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Background: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria.Methods: Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R(2) between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response.Results: In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p < 0.001) and improved prediction of UAE response on top of the clinical reference model (R(2) increase from 0.10 to 0.70; p < 0.001). In external validation, median change in UAE was -43 % [Q1-Q35: -63 to -23]. The classifier improved prediction of UAE response to losartan (R(2) increase from 0.20 to 0.59; p < 0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response.Conclusions: A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy.Background.Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short- and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy.Methods.Seventy-one hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, the patients received Losartan 50 mg, 100 mg, and 150 mg once daily in treatment periods each lasting 2 months. Thereafter, patients were followed prospectively during treatment with Losartan 100 mg o.d. with a total mean follow-up time of 36 months. At baseline, after 2, 4, and 6 months and then biannually, urinary and plasma CTGF levels[enzyme linked immunosorbent assay (ELISA) fibroGen], albuminuria (Turbidimetry), glomerular filtration rate (GFR)[51-creatinine ethylenediaminetetraacetic acid (51Cr-EDTA plasma clearance)] and 24 hours blood pressure (TM2420)) were determined.Results.Baseline levels of urinary and plasma CTGF were 7076 (5708 to 8770) ng/24 hours[geometric mean (95% CI)] and 12.7 (7.3) ng/mL[mean (SD)], respectively. Albuminuria, GFR, and arterial blood pressure at baseline were 1152 (937 to 1416) mg/24 hours, 88 (24) mL/min/1.73 m2, and 153/80 (17/9) mm Hg, respectively. Losartan significantly reduced urinary CTGF by 21% (9 to 31) (95% CI) initially (P<0.05 vs. baseline), with no further reduction after increasing dose. The sustained reduction in urinary CTGF was 22% (12 to 32) (P<0.05 vs. baseline). Rate of decline in GFR during the study was 3.2 (−1.6 to 15.9) mL/min/year[median (range)]. Reduction in urinary CTGF was correlated with a lower rate of decline in GFR (r= 0.23,P= 0.05). Plasma CTGF remained unchanged throughout the study.Conclusion.Our 3-year study demonstrates that Losartan persistently reduces urinary CTGF excretion, which is associated with a slower rate of decline in GFR. [ABSTRACT FROM AUTHOR]

Renoprotection with and without blood pressure reduction. AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown. We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM, N = 50) and nondiabetic renal patients (ND, N = 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into "good" and "poor" BP responders (BP+, BP-) according to BP response above or below group median. Baseline MAP in the BP- groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP- groups was -2 (-4, 3) mm Hg in DM and –1 (-6, 2) mm Hg in ND, versus -15 (-18, -12) mm Hg and -16 (-26, -18) mm Hg in BP+ groups (both P < 0.05). Albuminuria was reduced dose dependently both in BP- and BP+: with 100 mg, the reduction in albuminuria in DM BP- was -32% (-49, 13) versus -45% (-60, -38) in DM BP+ and -45% (-70,-7) versus –25% (-58, -6) in ND BP- and BP+ (all P > 0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients. Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target. [ABSTRACT FROM AUTHOR]

Background. Angiotensin II subtype‐1 receptor antagonists represent a valuable new class of drugs in the treatment of diabetic nephropathy. The aim of our study was to evaluate the optimal dose of losartan for renoprotection and blood pressure reduction in diabetic nephropathy. [ABSTRACT FROM PUBLISHER]