Metabolic control of kidney hemodynamics in normal and insulin-dependent diabetic subjects. Effects of acetoacetic, lactic, and acetic acids

Diabetes mellitus is associated with important changes in renal hemodynamics. The purpose of this study was to determine whether an increase in blood concentration patterns of ketone bodies and lactic acid, organic acids often elevated in poorly controlled insulin-dependent diabetes mellitus (IDDM), could contribute to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) regardless of changes in circulating levels of glucose and insulin. Six IDDM patients and six normal subjects were given a saline infusion (15 μmol · min-1 · kg-1) for 2 h, an acetoacetic acid infusion (15 μmol · min-1 · kg-1) for another 2 h, and then a saline infusion after an overnight fast during euglycemic insulin-glucose clamp. Acetoacetic acid infusion resulted in an increase of blood ketone bodies in the range of 0.7-1.5 mM from a basal value of 0.1-0.3 mM. GFR was 125 ± 16 and 136 ± 17 ml · min-1 · 1.73 m-2 in normal and IDDM subjects, respectively, during baseline saline infusion and 138 ± 21 (P < .01 vs. basal level) and 158 ± 15 ml · min-1 · 1.73 m-2 (P < .001 vs. basal level) during acetoacetic acid infusion. During the last saline infusion, renal hemodynamic patterns decreased again to baseline levels. Another six IDDM patients and six normal subjects were given saline, lactic acid, and saline infusions at the same rates of infusion after an overnight fast during euglycemic insulin-glucose clamp. Lactic acid concentration increased from ~0.5-0.8 to 1.0-1.5 mM in both groups. GFR was 125 ± 9 and 144 ± 18 ml · min-1 · 1.73 m-2 in normal and IDDM subjects, respectively, during baseline saline infusion and 135 ± 8 and 158 ± 16 ml · min-1 · 1.73 m-2 during lactic acid infusion (P < .01 vs. basal level). Acetoacetic acid and lactic acid infusion resulted in a 14.7 and 7.6% increase, respectively, in RPF compared with baseline values in normal subjects and in a 12.6 and 6.9% increase, respectively in IDDM subjects. With the same protocol of the previous organic acid infusion, another five normal and six IDDM patients were given an acetic acid infusion (15 μmol · kg-1 · min-1), resulting in an increase of plasma circulating levels of acetic acid from 0.1-0.2 to 0.3-0.4 mM, which was associated with negligible changes in ketone body and lactic acid concentrations. Neither GFR nor RPF were influenced by acetic acid administration. During acetoacetic acid and lactic acid infusion, both lactic and ketone body acid tubular reabsorption rates were three to five times higher than during saline infusion. In conclusion, lactic acid and acetoacetic acid infusion resulting in circulating patterns of these intermediate metabolites comparable with those often found in poorly controlled IDDM subjects induced a significant increase in GFR and RPF in normal and IDDM subjects. The increased GFR was associated with stimulation of organic acid tubular reabsorption rate and was not related to sodium and liquid overload, because it returned to basal value when saline alone was administered again.