Hakki Cetinkaya

Relationship between Serum Magnesium Levels and Cardiovascular Events in Chronic Kidney Disease Patients

Background: Magnesium is an essential ion for all living cells because over 300 enzymes require the presence of magnesium for their catalytic action. To date, no group has evaluated magnesium as a cardiovascular risk factor in chronic kidney disease (CKD) subjects, in which closely interrelated factors and potential confounders such as endothelial dysfunction, insulin resistance (the homeostasis model assessment (HOMA) index) and inflammation (expressed as serum C-reactive protein (CRP) levels) were also considered. Methods: Between March 2006 and December 2010, 283 CKD patients were followed up for time-to-event analysis until the occurrence of fatal or nonfatal cardiovascular events. Endothelium-dependent vasodilatation (flow-mediated dilatation; FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation) of the brachial artery were assessed noninvasively using high-resolution ultrasound. Results: From the univariate analysis of FMD, it appears that a higher magnesium level is associated with less endothelial dysfunction. When a multivariate analysis was performed, magnesium and estimated glomerular filtration rates (eGFR) maintained a strong positive correlation with FMD, supporting the hypothesis that higher levels of magnesium may protect against endothelial damage. In univariate Cox proportional hazards models, FMD, magnesium, high sensitivity CRP, the HOMA index, eGFR, comorbid diabetes, hypertension, smoking status, systolic blood pressure, serum phosphate and intact parathormone emerged as significant predictors for cardiovascular outcomes. Kaplan-Meier curves showed significantly higher cardiovascular mortality rates in CKD patients whose serum magnesium levels were below 2.05 mg/dl. Conclusions: This observational cohort study showed that magnesium may be an independent predictor of future cardiovascular outcomes and is the first study demonstrating such a role in etiologically diagnosed CKD patients, across different stages.

Plasma endocan levels associate with inflammation, vascular abnormalities, cardiovascular events, and survival in chronic kidney disease

Plasma endocan levels are elevated in a large number of diseases, and may reflect endothelial cell dysfunction. There are currently no data on endocan in patients with chronic kidney disease (CKD). Therefore, we measured plasma endocan in 251 patients with CKD (stage 1-5) and 60 control individuals. Plasma endocan concentrations correlated with estimated glomerular filtration rate (eGFR), different markers of inflammation (pentraxin 3 and high-sensitivity C-reactive protein), and vascular abnormalities (flow-mediated vasodilation (FMV) and carotid intima media thickness (CIMT)). All-cause mortality and cardiovascular events (CVE) were also analyzed with respect to plasma endocan. Patients with CKD showed significantly increased plasma endocan (4.7 [IQR 1.9-9.4] compared with controls [IQR 1.1-1.5] ng/ml), with values progressively higher across stages of CKD. On univariate analysis, plasma endocan concentrations correlated negatively with eGFR and FMV, but positively with both markers of inflammation and CIMT. However, on multivariate analysis only high-sensitivity C-reactive protein, FMV, and CIMT remained significantly associated with plasma endocan. On Cox survival analysis, endocan levels were associated with all-cause mortality and CVE in these patients. Thus, plasma endocan increases in the presence of decreasing eGFR and influences all-cause mortality and CVE in patients with CKD independent of traditional and nontraditional risk factors.

Red cell distribution width is independently related to endothelial dysfunction in patients with chronic kidney disease.

Background:Red cell distribution width (RDW) is a measure of erythrocyte size variability and has been shown as an independent predictor of mortality. The aim of this article was to evaluate the association of RDW with endothelial dysfunction in patients with chronic kidney disease (CKD). Methods:Patients with 1 to 5 stages of CKD were included in the study. Endothelial function was assessed with flow-mediated dilatation (FMD). Estimated glomerular filtration rate (eGFR) and carotid intima media thickness (CIMT) were determined. Clinicodemographic characteristics, biochemical values, complete blood counts, ferritin, C-reactive protein (CRP) and cholesterol levels were recorded. Spearmans correlation was used to determine correlates of RDW. Multivariate linear regression model was used to assess independent associates of FMD. Results:Overall, 367 patients with CKD 1 to 5 were included in the study. RDW showed a significant increase from stage 1 to stage 5 CKD. Median RDW was 13.5. Patients with RDW values higher than median had significantly lower hemoglobin, eGFR and FMD values and higher CIMT and CRP values compared with patients who had RDW values below median. RDW showed a significant positive correlation with the presence of diabetes mellitus, CIMT and CRP, whereas a significant negative correlation with eGFR, ferritin and FMD. Multivariate analysis showed independent predictors of FMD as RDW, presence of diabetes, hemoglobin, eGFR, CRP, and serum albumin. Conclusions:Multivariate regression model revealed RDW as a significant predictor of FMD independent of major confounding factors, such as diabetes, inflammation, anemia and kidney function in CKD.

Serum Sclerostin and Adverse Outcomes in Nondialyzed Chronic Kidney Disease Patients

BACKGROUND The chronic kidney disease (CKD)-mineral and bone disorder (MBD) syndrome is an important contributor to the CKD-associated cardiovascular disease and high mortality rates. Sclerostin, a protein synthesized in osteocytes, is a potent downregulator of bone metabolism and a novel candidate for the bone-vascular axis in CKD patients. We tested whether serum sclerostin values are predictive for all-cause mortality and cardiovascular events (CVEs) in a CKD population. METHODS Serum sclerostin was obtained from 173 CKD (stage 3-5) and 47 control patients, and its concentration was correlated with estimated glomerular filtration rate and to mineral and vascular abnormalities that are present in the CKD evolution. All-cause mortality and CVEs were also analyzed in relation to serum sclerostin values. RESULTS Patients with CKD showed higher sclerostin levels (median 63.5 pmol/L vs 52 pmol/L, P < .001) than controls, with values progressively higher across the CKD stages. In univariate analysis, serum sclerostin concentrations were correlated with gender, estimated glomerular filtration rate, flow-mediated dilatation, and endothelium-independent vasodilatation as markers of endothelial dysfunction and with different serum CKD-MBD-associated parameters. However, in multivariate analysis, only gender, fibroblast growth factor-23, phosphate, flow-mediated dilatation, and cholesterol remained significantly associated with sclerostin levels. During the observational period, there were 19 deaths and 50 CVEs. In survival analysis, different sclerostin levels were associated with all-cause mortality and CVEs in these patients. CONCLUSIONS This is the first study that shows that serum sclerostin values are associated, even after multiple adjustments, with fatal and nonfatal CVEs in a nondialyzed CKD population.

Longitudinal Analysis of Vascular Function and Biomarkers of Metabolic Bone Disorders before and after Renal Transplantation

Background/Aims: The role of chronic kidney disease-mineral bone disorder (CKD-MBD) reversibility in the amelioration of vascular function and in the reduction of the risk for cardiovascular events after renal transplantation is still unknown. Methods: We investigated the longitudinal relationship between the main biomarkers of CKD-MBD and the evolution of vascular function [flow-mediated dilatation (FMD)] after transplantation in a series of 161 patients with kidney failure maintained on chronic dialysis (5D-CKD). Results: Before transplantation, FMD in patients was markedly lower (–40%, p < 0.001) than in well-matched healthy subjects and increased by 27% after transplantation (p = 0.001). Fibroblast growth factor 23 (FGF23), 25-hydroxy-vitamin D (25OHVD) and serum phosphate (p < 0.01) were independently associated with simultaneous changes in FMD. Changes in classical risk factors and in risk factors related to CKD like the glomerular filtration rate, serum albumin, C-reactive protein and insulin resistance failed to independently explain the variability in FMD changes after transplantation. Conclusion: Endothelium-dependent vasodilatation improves after kidney transplantation, which is parallel to the dramatic fall in FGF23, the reduction in serum phosphorus and the increase in 25OHVD levels. If these associations are causal, a part of decline in cardiovascular risk after transplantation is related to partial resolution of CKD-MBD.

Nesfatin-1 in advanced lung cancer patients with weight loss.

The cachexia occurs frequently in lung cancer patients. Among appetite regulatory peptides, alteration of expressions of leptin and ghrelin is demonstrated in cachectic cancer patients, but nesfatin-1 has not been yet studied in cancer. We investigated serum nesfatin-1 level in advanced lung cancer patients. Forty-one lung cancer patients and 24 healthy subjects were included to the study. Nesfatin-1 serum levels were analyzed by ELISA kit. Serum nesfatin-1 levels were lower in lung cancer patients than in healthy subjects (0.52±0.19ng/ml vs 0.75±0.23ng/ml; p<0.001). In lung cancer patients with weight loss, nesfatin-1 levels were decreased compared to the patients without weight loss (0.44±0.16ng/ml vs 0.63±0.18ng/ml; p<0.001). Whereas, there were no any difference between patients without weight loss and control subjects (0.63±0.18ng/ml vs 0.75±0.23ng/ml; p:0.129) or between SCLC and NSCLC patients (0.53±0.18ng/ml vs 0.52±0.20ng/ml; p:0.458). No significant correlation was found between serum nesfatin-1 values and BMI. In conclusion, loss of fat mass may decrease serum nesfatin-1 level in lung cancer patients with weight loss. The future studies which explore biological significance of low serum nesfatin-1 level in cancer are needed.

A Longitudinal Study of Inflammation, CKD-Mineral Bone Disorder, and Carotid Atherosclerosis after Renal Transplantation

BACKGROUND AND OBJECTIVES The role of reversibility of nontraditional risk factors, like inflammation and CKD-mineral bone disorder, in the reduction of cardiovascular risk after renal transplantation is still scarcely defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS The longitudinal relationship between C-reactive protein, CKD-mineral bone disorder biomarkers, and intima media thickness was investigated in a series of 178 patients (age=32±10 years) with stage 5 CKD maintained on chronic dialysis who underwent echo-color Doppler studies of the carotid arteries before and after renal transplantation. Smokers and patients with diabetes were excluded from the study. In all patients, immunosuppression was performed by a standard regimen on the basis of calcineurin inhibitors. Healthy controls were specifically selected to match the age and sex distribution of the patients. Biochemical and intima media thickness assessments were repeated 6 months after transplantation. RESULTS Before transplantation, intima media thickness in patients with stage 5 CKD on dialysis (average=0.9±0.2 mm) was higher (P<0.001) than in well matched healthy controls (0.6±0.1 mm) and reduced substantially (-22%; 95% confidence interval, -24% to -20%) after transplantation (P=0.001). GFR (multivariable-adjusted β=0.23; P<0.001), C-reactive protein (β=0.15; P<0.001), and fibroblast growth factor 23 (β=0.28; P<0.001) were the strongest independent correlates of intima media thickness before transplantation. Similarly, longitudinal changes in the same biomarkers were the sole independent correlates of simultaneous changes in intima media thickness (C-reactive protein: β=0.25; fibroblast growth factor 23: β=0.26; P<0.001 for both) after renal transplantation. The evolution of intima media thickness after transplantation was largely independent of classic risk factors, including BP, LDL cholesterol, and insulin resistance, as measured by homeostatic model assessment. CONCLUSIONS Intima media thickness improves after renal transplantation. Such an improvement associates with parallel changes in serum C-reactive protein and fibroblast growth factor 23. These observations are in keeping with the hypothesis that the decline in cardiovascular risk after transplantation, in part, depends on partial resolution of nontraditional cardiovascular risk factors, like inflammation and CKD-mineral bone disorder.

Ramipril Lowers Plasma FGF-23 in Patients with Diabetic Nephropathy

Background/Aims: Ramipril attenuates renal Fibroblast growth factor-23 (FGF-23) expression, ameliorates proteinuria and normalizes serum phosphate in the diabetic Zucker rat with progressive renal disease suggesting that the renoprotective effect by this drug may be in part due to a FGF-23-lowering effect of angiotensin-converting enzyme (ACE) inhibition. Methods: In this nonrandomized study, we tested whether ACE-inhibition reduces circulating FGF-23 in type-2 diabetics with stage-1 chronic kidney disease (CKD) and proteinuria. Intact FGF-23, the eGFR, proteinuria and the endothelium-dependent flow-mediated (FMD) response to ischemia and other parameters were measured at baseline and after 12-weeks of treatment with ramipril (n = 68) or amlodipine (n = 32). Results: Blood Pressure (BP) fell to a similar extent (p < 0.001) in the two groups. However, 24 h proteinuria and the FMD improved more (both p < 0.01) in ramipril-treated patients than in amlodipine-treated patients. Changes in proteinuria (r = 0.47) and in FMD (r = -0.49) by ramipril were closely associated (p < 0.001) with simultaneous changes in FGF-23 and this link was confirmed in multiple regression analyses. In these analyses, the relationship between FMD and proteinuria changes attained statistical significance (p < 0.01) only in a model excluding FGF-23 suggesting that endothelial dysfunction and FGF-23 share a common pathway conducive to renal damage. Conclusion: Findings in this study contribute to generate the hypothesis that FGF-23 may be implicated in proteinuria and in endothelial dysfunction in diabetic nephropathy (clinicaltrials.gov (NCT01738945)).

Endothelial function in patients with familial Mediterranean fever-related amyloidosis and association with cardiovascular events

OBJECTIVES Secondary amyloidosis is the most important complication of FMF and endothelial function is more severely impaired. Elevated asymmetric dimethyl arginine (ADMA) may mediate the excess cardiovascular disease (CVD) risk of this group. We aimed to compare endothelial function characteristics, including ADMA, in patients with FMF-related amyloidosis and primary glomerulopathies and to define risk factors for a CVD event. METHODS We undertook a cross-sectional study with prospective follow-up including consecutive patients with FMF-related amyloidosis (n = 98) or other non-diabetic glomerulopathies (n = 102). All patients had nephrotic-range proteinuria and normal glomerular filtration rate. Flow-mediated dilatation (FMD) was assessed and ADMA levels, CRP and pentraxin 3 (PTX3) were determined. Patients were followed for cardiovascular events. RESULTS Amyloidosis patients secondary to FMF showed higher levels of ADMA, CRP and PTX3 and lower FMD as compared with patients with other glomerulopathies. Cardiovascular events (n = 54) were registered during 3 years of follow-up. Increased ADMA levels and lower FMD were observed in patients with cardiovascular risk in both groups, but especially in individuals with amyloidosis. CONCLUSION Patients with FMF-related amyloidosis have increased CVD event risk, probably related to the high ADMA levels, elevated inflammatory markers and decreased FMD measures observed in these patients.

Soluble TWEAK plasma levels increase after renal transplantation and associate with the improvement of endothelial function

Soluble TWEAK (sTWEAK) and asymmetric dimethyl arginine (ADMA) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). We tested the hypothesis that the improvement in endothelial function observed after renal transplantation is directly linked to the normalization of both sTWEAK and ADMA.