Renal Albumin Excretion

Abstract

Abstract-Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning catecholamine biosynthesis, storage, catabolism, receptor action, and postreceptor signal transduction. We studied 134 single nucleotide polymorphisms at 46 loci for a total of Ͼ51 000 genotypes. Albumin excretion heritability was 45.2Ϯ7.4% (Pϭ2ϫ10 Ϫ7), and the phenotype aggregated significantly with adrenergic, renal, metabolic, and hemodynamic traits. In the adrenergic system, excretions of both norepinephrine and epinephrine correlated with albumin. In the kidney, albumin excretion correlated with glomerular and tubular traits (Na ϩ and K ϩ excretion; fractional excretion of Na ϩ and Li ϩ ). Albumin excretion shared genetic determination (genetic covariance) with epinephrine excretion, and environmental determination with glomerular filtration rate and electrolyte intake/excretion. Albumin excretion associated with polymorphisms at multiple points in the adrenergic pathway: catecholamine biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention, diagnosis, and treatment. Key Words: hypertension Ⅲ metabolic Ⅲ inflammation Ⅲ glomerulus Ⅲ catecholamine Ⅲ receptor Ⅲ adrenergic A lbumin excretion is a risk factor for adverse cardiovascular events, even in subjects without primary glomerular disease. 1 For example, studies in essential hypertension indicate that the prevalence of microalbuminuria may reach up to 11% to 17% among even nondiabetic individuals. 1 Indeed, even albumin excretion values less than those typically cited as constituting microalbuminuria or incipient nephropathy 1-3 may signal cardiovascular risk.The sympathetic nervous system exerts minute-to-minute control over both blood pressure and renal function. 4 An excess of sympathetic transmitters elevates urinary albumin excretion; indeed, a half-century ago, King and Baldwin 5 showed that systemic infusion of catecholamines (norepinephrine or epinephrine) elevates albumin excretion in asso...

Urinary norepinephrine and epinephrine excretion rates are heritable, but not associated with office and ambulatory blood pressure

“…14 Similar results were reported more recently in a slightly larger sample showing that both plasma and urinary E and NE were significantly heritable and ranged from 0.49 to 0.72. 6,13 We are not aware of other heritability studies estimating the basal sympathetic tone by means of overnight urinary excretion rates of both NE and E. In principle, catecholamine levels in blood may more accurately reflect sympathetic activity than overnight urinary excretion rates of NE and E. However, collection of overnight urine for measurement of catecholamine excretion rates has a number of advantages. Catecholamine excretion rates provide an integrated measure of 'steady-state' operating levels of the sympathetic nervous Abbreviations: DZ, dizygotic twins; MZ, monozygotic twins.…”

“…However, very few studies investigated heritability of NE and E levels or excretion rates and none of these examined to what extent genetic and environmental influences on these catecholamines overlap. 5,6,[12][13][14] In the present study, we have used overnight urinary excretion rates of NE (U NE V) and E (U E V) as measures of basal sympathetic activity. The overnight urine collections were analyzed by radio immune assay (RIA) for NE and E. We aimed to determine the genetic and environmental contributions to U NE V and U E V and their association using bivariate genetic modeling, and examine the associations of U NE V and U E V with office and ambulatory BP in 91 AfricanAmerican and 101 European-American adolescent and young adult twins from the south-eastern USA.…”

Hereditary Determinants of Human Hypertension

“…Such intermediate phenotypes may be influenced earlier and more proximately by the genome than are ultimate disease/clinical traits such as hypertension, and therefore may assist in discovery of hypertension-predisposition loci. 2,3 Intermediate traits in physical, physiological/hemodynamic, 4 autonomic/sympathetic, 5-8 metabolic, 9 inflammatory, 9 oxidative, 5 endothelial, 10,11 and renal 12 pathways displayed significant heritability, typically exceeding that reported for blood pressure itself (eg, Figure 1). With the rapid advance of genome technologies, informed systematic phenotyping of sufficiently large numbers of subjects for genetic studies may now be the rate-limiting step in permitting substantive future advances in complex trait genetics.…”

Cardiovascular and Renal Complications in Obesity and Obesity-Related Medical Conditions: Role of Sympathetic Nervous Activity and Insulin Resistance

“…Thus, one could speculate that plasma norepinephrine levels in ESRD patients are reflective of the degree of sympathetic nerve activity. Rao et al [Rao, et al 2007] and Masuo et al [Masuo, et al 2007] have shown strong associations between β2-adrenoceptor polymorphisms, elevated plasma norepinephrine levels and elevated HOMA-IR (insulin resistance) or future renal injury, suggesting that stimulated sympathetic nerve activity associated with insulin resistance, may independently play a major role in the onset and development of ESRD without obesity or hypertension. However, the precise mechanisms underlying sympathetic activation in CKD and ESRD have not been clarified.…”