Renal kallikrein excretion: role of ethnicity, gender, environment, and genetic risk of hypertension

Background and objective: Alterations in renal kallikrein excretion are wel l-described in hypertension, and kallikrein excretion may predict risk of d eveloping hypertension, but kallikrein excretion has not been directly comp ared across several ethnic strata, nor have the effects of ethnicity, gende r, environment, and genetic risk of hypertension been simultaneously consid ered as determinants of kallikrein, Methods: We investigated determinants of kallikrein excretion in a cross-se ction of n = 204 normotensive subjects stratified by ethnicity (119 Caucasi an, 33 African-American, 52 Asian), gender (109 men, 95 women), environment (spontaneous electrolyte intake/excretion), and heredity (genetic risk (fa mily history) of hypertension). Results were interpreted by analysis of var iance (with Bonferroni post hoc comparison corrections), analysis of covari ance, multiple linear regression, and maximum likelihood. Results: Urinary kallikrein activity varied substantially (F = 5.30, P = 0. 006) across the three ethnic groups, with African-American values similar t o 50% lower than Caucasian (P = 0.005) or Asian (P = 0.02), Ethnicity and g ender (T = 3.24, P = 0.001) had independent effects on kallikrein, with wom en excreting similar to 50% more kallikrein than men, regardless of ethnici ty. Subjects at genetic risk of hypertension were over-represented (P = 0.0 48) in the lower stratum of a bimodal distribution of kallikrein excretion (chi-square = 29.6, P < 0.001), Potassium excretion was diminished in Afric an-Americans (P < 0.001 to P = 0.002), and in a multivariate analysis, pota ssium excretion was the strongest correlate of kallikrein excretion (T = 4. 10, P = 0.0001). In a subset of Caucasian and African-American individuals, African-Americans exhibited diminished excretion of not only kallikrein an d potassium, but also aldosterone (P = 0.003), suggesting a mechanistic lin k between potassium and kallikrein excretion in their ethnic variations. Conclusions: Kallikrein excretion is influenced by several independent dete rminants, both hereditary (gender, ethnicity, and genetic risk of hypertens ion) and environmental (potassium intake and excretion), Ethnicity and envi ronment may interact uniquely to influence kallikrein, as demonstrated by t he case of African-Americans with diminutions of both kallikrein and potass ium excretion. These results suggest a mechanism whereby kallikrein excreti on is diminished in African-Americans, as well as therapeutic strategies to correct this deficiency. Finally, the identified determinants of kallikrei n excretion will require analytic adjustment during genetic studies of this 'intermediate phenotype' in hypertension.