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Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort.

ABSTRACT: Cardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients.Among prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined the association of baseline GDF15 levels with all-cause mortality using unadjusted and case mix-adjusted death hazard ratios (HRs) that controlled for age, sex, race, ethnicity, diabetes, and dialysis vintage.The mean age ± SD of the 203 patients included in the study was 53.2 ± 14.5 years, and the cohort included 41% females, 34% African-Americans, and 48% Hispanics. GDF15 levels (mean ± SD 5.94 ± 3.90 ng/mL; range 1.58-39.8 ng/mL) were higher among older patients and were inversely associated with serum creatinine concentrations as a surrogate for muscle mass. Each 1.0 ng/mL increase in GDF15 was associated with an approximately 17-18% higher mortality risk in the unadjusted and case mix models (p < 0.05). Increments of about 1 SD (a 4.0 ng/mL increase in GDF15) were associated with a nearly 2-fold higher death risk. The highest GDF15 tertile was associated with higher mortality risk (reference: lowest tertile): the HRs (95% CI) were 3.19 (1.35-7.55) and 2.45 (1.00-6.00) in the unadjusted and the case mix-adjusted model, respectively. These incremental death trends were confirmed in cubic spline models.Higher circulating GDF15 levels are associated with higher mortality risk in hemodialysis patients. Future studies are needed to determine whether GDF15 may represent a novel therapeutic target for cardiovascular disease, wasting, and death in this population.

SUBMITTER: You AS

PROVIDER: S-EPMC5465654 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort.

You Amy S AS Kalantar-Zadeh Kamyar K Lerner Lorena L Nakata Tracy T Lopez Nancy N Lou Lidia L Veliz Mary M Soohoo Melissa M Jing Jennie J Zaldivar Frank F Gyuris Jeno J Nguyen Danh V DV Rhee Connie M CM

Cardiorenal medicine 20170202 2

<h4>Background/aims</h4>Cardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients.<h4>Methods</h4>Among prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined ...[more]

PMID: 28611789

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Project description:BACKGROUND:Studies examining the association of dialysate potassium concentration and mortality in hemodialysis patients show conflicting findings. We hypothesized that low dialysate potassium concentrations are associated with higher mortality, particularly in patients with high pre-dialysis serum potassium concentrations. METHODS:We evaluated 624 hemodialysis patients from the prospective Malnutrition, Diet, and Racial Disparities in Kidney Disease study recruited from 16 outpatient dialysis facilities over 2011-2015 who underwent protocolized collection of dialysis treatment characteristics every 6 months. We examined the association of dialysate potassium concentration, categorized as 1, 2, and 3 mEq/L, with all-cause mortality risk in the -overall cohort, and stratified by pre-dialysis serum potassium (< 5 vs. ?5 mEq/L) using case-mix adjusted Cox models. RESULTS:In baseline analyses, dialysate potassium concentrations of 1 mEq/L were associated with higher mortality, whereas concentrations of 3 mEq/L were associated with similar mortality in the overall cohort (reference: 2 mEq/L): adjusted hazard ratios (aHRs; 95% CI) 1.70 (1.01-2.88) and 0.95 (0.64-1.39), respectively. In analyses stratified by serum potassium, baseline dialysate potassium concentrations of 1 mEq/L were associated with higher mortality in patients with serum potassium ?5 mEq/L but not in those with serum potassium < 5 mEq/L: aHRs (95% CI) 2.87 (1.51-5.46) and 0.74 (0.27-2.07), respectively (p interaction = 0.04). These findings were robust with incremental adjustment for serum potassium, potassium-binding resins, and potassium-modifying medications. CONCLUSION:Low (1 mEq/L) dialysate potassium -concentrations were associated with higher mortality, particularly in hemodialysis patients with high pre-dialysis serum potassium. Further studies are needed to identify therapeutic strategies that mitigate inter-dialytic serum potassium accumulation and subsequent high dialysate serum potassium gradients in this population.

Project description:BackgroundCancer-related weight loss is associated with increased inflammation and decreased survival. The novel inflammatory mediator growth differentiation factor (GDF)15 is associated with poor prognosis in cancer but its role in cancer-related weight loss (C-WL) remains unclear. Our objective was to measure GDF15 in plasma samples of cancer subjects and controls and establish its association with other inflammatory markers and clinical outcomes.MethodsWe measured body weight, appetite, plasma GDF15, and other inflammatory markers in men with cancer-related weight loss (C-WL, n = 58), weight stable patients with cancer (C-WS, n = 72), and non-cancer controls (Co, n = 59) matched by age and pre-illness body mass index. In a subset of patients we also measured handgrip strength, appendicular lean body mass (aLBM), Eastern Cooperative Oncology Group (ECOG), and Karnofsky performance scores.ResultsGDF15, interleukin (IL)-6 and IL-8 were increased in C-WL versus other groups. IL-1 receptor antagonist, IL-4, interferon-gamma, tumour necrosis factor alpha, and vascular endothelial growth factor A were increased in C-WL versus C-WS, and Activin A was significantly downregulated in Co versus other groups. C-WL patients had lower handgrip strength, aLBM, and fat mass, and Eastern Cooperative Oncology Group and Karnofsky performance scores were lower in both cancer groups. GDF15, IL-6, and IL-8 significantly correlated with weight loss; GDF15 negatively correlated with aLBM, handgrip strength, and fat mass. IL-8 and Activin A negatively correlated with aLBM and fat mass. GDF15 and IL-8 predicted survival adjusting for stage and weight change (Cox regression P < 0.001 for both).ConclusionGDF15 and other inflammatory markers are associated with weight loss, decreased aLBM and strength, and poor survival in patients with cancer. GDF15 may serve as a prognostic indicator in cancer patients and is being evaluated as a potential therapeutic target for cancer-related weight loss.

Project description:ObjectivesAmong hemodialysis patients, clinical practice guidelines recommend dietary potassium restriction given concerns about potential hyperkalemia leading to malignant arrhythmias and mortality. However, there are sparse data informing recommendations for dietary potassium intake in this population. We thus sought to examine the relationship between dietary potassium intake and death risk in a prospective cohort of hemodialysis patients.Design and methodsAmong 415 hemodialysis patients from the prospective "Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease" cohort recruited across 16 outpatient dialysis clinics, information regarding dietary potassium intake was obtained using Food Frequency Questionnaires administered over October 2011 to March 2015. We first examined associations of baseline dietary potassium intake categorized as tertiles with mortality risk using Cox regression. We then examined clinical characteristics associated with low dietary potassium intake (defined as the lowest tertile) using logistic regression.ResultsIn expanded case-mix Cox analyses, patients whose dietary potassium intake was in the lowest tertile had higher mortality (ref: highest tertile) (adjusted hazard ratio 1.74, 95% confidence interval 1.14-2.66). These associations had even greater magnitude of risk following adjustment for laboratory and nutritional covariates (adjusted hazard ratio 2.65, 95% confidence interval 1.40-5.04). In expanded case-mix restricted cubic spline analyses, there was a monotonic increase in mortality risk with incrementally lower dietary potassium intake. In expanded case-mix logistic regression models, female sex; higher serum bicarbonate; and lower dietary energy, protein, and fiber intake were associated with low dietary potassium intake.ConclusionsIn a prospective cohort of hemodialysis patients, lower dietary potassium intake was associated with higher mortality risk. These findings suggest that excessive dietary potassium restriction may be deleterious in hemodialysis patients, and further studies are needed to determine the optimal dietary potassium intake in this population.

Project description:Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined.We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30-65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200-1799; and ?1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC>10 Agatston units), increased CAC (CAC?100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths).Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P<0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15?1800 ng/L was associated with CAC>10 (odds ratio 2.1; 95% CI 1.2-3.7; P=0.01), CAC?100 (odds ratio 2.6; 95% CI 1.4-4.9; P=0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1-5.9, P<0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1-5.8, P=0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P=0.025), the integrated discrimination index (0.028; P<0.0001) and the category-less net reclassification index (0.42; P=0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T.GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.

Dataset Information

Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort.

Publications

Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort.

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