Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy.

We evaluated relationships among two circulating molecular forms of brain natriuretic peptide (BNP32 and NT-proBNP), severity of hypertension (HTN), and cardiac hypertrophy in subjects with mild, moderate, and severe HTN. We prospectively studied 78 patients (43 males; mean age 51.4 +/- 11 yr) with essential HTN and 28 age- and sex-matched controls. BNP32 and NT-proBNP were measured by radioimmunoassay. In grade 1 HTN, BNP32 was not elevated and NT-proBNP was reduced (P = 0.030) compared with controls. However, log-transformed values of BNP32 and NT-proBNP were both increased with severity of HTN from grade 1 to 3 (P <0.0001 and P = 0.003, respectively). By multivariate analysis, log BNP32 was independently predicted by age (beta = 0.210, P = 0.026) and HTN grade (beta = 0.274, P = 0.004), whereas log NT-proBNP was independently predicted by sex (beta = 0.235, P = 0.012) and HTN grade (beta = 0.218, P = 0.0023). Two forms of BNP were measured in normal subjects and patients with essential HTN. In grade 1 HTN, BNP32 was unchanged and NT-proBNP was significantly reduced compared with controls. As severity increased in humans with grade 1 to 3 HTN, both BNP32 and NT-proBNP levels were increased while not being affected by the presence of left ventricular hypertrophy. The lack of activation of BNP32 together with the reduction of NT-proBNP in grade 1 HTN may represent an impaired response of the BNP system in the early phase of HTN. The later activation of both forms of BNP may be a late compensatory effect, because it correlates with severity of HTN rather than cardiac hypertrophy/remodeling.

Hepatocyte growth factor and left ventricular geometry in end-stage renal disease.

Hepatocyte growth factor is a pleiotropic cytokine with cardioprotective properties. Its serum concentration is markedly raised in end-stage renal disease. This study assessed the relation of hepatocyte growth factor (HGF) with left ventricular mass and geometry in end-stage renal disease. Serum HGF measurements and echocardiographic studies were performed in 185 patients receiving hemodialysis. Patients with serum HGF above the median (1.85 ng/mL) had more frequent cardiovascular complications. This cytokine was directly related to mean left ventricular wall thickness (r=0.23, P=0.002) and relative wall thickness (r=0.25, P=0.0001); a multivariate analysis showed that this relation was independent of other risk factors. Accordingly, the prevalence of left ventricular concentric geometry (either concentric left ventricular hypertrophy or remodeling) was much higher (n=49, 53%) among patients with HGF values above the median that in those with values < or =1.85 ng/mL (n=31, 34%). Furthermore, the risk for left ventricular concentric geometry was higher in patients with HGF values above the median (odds ratio, 2.57; 95% CI, 1.33 to 4.98; P=0.005), and multiple logistic regression analysis confirmed that this association was independent of other risk factors. In patients receiving hemodialysis, elevated serum HGF is associated with concentric left ventricular geometry. This is consistent with reports that link this cytokine to arterial remodeling and survival in patients with end-stage renal disease and suggests that it is part of a counterregulatory response aimed at attenuating cardiovascular damage in this high-risk population.

CNP production in the kidney and effects of protein intake restriction in nephrotic syndrome.

C-type natriuretic peptide (CNP) possesses well-established cardiovascular properties. Although present in the mammalian kidney, CNP production in human kidney and its modulation in human renal disease remain less defined. We investigated the presence of CNP in normal human kidney and in patients with nephrotic syndrome (NS). We also addressed whether or not a low-protein diet (LPD) alters plasma CNP and urinary CNP excretion in NS. In situ hybridization studies demonstrated CNP mRNA expression in tubular cells and glomeruli of normal human kidneys. CNP immunoreactivity was positive in proximal, distal, and medullary collecting duct tubular cells in both controls and patients with NS. The ratios of plasma CNP and urinary CNP to creatinine were significantly higher in patients with NS compared with controls. Urinary CNP, but not plasma CNP, was significantly lowered in patients with NS after an LPD. Similarly, the ratios of urinary protein to creatinine and urinary albumin to creatinine, but not urinary guanosine 3',5'-cyclic monophosphate to creatinine, decreased significantly with an LPD. These data confirm and extend previous reports and demonstrate for the first time the presence of CNP in human kidney with NS. We also report increased plasma CNP concentration and urinary CNP excretion in NS patients and a significant reduction of CNP excretion with an LPD. Our findings demonstrate that CNP metabolism is altered in patients with NS and support the hypothesis that activation of renal CNP can be partially offset by an LPD. These results underscore that the beneficial effect of an LPD on protein excretion is paralleled by a substantial reduction in intrarenal CNP release.