A Risk Marker for Hypertension and Nephropathy in Type 1 Diabetes
The relevance and significance of the plasma kallikrein/kinin system as a risk factor for the development of vascular complications in diabetic patients was explored in a cross-sectional study. We measured the circulating levels of plasma prekallikrein (PK) activity, factor XII, and high−molecular weight kininogen in the plasma of 636 type 1 diabetic patients from the Diabetes Control and Complications Trial/Epidemiology and Diabetes Intervention and Complications Study cohort. The findings demonstrated that type 1 diabetic patients with blood pressure ≥140/90 mmHg have increased PK levels compared with type 1 diabetic patients with blood pressure <140/90 (1.53 ± 0.07 vs. 1.27 ± 0.02 units/ml; P < 0.0001). Regression analysis also determined that plasma PK levels positively and significantly correlated with diastolic (DBP) and systolic blood pressures (SBP) as continuous variables (r = 0.17 and 0.18, respectively; P < 0.0001). In multivariate regression analysis, the semipartial r2 value for PK was 2.93% for SBP and 2.92% for DBP (P < 0.0001). A positive correlation between plasma PK levels and the urinary albumin excretion rate (AER) was also observed (r = 0.16, P < 0.0001). In categorical analysis, patients with macroalbuminuria had a significantly higher level of plasma PK than normoalbuminuric patients (1.45 ± 0.08 vs. 1.27 ± 0.02 units/ml; P < 0.01), whereas microalbuminuric patients had an intermediate PK value (1.38 ± 0.05 units/ml; P = NS). Among patients in the microalbuminuric subgroup, we observed a positive and independent correlation between PK and AER in univariate and multivariate regression analysis (r = 0.27, P < 0.03; n = 63). We concluded that in type 1 diabetes, 1) PK levels are elevated in association with increased blood pressure; 2) PK levels are independently correlated with AER and are categorically elevated in patients with macroalbuminuria; and 3) although the positive correlation between PK and AER within the subgroups of patients with microalbuminuria suggest that PK could be a marker for progressive nephropathy, longitudinal studies will be necessary to address this issue.
Address correspondence and reprint requests to Ayad a Jaffa, Ph.D., Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty St., P.O. Box 250776, Charleston, SC 29425. E-mail:.
Received for publication 10 December 2002 and accepted in revised form 10 February 2003.
ACEI, ACE inhibitor therapy; AER, albumin excretion rate; APTT; BK, bradykinin; BP, blood pressure; CI, confidence interval; DBP, diastolic BP; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology and Diabetes Intervention and Complications; GFR, glomerular filtration rate; HK, high−molecular weight kininogen; KKS, kallikrein/kinin system; MUSC, Medical University of South Carolina; OR, odds ratio; PK, prekallikrein; RPF, renal plasma flow; RVR, renal vascular resistance; SBP, systolic BP.