Plasma MBG (assessed by a competitive immunoassay), alkaline phosphatase and peripheral systolic blood pressure (SBP) were measured in 11 patients with stage III/IV CKD (9 males/2 females; 63+/-11 yrs), 8 patients requiring chronic hemodialysis (7M/1F; 59+/-11 yrs), and 10 healthy controls (6 males/4 females; 45+17 yrs). Multiple parameters including brachial artery flow-mediated dilation (FMDBA), aortic pulse-wave velocity (aPWV), carotid intimal medial thickness (cIMT) and carotid SBP were also assessed in patients with stage III/IV CKD and healthy age matched controls. Plasma MBG levels increased in patients with stage III/IV CKD by 60% (0.79+/-0.19 nmol/L vs. 0.50+/-0.18 nmol/L, P<0.05) and 2.5-fold in hemodialysis (1.27+/-0.46 nmol/L vs. 0.50+/-0.18 nmol/L, P<0.01 by 1-way ANOVA followed by Newman-Keuls test) when compared to controls, respectively. SBP was significantly higher in patients on dialysis compared to controls (140+/-19 mmHg vs. 121+/-10 mmHg, respectively, P<0.05 by 1-way ANOVA). Plasma alkaline phosphatase increased in patients with stage III/IV CKD by 70% (81.6+/-16.9 IU/L vs. 47.7+/-13.9 IU/L, P<0.01) and remained elevated in hemodialysis (90.0+/-26.4 IU/L vs. 47.7+/-13.9 IU/L, P<0.01 by 1-way ANOVA followed by Newman-Keuls test) vs. controls, respectively. Carotid SBP (134+/-18 mmHg vs. 115+/-19 mmHg, P<0.05, t-test), aPWV (10.83+/-3.47 m/s vs. 6.93+/-1.74 m/s, P<0.01, t-test), and cIMT (0.80+/-0.26 mm vs. 0.50+/-0.08 mm, P<0.01, t-test) increased, and eGFR (36.8+/-9.3 vs. 95.4+/-15.0, ml/min/1.73m2, P<0.01, t-test) and FMDBA (3.44+/-2.37 % vs. 6.94+/-4.4 %, P<0.05, t-test) decreased in patients with stage III/IV CKD in comparison to healthy controls. Plasma MBG correlated positively with carotid and peripheral SBP, aPWV, cIMT, and alkaline phosphatase and negatively with FMDBA in the whole cohort. After adjustment, heightened plasma MBG remained significantly associated with higher alkaline phosphatase and SBP in linear regression model. Thus, an endogenous NKA steroidal inhibitor, MBG, is implicated in the development of CKD. Heightened plasma MBG in CKD and dialysis patients is associated with higher level of alkaline phosphatase, a marker of a vascular fibrosis, calcification and tissue destruction in CKD, and with progressive kidney function decline. MBG, being a pro-hypertensive and pro-fibrotic factor, may independently contribute to cardiovascular risk via increased SBP or vascular dysfunction. Plasma MBG may be useful as a marker of severity of CKD and may represent a CKD therapeutic target for a therapy with antibody, aimed to bind circulating MBG, to reduce blood pressure, reduce renal fibrosis and improve kidney function. Digifab, a Fab fragment of ovine anti-digoxin antibody, which successfully binds MBG, and which are used in humans, can be applied for MBG immunoneutralization in clinical studies.
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