Serum GDF15 Levels Research Articles

8073 Association Between Serum GDF15 Level And Metabolic Parameters in Severely Obese Men Undergoing Weight Loss From Lifestyle Intervention

Abstract Disclosure: S. Bathina: None. V. Fuenmayor Lopez: None. M. Prado: None. G. Colleluori: None. D.T. Villareal: None. R.C. Villareal: None. Background: Growth Differentiation factor (GDF-15), member of TGF-β superfamily was identified as marker of aging, frailty, and metabolic disorders. Several clinical studies demonstrated an association between GDF15 with obesity and cardiovascular disease. However, information on the changes in GDF15 and its relationship to changes in metabolic and body composition parameters in the population of severely obese subjects undergoing weight loss (WL) remains lacking. Objective: The objective of this study is to evaluate the influence of WL on serum GDF15 level and its relationship to glucometabolic parameters in severely obese hypogonadal men. Method: Data from 116 severely obese (BMI ≥35 kg/m2) hypogonadal men participating in an ongoing clinical trial of WL from lifestyle intervention±anastrozole, aged 35-65 years old (NCT03490513) were analyzed. Hemoglobin A1C (A1C) was measured by HPLC, lipid profile by colorimetric method (except LDL was calculated), testosterone (T) and estradiol (E2) LC-MS and GDF-15 by ELISA. Body composition was measured by DXA. Results: The mean age of the participants was 51.4±7.6 years with mean BMI 41.8 ±5.4 kg/m2. At baseline, serum GDF15 positively correlated with age (r=0.25, p=0.01), fasting blood glucose (r=0.29, p=0.004) and A1C (r=0.39, p<0.001) but no correlation was found for lipid parameters and with T and E2. GDF15 was negatively correlated with total lean mass (r= -0.23, p=0.03), appendicular lean mass (r= -0.30, p=0.02), and fat-free mass (r= -0.22, p=0.03), but positively correlated with visceral adipose tissue volume (r=0.22, p=0.03). Average WL was 4.2±4.7% and 5.8±8.5% at 6months (6M) and 12 months (12M), respectively. Overall GDF15 levels increased by 9.4±84.7% at 6M and 18.4±128.0% at 12M. At 12M, changes in GDF15 levels positively correlated with changes in A1C (r= 0.26, p<0.05), and negatively with changes in total cholesterol ( r= -0.30, p=0.05), Triglycerides (r= -0.35, p=0.02) and E2 (r=-0.31, p=0.028). For LDL cholesterol changes, a negative correlation with GDF15 changes was observed at 6M (r= -0.27, p=0.047). There was no correlation between changes in GDF15 with changes in body weight and changes in body composition parameters. A comparison for those with significant WL (≥5%) vs. those with less WL showed that at 6M, GFD15 levels were reduced among those with WL of ≥5% (-19.5±42.3%) vs <5% (+19.8±93.9%), p=0.07, and at 12M (≥5% (-29.5±38.7) vs <5% (+0.61±69%), p<0.1). Conclusion: We demonstrated that changes in serum GDF15 in severely obese men undergoing WL was associated with alteration in cardiometabolic parameters. Our results show a new perspective on the potential role of GDF15 in cardiometabolic disorders associated with severe obesity. Aside from GDF15 used as a biomarker for health, it may also be used as target for drug development in modifying potential cardiometabolic complications in severe obesity. Presentation: 6/1/2024

Abstract P194: Metabolic effects of GDF15 and Activin A on trophoblasts

Preeclampsia (PE), a pregnancy-related complication, is a major cause of maternal and fetal morbidity and mortality. The pathophysiology is not fully elucidated. Activin A and GDF15 are part of the TGFβ superfamily and markers for trophoblast differentiation. Both are senescence associated secretory phenotype (SASP) factors that have been associated with cardiovascular disease. Mitochondrial dysfunction is associated with SASP and both have been described in PE. Serum levels of GDF15 and Activin A, were elevated in the maternal blood prior to the onset of PE and found to be elevated in placental tissue of women with PE. BeWo cells were metabolically reprogrammed to a physiological glucose-environment by cultivating them for 10-15 passages in a cell culture medium with 5.5 mM glucose as opposed to the standard high-glucose environment at 17.1mM. Next, BeWo cells were differentiated into multinucleated syncytiotrophoblasts with Forskolin, and with DMSO as solvent control to model cytotrophoblasts. Subsequently, these two trophoblast differentiation states were treated with GDF15 (20 ng/ml) and Activin A (20ng/ml) and the cell metabolic profile was analyzed. Additionally, a single cell human trophoblast organoid transcriptomics dataset from Shannon et al. was investigated for expression patterns of GDF15 and INHBA (Activin A) together with the overall metabolic profile of trophoblast cells. Treating BeWo cells with Activin A and GDF15 leads to an increase in mitochondrial activity, shown by elevated ATP levels in syncytiotrophoblast and an increase in mitochondrial membrane potential in cytotrophoblasts. Additionally, the oxygen consumption rate is significantly higher in syncytiotrophoblasts after Activin A and GDF15 treatment. In human trophoblast organoids, syncytiotrophoblasts showed the lowest metabolic activity measured by the expression of genes related to glycolysis and mitochondrial respiratory chain. Furthermore, GDF15 and INHBA (Activin A) were strongly expressed in syncytiotrophoblasts. Together, Activin A and GDF15 stimulation increases the metabolic activity in BeWo cells. As preeclampsia is associated with mitochondrial dysfunction as well as with senescence, our data indicate a potential role of Activin A and GDF15 in preeclampsia development.

Liujunzi decoction attenuates cisplatin-induced anorexia in rats via inhibiting PERK/eIF2α/ATF4/CHOP pathway and GDF15/GFRAL expression

Background and aimLiujunzi Decoction (LJZD), also called Rikkunshito, is a traditional formula that has proven effective in clinical treatment against chemotherapy-induced anorexia (CIA). Previous study indicated the importance of GDF15/GFRAL axis in the pathogenesis of CIA, and suggested the potential connection between endoplasmic reticulum stress and GDF15 expression. However, further exploration is required to determine whether the mechanism of LJZD against CIA is related to the PERK/eIF2α/ATF4/CHOP signaling and GDF15/GFRAL expression. MethodsThe CIA model of rats was established via intraperitoneal injection of cisplatin, and the rats were given LJZD orally for 72 ​h. Food intake and body weight were recorded daily. The expression of GDF15/GFRAL and ER stress factors, as well as the histological injuries were investigated. ResultsLJZD led to a significant increase in food intake in rats and a decrease in serum GDF15 levels at 24 ​h and 72 ​h after cisplatin injection. This effect may be associated with the inhibition of Gdf15 transcription and the amelioration of pathological injuries or endoplasmic reticulum stress in the liver and ileum. Moreover, LJZD suppressed the cisplatin-induced activation of the hepatic and ileal PERK/eIF2α/ATF4/CHOP pathway, resulting in the alleviation of central GDF15/GFRAL expression. ConclusionLJZD effectively improves cisplatin-induced anorexia in a rat model, which might be attributed to its inhibition of the PERK/eIF2α/ATF4/CHOP pathway and GDF15/GFRAL expression activated by cisplatin.

#1258 Moderate-severe intrarenal arteriosclerosis and circulating GDF-15 levels may influence the cardiac-renal prognosis of IgAN patients

Abstract Background and Aims The cardiovascular risk among patients with IgA nephropathy (IgAN) is gradually garnering increased attention. The KDIGO guidelines explicitly emphasize the importance of evaluating cardiovascular risk in the management of IgAN patients and implementing appropriate interventions when necessary. The aim of this study was to investigate the risk factors affecting cardiac-renal prognosis in patients with IgAN. Method This is a retrospective study. A total of 353 IgAN patients with regular follow-up for at least 1 year at Beijing Anzhen Hospital were recruited. Patients were divided into group A (n = 85, yes) and group B (n = 268, no) according to the occurrence of cardio-renal composite endpoint events. Clinical and pathological characteristics of the two groups were compared and analyzed. The risk factors affecting the cardiac and renal prognosis in IgAN patients were analyzed by univariate and multivariate Cox models. In addition, serum GDF-15 of IgAN patients were detected. Results Approximately 14.7% (52/353) of IgAN patients presented with cardiovascular diseases at the time of renal biopsy. 55.8% (197/353) patients presented with hypertension. Prognostic analysis showed that hypertension (HR, 1.810; 95% confidence interval, 1.073 to 3.053; P = 0.026), 24-hour urinary protein (24 hUTP) (HR, 1.081; 95% confidence interval, 1.006 to 1.162; P = 0.033), eGFR (HR, 0.980; 95% confidence interval, 0.973 to 0.987; P<0.001), the presence of endocapillary proliferation (E1) (HR, 1.697; 95% confidence interval, 1.079 to 2.669; P = 0.022), tubular atrophy/interstitial fibrosis (T2) (HR, 3.757; 95% confidence interval, 1.959 to 7.203; P < 0.001), and moderate-severe intrarenal arteriosclerosis (HR, 3.320; 95% confidence interval, 1.289 to 8.548; P = 0.013) are independent risk factors affecting the cardiac-renal prognosis of IgAN. In IgAN patients with moderate-severe intrarenal arteriosclerosis, 24-hour urinary protein (24 hUTP) (HR, 1.131; 95% confidence interval, 1.014 to 1.261; P = 0.028), eGFR (HR, 0.982; 95% confidence interval, 0.971 to 0.993; P = 0.001) and E1 (HR, 2.583; 95% confidence interval, 1.379 to 4.841; P = 0.003) are independent risk factors affecting the cardiac-renal prognosis of IgAN patients. The serum GDF-15 level is positively correlated with 24 hUTP (r = 0.405, P < 0.001) and negatively correlated with eGFR (r = −0.606, P < 0.001). Compared with those with benign cardio-renal composite outcome, the serum level of GDF-15 in IgAN with poor cardio-renal composite outcome were significantly higher (1591.69 (1001.65, 2546.36) pg/ml vs 775.85 (546.82, 1310.29) pg/ml, P < 0.001). Conclusion The occurrence of cardiovascular diseases in patients with IgAN is frequently observed. In addition to the conventional risk factors associated with IgAN, including hypertension, initial proteinuria, eGFR, E1 and T2 lesion, moderate-severe intrarenal arteriosclerosis also contributes to the cardiac-renal prognosis of individuals with IgAN. In IgAN patients with moderate-severe intrarenal arteriosclerosis, Oxford-E lesion is an independent risk factor affecting the cardiac-renal prognosis of IgAN patients. This study suggested that the impairment of endothelial cells could potentially serve as a link between heart and kidney disease. The circulating levels of GDF-15 might contribute to the cardiac-renal prognosis of IgAN.

Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients.

To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRPwere measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient's clinical characteristics, complications, and poor outcomes.

Growth differentiation factor-15 and metabolic features in chronic heart failure: Insights from the SUPPORT Trial -GDF15 across the BMI spectrum

BackgroundGDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood. MethodsWe assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 65.9 ± 10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m2; n = 50], healthy weight [18.5–22.9; n = 27 5], overweight [23–24.9; n = 234], and obese [≥25; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death. ResultsCompared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21–596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2–81.0]). Persistently high GDF15 levels (≥1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [95%CI 1.1–2.9]). ConclusionsIn underweight patients with CHF, GDF15 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome.

GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

Elevated interleukin 8 and matrix metalloproteinase 9 levels are associated with myocardial pathology in users of anabolic-androgenic steroids.

In the current paper, we aim to explore the effect of both current and former long-term anabolic-androgenic steroid (AAS) use on regulation of systemic inflammatory markers and mediators of extracellular matrix (ECM) remodelling and their association with hormones and echocardiographic myocardial pathology in weightlifters. In a cross-sectional study, 93 weightlifting AAS users, of whom 62 were current and 31 were past users, with at least 1-year cumulative AAS use (mean 11 ± 7 accumulated years of AAS use), were compared with 54 non-using weightlifting controls (WLCs) using clinical interview, blood pressure measurements, and echocardiography. Serum levels of interleukin (IL)-6, IL-8, tumour necrosis factor (TNF), interferon (IFN)-γ, growth differentiation factor (GDF)-15, and matrix metalloproteinase (MMP)-9, sex hormones, and lipids were analysed. It was found that serum levels of IL-8, GDF-15, and MMP-9 were significantly increased in current AAS users compared with former users and WLCs. Matrix metalloproteinase 9, but not IL-8, correlated consistently with sex hormone levels, and sex hormone levels correlated consistently with mean wall thickness, in current users. Moreover, HDL cholesterol was significantly lower in current vs. former AAS users and significantly inversely correlated with MMP-9 in current users. Further, in current users, MMP-9 and IL-8 correlated with markers of myocardial strain, and MMP-9 also correlated with indices of cardiac mass, which was not seen in former users. Mediation analyses suggested that MMP-9 could partly explain hormone-induced alterations in markers of myocardial damage in current users. Long-term AAS is associated with increased levels of markers of inflammation and ECM remodelling, which seems to have a hormone-dependent (MMP-9) and a hormone-independent (IL-8) association with markers of myocardial dysfunction.

Evaluation of the relationship between atherosclerosis and Helicobacter pylori infection with measurement of growth differentiation factor 15 and atherosclerosis indicators in adults with no comorbidity

BackgroundThe aim of this study was to investigate presence of subclinical atherosclerosis by measuring carotid intima-media thickness (CIMT) in patients with Helicobacter pylori (HP) and to assess effects of HP on atherosclerosis by evaluating markers of atherosclerosis and blood growth differentiation factor (GDF-15) levels. Materials and methodsThis cross-sectional study included 59 patients without comorbid disease who had HP and 30 healthy controls without HP in upper endoscopic biopsy. In order to assess atherosclerosis, the CIMT measurement was performed by sonography. Serum GDF-15 level was measured by ELISA method. In all patients, atherosclerosis markers were recorded. Atherogenic indices were calculated, including Castelli risk index I and II (TG/HDL-c and LDL-c/HDL-c, respectively), plasma atherogenic index (PAI; log TG/HDL-c), non-HDL-c (TH-HDL-c) and atherogenic coefficient (AC; non-HDL-HDL-c). ResultsThe GDF-15 level and CIMT were significantly higher in HP-positive group when compared to HP-negative group (p≤0.001). There was a significant correlation between serum GDF-15 level and CIMT (r=0.445; p≤0.001). There was no correlation between other atherosclerosis markers and serum GDF-15 level or CIMT. The bacterial intensity on endoscopic specimen was only correlated with CIMT (p<0.001). Vitamin B12 and D levels were comparable among groups. ConclusionThis study suggested that there was a correlation between GDF-15 level and subclinical atherosclerosis development in patients with HP. However, GDF-15 level, which was found to be elevated while atherogenic indices were normal, can be an earlier marker for subclinical atherosclerosis.

Abstract LB_C02: A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels

Abstract Background: Cancer cachexia is a complex metabolic syndrome characterized by involuntary weight loss, muscle wasting and weakness leading to resistance to therapy and high mortality. Elevated levels of circulating GDF-15, an inflammatory cytokine involved in stress response and body weight regulation, are common in cancer pts with cachexia. Furthermore, GDF-15 expression increases in proportion to disease severity, and preclinical models have shown that elevated levels of circulating GDF-15 elicit cachexia. AV-380 is an antibody that binds with high affinity to GDF-15 resulting in its elimination from circulation. It has been shown to reverse weight loss and increase recovery of muscle in animal cancer models and was well tolerated without serious AEs in a phase 1 study in healthy subjects. The current study is designed to determine if adding AV-380 to standard-of-care (SoC) chemotherapy will confer additional clinically meaningful benefits in metastatic cancer pts with cachexia. Methods: This is an open-label, dose escalation, multicenter phase 1b study to assess the safety, PK, and PD of AV-380. Eligible pts must be ≥18 years of age, have confirmed metastatic colorectal or pancreatic cancer, actively receiving 1st-line SoC chemotherapy (&amp;gt;2 cycles of FOLFOX/FOLFOXIRI±bevacizumab for colorectal, FOLFOX/FOLFIRINOX for pancreatic), have cachexia defined by Fearon criteria (weight loss &amp;gt;5% over past 6 months w/o simple starvation, or BMI &amp;lt;20 kg/m2 or sarcopenia plus any degree of weight loss &amp;gt;2%), life expectancy ≥3 months, GDF-15 &amp;gt;1200 pg/mL, and ECOG PS 0/1. Those with brain metastases (unless treated and stable for ≥2 weeks prior to study treatment), significant cardiovascular disease, corrected QT interval &amp;gt;460 ms, uncontrolled pleural or pericardial effusion, parenteral nutrition, or non-cancer related cachexia are excluded. Primary endpoints are AE characterization, serum PK parameters, and serum levels of GDF-15; secondary endpoints include assessments of weight/BMI, cachexia measures, and anti-AV-380 antibodies; and exploratory endpoints include best objective response and biomarkers. Five escalating dose cohorts of AV-380 are planned (50, 100, 200, 400, 800 mg IV) with 4-6 pts in each and following a standard 3+3 design. Dose de-escalation will be performed if the lowest dose cohort is successful. The study is structured into 28-day courses with Course 1 being the single-dose phase of AV-380 and Course 2 starting the multiple-dose phase where AV-380 is administered every 14 days. Pts will remain enrolled until they start 2nd-line systemic anticancer therapy, have unacceptable toxicity related to AV-380, complete 4 courses of AV-380, withdraw consent, or sponsor terminates study. Statistical analyses will be done by cohort and summarized descriptively. Clinicaltrials.gov: NCT05865535 Encore abstract. Originially accepted at the annual Cancer Cachexia Society meeting, 28-30 September 2023, Edinburgh Scotland. Citation Format: Arvind Chaudhry, RIchard Zuniga, J. Eva Selfridge, Bruno Bastos, Vipin Lohiya, Martin Birkhofer. A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C02.

Evaluation of the relationship between atherosclerosis and Helicobacter pylori infection with measurement of growth differentiation factor 15 and atherosclerosis indicators in adults with no comorbidity

BackgroundThe aim of this study was to investigate presence of subclinical atherosclerosis by measuring carotid intima-media thickness (CIMT) in patients with Helicobacter pylori (HP) and to assess effects of HP on atherosclerosis by evaluating markers of atherosclerosis and blood growth differentiation factor (GDF-15) levels. Materials and methodsThis cross-sectional study included 59 patients without comorbid disease who had HP and 30 healthy controls without HP in upper endoscopic biopsy. In order to assess atherosclerosis, the CIMT measurement was performed by sonography. Serum GDF-15 level was measured by ELISA method. In all patients, atherosclerosis markers were recorded. Atherogenic indices were calculated, including Castelli risk index I and II (TG/HDL-c and LDL-c/HDL-c, respectively), plasma atherogenic index (PAI; log TG/HDL-c), non-HDL-c (TH-HDL-c) and atherogenic coefficient (AC; non-HDL-HDL-c). ResultsThe GDF-15 level and CIMT were significantly higher in HP-positive group when compared to HP-negative group (p≤0.001). There was a significant correlation between serum GDF-15 level and CIMT (r=0.445; p≤0.001). There was no correlation between other atherosclerosis markers and serum GDF-15 level or CIMT. The bacterial intensity on endoscopic specimen was only correlated with CIMT (p<0.001). Vitamin B12 and D levels were comparable among groups. ConclusionThis study suggested that there was a correlation between GDF-15 level and subclinical atherosclerosis development in patients with HP. However, GDF-15 level, which was found to be elevated while atherogenic indices were normal, can be an earlier marker for subclinical atherosclerosis.

#5536 CIRCULATING LEVELS OF COPEPTIN, GROWTH DIFFERENTIATION FACTOR 15 (GDF15) AND INTERLEUKIN 6 (ILA-6) IN PATIENTS WITH ADVANCED KIDNEY DISEASE

Abstract Background and Aims The search for new serum biomarkers of cardiovascular risk and mortality in patients with CKD is relevant to improve the monitoring of these patients. Copeptin is a glycopeptide that is released equimolarly with arginine-vasopressin. GDF-15 is a cytokine involved in macrophage activation processes and is a marker of response to oxidative stress, and IL-6 as a marker of systemic inflammation. Objective: To study the serum levels of copeptin, GDF-15 and IL-6 in patients with advanced CKD. Method Cross-sectional study in 32 patients with advanced CKD. In all patients, the estimated glomerular filtration rate (eGFR) was determined by CKD-EPI, the albumin/creatinine ratio (CrAI) and the serum concentrations of copeptin (immunofluorescence, Thermo Fisher), GDF-15 (chemiluminescence, Roche Diagnostics International) and IL-6 (Siemens Healthineers). Results were compared to laboratory reference values (RVs) for copeptin (VN&amp;lt;4.2 pmol/L) and IL-6 (VN&amp;lt;4.4 pg/mL). The VR of GDF-15 (708±227 pg/ml) corresponds to own data from 10 Blood Bank donors. Results for copeptin and GDF-15 (normal distribution) are shown as mean ± SD. IL-6 results (without normal distribution) as median and interquartile range. Results In CKD we observed an increase in copeptin (26.9±22 pmol/l, 90% &amp;gt;4.2 VR) and GDF-15 (4703±2683 pg/ml p&amp;lt;0.0001 vs. control population). Median IL6 3.2 pg/ml (IQR: 2.7-5.1, 35% &amp;gt;4.4 VR). We did not find differences in the levels of copeptin, GDF-15 or IL-6 based on age, sex and presence or absence of diabetes. A significant correlation was found between GDF15 levels and eGFR (r=-0.54 p&amp;lt;0.002). Conclusion Serum levels of copeptin and GDF-15, but not IL6, are increased in CKD patients. Our data suggest a significant inverse relationship between GDF15 and eGFR. More studies are needed to know the possible role of GDF-15 on the progression of kidney damage and cardiovascular complications in patients with CKD.

Correlation between serum GDF-15 level and pulmonary vascular morphological changes and prognosis in patients with pulmonary arterial hypertension.

To investigate how serum GDF-15 concentration affects pulmonary artery hemodynamics and pulmonary vascular morphological changes in patients with pulmonary arterial hypertension. A total of 45 patients admitted to our hospital from December 2017 to December 2019, were selected for the study. Pulmonary vascular hemodynamics and pulmonary vascular morphology were detected by RHC and IVUS. Serum GDF-15 levels were detected by enzyme-linked immunosorbent assay (ELISA). Based on the concentration of GDF-15, the patients were divided into two groups-the normal GDF-15 group (GDF-15 <1,200 pg/ml, 12 cases) and the elevated GDF-15 group (GDF-15 ≥1,200 pg/ml, 33 cases). A statistical analysis was performed to compare the effects of normal blood GDF-15 levels and high serum GDF-15 levels on hemodynamics and pulmonary vascular morphology in each group of patients. The average levels of RVP, sPAP, dPAP, mPAP, and PVR in patients with elevated GDF-15 levels were higher than those in patients with normal GDF-15 levels. The difference between the two groups was statistically significant (P < 0.05). The average levels of Vd, elastic modulus, stiffness index β, lesion length, and PAV in the normal GDF-15 group were lower than those in the elevated GDF-15 group. The average levels of compliance, distensibility, and minimum l umen area were higher than those in the elevated GDF-15 group. The difference between the two groups was statistically significant (P < 0.05). The survival analysis results showed that the 1-year survival rate of patients with normal GDF-15 levels and elevated GDF-15 levels was 100% and 87.9%, respectively, and that the 3-year survival rate of patients with normal GDF-15 levels and elevated GDF-15 levels was 91.7% and 78.8%, respectively. The survival rates of the two groups were compared by the Kaplan Meier method, and the difference was not statistically significant (P > 0.05). Patients with pulmonary arterial hypertension with elevated GDF-15 levels have higher pulmonary arterial pressure, higher pulmonary vascular resistance, and more serious pulmonary vascular lesions, which are potentially more harmful. There was no statistically significant difference in survival rates among patients with different serum GDF-15 levels.

Novel blood-based biomarker candidates in screening for colorectal cancer.

244 Background: Colorectal cancer (CRC) is the third most common cancer worldwide motivating national screening strategies utilizing fecal immunochemical tests (FIT). Blood-based biomarkers could be an alternative method to increase compliance in population-based screening programs for early detection of CRC. We aimed to identify new blood-based biomarkers that could be potential candidates for use in colorectal cancer screening. Methods: In a nested cohort study of 1967 FIT positive participants of the Danish CRC screening program serum levels of GDF-15, hepsin, IL-8, keratin1-10, L1CAM, MIA, monocyte MCP-1, NSE and OPG were measured using the Luminex xMAP immunoassay platform. Main outcomes were CRC vs non-CRC and CRC, high-risk adenomas (HRA) or medium-risk adenomas (MRA) vs low-risk adenomas (LRA) or clean colorectum. Odds ratios for associations between biomarker expressions and outcomes were calculated using logistic regression models and visualized by area under the receiver operating characteristic (ROC) curve (AUC). Analyses were made on the Luminex biomarkers alone and with addition of clinical and demographic information. Results: FIT-induced colonoscopies detected 240 CRCs and 625 HRA or MRA. Multivariate analyses using all biomarkers and age found hepsin, IL-8 and OPG significantly (p&lt;0.001) associated in relation to the main outcome (CRC vs non-CRC) with odds ratios of 0.74 [0.59-0.92], 2.59 [2.12-3.15] and 0.90 [0.82-0.99], respectively. The full model using all biomarkers and age presented an AUC of 0.73 [0.70-0.77]. Conclusions: Changed serum levels of nine novel biomarkers seem to be potential predictors for early detection of CRC, especially hepsin, IL-8 and OPG. [Table: see text]

Significant increase of serum extracellular vesicle-packaged growth differentiation factor 15 in type 2 diabetes mellitus: a cross-sectional study

BackgroundGrowth differentiation factor 15 (GDF15) is a stress-inducible factor involved in the inflammatory progression of many complications, including type 2 diabetes mellitus (T2DM). Growing evidence suggests that molecules in extracellular vesicles (EVs) are associated with diabetes or diabetes-related complications. However, the correlation between serum extracellular vesicle-derived growth differentiation factor15 (EV-GDF15) and T2DM is unknown. The aim of this cross-sectional study is to investigate whether serum EV-GDF15 is associated with T2DM incidence.Methods116 individuals, including 78 T2DM and 38 non-T2DM, were recruited as participants. The concentrations of serum EV-GDF15 and serum GDF15 were determined by Luminex assay. Serum EVs were obtained by ultracentrifugation. Multivariate stepwise regression analysis was used to determine the association between serum GDF15 levels and fasting plasma glucose (FPG) as well as glycated hemoglobin (HbA1c). The association of serum EV-GDF15 levels with T2DM was determined by multivariate logistic regression analysis.ResultsOur data showed that the levels of serum EV-GDF15 and serum GDF15 were significantly increased in T2DM patients compared with non-T2DM subjects (EV-GDF15 levels, 13.68 (6.61–23.44) pg/mL vs. 5.56 (3.44–12.09) pg/mL, P < 0.001; and serum GDF15 levels, 1025.49 (677.87–1626.36) pg/mL vs. 675.46 (469.53–919.98) pg/mL, P < 0.001). There was a linear correlation between EV-GDF15 levels and fasting plasma glucose (FPG) and Hemoglobin A1C (HbA1c) levels (normalized β = 0.357, P < 0.001; normalized β = 0.409, P < 0.001, respectively). Elevated levels of EV-GDF15 were accompanied by an increase in the proportion of patients with T2DM (from 47.5 to 78.9%) and a progressive independent association with the incidence of T2DM (from OR = 3.06, 95% CI 1.02–9.19, P = 0.047 to OR = 3.75, 95% CI 1.14–12.26, P = 0.029). Notably, high levels of serum GDF15 plus high levels of serum EV-GDF15 were significantly associated with T2DM more than either alone.ConclusionThis study elucidated that increased levels of GDF15 in serum EVs were independently associated with T2DM.

The diagnostic and prognostic value of growth differentiation factor-15 in systemic lupus erythematosus-associated pulmonary arterial hypertension.

Growth-differentiation factor (GDF)-15 is a member of transforming growth factor-β-related cytokine and may respond to right ventricular overload. The objective of this article was to assess the diagnosis and prognostic value of GDF-15 in systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). Serum samples were obtained from 65 patients with SLE-PAH, 51 sex and age matched patients of SLE without PAH (SLE-non-PAH), and 32 healthy controls. Serum GDF-15 level was detected by enzyme-linked immunosorbent assayand the optimal cut-off point was determined by receiver operating characteristiccurve. The primary end-point was death from any cause and the secondary end-point was target goal achievement (TGA). Cox regression analyses and Kaplan-Meier method were performed to identify the prognostic value of GDF-15. Serum GDF-15 levels were significantly higher in SLE-PAH patients (1112.14 ± 781.80 pg/mL) than SLE-non-PAH patients (810 ± 408 pg/mL) and healthy controls (442 ± 139 pg/mL) at baseline. The optimal cut-off value of GDF-15 in the diagnosis of SLE-PAH was 733 pg/mL (AUC = 0.84). In patients with SLE-PAH, GDF-15 level was associated with 6 minwalking distance (ρ = -0.385, p = 0.017) and higher serum N terminal-pro brain natriuretic peptide (NT-proBNP) (ρ = 0.605, p < 0.001). Patients with GDF-15 > 733 pg/mL were more likely to death (adjusted hazard ratio[HR] = 4.01, 95% confidence intervals[CI]:1.23-6.27, p = 0.041) and less likely to achieve treatment goal (adjusted HR = 0.57, 95% CI:0.23-0.79, p = 0.028). In addition, patients with simultaneous elevation of GDF-15 and NT-proBNP showed lower proportion of TGA (p = 0.046). In conclusion, GDF-15 is a new and promising biomarker of development and prognosis in SLE-PAH. The combination of GDF-15 and NT-proBNP may provide more accurate prognostic information.

PS-P01-10: MASKED HYPERTENSIVE EFFECT AND GROWTH DIFFERENTIATION FACTOR 15

Background: Growth differentiation factor 15 [GDF15], a possible biomarker of mitochondrial function related to ageing was reported to be associated an increased risk of cardiovascular events. However, there were no previous data that investigated the relationship between masked hypertensive effect and serum GDF15 level. Methods: In outpatients clinic in which evaluated frailty in elderly patients, we evaluated clinic, home and 24-hr ambulatory BP, and serum GDF15 level in 116 hypertensive patients. Clinic BP was automatically measured twice in a sitting position [HBP-9035, Fukuda-Colin, Japan]; home BP [HBP], 3 times in the morning and evening for 5 days [HEM-7080IC, Omron, Japan]; and ambulatory BP [ABP], at 30-minute intervals for 24 hours [TM-2441, A&amp;D, Japan]. Results: Mean age was 77.6 ± 7.3 years [male 37.1 percent]. Clinic BP was 132.9 ± 18.7 / 73.9 ± 12.7 mmHg, and pulse rate 77.2 ± 14.4 bpm. GDF15 had a skewed deviation, and median GDF15 was 1.53 [25–75 percentile, 1.25–2.08] ng/ml. Natural log-transformed GDF15 [LnGDF15] was negatively related to clinic BP [systolic BP, r = -0.338, P &lt; 0.001; diastolic BP, r = -0.335, P &lt; 0.001], but not to home systolic BP [r = -0.112, P = 0.252] or awake ambulatory systolic BP [r = -0.080, P = 0.426]. LnGDF15 was significantly related to masked hypertensive effect assessed by ABP [SBP r = 0.273, P = 0.006] and that by home BP [SBP r = 0.382, P &lt; 0.001]. In tertile analysis of GDF15, masked hypertensive effect assessed by ABP and HBP were significantly increased across tertile of GDF15. Masked hypertensive effect was significantly greater across tertile of GDF15 even after adjustment for age, sex, BMI, antihypertensive medication use, diabetes, dyslipidemia, smoking habit, alcohol drinking habit. Conclusion: An increased GDF15 can be associated with an increased masked hypertensive effect in elderly hypertensive patients.

COULD GROWTH DIFFERENTIATION FACTOR-15 BE A NEW INFLAMMATORY PATHWAY IN PSORIASIS VULGARIS?

Amaç&#x0D; Psoriasis vulgaris kronik inflamatuvar bir hastalık olup,&#x0D; etyopatogenezde T hücrelerin önemli rol oynadığı inflamatuvar&#x0D; mekanizmalar rol almaktadır. Son yıllarda&#x0D; psoriasisin sadece deriye sınırlı olmayıp aynı zamanda&#x0D; bazı komorbiditeler ile ilişkili olduğu gösterilmiştir.&#x0D; Büyüme farklılaşma faktörü-15 (GDF-15), dönüştürücü&#x0D; büyüme faktörü beta süper ailesinin (TGF-ß) bir&#x0D; üyesidir ve inflamasyonla artmaktadır. Bu çalışmada;&#x0D; serum GDF-15 düzeyi ve bunun hastalığın etyopatogenezinde&#x0D; rolü olduğu düşünülen tümör nekrozis&#x0D; faktör alfa (TNF-α) ve diğer metabolik parametrelerle&#x0D; arasındaki ilişkinin değerlendirilmesi amaçlandı.&#x0D; Gereç ve Yöntem&#x0D; Çalışmaya 41 psoriasis vulgarisli hasta ve 41 sağlıklı&#x0D; kontrol dahil edildi. Tüm katılımcıların dermatolojik&#x0D; muayenesi yapıldı ve psoriasis alan ve şiddet indeksi&#x0D; (PAŞİ) skoru hesaplandı. Tüm katılımcıların boy,&#x0D; kilo ölçümleri, sistolik ve diastolik kan basınçları, bel&#x0D; ve kalça çevreleri, lipit profilleri, biyokimyasal parametreleri&#x0D; değerlendirildi. Serum GDF-15 ve TNF-α&#x0D; düzeyleri ELİSA yöntemi ile ölçüldü.&#x0D; Bulgular&#x0D; Hasta ve kontrol grubu arasında yaş, cinsiyet, lipit&#x0D; profilleri, biyokimyasal parametreler ve yüksek-sensitif&#x0D; C-reaktif protein (hs-CRP) düzeyleri açısından&#x0D; anlamlı fark gözlenmedi. Hasta grubunda kontrol grubuna&#x0D; kıyasla serum GDF-15 ve TNF-α düzeyleri anlamlı&#x0D; derecede yüksek bulundu (p

GDF15 and its association with cognitive performance over time in a longitudinal study of middle-aged urban adults

Serum GDF15 levels are correlated with multiple neurodegenerative diseases. Few studies have tested this marker’s association with middle-aged cognitive performance over time, and whether race affects this association is unknown. We examined associations of initial serum GDF15 concentrations with longitudinal cognitive performance, spanning domains of global mental status, visual and verbal memory, attention, fluency, and executive function in a sub-sample of adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 776, Agev1:30-66y, 45.6 % male, 57.0 % African American, 43.0 % below poverty). This analysis consisted of mixed-effects regression models applied to the total selected sample, while also stratifying the analyses by race in the main analyses and further stratifying by sex, age group and poverty status in an exploratory analysis. Our main findings, which passed multiple testing and covariate-adjustment, indicated that GDF15 was associated with poorer baseline performance on several cognitive tests, including animal fluency [overall sample: (Model 1: γ0 ± SE: −0.664 ± 0.208, P < 0.001; Model 2, γ0 ± SE: −0.498 ± 0.217, P < 0.05)]. Among White adults, GDF15 was linked to poorer performance on a brief test of attention (Model 1: γ0 ± SE: −0.426 ± 0.126, P < 0.001; Model 2, γ0 ± SE: −0.281 ± 0.139, P < 0.05); and Trailmaking test, part B (Model 1: γ0 ± SE: +0.129 ± 0.040, P < 0.001; Model 2, γ0 ± SE: +0.089 ± 0.041, P < 0.05), the latter being also linked to higher GDF15 among individuals living below poverty. Among women, GDF15 was associated with poor global mental status (Normalized MMSE: Model 1: γ0 ± SE: −2.617 ± 0.746, P < 0.001; Model 2: γ0 ± SE: −1.729 ± 0.709, P < 0.05). GDF15 was not associated with decline on any of the 11 cognitive test scores considered in ∼ 4 years of follow-up. In sum, we detected cross-sectional associations between GDF15 and cognition, although GDF15 did not predict rate of change in cognitive performance over time among a sample of middle-aged adults. More longitudinal studies are needed to address the clinical utility of this biomarker for early cognitive defects.

Growth differentiation factor 15 is not associated with glycemic control in patients with type 2 diabetes mellitus treated with metformin: a post-hoc analysis of AIM study

BackgroundGrowth differentiation factor 15 (GDF15) was newly discovered to be a promising target of metformin. The study was aimed to investigate the relationship between GDF15 and glycemic control after metformin treatment in patients with type 2 diabetes mellitus.MethodsThe study was a post-hoc analysis of AIM (the effect of Acarbose on glycemic variability in patients with type 2 diabetes mellitus using premixed Insulin compared to Metformin) study. The participants were randomly assigned to 12 weeks of metformin (MET) or acarbose (ACA) treatment combined with insulin. Serum GDF15 levels of 51 subjects from MET group and 53 subjects from ACA group were measured at baseline and after a 12-week treatment. Fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG) and glycated hemoglobin A1c (HbA1c) were measured at baseline and endpoint.ResultsAfter a 12-week treatment, serum GDF15 levels significantly increased in MET group [baseline vs. endpoint, 936.70 (741.00, 1205.40) pg/mL vs. 1265.20 (1027.90, 1634.00) pg/mL, P < 0.001], but not in ACA group [baseline vs. endpoint, 920.60 (701.45, 1332.55) pg/mL vs. 893.80 (663.25, 1284.05) pg/mL, P = 0.944]. However, there were no significant differences of glycemic control parameters (ΔFPG, Δ2-h PG and ΔHbA1c) between subgroups of MET group divided by median of ΔGDF15 (all P > 0.05). Spearman correlation coefficient and analysis of covariance after adjustment for baseline HbA1c levels showed that ΔGDF15 was not correlated with ΔFPG, Δ2-h PG and ΔHbA1c (all P > 0.05).ConclusionSerum GDF15 levels were significantly elevated after metformin treatment in patients with type 2 diabetes mellitus. However, the increase was not an indicator of the glucose-lowering effect of metformin.Trial registrationClinicaltrials.gov, NCT02438397. Registered 8 May 2015.