Supplementary Material for: Association of Functional Kallikrein-1 Promoter Polymorphisms and Acute Kidney Injury: A Case-Control and Longitudinal Cohort Study

<p><b><i>Background:</i></b> Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI). <b><i>Methods:</i></b> We first evaluated the potential role of functional multiallelic <i>KLK1</i> promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C-rich repeat region of the proximal <i>KLK1</i> promoter was determined by direct Sanger/capillary resequencing. <b><i>Results:</i></b> 16 alleles were identified in a complex, polymorphic G/C-rich region of the <i>KLK1</i> proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the <i>KLK1</i> risk-allele (I or G) carrier state was associated with the composite of ≥2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The <i>KLK1</i> risk-allele carrier state was also marginally associated with the composite of ≥2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06). <b><i>Conclusions:</i></b><i>KLK1</i> promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings.</p>