Early Alteration in Glomerular Reserve in Humans at Genetic Risk of Essential Hypertension

Abstract

Abstract-Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. , although cGMP did not change during the amino acid infusion (Pϭ0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (Pϭ0.0013), accounting for Ϸ45% of the variance in GFR response. Decline in FE Li ϩ, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (rϭϪ0.506, Pϭ0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FHϩ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FHϩ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FHϩ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO· in the kidney. Corresponding changes in GFR and fractional excretion of Li ϩ suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension. (Hypertension. 2001;37:898-906.)

Progression of Chronic Kidney Disease: Adrenergic Genetic Influence on Glomerular Filtration Rate Decline in Hypertensive Nephrosclerosis

“…Selective pharmacologic reduction of sympathetic activity attenuates progression of chronic renal disease [12]. A role for heredity in control of glomerular hemodynamics was also suggested by our observation [44] that genetic risk (family history) of hypertension predicts the GFR response to amino acids.…”

Distinct Renal Injury in Early Atherosclerosis and Renovascular Disease

“…GFR failure to respond to challenge may also indicate an early pathophysiological mechanism that can accompany altered tubular reabsorption. 24 Conversely, renovascular dysfunction was not substantially augmented by concurrent HC. These in vivo findings were supported by morphological examination of the stenotic HCϩRAS kidney, which revealed a marked increase in tubulointerstitial accompanied by less pronounced glomerular injury and milder vascular changes.…”

Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes

“…However, in these experiments, blood pressure increased in both groups and there were no interactions with diabetes status that would explain their disparate renal hemodynamic responses. Among individuals with a family history of hypertension, who had higher systolic blood pressure (even though normal by conventional criteria), a blunted GFR response to amino acids was also observed (39). In another study, people with a family history of severe hypertension had a diminished urine flow response to L-arginine infusion (20).…”

“…However, insulin levels were three-to fourfold higher in diabetic patients. A recent study of people with a family history of hypertension also found higher insulin levels than in controls and an inverse correlation between insulin and the GFR response to a mixed amino acid infusion (39). Higher insulin levels indicate the development of insulin resistance, which may lead to impaired endothelial-dependent vasodilation (51).…”