Impact of vitamin A on clinical outcomes in haemodialysis patients

Background. Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study. Methods. We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations. Results. Patients had a mean age of 66 ± 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) μmol/L, respectively. Patients with retinol concentrations in the first quartile (3.9 μmol/L; HR 1.81, 95% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95% CI 1.41-3.50) and fatal infection (HR 2.19, 95% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 μmol/L) were more likely to die of any cause (HR 1.43, 95% CI 1.14-1.80), experience SCD (HR 1.97, 95% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95% CI 1.10-1.85). Conclusion. This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patient

Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients

Background Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients. Methods TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR. Results LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34–0.62); Th: r = 0.44 (0.32–0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean ∆LVMI (ASE-CMR): 19.5 ± 19.48 g/m2, p < 0.001; mean ∆LVMI (Th-CMR): 15.9 ± 15.89 g/m2, p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in ∆LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737–0.901) and 0.808 (0.723–0.892) for Th and ASE, respectively). Conclusions The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients

Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients

Aims Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients. Methods and results This study examined the association of homoarginine with cardiovascular outcomes in 1255 diabetic haemodialysis patients from the German diabetes and dialysis study. During a median of 4 years of follow-up, hazard ratios (HR) (95% CI) for reaching the following pre-specified, adjudicated endpoints were determined: SCD, myocardial infarction, stroke, death due to heart failure, and combined cardiovascular events. There was a strong association of low homoarginine concentrations with the presence of congestive heart failure and left ventricular hypertrophy as well as increased levels of brain natriuretic peptide. Per unit decrease in homoarginine, the risk of SCD increased three-fold (HR 3.1, 95% CI 2.0–4.9), attenuating slightly in multivariate models (HR 2.4; 95% CI 1.5–3.9). Patients in the lowest homoarginine quintile experienced a more than two-fold increased risk of SCD, and more than three-fold increased risk of heart failure death than patients in the highest quintile, which accounted for the high incidence of combined cardiovascular events. Low homoarginine showed a trend towards increased risk of stroke, however, myocardial infarction was not meaningfully affected. Conclusion Low homoarginine is a strong risk factor for SCD and death due to heart failure in haemodialysis patients. Further studies are needed to elucidate the underlying mechanisms, offering the potential to develop new interventional strategies

Glycaemic control and antidiabetic therapy in patients with diabetes mellitus and chronic kidney disease - cross-sectional data from the German Chronic Kidney Disease (GCKD) cohort

Background: Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD. Methods: The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) between 30-60 mL/min/1.73 m(2) or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure. Results: At baseline, DM was present in 1842 patients (35 %) and the median HbA1C was 7.0 % (25th-75th percentile: 6.8-7.9 %), equalling 53 mmol/mol (51, 63);24.2 % of patients received dietary treatment only, 25.5 % oral antidiabetic drugs but not insulin, 8.4 % oral antidiabetic drugs with insulin, and 41.8 % insulin alone. Metformin was used by 18.8 %. Factors associated with an HbA1C level >7.0 % (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m(2), 95 % CI 1.02-1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 % CI 1.04-1.18), treatment with insulin alone (OR = 5.63, 95 % CI 4.26-7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 % CI 2.77-6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides. Conclusions: Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 % receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels

The association between parathyroid hormone and mortality in dialysis patients is modified by wasting

Background. The association between parathyroid hormone (PTH) level and mortality in dialysis patients is controversial. We hypothesized that wasting, a common condition potentially related to adynamic bone disease, modifies the association of PTH with mortality and cardiovascular events (CVE), respectively

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min −1 per 1.73 m 2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters ( n  = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation) https://doi.org/10.13039/501100003042German Society of Internal Medicine 361357Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) https://doi.org/10.13039/501100002347KfH (Kuratorium für Heimdialyse und Nierentransplantation e.V.—Stiftung Präventivmedizin- no grant numberDeutsche Forschungsgemeinschaft (German Research Foundation) https://doi.org/10.13039/50110000165

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min per 1.73 m or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35-2.30), CV death (HR 2.18, 95% CI: 1.50-3.16), MACE (HR 1.38, 95% CI: 1.12-1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56-2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups. Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence. Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials. Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation

Differential prognostic utility of adiposity measures in chronic kidney disease

Objective Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD. Methods The German Chronic Kidney Disease (GCKD) study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate (eGFR): 30–60 mL/min/1.73 m2, or >60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC and BMI with all-cause death, major cardiovascular events (MACE: a composite of non-fatal stroke, non-fatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria (AIC) were calculated. Models included sex interactions with adiposity measures. Results A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (HR 1.080 per cm; 95% CI 1.009–1.155), but not in men. Irrespective of sex, WC was associated with all-cause death (HR 1.014 per cm; 95% CI 1.005–1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death including WC offered the best (lowest) AIC. Conclusion In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause, but BMI was not

Interactive exploration of adverse events and multimorbidity in CKD

Background: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. Methods: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73 m2 and an overt proteinuria. Cardiovascular, cerebrovascular and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. Results: Over a median of 6.5 years, 10 271 events occurred in 2947 participants (56.5%), of which 680 participants (13.0%) died. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney) and 66.0 (infection). Participants with presumed diabetic kidney disease and men were more prone to experiencing events. Conclusion: This comprehensive explorative tool to visualize adverse events (https://www.gckd.org/studienhintergrund/previous-study-results/event-analysis/), their combination, mortality and multimorbidity among persons with CKD may serve as a valuable resourec for patient care, identification of high-risk groups, health services and public health policy planning