Serum Growth Differentiation Factor 15 Research Articles

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.

Growth differentiation factor-15 serum concentrations reflect disease severity and anemia in patients with inflammatory bowel disease.

Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality. Growth-differentiation factor-15 (GDF-15) is often over-expressed under stress conditions, such as inflammation, malignancies, heart failure, myocardial ischemia, and many others. To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases. An additional aim was to determine possible associations between GDF-15 and multiple clinical, anthropometric and laboratory parameters in patients with IBD. This cross-sectional study included 90 adult patients diagnosed with IBD, encompassing both Crohn's disease (CD) and ulcerative colitis (UC), and 67 healthy age- and sex-matched controls. All patients underwent an extensive workup, including colonoscopy with subsequent histopathological analysis. Disease activity was assessed by two independent gastroenterology consultants specialized in IBD, employing well-established clinical and endoscopic scoring systems. GDF-15 serum concentrations were determined following an overnight fasting, using electrochemiluminescence immunoassay. In patients with IBD, serum GDF-15 concentrations were significantly higher in comparison to the healthy controls [800 (512-1154) pg/mL vs 412 (407-424) pg/mL, P < 0.001], whereas no difference in GDF-15 was found between patients with CD and UC [807 (554-1451) pg/mL vs 790 (509-956) pg/mL, P = 0.324]. Moreover, multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age, sex, and C-reactive protein levels (P = 0.016 and P = 0.049, respectively). Finally, an association between GDF-15 and indices of anemia was established. Specifically, negative correlations were found between GDF-15 and serum iron levels (r = -0.248, P = 0.021), as well as GDF-15 and hemoglobin (r = -0.351, P = 0.021). Accordingly, in comparison to IBD patients with normal hemoglobin levels, GDF-15 serum levels were higher in patients with anemia (1256 (502-2100) pg/mL vs 444 (412-795) pg/mL, P < 0.001). For the first time, we demonstrated that serum concentrations of GDF-15 are elevated in patients with IBD in comparison to healthy controls, and the results imply that GDF-15 might be involved in IBD pathophysiology. Yet, it remains elusive whether GDF-15 could serve as a prognostic indicator in these patients.

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.

[Correlation between serum growth differentiation factor 11 level and severity of coronary artery disease in patients with acute myocardial infarction].

Objective: To investigate the correlation between serum growth differentiation factor 11 (GDF11) level and coronary artery lesions in patients with ST-segment elevation myocardial infarction (STEMI), and the predictive efficacy of nomogram risk prediction model based on GDF11 combined with traditional risk factors on the occurrence of STEMI. Methods: This study was a retrospective cross-sectional study. Patients hospitalized in the Department of Cardiology of the 904th Hospital of Joint Logistic Support Force of People's Liberation Army of China from 2016 to 2018 were selected and divided into control group and STEMI group. The demographic data, blood lipid level, laboratory indicators of blood and GDF11 level were collected. Logistic regression analysis screened out independent correlated factors for the occurrence of STEMI. Spearman correlation analysis clarified the correlation of each indicator with the SYNTAX or Gensini scores. A nomogram risk prediction model for the risk of STEMI occurrence and the receiver operating characteristic curve was used to compare the prediction efficiency of each model. Results: A total of 367 patients were enrolled, divided into control group (n=172) and STEMI group (n=195), age (66.5±11.8), male 222 (60.49%). The serum GDF11 level of STEMI group was significantly lower than that of the control group (36.20 (16.60, 70.75) μg/L vs. 85.00 (53.93, 117.10) μg/L, P<0.001). The results of multivariate logistic regression analysis showed serum GDF11(OR=0.98, 95%CI: 0.97-0.99) and traditional independent risk factors such as smoking, diabetes, C-reactive protein, homocysteine, lipoprotein (a) and apolipoprotein A1/B were independent correlate factors for the occurrence of STEMI (P<0.05). Spearman correlation analysis showed that serum GDF11 was negatively correlated with SYNTAX score and Gensini score (P<0.05). The nomogram model constructed by serum GDF11 combined with traditional independent risk factors (AUC=0.85, 95%CI: 0.81-0.89) had better predictive value for the occurrence of STEMI than the traditional nomogram model constructed by independent risk factors(AUC=0.80, 95%CI:0.75-0.84) or serum GDF11 (AUC=0.76, 95%CI: 0.72-0.81), all P<0.01. Conclusions: Serum GDF11 is an independent correlate factor in the occurrence of STEMI and is negatively correlated with the severity of coronary artery lesions in patients with STEMI. The nomogram model constructed based on GDF11 combined with traditional risk factors can be a good predictor for the occurrence of STEMI.

GDF11 level and its effect on prognosis in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the proliferation of CD34 positive self-renewing malignant hematopoietic stem cells. Previous studies have shown that the transforming growth factor beta (TGFβ) pathway plays a role in AML pathogenesis, especially by affecting the microenvironment. Growth differentiation factor 11 (GDF11) is a member of the TGFβ superfamily, involved in embryological development and known as rejuvenating factor. In this study, our aim was to determine the serum GDF11 level in patients with AML, to compare it with the control group, to determine its relationship with follistatin, vimentin, and E-cadherin levels, and to determine whether GDF11 influences AML prognosis. Serum GDF11, vimentin, follistatin, and E-cadherin levels of newly diagnosed or relapsed/refractory AML patients and age- and gender-matched control group were measured by enzyme-linked immunosorbent assay. Serum GDF11 level was higher in the patient group (263.87 ± 126.54 ng/L) compared to the control group (211.54 ± 61.47 ng/L; p = 0.035). GDF11 level did not change according to age, gender, hemoglobin level, and bone marrow blast rate. No correlation was found between GDF11 level, response rates, and survival status of the patients. A positive correlation was detected between GDF11, E-cadherin, and vimentin levels. As a conclusion, increased serum GDF11 levels in AML patients may be linked to the regeneration ability of leukemic stem cells. There is a need for studies investigating GDF11 expression in myeloblasts.

Serum biomarkers associated with liver fibrosis in patients with type 2 diabetes

BACKGROUND: The diagnosis of liver fibrosis is an important task in the management of patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The currently used diagnostic methods have a number of disadvantages such as invasiveness and high cost, or insufficient sensitivity and specificity. Therefore, the search for new non-invasive markers of liver fibrosis remains an actual challenge.AIM: To assess a diagnostic value of serum growth differentiation factor-15 (GDF-15), microfibril-associated glycoprotein 4 (MFAP-4), collagen type IV alpha1 (COL4alpha1), Mac-2 binding protein (M2BPGI) and chitinase-3-like protein 1 (YKL-40) as markers of liver fibrosis in patients with type 2 diabetes and NAFLD.MATERIALS AND METHODS: A single center cross-sectional observational study was performed. The study included 74 patients, 23 men and 51 women, aged 18 to 74 years. Liver elastography was used as reference method for the fibrosis evaluation. APRI and fib-4, non-invasive fibrosis indices, were assessed. Serum concentrations of GDF-15, MFAP-4, COL4alpha1, M2BPGI, and YKL-40 were determined by ELISA. ROC analysis was used to evaluate the sensitivity and specificity of serum markers for the diagnosis of the liver fibrosis.RESULTS: Liver fibrosis stage 1 was verified in 16 subjects, stage 2 in 12, stage 3 in 7, and stage 4 in 19. Patients with advanced liver fibrosis (stages 3–4), compared with those without severe fibrosis (stages 0–2), had higher levels of GDF-15 (p=0.003), COL4alpha1 (p=0.007), and YKL-40 (p=0.04). Patients with stage 1-2 liver fibrosis had higher levels of COL4alpha compared to those without any signs of fibrosis (p=0.02). There were no significant differences in the level of MFAP-4 and M2BPGI between patients with different severity of fibrosis. According to the ROC analysis, GDF-15, COL4alpha1 and YKL-40 have diagnostic value in the detection of severe liver fibrosis comparable to that of the APRI and fib-4 indices.CONCLUSION: GDF-15, COL4alpha1 and YKL-40 could be considered as promising non-invasive markers of liver fibrosis in patients with type 2 diabetes and NAFLD.

Serum Growth Differentiation Factor 15 Levels Predict the Incidence of Frailty among Patients with Cardiometabolic Diseases

Introduction: Frailty is a crucial health issue among older adults. Growth differentiation factor 15 (GDF15) is associated with inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction, which are possible pathogeneses of frailty. However, few longitudinal studies have investigated the association between GDF15 and the incidence of frailty. Therefore, we investigated whether high serum GDF15 levels are associated with the incidence of frailty. Methods: A total of 175 older adults (mean age: 77 ± 6 years; 63% women) with cardiometabolic diseases and no frailty out of the two criteria at baseline participated. Individuals with severe renal impairment or severe cognitive impairment were excluded. Serum GDF15 levels were measured at baseline. Patients were asked to assess frailty status at baseline and annually during follow-up using the modified version of the Cardiovascular Health Study (mCHS) and the Kihon Checklist (KCL). We examined the association between GDF15 tertiles and each frailty measure during follow-up (median 38–39 months). In the multivariate Cox regression analysis, with the GDF15 tertile groups as the explanatory variables, hazard ratios (HRs) and 95% confidence intervals (CIs) for incident frailty were calculated after adjusting for covariates and using the lowest tertile group as the reference. Results: During the follow-up period, 25.6% and 34.0% of patients developed frailty, as defined by the mCHS and KCL, respectively. The highest GDF15 tertile group had a significantly higher incidence of mCHS- or KCL-defined frailty than the lowest GDF15 tertile group. Multivariate Cox regression analysis revealed that the adjusted HRs for incident mCHS- and KCL-defined frailty in the highest GDF15 tertile group were 3.9 (95% CI: 1.3–12.0) and 2.7 (95% CI: 1.1–6.9), respectively. Conclusion: High serum GDF15 levels predicted the incidence of frailty among older adults with cardiometabolic diseases and could be an effective marker of the risk for frailty in interventions aimed at preventing frailty, such as exercise and nutrition.

Growth Differentiation Factor 15 and Diet Quality Trajectory Interact to Determine Frailty Incidence among Middle-Aged Urban Adults

BackgroundElevated plasma growth differentiation factor 15 (GDF15) and poor diet quality may be associated with increased frailty incidence, although their interactive associations have not been assessed in urban middle-aged adults. ObjectivesWe aimed to examine GDF15 and its interactive association with diet quality in relation to frailty incidence among a sample of middle-aged urban adults. MethodsThe relationship between GDF15 and diet quality trajectories in relation to incident frailty was examined in a longitudinal study of participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (2004–2017). Serum GDF15 concentration and frailty incidence were primary exposure and outcome, respectively. Group-based trajectory models were used to assess diet quality trajectories (≤3 visits/participant, N = 945, N′ = 2247 observations) using the Healthy Eating Index 2010 version (HEI-2010), Dietary Inflammatory Index, and mean adequacy ratio (MAR). Cox proportional hazards models were used, testing interactive associations of GDF15 and diet quality trajectories with frail/prefrail incidence (N = 400 frailty-free at first visit, N′ = 604 observations, n = 168 incident frail/prefrail). ResultsBoth elevated GDF15 and lower diet quality trajectories were associated with a lower probability of remaining nonfrail (≤13 y follow-up). Among females, the “high diet quality” HEI-2010 trajectory had a hazard ratio (HR) of 0.15 [95% confidence interval (CI): 0.04, 0.54; P = 0.004; fully adjusted model] when compared with the “low diet quality” trajectory group. Among males only, there was an antagonistic interaction between lower HEI-2010 trajectory and elevated GDF15. Specifically, the HR for GDF15-frailty in the higher diet quality trajectory group (high/medium combined), and among males, was 2.69 (95% CI: 1.06, 6.62; P = 0.032), whereas among the lower diet quality trajectory group, the HR was 0.94 (95% CI: 0.49, 1.80; P = 0.86). Elevated GDF15 was independently associated with frailty among African American adults. ConclusionsPending replication, we found an antagonistic interaction between GDF15 and HEI-2010 trajectory in relation to frailty incidence among males.

The Relationship Between Serum Growth Differentiation Factor-15 (GDF-15) Levels and Clinical Outcomes in Infertile Women Receiving In-vitro Fertilization Treatment

Objective: It has been reported in many studies that Growth Differentiation Factor-15 (GDF-15) has an important role in physiological or pathological processes. As there is no study in the current scientific literature examining the status of GDF-15 in infertility and its treatment outcomes, we aimed to investigate this.&#x0D; Material and methods: According to their ovarian reserve characteristics, 88 infertile women were divided into three groups: normal ovarian reserve (NOR), diminished ovarian reserve (DOR), and polycystic ovary syndrome (PCOS). Estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), and GDF-15 levels were measured in their serum. The antagonist protocol patients' total oocyte, meiosis II (MII) oocytes, embryo count, and clinical pregnancy rates were documented.&#x0D; Results: In terms of serum GDF-15 concentrations, there was no statistically significant difference among the mean values of the three study groups. The mean FSH level at baseline was substantially higher in the DOR group compared to the PCOS group. The median serum AMH levels of all three groups were found to be statistically different. The antagonist protocol patients' total oocytes, meiosis II (MII) oocytes, embryo count, and clinical pregnancy rates were documented.&#x0D; Conclusion: In the present study, a significant and strong correlation between serum GDF-15 level and consequent embryo number was detected. Thereby, serum GDF-15 level may be considered to be a biomarker for predicting IVF clinical outcomes.

Association between Serum GDF-15 and Cognitive Dysfunction in Hemodialysis Patients.

Cognitive dysfunction is more frequent in end-stage renal disease (ESRD) patients undergoing hemodialysis compared with the healthy population, emphasizing the need for early detection. Interest in serum markers that reflect cognitive function has recently increased. Elevated serum growth differentiation factor 15 (GDF-15) levels are known to be associated with an increased risk of decreased renal function and cognitive dysfunction. This study investigated the relationship between GDF-15 and cognitive dysfunction in hemodialysis patients using a retrospective analysis of 92 individuals aged ≥ 18 years. Cognitive function was assessed using the Korean version of the Mini-Mental Status Examination (K-MMSE), categorizing patients into normal (≥24 points) and cognitive dysfunction (<24 points). As a result, serum GDF-15 concentrations were at significantly higher levels in the cognitive dysfunction group (7500.42 pg/mL, p = 0.001). Logistic regression indicated an increased risk of K-MMSE scores < 24 points when serum GDF-15 exceeded 5408.33 pg/mL. After indoxyl sulfate exposure in HT22 cells, HT22 cells survival was decreased and GDF-15 expression in HT22 cells was increased. Similarly, exposure to indoxyl sulfate in mouse brain tissue resulted in an increased expression of GDF-15. This study highlights the potential of serum GDF-15 as a marker for cognitive dysfunction in hemodialysis patients, offering a valuable screening tool. Serum GDF-15 is related to cognitive dysfunction in hemodialysis patients and may be helpful in screening for cognitive dysfunction in hemodialysis patients.

Candesartan protects from cisplatin-induced kidney damage via the GDF-15 pathway.

The aim of this study was to explore the protective effect of candesartan against cisplatin-induced kidney damage, with a specific focus on the growth differentiation factor 15 (GDF-15) pathway. 24 adult female Wistar rats, with a weight range of 200-210 grams, were enrolled in the study. Eight rats were included as a normal control group and did not receive any medication. 16 rats were administered cisplatin at a dosage of 2.5 mg/kg/day twice a week for 4 weeks (total dose 20 mg/kg). Then, they were randomly divided into two groups and treated with 1 ml/kg/day tap water or 8 mg/kg/day candesartan via oral gavage daily for 4 weeks. At the end of the treatment period, animals were sacrificed, and their kidneys were assessed histologically. In addition, plasma malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), creatinine, and GDF-15 levels were assessed. Treatment with candesartan resulted in a significant rise in serum GDF-15 levels and a significant reduction in levels of serum MDA, TNF-α, IL-6, and creatinine compared to the cisplatin and saline group. Candesartan treatment effectively protected the kidney injury, and histopathological examinations of the kidneys confirmed these results. This study demonstrates that candesartan alleviates cisplatin-induced renal toxicity by further increasing GDF-15, downregulating inflammatory markers, and reducing oxidative stress.

Acute Exercise Increases GDF15 and Unfolded Protein Response/Integrated Stress Response in Muscle in Type 2 diabetes.

Regular exercise is a key prevention strategy for obesity and type 2 diabetes (T2D). Exerkines secreted in response to exercise or recovery may contribute to improved systemic metabolism. Conversely, an impaired exerkine response to exercise and recovery may contribute to cardiometabolic diseases. We investigated if the exercise-induced regulation of the exerkine, growth/differentiation factor 15 (GDF15) and its putative upstream regulators of the unfolded protein response (UPR)/integrated stress response (ISR) is impaired in skeletal muscle in patients with T2D compared with weight-matched glucose-tolerant men. Thirteen male patients with T2D and 14 age- and weight-matched overweight/obese glucose-tolerant men exercised at 70% of VO2max for 1-h. Blood and skeletal muscle biopsies were sampled before, immediately after, and 3-h into recovery. Serum and muscle transcript levels of GDF15 and key markers of UPR/ISR were determined. Additionally, protein/phosphorylation levels of key regulators in UPR/ISR were investigated. Acute exercise increased muscle gene expression and serum GDF15 levels in both groups. In recovery, muscle expression of GDF15 decreased toward baseline, whereas serum GDF15 remained elevated. In both groups, acute exercise increased the expression of UPR/ISR markers, including ATF4, CHOP, EIF2K3 (encoding PERK) and PPP1R15A (encoding GADD34), of which only CHOP remained elevated 3-h into recovery. Downstream molecules of the UPR/ISR including XBP1-U, XBP1-S, and EDEM1 were increased with exercise and 3-h into recovery in both groups. The phosphorylation levels of eIF2α-Ser51, a common marker of UPR and ISR, increased immediately after exercise in controls, but decreased 3-h into recovery in both groups. In conclusion, exercise-induced regulation of GDF15 and key markers of UPR/ISR are not compromised in patients with type 2 diabetes compared with weight-matched controls.

A method of quantitative chemiluminescence immunoassay for the concentration of Growth differentiation factor-15

Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor (TGF-β) superfamily, and is expressed and secreted in response to inflammation, oxidative stress and hypoxia. It has been shown in several studies to be a predictor of heart failure. However, the only kits available on the market are ELISA kits, which are costly and error-prone and are not conducive for clinical use. Here, we developed a chemiluminescence kit which optimized the reaction conditions and the reaction time was reduced to 10 min. We further proved that it can be used to measure GDF-15 in serum or plasma accurately and fastly, and provide additional information for the diagnosis of heart failure disease. Methodological comparison and clinical study verified this method is a reliable, economical and highly automated blood test method.•All necessary steps and the reagents needed are provided.•Reliability of the chemiluminescence immunoassay was verified by analyzing serum GDF-15 levels from different groups.•GDF-15 can provide clinicians with reliable prediction and disease assessment of heart failure.

Association Between Growth Differentiation Factor 15 (GDF15) and Glucose Metabolism in Patients With Acromegaly

Objective: To analyze the changes of serum growth differentiation factor-15 (GDF-15) and its influencing factors in patients with acromegaly, and to investigate its correlation with glucose metabolism. Methods: Sixty acromegaly patients were recruited from the Endocrinology Department of the First Affiliated Hospital of Chongqing Medical University from July 2021 to September 2023, and thirty healthy persons matched in gender, age and body mass index as nomal controls were selected in the same period. To collect clinical and laboratory data, conduct statistical processing, and analyze the level changes and influencing factors of GDF-15. Results: Compared with nomal controls, the level of GDF-15 increased significantly in patients with acromegaly (P &lt;0.05). After operation, the level of GDF-15 decreased gradually with the decrease of serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1). The level of GDF-15 decreased significantly at 3 and 6 months after operation compared with pre-operation level(P &lt;0.05); Compared with 3 months after operation, the GDF-15 level decreased significantly at 6 months after operation(P &lt;0.05). In univariate linear correlation analysis the GDF-15 was positively correlated with GH, IGF-1, FPG, HbA1c, FINS, HOMA-IR (r=0.503, 0.623, 0.427, 0.476, 0.345, 0.419, P &lt;0.05) and negatively correlated with HOMA-β, AUCINS(r=-0.342,-0.261,P &lt;0.05) in pre-operation patients with acromegaly. Multivariate linear regression analysis showed that IGF-1,HOMR-IR,HOMA-β and AUCINS were all identified as the positive predictors of the serum GDF-15 in patients with acromegaly (P &lt;0.05). Conclusions: The level of serum GDF-15 increased in patients with acromegaly, and decreased significantly after operation. The serum GDF-15 was closely related to glucose metabolism in patients with acromegaly.

Biomarkers of disability worsening in inactive primary progressive multiple sclerosis

ObjectiveTo investigate serum biomarkers of progression in inactive primary progressive multiple sclerosis (PPMS). MethodsWe measured protein biomarkers (growth differentiation factor-15 (GDF-15), dickkopf-1 (DKK-1), neuron specific enolase (NSE) and cathepsin-D) in serum samples from 39 patients with inactive PPMS included in a clinical trial enrolling people with PPMS (clinicaltrials.gov identifier NCT02913157) and investigated the association of these biomarker levels with clinical disability at baseline and during follow-up. We then performed a meta-analysis of publicly available transcriptomic datasets to investigate the gene expression of these biomarkers in the CNS in progressive MS. ResultsWhen compared with healthy controls, people with PPMS had higher serum levels of GDF-15, DKK-1 and cathepsin-D at baseline. These findings match those in our meta-analysis which found increased expression of GDF-15 and cathepsin-D in the CNS in progressive MS. At baseline, elevated serum DKK-1 was associated with worse Expanded Disability Status Scale (EDSS) and nine-hole peg test (9HPT) scores. None of the other biomarkers levels significantly correlated with EDSS, Timed 25-Foot Walk Test (T25FWT), 9HPT, or cognitive measures. However, serum GDF-15 and cathepsin-D were higher at baseline in participants who developed worsening disability. Our receiver operating characteristic curve showed that higher serum GDF-15 and cathepsin-D at baseline significantly discriminated between participants who worsened in T25FWT and 9HPT and those who remained stable. ConclusionsPatients with PPMS have altered levels of GDF-15, DKK-1 and cathepsin-D in serum, and GDF-15 and cathepsin-D may have predictive value in progression free of inflammatory activity in PPMS.

Growth differentiation factor 15 (GDF15) elevation in children with newly diagnosed cancer.

Growth differentiation factor 15 (GDF15), an inflammatory marker and mediator of adult cancer cachexia, remains largely unexplored in children. GDF15 increases nausea, vomiting, and anorexia in cancer and contributes to malnutrition, with the potential to be a cachexia therapeutic target. No studies have examined GDF15 in children with newly diagnosed cancer. Our pilot study compares GDF15 in children with newly diagnosed cancer to age- and sex-matched controls and correlates levels with anthropometric measurements and quality of life (QOL). Children with newly diagnosed cancer aged 2-21 years were enrolled with serum GDF15 ELISA, anthropometric measures [height, weight, and mid-upper arm circumference (MUAC)], and QOL assessments (using PedsQL™ Core and Gastrointestinal Modules), which were collected at baseline and repeated 3 months later. Serum GDF15 levels were obtained from age- and sex-matched controls for comparison. A total of 57 participants enrolled (N=30, cancer group; N=27, control group) with a median age of 8.8 years (IQR 5.6-15.9 years). The participants were primarily male (54.4%), white (82.5%), and non-Hispanic (82.5%). Cancer diagnoses included acute lymphoblastic leukemia (N=8), lymphoma (N=8), neuroblastoma (N=5), soft tissue tumors (N=4), acute myeloid leukemia (N=2), and single participants with brain, kidney, and bone tumors. Baseline GDF15 was higher in the cancer cohort compared to the control cohort (median=614.6pg/mL and 320.5pg/mL, respectively; p<0.001). When examining participants with evaluable baseline and 3-month follow-up GDF15 levels (N=18), GDF15 was not statistically different (median=657.1pg/mL and 675.3pg/mL, respectively; p=0.702). A total of 13 of the 30 participants and 21 caregivers completed the PedsQL™ Core and Gastrointestinal symptom modules. QOL scores did not differ significantly at 3-month follow-up compared to baseline, but diarrhea worsened (p=0.017). Median participant response for diarrhea at baseline was 92.9 (IQR=92.9-96.4; N=13), which was significantly better than the follow-up (median=78.6; IQR= 71.4-92.9; p=0.017). There were no correlations between change in height, weight, or MUAC and change in GDF15 levels (p=0.351, 0.920, and 0.269 respectively). GDF15 was elevated in children with cancer at diagnosis compared to controls but did not correlate with anthropometric measurements or QOL. This pilot study will inform future prospective studies to better describe the natural history of GDF15 and its role in cachexia and as a potential therapeutic target.

Serum-based biomarkers associated with lung cancer risk and cause-specific mortality in the German randomized Lung Cancer Screening Intervention (LUSI) trial.

Lung cancer (LC) screening can be optimized using individuals' estimated risks of having a detectable lung tumor, as well as of mortality risk by competing causes, to guide decisions on screening eligibility, ideal screening intervals and stopping ages. Besides age, sex and smoking history, blood-based biomarkers may be used to improve the assessment of LC risk and risk of mortality by competing causes. In the German randomized Lung Screening Intervention Trial (LUSI), we measured growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), C-reactive protein (CRP) and N-terminal pro-brain natriuretic protein (NT-proBNP), in blood serum samples collected at start of the trial. Participants in the computed tomography (CT)-screening arm also had a pulmonary function test. Regression models were used to examine these markers as predictors for impaired lung function, LC risk and mortality due to LC or other causes, independently of age, sex and smoking history. Our models showed increases in LC risk among participants with elevated serum levels of GDF-15 [odds ratio (OR)Q4-Q1 =2.47, 95% confidence interval (CI): 1.49-4.26], IL-6 [ORQ4-Q1 =2.36 (1.43-4.00)] and CRP [ORQ4-Q1 =1.81 (1.08-2.75)]. Likewise, proportional hazards models showed increased risks for LC-related mortality, hazard ratio (HR)Q4-Q1 of 4.63 (95% CI: 2.13-10.07) for GDF-15, 3.56 (1.72-7.37) for IL-6 and 2.34 (1.24-4.39) for CRP. All four markers were associated with increased risk of mortality by causes other than LC, with strongest associations for GDF-15 [HRQ4-Q1 =3.04 (2.09-4.43)] and IL-6 [HRQ4-Q1 =2.98 (2.08-4.28)]. Significant associations were also observed between IL-6, CRP, GDF-15 and impaired pulmonary function [chronic obstructive pulmonary disease (COPD), preserved ratio impaired spirometry (PRISm)]. Multi-marker models identified GDF-15 and IL-6 as joint risk predictors for risk of LC diagnosis, without further discrimination by CRP or NT-proBNP. A model based on age, sex, smoking-related variables, GFD-15 and IL-6 provided moderately strong discrimination for prediction of LC diagnoses within 9 years after blood sampling [area under the curve (AUC) =74.3% (57.3-90.2%)], compared to 67.0% (49.3-84.8%) for a model without biomarkers. For mortality by competing causes, a model including biomarkers resulted in an AUC of 76.2% (66.6-85.3%)], compared to 70.0% (60.9-77.9%) a model including age, sex and smoking variables. Serum GDF-15 and IL-6 may be useful indicators for estimating risks for LC and competing mortality among long-term smokers participating in LC screening, to optimize LC screening strategies.

Growth differentiation factor-15 is an IFN-γ regulated mediator of infection-induced weight loss and the hepatic FGF21 response

Infections are often accompanied by weight loss caused by alterations in host behavior and metabolism, also known as sickness behaviors. Recent studies have revealed that sickness behaviors can either promote or impede survival during infections depending on factors such as the type of infectious pathogen. Nevertheless, we have an incomplete understanding of the underlying mechanisms of sickness behaviors. Furthermore, although the host immune responses to infections have long been known to contribute to the induction of sickness behaviors, recent studies have identified emerging cytokines that are also key regulators of host metabolism during infection and inflammation, such as growth differentiation factor 15 (GDF-15). GDF-15 is a distant member of the TGF-β superfamily that causes weight loss by suppressing appetite and food consumption and causing emesis. These effects require activation of neurons that express the only known GDF-15 receptor, the GFRAL receptor. GDF-15 also functions in the periphery including the induction of ketogenesis and immunoregulation. Nevertheless, the functions and regulation of GDF-15 during live infections is not yet known. Murine infection with avirulent Toxoplasma gondii is an established model to understand infection-induced weight loss. Past studies have determined that acute T. gondii infection causes weight loss due to diminished food consumption and increased energy expenditure through unknown mechanisms. Additionally, our lab previously demonstrated that T. gondii causes upregulation in serum GDF-15 in an IFN-γ-dependent manner during the post-acute phase of the infection. In this study, we interrogated the in-vivo functions and immune regulation of GDF-15 during Toxoplasma gondii infection. First, we found that in wild-type mice, acute T. gondii infection caused a significant weight loss that is preceded by elevation of serum levels of IFN-γ and GDF-15. To determine whether IFN-γ regulates GDF-15, we neutralized IFN-γ on days 5 and 6 and measured GDF-15 on day 7 and found that serum but not tissue levels of GDF-15 decreased after IFN-γ neutralization. Additionally, exogenous IFN-γ was sufficient to elevate serum GDF-15 in the absence of infection. Next, we compared the outcomes of T. gondii infection between WT and Gdf15−/− mice. We observed that the weight trajectories were declining in WT mice while they were increasing in Gdf15−/−mice during the acute phase of the infection. This difference in trajectories extended throughout the chronic infection resulting to an overall weight loss relative to initial weights in WT mice but not Gdf15−/−mice. Then, we determined that GDF-15 is not essential for survival and immunoregulation during T. gondii infection. We also demonstrated that GDF-15 is required for the induction of FGF21, stress-induced cytokine with prominent roles in regulating host metabolism. Finally, we discovered a cytokine cascade IFN-γ-GDF-15-FGF21 that is likely involved in the regulation of host metabolism. Overall, our study provides evidence that IFN-γ contributes to the regulation of host metabolism during infection by inducing GDF-15 and FGF21. GDF-15 orchestrates changes in host metabolism that supports the host immune response in clearing the infection. These physiological alterations induce FGF21, which in turn, orchestrates the adaptive responses to the effects of GDF-15, which can be detrimental when protracted.

Serum growth differentiation factor-15 (GDF-15) is a biomarker of cardiac manifestations in children with COVID-19

BackgroundCOVID-19 leads to severe overwhelming inflammation in some patients mediated by various cytokines (cytokine storm) that usually leads to severe illness accompanied by cardiovascular manifestations. Growth differentiation factor-15 is a cytokine induced by stress and is associated with inflammatory processes in the lung and heart. This study aimed to measure the level of serum growth differentiation factor (GDF-15) in children with COVID-19 and to correlate it with the disease severity, cardiac affection, and the outcome of COVID-19.MethodsA cross-sectional study was conducted on 144 children; 72 children diagnosed with COVID-19, and 72 healthy children. The severity of COVID-19 was assessed clinically, laboratory, and radiologically. Echocardiography was done within 48 h of admission for COVID-19 patients. Serum GDF-15 was measured by ELISA for both patients and controls.ResultsSerum GDF-15 level was significantly higher in patients with COVID-19 than in controls (p < 0.01). In COVID-19 patients with severe clinical grading, those who were hospitalized in the PICU, and those who died, serum GDF-15 levels were greater. individuals with cardiac manifestations exhibited significantly higher serum GDF-15 levels than individuals without them. In children with COVID-19, increased GDF-15 was correlated to poorer ejection fraction and higher INR using multivariate linear regression analysis.ConclusionSerum GDF-15 is a promising biomarker of COVID-19, it can be used as a predictor of cardiac manifestations in children with COVID-19 and severe disease.

Abstract 16679: Growth Differentiation Factor 15 in the Initial Evaluation of Suspected Coronary Artery Disease

Introduction: The cytokine growth differentiation factor 15 (GDF-15) is expressed in several tissues including cardiomyocytes, and is up-regulated in conditions of tissue injury and stress. Hypothesis: We hypothesized that serum GDF-15 can predict obstructive CAD and need of revascularization among acutely admitted chest pain patients. Further, we assessed whether the combination of GDF-15 and coronary artery calcium (CAC) scoring could identify a subgroup with low risk of obstructive CAD, in whom a full coronary CT angiography (CCTA) could be avoided. Methods: GDF-15 was measured, using the assay on Cobas e801 (Roche Diagnostics), in 537 patients with chest pain and high-sensitivity cardiac troponin T concentrations ≤99th percentile. All participants underwent CAC scoring and CCTA. Obstructive CAD was defined as &gt;50% lumen diameter narrowing. Associations of GDF-15 with obstructive CAD and 30-days revascularization were calculated by multivariable logistic regression adjusting for age, sex, smoking, hypertension, HbA1c, LDL-cholesterol, GFR and prior AMI. We also evaluated whether GDF-15 could improve sensitivity and negative predictive value (NPV) of CAC=0 for ruling out the presence of obstructive CAD. Results: The median (25th-75th percentile) age was 56 (49-65) years, 217 (40.4%) of the patients were women, 83 (15.5%) had obstructive CAD, and 49 (9.1%) had revascularization within 30 days. After multivariable adjustment, elevated GDF-15 (≥1200pg/mL) predicted obstructive CAD at baseline with OR (95%CI) of 2.23 (1.14-4.36), p=0.02. The OR (95%CI) for 30-days revascularization was 2.33 (1.08-5.03), p=0.03. For CAC=0, we observed a sensitivity (95%CI) and NPV (95%CI) of 94.0% (86.5%-98.0%) and 98.0% (95.3%-99.3%) in ruling out obstructive CAD. For patients having both CAC=0 and GDF-15 levels below median (&lt;730pg/mL), sensitivity (95%CI) and NPV (95%CI) for obstructive CAD were 97.6% (91.6%-99.7%) and 98.7 (95.2%-99.8%), respectively. Conclusions: Elevated serum GDF-15 predicts obstructive CAD and 30 days revascularization among patients with chest pain, but without AMI. The combination of low GDF-15 levels and CAC=0 appears promising for the identification of low-risk patients, who can possibly be discharged without a full CCTA.