Early alteration in glomerular reserve in humans at genetic risk of essential hypertension - Mechanisms and consequences

Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a cru cial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypert ension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratifi ed by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusi on of mixed amino acids. Before and during amino acid administration, we me asured glomerular filtration rate (GFR), putative second messengers of amin o acids (nitric oxide [NO] metabolites and cGMP), serum insulin and amino a cid concentrations, and the FELi+ as an index of renal proximal tubular rea bsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43 +/- 8.16% versus 31.0+/-13.4% rise, P=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P<0.01) with the change in urinary NO m etabolite excretion; a diminished rise in urinary NO metabolite excretion i n the FH+ group (P=0.0105) suggested a biochemical mechanism for the differ ent GFR responses between FH groups: a relative inability to convert argini ne to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol . h(-1)/1.73 m(2), P=0.001), although cG MP did not change during the amino acid infusion (P=0.703). FH status, base line GFR, and baseline serum insulin jointly predicted GFR response to amin o acids (P=0.0013), accounting for <approximate to>45% of the variance in G FR response. Decline in FELi+, an inverse index of proximal tubular reabsor ption, paralleled increase in GFR (r=-0.506, P=0.01), suggesting difference s in proximal tubular reabsorption during amino acids between the FH groups . GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isole ucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, su ggesting a novel form of insulin resistance (to the amino acid-translocatin g action of insulin) in FH + subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenot ype seen even in still-normotensive subjects at genetic risk of hypertensio n and is linked to impaired formation of NO in the kidney. Corresponding ch anges in GFR and fractional excretion of Li+ suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechani sm. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glom erular reserve phenotype may be useful in genetic studies of renal traits p receding or predisposing to hypertension.