Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: 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/1.73m2 and an overt proteinuria. Cardio-, cerebro- 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 total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. 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 diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Association of osteopontin with kidney function and kidney failure in chronic kidney disease patients: the GCKD study.

BACKGROUND: Osteopontin (OPN), synthesized in the thick ascending limb of Henle's loop and in the distal tubule, is involved in the pathogenesis of kidney fibrosis, a hallmark of kidney failure (KF). In a cohort of chronic kidney disease (CKD) patients, we evaluated OPN's association with kidney markers and KF. METHODS: OPN was measured from baseline serum samples of German Chronic Kidney Disease study participants. Cross-sectional regression models for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) as well as Cox regression models for all-cause mortality and KF were evaluated to estimate the OPN effect. Additionally, the predictive ability of OPN and time-dependent population-attributable fraction were evaluated. RESULTS: Over a median follow-up of 6.5 years, 471 KF events and 629 deaths occurred among 4950 CKD patients. One-unit higher log(OPN) was associated with 5.5 mL/min/1.73 m2 lower eGFR [95% confidence interval (95% CI) -6.4 to -4.6] and 1% change in OPN with 0.7% higher UACR (estimated effect 0.7, 95% CI 0.6-0.8). Moreover, higher OPN levels were associated with a higher risk of KF [hazard ratio (HR) 1.4, 95% CI 1.2-1.7] and all-cause mortality (HR 1.5, 95% CI 1.3-1.8). After 6 years, 31% of the KF events could be attributed to higher OPN levels (95% CI 3%-56%). CONCLUSIONS: In this study, higher OPN levels were associated with kidney function markers worsening and a higher risk for adverse outcomes. A larger proportion of KF could be attributed to higher OPN levels, warranting further research on OPN with regards to its role in CKD progression and possible treatment options.

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 study is a prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 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 adverse cardiovascular events (MACE: a composite of nonfatal stroke, nonfatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), and 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 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 (hazard ratio 1.080 per cm; 95% CI 1.009-1.155) but not in men. Irrespective of sex, WC was associated with all-cause death (hazard ratio 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) Akaike information criteria. 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.

Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study.

RATIONALE & OBJECTIVE: Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent). EXPOSURE: Serum levels of H-FABP and hs-TNT were measured at study entry. OUTCOME: Noncardiovascular (non-CV) death, CV death, combined major adverse CV events (MACE), and hospitalization for congestive heart failure (CHF). ANALYTICAL APPROACH: Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors. RESULTS: During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]). LIMITATIONS: Single-point measurements of H-FABP and hs-TNT. Uncertain generalizability to non-European populations. CONCLUSIONS: In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies.

Protective effects of spironolactone on vascular calcification in chronic kidney disease.

BACKGROUND: Vascular calcification is common in chronic kidney disease (CKD) and associated with increased cardiovascular mortality. Aldosterone has been implicated as an augmenting factor in the progression of vascular calcification. The present study further explored putative beneficial effects of aldosterone inhibition by the mineralocorticoid receptor antagonist spironolactone on vascular calcification in CKD. METHODS: Serum calcification propensity was determined in serum samples from the MiREnDa trial, a prospective, randomized controlled clinical trial to investigate efficacy and safety of spironolactone in maintenance hemodialysis patients. Experiments were conducted in mice with subtotal nephrectomy and cholecalciferol treatment, and in calcifying primary human aortic smooth muscle cells (HAoSMCs). RESULTS: Serum calcification propensity was improved by spironolactone treatment in patients on hemodialysis from the MiREnDa trial. In mouse models and HAoSMCs, spironolactone treatment ameliorated vascular calcification and expression of osteogenic markers. CONCLUSIONS: These observations support a putative benefit of spironolactone treatment in CKD-associated vascular calcification. Further research is required to investigate possible improvements in cardiovascular outcomes by spironolactone and whether the benefits outweigh the risks in patients with CKD.

Establishing Core Cardiovascular Outcome Measures for Trials in Hemodialysis: Report of an International Consensus Workshop.

Cardiovascular disease (CVD) affects more than two-thirds of patients receiving hemodialysis and is the leading cause of death in this population, yet CVD outcomes are infrequently and inconsistently reported in trials in patients receiving hemodialysis. As part of the Standardised Outcomes in Nephrology-Haemodialysis (SONG-HD) initiative, we convened a consensus workshop to discuss the potential use of myocardial infarction and sudden cardiac death as core outcome measures for CVD for use in all trials in people receiving hemodialysis. Eight patients or caregivers and 46 health professionals from 15 countries discussed selection and implementation of the proposed core outcome measures. Five main themes were identified: capturing specific relevance to the hemodialysis population (acknowledging prevalence, risk, severity, unique symptomology, and pathophysiology), the dilemmas in using composite outcomes, addressing challenges in outcome definitions (establishing a common definition and addressing uncertainty in the utility of biomarkers in hemodialysis), selecting a meaningful metric for decision making (to facilitate comparison across trials), and enabling and incentivizing implementation (by ensuring that cardiologists are involved in the development and integration of the outcome measure into registries, trial design, and reporting guidelines). Based on these themes, participants supported the use of myocardial infarction and sudden cardiac death as core outcome measures of CVD to be reported in all hemodialysis trials.

Drugs linked to plasma homoarginine in chronic kidney disease patients-a cross-sectional analysis of the German Chronic Kidney Disease cohort.

BACKGROUND: Elevated plasma concentrations of symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) and a lower plasma concentration of the structurally related homoarginine are commonly observed in patients with chronic kidney disease (CKD) and independently predict total mortality as well as progression of renal disease. We aimed to identify drugs that may alter this adverse metabolite pattern in a favourable fashion. METHODS: Plasma ADMA, SDMA, homoarginine and l-arginine were determined by liquid chromatography-tandem mass spectrometry in 4756 CKD patients ages 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 and overt proteinuria who were enrolled in the German Chronic Kidney Disease (GCKD) study. Associations between laboratory, clinical and medication data were assessed. RESULTS: Intake of several commonly used drugs was independently associated with plasma concentrations of homoarginine and/or related metabolites. Among these, the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate was associated with the most profound differences in ADMA, SDMA and homoarginine plasma concentrations: 66 patients taking fenofibrate had a multivariable adjusted odds ratio (OR) of 5.83 [95% confidence interval (CI) 2.82-12.03, P < 0.001] to have a plasma homoarginine concentration above the median. The median homoarginine plasma concentration in patients taking fenofibrate was 2.30 µmol/L versus 1.55 in patients not taking the drug (P < 0.001). In addition, fibrates were significantly associated with lower plasma SDMA and higher l-arginine concentrations. In contrast, glucocorticoids were associated with lower plasma homoarginine, with adjusted ORs of 0.52 (95% CI 0.40-0.67, P < 0.001) and 0.53 (95% CI 0.31-0.90, P = 0.018) for prednisolone and methylprednisolone, respectively. CONCLUSIONS: In a large cohort of CKD patients, intake of fenofibrate and glucocorticoids were independently associated with higher and lower plasma homoarginine concentrations, respectively. Effects on plasma homoarginine and methylarginines warrant further investigation as potential mechanisms mediating beneficial or adverse drug effects.

Identifying critically important cardiovascular outcomes for trials in hemodialysis: an international survey with patients, caregivers and health professionals.

BACKGROUND: Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in people on hemodialysis (HD). Cardiovascular outcomes are reported infrequently and inconsistently across trials in HD. This study aimed to identify the priorities of patients/caregivers and health professionals (HPs) for CVD outcomes to be incorporated into a core outcome set reported in all HD trials. METHODS: In an international online survey, participants rated the absolute importance of 10 cardiovascular outcomes (derived from a systematic review) on a 9-point Likert scale, with 7-9 being critically important. The relative importance was determined using a best-worst scale. Likert means, medians and proportions and best-worst preference scores were calculated for each outcome. Comments were thematically analyzed. RESULTS: Participants included 127 (19%) patients/caregivers and 549 (81%) HPs from 53 countries, of whom 530 (78%) completed the survey in English and 146 (22%) in Chinese. All but one cardiovascular outcome ('valve replacement') was rated as critically important (Likert 7-9) by all participants; 'sudden cardiac death', 'heart attack', 'stroke' and 'heart failure' were all rated at the top by patients/caregivers (median Likert score 9). Patients/caregivers ranked the same four outcomes as the most important outcomes with mean preference scores of 6.2 (95% confidence interval 4.8-7.5), 5.9 (4.6-7.2), 5.3 (4.0-6.6) and 4.9 (3.6-6.3), respectively. The same four outcomes were ranked most highly by HPs. We identified five themes underpinning the prioritization of outcomes: 'clinical equipoise and potential for intervention', 'specific or attributable to HD', 'severity or impact on the quality of life', 'strengthen knowledge and education', and 'inextricably linked burden and risk'. CONCLUSIONS: Patients and HPs believe that all cardiovascular outcomes are of critical importance but consistently identify sudden cardiac death, myocardial infarction, stroke and heart failure as the most important outcomes to be measured in all HD trials.

Status of periodontal health in German patients suffering from chronic kidney disease-Data from the GCKD study.

AIM: To assess the prevalence and severity of periodontitis in patients with moderate chronic kidney disease (CKD) and comparing the results with the self-reported periodontitis awareness of the study subjects. MATERIAL AND METHODS: The periodontal status of 270 patients with moderate CKD randomly selected from a cohort of 5,217 subjects participating in the prospective observational German Chronic Kidney Disease (GCKD) project was analysed by recording bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment level (CAL). Furthermore, the awareness of the study subjects of their periodontal conditions was evaluated by a self-reported questionnaire. RESULTS: 24.4% of the CKD study patients showed no or only mild signs of periodontal disease, 47.6% displayed moderate and 27% severe periodontitis. Questionnaire data revealed that 62.3% of the study subjects with severe periodontitis were not aware of the presence of the disease, 44.4% denied having received any systematic periodontal therapy so far, although 50% of them indicated to visit their dentist regularly for professional tooth cleanings. CONCLUSION: While the clinical study data confirm an increased prevalence of periodontitis in CKD patients, their self-reported awareness of periodontitis was low.

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. TRIAL REGISTRATION: The data was derived from the following clinical trial: NCT01691053 , registered on 19 September 2012 before enrollment of the first participant.

Association Between Dietary Patterns and Kidney Function in Patients With Chronic Kidney Disease: A Cross-Sectional Analysis of the German Chronic Kidney Disease Study.

OBJECTIVE: In the general population, "healthy" dietary patterns are associated with improved health outcomes, but data on associations between observance of specific dietary patterns and kidney function in patients with chronic kidney disease (CKD) are sparse. METHODS: Dietary intake was evaluated using food frequency questionnaires in patients with moderately severe CKD under nephrology care enrolled into the observational multicenter German CKD study. The Dietary Approaches to Stop Hypertension (DASH) diet score, Mediterranean diet score, and German Food Pyramid Index (GFPI) were calculated and their association with estimated glomerular filtration rate (eGFR) and albuminuria was assessed by multivariable linear regression analysis, adjusted for gender, age, body mass index, energy intake, smoking status, alcohol intake, education, high-density lipoprotein-cholesterol (HDL- cholesterol), low-density lipoprotein-cholesterol (LDL-cholesterol), hypertension, and diabetes mellitus. RESULTS: A total of 2,813 patients (41% women; age 60.1 ± 11.6 years) were included in the analysis. High DASH diet score and GFPI were associated with lower systolic blood pressure and lower intake of antihypertensive medication, higher HDL, and lower uric acid levels. Mediterranean-style diet was associated with lower prevalence of diabetes mellitus. Higher DASH and Mediterranean diet scores were associated with higher eGFR (ß-coefficient = 1.226, P < .001; ß-coefficient = 0.932, P = .007, respectively). In contrast, GFPI was not associated with eGFR. For the individual components of the dietary patterns, higher intake of nuts and legumes, cereals, fish, and polyunsaturated fats was associated with higher eGFR and higher intake of dairy, composed of low- and whole-fat dairy, was associated with lower eGFR. No association was found between dietary patterns and albuminuria. CONCLUSION: Higher observance of the DASH or Mediterranean diet, but not German food pyramid recommendations, was associated with higher eGFR among patients with CKD. Improving dietary habits may offer an opportunity to better control comorbidities and kidney function decline in patients with CKD.

A randomized controlled trial of the effect of spironolactone on left ventricular mass in hemodialysis patients.

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease.

Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.

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.

Long-Term Survivor Characteristics in Hemodialysis Patients with Type 2 Diabetes.

BACKGROUND: Data concerning long-term mortality predictors among large, purely diabetic hemodialysis collectives are scarce. METHODS: We used data from a multicenter, prospective, randomized trial among 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) and its observational follow-up study. The association of 10 baseline candidate variables with mortality was assessed by Cox proportional hazards regression. RESULTS: Overall, 103 participants survived the median follow-up of 11.5 years. Significant predictors of mortality were age (hazard ratio [HR] 1.03, 95% CI 1.02-1.04), cardiovascular (HR 1.42, 95% CI 1.25-1.62) and peripheral vascular disease (HR 1.55, 95% CI 1.36-1.76), higher hemoglobin A1c (HbA1c; HR 1.08, 95% CI 1.03-1.14), and loss of self-dependency (HR 1.20, 95% CI 1.03-1.39). Higher albumin (HR 0.72, 95% CI 0.59-0.89) and body mass index (BMI; HR 0.98, 95% CI 0.96-0.99) had protective associations. There was no significant association with sex, diabetes duration, and cerebrovascular diseases. Subgroup analyses by age and diabetes duration showed stronger associations of cardiovascular disease, HbA1c, albumin, BMI, and loss of self-dependency in younger patients and/or shorter diabetes duration. Loss of self-dependency and energy resources (albumin, BMI) increased mortality more severely in women, whilst the impact of cardiovascular and peripheral vascular diseases was more pronounced in men. CONCLUSION: Long-term mortality risk in patients with T2DM on hemodialysis was associated with higher age, vascular diseases, HbA1c, loss of self-dependency, and low energy resources. Interestingly, it does not vary between sexes. Further individualized prognosis estimation and therapy should strongly depend on age, diabetes duration, and gender.

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.

Long-term effects following 4 years of randomized treatment with atorvastatin in patients with type 2 diabetes mellitus on hemodialysis.

The 4D (Die Deutsche Diabetes Dialyse) Study was a randomized, double-blind trial comparing 4 years of treatment with atorvastatin to placebo in 1255 hemodialysis patients with type 2 diabetes. The primary end point of cardiovascular events (cardiac death, myocardial infarction, and stroke) was non-significantly reduced by 8%. However, long-term effects remained uncertain. Therefore, surviving patients were invited to a follow-up survey done by questionnaire. Post-trial statin therapy was at nephrologist discretion, and outcomes were centrally adjudicated and analyzed by intention to treat and time to first event in the original treatment groups. Median overall follow-up was 11.5 years. Post-trial statin use and low-density lipoprotein cholesterol levels did not differ between groups. Statin treatment non-significantly affected the former primary outcome (relative risk, 0.91; 95% confidence interval, 0.78-1.07). The risk of all cardiac events combined and the risk of cardiac death were significantly lower in the original statin group compared to placebo (0.83, 0.70-0.97, and 0.80, 0.66-0.97). No significant effect was detected on cerebrovascular events, fatal stroke, fatal cancer, non-vascular, or all-cause death. No rhabdomyolysis was reported. Thus, after 4 years of atorvastatin treatment in diabetic hemodialysis patients, similar effects on outcomes were found after 11.5 years of follow-up as were found at the end of the original study. There was no evidence of emerging hazards in the long term, confirming current clinical practice guidelines.

Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP).

BACKGROUND: The absolute and relative importance of smoking to vascular and nonvascular outcomes in people with chronic kidney disease (CKD), as well its relevance to kidney disease progression, is uncertain. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 9,270 participants with CKD enrolled in SHARP. PREDICTOR: Baseline smoking status (current, former, and never). OUTCOMES: Vascular events, site-specific cancer, ESRD, rate of change in estimated glomerular filtration rate (eGFR), and cause-specific mortality. RESULTS: At baseline, 1,243 (13%) participants were current smokers (median consumption, 10 cigarettes/day); 3,272 (35%), former smokers; and 4,755 (51%), never smokers. Median follow-up was 4.9 years. Vascular event rates were 36% higher for current than never smokers (2,317 events; relative risk [RR], 1.36; 95% CI, 1.19-1.55), reflecting increases in both atherosclerotic (RR, 1.49; 95% CI, 1.26-1.76) and nonatherosclerotic (RR, 1.25; 95% CI, 1.05-1.50) events. Cancer was 37% higher among current smokers (632 events; RR, 1.37; 95% CI, 1.07-1.76), with the biggest RRs for lung (RR, 9.31; 95% CI, 4.37-19.83) and upper aerodigestive tract (RR, 4.87; 95% CI, 2.10-11.32) cancers. For 6,245 patients not receiving dialysis at baseline, ESRD incidence did not differ significantly between current and never smokers (2,141 events; RR, 1.02; 95% CI, 0.89-1.17), nor did estimated rate of change in eGFR (current smokers, -1.77±0.14 [SE]; never smokers, -1.70±0.07mL/min/1.73m(2) per year). All-cause mortality was 48% higher among current smokers (2,257 events; RR, 1.48; 95% CI, 1.30-1.70), with significant increases in vascular (RR, 1.35; 95% CI, 1.07-1.69) and nonvascular (RR, 1.60; 95% CI, 1.34-1.91) causes of death, especially cancer (RR, 2.32; 95% CI, 1.58-3.40) and respiratory (RR, 2.25; 95% CI, 1.51-3.35) mortality. LIMITATIONS: Smoking status not assessed during follow-up. CONCLUSIONS: In this study of patients with CKD, smoking significantly increased the risks for vascular and nonvascular morbidity and mortality, but was not associated with kidney disease progression. The associations with vascular and neoplastic disease are in keeping with those observed in the general population and are likely modifiable by cessation.

Lipoprotein(a) concentrations, apolipoprotein(a) isoforms and clinical endpoints in haemodialysis patients with type 2 diabetes mellitus: results from the 4D Study.

BACKGROUND: High lipoprotein(a) [Lp(a)] concentrations and low molecular weight (LMW) apolipoprotein(a) [apo(a)] isoforms are associated with cardiovascular disease and mortality in the general population. We examined the association of both with all-cause mortality and cardiovascular endpoints in haemodialysis patients with diabetes mellitus. METHODS: This is a post hoc analysis of the prospective 4D Study (German Diabetes Dialysis Study) that evaluated atorvastatin compared with placebo in 1255 haemodialysis patients with type 2 diabetes mellitus (median follow-up 4 years). The association of natural logarithm-transformed Lp(a) concentrations (increment one unit) and apo(a) isoforms with outcomes was analysed by Cox proportional hazards regression. The influence of age (median 66 years) was evaluated by stratified survival analyses. RESULTS: The median baseline Lp(a) concentration was 11.5 mg/dL (IQR 5.0-41.8). A quarter of patients had at least one LMW apo(a) isoform. Increased Lp(a) concentrations were associated with all-cause mortality in the total group [hazard ratio (HR) 1.09 (95% CI 1.03-1.16), P = 0.004]. LMW apo(a) isoforms were only associated with all-cause mortality in patients ≤ 66 years [HR 1.38 (95% CI 1.05-1.80), P = 0.02]. The strongest association for Lp(a) concentrations and LMW apo(a) isoforms was found for death due to infection in patients ≤ 66 years [HR 1.39 (95% CI 1.14-1.71), P = 0.001; HR 2.17 (95% CI 1.26-3.75), P = 0.005]. Lp(a) concentrations were also associated with fatal stroke in patients ≤66 years of age [HR 1.54 (95% CI 1.05-2.24), P = 0.03]. Neither Lp(a) nor LMW apo(a) isoforms were associated with other atherosclerosis-related events. CONCLUSIONS: High Lp(a) concentrations and LMW apo(a) isoforms are risk predictors for all-cause mortality and death due to infection in haemodialysis patients with diabetes mellitus. These associations are modified by age.