Cognitive Impairments and Dysexecutive Behavioral Disorders in Chronic Kidney Disease.

The purpose of this study was to characterize cognitive impairments and behavioral disorders in a sample of patients with chronic kidney disease (CKD). A total of 52 patients with CKD were prospectively recruited over a 344-day period. Cognitive functions (memory, action speed, executive function, and language) and behavioral characteristics were assessed with a standardized comprehensive battery. The patients' performances were interpreted with a validated method on the basis of normative data from 1,003 healthy control subjects. Brain MRI and biological data were collected. Multivariable linear regression models and bootstrap analyses were used to identify risk factors for cognitive impairment. Cognitive impairment was observed in 32.5% (95% confidence interval: 17%-48%) of the 40 included patients with full data sets. Action speed and executive functions were the most frequently impaired domains. Dysexecutive behavioral disorders were observed in 27% of patients, and depression was observed in 32.5%. Cognitive impairment was independently associated with stroke volume, high serum parathyroid hormone and uric acid levels, and low serum glucose levels (adjusted R2=0.54, p<0.001 One-third of patients with CKD had cognitive impairments (action speed and executive functions), behavioral dysexecutive disorders (hypoactivity with apathy, irritability, or anosognosia), or depression.

Levels of Indoxyl Sulfate in Kidney Transplant Patients, and the Relationship With Hard Outcomes.

BACKGROUND: Indoxyl sulfate (IS) is a protein-bound uremic toxin that is known to be associated with the risk of cardiovascular (CV) disease and death in both predialysis and dialysis patients. Data on levels of protein-bound uremic toxins in kidney transplant patients are scarce. The study's objective was to evaluate the levels of IS in kidney transplant patients and the relationship with hard outcomes. METHODS AND RESULTS: In 311 kidney transplant patients, IS levels were measured immediately before transplantation (T0), and 1 month (M1) and 12 months (M12) afterwards. Over a mean±standard deviation follow-up period of 113±29 months, a total of 55 deaths, 70 CV events and 71 graft losses were recorded. We observed a rapid significant decrease (below or near the normal value) in IS levels after kidney transplantation. Total and free IS levels at M12 were significantly higher in non-transplant patients than in transplant patients (P=0.003 and <0.0001 respectively), despite having similar estimated glomerular filtration rates. Lastly, IS levels were not associated with overall mortality, CV events or graft loss at T0, M1 or M12. CONCLUSIONS: IS levels were significantly lower in kidney transplant receipts than in non-recipients suggesting that kidney transplantation protects against an increase in IS levels. IS levels were not associated with hard outcomes in kidney transplant patients. (Circ J 2016; 80: 722-730).

The Addition of Vascular Calcification Scores to Traditional Risk Factors Improves Cardiovascular Risk Assessment in Patients with Chronic Kidney Disease.

BACKGROUND: Although a variety of non-invasive methods for measuring cardiovascular (CV) risk (such as carotid intima media thickness, pulse wave velocity (PWV), coronary artery and aortic calcification scores (measured either by CT scan or X-ray) and the ankle brachial index (ABI)) have been evaluated separately in chronic kidney disease (CKD) cohorts, few studies have evaluated these methods simultaneously. Here, we looked at whether the addition of non-invasive methods to traditional risk factors (TRFs) improves prediction of the CV risk in patients at different CKD stages. METHODS: We performed a prospective, observational study of the relationship between the outputs of non-invasive measurement methods on one hand and mortality and CV outcomes in 143 patients at different CKD stages on the other. During the follow-up period, 44 patients died and 30 CV events were recorded. We used Cox models to calculate the relative risk for outcomes. To assess the putative clinical value of each method, we also determined the categorical net reclassification improvement (NRI) and the integrated discrimination improvement. RESULTS: Vascular calcification, PWV and ABI predicted all-cause mortality and CV events in univariate analyses. However, after adjustment for TRFs, only aortic and coronary artery calcification scores were found to be significant, independent variables. Moreover, the addition of coronary artery calcification scores to TRFs improved the specificity of prediction by 20%. CONCLUSION: The addition of vascular calcification scores (especially the coronary artery calcification score) to TRFs appears to improve CV risk assessment in a CKD population.

Uremic toxicity and sclerostin in chronic kidney disease patients.

BACKGROUND AND AIMS: Sclerostin is a circulating inhibitor of the Wnt/ß-catenin pathway and may have a role in chronic kidney disease (CKD)-mineral and bone disorder. Blood sclerostin levels are known to be elevated in patients undergoing maintenance dialysis. The aims of the present study were to evaluate sclerostin levels in patients at different CKD stages and study potential associations between sclerostin levels and (i) biochemical parameters that are disturbed in CKD, (ii) markers of vascular disease and (iii) mortality. METHODS: One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry tests and assays for sclerostin, protein-bound uremic toxins (indoxylsulphate [IS] and p-cresyl sulphate [PCS]) and the toxin ß2 microglobulin (ß2M) were performed. Aortic and coronary calcification and arterial stiffness were assessed by multislice spiral computed tomography and pulse wave velocity measurements. The enrolled patients were prospectively monitored for mortality. RESULTS: Sclerostin levels were found to be elevated in CKD patients (especially those on hemodialysis). Furthermore, sclerostin levels were positively correlated with inflammation markers, phosphate, fibroblast growth factor 23, IS, PCS, ß2M and arterial stiffness. A multivariate linear regression analysis indicated that sclerostin levels were independently associated with IS, PCS and ß2M levels. Elevated serum sclerostin appeared to be associated with mortality (independently of age and inflammation). However, this association disappeared after adjustment for a propensity score including age, phosphate, interleukin-6, CKD stage and PCS. CONCLUSION: Our results indicate that sclerostin levels are elevated in CKD patients and are associated with inflammation, vascular lesions, uremia and (potentially) mortality.

Vascular calcification in chronic kidney disease: are biomarkers useful for probing the pathobiology and the health risks of this process in the clinical scenario?

Patients with chronic kidney disease (CKD) are at a particularly high risk for cardiovascular disease. Vascular calcification (VC) is considered a cardiovascular risk marker, so in CKD patients screening for the presence of VC is suggested in current guidelines. VC is the result of both passive and active processes that involve a variety of proteins and factors. In the CKD population, numerous studies have identified circulating biomarkers potentially responsible for VC and have evaluated their link with this process. This narrative review, and an accompanying analysis performed on the Amiens CKD database, focuses on selected VC biomarkers-namely phosphate, fibroblast growth factor 23 (FGF23), osteopontin (OPN), osteoprotegerin (OPG), matrix Gla protein and fetuin A-all of which have been implicated as major players in VC in experimental studies in vitro or in animal models. None of the VC biomarkers considered in this review have qualified as a reliable predictor of meaningful clinical events or as a valid indicator of the risk of having VC. In the analysis based on the Amiens-CKD database, no biomarker outperformed age and the classical risk factors as a predictor of VC either in the aorta or in the coronaries. Well-designed clinical trials are now urgently needed to test the potential value of these biomarkers as a guide for interventions targeting VC.

Association between free light chain levels, and disease progression and mortality in chronic kidney disease.

Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa (κ) and lambda (λ) and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain κ and λ levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC κ and λ levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC κ and λ levels were independently associated with CKD stages and ß2 microglobulin levels. Elevated FLC κ and λ levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC κ and λ levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors.

Does p-cresylglucuronide have the same impact on mortality as other protein-bound uremic toxins?

BACKGROUND: Uremic toxins are emerging as important, non-traditional cardiovascular risk factors in chronic kidney disease (CKD). P-cresol has been defined as a prototype protein-bound uremic toxin. Conjugation of p-cresol creates p-cresylsulfate (PCS) as the main metabolite and p-cresylglucuronide (PCG), at a markedly lower concentration. The objective of the present study was to evaluate serum PCG levels, determine the latter's association with mortality and establish whether the various protein-bound uremic toxins (i.e. PCS, PCG and indoxylsulfate (IS)) differed in their ability to predict mortality. METHODOLOGY/PRINCIPAL FINDINGS: We studied 139 patients (mean ± SD age: 67±12; males: 60%) at different CKD stages (34.5% at CKD stages 2-3, 33.5% at stage 4-5 and 32% at stage 5D). A recently developed high-performance liquid chromatography method was used to assay PCG concentrations. Total and free PCG levels increased with the severity of CKD. During the study period (mean duration: 779±185 days), 38 patients died. High free and total PCG levels were correlated with overall and cardiovascular mortality independently of well-known predictors of survival, such as age, vascular calcification, anemia, inflammation and (in predialysis patients) the estimated glomerular filtration rate. In the same cohort, free PCS levels and free IS levels were both correlated with mortality. Furthermore, the respective predictive powers of three Cox multivariate models (free PCS+other risk factors, free IS+other risk factors and free PCS+other risk factors) were quite similar--suggesting that an elevated PCG concentration has much the same impact on mortality as other uremic toxins (such as PCS or IS) do. CONCLUSIONS: Although PCG is the minor metabolite of p-cresol, our study is the first to reveal its association with mortality. Furthermore, the free fraction of PCG appears to have much the same predictive power for mortality as PCS and IS do.

The clinical impact of plasma leptin levels in a cohort of chronic kidney disease patients.

BACKGROUND: Recent research has clarified the relationship between adipokines, metabolic syndrome (MS) and cardiovascular disease (CVD). The results of animal and clinical studies have revealed a positive relationship between leptin and vascular smooth muscle cell counts and calcification, arterial rigidity, carotid thickness and the incidence of CVD. However, despite leptin fulfilling the definition of a uremic toxin, its exact role in chronic kidney disease (CKD) has yet to be determined. METHODS: One hundred and forty-two CKD patients (stages 2-5D) participated in this study, and were followed for a minimum of 20 months at Amiens University Medical Center. RESULTS: Leptin was negatively correlated with the glomerular filtration rate (GFR), total adiponectin (TAdip) and high-molecular weight adiponectin and positively correlated with age, waist circumference, body mass index (BMI), aortic calcification score (ACS), C-reactive protein (CRP), triglycerides, insulin and parathormone (PTH). Leptin and insulin were significantly correlated with the MS score. The BMI, insulin, MS score and PTH were independent predictors of leptin levels (P = 0.002, 0.016, 0.028 and 0.017, respectively). Leptin, insulin and TAdip were independent predictors of the presence of MS (P = 0.05, 0.04 and 0.04). However, leptin levels were not significantly predictive of the clinical outcomes. CONCLUSIONS: Our study was the first to demonstrate a significant, independent link between leptin and MS (but not clinical outcomes) and PTH in patients at different CKD stages. Future studies will have to assess the involvement of leptin in MS and clinical outcomes in CKD, and the potential modulation of leptin by PTH.

Prognostic implications of plasma myoglobin levels in patients with chronic kidney disease.

PURPOSE: Poor cardiovascular outcomes in chronic kidney disease (CKD) patients have prompted nephrologists to look for biomarkers that may improve risk stratification in this population. The objective of this study was to evaluate plasma myoglobin (Mb) levels according to the CKD stage and to determine whether they are associated with overall, cardiovascular (CV) mortality, CV events, and renal outcomes. METHODS: Plasma Mb levels were determined in 140 CKD patients at different stage (mean ± SD age: 67 ± 12; males: 61%) who were prospectively monitored for overall and CV mortality, CV events and CKD progression. Twenty-seven healthy subjects served as controls. RESULTS: Plasma Mb levels were higher in CKD patients than in controls and progressively increased as the glomerular filtration rate fell. Hemoglobin levels, CKD stage, the aortic calcification score and brain natriuretic peptide levels were associated with plasma Mb concentrations. In a multivariate analysis, only CKD stage was associated with Mb levels. During follow up (mean duration: 968 ± 374 days), 44 patients died and 63 had a cardiovascular event. In a crude analysis, plasma Mb >73.8 µg/l predicted overall and cardiovascular mortality and the occurrence of cardiovascular events (p = 0.01, 0.05 and 0.01, respectively). However, this association was lost after adjustment for other prognostic factors for mortality. Plasma Mb was not a significant predictor of the progression of CKD either. CONCLUSIONS: Plasma Mb levels were significantly higher in predialysis or dialyzed CKD patients than in healthy controls. However, we could not identify a relevant clinical outcome associated with this elevation. Larger studies are needed to confirm the present results.

Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients.

Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.