Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort.

SIGNIFICANCE STATEMENT: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population. BACKGROUND: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration. METHODS: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status. RESULTS: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables. CONCLUSIONS: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices.

Hyponatraemia and fluid overload are associated with higher risk of mortality in dialysis patients.

BACKGROUND: The 5-year mortality rate for haemodialysis patients is over 50%. Acute and chronic disturbances in salt and fluid homeostasis contribute to poor survival and are established as individual mortality risk factors. However, their interaction in relation to mortality is unclear. METHODS: We used the European Clinical Database 5 to investigate in a retrospective cohort analysis the relationship between transient hypo- and hypernatremia, fluid status and mortality risk of 72 163 haemodialysis patients from 25 countries. Incident haemodialysis patients with at least one valid measurement of bioimpedance spectroscopy were followed until death or administrative censoring from 1 January 2010 to 4 December 2019. Fluid overload and depletion were defined as >2.5 L above, and -1.1 L below normal fluid status, respectively. N = 2 272 041 recorded plasma sodium and fluid status measurements were available over a monthly time grid and analysed in a Cox regression model for time-to-death. RESULTS: Mortality risk of hyponatremia (plasma sodium <135 mmol/L) was slightly increased when fluid status was normal [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.18-1.35], increased by half when patients were fluid depleted (HR 1.56, 95% CI 1.27-1.93) and accelerated during fluid overload (HR 1.97, 95% CI 1.82-2.12). CONCLUSIONS: Plasma sodium and fluid status act independently as risk factors on mortality. Patient surveillance of fluid status is especially important in the high-risk subpopulation of patients with hyponatremia. Prospective patient-level studies should examine the effects of chronic hypo- and hypernatremia, risk determinants, and their outcome risk.

Development and validation of a self-regulation scale within the German version of the Early Development Instrument.

BACKGROUND: Early childhood self-regulation (SR) is key for many health- and education-related outcomes across the life span. Kindergarten age is a crucial period for SR development, and within this developmental window, potential SR difficulties can still be compensated for (e.g., through interventions). However, efficient measurement of SR through brief, comprehensive, and easy-to-use instruments that identify SR difficulties are scarce. To address this need, we used items of an internationally applied kindergarten teacher questionnaire-the Early Development Instrument (EDI) - to develop and validate a specific SR measurement scale. METHODS: The psychometric evaluation and validation of the selected SR-items was performed in data collected with the German version of the EDI (GEDI), in two independent data sets - (a) the development dataset, with 191 children, and b) the validation dataset, with 184 children. Both included three- to six-year-old children and contained retest and interrater reliability data. First, three independent raters-based on theory-selected items eligible to form a SR scale from the two SR-relevant GEDI domains "social competence" and "emotional maturity". Second, exploratory and confirmatory factor analysis using structural equation modeling examined the item structure across both data sets. This resulted in a defined SR scale, of which internal consistency, test-retest and interrater reliability, cross-validation, and concurrent validity using correlation and descriptive agreements (Bland-Altman (BA) plots) with an existing validated SR-measuring instrument (the Kindergarten Behavioral Scales) were assessed. RESULTS: Confirmatory factor analysis across both data sets yielded the best fit indices with 13 of the GEDI 20 items initially deemed eligible for SR measurement, and a three-factor structure: a) behavioral response inhibition, b) cognitive inhibition, c) selective or focused attention (RMSEA: 0.019, CFI: 0.998). Psychometric evaluation of the resulting 13-item-GEDI-SR scale revealed good internal consistency (0.92), test-retest and interrater reliability (0.85 and 0.71, respectively), validity testing yielded stability across populations and good concurrent validity with the Kindergarten Behavioral Scales (Pearson correlation coefficient: mean 0.72, range 0.61 to 0.84). CONCLUSIONS: The GEDI contains 13 items suitable to assess SR, either as part of regular EDI developmental monitoring or as a valid stand-alone scale. This short 13-item (G)EDI-SR scale may allow early detection of children with SR difficulties in the kindergarten setting in future and could be the basis for public health intervention planning. To attain this goal, future research should establish appropriate reference values using a representative standardization sample.

High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients.

BACKGROUND: The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. METHODS: To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. RESULTS: A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 patients died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. CONCLUSIONS: Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in patients on dialysis. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.

Prognostic Value of High-Sensitivity Versus Conventional Cardiac Troponin T Assays Among Patients With Type 2 Diabetes Mellitus Undergoing Maintenance Hemodialysis.

BACKGROUND: Mortality is high among patients undergoing hemodialysis for whom cardiac troponin concentration is a strong predictor of outcome. Modern troponin assays allow measurement of very low concentrations. STUDY DESIGN: Using data from a randomized controlled trial, a cohort analysis to evaluate the prognostic value of very low cardiac troponin T (TnT) concentrations. SETTING & PARTICIPANTS: 1,255 patients with end-stage renal disease and type 2 diabetes mellitus undergoing maintenance hemodialysis from the German Diabetes and Dialysis Study (4D) who had a median follow-up of 4 years. INDEX TEST, REFERENCE TEST, AND OUTCOME: Cardiac TnT was measured using a high-sensitivity assay (hs-TnT) and a conventional assay (conventional TnT) in a subpopulation (n=1,034) with valid measurements for both assays. Outcome measures were all-cause mortality and a composite cardiovascular end point including cardiac death, myocardial infarction, or stroke. RESULTS: Among the 1,034 study participants, 505 died and 377 had a cardiovascular event. Both hs-TnT and conventional TnT concentrations were associated with mortality and cardiovascular events in models adjusted for cardiovascular risk factors and dialysis-associated variables. 455 (44%) patients with very low TnT concentrations (hs-TNT < 50ng/L) would have been classified as normal by the conventional TnT assay. Among these patients, hs-TnT concentrations were also associated with mortality. LIMITATIONS: The study of patients with type 2 diabetes may limit generalizability. These findings have not been externally validated. CONCLUSIONS: In patients with type 2 diabetes mellitus receiving hemodialysis, cardiac TnT is associated with long-term mortality and cardiovascular outcomes. Concentrations of TnT not measurable with acceptable precision using a conventional TnT assay were associated with a poor prognosis when measured using a high-sensitivity assay.

Greater fluid overload and lower interdialytic weight gain are independently associated with mortality in a large international hemodialysis population.

Background: Fluid overload and interdialytic weight gain (IDWG) are discrete components of the dynamic fluid balance in haemodialysis patients. We aimed to disentangle their relationship, and the prognostic importance of two clinically distinct, bioimpedance spectroscopy (BIS)-derived measures, pre-dialysis and post-dialysis fluid overload (FOpre and FOpost) versus IDWG. Methods: We conducted a retrospective cohort study on 38 614 incident patients with one or more BIS measurement within 90 days of haemodialysis initiation (1 October 2010 through 28 February 2015). We used fractional polynomial regression to determine the association pattern between FOpre, FOpost and IDWG, and multivariate adjusted Cox models with FO and/or IDWG as longitudinal and time-varying predictors to determine all-cause mortality risk. Results: In analyses using 1-month averages, patients in quartiles 3 and 4 (Q3 and Q4) of FO had an incrementally higher adjusted mortality risk compared with reference Q2, and patients in Q1 of IDWG had higher adjusted mortality compared with Q2. The highest adjusted mortality risk was observed for patients in Q4 of FOpre combined with Q1 of IDWG [hazard ratio (HR) = 2.66 (95% confidence interval 2.21-3.20), compared with FOpre-Q2/IDWG-Q2 (reference)]. Using longitudinal means of FO and IDWG only slightly altered all HRs. IDWG associated positively with FOpre, but negatively with FOpost, suggesting a link with post-dialysis extracellular volume depletion. Conclusions: FOpre and FOpost were consistently positive risk factors for mortality. Low IDWG was associated with short-term mortality, suggesting perhaps an effect of protein-energy wasting. FOpost reflected the volume status without IDWG, which implies that this fluid marker is clinically most intuitive and may be best suited to guide volume management in haemodialysis patients.

HDL Cholesterol Efflux Does Not Predict Cardiovascular Risk in Hemodialysis Patients.

The cardioprotective effect of HDL is thought to be largely determined by its cholesterol efflux capacity, which was shown to inversely correlate with atherosclerotic cardiovascular disease in populations with normal kidney function. Patients with ESRD suffer an exceptionally high cardiovascular risk not fully explained by traditional risk factors. Here, in a post hoc analysis in 1147 patients with type 2 diabetes mellitus on hemodialysis who participated in the German Diabetes Dialysis Study (4D Study), we investigated whether the HDL cholesterol efflux capacity is predictive for cardiovascular risk. Efflux capacity was quantified by incubating human macrophage foam cells with apoB-depleted serum. During a median follow-up of 4.1 years, 423 patients reached the combined primary end point (composite of cardiac death, nonfatal myocardial infarction, and stroke), 410 patients experienced cardiac events, and 561 patients died. Notably, in Cox regression analyses, we found no association of efflux capacity with the combined primary end point (hazard ratio [HR], 0.96; 95% confidence interval [95% CI], 0.88 to 1.06; P=0.42), cardiac events (HR, 0.92; 95% CI, 0.83 to 1.02; P=0.11), or all-cause mortality (HR, 0.96; 95% CI, 0.88 to 1.05; P=0.39). In conclusion, HDL cholesterol efflux capacity is not a prognostic cardiovascular risk marker in this cohort of patients with diabetes on hemodialysis.

Copeptin Associates with Cause-Specific Mortality in Patients with Impaired Renal Function: Results from the LURIC and the 4D Study.

BACKGROUND: In chronic kidney disease (CKD) arginine vasopressin (AVP) cannot efficiently act via renal V2-receptors. AVP is upregulated leading to augmented activation of V1a- and V1b-receptors, which might contribute to the increase in cardiovascular and infectious complications in CKD. Here, we evaluate copeptin, a surrogate of AVP, and its association with cause specific mortality among patients within the whole spectrum of renal function. METHODS: Copeptin was measured in baseline samples from the LURIC (n = 3131 patients with coronary angiograms) and the 4D-Study (n = 1241 type 2 diabetic hemodialysis patients). Patients were stratified into 4 groups: estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2, 60-89 mL/min/1.73 m2, <60 mL/min/1.73 m2, and hemodialysis. The association of copeptin with mortality was assessed by Cox proportional hazards regression during 9.9 years of median follow-up in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study and 4 years of median follow-up in the German Diabetes Dialysis Study (4D-Study). RESULTS: Median copeptin increased with decreasing eGFR: 5.6 [interquartile range (IQR), 3.1-8.1] pmol/L (eGFR ≥90 mL/min/1.73 m2), 6.7 (2.9-10.5) pmol/L (eGFR 60-89 mL/min/1.73 m2), 15.3 (6.7-23.9) pmol/L (eGFR <60 mL/min/1.73 m2), and 80.8 (51.2-122) pmol/L (hemodialysis), respectively. Per SD increase in copeptin, the risk of coronary, infectious, and all-cause mortality increased by 25, 30, and 15% [hazard ratios (HR), 1.25; 95% CI, 1.13-1.39; HR, 1.30; 95% CI, 0.98-1.71; and HR, 1.15; 95% CI, 1.05-1.25], respectively, in patients with eGFR 60-89 mL/min/1.73 m2. Except for coronary death, results were similar among patients with more advanced renal disease. No significant association was found in patients with normal renal function. CONCLUSIONS: Copeptin concentrations were independently associated with coronary, infectious, and all-cause mortality in patients with renal impairment. In patients with normal renal function no significant association was found.

High-Density Lipoprotein Subclasses, Coronary Artery Disease, and Cardiovascular Mortality.

BACKGROUND: The inverse relationship between HDL cholesterol and cardiovascular mortality is weakened in coronary artery disease (CAD). We aimed to investigate the associations of HDL particle concentrations with cardiovascular mortality and the impact of CAD on these associations. We also sought to comparatively evaluate HDL cholesterol and HDL particle concentrations in predicting cardiovascular mortality. METHODS: Total and subclass HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy in 2290 participants of the LUdwigshafen RIsk and Cardiovascular Health study referred for coronary angiography. The participants were prospectively followed over a median (interquartile range) duration of 10.0 (6.1-10.6) years. RESULTS: The mean (SD) age of the participants (1575 males, 715 females) was 62.9 (10.4) years; body mass index, 27.6 (4.1) kg/m2; HDL cholesterol, 39 (11) mg/dL [1 (0.29) mmol/L]; and total HDL particle concentration, 24.1 (5.8) µmol/L. Of the participants, 434 died from cardiovascular diseases. In multivariate analyses, tertiles of total HDL particle concentrations were inversely related to cardiovascular mortality (hazard ratio for third vs first tertile = 0.55, P < 0.001). This association was primarily mediated by small HDL particles (P < 0.001). Adding total or small HDL particle concentrations rather than HDL cholesterol to multivariate prediction models improved performance metrics for cardiovascular mortality. The presence of CAD had no impact on the associations between HDL particle concentrations and cardiovascular mortality. CONCLUSIONS: High HDL particle concentration is consistently and independently of CAD associated with decreased cardiovascular mortality. Whether the inverse relationship between HDL particle concentration and cardiovascular mortality may be translated into novel therapies is under investigation.

Heart Failure with Preserved and Reduced Ejection Fraction in Hemodialysis Patients: Prevalence, Disease Prediction and Prognosis.

BACKGROUND/AIMS: Heart failure (HF) is a main cause of mortality of hemodialysis (HD) patients. While HF with reduced ejection fraction (HFrEF) is known to only affect a minority of patients, little is known about the prevalence, associations with clinical characteristics and prognosis of HF with preserved ejection fraction (HFpEF). METHODS: We included 105 maintenance HD patients from the Medical University of Vienna into this prospective single-center cohort study and determined the prevalence of HFpEF (per the 2013 criteria of the European Society of Cardiology) and HFrEF (EF <45%), using standardized post-HD transthoracic echocardiography. We also assessed clinical, laboratory and volume status parameters (by bioimpedance spectroscopy). These parameters served to calculate prediction models for both disease entities, while clinical outcomes (frequency of cardiovascular hospitalizations and/or cardiac death) were assessed prospectively over 27±4 months of follow-up. RESULTS: All but 4 patients (96%) had evidence of diastolic dysfunction. 70% of the entire cohort fulfilled HF criteria (81% HFpEF, 19% HFrEF). Age, female sex, body mass index, blood pressure and dialysis vintage were predictive of HFpEF (sensitivity 86%, specificity 63%; AUC 0.87), while age, female sex, NT pro-BNP, history of coronary artery disease and atrial fibrillation were predictive of HFrEF (sensitivity 85%, specificity 90%; AUC 0.95). Compared to patients without HF, those with HFpEF and HFrEF had a higher risk of hospitalization for cardiovascular reason and/or cardiac death (adjusted HR 4.31, 95% CI 0.46-40.03; adjusted HR 3.24, 95% CI 1.08-9.75, respectively). CONCLUSION: Diastolic dysfunction and HFpEF are highly prevalent in HD patients while HFrEF only affects a minority. Distinct patient-specific characteristics predict diagnosis of either entity with good accuracy.

Applied immuno-epidemiological research: an approach for integrating existing knowledge into the statistical analysis of multiple immune markers.

BACKGROUND: Immunologists often measure several correlated immunological markers, such as concentrations of different cytokines produced by different immune cells and/or measured under different conditions, to draw insights from complex immunological mechanisms. Although there have been recent methodological efforts to improve the statistical analysis of immunological data, a framework is still needed for the simultaneous analysis of multiple, often correlated, immune markers. This framework would allow the immunologists' hypotheses about the underlying biological mechanisms to be integrated. RESULTS: We present an analytical approach for statistical analysis of correlated immune markers, such as those commonly collected in modern immuno-epidemiological studies. We demonstrate i) how to deal with interdependencies among multiple measurements of the same immune marker, ii) how to analyse association patterns among different markers, iii) how to aggregate different measures and/or markers to immunological summary scores, iv) how to model the inter-relationships among these scores, and v) how to use these scores in epidemiological association analyses. We illustrate the application of our approach to multiple cytokine measurements from 818 children enrolled in a large immuno-epidemiological study (SCAALA Salvador), which aimed to quantify the major immunological mechanisms underlying atopic diseases or asthma. We demonstrate how to aggregate systematically the information captured in multiple cytokine measurements to immunological summary scores aimed at reflecting the presumed underlying immunological mechanisms (Th1/Th2 balance and immune regulatory network). We show how these aggregated immune scores can be used as predictors in regression models with outcomes of immunological studies (e.g. specific IgE) and compare the results to those obtained by a traditional multivariate regression approach. CONCLUSION: The proposed analytical approach may be especially useful to quantify complex immune responses in immuno-epidemiological studies, where investigators examine the relationship among epidemiological patterns, immune response, and disease outcomes.

HDL cholesterol, apolipoproteins, and cardiovascular risk in hemodialysis patients.

High concentrations of HDL cholesterol are considered to indicate efficient reverse cholesterol transport and to protect from atherosclerosis. However, HDL has been suggested to be dysfunctional in ESRD. Hence, our main objective was to investigate the effect of HDL cholesterol on outcomes in maintenance hemodialysis patients with diabetes. Moreover, we investigated the associations between the major protein components of HDL (apoA1, apoA2, and apoC3) and end points. We performed an exploratory, post hoc analysis with 1255 participants (677 men and 578 women) of the German Diabetes Dialysis study. The mean age was 66.3 years and the mean body mass index was 28.0 kg/m(2). The primary end point was a composite of cardiac death, myocardial infarction, and stroke. The secondary end point included all-cause mortality. The mean duration of follow-up was 3.9 years. A total of 31.3% of the study participants reached the primary end point and 49.1% died from any cause. HDL cholesterol and apoA1 and apoC3 quartiles were not related to end points. However, there was a trend toward an inverse association between apoA2 and all-cause mortality. The hazard ratio for death from any cause in the fourth quartile compared with the first quartile of apoA2 was 0.63 (95% confidence interval, 0.40 to 0.89). The lack of an association between HDL cholesterol and cardiovascular risk may support the concept of dysfunctional HDL in hemodialysis. The possible beneficial effect of apoA2 on survival requires confirmation in future studies.

Prophylactic CMV therapy does not improve three-yr patient and graft survival compared to preemptive therapy.

Despite increasing evidence in favor of prophylactic valganciclovir treatment in kidney transplant recipients for the prevention of cytomegalovirus (CMV) infection, the impact of preemptive vs. prophylactic treatment on long-term clinical outcomes is unclear. In this retrospective study, 187 kidney transplant recipients with serologic intermediate-risk constellation (recipient CMV IgG positive) received either preemptive or prophylactic treatment with valganciclovir. Patient survival (primary endpoint), graft survival, viremia rates, and other CMV-related outcomes were analyzed. Prophylactic therapy reduced the rates for CMV viremia during the first year (hazard ratio: 0.48, 95% confidence interval [CI] 0.30-0.75; p < 0.001). There was a trend for higher three-yr patient mortality in the prophylactic group (hazard ratio: 5.08, 95% CI 0.62-41.3; p = 0.091), and the rate of graft loss was not reduced (hazard ratio: 0.93, 95% CI 0.32-2.68; p = 0.894). Estimated glomerular filtration rate over three yr was on average 6.8 mL/min/1.73 m(2) lower in the prophylactic group (95% CI -11.68 to -1.81; p = 0.007) using a multivariate random effects model but showed more improvement over time. Prophylactic valganciclovir treatment reduced the rate of CMV infections during the first year post-transplant but no effects of prophylactic treatment on patient and graft survival or kidney function over three yr were observed.

Within- and between-group regression for improving the robustness of causal claims in cross-sectional analysis.

BACKGROUND: A major objective of environmental epidemiology is to elucidate exposure-health outcome associations. To increase the variance of observed exposure concentrations, researchers recruit individuals from different geographic areas. The common analytical approach uses multilevel analysis to estimate individual-level associations adjusted for individual and area covariates. However, in cross-sectional data this approach does not differentiate between residual confounding at the individual level and at the area level. An approach allowing researchers to distinguish between within-group effects and between-group effects would improve the robustness of causal claims. METHODS: We applied an extended multilevel approach to a large cross-sectional study aimed to elucidate the hypothesized link between drinking water pollution from perfluoroctanoic acid (PFOA) and plasma levels of C-reactive protein (CRP) or lymphocyte counts. Using within- and between-group regression of the individual PFOA serum concentrations, we partitioned the total effect into a within- and between-group effect by including the aggregated group average of the individual exposure concentrations as an additional predictor variable. RESULTS: For both biomarkers, we observed a strong overall association with PFOA blood levels. However, for lymphocyte counts the extended multilevel approach revealed the absence of a between-group effect, suggesting that most of the observed total effect was due to individual level confounding. In contrast, for CRP we found consistent between- and within-group effects, which corroborates the causal claim for the association between PFOA blood levels and CRP. CONCLUSION: Between- and within-group regression modelling augments cross-sectional analysis of epidemiological data by supporting the unmasking of non-causal associations arising from hidden confounding at different levels. In the application example presented in this paper, the approach suggested individual confounding as a probable explanation for the first observed association and strengthened the robustness of the causal claim for the second one.

Homoarginine, kidney function and cardiovascular mortality risk.

BACKGROUND: Homoarginine is a novel biomarker for cardiovascular diseases. In the present large cohort study, we evaluate how homoarginine is linked to kidney function and examine the potential interaction of homoarginine and kidney function as predictors of cardiovascular outcomes. METHODS: Serum homoarginine (mean: 2.41 ± 1.05 µmol/L), cystatin C and creatinine-based estimated GFR (eGFR, mean: 86.2 ± 23.0 mL/min per 1.73 m(2)) were measured in 3037 patients (mean age: 62.8 ± 10.6 years; 31.5% women) who were referred to coronary angiography. RESULTS: Homoarginine was positively associated with eGFR (age- and gender-adjusted partial correlation coefficient: 0.20, P < 0.001); using multiple regression analysis, eGFR emerged as an independent predictor of serum homoarginine (ß = 0.10, SE 0.01, P < 0.001). Overall cardiovascular mortality was 18.5% (563 cardiovascular deaths) after 9.9 years. Multivariate Cox proportional hazard analysis revealed that compared with participants in the highest gender-specific homoarginine tertile, those in the lowest tertile were at increased risk of cardiovascular death [multivariate-adjusted HR 1.47; 95% confidence interval (95% CI) 1.15-1.87, P = 0.002]. After adjustment for confounders, both homoarginine and eGFR were associated independently with cardiovascular mortality, with a strong synergistic interaction (P for interaction 0.005). After stratifying the cohort into persons with eGFRs <60 and ≥60 mL/min per 1.73 m(2), there was a stronger association between homoarginine and cardiovascular mortality in patients within eGFR below 60 (mean: 46.5 ± 12.0 mL/min per 1.73 m(2); HR per log SD increment of homoarginine 0.78; 95% CI 0.65-0.95, P = 0.013) compared to those with eGFR values ≥60 mL/min per 1.73 m(2). Subgroup analysis revealed that homoarginine is exclusively associated with death due to heart failure in subjects with eGFR values <60 mL/min per 1.73 m(2) (HR per log SD 0.56; 95% CI 0.37-0.85; P = 0.006). CONCLUSIONS: Low homoarginine is strongly related to decreased kidney function, adverse cardiovascular events and death due to heart failure. The relationship between low homoarginine and adverse cardiovascular outcomes is most obvious when kidney function is impaired.

Plant sterols and atherosclerosis.

PURPOSE OF REVIEW: Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe. RECENT FINDINGS: Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health. SUMMARY: Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.

Associations of abnormal fluid status, plasma sodium disorders, and low dialysate sodium with mortality in hemodialysis patients.

BACKGROUND: Abnormal fluid and plasma sodium concentrations are established prognostic factors for hemodialysis patients. However, the cumulative effects of abnormal salt and water and potential effect modifications and the effect of dialysate sodium remain incompletely understood. METHODS: The study followed 68,196 incident hemodialysis patients from 875 dialysis clinics in 25 countries over 10 years (2010-2020) investigating dose-response patterns between cumulative exposure time of fluid overload/depletion (measured by bioimpedance spectroscopy using the Fresenius Body Composition Monitor [BCM]), abnormal plasma sodium levels, low dialysate sodium, and all-cause mortality. We calculated time-varying cumulative exposure (in months) of relative fluid overload (any degree; >7% or severe; >13 or >15% in women or men, respectively) and fluid depletion (<-7%), hypo- or hypernatremia (sodium <135 or >145 mmol/L, respectively), low dialysate sodium (≤138 mmol/L), and estimated hazard ratios (HRs) for all-cause mortality using a multivariable Cox model. RESULTS: Of 2,123,957 patient-months, 61% were spent in any degree of fluid overload, 4% in fluid depletion, 11% in hyponatremia, and 1% in hypernatremia. Any degree of fluid overload was associated with higher all-cause mortality (HR peak at 3.42 (95% confidence intervals: 3.12-3.75) relative to no exposure), and this association with all-cause mortality appeared to be stronger with severe fluid overload. The risk pattern associated with hyponatremia was approximately linear in the first four patient-months and then plateaued after the fourth patient-month. We did not observe effect modification between fluid overload and hyponatremia. CONCLUSION: Even mild fluid overload was associated with higher mortality in hemodialysis patients. Whether a more stringent fluid management results in clinical improvement requires further investigation.

Interleukin-16 is increased in dialysis patients but is not a cardiovascular risk factor.

Oxalate, a uremic toxin that accumulates in dialysis patients, is associated with cardiovascular disease. As oxalate crystals can activate immune cells, we tested the hypothesis that plasma oxalate would be associated with cytokine concentrations and cardiovascular outcomes in dialysis patients. In a cohort of 104 US patients with kidney failure requiring dialysis (cohort 1), we measured 21 inflammatory markers. As IL-16 was the only cytokine to correlate with oxalate, we focused further investigations on IL-16. We searched for associations between concentrations of IL-16 and mortality and cardiovascular events in the 4D cohort (1255 patients, cohort 2) and assessed further associations of IL-16 with other uremic toxins in this cohort. IL-16 levels were positively correlated with pOx concentrations (ρ = 0.39 in cohort 1, r = 0.35 in cohort 2) and were elevated in dialysis patients when compared to healthy individuals. No significant association could be found between IL-16 levels and cardiovascular events or mortality in the 4D cohort. We conclude that the cytokine IL-16 correlates with plasma oxalate concentrations and is substantially increased in patients with kidney failure on dialysis. However, no association could be detected between IL-16 concentrations and cardiovascular disease in the 4D cohort.

Plant sterols and cardiovascular disease: a systematic review and meta-analysis.

The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case-control, five nested case-control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD.