Growth Differentiation Factor-15 Levels In Patients Research Articles

Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy

IntroductionGrowth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials.MethodsPatients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes.ResultsBaseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively).ConclusionsGDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.

GDF-15 and mtDNA Deletions Are Useful Biomarkers of Mitochondrial Dysfunction in Insulin Resistance and PCOS.

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m2, which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging.

Growth differentiation factor 15 is not modified after weight loss induced by liraglutide in South Asians and Europids with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor (GLP-1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP-1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26weeks of treatment with daily liraglutide (n=44) or placebo (n=50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. HIGHLIGHTS: What is the central question of this study? Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP-1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)? What is the main finding and its importance? Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite-suppressing effect of liraglutide is likely exerted via pathways other than GDF15.

Serum growth differentiation factor 15 as a biomarker for malnutrition in patients with acute exacerbation of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that often coexists with malnutrition during acute exacerbation (AECOPD) and significantly affects the prognosis. Previous studies have shown that growth differentiation factor 15 (GDF15) levels promote appetite suppression, weight loss, and muscle weakness, and are markedly high in peripheral blood following inflammatory stimulation. However, it is still unknown whether serum GDF15 levels can be used to predict malnutrition in patients with AECOPD. A total of 142 patients admitted to the Department of Respiratory Medicine at Anshun People's Hospital between December 2022 and August 2023 were selected for this study. The participants were divided into two groups: malnutrition group (n = 44) and non-malnutrition group (n = 98) based on a body mass index (BMI) < 18.5 kg/m2, according to the Global Leadership Initiative on Malnutrition (GLIM) criteria. Serum GDF15 levels were measured using the enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Spearman correlation analysis was used to examine the association between serum GDF15 levels, baseline data, and clinical indicators. Binary logistic regression was used to identify the independent risk factors for AECOPD combined with malnutrition. The predictive value of serum GDF15, albumin (ALB), and a combination of these was evaluated to identify malnutrition in patients with AECOPD using a receiver operating characteristic (ROC) curve. Serum GDF15 levels in patients with malnutrition and AECOPD were significantly higher than those in patients without malnutrition, whereas the serum ALB levels were significantly lower than those in patients without malnutrition (p < 0.001). Moreover, serum GDF15 levels were negatively correlated with BMI (r = -0.562, p < 0.001), mid-arm circumference (r = -0.505, p < 0.001), calf circumference (r = -0.490, p < 0.001), total protein (r = -0.486, p < 0.001), ALB (r = -0.445, p < 0.001), and prognostic nutritional index (r = -0.276, p = 0.001), and positively correlated with C-reactive protein (r = 0.318, p < 0.001), COPD assessment test score (r = 0.286, p = 0.001), modified medical research council classification (r = 0.310, p < 0.001), and global initiative for chronic obstructive pulmonary disease grade (r = 0.177, p = 0.035). Furthermore, serum GDF15 levels were an independent risk factor for malnutrition in patients with AECOPD (OR = 1.010, 95% CI, 1.003∼1.016). The optimal cut-off value of serum GDF15 level was 1,092.885 pg/mL, with a sensitivity of 65.90% and a specificity of 89.80%, while the serum ALB level was 36.15 g/L, with a sensitivity of 86.40% and a specificity of 65.00%, as well as a combined sensitivity of 84.10% and a specificity of 73.90%. Serum GDF15 and serum ALB levels had a good predictive ability (AUC = 0.856, AUC = 0.887), and the ROC revealed a greater combined prediction value for the two (AUC = 0.935). Serum GDF15 levels could be used as a potential biomarker in the prediction of malnutrition in patients with AECOPD, offering a guidance for future clinical evaluation of malnutrition.

Evaluation of the relation between subclinical systolic dysfunction defined by four-dimensional speckle-tracking echocardiography and growth differentiation factor-15 levels in patients with acromegaly.

In patients with acromegaly, the long-term presence of elevated GH and IGF-1 levels is associated with an unfavorable cardiovascular risk profile. We aimed to assess the relationship of four-dimensional speckle tracking echocardiographic (4DSTE) measurements with growth differentiation factor-15 (GDF-15) levels and the Framingham Cardiovascular Risk Score (FRS) in patients with acromegaly. A single-center, cross-sectional study was conducted. The study included 40 acromegaly and 32 age- and gender-matched controls. Anthropometric, biochemical, and echocardiographic assessments were performed. GDF-15 levels were measured using ELISA. In the controlled acromegaly group, global longitudinal (GLS), circumferential (GCS), area (GAS), and radial (GRS) strain measurements identified by 4DSTE were lower than those of the controls (p < 0.05). Moreover, strain parameters were lower in active acromegaly patients than in controls, but the difference was not statistically significant. The GLS was negatively correlated with age, the estimated disease duration, and FRS. Serum GDF-15 levels showed no significant difference between the acromegaly and control groups. In patients with acromegaly, serum GDF-15 levels were positively correlated with age, waist-to-hip ratio, systolic and diastolic blood pressure, FRS, fasting plasma glucose, and HbA1c, but not with strain parameters. The multiple regression analysis revealed that FRS was an independent factor associated with serum GDF-15 levels in patients with acromegaly and the overall cohort (p < 0.001). Our study demonstrates that while LVEF was within normal limits, global strain parameters (GLS, GCS, GAS, and GRS) measured by using a novel imaging technique, 4DSTE, were lower in patients with acromegaly, suggesting the presence of subclinical systolic dysfunction in patients with acromegaly. GDF-15 can be a potential predictor of cardiovascular risk in patients with acromegaly.

Serum Levels of Growth Differentiation Factor 15 as a Biomarker for Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus

Background: Growth Differentiation Factor 15 (GDF-15) has been identified as a biomarker of cellular stress conditions and has demonstrated functional implications in kidney disease, metabolic disorders, and diabetes. However, the relationship between GDF-15 and the coexistence of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) remains unclear. This study aims to investigate the association between GDF-15 levels and the presence of CKD in patients with T2DM, then analyze the cut off value. Method: A cross-sectional study was conducted, enrolling a total of 60 patients. T2DM patients were categorized into two groups based on the presence or absence of CKD. Serum GDF-15 levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Results: The study population (n=60) predominantly consisted of male individuals with an average age of 53 years. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.846 (95% CI = 0.748 – 0.945) with a statistically significant p-value of &lt; 0.001. The optimal cut-off value for serum GDF-15 to detect the presence of CKD was determined as 362.80 pg/mL, with corresponding sensitivity and specificity values of 77% and 79%, respectively. Furthermore, a significant association between GDF-15 levels and both T2DM without CKD and T2DM with CKD was observed (p &lt; 0.001). Conclusion: There is a significant association observed between serum GDF-15 levels in patients with type 2 diabetes mellitus (DM) and the presence of CKD. The cut of value GDF-15 to detect the presence of CKD was determined as 362.80 pg/mL with sensitivity and specificity values of 77% and 79%, this is can be considered as a potential biomarker for the detection of CKD in individuals with T2DM.

Serum GDF-15 Levels in Patients with Parkinson's Disease, Progressive Supranuclear Palsy, and Multiple System Atrophy.

Serum growth differentiation factor 15 (GDF-15) levels are elevated in patients with Parkinson's disease (PD) and may help differentiate these patients from healthy individuals. We aimed to clarify whether serum GDF-15 levels can help differentiate PD from atypical parkinsonian syndromes and determine the association between serum GDF-15 levels and clinical parameters. We prospectively enrolled 46, 15, and 12 patients with PD, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA), respectively. The serum GDF-15 level in patients with PD (1394.67 ± 558.46 pg/mL) did not differ significantly from that in patients with PSP (1491.27 ± 620.78 pg/mL; p = 0.573) but was significantly higher than that in patients with MSA (978.42 ± 334.66 pg/mL; p = 0.017). Serum GDF-15 levels were positively correlated with age in patients with PD (r = 0.458; p = 0.001); PSP (r = 0.565; p = 0.028); and MSA (r = 0.708; p = 0.010). After accounting for age differences, serum GDF-15 levels did not differ significantly between patients with PD and MSA (p = 0.114). Thus, age has a strong influence on serum GDF-15 levels, which may not differ significantly between patients with PD and atypical parkinsonian syndromes such as PSP and MSA.

Growth differentiation factor‑15 in patients with gestational diabetes mellitus and its relationship with microalbuminuria.

Gestational diabetes mellitus (GDM) is a common pregnancy-related complication and growth differentiation factor-15 (GDF-15) is involved in a number of diseases; therefore, the aim of the present study was to investigate the level and clinical significance of serum GDF-15 levels in patients with GDM. A total of 237 pregnant women at 20-24 weeks of gestation were selected and assigned to a normal pregnancy group (70 patients) and a GDM group (167 patients) according to the presence or absence of GDM. The general clinical data of the two groups were collected. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, glycated hemoglobin, fasting insulin, 24-h urinary albumin and serum GDF-15 levels were measured. The results showed that the body mass index (BMI) of the GDM group was higher than that of the normal pregnancy group. Fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose, fasting insulin, glycated hemoglobin and GDF-15 levels and the positive rate of microalbuminuria were significantly higher in the GDM group compared with the normal pregnancy group. GDF-15 levels were positively correlated with BMI, fasting plasma glucose, glycated hemoglobin, homeostasis model assessment-insulin resistance and fasting insulin levels. Logistic regression analysis suggested that elevated GDF-15 levels are an independent risk factor for microalbuminuria. In conclusion, serum GDF-15 levels are strongly associated with GDM and elevated GDF-15 levels are an independent risk factor for microalbuminuria. Serum GDF-15 may act as a novel biomarker for predicting microalbuminuria in GDM patients.

Effect of supervised exercise training on exercise capacity, pulmonary function and growth differentiation factor 15 levels in patients with interstitial lung disease: A preliminary study

BACKGROUND: Interstitial lung disease is characterized by exertion dyspnea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance and could be a possible biomarker in interstitial lung disease. OBJECTIVE: To evaluate the effect of supervised exercise (endurance and resistance) training (SET) on exercise capacity, pulmonary function parameters and GDF15 levels in patients with interstitial lung disease (PwILD). METHODS: In this non-randomized case-control trial, the experimental group comprised of 10 PwILD (7 women and 3 men) while the control group consisted of of 18 apparently healthy participants s 11 women and 7 men). All subjects completed an 8-week supervised exercise training program, at a rate of twice a week. Dyspnea was evaluated using the Shortness of Breath Respiratory Questionnaire. Exercise capacity was measured using the 6-min walk test while the heart rate (HR) was monitored before and after the exercise training. GDF15 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: PwILD had significantly shorter 6-min walk distance than the control subjects at both the 1st and the 15th visit. However, both groups improved significantly in this test. The change (pre to post-exercise) in HR value was smaller in PwILD compared to the controls. Moreover, PwILD had higher Shortness of Breath Respiratory Questionnaire score than controls. The mean pre and post GDF15 values in both groups remained statistically unchanged. However the GDF15 values of the PwILD patients were significantly higher compared to the controls with respect to pre and post exercise training respectively. CONCLUSION: Supervised exercise training did not affect GDF15 levels in both patient and control groups but its values in PwILD were significantly higher compared to those of controls (p⩽0.05). The exercise capacity and dyspnea in these patients improved after exercise training program.

Circulating growth differentiation factor-15 as a novel biomarker in heart transplant.

AimsThis study aimed to examine (i) whether circulating growth differentiation factor‐15 (GDF‐15) is associated with acute cellular cardiac allograft rejection (ACR); (ii) a longitudinal trend of GDF‐15 after heart transplantation; and (iii) the prognostic value of GDF‐15 in predicting a composite outcome of severe primary graft dysfunction (PGD) and 30 day mortality post‐transplant.Methods and resultsSerum samples were collected before heart transplantation and at every endomyocardial biopsy (EMB) post‐heart transplantation in de novo transplant patients. A total of 60 post‐transplant serum samples were matched to the corresponding EMBs. Seven (12%) were considered International Society for Heart Lung Transplantation Grade 1R ACR, and one (2%) was identified as Grade 2R ACR. GDF‐15 levels in patients with ACR were not different from those in the non‐rejection group (6230 vs. 6125 pg/mL, P = 0.27). GDF‐15 concentration gradually decreased from 8757 pg/mL pre‐transplant to 5203 pg/mL at 4 weeks post‐transplant. The composite adverse outcome of PGD and 30 day mortality was significantly associated with increased post‐operative GDF‐15 (odds ratio: 40; 95% confidence interval: 2.01–794.27; P = 0.005) and high inotrope score post‐transplant (odds ratio: 18; 95% confidence interval: 1.22–250.35; P = 0.01).ConclusionsCirculating GDF‐15 concentration was markedly elevated in patients with end‐stage heart failure and decreased after heart transplantation. GDF‐15 was significantly associated with post‐transplant PGD and mortality. A lack of association between ACR and GDF‐15 did not support routine use of GDF‐15 as a biomarker to detect ACR. However, GDF‐15 may be potentially useful to determine heart transplant recipients at high risk for adverse post‐transplant outcomes. We suggest that GDF‐15 levels in recipient serum can provide risk stratification for severe PGD including death during post‐operative period. This novel biomarker may serve to inform and guide timely interventions against severe PGD and adverse outcomes during the first 4 weeks after transplantation. Further studies to support the utility of GDF‐15 in heart transplantation are required.

Growth Differentiation Factor 15 Predicts Cancer Death in Patients With Cardiovascular Risk Factors: The J-HOP Study.

Background: Disease-related anorexia-cachexia is associated with poor prognosis of patients with cardiovascular disease (CVD) or cancer. Growth differentiation factor-15 (GDF-15) has emerged as a central regulator of appetite and body weight. However, the exact role of GDF-15 in lean patients has not been elucidated.Aim: Our aim is to evaluate whether the association of GDF-15 with mortality, including cancer death, differs according to body mass index (BMI) level.Methods and Results: We collected blood samples from 4,061 patients with CV risk factors who were enrolled in the nationwide practice-based J-HOP (Japan Morning Surge-Home Blood Pressure) study. Serum GDF-15 levels were determined by immunoassay analysis. During a mean follow-up period of 6.6 years, we observed 174 (6.7/1000 person-year) all-cause deaths, 68 (2.6/1000 person-year) cancer deaths, and 56 (2.2/1000 person-year) CV deaths. Patients were stratified according to the cut-points of GDF-15 at 1,200 ng/L and BMI at 22.5 and 25.0 kg/m2. The association between the GDF-15/BMI based study groups and each outcome was evaluated by Cox-proportional hazard models with adjustment for established risk factors. The multivariate Cox regression model showed that patients with elevated GDF-15 (≥1,200 ng/L) and low BMI (<22.5 kg/m2) were significantly associated with increased risk of all outcomes [all-cause death, hazard ratio (HR) 3.15, 95% confidence interval (CI) 1.85–5.34, p < 0.001; cancer death, HR 3.52, 95%CI 1.64–7.57, p = 0.001; CV death, HR 2.88, 95%CI 1.20–6.92, p = 0.018, respectively] compared to a reference group with non-elevated GDF-15 and normal BMI (22.5–25.0 kg/m2). In analyses of a subgroup with low BMI (<22.5 kg/m2), patients with elevated GDF-15 had 4.79-fold increased risk of cancer death and 11-fold greater risk of CV death when compared with patients with non-elevated GDF-15 (<1,200 ng/L) after adjustment for established risk factors.Conclusion: In patients with CV risk factors, GDF-15 was associated with all-cause, cancer, and CV death. This relationship was especially remarkable in patients with low BMI. The serum GDF-15 levels in patients with low BMI might be a useful marker to identify the potential for anorexia-cachexia associated with CVD and cancer.

Serum growth differentiation factor-15 (GDF-15) level in behcet's disease patients: Relation to clinical characteristics, musculoskeletal ultrasound findings and disease activity

Aim of the workThis study was conducted to assess serum level of growth differentiation factor-15(GDF-15) in Behcet’s disease (BD) patients and its relationship with clinical characteristics, ultrasound findings and disease activity. Patients and methodsStudy included 30 BD patients and 20 matched healthy controls. Visual analog scale (VAS)-pain of affected joints and Behcet’s disease current activity form (BDCAF) were assessed. The most affected joints and surrounding soft tissues were assessed by musculoskeletal ultrasound (MSUS).Serum GDF-15 level was measured. ResultsPatients were 23 males and 7 females (M:F 3.3:1) with a mean age of 34.6 ± 8.6 years and mean disease duration of 6.6 ± 4.5 years. 18(60%) had arthritis and arthralgia. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were 26.2 ± 21.2 mm/1sthr and 50.4 ± 37 mg/dl respectively. There was significant increase of GDF-15 levels in patients with articular affection (3492.3 ± 4618.8 ng/ml) compared to those without (338.9 ± 90.3 ng/ml) and controls (322 ± 78.8 ng/ml) (p < 0.001).As regard MSUS, knee (n = 8) and ankle joints (n = 8) were the most commonly affected joints. Synovitis was present in 13 patients, enthesopathy was present in 10. GDF-15 significantly correlated with ESR and CRP (r = 0.48;p = 0.008 and r = 0.73, p = 0.005) and both remained significant on regression analysis that ESR (p = 0.019 and p = 0.007 respectively). At a serum GDF-15 cut-off point of 570 ng/ml for patients with peripheral arthritis/arthralgia the sensitivity and specificity were 88.9% and 91.7% respectively. ConclusionSerum GDF-15 can be used as a marker for articular affection in BD patients and is associated with the MSUS imaging visualizing subclinical inflammatory changes.

GDF-15 and neutrophils in patients with heart failure and type 2 diabetes mellitus

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was funded by (subject of fundamental scientific research on a state assignment № АААА-А17-117052310073-6 от 23.05.2017 Introduction. Growth differentiation factor-15 (GDF-15) is a biomarker associated with inflammatory processes in the pathogenesis of chronic heart failure (CHF) which expresses in cardiomyocytes under pathological conditions. The relationship between the level of GDF-15 and type 2 diabetes mellitus (T2DM) has also been proven. It is necessary to study GDF-15 in patients with CHF and T2DM. Aim To investigate the association between serum GDF-15 levels in patients with CHF of ischemic etiology and the concentration of the main leukocyte fractions depending on presence or absence of T2DM. Material and methods. The study included 42 patients. The patients were divided into 2 groups. The first group consisted of patients with CHF and T2DM (n = 14). The second group consisted of patients with CHF without T2DM (n = 28). Determination of GDF-15 concentration was carried out by enzyme-linked immunosorbent assay (BioVendor, Czech Republic). The absolute concentration of lymphocytes, neutrophils, as well as the ratio of neutrophils to lymphocytes in the blood were analyzed. Statistical analysis was performed using the Statistica software (v.10.0). The data were described as a median and interquartile range, the Mann-Whitney test was used to compare them. The correlation analysis was tested using the Spearman"s correlation coefficient. Results and discussion. The average level of the GDF-15 in the study groups was comparable: 2389 (2104; 3375) pg/ml and 2309 (2047; 3014) pg/ml in the first and second groups, respectively (p = 0.6). In the general cohort of CHF patients, the GDF-15 concentration was not correlate with the lymphocytes concentration (r = -0.001, p = 0.95), neutrophils (r = -0.14, p = 0.4) and the ratio of neutrophils to lymphocytes (r = -0.12, p = 0.25). At the same time, in the group of patients with T2DM, a significant negative correlation was revealed between the concentration of GDF-15 in the serum and the concentration of neutrophils (r = -0.6, p = 0.022). While both other analyzed parameters did not demonstrate significant correlations with GDF-15 (p &amp;gt; 0.05). In the group of CHF patients without T2DM, no correlations were found between GDF-15 and the studied parameters, including neutrophils (r = 0.02, p = 0.3). Along with this the median of the neutrophils concentration did not vary among groups (3.5 (2.3; 5.3) vs 3.2 (2.7; 4.1) * 109 / l; p = 0.8). Conclusion The concentration of the inflammatory marker GDF-15 in the blood of patients with CHF in combination with T2DM correlates with the concentration of neutrophils. In the absence of T2DM, no significant correlations were found between GDF-15 and the main leukocyte fractions. The results obtained indicate the possible prospect of using the GDF-15 biomarker in a cohort of patients with CHF in combination with T2DM.

Plasma growth differentiation factor 15: a novel tool to detect early changes of hereditary transthyretin amyloidosis.

AimsHereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease‐modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF‐15) levels could aid detection of early pathological changes in ATTRv amyloidosis.Methods and resultsWe retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF‐15 levels in these subjects as related to levels of brain natriuretic peptide and high‐sensitivity troponin T, echocardiographic features, 99mTc‐pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF‐15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P < 0.01). Plasma GDF‐15 levels were significantly correlated with plasma brain natriuretic peptide values (P < 0.01), serum high‐sensitivity troponin T values (P < 0.05), and interventricular septal thickness at end‐diastole (P < 0.01) in patients with ATTRv amyloidosis. Plasma GDF‐15 levels in patients with PYP‐positive ATTRv amyloidosis were significantly higher than those in patients with PYP‐negative ATTRv amyloidosis (P < 0.01). Plasma GDF‐15 levels in patients with late gadolinium enhancement‐positive ATTRv amyloidosis were significantly higher than those in patients with late gadolinium enhancement‐negative ATTRv amyloidosis (P < 0.01). Groups of patients with different TTR genotypes manifested different plasma GDF‐15 levels.ConclusionsGrowth differentiation factor 15 may reflect early pathological changes of ATTRv amyloidosis.

The value of growth differentiation factor-15 and extravascular lung water index in severity grading of acute respiratory distress syndrome patients and their prognosis prediction

To investigate the value of growth differentiation factor-15 (GDF-15) and extravascular lung water index (EVLWI) in severity grading and prognosis prediction of patients with acute respiratory distress syndrome (ARDS). Patients with ARDS aged 18-75 years admitted to the department of respiratory intensive care unit (RICU) of Zhengzhou Central Hospital Affiliated to Zhengzhou University from January 2019 to February 2020 were enrolled. All patients were treated with conventional therapies such as mechanical ventilation, anti-infection, stabilization of water, electrolytes and acid-base environment, blood purification and nutritional support according to their conditions. Besides, the pulse-indicated continuous cardiac output (PiCCO) was performed after admission to the department, and EVLWI before treatment and at 24, 48 and 72 hours of treatment were recorded. Serum GDF-15 level was measured by enzyme linked immunosorbent assay (ELISA) during the same period. Patients were classified as mild, moderate, and severe degree according to the 2012 Berlin Definition of ARDS, and EVLWI and GDF-15 levels in patients with different disease levels before and after treatment were compared. In addition, the length of intensive care unit (ICU) stay, ICU mortality, and 28-day mortality of patients with different GDF-15 or EVLWI levels were analyzed comparatively, with the GDF-15 3 458 ng/L and EVLWI 15 mL/kg as the cut point. A total of 82 patients with ARDS were enrolled, including 22 patients with mild ARDS, 28 patients with moderate ARDS, and 32 patients with severe ARDS. The GDF-15 and EVLWI levels in patients with moderate and severe ARDS at each time point before and after treatment were higher than those in patients with mild ARDS. Both GDF-15 and EVLWI levels in patients with severe ARDS were higher than those in the patients with moderate ARDS. The differences were statistically significant at all the time points except for the difference of GDF-15 levels at 24 hours after treatment (ng/L: 3 900.41±546.43 vs. 3 695.66±604.73, P > 0.05). [GDF-15 (ng/L): 3 786.11±441.45 vs. 3 106.83±605.09 before treatment, 3 895.48±558.96 vs. 3 333.29±559.66 at 48 hours, 3 397.33±539.56 vs. 3 047.53±499.57 at 72 hours; EVLWI (mL/kg): 19.06±1.91 vs. 14.31±1.50 before treatment, 18.56±2.23 vs. 13.26±1.69 at 24 hours, 17.23±1.76 vs. 12.45±1.36 at 48 hours, 15.47±1.81 vs. 11.13±2.19 at 72 hours, all P < 0.05]. According to the cut-off value, there were 23 patients with GDF-15 ≥ 3 458 ng/L and GDF-15 < 3 458 ng/L respectively and there were 23 patients with EVLWI ≥ 15 mL/kg and EVLWI < 15 mL/kg respectively. The length of ICU stay and 28-day mortality in patients with high GDF-15 were significantly higher than those in patients with low GDF-15 [length of ICU stay (days): 21.22±2.69 vs. 15.37±3.14, 28-day mortality: 56.5% vs. 21.7%, both P < 0.05]. The length of ICU stay and 28-day mortality in patients with high EVLWI were also significantly higher than those in patients with low EVLWI [length of ICU stay (days): 18.45±2.61 vs. 14.98±2.75, 28-day mortality: 47.8% vs. 17.4%, both P < 0.05]. To some extent, GDF-15 and EVLWI levels reflect the severity of patients with ARDS, and high GDF-15 and EVLWI levels are significantly associated with poor prognosis in patients with ARDS.

Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions.

Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins. In this study, we aimed to validate the diagnostic reliability of FGF21 and GDF15 assays in MDs and to evaluate a possible correlation between serum levels of the two biomarkers with genotype of MD patients. Serum FGF21 and GDF15 levels were measured by a quantitative ELISA. Our results showed increased serum FGF21 and GDF15 levels in MD patients; however, GDF15 measurement seems to be more sensitive and specific for screening tests for MD than FGF21. Moreover, we showed a positive correlation with both FGF21 and GDF15 levels and the number of COX-negative fibers. Finally, we also demonstrated that the increase of FGF21 and GDF15 was related to MDs caused by mitochondrial translation defects, and multiple and single mtDNA deletions, but not to MDs due to mutations in the respiratory chain subunits.

Comment on "Research on values of GDF-15 level in the diagnosis of primary liver cancer and evaluation of chemotherapeutic effect".

Objective To investigate the values of growth differentiation factor-15 (GDF-15) level in the diagnosis of primary liver cancer and evaluation of chemotherapeutic effect. Patients and methods 92 patients with liver cancer treated from June 2015 to May 2016 were selected as liver cancer group; 53 patients with benign liver lesion were selected as benign liver disease group, and 40 healthy subjects receiving physical examination were selected as healthy control group. Fasting venous blood was drawn from objects of study in the early morning at 1 d after admission and at the last day after chemotherapy (liver cancer group), and the serum GDF-15 level was measured. Results The serum GDF-15 levels in patients in liver cancer group and benign liver disease group were significantly higher than those in healthy control group and benign liver disease group (p 0.05). The ROC curve analysis showed that the threshold value of GDF-15 was 1573.23 ng/L, and the sensitivity, specificity, and accuracy were 81.23%, 83.99%, and 83.62%, respectively. The serum GDF-15 level in patients with progressive disease was significantly higher than those in patients with partial remission and stable disease, and the serum GDF-15 level in patients with stable disease was significantly higher than that in patients with partial remission (p Conclusions The serum GDF-15 level has certain clinical values in the diagnosis of primary liver cancer and evaluation of chemotherapeutic effect.

Research on values of GDF-15 level in the diagnosis of primary liver cancer and evaluation of chemotherapeutic effect.

To investigate the values of growth differentiation factor-15 (GDF-15) level in the diagnosis of primary liver cancer and evaluation of chemotherapeutic effect. 92 patients with liver cancer treated from June 2015 to May 2016 were selected as liver cancer group; 53 patients with benign liver lesion were selected as benign liver disease group, and 40 healthy subjects receiving physical examination were selected as healthy control group. Fasting venous blood was drawn from objects of study in the early morning at 1 d after admission and at the last day after chemotherapy (liver cancer group), and the serum GDF-15 level was measured. The serum GDF-15 levels in patients in liver cancer group and benign liver disease group were significantly higher than those in healthy control group and benign liver disease group (p<0.05). The serum GDF-15 levels in patients with stage III and IV liver cancer were significantly higher than those in patients with stage I and II liver cancer, and the serum GDF-15 level in patients with stage IV liver cancer was significantly higher than that in patients with stage III liver cancer (p<0.05). There was no significant difference in serum GDF-15 level among patients with different clinical data (p>0.05). The ROC curve analysis showed that the threshold value of GDF-15 was 1573.23 ng/L, and the sensitivity, specificity, and accuracy were 81.23%, 83.99%, and 83.62%, respectively. The serum GDF-15 level in patients with progressive disease was significantly higher than those in patients with partial remission and stable disease, and the serum GDF-15 level in patients with stable disease was significantly higher than that in patients with partial remission (p<0.05). The serum GDF-15 level has certain clinical values in the diagnosis of primary liver cancer and evaluation of chemotherapeutic effect.

Growth differentiation factor 15 (GDF15) is a prognosis biomarker of sequelae handicap after the occurrence of an ischemic stroke

Growth differentiation factor-15 (GDF15) is considered a poor prognosis biomarker in many cardiovascular pathological situations; however, its interest in the field of neurovascular disease such as ischemic stroke has been poorly explored so far. Our work consisted of evaluating GDF15 levels in patients hospitalized in the acute phase of ischemic stroke, who received a revascularization treatment either by fibrinolysis or thrombectomy. The main objective of our study was to evaluate the association between plasma levels of GDF15 and functional recovery at 3 months. In total, 174 patients were included between January 15th and September 30th 2017 in the University Hospital of Dijon. Biological samples were taken at the patient admission (D0) and at D1, D3 and D7. Patients were contacted by phone at 3 months in order to evaluate the Rankin score (functional disability). GDF15 plasma levels were measured by an ELISA method. In all patients, the GDF15 plasma levels at D0, D1, D3 and D7 were significantly higher in patients with a sequelae handicap (Rankin score ≥ 2) compared to patients without disabilities (Rankin score to 0 or 1). In a univariate logistic regression analysis, we found a significant increase in the odds ratio (OR) of the risk of having a Rankin score ≥ 2 with a GDF15 plasma level found in the last tertile. In addition, GDF15 levels were significantly higher in patients treated with thrombectomy than with fibrinolysis. Therefore, GDF15 appears as a relevant biomarker of poor prognosis and of sequelae handicap after ischemic stroke. Plasma levels of GDF15 being most important in patients with thrombectomy than with fibrinolysis, they may reflect the difference of the initial clinical severity, related to an occlusion of a proximal artery. Finally, after thrombectomy, GDF15 decrease could signal effective recanalization of the occluded artery.

Growth Differentiation Factor-15 (GDF-15) Is a New Biomarker with Independent Prognostic Significance for Survival and Renal Outcomes in Different Cohorts of Patients with Light Chain (AL) Amyloidosis

Growth differentiation factor-15 (GDF-15), a member of TGF-beta family, is involved in several pathological conditions, which include inflammation, cancer, cardiovascular, pulmonary and renal diseases. Serum GDF-15 levels add prognostic information to conventional prognostic factors, such as NT-proBNP and troponins, in cardiovascular disorders and also have shown to be associated with renal damage and risk of end stage renal disease in patients with diabetes. Based on the above data, we evaluated the prognostic value of GDF-15 levels in patients with AL amyloidosis and showed that in a cohort of 77 patients GDF-15 was associated with early death, shorter survival and progression to dialysis, independently of the cardiac biomarkers and renal stage. In order to validate the prognostic value of serum levels of GDF-15, we evaluated GDF-15 in two independent cohorts of patients treated in two different centers (Pavia Amyloidosis Center and Department of Clinical Therapeutics, Athens).Circulating levels of GDF-15 were measured by a novel pre-commercial immunoassay (Roche Diagnostics) in stored serum. The Pavia cohort included 202 and the Athens cohort included 107 patients with AL amyloidosis. Standard criteria were used for the diagnosis, evaluation of organ involvement and cardiobiomarker-based risk stratification. Renal staging was based on the system proposed by Palladini et al, based on baseline proteinuria >5 gr/day and eGFR <50 ml/min.Median age and involved FC (iFLC) levels were similar between the two cohorts but there were differences in other baseline characteristics including heart involvement (77% vs 62% for Pavia vs Athens, p=0.007), Mayo stage (15%, 43% & 42% for stage 1, 2 & 3 in Pavia cohort, vs 26%, 43% & 31% in Athens cohort, p=0.04, but stage 3B was similar, 22% vs 24%). Also there were differences in peripheral nerve involvement (11% in Pavia vs 25% in Athens cohort, p=0.001). Renal involvement (67% vs 72%, p=0.415), median eGFR and renal stage distribution were similar between the two cohorts (p=0.544). Median follow up for the Pavia cohort was 18 months and for the Athens cohort was 45 months (p<0.001). Survival at 2 years was 59% for Pavia and 56% for Athens cohort.Median GDF-15 levels was 3027 pg/ml in Pavia (range 624 to >100000 pg/ml) and 3854 pg/ml (range 626-71475 pg/ml) in Athens cohort (p=0.09); the upper quartile of GDF-15 levels however was ≥5658 pg/ml for the Pavia and ≥7553 pg/ml for Athens cohort, while 90% and 94% of patients in the two cohorts had GDF-15 levels >1200 pg/ml (the upper limit of normal for individuals without cardiovascular disease).We then evaluated the prognostic significance of GDF-15 levels in the two cohorts by applying the previously identified cutoff of 7575 pg/ml. GDF-15 above cutoff was associated with significantly shorter survival both in Pavia (17 months vs not reached, p=0.003) and in Athens cohort (13 vs 47 months, p=0.03) (Figure 1). A multivariate model that included Mayo stage, separately for each cohort was applied. In both cohorts GDF-15 retained independent prognostic significance over Mayo stage, having a hazard ratio (HR) of 1.9 (95% CI 1.2-3.3, p=0.01) in Pavia cohort (the respective HRs for Mayo stage -2 vs -1 was 2.1 and for stage -3 vs stage -1 was 4); in Athens cohort HR for GDF-15 was 1.8 (95% CI 1.2-3.6, p=0.03) and the respective HRs for Mayo stage -2 vs -1 was 5.3 and for stage 3- vs stage -1 was 6.8.We then evaluated the prognostic significance regarding renal outcomes (dialysis): GDF-15 >4000 pg/ml was associated with a HR of 6 (95% CI 2015.6, p=0.001) in Athens cohort (progression to dialysis within 2 years in 7% vs 47%); however, very few events have occurred in Pavia cohort and analysis was inconclusive. Although renal stage discriminated 3 groups in univariate analysis (p=0.03), in multivariate analysis, GDF-15 >4000 pg/ml outperformed renal stage and was the only independent prognostic factor for dialysis risk.In conclusion, our study validated and confirmed in two independent cohorts, with differences in their characteristics, the prognostic value of GDF-15, which emerges as a novel biomarker with prognostic implications for different outcomes in patients with AL amyloidosis. Importantly, GDF-15 emerges also as new biomarkers for renal outcomes in patients with AL amyloidosis. [Display omitted] [Display omitted] DisclosuresKastritis:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria. Merlini:Takeda and Janssen-Cilag: Honoraria. Terpos:Genesis: Consultancy, Honoraria, Other: Travel expenses; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palladini:Prothena: Honoraria.