Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease.

BACKGROUND: Atherosclerotic cardiovascular disease, malnutrition, and increased levels of pro-inflammatory cytokines are common features in patients with chronic renal failure, and contribute to the high mortality rate observed in these patients. A diverse group of soluble cellular adhesion molecules (CAM) (sVCAM-1, sICAM-1 and sE-selectin) are expressed on the surface of vascular endothelial cells in response to pro-inflammatory cytokines and may play an important role in the atherogenic process. METHODS: Serum levels of sVCAM-1, sICAM-1 (n=87) and sE-selectin (n=71) were analysed in a cohort of 88 patients (50+/-1 years) with chronic renal failure. The presence of malnutrition (subjective global assessment (SGA) and serum albumin), inflammation (C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), and serum hyaluronan), and cardiovascular disease (CVD) were assessed at a time-point close to the start of dialysis treatment (GFR 7+/-1 ml/min). Blood lipid parameters were also assessed. RESULTS: Significant correlations were observed between Log high-sensitivity CRP (hsCRP) and sVCAM-1 (R=0.39; P<0.01) and sICAM-1 (R=0.47; P:<0.001) levels but not between Log hsCRP and sE-selectin levels in 60 patients examined with a hsCRP assay. Also serum concentrations of Log hyaluronan correlated significantly to sVCAM-1 (R=0.34; P<0.01) and sICAM-1 (R=0.29; P<0.05) levels. Malnourished patients (SGA>1) had elevated serum concentrations of sVCAM-1 (1436+/-94 vs. 1105+/-53 ng/ml; P<0.01) compared to well-nourished patients (SGA 1). Patients with clinical signs of CVD (n=26) had elevated serum levels of sICAM-1 (282+/-18 vs. 242+/-9 ng/ml; P<0.05) compared to 61 patients without signs of CVD. Plasma Log lipoprotein (a) (Lp(a)) levels correlated significantly with sVCAM-1 (R=0.30; P<0.01). Survival analysis by the Cox regression model showed that elevated sICAM-1 was, independent of age, SGA, CVD, and Log CRP, significantly related to an increased mortality rate. CONCLUSIONS: Elevated serum concentrations of soluble adhesion molecules are found in pre-dialysis patients who are malnourished, inflamed, and have signs of cardiovascular disease. These data also suggest that sICAM-1 is an independent predictor of mortality in pre-dialysis patients. Further studies are needed to determine if inflammation causes accelerated atherogenesis via effects on soluble adhesion molecules or if elevated serum levels of soluble adhesion molecules are merely markers of endothelial activation in patients with chronic renal failure.     

Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS--a study of 274 Men

The impact of renin-angiotensin system (RAS) gene polymorphism on the prognosis of IgA nephropathy (IgAN) is still debated. A longitudinal study of renal prognosis in patients with IgAN was conducted to search retrospectively for a genotype-phenotype association between RAS polymorphisms and end-stage renal failure (ESRF). A classification based on serum creatinine (S(cr)) and 24-h proteinuria (24-P) measured at the time of renal biopsy was used to estimate the risk of ESRF in IgAN: stage 1 (S(cr) 150 micromol/L and 24-P < 1 g or S(cr) < or = 150 micromol/L and 24-P > or = 1 g), stage 3 (S(cr) > 150 micromol/L and 24-P > or = 1 g). Deletion/insertion polymorphism (D/I) of the angiotensin I converting enzyme gene, M235T polymorphism (T/M) of the angiotensinogen gene and A1166C polymorphism (C/A) of the angiotensin II type 1 receptor gene were determined in 274 Caucasian men with biopsy-proven IgAN (n = 86, 112, and 76 in stages 1, 2, and 3, respectively). Mean global follow-up was 6 +/- 5 yr after renal biopsy. For stages 1, 2, and 3, ESRF developed in 7 (8. 1%), 39 (34.8%), and 49 (64.4%) cases (P: < 0.0001), 11.7 +/- 4, 5.4 +/- 4, and 2 +/- 2 yr, respectively, after renal biopsy (P: < 0.001). The distributions of the three genotypes into the three stages were similar. Different distributions were observed when patients were grouped by stage and genotype: ID+DD: 72% in stage 1 versus 84.6% in stages 2 + 3 (P: = 0.02; kappa = 0.14); MT+TT: 66.2% in stages 1 + 2 versus 78.9% in stage 3 (P: = 0.04; kappa = 0.09); and AA+AC: 89.9% in stages 1 + 2 versus 97.4% in stage 3 (P: = 0.04; kappa = -0.1). However, with the use of the Cox proportional hazard model, none of the three genotypes was found to have predictive value for renal survival. Compared with S(cr) and 24-P, genotypes DD, TT, and AA are unlikely to serve as clinically useful predictors of ESRF in IgAN.     

Impaired renal function is associated with markers of endothelial dysfunction and increased inflammatory activity.

BACKGROUND: Patients with end-stage renal disease (ESRD) as well as those with mild renal insufficiency are at increased risk for the development of cardiovascular disease, which cannot be attributed entirely to traditional risk factors. Endothelial dysfunction and chronic inflammatory activity, two important phenomena in atherogenesis, can be found in ESRD. At present, it is unclear whether endothelial dysfunction and chronic inflammatory activity are related to renal function in the pre-dialysis stage. METHODS: In a cross-sectional, single-centre study, four groups of 20 subjects with renal function ranging from a normal, calculated creatinine clearance (>90 ml/min) to a pre-dialysis situation (<31 ml/min) were investigated. We measured markers of endothelial function [von Willebrand factor (vWf), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and E-selectin (ES)], and markers of inflammatory activity [secretory phospholipase A(2) (sPLA(2)) and C-reactive protein (CRP)]. Using these markers, composite endothelial function and inflammatory activity scores were constructed. RESULTS: Creatinine clearance correlated with the endothelial function score (r=-0.43, P<0.001), the inflammatory activity score (r=-0.53, P<0.05), vWf (r=-0.54, P<0.001), sVCAM-1 (r=-0.50, P<0.001), sPLA(2) (r=-0.28, P<0.05), homocysteine (r=-0.61, P<0.001), age (r=-0.54, P<0.001) and blood pressure (r=-0.44, P<0.001). In multivariate analyses, creatinine clearance was an independent determinant of the endothelial function score (beta=-0.34, P=0.006), plasma vWf (beta=-0.37, P=0.022) and sICAM-1 (beta=-0.33, P=0.012). The relationship of creatinine clearance with sVCAM-1 and endothelial function score was not significant when plasma homocysteine was added to the model. Creatinine clearance was also a determinant of the inflammatory activity score (beta=-0.31, P=0.025) and sPLA(2) (beta=-0.32, P=0.024), although this was no longer significant after correction for systolic blood pressure. CONCLUSIONS: Renal dysfunction is associated with markers of endothelial dysfunction and inflammatory activity. Plasma homocysteine may be an intermediate factor in the relationship between endothelial dysfunction and renal function, while blood pressure may modulate the association between inflammatory activity and renal function.     

Circulating soluble adhesion molecules in ANCA-associated vasculitis.

BACKGROUND: To evaluate whether changes in concentrations of soluble (s) E-selectin, sP-selectin, sL-selectin, intercellular adhesion molecule 1 (sICAM-1), and vascular cell adhesion molecule 1 (sVCAM-1) reflect disease activity in patients with ANCA-associated vasculitis and whether serum levels of these adhesion molecules are related to the degree of renal failure in patients with chronic renal failure (CRF). SUBJECTS AND METHODS: A sandwich ELISA was used to measure these soluble adhesion molecules in (i) sera from 20 patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (10 patients with Wegener's granulomatosis (WG) and 10 patients with microscopic polyangiitis (MPA)), obtained at the time of diagnosis and during the remission period; (ii) sera from 40 patients with CRF not undergoing haemodialysis. RESULTS: At the time of diagnosis, serum levels of sE-selectin, sICAM-1 and sVCAM-1 (88+/-42 ng/ml, 437+/-184 ng/ml, 1720+/-1174 ng/ml respectively) were significantly higher in patients with ANCA-associated vasculitis than in healthy controls (P<0.0001, P=0.002 and P=0.001 respectively). Serum sP-selectin values did not differ from those obtained in normal donors. In contrast, sL-selectin levels (940+/-349 ng/ml) were significantly lower in patients than those recorded in healthy controls (P<0.0001). A significant decrease in concentrations of sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 was observed between active and remission phases (P<0.0001, P=0.002, P=0.001 and P=0.001 respectively). No significant differences were observed in sL-selectin levels between active and remission phases. sL-selectin concentrations (802+/-306 ng/ml) during the remission phase remained lower than those observed in healthy controls (P<0.0001). No correlation was observed between serum creatinine and sE-selectin, sP-selectin, sICAM-1 and sVCAM-1 in patients of the CRF group. A slight negative correlation was established between creatinine and sL-selectin concentration. CONCLUSIONS: Increased serum levels of sE-selectin, sICAM-1, and sVCAM-1 and decreased levels of sL-selectin in active ANCA-associated vasculitis, and the normalization of sE-selectin, sICAM-1, and sVCAM-1 during the remission phase suggest that the concentration of soluble levels of these adhesion molecules reflects disease activity. The decrease in sP-selectin levels between active and inactive phases also suggest that this receptor may reflect clinical activity. The lack of correlation between serum levels of sE-selectin, sP-selectin, sICAM-1, and sVCAM-1 and the degree of renal failure in patients with CRF suggests that the mechanism of clearance of these molecules is not renal.     

Soluble adhesion molecules in end-stage renal disease: a predictor of outcome.

BACKGROUND: Inflammation is thought to contribute to initiation and aggravation of atherosclerosis through a process predominantly mediated by adhesion molecules. The aims of this study were to investigate the association between the concentrations of circulating soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules and clinical outcome, and to evaluate the effect of antihypertensive drugs on sICAM-1 and sVCAM-1 concentrations in end-stage renal disease (ESRD) patients. METHODS: We prospectively investigated 310 (191 males) incident ESRD patients, 53+/-12 years old, shortly before the start of renal replacement therapy. Glomerular filtration rate (GFR) was 6.4 (range 0.8-16.5) ml/min/1.73 m(2). Plasma sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) kits. Survival was determined from the day of examination, with a mean follow-up period of 39 (range 1-123) months. RESULTS: In non-adjusted analysis, high sICAM-1 and sVCAM-1 levels were associated with all-cause and cardiovascular (P<0.001) mortality. After adjusting for age, gender, diabetes mellitus, serum cholesterol, C-reactive protein (CRP), subjective global assessment and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), the association between high sICAM-1 and mortality remained significant for all-cause (HR 1.9; CI 1.2-2.9, P = 0.004) and cardiovascular (HR 1.8; CI 1.1-3.1, P = 0.02) mortality, and a high sVCAM-1 was associated with all-cause mortality (HR 1.7; CI 1.04-2.7, P = 0.03). Furthermore, the concentration of sICAM-1, but not sVCAM-1, was lower in patients receiving ACEI/ARB (254+/-83 vs 275+/-92 ng/ml; P<0.05) or patients receiving calcium channel blockers (CCB, 251+/-75 vs 273+/-95 ng/ml; P<0.05) than in non-users. CONCLUSIONS: In ESRD patients, sICAM-1 and sVCAM-1 are independent predictors of all cause and cardiovascular death. The use of ACEI/ARB or CCB was associated with decreased concentrations of soluble adhesion molecules.     

Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure

BACKGROUND: Hyperphosphatemia and disturbances in calcium or parathyroid hormone (PTH) metabolism contribute to the high incidence of cardiovascular disease and renal osteodystrophy in chronic renal failure (CRF). We evaluated the effect of hyperphosphatemia on the cardiovascular system, on renal function, and on bone in experimental uremia. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx) with minipump implantation, delivering 1-34 rat PTH (physiologic rate), or were sham-operated and received vehicle. Only phosphorus content (low-phosphorus (LP) 0.2%; high-phosphorus (HP) 1.2%) differentiated diets. We divided the groups as follows: PTx +Nx +LP; sham + LP; PTx + Nx + HP; and sham + HP. Tail-cuff pressure and weight were measured weekly. After 2 months, biochemical, arterial, and myocardial histology and bone histomorphometry were analyzed. RESULTS: Heart weight normalized to body weight (heart weight/100 g body weight) was higher in PTx + Nx + HP rats (PTx + Nx + HP = 0.36 +/- 0.01 vs. sham + HP = 0.29 +/- 0.01, PTx + Nx + LP = 0.32 +/- 0.01, sham + LP = 0.28 +/- 0.01) (P < 0.05). Serum creatinine levels were higher in PTx + Nx + HP rats than in PTx + Nx + LP rats (1.09 +/- 0.13 vs. 0.59 +/- 0.03 mg/dL) (P < 0.05). Levels of PTH did not differ significantly between the groups. Myocardial and arterial histology detected no vascular calcification or fibrosis. Bone histomorphometry revealed an association, unrelated to uremia, between HP diets and decreased trabecular connectivity. CONCLUSION: Myocardial hypertrophy, impaired renal function, and adverse effects on bone remodeling were associated with hyperphosphatemia and were not corrected by PTH replacement. Although no vascular calcification was observed in this model, we cannot rule out an adverse effect of hyperphosphatemia on the vascular bed. Our finding underscores the importance of phosphorus control in reducing morbidity and mortality in CRF patients.     

Association between endothelial progenitor cell depletion in blood and mild-to-moderate renal insufficiency in stable angina.

BACKGROUND: Low blood counts of CD34/kinase-insert domain receptor double-positive cells (CD34(+)/KDR(+) cells)-a leukocytes subpopulation enriched for bone marrow-derived endothelial progenitor cells (EPC)- predict adverse outcomes in coronary artery disease (CAD). The dependence of EPC numbers on the glomerular filtration rate (GFR), another prognostic factor, has not been reported in CAD yet. Our aim was to assess CD34(+)/KDR(+) cell counts versus GFR in stable angina. METHODS: We studied 102 stable angina men with severe angiographic CAD and normal left-ventricular systolic function. CD34(+)/KDR(+) cells were enumerated by flow cytometry. RESULTS: With lowering GFR, CD34(+)/KDR(+) cell numbers (% of lymphocytes, median and interquartile range) decreased: 0.04 (0.03-0.06), 0.03 (0.02-0.05) and 0.02 (0.01-0.03)% for GFR >or=90, 60-89 and 30-59 ml/min/1.73 m(2), respectively (P < 0.001 for trend). CD34(+)/KDR(+) cell counts correlated with GFR (r = 0.25, P = 0.01), CAD extension score (r = -0.20, P = 0.04), soluble form of vascular cell adhesion molecule-1 (sVCAM-1) (r = -0.22, P = 0.03) and homocysteine (r = -0.20, P = 0.04) levels. A GFR <90 ml/min/1.73 m(2) was associated with insignificantly higher plasma erythropoietin concentrations (r = -0.22, P = 0.09 for trend) that correlated with haemoglobin levels (r = -0.33, P = 0.01, n = 59). The GFR-CD34(+)/KDR(+) cells relation was attenuated, yet maintained (beta = 0.19 +/- 0.09, P = 0.04) on adjustment for the remaining multivariate determinants of CD34(+)/KDR(+) cell numbers: sVCAM-1 (beta = -0.20 +/- 0.09, P = 0.03) and haemoglobin (beta = 0.18 +/- 0.09, P = 0.05). CONCLUSIONS: Mild-to-moderate renal dysfunction accompanying stable angina is associated with CD34(+)/KDR(+) cell depletion, which partially depends on concomitant endothelial dysfunction and a tendency to anaemia (despite insignificantly higher erythropoietin) irrespective of an angiographic CAD extent. This may exacerbate an imbalance between endothelial injury and EPC-mediated repair, thus contributing to high cardiovascular risk in CAD coexisting with renal insufficiency.     

Endogenous endothelins mediate increased acidification in remnant kidneys

Because endothelins (ET) mediate increased renal acidification induced by dietary acid and animals with reduced renal mass exhibit increased urinary ET-1 excretion, the hypothesis that ET mediate increased renal acidification in remnant kidneys was tested. Four weeks before the study, rats underwent a 5/6 nephrectomy (Nx) and a microdialysis apparatus was inserted into the remnant left kidney and the left kidney of sham-treated control animals, for measurements of renal ET-1 contents. Nx animals exhibited greater ET-1 addition to the renal dialysate than did control animals (681 +/- 91 versus 290 +/- 39 fmol/g kidney wt per min, P < 0.002) and greater urinary ET-1 excretion (346 +/- 79 versus 125 +/- 24 fmol/d, P < 0.02). Urinary net acid excretion rates were similar for Nx and control animals (732 +/- 106 versus 1005 +/- 293 microEq/d, P = 0.4), but Nx animals exhibited greater in situ HCO(3)(-) reabsorption in proximal (972.3 +/- 77 versus 482.6 +/- 42.4 pmol/min, P < 0.001) and distal (62.7 +/- 6.7 versus 24.3 +/- 2.5 pmol/min, P < 0.001) tubules. Orally administered bosentan, an ET(A/B) receptor antagonist, decreased urinary net acid excretion in Nx animals (to 394 +/- 99 microEq/d, P < 0.04 versus without bosentan); the decrease was mediated by decreased HCO(3)(-) reabsorption in both the proximal and distal tubules. Furthermore, bosentan decreased blood base excess in Nx animals (0.1 +/- 0.3 to -0.12 +/- 0.03 microM/ml blood, P < 0.002), consistent with acid retention. The data demonstrate that endogenous ET mediate increased urinary acid excretion in the remnant kidneys of Nx animals.     

Monocyte-related determinants of inflammation in patients on peritoneal dialysis

AIMS: We studied markers of monocyte activation, i.e., the cell surface expression of CD11b and CD62L, and the serum concentrations of monocyte chemotactic protein 1 (MCP-1; a monocyte-specific chemoattractant) and soluble vascular cell adhesion molecule 1 (sVCAM-1; an adhesion molecule involved in monocyte recruitment) in 20 patients on peritoneal dialysis (PD), in 25 patients with chronic renal insufficiency, and in 27 healthy subjects. RESULTS: Monocytes obtained from the peripheral blood of PD patients had a significantly higher expression of CD62L (p = 0.02) as compared with monocytes from healthy subjects and a lower CD11b/CD18 expression as compared with monocytes collected from healthy subjects (p < 0.001) and from patients with renal insufficiency (p < 0.001). Monocytes from PD patients had, however, the capacity to increase the expression of CD11b following stimulation with a potent chemotactic factor. The serum concentrations of MCP-1 and sVCAM-1 were higher in PD patients (575 +/- 51 and 1,517 +/- 89 ng/ml) than in healthy subjects (225 +/- 17 and 668 +/- 64 ng/ml, respectively; p < 0.001 for both comparisons). There was a correlation between the levels of sVCAM-1 and MCP-1 (r = 0.48, p < 0.05) in patients on PD, but neither correlated with the monocyte expression of CD11b/CD18 or CD62L. The concentration of C-reactive protein was higher in patients on PD as compared with healthy subjects and correlated significantly with the concentration of sVCAM-1 (r = 0.63, p < 0.01). CONCLUSIONS: Monocytes in the peripheral circulation of patients on PD have a CD62L(high)/CD11b(low) phenotype, indicating that they have not undergone complete differentiation. Patients also have an increase in the systemic chemotactic activity for monocytes in combination with increased levels of sVCAM-1 and C-reactive protein. These inflammatory aberrations may play a pathophysiological role in the response to inflammatory and infectious diseases in patients on PD.     

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin.

BACKGROUND: Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). METHODS: We performed a cross-sectional study of 85 incident patients (51 +/- 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor (<500 mg/day; n = 40) or severe (>/=500 mg/day; n = 45) proteinuria. Clinical and anthropometric data, along with ultrasonographic flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thicknesses (CIMT), were recorded in each group. Circulating NAMPT/visfatin, adiponectin (normalized to BMI), AHSG/fetuin-A and hsCRP levels were also measured using commercial ELISA. RESULTS: Plasma NAMPT/visfatin, CIMT, HOMA index and hsCRP levels were all significantly higher in diabetics than in control subjects, and all but CIMT correlated with proteinuria (rho = 0.46; P < 0.001, rho = 0.54; P > 0.05, rho = 0.32; P = 0.003, rho = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (rho = -0.54; P < 0.001, rho = -0.56; P < 0.001, rho = -0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r(2) = -0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r(2) = -0.33, P = 0.006) were independently related to FMD. CONCLUSIONS: The present study suggests that the presence of proteinuria, regardless of the degree of renal function impairment, is an important predictor of endothelial dysfunction in early diabetic nephropathy and that it is associated with altered circulating levels of NAMPT/visfatin and adiponectin.     

Endothelial dilatory function predicts individual susceptibility to renal damage in the 5/6 nephrectomized rat

In experimental animal models of renal disease the degree of renal damage varies between individuals. This could be caused by variation in the noxious event or by differences in individual susceptibility. Intact endothelial function is assumed to provide a defense mechanism against progressive renal damage. This study hypothesized that interindividual differences in renal endothelial function might be involved in individual susceptibility to renal damage, and it investigated whether endothelial function of small renal arteries before induction of 5/6 nephrectomy (5/6 Nx) in rats was related to development of renal damage after 5/6 Nx. Wistar rats underwent 5/6 Nx, and small renal arteries of the removed right kidney were investigated for endothelium-dependent relaxation to acetylcholine (ACh, 10(-8) to 10(-4) mol/L). The contribution of underlying endothelial dilative mediators, NO, prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF), was assessed using the inhibitors, L-NMMA, indomethacin, and charybdotoxin+apamin, respectively. After 5/6 Nx, proteinuria developed in each rat ranging from 22 to 278 (84 +/- 14) mg/24 h at week 5 (n = 23). Interestingly, a significant inverse correlation between individual ACh-relaxation (expressed as area under curve in arbitrary units) and proteinuria 5 wk after 5/6 Nx was found (r = -0.54; P = 0.008; n = 23). An inverse correlation was also found between individual NO contribution as well as PG contribution and proteinuria 5 wk after 5/6 Nx (r = -0.86, P = 0.001, n = 11; and r = -0.74, P = 0.01, n = 11, respectively). In addition, individual ACh-relaxation was positively correlated with GFR measured 6 wk after 5/6 Nx (r = 0.58; P = 0.016; n = 17). This study demonstrates for the first time that individual renal endothelial dilatory function of the healthy rat predicts susceptibility to renal damage after 5/6 Nx, which seems to depend on individual endothelial NO and PG activity.     

Effects of enalapril and eprosartan on the renal vascular nitric oxide system in human essential hypertension

BACKGROUND: Experimental data in humans on the contribution of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers to the nitric oxide system of the renal vasculature are inconsistent. Enalapril and eprosartan, alone and in combination, were used to determine their short-term effects on the renal nitric oxide system and renal hemodynamics of human subjects with essential hypertension. METHODS: Twenty male, white patients (27 +/- 1 years) with mild essential hypertension (143 +/- 11/95 +/- 6 mm Hg) were included in a double-blind, randomized, placebo-controlled, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or combination of both drugs (10 and 300 mg/day, respectively) each over a one week period followed by a two-week washout phase. After each study phase the glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined. Basal nitric oxide synthesis of the renal vasculature was assessed by the decrease in RPF after inhibition of nitric oxide synthase with NG-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg). RESULTS: After one week of therapy, the combination therapy decreased casual blood pressure by 5 +/- 2/3 +/- 1 mm Hg versus placebo (P < 0.01). Neither enalapril alone (-2 +/- 2/1 +/- 2 mm Hg, NS vs. placebo) nor eprosartan alone (-1 +/- 1/0 +/- 2 mm Hg, NS vs. placebo) had a clear-cut significant effect on casual blood pressure. In the combination phase, RPF increased by 123 +/- 36 mL/min (P < 0.01). Neither enalapril alone (+59 +/- 46 mL/min, P = 0.21) nor eprosartan alone (+113 +/- 51 mL/min, P = 0.06) had a clear-cut significant effect on RPF. Changes of RPF induced by treatment correlated with the L-NMMA induced decrease in RPF in the combination (r = 0.70, P < 0.01) and eprosartan phase (r = 0.86, P < 0.001), but not in the enalapril phase (r = -0.44, P = 0.10). Renal vascular resistance was reduced by each active treatment with the most prominent reduction in the combination phase. GFR was unaffected by any treatment. CONCLUSIONS: In contrast to the effects of either substance alone, a combination of half the dose of eprosartan with half the dose of enalapril had a prominent effect on renal perfusion. The effects of eprosartan on RPF are mediated, at least in part, by an increased bioavailability of nitric oxide in the renal vasculature.     

Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration in patients with mild-to-moderate renal failure

BACKGROUND: Patients with renal insufficiency have an increased risk of cardiovascular disease that is not fully explained by the presence of known cardiovascular risk factors. In patients with end-stage renal disease, increased serum concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), has been linked to excess cardiovascular morbidity. We investigated, in patients with mild-to-moderate renal failure, the relationship between plasma ADMA and three surrogate markers of atherosclerosis that have been shown to have prognostic value, namely carotid intima-media thickness (IMT), plasma soluble vascular cell adhesion molecule-1 (sVCAM-1), and plasma C-reactive protein (CRP). METHODS: We used baseline data of an ongoing randomized trial in which the effects of oxidative stress-lowering treatment on vascular function and structure are studied in patients with chronic nondiabetic renal failure without clinical evidence of atherosclerosis (GFR 15 to 70 mL/min/per 1.73 m(2) according to the Cockcroft-Gault equation; ATIC study). RESULTS: Data from 93 patients were used. Creatinine clearance was inversely related to plasma ADMA concentration (standardized beta after adjustment = -0.342, P = 0.023). Plasma ADMA was strongly related to carotid IMT in univariate (beta = 0.459, P < 0.0001) and multivariate analysis (beta= 0.444, P < 0.0001). Plasma ADMA was also significantly related with plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) in univariate (beta = 0.260, P = 0.010) and multivariate (beta = 0.242, P = 0.022) analysis. Plasma ADMA was not significantly related to C-reactive protein (beta = -0.134, P = 0.204). CONCLUSION: In patients with mild-to-moderate renal failure, renal function is inversely associated with plasma ADMA, which, in turn, is positively associated with carotid IMT and plasma sVCAM-1 concentration. Increased plasma ADMA may be a link between renal function and cardiovascular disease in patients with mild-to-moderate renal failure.     

ACE and non-ACE pathways in the renal vascular response to RAS interruption in type 1 diabetes mellitus

BACKGROUND: The enormous contribution of renin-angiotensin system (RAS) interruption with ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers (ARB) in the treatment of diabetic nephropathy has led to interest in the factors involved in angiotensin II (Ang II) generation. In normal subjects, RAS interruption using an ARB produced a 50% greater renal plasma flow (RPF) rise than with an ACE inhibitor, suggesting a substantial contribution of non-ACE pathways. Moreover, immunohistochemistry studies in kidneys of overtly proteinuric diabetic subjects showed up-regulation of chymase, an alternative Ang II-generating enzyme. Our aim was to determine the degree to which the non-ACE pathways contribute to RAS activation in type 1 diabetes mellitus (DM). METHODS: Type 1 DM patients (N= 37, 14 M/23 F; age 31 +/- 2 years; DM duration 16 +/- 1.7 years; HbA1c 7.7.0 +/- 0.3%) were studied on a high-salt diet. They received captopril 25 mg po one day and candesartan 16 mg po the next day. RPF and glomerular filtration rate (GFR) were measured before and up to 4 hours after drug administration. RESULTS: Both captopril and candesartan induced a significant rise in RPF (baseline vs. peak <0.0001 for both), and the rise was concordant for the 2 drugs (r= 0.77, P < 0.001). However, the RPF responses were not significantly different between the 2 drugs (captopril 72 +/- 11 mL/min/1.73 m(2), candesartan 75 +/- 12, P= 0.841). CONCLUSION: In predominantly normoalbuminuric, normotensive type 1 DM, activation of the intrarenal RAS reflects a mechanism involving primarily the classic ACE pathway.     

Adiponectin level is reduced and inversely correlated with the degree of proteinuria in type 2 diabetic patients

AIMS: Adiponectin seems to be an important modulator for metabolic and vascular diseases. We aimed to measure plasma adiponectin levels in type 2 diabetic patients and investigate any association with the severity of proteinuria. METHODS: 80 patients (mean age, 46.9 +/- 5.1 years; body mass index (BMI), 25.8 +/- 1.98 kg/m2) and 47 healthy volunteers (mean age, 46.1 +/- 5.5 years; BMI 26.74 +/- 2.23 kg/m2) were included. Plasma adiponectin concentration, insulin levels, homeostasis model assessment (HOMA) indices, calculated glomerular filtration rate (GFR), high sensitive C reactive protein (hsCRP) and biochemistry panel were determined in all subjects. The association between adiponectin concentration and proteinuria was evaluated. Additionally, the relationship between adiponectin and hsCRP and calculated GFR were also investigated. RESULTS: Adiponectin levels in patients were significantly lower than those of controls (n = 80; 8.76 +/- 4.50 microg/ml for patients, n = 47; 24.27 +/- 5.59 microg/ml for controls, p < 0.001). Plasma adiponectin levels in patients with proteinuria were significantly lower than those without proteinuria (n = 43; 6.81 +/- 2.82 microg/ml for proteinuria, n = 37; 11.98 +/- 3.32 microg/ml for no proteinuria, p < 0.001). There was a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r = -0.433, p < 0.001). There were also significant negative correlations between adiponectin concentrations and insulin levels as well as HOMA index in the patient group (r = -0.322, p = 0.004; r = -0.301, p = 0.032). Additionally there was a significant negative correlation between adiponectin and hsCRP levels in the patient group (r = -0.872, p < 0.001). CONCLUSION: The results show that adiponectin is lower in patients with type 2 diabetes and the levels are negatively correlated with the severity of proteinuria.     

Intercellular adhesion molecule-1 mediated interactions and leucocyte infiltration in IgA nephropathy

Background: Mononuclear leucocytes have a role in IgA nephropathy (IgAN). Renal leucocyte recruitment is mediated by adhesive interactions between leucocytes and their ligands on renal cells. Methods: We have assessed interstitial and glomerular leucocytes by avidin-biotin-peroxidase with monoclonal antibodies (MA) against leucocytes (CD45), {beta}2-integrin (CD18), monocyte-macrophages (CD14), T (CD3) and T-cell subsets (CD4, CD8), and intercellular adhesion molecule 1 (ICAM-1) (CD54), and analysed their relation with the abnormal expression of ICAM-1 on proximal tubule epithelium in sequential renal sections from 48 patients with IgAN stratified according to the severity of the interstitial cellular infiltration observed by light microscopy. Results: In IgAN without (n=15) and with (n=7) interstitial cellular infiltration of 1+, ICAM-1 expression on vascular endothelium was unchanged with respect to that observed in the normal kidney; the proximal tubule epithelium was negative for this stain. In IgAN with interstitial cellular infiltration of 2+ (n=10), 3+ (n=11), and 4+ (n=5), ICAM-1⁺ stain was observed on the proximal tubule epithelium, the median value of its quantitative expression being 0.3, 0.1, and 0.2 (P=0.0008), respectively. The tubular ICAM-1⁺ stain was significantly associated with the interstitial leucocytes identified by MA, and correlated with CD45⁺ (r=0.59, P=0.02), CD14⁺ (r=0.54, P<0.02), and CD3⁺ (r=0.51, P=0.02) interstitial leucocytes in IgAN with interstitial cellular infiltration. Interstitial ICAM-1⁺ and CD18⁺ leucocytes were correlated (r=0.56, P<0.001). Correlation was found between the quantitative tubular expression of ICAM-1⁺ and the number of CD45⁺ (r=0.98, P<0.0001), CD3⁺ (r=0.48, P=0.02), and CD8⁺ (r=0.76, P<0.02) glomerular leucocytes. Conclusion: Our results suggest that tubular and interstitial ICAM-1⁺ cells may participate in adhesive interactions with interstitial leucocytes. Interstitial T-cells and macrophages as well as glomerular T-cells bearing predominantly CD8⁺ phenotype could play a role in the induction of the tubular expression of ICAM-1 in IgAN.     

Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.     

Serum visfatin concentration and endothelial dysfunction in chronic kidney disease.

BACKGROUND: Endothelial dysfunction (ED) is common in patients with moderate to advanced chronic kidney disease (CKD). Recently, visfatin, a protein with insulin-mimetic properties, was shown to be associated with sVCAM-1. Thus, we hypothesised that visfatin may be a marker of ED in CKD. METHODS: We studied 406 patients with different stages of non-diabetic CKD (50% males, 46 +/- 12 years), testing the relationship between flow-mediated dilatation (FMD), assessed by high resolution brachial ultrasonography, and plasma adiponectin and visfatin concentrations. Eighty healthy volunteers (50% males, 46 +/- 11 years) served as matched controls. RESULTS: Compared to healthy controls, ED was observed in all stages of CKD (Stages 1-5) and correlated strongly with the reduction in estimated glomerular filtration rate (eGFR). Whereas visfatin concentrations were found to be increased in all but CKD stages 1 and 2, adiponectin levels were found to be increased in all patients but CKD stage 1. Visfatin and adiponectin levels were strongly correlated with eGFR (rho = -0.62 and rho = -0.72, respectively, P < 0.001 for both). FMD levels were negatively correlated with both visfatin and adiponectin levels (rho = -0.53 and, rho = -0.57, respectively, P < 0.001 for both). In a multiple regression model, eGFR levels (Beta = 0.74, P < 0.001), visfatin (Beta = -0.15, P < 0.001), age (Beta = 0.06, P < 0.01), adiponectin (Beta = 0.09, P < 0.05), HOMA-IR (Beta = 0.07, P < 0.05) and hsCRP (Beta = -0.08, P < 0.05) were all found to be significantly related to FMD. CONCLUSIONS: We conclude that the circulating levels of visfatin and adiponectin are associated with ED in all stages of CKD, independently of inflammation and insulin resistance.     

Association of MEGSIN 2093C-2180T haplotype at the 3' untranslated region with disease severity and progression of IgA nephropathy.

BACKGROUND: MEGSIN is a gene predominantly expressed in the renal mesangium, and is upregulated in IgA nephropathy (IgAN). Our previous study has shown that the 2093C and 2180T alleles at the 3' untranslated region (3'UTR) of the gene are associated with susceptibility to IgAN, but the relationships of these genetic variants with the clinical manifestations and renal histological lesions of IgAN have not been examined previously. METHODS: 302 IgAN patients followed up for 52.8+/-22.5 months were investigated. Haplotypes at the 3'UTR were constructed using the 2093C/T and 2180C/T alleles. The genotype-phenotype relationship was studied by correlations of haplotypes and the clinical data and renal histopathological changes. RESULTS: The 2093C-2180T haplotype was present more often in patients with disease that progressed more rapidly (chi2((C-T/others)) = 8.429, P = 0.004), and was also correlated with hypertension (chi2((C-T/others)) = 6.459, P = 0.012), severe proteinuria (>or=2 g/d) (chi2((C-T/others)) = 6.332, P = 0.013), and Lee's class IV and V histological changes (chi2((C-T/others)) = 9.640, P = 0.008). CONCLUSION: In this Chinese population, the 2093C-2180T haplotype at the 3'UTR of MEGSIN gene is associated with more severe forms of IgAN, and more rapid disease progression. This provides further evidence for the involvement of genetic variations of MEGSIN in the pathogenesis of IgAN.     

Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers

BACKGROUND: Inflammation and oxidative stress have been incriminated in the pathogenesis of IgA nephropathy (IgAN). The aim of the present study was to assess whether markers reflecting these pathophysiologic processes, namely C-reactive protein (CRP) and advanced oxidation protein products (AOPP), would allow-in conjunction with clinical and histopathologic parameters-to predict disease progression. METHODS: Between 1994 and 1997, 120 adult patients with biopsy-proven IgAN were included in a prospective cohort study, and followed until the end of 2002 or start of dialysis. In every patient, we determined plasma levels of CRP and AOPP. These parameters were included, together with clinical data, in a multivariate Cox proportional hazard regression analysis, with halving of baseline creatinine clearance as the primary renal end point. RESULTS: A total of 51 patients reached the renal end point, including 30 who had to start dialysis. With multivariate analysis, the most potent independent risk factors of poor renal outcome were proteinuria > or =1 g/day [proportional hazard risk (HR) = 23.7, P= 0.0001], hypertension (HR = 8.13, P= 0.008), and AOPP plasma level (HR = 1.09 per 10 micromol/L, P= 0.042), whereas angiotensin II inhibitors were protective (HR = 0.19, P= 0.001). CONCLUSION: Our data support the role of oxidative stress in the pathogenesis of IgAN and suggest that patients with proteinuria > or =1 g/day should be eligible for early implemented antioxidant and/or anti-inflammatory therapeutic strategies, with AOPP plasma level as a surrogate marker to evaluate their effects.