders, those in the high acid load group had 1.7 meq/L lower total carbon dioxide (CO2) and 2.2 meq/L higher anion gap than those in the low acid load group. Use of gabapentin alone was not associated with differences in total CO2 or anion gap. Use of metformin alone was associated with 0.7 meq/L lower total CO2 and 1.0 meq/L higher anion gap. Use of metformin with gabapentin was associated with 1.8 meq/L lower total CO2 and 2.4 meq/L higher anion gap. The higher anion gap was not explained by higher serum lactate levels. The acid load from medications was not associated with differences in urinary ammonium, titratable acid, or pH. Conclusions: Medications containing acid salts, particularly metformin hydrochloride and gabapentin hydrochloride, are sources of an exogenous acid load. These agents may influence serum total CO2 levels and serum anion gap in individuals with CKD. Clinical Trial registry name and registration number: Investigations of the Optimum Serum Bicarbonate Level in Renal Disease, NCT01574157.