Mutlu Saglam

FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease.

Studies in animals show that fibroblast growth factor (FGF)-23 interferes with vascular reactivity induced by the nitric oxide (NO) system. To investigate the relationship between circulating FGF-23 levels and the response of forearm blood flow to ischemia (flow-mediated vasodilatation, FMD) and nitroglycerin, we tested 183 patients with stage 3-4 chronic kidney disease (CKD). None of them had cardiovascular complications or were taking drugs interfering with vascular function. Patients with FGF-23 levels above the median had significantly lower glomerular filtration rate, FMD, and fetuin-A levels (an anti-inflammatory molecule and potent inhibitor of calcification). They also had higher proteinuria and phosphate levels when compared to patients whose FGF-23 levels were below the median. The response to nitroglycerin was not different between the two groups. Multiple regression analysis showed that the relationship between FGF-23 and FMD was only modestly sensitive to adjustment for classical risk factors, biomarkers of bone mineral metabolism, high-sensitivity C-reactive protein, and homeostatic model assessment index. Adjustment for asymmetrical dimethyl arginine (ADMA) weakened the strength of this link; however, it remained highly significant. There was no independent association between FGF-23 and nitroglycerin. Thus, attenuation of FMD by ADMA suggests that this endogenous inhibitor of NO synthase may, in part, mediate the vascular effects of FGF-23 in patients with CKD.

Comparison of Calcium Acetate and Sevelamer on Vascular Function and Fibroblast Growth Factor 23 in CKD Patients: A Randomized Clinical Trial

BACKGROUND Fibroblast growth factor 23 (FGF-23) is a marker of endothelial dysfunction and atherosclerotic complications in patients with chronic kidney disease (CKD). Because previous studies suggested that sevelamer may exert effects on FGF-23 level and endothelial function independently of its phosphate-lowering action, we tested the effect of sevelamer versus calcium acetate on vascular function and FGF-23 levels. STUDY DESIGN Randomized prospective open-label trial. SETTING & PARTICIPANTS Patients with stage 4 CKD with hyperphosphatemia (n = 100). INTERVENTION An 8-week intervention with sevelamer (n = 47) and calcium acetate (n = 53). OUTCOMES The primary study outcome was change in flow-mediated vasodilatation in the forearm. The secondary outcome was change in FGF-23 levels. RESULTS Serum phosphate levels decreased in both treatment arms (P < 0.001), but more markedly in the sevelamer group (P < 0.001). Flow-mediated vasodilatation increased from 6.1% to 7.1% (P < 0.001) in sevelamer-treated patients, whereas it was unchanged in the calcium-acetate group (6.0% vs 6.0%). In a combined analysis, treatment-induced changes in flow-mediated vasodilatation were (P < 0.001) associated with simultaneous changes in FGF-23 levels (-27.1% [-33.2% to -8.8%] for the sevelamer group; 3.5% [-8.4% to 12.1%] for the calcium acetate group), as well as with C-reactive protein and fetuin A levels. These relationships were confirmed in multiple regression analysis adjusting for changes in serum phosphate levels and other factors. LIMITATIONS Unblinded randomized controlled study that cannot establish mechanisms of effect. CONCLUSIONS In hyperphosphatemic patients with stage 4 CKD, treatment with phosphate lowering induces measurable improvements in flow-mediated vasodilatation. Furthermore, independently of serum phosphate level, FGF-23 level changes induced by phosphate binders are associated with simultaneous changes in flow-mediated vasodilatation. These observations are compatible with the hypothesis that FGF-23 may contribute to vascular dysfunction in this population.

Short-Term Treatment with Sevelamer Increases Serum Fetuin-A Concentration and Improves Endothelial Dysfunction in Chronic Kidney Disease Stage 4 Patients

BACKGROUND AND OBJECTIVES Vascular calcification and endothelial dysfunction contribute to the development of cardiovascular disease in patients with chronic kidney disease (CKD). Sevelamer, a non-calcium-based phosphate binder, has been shown to attenuate cardiovascular calcification in CKD patients, although the exact mechanism has not been clarified. This study was designed to investigate the effect of short-term sevelamer treatment on both serum fetuin-A concentrations and endothelial dysfunction seen in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty nondiabetic stage 4 CKD patients whose phosphate levels were > or =5.5 mg/dl were enrolled in this 8-wk randomized prospective study. Thirty-six healthy volunteers served as matched controls. Patients were treated with either sevelamer (n = 25, 12 males) or calcium acetate (n = 25, 13 males). Fetuin-A, high-sensitivity C-reactive protein, Ca x PO4 product, flow-mediated dilation (FMD), insulin, and homeostasis model assessment (HOMA) were obtained at baseline and after the treatment period. RESULTS As expected, CKD patients had significantly lower levels of fetuin-A and FMD, and significantly higher levels of intact parathyroid hormone, Ca x PO4 product, and high-sensitivity C-reactive protein than controls (P < 0.001 for all). The use of sevelamer led to a significant increase in the fetuin-A concentration with improvement in FMD, whereas no significant difference was observed in the calcium acetate group. In a multiple regression analysis, FMD levels were independently related to fetuin-A both before (beta = 0.63, P < 0.001) and after (beta = 0.38, P = 0.004) treatment. CONCLUSIONS This small, randomized, prospective study shows that short-term sevelamer treatment significantly increases fetuin-A levels and improves FMD in nondiabetic stage 4 CKD patients.

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.

Novel Links between the Long Pentraxin 3, Endothelial Dysfunction, and Albuminuria in Early and Advanced Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Albuminuria and inflammation predict cardiovascular events. Pentraxin 3, an inflammatory mediator produced by, among others, endothelial cells, may have a role in atherogenesis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In 207 Swedish patients with stage 5 chronic kidney disease and 79 Turkish patients with type 2 diabetes and proteinuria and normal renal function, whether serum pentraxin 3 levels are associated with albuminuria and endothelial dysfunction was studied. RESULTS Patients with stage 5 chronic kidney disease and a high degree of albuminuria more often had diabetes and higher levels of pentraxin 3, vascular cellular adhesion molecule-1, and blood pressure. Moreover, pentraxin 3 was independently associated with 24-h urinary albumin excretion. In patients with type 2 diabetes, pentraxin 3 was significantly higher than in control subjects. Patients with type 2 diabetes and more proteinuria had higher pentraxin 3, C-reactive protein, glycosylated hemoglobin, insulin, and homeostasis model assessment index as well as lower flow-mediated dilation and serum albumin. Pentraxin 3 was positively correlated with C-reactive protein, homeostasis model assessment index, and carotid intima-media thickness and negatively with flow-mediated dilation. Pentraxin 3 and glomerular filtration rate were independently associated with 24-h urinary protein excretion. Only pentraxin 3 and proteinuria were significantly and independently associated with flow-mediated dilation. CONCLUSIONS In two different renal cohorts, one of stage 5 chronic kidney disease and one of type 2 diabetes and normal renal function, pentraxin 3 was independently associated with proteinuria. Moreover, both pentraxin 3 and proteinuria were associated with endothelial dysfunction in patients with type 2 diabetes.

Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes

INTRODUCTION Systemic inflammation, endothelial dysfunction and arterial thickening contribute to the elevated cardiovascular risk of dialysis patients. However, the course of these derangements and their relative contribution to the cardiovascular risk of nondialysed chronic kidney disease (CKD) are scarcely investigated. METHODS Flow-mediated dilatation (FMD) and intima-media thickness (IMT) were assessed in 304 nondialysed CKD patients Stages 1-5 (mean age 46 ± 12 years, 158 men), together with routine biochemical measurements, C-reactive protein (CRP) and insulin resistance. Patients were then followed for time-to-event analysis of cardiovascular outcomes (fatal and nonfatal). RESULTS CRP and IMT increased, while FMD decreased in parallel with estimated glomerular filtration rate (eGFR) decline (P < 0.001 for all). CRP and intact parathormone, as well as eGFR, appeared as strong determinants of FMD and IMT in multivariate analyses. After a median follow-up of 41 (range 6-46) months, 30 fatal and 59 nonfatal cardiovascular events occurred. In univariate analysis, FMD, IMT and CRP were significant predictors of outcome. In a multivariate Cox model excluding IMT, both FMD [hazard ratios 0.52 (95% confidence intervals 0.37-0.73) per %] and CRP [1.07 (1.03-1.11) per mg/L] predicted cardiovascular outcomes independently of confounders. In a model excluding FMD, only CRP (and not IMT) was a significant predictor. CONCLUSIONS Endothelial dysfunction, arterial thickening and inflammation occur in parallel with the decline in eGFR, contributing to the increased cardiovascular risk of nondialysed CKD. Our results support the use of FMD over IMT measurements to monitor nondialysed CKD patients at risk.

Anatomical variations of hepatic arterial system, coeliac trunk and renal arteries: an analysis with multidetector CT angiography

The purpose of our investigation was to determine the anatomical variations in the coeliac trunk-hepatic arterial system and the renal arteries in patients who underwent multidetector CT (MDCT) angiography of the abdominal aorta for various reasons. A total of 100 patients were analysed retrospectively. The coeliac trunk, hepatic arterial system and renal arteries were analysed individually and anatomical variations were recorded. Statistical analysis of the relationship between hepatocoeliac variations and renal artery variations was performed using a chi(2) test. There was a coeliac trunk trifurcation in 89% and bifurcation in 8% of the cases. Coeliac trunk was absent in 1%, a hepatosplenomesenteric trunk was seen in 1% and a splenomesenteric trunk was present in 1%. Hepatic artery variation was present in 48% of patients. Coeliac trunk and/or hepatic arterial variation was present in 23 (39.7%) of the 58 patients with normal renal arteries, and in 27 (64.3%) of the 42 patients with accessory renal arteries. There was a statistically significant correlation between renal artery variations and coeliac trunk-hepatic arterial system variations (p = 0.015). MDCT angiography permits a correct and detailed evaluation of hepatic and renal vascular anatomy. The prevalence of variations in the coeliac trunk and/or hepatic arteries is increased in people with accessory renal arteries. For that reason, when undertaking angiographic examinations directed towards any single organ, the possibility of variations in the vascular structure of other organs should be kept in mind.

Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes.

BACKGROUND AND OBJECTIVES Chronic kidney disease (CKD) conveys high mortality rates. Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin 3 (PTX3) are predictors of mortality in dialysis patients and determinants of endothelial dysfunction. Now, we hypothesize that both sTWEAK and PTX3 act as biomarkers of cardiovascular outcomes in nondialysis CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Cross-sectional analysis in which flow-mediated dilation (FMD) and intima-media thickness (IMT) were assessed in 257 nondialysis stage 1 to 5 CKD patients (mean age, 52 ± 12 years; 130 men), together with biochemical measurements and sTWEAK and PTX3 assessments. Patients were followed for cardiovascular outcomes. RESULTS PTX3 and IMT increased, whereas FMD and sTWEAK decreased across CKD stages (P<0.001 for all). Both PTX3 and sTWEAK appeared as strong determinants of FMD in multivariate analysis. The univariate associations of sTWEAK and PTX3 with IMT were dependent on estimated GFR. After a median of 39 months (range, 2 to 43 months), 22 fatal and 57 nonfatal cardiovascular events occurred. In a Cox model excluding PTX3, decreasing sTWEAK concentration was associated with increased risk of cardiovascular events independently of basic confounders (age, gender, estimated GFR, C reactive protein, diabetes, and cardiovascular comorbidity) and FMD. In a model excluding sTWEAK, circulating levels of PTX3 were directly associated with cardiovascular outcomes independently of basic confounders, but this association was lost after adjustment for FMD. CONCLUSIONS Both PTX3 and sTWEAK levels associated with the endothelial dysfunction observed with progressive kidney failure. Additionally, both biomarkers impacted the predictability of cardiovascular outcomes.

ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction

Asymmetric dimethyl-arginine (ADMA), a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of nitric oxide synthesis. The increased protein turnover that accompanies proteinuric secondary amyloidosis may increase circulating levels of ADMA, and this may contribute to endothelial dysfunction. We performed a cross-sectional study of 121 nondiabetic proteinuric patients with normal GFR (including 39 patients with nephrotic-range proteinuria and secondary amyloidosis) and 50 age-, sex-, and BMI-matched healthy controls. The proteinuric patients had higher levels of serum ADMA, symmetric dimethyl-arginine (SDMA), high-sensitivity C-reactive protein (hsCRP), and insulin resistance (homeostasis model assessment index) than controls. Compared with controls, brachial artery flow-mediated dilatation (FMD), serum L-Arginine, and the L-Arginine/ADMA ratio were significantly lower among proteinuric patients, suggesting greater endothelial dysfunction. When patients with secondary amyloidosis were compared with patients with glomerulonephritis who had similar levels of proteinuria, those with amyloidosis had higher ADMA and SDMA levels and lower L-Arginine/ADMA ratios and FMD measurements (P < 0.001 for all). Finally, even after adjusting for confounders, ADMA level correlated with both proteinuria and the presence of secondary amyloidosis, and was an independent predictor of FMD. We propose that ADMA synthesis may be increased in chronic kidney disease, especially in secondary amyloidosis, and this may explain part of the mechanism by which proteinuria increases cardiovascular morbidity and mortality.

Endothelial functions improve with decrease in asymmetric dimethylarginine (ADMA) levels after renal transplantation.

Background. Chronic kidney disease (CKD) is associated with increased cardiovascular events. The relationships between the markers of inflammation and endothelial dysfunction were investigated both before and after living donor kidney transplantation. Methods. Twenty-seven renal transplant patients were studied. Eleven patients (six male, five female) were on cyclosporine A, whereas 16 patients (nine male, seven female) were treated with tacrolimus based regimes. Twenty-seven subjects (12 males, 15 females) were studied as controls. Plasma adiponectin, high sensitive C reactive protein (hsCRP), Asymetric dimethyl arginine (ADMA) levels were studied before transplantation and on days 1, 3, 7, 14, and 28. The brachial artery flow mediated dilatation (FMD) was studied before transplantation and on the 28th day. Results. Serum hsCRP and ADMA levels decreased significantly from the first posttransplantation day on each measurement (P<0.001 for all) while the decrement of plasma adiponectin started in the third day (P<0.001 for all). The FMD was lower in the patients than the control group (P<0.001) and improved significantly in the 28th day of transplantation (P<0.001). Conclusions. The results indicate that ADMA is associated with FMD in CKD both before and after kidney transplantation. Endothelial functions improve at the very beginning of the posttransplantation period with accompanying reduction in ADMA and hsCRP levels.