Intensive Antihypertensive Treatment with Angiotensin Receptor Blocker Combined with Hydrocholorthiazide Reduces Urinary Angiotensinogen in Patients with Type 2 Diabetes Mellitus

Purpose: Local activation of rennin-angiotensin system (RAS) is involved in the progression of chronic kidney disease (CKD). One of the RAS components, angiotensinogen (AGT) has been known to be a potential surrogate biomarker for the renal RAS activity. Measuring the daily urinary excretion of AGT (U-AGT), the present study addressed whether the intensive blood pressure (BP) lowering with combined antihypertensive agents could improve such an abnormality in diabetic CKD patients. Methods: Uncontrolled hypertensive patients with type 2 diabetes with mild to moderate nephropathy previously receiving angiotensin receptor blockers (ARB) in an optimal dose alone were recruited for a better blood pressure (BP) control. Urinary specimens were subjected to a quantitative measurement of a daily urinary protein (U-prot) and U-AGT. After the baseline measurement, intensive antihypertensive therapy was attempted by switching the ARB dose to a fixed combination formula of candesartan 8 mg plus hydrochlorthiazide (HCTZ) 6.25 mg and the patients were followed up for 24 weeks. Comparison of parameters was then made between the values at the baseline and the end of the study. Results: At baseline, there was a significant positive correlation between U-AGT and U-prot, and between U-AGT and serum creatinine (Cr) concentration. In addition, U-AGT was inversely correlated with estimated glomerular filtration rate (e-GFR). Switching the antihypertensive regime from ARB alone to the combined ARB/HCTZ significantly reduced BP, U-AGT and U-prot. The magnitude of the reduction in U-prot was positively correlated with that in U-AGT. A stepwise regression analysis showed that HbA1c, e-GFR and the reduction in U-prot in response to the intensive antihypertensive therapy were positively correlated with the reduction in U-AGT. Conclusion: U-AGT is increased and positively correlated with U-prot in patients with type 2 diabetic nephropathy. Intensive antihypertensive treatment with ARB combined with HCTZ reduces both U-AGT and U-prot, presumably via an amelioration of an accelerated renal RAS activity. These data also suggest that U-AGT can be used as a potential therapeutic surrogate biomarker for the activated renal RAS in patients with diabetic nephropathy.