Biocompatibility study based on differential sequestration kinetics of CD14+CD16+ blood monocyte subsets with different dialyzers

The immune defect in hemodialysis (HD) patients is associated with a monocyte dysfunction, including an increase in the production of proinflammatory cytokines. Blood membrane contact leads to an increase in cellular activation and sequestration into the capillary bed of the lung. The influence of the sequestration on the number of mature monocytes was studied by analyzing the fate of monocytes, particularly, the CD14+CD16+ subpopulation, during HD treatment. In thirty stable HD patients, the distinct cell populations were determined by differential blood counts and flow cytometry. Patients with diabetes or systemic vasculitis, those showing evidence of infectious complications or malignancy, or those taking immunosuppressive medications were excluded from the study. Cells from this study population were analyzed before the start, 30 min thereafter, and at the end of HD treatment, each time using a different dialyzer: hemophan, methylmethacrylate (PMMA), triacetate membrane, cuprophane/vitamin E, acrylonitrile, and sodium methallylsulfonate polymer (AN69). The CD14+CD16+ subset decreased at 30 min and remained suppressed for the course of dialysis. To examine whether currently used biocompatible membranes differ in their effect on the sequestration of monocyte subpopulations, temporal monocytic changes were comparatively analyzed during HD with a different dialyzer. The drop in the first 30 min until the end of HD treatment was significant (p<0.05), very uniform, and sharp in all patients, and was independent upon membrane type. The CD14+CD16+ monocyte subpopulation showed increased and longer margination from the blood circulation during HD. Given the fact that CD14+CD16+ monocytes represent a sensitive marker for inflammation or cellular activation, the depletion of these cells may offer an easily accessible parameter that is more sensitive than complement activation for biocompatibility studies on forthcoming, improved dialyzer membranes.     

Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis

PurposeLow 25-hydroxyvitamin D (25D), increased levels of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were reported to be risk factors for mortality in chronic kidney disease (CKD). However, the independent associations of these factors with cardiovascular disease (CVD), the leading cause of death among CKD patients, remain unclear. Our purpose was to identify which of these factors predict incident CVD in CKD.MethodsIn this prospective cohort study, we enrolled 738 predialysis outpatients in the two nephrology departments. We employed Cox proportional hazards analyses to elucidate predictors of the endpoint, defined as fatal or non-fatal cardiovascular event requiring hospitalization. Multiple imputation was performed for missing values.ResultsMean estimated glomerular filtration rate (eGFR) was 35 mL/min/1.73 m². During a median duration of 4.4 years, 86 patients developed the endpoint, of whom 62 patients achieved it before the initiation of dialysis. Multivariable analyses revealed that high serum intact FGF23 levels predicted the outcome preceding dialysis initiation (hazard ratio (HR) per lnFGF23 (SD), 1.64 (1.27–2.30)), while 25D, PTH, and bone-specific ALP did not. Adding FGF23 to the conventional model of age, sex, diabetes, prior CVD, pulse pressure, and eGFR, led to a net reclassification improvement of 6.87% (P = 0.04). Not censoring the patients at the start of dialysis and continuing follow-up even after dialysis, FGF23 levels did not predict the outcome (HR, 1.16 (0.91–1.48)). Complete case analyses yielded similar results.ConclusionsIntact FGF23 levels in predialysis CKD predicted incident cardiovascular events requiring hospitalization before starting dialysis, but did not predict events during the entire follow-up period, including post dialysis initiation.     

Activation of peripheral blood CD14+ monocytes occurs in diabetes

Blood levels of inflammatory markers associated with endothelial dysfunction and atherosclerosis are increased in diabetic patients; the highest levels occur in poorly controlled diabetes. We investigated the activation state of peripheral blood monocytes in diabetes with respect to scavenger receptor (CD36) expression and monocyte chemoattractant protein-1, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and peroxisome proliferator-activated receptors mRNA expression. CD14(+) monocytes were isolated from peripheral blood of type 1 and type 2 diabetic patients with good (HbA(1c) <7.0%) or poor (>9.4%) glycemic control and a group of nondiabetic subjects. Monocytes from diabetic subjects displayed increased CD36 cell surface expression (P < 0.0005) and increased uptake of oxidized LDL (P < 0.05). Monocyte chemoattractant protein-1 gene expression was increased in monocytes from both groups of diabetic subjects (P < 0.05). Both CD68 and peroxisome proliferator-activated receptor-gamma gene expression were increased in the poorly controlled diabetic group (P < 0.05 for each), whose monocytes also displayed increased attachment to endothelial monolayers (P < 0.0005 vs. nondiabetic control subjects). In poorly controlled diabetes, CD14(+) monocytes are functionally activated and show some of the differentiation markers associated with macrophages. These monocytes also demonstrate an increased ability for attachment to normal endothelial cells, one of the early stages in atherogenesis.     

Functional variants in the lymphotoxin-alpha gene predict cardiovascular disease in dialysis patients

TNF-beta that is encoded by lymphotoxin-alpha gene (LTA) regulates adhesion molecules and IL-6. Previously, a genome-wide case-control study showed that LTA gene variants predisposed to cardiovascular disease (CVD). In a prospective study of 775 dialysis patients, LTA and IL-6 gene variants were tested as independent predictors of CVD risk. Four polymorphisms in the LTA gene and one in the IL-6 gene were genotyped. CVD events were ascertained from medical records. During a mean follow-up of 2.6 yr, 294 first-incident CVD events occurred. The LTA 26Asn variant predicted higher adjusted CVD risk (hazard ratio HR 1.33 for each additional copy of Asn allele; 95% confidence interval 1.14 to 1.55; P = 0.0003). Two other nonsynonymous polymorphisms in the LTA, 13Agr and 51Pro, were associated with lower inflammatory activity and CVD risk. LTA haplotypes (based on all four single-nucleotide polymorphisms) were associated with inflammatory markers and predicted CVD risk (P = 0.005) after adjustment. These LTA genotype associations were independent of the IL-6 -174G/C genotype association that was reported recently. LTA and IL-6 gene variants independently predicted risk for CVD among dialysis patients, suggesting that susceptibility in multiple inflammatory pathways contribute to the development of CVD.     

High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients

Lipoprotein(a) [Lp(a)] levels are increased in dialysis patients, suggesting that they may play a role in the elevated atherosclerotic cardiovascular disease (ASCVD) risk in this population. Few prospective studies of Lp(a) level, apolipoprotein(a) [apo(a)] size, and ASCVD have been performed in the dialysis population. An inception cohort of 833 incident dialysis patients were followed prospectively. Baseline Lp(a) was measured by apo(a) size-independent ELISA and apo(a) size by Western blot after SDS-agarose gel electrophoresis. A combined prospective nonfatal and fatal ASCVD end point included myocardial infarction, coronary revascularization, cerebrovascular accident, carotid endarterectomy, peripheral revascularization, gangrene, or limb amputation. Survival analyses were performed with adjustment for baseline demographics, comorbid conditions, ASCVD risk factors, albumin, lipids, and C-reactive protein. Median follow-up was 27.4 mo, with 297 ASCVD events, 130 non-ASCVD deaths, and seven losses to follow-up over 1649 person-years. In multivariate Cox regression models, both high Lp(a) concentration (>/=53 nmol/L) and low molecular weight (LMW) apo(a) isoforms (123 nmol/L, the relative hazard (RH) of ASCVD was 1.73 (P < 0.0005), compared with high molecular weight apo(a) and Lp(a) level <123 nmol/L. No interactions by age, race, gender, diabetes, or ASCVD were present. Both LMW apo(a) size and high Lp(a) level predict ASCVD risk in dialysis patients, but the association of ASCVD with LMW isoforms is stronger than the association with high Lp(a) concentration.     

Associations between bioelectrical impedance parameters and cardiovascular events in chronic dialysis patients

Purpose

Malnutrition and fluid overload contribute to the poor cardiovascular prognosis of dialysis patients. Since bioelectrical impedance analysis is an option for the evaluation of body composition and for the monitoring of hydration state, it may assist in the identification of subjects at high cardiovascular risk. The objective of this study was to evaluate the association between bioelectrical impedance parameters and cardiovascular events.

Methods

The association between bioelectrical impedance parameters and fatal and non-fatal cardiovascular outcome was evaluated in 145 dialysis patients.

Results

The mean age of the population studied was 54.9 ± 15.4 years, 49.7 % were males, and 35.9 % had diabetes. Forty (27.6 %) patients developed cardiovascular events during the 16 months (8; 32) of follow-up. Comparison of patients with and without cardiovascular events revealed higher extracellular mass/body cell mass (ECM/BCM) and extracellular water/total body water ratios and higher C-reactive protein levels in the former. Survival analysis showed that an ECM/BCM ratio >1.2 and a phase angle <6° were associated with poor cardiovascular prognosis. Among nondiabetic patients, these parameters and capacitance were independently associated with cardiovascular events, suggesting that poor nutritional status and fluid overload are associated with the occurrence of these events.

Conclusions

Phase angle, capacitance and ECM/BCM ratio are valuable parameters for the evaluation of cardiovascular prognosis, supporting the use of bioelectrical impedance for the clinical assessment of dialysis patients.     

Proinflammatory CD14+CD16+ Monocytes Are Associated With Subclinical Atherosclerosis in Renal Transplant Patients

Atherosclerotic cardiovascular disease is a major cause of death in renal transplant (TX) recipients. Atherosclerotic lesions are characterized by monocytic infiltration. Circulating monocytes can be divided into functionally distinct subpopulations, among which CD14++CD16+ and CD14+CD16+ monocytes (summarized as CD16+ monocytes) are proinflammatory cells. We hypothesized that the frequency of circulating CD16+ monocytes is associated with subclinical atherosclerosis in TX patients. Monocyte subpopulations were quantified in 95 TX and 31 hemodialysis patients (HD). In TX patients, subclinical atherosclerosis was determined by carotid intima media thickness (IMT) measurement. TX patients had lower frequencies of CD16+ monocytes than HD patients. When stratifying by immunosuppressive treatment, patients on methylprednisolone (MP) therapy had fewer CD14+CD16+ monocytes than patients not receiving MP. CD14+CD16+ monocytes decrease very shortly after transplantation. CD14+CD16+ monocyte frequency correlated with IMT in TX recipients (r = 0.34, p < 0.001). This correlation was most pronounced among patients without MP treatment (r = 0.55, p = 0.02). In a multivariate regression analysis, the association of CD14+CD16+ monocytes with IMT was independent from traditional cardiovascular risk factors. The frequency of proinflammatory CD14+CD16+ monocytes is independently associated with subclinical atherosclerosis in transplant recipients. Further studies on the association between circulating leukocytes and atherosclerosis should take monocyte heterogeneity into account.     

Sarcopenia and cardiovascular risk indices: Its impact on cardiovascular events and mortality in dialysis patients

Background: Sarcopenia is a common complication in end-stage renal disease. Low muscle strength and muscle mass are risk factors for cardiovascular disease and mortality in patients undergoing dialysis. We studied the relation between sarcopenia and pre-atherosclerotic markers and its effect on cardiovascular events and death in dialysis patients. Methods: We measured muscle strength, muscle mass, carotid intima-media thickness, and pulse wave velocity in 106 patients. Sarcopenia was diagnosed according to the EWGSOP-2 suggestions. Patients with low muscle strength and low muscle mass were considered sarcopenic. The follow-up period for cardiovascular events and mortality was 24 months. Results: The mean age and dialysis duration were 57.4 ± 16.6 and 6.5 ± 4.9 years, respectively. Of all patients, 53 (50%) were male and 70 (66%) were on hemodialysis treatment. Sarcopenia and low muscle strength were seen in 47.1% and 88.7%, respectively. Hemodialysis patients were more likely to be sarcopenic than peritoneal dialysis patients (p = 0.001). Ferritin and Kt/V levels were higher, and body mass index was lower significantly in sarcopenic patients (p < 0.001). There was no significant difference in carotid intima-media thickness and pulse wave velocity measurements between the groups (p = 0.62 and p = 0.68, respectively). There was no statistically significant difference in cardiovascular events and mortality in cases with and without sarcopenia (p = 0.43 and p = 0.17, respectively). Conclusion: There was no association between sarcopenia and pre-atherosclerotic markers, cardiovascular events, and all-cause mortality in dialysis patients. Techniques to detect low muscle strength and muscle mass need standardization, and new specific cut-off levels must be defined for dialysis patients.     

Baseline hyponatremia does not predict two-year mortality in patients with chronic peritoneal dialysis

Purpose: Hyponatremia is a common electrolyte abnormality in a variety of medical conditions. Lower predialysis serum sodium concentration is associated with an increased risk of death in oligoanuric patients on hemodialysis. However, whether hyponatremia affects the short-term mortality in chronic peritoneal dialysis (CPD) patients remains unclear. Methods: We conducted a cross-sectional and two-year follow-up review retrospectively, and 318 patients with CPD were enrolled in a medical center. Serum sodium levels were measured at baseline and categorized as quartile of Na: quartile 1 (124–135?mEq/L), quartile 2 (136–139), quartile 3 (140–141) and quartile 4 (142–148). Mortality and cause of death were recorded for longitudinal analyses. Results: The patients with higher quartile (higher serum sodium) had a trend of lower age, peritoneal dialysis (PD) duration, co-morbidity index, D/P Cr and white blood cell counts and higher renal Kt/Vurea (Kt/V) and serum albumin level. Stepwise multiple linear regression analysis showed that serum sodium level was positively associated with albumin, residual renal Kt/V and negatively associated with age and PD duration in CPD patients. After two-year follow-up, stepwise multivariate Cox proportional hazards model demonstrated that age, co-morbidity index and serum albumin were the significant risk factors for all-cause two-year mortality, but not serum sodium levels. Conclusions: Serum sodium level in CPD patients is associated with nutritional status, residual renal function and duration of PD. However, baseline serum sodium level is not an independent predictor of two-year mortality in CPD patients.     

A simple score predicts future cardiovascular events in an inception cohort of dialysis patients

Vascular calcifications are very common in dialysis patients and have been shown to be associated independently with outcome. However, all of these studies used prevalent patients on dialysis since many years. We investigated vascular calcifications in an inception cohort of dialysis patients and followed them for cardiovascular disease outcomes during an average observation period of 66 months. One hundred and fifty-four Caucasian dialysis patients were enrolled in one Austrian dialysis center. Standardized plain radiographs from the pelvis and calves were carried out in all patients at the start of dialysis therapy. Vascular calcifications were assessed by a single radiologist. At the start of renal replacement therapy, 67.5% of the patients showed vascular calcifications. During follow-up, 29.9% of patients suffered a cardiovascular event. An additive 'vascular risk score', constructed from the presence of vascular calcifications and/or previous cardiovascular events before the start of dialysis treatment, showed the strongest independent association with cardiovascular events in the Cox regression model adjusted for various risk factors. The presence of each of these two conditions was associated with a hazard ratio of 2.03 (95% confidence interval 1.19-3.46) and a hazard ratio twice as high if both conditions were present. In summary, vascular calcifications on plain X-rays of pelvis and calves are largely present in incident dialysis patients. A history of a cardiovascular event in the predialysis period together with vascular calcifications at the beginning of dialysis therapy is a more powerful predictor of a cardiovascular event than age, smoking, diabetes, or other traditional risk factors.     

Enhanced platelet reactivity with erythropoietin but not following transfusion in dialysis patients

Although the haemostatic defects that occur in uraemia are complex,a major factor is the anaemia of renal failure. This may nowbe corrected by recombinant human erythropoietin (rHuEpo) therapyrather than by repeated blood transfusion. Platelet reactivityto shear stress and collagen was measured using non-anticoagulatedblood to study the effect of erythropoietin or blood transfusionon platelet function. Twenty dialysis patients were commencedon 25–50 U/kg rHuEpo twice weekly. The dose was adjustedafter 3 months to maintain target Hb 10–10.5 g/dl. A further15 patients were studied before and 10–12 days after receivingblood transfusion. Baseline platelet reactivity was subnormalin both groups versus control (P<0.0001). In the rHuEpo group,a significant increase in platelet reactivity was observed at2 months (P<0.005) which disappeared at 3 months. This wasnot related to the increase in Hb (7.3±0.3 to 10.2±0.3g/dl, P<0.0001). There was no change in platelet reactivityafter transfusion, despite an increase in Hb (6.2±0.2to 8.8±0.2 g/dl, P<0.0001) similar to that occurringin the rHuEpo group. We conclude that after rHuEpo therapy butnot after transfusion a transient increase in platelet reactivityoccurs which is dissociated from changes in platelet and redcell numbers.     

Associations of vitamin K status with mortality and cardiovascular events in peritoneal dialysis patients

International Urology and Nephrology - Vitamin K deficiency, expressed by a high level of desphospho-uncarboxylated matrix GLA protein (dp-ucMGP), is highly prevalent in dialysis patients. However,...     

Patterns of CD4/CD8 T-cell ratio in dialysis effluents predict the long-term outcome of peritonitis in patients undergoing peritoneal dialysis.

BACKGROUND: The peritoneal immune compartment is a microenvironment with a particular T-cell repertoire and susceptible to local inflammation. To clarify the role of T lymphocytes in peritoneal immunity, the changes in T-cell subpopulations in peritoneal dialysis effluents (PDEs), and their influence on the response to the treatment of peritonitis and on its prognosis were studied in patients undergoing long-term, continuous ambulatory peritoneal dialysis (CAPD). METHODS: A cohort of 36 patients treated with CAPD and who had histories of peritonitis were divided into a group with rapid and a group with delayed response to antibiotics, and were followed for 3 years. CD4/CD8 T-cell ratios, T-cell cytokine mRNA expression patterns and transforming growth factor-beta1 (TGF-beta1) concentrations were examined in PDE during bouts of peritonitis. The change in 4 h D/P creatinine during the peritoneal equilibration test (PET) between year 0 and year 3 was expressed as deltaD/P creatinine. RESULTS: The serial changes in T-cell subsets in PDE during peritonitis showed two patterns: (i) pattern 1, manifest as a progressive increase in the CD4/CD8 ratio, and associated with a rapid response to treatment; and (ii) pattern 2, manifest as a progressive decrease in the CD4/CD8 ratio, and associated with a delayed response to treatment. The major T-cell phenotypes in PDE during peritonitis were Th1-CD4(+) and Tc2-CD8(+), determined by cloning techniques, RT-PCR and double immunofluorescence staining. TGF-beta1 in the effluent was undetectable in pattern 1 after 7-8 days, but remained detectable at 2 weeks in pattern 2. Pattern 2 patients had a significantly greater decrease (deltaD/P creatinine: -0.198+/-0.086) in solute transport than pattern 1 patients (deltaD/P creatinine: -0.036+/-0.077, P<0.05). CONCLUSIONS: These results suggest that a progressive decrease of the CD4/CD8 ratio in PDE correlates with a persistent expression of TGF-beta1, and plays a pathogenetic role in the evolution of peritonitis, PET deterioration and peritoneal fibrosis. Therefore, patterns of CD4/CD8 T-cell ratio in PDE may predict clinical outcomes of peritonitis in CAPD patients.     

Correlation analysis of low-level serum uric acid and cardiovascular events in patients on peritoneal dialysis

Background

The impact of serum uric acid (SUA) on development of cardiovascular disease (CVD) in patients undergoing peritoneal dialysis (PD) remains controversial, especially the impact of hypouricemia (HUA) on CVD. The aim of our study was to investigate the influence of low-level SUA on cardiovascular (CV) events in PD patients.

Methods

A retrospective cohort study was conducted.728 PD patients from February 1, 2010 to May 31, 2019 were enrolled. All demographic and laboratory data were collected at baseline and 6 months after PD treatment. The study cohort was divided into four groups according to SUA level (μmol/L) after 6 months of PD: Group1 (<?360), Group2 (360–420), Group3 (420–480), Group4 (≥?480). The clinical characteristics of each group were analyzed. With Group2 as reference, logistic regression analysis was performed to investigate the correlation between SUA levels and risk of CV events in patients undergoing PD. Use Kaplan–Meier method to generate CV events risk graph.

Results

728 patients were enrolled in this study, including 403 (55.4%) males and 325 (44.6%) females, with an average age of 48.66?±?13.98 years; of which 158 (21.7%) patients developed CV events. Multivariate COX regression showed that after adjusting for multiple clinical factors, Group1 (HR?=?1.92, 95% CI 1.17–3.15, P?=?0.01), Group3 (HR?=?1.89, 95% CI 1.13–3.15, P?=?0.015), and Group4 (HR?=?2.38, 95% CI 1.35–4.19, P?=?0.003) are all independent risk factors for developing CV events. The Kaplan–Meier risk curve of CV events showed that the risk of CV events in the Group1, Group3 and Group4 were significantly higher (Log-Rank?=?12.67; P?=?0.005). Restricted cubic spline (RCS) showed that SUA level is non-linearly associated with the risk of CV events, showing an U-shaped curve (\(\chi_{4}^{2}\)=13.3 P?=?0.01).

Conclusions

Our study suggested that patients with SUA level less than 360 μmol/L also exhibited the higher risk for developing CV events, an U-shaped association between SUA level and risk of CV events in patients undergoing PD. Both SUA levels below 360 μmol/L and above 420 μmol/L were found to be significant risk factors for developing CV events in patients undergoing long-term PD.