Background and objective: Alterations in renal kallikrein excretion are well-described in hypertension, and kallikrein excretion may predict risk of developing hypertension, but kallikrein excretion has not been directly compared across several ethnic strata, nor have the effects of ethnicity, gender, environment, and genetic risk of hypertension been simultaneously considered as determinants of kallikrein.

Methods: We investigated determinants of kallikrein excretion in a cross-section of n= 204 normotensive subjects stratified by ethnicity (119 Caucasian, 33 African-American, 52 Asian), gender (109 men, 95 women), environment (spontaneous electrolyte intake/excretion), and heredity (genetic risk (family history) of hypertension). Results were interpreted by analysis of variance (with Bonferroni post hoc comparison corrections), analysis of covariance, 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∼ 50% lower than Caucasian (P= 0.005) or Asian (P= 0.02). Ethnicity and gender (T= 3.24, P= 0.001) had independent effects on kallikrein, with women excreting∼ 50% more kallikrein than men, regardless of ethnicity. Subjects at genetic risk of hypertension were over-represented (P= 0.048) in the lower stratum of a bimodal distribution of kallikrein excretion (chi-square= 29.6, P< 0.001). potassium excretion was diminished in african-americans (P< 0.001 to P= 0.002), and in a multivariate analysis, potassium 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 and potassium, but also aldosterone (P= 0.003), suggesting a mechanistic link between potassium and kallikrein excretion in their ethnic variations.

Conclusions: Kallikrein excretion is influenced by several independent determinants, both hereditary (gender, ethnicity, and genetic risk of hypertension) and environmental (potassium intake and excretion). Ethnicity and environment may interact uniquely to influence kallikrein, as demonstrated by the case of African-Americans with diminutions of both kallikrein and potassium excretion. These results suggest a mechanism whereby kallikrein excretion is diminished in African-Americans, as well as therapeutic strategies to correct this deficiency. Finally, the identified determinants of kallikrein excretion will require analytic adjustment during genetic studies of this ‘intermediate phenotype’in hypertension.