On the mechanism of growth hormone-induced stimulation of renal acidification in humans: effect of dietary NaCl

Sustained administration of growth hormone (GH) to human subjects with NH₄Cl-induced chronic metabolic acidosis (CMA) results in a large (4.5±0.5 mmol/l) increase in the plasma HCO₃^- concentration, as mediated by a large increase in renal net acid excretion. The renal mechanism(s) responsible for the potent stimulation of renal hydrogen ion secretion by GH remain to be elucidated. Accordingly, we have assessed the Na⁺ dependence of prolonged GH-stimulated renal acidification in four normal NaCl-restricted subjects (Na⁺ intake 0.3 mmol⋅kg^-1⋅day^-1) during CMA (4.2 mmol of NH₄Cl⋅kg^-1⋅day^-1 for 7 days), CMA plus GH (0.1 unit/kg every 12 h for 5 days) and then CMA plus GH plus NaCl (1.7 mmol⋅kg^-1⋅day^-1 for 6 days). During CMA, urine Na⁺ excretion averaged 22.4±4.1 mmol/24 h. In response to GH administration, urinary net acid excretion was essentially unchanged, and the accumulated increment over 5 days of GH treatment was not different from zero (14±12 mmol; not significant). The plasma HCO₃^- concentration increased only slightly, from 14.2±0.8 to 15.0±1.1 mmol/l (P < 0.05). Despite the constraint on net acid excretion imposed by NaCl restriction, renal ammonia production increased, as suggested by increases in urine pH from 5.58±0.05 to 5.82±0.04 (P < 0.005) and unchanged NH₄⁺ excretion (202±17 to 211±19 mmol/24 h; not significant). In response to dietary NaCl, urine pH decreased to 5.27±0.1 (P < 0.001) and a large increment in net acid excretion accumulated (233±20 mmol; P < 0.05), in association with an increase in plasma HCO₃^- to 18.7±1.3 mmol/l (P < 0.001), a plasma HCO₃^- value similar to that reported previously in salt-replete, NH₄Cl-fed subjects. These results demonstrate for the first time in any species that the acid excretory effect of GH administration is critically dependent on the availability of a surfeit of Na⁺ for tubular reabsorption. GH and/or insulin-like growth factor-1 affect renal acid excretion proximally (by stimulation of NH₃ production) and by a Na⁺-transport-dependent mechanism in the collecting duct (voltage-driven acidification) in humans. The present results indicate that an isolated increase in renal NH₃ production is insufficient to obligate an increase in net acid excretion.