The purpose of the present study was to assess whether a moderate increase in ketonemia interferes with renal uptake of energy-providing substrates, and whether it may promote natriuresis similar to that occurring spontaneously during the early phase of starvation. To this end, the sodium salt of D(-)3-hydroxybutyrate (3OHB) was infused to 10 anesthetized dogs at a rate of 20 mumol/kg.min-1 over 135 minutes. To allow comparison, an equivalent amount of sodium was infused as sodium bicarbonate to 10 other dogs (to induce an alkalinization similar to that resulting from the utilization of the sodium salt of 3OHB), while 10 additional dogs received an equimolar infusion of NaCl to provide reference values. Before 3OHB or bicarbonate infusion, lactate represented the major fuel taken up by the kidney (28 +/- 3 mumol/100 g kidney.min-1 on average). While small but significant amounts of 3OHB were taken up by the kidney in control conditions (0.7 +/- 0.1 mumol/100 g.min-1; P < .05), there was no significant uptake of free fatty acids (FFA) or glucose. Upon 3OHB infusion, which increased plasma 3OHB levels to 1.7 mmol/L, the renal uptake of this substrate increased to 25 +/- 3 mumol/100 g.min-1, in proportion to renal 3OHB availability (r = .73, P < .001). Despite an increase in arterial lactate levels that occurred during 3OHB infusion, renal lactate uptake and the extraction ratio of this substrate were decreased (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)