IL-33 and ST2 levels in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events, and survival.

OBJECTIVE: Increased inflammation, associated with the increase in chronic kidney disease (CKD) stage, has a very important influence in vascular injury and cardiovascular diseases. In this study, we aimed to investigate the levels of IL-33 and ST2 in the different stages of CKD and to determine their effect on vascular damage and cardiovascular events (CVE). METHODS: This was an observational cohort study in which serum IL-33 and ST2 were obtained from 238 CKD (stages 1-5) patients. We examined the changes in IL-33/ST2 levels in CKD patients, as well as the association with a surrogate of endothelial dysfunction. Fatal and non-fatal CVE were recorded for a mean of 24 months. We also performed a COX regression analysis to determine the association of IL-33/ST2 levels with CVE and survival. RESULTS: IL-33 and ST2 levels were significantly increased and estimated glomerular filtration rates (eGFR) were decreased. Flow-mediated dilatation (FMD) was significantly decreased from stage 1 to stage 5 CKD. IL-33 and ST2 levels were associated with FMD, and ST2 was a predictor. Multivariate Cox analysis showed that the presence of diabetes mellitus, smoking, and proteinuria and haemoglobin, Hs-CRP, IL-33, and ST2 were associated with the risk of CVE. Kaplan-Meier survival curves showed that patients with IL-33 and ST2 levels below the median value (IL-33 = 132.6 ng/L, ST2 = 382.9 pg/mL) had a higher cumulative survival compared with patients who had IL-33 and ST2 levels above the median value (log-rank test, p = 0.000). CONCLUSION: This is the first study that demonstrates that serum IL-33 and ST2 are associated with vascular injury, cardiovascular events, and survival in CKD patients.

Chitotriosidase as a novel biomarker of early atherosclerosis in hemodialysis patients.

INTRODUCTION: Increasing evidence suggests that inflammation and increased macrophage activity have a central role in pathogenesis of atherosclerosis. It is shown that chitotriosidase (CHIT-1) is a marker of macrophage activity in atherosclerotic plaque, and is found associated with severity of atherosclerotic lesion. There is no data about CHIT-1 activity of hemodialysis patients in the literature. Thus, we hypothesized that in hemodialysis patients, CHIT-1 levels might be a novel biomarker in early atherosclerosis. METHODS: Forty-five hemodialysis patients were included in the study (age: 61.93 ± 13.34). Intima media thickness (IMT) was evaluated with high-resolution B-mode ultrasonography. Biomarker levels were measured in serum of patients. FINDINGS: We found positive correlation among IMT, age (R: 0.426, P: 0.004) and, CHIT-1 value (R: 0.462, P: 0.001) in spearman correlation analysis. When age, CRP, creatinine, P, Alb, CHIT-1 were chosen as measures that can effect IMT in multiple regression model, IMT level was related with CHIT-1 (Beta: 0,396, P: 0.012) and age (Beta: 0,313 P: 0,048) independently. DISCUSSION: In conclusion, this is the first report showing that serum CHIT-1 level was related independently with carotid IMT in hemodialysis patients. This biomarker might have an unknown role in the development of atherosclerosis during uremia.

Thyroid function and cardiovascular events in chronic kidney disease patients.

BACKGROUND AND AIMS: Abnormalities of thyroid function are commonly seen in chronic kidney disease (CKD) patients. They are associated with adverse clinical conditions such as atherosclerosis, endothelial dysfunction, inflammation and abnormal blood pressure variability. We investigated the association between thyroid disorders and endothelial function, assessed by flow-mediated dilatation (FMD) and carotid intima-media thickness (CIMT), and cardiovascular events (CVE) in CKD patients. MATERIALS AND METHODS: This observational cohort study included 305 CKD (stages 1-5) patients. Routine biochemistry, including free T3, free T4 and thyroid stimulating hormone, fibroblast growth factor-23 (FGF-23) and FMD, CIMT were measured. We divided patients into four groups according to thyroid hormone status: euthyroidism, subclinical hyperthyroidism, subclinical hypothyroidism, and euthyroid sick syndrome. Fatal and composite CVE were recorded for a median 29 months. RESULTS: Patients with subclinical hypothyroidism had a higher prevalence of hypertension and diabetes and also were more likely to have higher values of systolic CIMT, phosphorus, intact parathormone (iPTH), FGF-23, homeostasis model assessment-insulin resistance and lower levels of FMD than euthyroid patients. In the unadjusted survival analysis, subclinical hypothyroidism and euthyroid sick syndrome were associated with an increased risk for the outcome as compared with euthyroidism [hazard ratio 30.63 (95 % confidence interval 12.27-76.48) and 12.17 (3.70-39.98), respectively]. The effects of subclinical hypothyroidism and euthyroid sick syndrome were maintained even in fully adjusted models. CONCLUSION: We demonstrated that subclinical hypothyroidism and euthyroid sick syndrome are associated with increased CVE in CKD patients. Further studies are needed to explore these issues.

The Relationship Between Plasma Whole Blood Viscosity and Cardiovascular Events in Patients With Chronic Kidney Disease.

BACKGROUND: Plasma levels of estimated whole blood viscosity (eWBV) have been increased by endothelial inflammation. Because there were no consistent data for assessing the eWBV levels for prediction of cardiovascular event (CVE) in patients with chronic kidney disease (CKD). We aimed to investigate the relationship between plasma eWBV levels and CVEs in patients with CKD. MATERIALS AND METHODS: We conducted a prospective, cross-sectional, long-term follow-up study, assessing the relationship between plasma eWBV levels and CVE (either fatal or nonfatal) in patients with newly diagnosed CKD. We also evaluated estimated glomerular filtration rate (eGFR), pentraxin 3 (PTX3), high-sensitivity C-reactive protein (hsCRP), and flow-mediated dilatation (FMD). RESULTS: Study patients were divided into 2 groups: patients with CVE and patients without CVE. The eWBV levels were higher in patients with CVE. Additionally, PTX3 and hsCRP were higher, and FMD and eGFR were lower in patients with CVE compared to those without CVE. According to the Cox regression analysis, WBV, plasma asymmetric dimethylarginine levels, FMD, hsCRP, eGFR, systolic blood pressure, calcium, and history of diabetes were independent predictors of CVEs in patients with CKD. Kaplan Meier survival curves were generated to establish the impact of the WBV on the cumulative survival of the cohort. Patients with eWBV values higher than 5.2 centipoise (cP) had lower survival rates when compared to patients with eWBV values lower than 5.2 cP (log rank = 4.49 df = 1 P = .034). CONCLUSION: In conclusion, plasma eWBV levels may increase the presence of lower eGFR and affect CVE in patients with CKD independent of classical and unconventional risk factors.

Endostatin in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events and survival.

BACKGROUND AND AIMS: Endostatin, generated from collagen XVIII, and endorepellin, possess dual activity as modifiers of both angiogenesis and endothelial cell autophagy. Plasma endostatin levels are elevated in a large number of diseases, and may reflect endothelial cell dysfunction. Few data on endostatins are available for patients with chronic kidney disease (CKD). We tested whether serum endostatin values are predictive for all-cause mortality and cardiovascular events (CVEs) in a CKD population. MATERIALS AND METHOD: A total of 519 CKD pre-dialysis patients were included. Baseline plasma endostatin levels were measured in all patients. All included patients were followed-up (time-to-event analysis) until occurrence of death, fatal or nonfatal CVEs. Fatal and nonfatal CVE including death, stroke, and myocardial infarction were recorded prospectively RESULTS: The mean age of the patients was 52.2±12.3years. There were 241 (46.4%) males, 111 (21.4%) had diabetes, 229 (44.1%) were smokers and 103 (19.8%) had a previous CVE. After a median follow-up of 46months, 46 patients died and 172 had a new CVE. In the univariable Cox survival analysis, higher endostatin levels were associated with a higher risk for both outcomes. However, after adjusting for traditional (age, gender, smoking status, diabetes, systolic blood pressure, HDL and total cholesterol) and renal-specific (eGFR, proteinuria and hsCRP) risk factors, endostatin levels remained associated only with the CVE outcome (HR=1.88, 95% CI 1.37-2.41 for a 1 SD increase in log endostatin values). CONCLUSION: Endostatin levels are independently associated with incident CVE in CKD patients, but show limited prediction abilities for all-cause mortality and CVE above traditional and renal-specific risk factors.

Osteoprotegerin in Chronic Kidney Disease: Associations with Vascular Damage and Cardiovascular Events.

Vascular injury and dysfunction contribute to cardiovascular disease, the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG) is a soluble member of the tumor necrosis factor receptor superfamily that has been linked to atherogenesis and endothelial dysfunction. Elevated circulating OPG levels predict future cardiovascular events (CVE). Our aim was to evaluate the determinants of circulating OPG levels, to investigate the relationship between OPG and markers of vascular damage and to test whether OPG improves risk stratification for future CVE beyond traditional and renal-specific risk factors in a CKD population. 291 patients with CKD stage 1-5 not on dialysis were included in the study. In the multivariate analysis, OPG was a significant predictor for flow-mediated dilatation, but not for carotid intima media thickness levels. During follow-up (median 36 months, IQR = 32-42 months), 87 patients had CVE. In the Cox survival analysis, OPG levels were independently associated with CVE even after adjustment for traditional and renal-specific cardiovascular risk factors. The addition of OPG to a model based on commonly used cardiovascular factors significantly improved the reclassification abilities of the model for predicting CVE. We show for the first time that OPG improves risk stratification for CVE in a non-dialysis CKD population, above and beyond a model with established traditional and renal-specific cardiovascular risk factors, including estimated glomerular filtration rate and fibroblast growth factor 23.

Relevance of uric acid and asymmetric dimethylarginine for modeling cardiovascular risk prediction in chronic kidney disease patients.

BACKGROUND: Both elevated serum uric acid and serum asymmetric dimethylarginine (ADMA) are risk factors for cardiovascular disease. We hypothesized that combined elevation of uric acid and ADMA amplifies the risk of all-cause mortality and/or cardiovascular events (CVE) in patients with chronic kidney disease (CKD). METHODS: A total of 259 patients with CKD stages 1-5 were followed up in a time-to-event analysis for all-cause mortality and fatal and non-fatal CVE (including death, stroke, and myocardial infarction). Baseline measurements included serum uric acid and ADMA and endothelial function [ultrasound determined flow-mediated dilatation (FMD)]. RESULTS: As a measure of endothelial function, log FMD value was positively associated with log eGFR, but negatively associated with log ADMA and log uric acid levels. During follow-up (median 38 months), 24 (9.3 %) deaths, 90 (34.7 %) CVE, and 95 (36.7 %) deaths and CVE (composite outcome) occurred. In the univariate Cox analysis, patients with both serum uric acid and ADMA levels above the median had an increased risk of all-cause mortality, CVE, and the composite outcome (HR 5.06, 95 % CI 2.01-12.76; HR 4.75, 95 % CI 2.98-7.59; and HR 4.13, 95 % CI 2.66-6.43, respectively). However, after adjustment for renal-specific risk factors (glomerular filtration rate, proteinuria, and hsCRP), this association was maintained only for CVE and the composite outcome. The addition of both biomarkers into a model with traditional and renal-specific risk factors did not increase the prediction abilities of the model for none of the three outcomes. CONCLUSION: Elevated serum uric acid and ADMA levels are associated with an increased cardiovascular risk, but their combination does not improve risk prediction. The effects are not additive, possibly because uric acid may lie in the causal pathway by which ADMA acts.

Ultrasonographic evaluation of the femoral cartilage thickness in patients with chronic renal failure.

OBJECTIVE: To investigate the effects of chronic renal failure (CRF) on the distal femoral cartilage thickness by using ultrasonography and to determine the relationship between cartilage thickness and certain disease-related parameters. DESIGN: Fifty-seven CRF patients (41 male and 16 female) (mean [SD] age, 44.7 [12.1] years) and 60 healthy controls (41 male and 19 female) (mean [SD] age, 43.5 [13.3] years) were enrolled in this study. Demographic and clinical characteristics were recorded. Cartilage thickness measurements were taken from the medial and lateral condyles, and intercondylar areas of both knees. RESULTS: Groups were similar in terms of age, weight, height, body mass index and gender (all p>0.05). The mean cartilage thickness was found to be less in CRF patients than in controls (statistically significant for medial condyles and intercondylar areas both in right and the left knees [all p<0.05]). Cartilage thickness showed no correlation with eGFR, and with the levels of serum urea, creatinine, calcium, magnesium, phosphor, hemoglobin, uric acid and as well as steroid use (all p>0.05) in CRF patients. CONCLUSION: In the light of our findings, we imply that patients with CRF have thinner femoral cartilage than healthy controls. This result may support the view that patients with CRF are at increased risk for developing early knee osteoarthritis. Last but not least, clinicians should be aware of the importance of rehabilitation strategies aimed at decreasing onset and progression of knee osteoarthritis in patients with CRF.

Serum neutrophil gelatinase-associated lipocalin is associated with cardiovascular events in patients with chronic kidney disease.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family best known as a novel and early marker of acute kidney injury (AKI). Recent data suggest that NGQueryAL is not only a marker of AKI, but also an important player in the vascular remodeling, atherosclerotic plaque stability and thrombus formation. We conducted this study to investigate the association of serum NGAL levels with fatal and composite (fatal and non-fatal) cardiovascular events (CVE) in a cohort of patients with stage 1-5 CKD. METHODS: This was an observational cohort study in which serum NGAL was obtained from 298 CKD (stages 1-5) patients. Fatal and composite CVE were recorded for a median 41 months. We examined alteration of serum NGAL through CKD groups as well as association with inflammatory markers. We also performed a Cox regression analysis to determine the association of NGAL with predefined clinical outcomes. RESULTS: The median value of NGAL was 50.5 ng/mL (IR 47.6-54.9 ng/mL), and higher NGAL values were recorded in diabetic patients. In a multiple linear regression model, including all univariate associates of NGAL, only log eGFR, log hs-CRP and log HDL cholesterol maintained an independent association with log NGAL. During the observational period, 30 patients died due to cardiovascular causes and 69 non-fatal CVE were registered. In the fully adjusted model, we observed a 2.08-fold increase in the risk of fatal CVE and a 1.50-fold increase in the risk of fatal and non-fatal CVE for each increment of 1 SD in log NGAL values. CONCLUSIONS: This is the first study that shows that serum NGAL is associated with cardiovascular events (fatal and non-fatal) in patients with CKD, independently of traditional risk factors, renal function and inflammation.

The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) risk is substantially increased in subjects with chronic kidney disease (CKD). The Triglycerides (TG) to High-Density Lipoprotein Cholesterol (HDL-C) ratio is an indirect measure of insulin resistance and an independent predictor of cardiovascular risk. No study to date has been performed to evaluate whether the TG/HDL-C ratio predicts CVD risk in patients with CKD. METHODS: A total of 197 patients (age 53±12 years) with CKD Stages 1 to 5, were enrolled in this longitudinal, observational, retrospective study. TG/HDL-C ratio, HOMA-IR indexes, serum asymmetric dimethyl arginine (ADMA), high sensitivity C-reactive protein (CRP), parathyroid hormone (PTH), calcium, phosphorous, estimated glomerular filtration rate (eGFR), and albumin levels were measured. Flow mediated vasodilatation (FMD) of the brachial artery was assessed by using high-resolution ultrasonography. RESULTS: A total of 11 cardiovascular (CV) deaths and 43 nonfatal CV events were registered in a mean follow-up period of 30 (range 9 to 35) months. Subjects with TG/HDL-C ratios above the median values (>3.29) had significantly higher plasma ADMA, PTH, and phosphorous levels (p=0.04, p=0.02, p=0.01 respectively) and lower eGFR and FMD values (p=0.03, p<0.001 respectively). The TG/HDL-C ratio was an independent determinant of FMD (ß=-0.25 p=0.02) along with TG, HDL-C, hsCRP, serum albumin, phosphate levels, systolic blood pressure, PTH, eGFR and the presence of diabetes mellitus. The TG/HDL-C ratio was also a significant independent determinant of cardiovascular outcomes [HR: 1.36 (1.11-1.67) (p=0.003)] along with plasma ADMA levels [HR: 1.31 (1.13-1.52) (p<0.001)] and a history of diabetes mellitus [HR: 4.82 (2.80-8.37) (p<0.001)]. CONCLUSION: This study demonstrates that the elevated TG/HDL-C ratio predicts poor CVD outcome in subjects with CKD. Being a simple, inexpensive, and reproducible marker of CVD risk, the TG/HDL-C ratio may emerge as a novel and reliable indicator among the many well-established markers of CVD risk in CKD. SYSTEMATIC REVIEW REGISTRATION: Clinical trial registration number and date: NCT02113462 / 10-04-2014.

Effects of androgen replacement therapy on cornea and tear function in men with idiopathic hypogonadotropic hypogonadism.

PURPOSE: Idiopathic hypogonadotropic hypogonadism (IHH) is an endocrine disorder defined with the presence of typical clinical signs and symptoms plus laboratory confirmation of serum testosterone (T) levels lower than 300 ng/dl. Androgen replacement therapy (ART) is the first-step treatment of male IHH. To date, no clinical trial, which investigates the changes on corneal structure and tear function, of systemic ART in men have been published. The objective of this study was to investigate the effects of ART on cornea and tear function in patients with IHH. MATERIALS AND METHODS: This prospective, interventional study was conducted at the Gulhane Military Medical Academy, Ankara, Turkey, a tertiary referral military hospital. Thirty-four eyes of 17 men with IHH patients were evaluated with Schirmer I test, ultrasound pachymeter, applanation tonometer and confocal microscopy. A Testosterone compound (Sustanon® 250 mg) was administered by intramuscular injection in the course of a 3-week period to induce puberty, and human chorionic gonadotropin (Pregnyl® 5000 IU) was administered twice weekly for 3 months to induce fertility. The patients were re-evaluated at the third month of the treatment. Main Outcome Measures were Schirmer score, central corneal thickness (CCT), intraocular pressure (IOP), endothelial cell density, coefficient of variation and cell shape. RESULTS: Schirmer scores showed similar results after the treatment compared to pre-treatment levels (p = 0.14). There was no statistically significant difference in CCT and IOP compared to baseline data (p = 0.96, p = 0.73, respectively), and no significant differences were found in corneal endothelial cell density, percentage of cell size variability or hexagonality (p = 0.83, p = 0.58, p = 0.64, respectively). CONCLUSIONS: This is the first study that investigates the effects of ART on corneal structure and tear function in men. ART seems to have no short-term effects on corneal structure and tear function. Further publications of larger, long-term and controlled studies 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 ß=0.23; P<0.001), C-reactive protein (ß=0.15; P<0.001), and fibroblast growth factor 23 (ß=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: ß=0.25; fibroblast growth factor 23: ß=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)).

Mitral annular calcification and the serum osteocalcin level in patients with chronic kidney disease.

OBJECTIVE: To determine the relationships between inflammatory mediators, mitral annular calcification (MAC), and osteocalcin in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Echocardiographic data for 60 patients diagnosed as CKD were retrospectively evaluated. The patients were divided into 2 groups; patients with MAC (MAC+ group) and patients without MAC (MAC- group). The relationships between biochemical markers-including osteocalcin-and MAC were evaluated. RESULTS: The study included 19 female and 41 male patients. In all, 29 patients were MAC+ and 31 were MAC-. High-sensitive C-reactive protein (hsCRP) and osteocalcin levels were significantly higher in the MAC+ group (p < 0.05). The eGFR was lower, serum calcitonin (we could not obtain calcitonin data for 15 patients), Ca, PO4, CaxPO4, the erythrocyte sedimentation rate, red cell distribution width, the neutrophil/Lymphocyte rate, and PTH were higher in the MAC+ group; however, the differences between the groups were not significant (p > 0.05). The mitral E/A ratio, mitral peak Ea velocity, tricuspid E/A ratio, hsCRP, and the osteocalcin level were strongly correlated with MAC. Multivariate logistic regression analysis showed that only the osteocalcin level and mitral E/A ratio were independent variables, each with an independent effect on MAC. CONCLUSION: CKD patients in the MAC+ group had higher osteocalcin levels than those in the MAC- group, and left ventricular diastolic dysfunction was more common in the MAC+ group.

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.

The relationship between IL-10 levels and cardiovascular events in patients with CKD.

BACKGROUND AND OBJECTIVES: Cardiovascular disease is the leading cause of death in patients with CKD. IL-10 is considered an antiatherosclerotic cytokine. However, previous studies have failed to observe an association between IL-10 and cardiovascular disease in CKD. This study aimed to evaluate whether serum IL-10 levels were associated with the risk of cardiovascular events in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Four hundred three patients with stages 1-5 CKD were followed for a mean of 38 (range=2-42) months for fatal and nonfatal cardiovascular events. IL-10 and IL-6 were measured at baseline together with surrogates of endothelial function (flow-mediated dilatation) and proinflammatory markers (high-sensitivity C-reactive protein and pentraxin-3). The association between IL-10 and flow-mediated dilatation through linear regression analyses was evaluated. The association between IL-10 and the risk of cardiovascular events was assessed with Cox regression analysis. RESULTS: IL-10, IL-6, high-sensitivity C-reactive protein, and pentraxin-3 levels were higher among participants with lower eGFR. Both fatal (25 of 200 versus 6 of 203 patients) and combined fatal and nonfatal (106 of 200 versus 23 of 203 patients) cardiovascular events were more common in patients with IL-10 concentration above the median. Flow-mediated dilatation was significantly lower in patients with higher serum IL-10 levels, but IL-10 was not associated with flow-mediated dilatation in multivariate analysis. Kaplan-Meier survival curves showed that patients with IL-10 below the median value (<21.5 pg/ml) had higher cumulative survival compared with patients who had IL-10 levels above the median value (log-rank test, P<0.001). CONCLUSIONS: IL-10 levels increase along with the reduction of kidney function. Higher serum IL-10 levels were associated with the risk of cardiovascular events during follow-up. We speculate that higher IL-10 levels in this context signify an overall proinflammatory milieu.

Monocyte count/HDL cholesterol ratio and cardiovascular events in patients with chronic kidney disease.

BACKGROUND AND AIM: Previous studies showed that renal dysfunction was associated with both a reduction in serum high-density lipoprotein (HDL) cholesterol concentration and increased circulating monocyte count. We aimed to investigate the effect of circulating monocyte to serum HDL cholesterol ratio (M/H ratio) on fatal and composite cardiovascular events, in an observational cohort study of chronic kidney disease (CKD) patients. MATERIALS AND METHODS: A total of 340 subjects with stage 1-5 CKD were followed for a mean follow-up period of 33 (range 2-44) months and assessed for fatal and nonfatal CV events. M/H ratio was calculated for all patients. All-cause mortality and CVE were also analyzed in relation to M/H ratio. RESULTS: Monocyte/HDL cholesterol ratio was negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.43, P < 0.001). Notably, both fatal and combined fatal and nonfatal cardiovascular events were more common in patients having a M/H ratio in the third tertile was associated with a hazard ratio of 2.24 and 4.91, respectively, for fatal and composite cardiovascular events compared to being in the first tertile. CONCLUSION: Monocyte/HDL cholesterol ratio was increased with decreasing eGFR in predialytic CKD patients. Most importantly, we report for the first time that an increased M/H ratio was cross-sectionally associated with a worse cardiovascular profile and arose as independent predictors of major cardiovascular events during follow-up.

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

BACKGROUND: 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. MATERIALS AND METHODS: One hundred and seventy-five kidney transplant recipients (71% men; 31·6 ± 9·4 years) were studied immediately before and on the 180th day post-transplantation. At each visit, blood samples were taken to assess circulating levels of sTWEAK and ADMA. Brachial artery endothelium-dependent vasodilatation (FMD) assessments were also performed. RESULTS: Renal transplantation was followed by an improvement in FMD. This improvement was paralleled by an increase in sTWEAK and a reduction in ADMA after transplantation (P < 0·001 for all). Cross-sectionally, both molecules associated with FMD before as well as after transplantation (P < 0·001 for all). Longitudinally, the changes observed in sTWEAK (ß = 0·26, P < 0·001) and ADMA (ß = -0·44, P < 0·001) levels were independently associated with the improvement of FMD (r(2)  = 0·30). CONCLUSIONS: Renal transplantation is followed by an improvement of FMD that is independently associated with the normalization of both sTWEAK and ADMA concentrations. We identify two surrogate biomarkers of endothelial function with potential as therapeutic targets.