Growth Differentiation Factor 15 Levels Research Articles

Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight

Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.

Abstract 5282: Mitotane induces GDF-15 expression in vitro and in vivo: A potential therapy-induced mechanism of immune escape in adrenocortical carcinoma

Abstract Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis and limited treatment options. The only approved therapy is mitotane, an adrenal toxicant, alone or in combination with cytotoxic chemotherapy. Response rate is only ~20%. Results of later line immune checkpoint inhibition (ICI) in ACC are disappointing, most likely due to an immunologically cold, immunosuppressive microenvironment. Among the factors induced in mitotane-treated ACC cell lines, we previously found growth/differentiation factor 15 (GDF-15), an anti-inflammatory cytokine physiologically expressed during pregnancy. Aim: As GDF-15 is an emerging mediator of tumor immune escape, we investigated changes in GDF-15 secretion upon mitotane treatment in ACC in vitro and in vivo, and explored a potential correlation with response to therapy and survival. Methods: Four different human ACC cell lines (NCI-H295R, CU-ACC1, CU-ACC2 and JIL-2266) were treated with mitotane. GDF-15 secretion and expression were determined by ELISA and immunoblot. GDF-15 levels in sera of 142 ACC patients (94 prior and 48 during mitotane) were analyzed by ELISA and correlated with survival from the time point of blood collection. GDF-15 serum levels were quantified in three responders and seven non-responders to ICI treatment. Results: In vitro, 24h treatment with 25 µM mitotane-induced GDF-15 secretion and expression in all cell lines by up to one order of magnitude. In 32 patient samples, GDF-15 serum concentrations increased from 0.6±1 ng/l prior mitotane to 2.1 ± 2.7 ng/l after mitotane initiation, p<0.0001.Importantly, patients with low serum GDF-15 levels before and during mitotane treatment had a significantly longer overall survival compared to patients with higher GDF-15 serum levels. This association retained statistical significance after adjustment for the known prognostic factors Ki67 and ENSAT tumour stage in the mitotane treated group (95% CI 1.15-.1.73, HR1.41, p=0.001). In an exploratory cohort of three responders and seven non-responders to ICI we found a trend for higher GDF-15 serum concentrations in the non-responders. Conclusion: Mitotane induces GDF-15 both in vivo and in vitro and potentially contributes to the poor response rates to ICI in ACC. Citation Format: Isabel Weigand, Tanja Anderlik, Jochen Schreiner, Hanna Remde, Otilia Kimpel, Laura-Sophie Landwehr, Eva Hoster, Florian Wedekink, Alexandra S. Triebig, Tanja Maier, Jörg Wischhusen, Martin Reincke, Martin Fassnacht, Matthias Kroiss. Mitotane induces GDF-15 expression in vitro and in vivo: A potential therapy-induced mechanism of immune escape in adrenocortical carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5282.

Implication of serum growth differentiation factor-15 level in patients with renal diseases.

The synthesis of growth differentiation factor-15 (GDF-15) is induced by inflammation, hypoxia, and oxidative stress and is receiving great interest as a predictive biomarker for cardiovascular disease. However, its detailed impact on patients with renal disease remains uncertain. Patients who underwent renal biopsy for evaluation of renal disease between 2012 and 2017 in our institute were prospectively included. Serum GDF-15 levels were measured and its association with baseline characteristics and its impact on the 3-year composites of renal prognosis (composites of > 1.5 folds of serum creatinine and renal replacement therapy) were investigated. A total of 110 patients (64 [42, 73] years old, 61 men) were included. The median serum GDF-15 level at baseline was 1885 (998, 3496) pg/mL. A higher serum GDF-15 level was associated with comorbidities including diabetes mellitus, anemia, renal impairment, and pathologic features including crescent formation, hyaline degeneration, and interstitial fibrosis (p < 0.05 for all). Serum GDF-15 level was a significant predictor of 3-year composite renal outcomes with an odds ratio per 100pg/mL of 1.072 (95% confidence interval 1.001-1.103, p = 0.036) after adjustment for potential confounders. Serum GDF-15 levels were associated with several renal pathological features and renal prognosis in patients with renal diseases.

FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability

BackgroundMigraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors.MethodsWe collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied.ResultsIn the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880.ConclusionSerum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability.

Serum growth differentiation factor-15 and non-esterified fatty acid levels in patients with coronary artery disease and hyperuricemia

BackgroundHigh serum NEFA and GDF-15 are risk factors for CAD and have been linked to detrimental cardiovascular events. It has been hypothesized that hyperuricemia causes CAD via the oxidative metabolism and inflammation. The current study sought to clarify the relationship between serum GDF-15/NEFA and CAD in individuals with hyperuricemia.MethodsBlood samples collected from 350 male patients with hyperuricemia(191 patients without CAD and 159 patients with CAD, serum UA > 420 μmol/L) to measure serum GDF-15 and NEFA concentrations with baseline parameters.ResultsSerum circulating GDF-15 concentrations(pg/dL) [8.48(6.67,12.73)] and NEFA levels(mmol/L) [0.45(0.32,0.60)] were higher in hyperuricemia patients with CAD. Logistic regression analysis revealed that the OR (95% CI) for CAD were 10.476 (4.158, 26.391) and 11.244 (4.740, 26.669) in quartile 4 (highest) respectively. The AUC of the combined serum GDF-15 and NEFA was 0.813 (0.767,0.858) as a predictor of whether CAD occurred in male with hyperuricemia.ConclusionsCirculating GDF-15 and NEFA levels correlated positively with CAD in male patients with hyperuricemia and measurements may be a useful clinical adjunct.

Abstract P309: Biomarkers of Mitochondrial Dysfunction and Inflammaging in Older Adults and Blood Pressure Variability

Background: Most physiopathological mechanisms underlying Blood Pressure (BP) Variability (BPV) are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging", and the hallmark “mitochondrial dysfunction” due to age-related stress. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine Growth/Differentiation Factor 15 (GDF-15) and two inflammatory biomarkers, Interleukin 6 (IL-6) and Tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. Methods: The study population consisted of 1,096 community-dwelling participants [median age 75 (72-78) years; 699 females, 63.7%] aged ≥70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a 4-year period. Systolic (SBPV) and diastolic BPV (DBPV) were determined through several indicators taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Results: Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for relevant covariates [adjusted 1-SD increase in GDF-15: β (SE)= 0.07 (0.04), p&lt; 0.044, for Coefficient of Variation%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Conclusion: Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.

Berberine Ameliorates Obesity by Inducing GDF15 Secretion by Brown Adipocytes.

Berberine (BBR), which is a compound derived from the Chinese medicinal plant Coptis chinensis, promotes weight loss, but the molecular mechanisms are not well understood. Here, we show that BBR increases the serum level of growth differentiation factor 15 (GDF15), which is a stress response cytokine that can reduce food intake and lower body weight in diet-induced obese (DIO) mice. The body weight and food intake of DIO mice were decreased after BBR treatment, and the weight change was negatively correlated with the serum GDF15 level. Further studies show that BBR induced GDF15 mRNA expression and secretion in the brown adipose tissue (BAT) of DIO mice and primary mouse brown adipocytes. In addition, we found that BBR upregulates GDF15 mRNA expression and secretion by activating the integrated stress response (ISR) in primary mouse brown adipocytes. Overall, our findings show that BBR lowers body weight by inducing GDF15 secretion via the activation of the ISR in BAT.

GDF15 plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets.

Mounting evidence points to a link between growth differentiation factor-15 (GDF15) expression and the onset and progression of diabetes mellitus. However, the exact role of GDF15 in pancreatic β-cell function is unclear. To examine the role of GDF15 in β-cell function, bioinformatics analysis and functional experiments involving GDF15 silencing and overexpression were performed in INS-1 cells and human islets. Public microarray and RNA-seq expression data showed that islets obtained from diabetic donors express high levels of GDF15 compared to islets obtained from normal donors. Moreover, analysis of RNA-seq expression data revealed that GDF15 expression correlates positively with that of insulin (INS), KCNJ11, GLUT1, MAFA, INSR and negatively with that of Glucokinase (GCK) and Alpha-Ketoglutarate Dependent Dioxygenase (FTO). No T2D-associated genetic variants in the GDF15 were found to pass genome-wide significance in the TIGER portal. Expression silencing of Gdf15 in INS-1 cells reduced insulin release, glucose uptake levels, increased reactive oxygen species (ROS) production and apoptosis levels. While Gdf15-silenced cells downregulated mRNA expression of Ins, Pdx1, Mafa, and Glut2 genes, its overexpression human islets was associated with increased insulin secretion and upregulated expression of MAFA and GLUT1 but not INS or GCK. Silencing of Pdx1 or Mafa in INS-1 cells did not affect the expression of GDF15. These findings suggest that GDF15 plays a significant role in pancreatic β-cell function.

Growth Differentiation Factor-15 Predicts Mortality and Heart Failure Exacerbation But Not Ventricular Arrhythmias in Patients With Cardiomyopathy.

Background Heart failure (HF) has been increasing in prevalence, and a need exists for biomarkers with improved predictive and prognostic ability. GDF-15 (growth differentiation factor-15) is a novel biomarker associated with HF mortality, but no serial studies of GDF-15 have been conducted. This study aimed to investigate the association between GDF-15 levels over time and the occurrence of ventricular arrhythmias, HF hospitalizations, and all-cause mortality. Methods and Results We used a retrospective case-control design to analyze 148 patients with ischemic and nonischemic cardiomyopathies and primary prevention implantable cardioverter-defibrillator (ICD) from the PROSe-ICD (Prospective Observational Study of the ICD in Sudden Cardiac Death Prevention) cohort. Patients had blood drawn every 6 months and after each appropriate ICD therapy and were followed for a median follow-up of 4.6 years, between 2005 to 2019. We compared serum GDF-15 levels within ±90 days of an event among those with a ventricular tachycardia/fibrillation event requiring ICD therapies and those hospitalized for decompensated HF. A comparator/control group comprised patients with GDF-15 levels available during 2-year follow-up periods without events. Median follow-up was 4.6 years in the 148 patients studied (mean age 58±12, 27% women). The HF cohort had greater median GDF-15 values within 90 days (1797 pg/mL) and 30 days (2039 pg/mL) compared with the control group (1062 pg/mL, both P<0.0001). No difference was found between the ventricular tachycardia/fibrillation subgroup within 90 days (1173 pg/mL, P=0.60) or 30 days (1173 pg/mL, P=0.78) and the control group. GDF-15 was also significantly predictive of mortality (hazard ratio, 3.17 [95% CI, 2.33-4.30]). Conclusions GDF-15 levels are associated with HF hospitalization and mortality but not ventricular arrhythmic events.

Association between physical activity, growth differentiation factor 15 and bodyweight in older adults: A longitudinal mediation analysis

Late-life aging is often associated with appetite reduction and weight loss. Physical activity (PA) may prevent these processes, but the molecular mechanisms involved remain elusive. The present study investigated the putative mediating aspect of growth differentiation factor 15 (GDF-15), a stress signalling protein involved in aging, exercise and appetite control, on the association between PA and late-life-associated weight loss. One thousand eighty-three healthy adults (63.8% women) aged 70years and over who participated in the Multidomain Alzheimer Preventive Trial were included. Bodyweight (kg) and PA levels (square root of metabolic equivalent of task-min/week) were assessed repeatedly from baseline to the 3-year visit, whereas plasma GDF-15 (pg/mL) was measured at the 1-year visit. Multiple linear regressions were performed to test the association between first-year mean PA level, 1-year visit GDF-15 concentration and subsequent bodyweight changes. Mediation analyses were used to investigate whether GDF-15 mediated the association between first-year mean PA levels and consecutive bodyweight changes. Multiple regression analyses demonstrated that higher first-year mean PA levels significantly predicted lower GDF-15 and bodyweight at 1year (B=-2.22; SE=0.79; P=0.005). In addition, higher 1-year visit GDF-15 levels were associated with faster subsequent bodyweight loss (Time×GDF-15 interaction B=-0.0004; SE=0.0001; P=0.003). Mediation analyses confirmed that GDF-15 mediated the association between first-year mean PA levels and subsequent bodyweight changes (mediated effect ab=0.0018; bootstrap SE=0.001; P<0.05) and revealed that mean PA had no direct effect on subsequent bodyweight changes (c' =0.006; SE=0.008; P>0.05). This study suggests that GDF-15 may be one of the molecules mediating the link between PA and late-life weight loss, but mechanistic studies are necessary to further support the present findings.

Association between growth differentiation factor 15 levels and gestational diabetes mellitus: A combined analysis.

Gestational diabetes mellitus (GDM) is a common glucose metabolism disease occurs in pregnancy that affects both maternal and neonatal health. Recently, increasing studies have attached importance to the relationship between growth differentiation factor 15 (GDF-15) and GDM, but the results were inconclusive. Therefore, we conducted a meta-analysis to examine the association between GDF-15 and GDM. A systematical search was performed in Gene Expression Omnibus (GEO), PubMed and Google Scholar till Oct 27, 2022. We first calculated the mean and standard deviation of GDF-15 expression levels from the included eligible datasets and articles. Then, a meta-analysis was conducted to depict the difference in GDF-15 mRNA or GDF-15 protein expression between case and control groups by using conservative random effect model. Moreover, the potential publication bias was checked with the aid of Begg's test and Egger's test. Finally, sensitivity analyses were performed by changing the inclusion criteria. In summary, 12 GEO datasets and 5 articles were enrolled in our study, including 789 GDM patients and 1202 non-GDM pregnant women. It was found that the expression levels of GDF-15 mRNA and GDF-15 protein in late pregnancy were significantly higher in GDM patients compared with non-GDM pregnant women, with the standard mean difference (SMD) and 95% confidence interval (95% CI) of 0.48 (0.14, 0.83) and 0.82 (0.32-1.33), respectively. Meanwhile, a slightly weakened association between GDF-15 protein levels and GDM was also observed in the middle pregnancy, with SMD (95% CI) of 0.53 (0.04-1.02). In all, our results suggested that the expression levels of GDF-15 were significantly higher in GDM patients compared with non-GDM pregnant women, especially in the late pregnancy.

Markers of coagulation and inflammation and adverse events in patients with active cancer and atherosclerosis: common features and differences

Introduction. Thrombotic complications (TC) in different vascular systems dictate the fate of high-risk patients. In cardiological practice, patients with advanced atherosclerotic vascular disease (MFA) represent the most vulnerable group. Malignant neoplasm (MN) is one of the most significant risk factors for developing TCs, especially in the context of antineoplastic therapy. The presence of significant differences in the mechanisms of thrombogenesis in malignant neoplasms and atherosclerosis determines the appropriateness of a comparative study of markers of coagulation activation and endothelial damage in order to identify common features and differences specific to each pathology. Aim. To examine markers of coagulation activation and growth factors in active cancer and advanced atherosclerotic vascular disease, to identify their common features and differences specific to each pathology. Materials and methods. A total of 22 patients with MN (Group 1) and 58 patients with MFA (Group 2) were enrolled in the study. The assessed biomarkers included: von Willebrand factor (VWF), D-dimer, growth differentiation factor-15 (GDF-15) and vascular endothelial growth factor A (VEGF-A). Results. Patients with MN had an increased likelihood of disease progression within 6 months at D-dimer level &gt; 1121 ng/mL (OR = 10.5; 95% CI 1.4–81.0, p = 0.014) or VWF &gt; 189% (OR 10.5, 95% CI 1.36–81.0, p = 0.014); the likelihood of death within two years of follow-up at D-dimer level &gt; 1121 ng/mL (OR = 7.0; 95% CI 0.97–50.57, p = 0.04), or VWF &gt; 203% (OR = 10, 5, 95% CI 1.36–81.06, p = 0.014). In patients with MFA, the likelihood of prognosis determining events within one-year of follow-up was determined by increased levels of VWF &gt; 157% (OR = 9.2, 95% CI 1.02–82.8, p = 0.048) and GDF-15 &gt; 1548 pg/ml (OR = 5.7; 95% CI 1.09–29.5, p = 0.04). Conclusions. Endothelial damage and coagulation activation are more pronounced in patients with MN than in patients with MFA. In patients with malignant neoplasms, the outcomes were associated with D-dimer and VWF levels, and in patients with MFA – with VWF and GDF-15 levels.

Altered circulating GDF-15 level predicts sex hormone imbalance in males with major depressive disorder

BackgroundIt has been hypothesized that higher growth differentiation factor 15 (GDF15) level and lower testosterone/ estradiol (T/E) ratio are associated with major depressive disorder (MDD), yet the underlying effect of serum GDF15 on hinting the T/E ratio imbalance is not fully understood. We observed the correlation between serum T/E ratio and circulating GDF15 in male depressed cohort.MethodsThe sample consisted of participants (aged 18 ~ 65 years) from the Renmin Hospital of Wuhan University with MDD (n = 412) defined according to a Structured Clinical Interview for DSM-V (SCID), and male healthy controls (n = 137). Serum levels of testosterone, estradiol, and depression risk biomarkers (thyroid hormone, lipids, hs-CRP, Tenascin-C [TNC], GDF15, KLF4, Gas6, and sgp130) were measured. The associations among log-transformed T/E ratio and these biomarkers were analyzed using univariate correlation analysis, category analyses, and linear regression adjusting for standard risk factors.ResultsOf the sample, 36.89% had lower T/E ratio (< 10:1) and 10.20% had higher T/E ratio (> 20:1). After multivariable adjustment, T/E ratio was negatively associated with GDF15 (-0.095 [95% CI -0.170 ~ -0.023] standard deviation [SD] change per SD increase in lg[T/E], P = 0.015) and inversely related to TNC (-0.085 [95% CI -0.167 ~ 0.003] standard deviation [SD] change per SD increase in lg[T/E], P = 0.048). Serum T/E ratio was negatively associated with GDF15 level in both FT3, TSH and HDL strata, whereas this association was not observed in TNC. In T/E ratio strata analyses, there is a significant and negative correlation among T/E ratio and GDF15 in depressive patients with sex hormone imbalance, yet this relationship was not investigated in patients with sex hormone balance.ConclusionIn our community-based observation, circulating GDF-15 level was greatly and inversely associated with serum T/E ratio, indicating that higher GDF-15 alerts sex hormone imbalance in patients with MDD.

A Review on Biomarkers for Early Diagnosis of Diabetic Kidney Disease

Introduction: To assess the potential of galectin-3 and growth differentiation factor-15 (GDF-15) biomarkers for the early detection of diabetic kidney disease (DKD). Methodology: This was a cross-sectional study conducted over a period of 1.2 years. Patients were stratified based on estimated glomerular filtration rate (eGFR) and albuminuria level. The receiver operating characteristic (ROC) curve was plotted to assess the diagnostic potential of biomarkers. Conclusion: In DKD patients the galectin-3 and GDF-15 levels were inversely related to the eGFR which was further confirmed by the ROC curve demonstrating the potential of galectin-3 and GDF-15 as a biomarker.

A Story of PA/BSA and Biomarkers to Diagnose Pulmonary Hypertension in Patients with Severe Aortic Valve Stenosis-The Rise of IGF-BP2 and GDF-15.

(1) Background: Currently, echocardiography is the primary non-invasive diagnostic method used to screen patients with severe aortic valve stenosis (AS) for pulmonary hypertension (PH) by estimating systolic pulmonary artery pressure (sPAP). Other radiological methods have been a focus of research in the past couple of years, as it was shown that by determining the pulmonary artery (PA) diameter, prognostic statements concerning overall mortality could be made in these patients. This study compared established and novel cardiovascular biomarkers with the PA/BSA value to detect PH in patients with severe AS. (2) Methods: The study cohort comprised 188 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR), who were then divided into two groups based on PA/BSA values obtained through CT-angiography. The presence of PH was defined as a PA/BSA ≥ 16.6 mm/m2 (n = 81), and absence as a PA/BSA < 16.6 mm/m2 (n = 107). Blood samples were taken before TAVR to assess cardiovascular biomarkers used in this study, namely brain natriuretic peptide (BNP), cardiac troponin I (cTnI), high-sensitive troponin (hsTN), soluble suppression of tumorigenesis-2 (sST2), growth/differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), insulin-like growth factor binding protein 2 (IGF-BP2), and soluble urokinase-type plasminogen activator receptor (suPAR). (3) Results: Patients with a PA/BSA ≥ 16.6 mm/m2 showed significantly higher levels of BNP (p = <0.001), GDF-15 (p = 0.040), and H-FABP (p = 0.007). The other investigated cardiovascular biomarkers did not significantly differ between the two groups. To predict a PA/BSA ≥ 16.6 mm/m2, cut-off values for the biomarkers were calculated. Here, GDF-15 (p = 0.029; cut-off 1172.0 pg/mL) and BNP (p < 0.001; cut-off 2194.0 pg/mL) showed significant results. Consequently, analyses of combined biomarkers were performed, which yielded IGF-BP2 + BNP (AUC = 0.721; 95%CI = 0.585−0.857; p = 0.004) as the best result of the two-way analyses and GDF-15 + IGF-BP2 + BNP (AUC = 0.727; 95%CI = 0.590−0.864; p = 0.004) as the best result of the three-way analyses. No significant difference regarding the 1-year survival between patients with PA/BSA < 16.6 mm/m2 and patients with PA/BSA ≥ 16.6 mm/m2 was found (log-rank test: p = 0.452). (4) Conclusions: Although PA/BSA aims to reduce the bias of the PA value caused by different body compositions and sizes, it is still a controversial parameter for diagnosing PH. Combining the parameter with different cardiovascular biomarkers did not lead to a significant increase in the diagnostic precision for detecting PH in patients with severe AS.

Effects of early standardized enteral nutrition on preventing acute muscle loss in the acute exacerbation of chronic obstructive pulmonary disease patients with mechanical ventilation.

To investigate the effects of early standardized enteral nutrition (EN) on the cross-sectional area of erector spine muscle (ESMcsa), plasma growth differentiation factor-15 (GDF-15), and 28-day mortality of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients with invasive mechanical ventilation (MV). A total of 97 AECOPD patients with invasive MV were screened in the ICUs of the First People's Hospital of Lianyungang. The conventional EN group (stage I) and early standardized EN group (stage II) included 46 and 51 patients, respectively. ESMcsa loss and GDF-15 levels on days 1 and 7 of ICU admission and 28-day survival rates were analyzed. On day 7, the ESMcsa of the early standardized EN group was significantly higher than that of the conventional EN group, while the plasma GDF-15 levels were significantly lower than those in the conventional EN group (ESMcsa: 28.426±6.130 cm2 vs. 25.205±6.127 cm2; GDF-15: 1661.608±558.820 pg/mL vs. 2541.000±634.845 pg/mL; all P<0.001]. The 28-day survival rates of the patients in the early standardized EN group and conventional EN group were 80.40% and 73.90%, respectively (P=0.406). ESMcsa loss in AECOPD patients with MV was correlated with GDF-15 levels, both of which indicated acute muscular atrophy and skeletal muscle dysfunction. Early standardized EN may prevent acute muscle loss and intensive care unit-acquired weakness (ICU-AW) in AECOPD patients.

Study of growth differentiation factor-15 in polytransfused children with β-thalassemia.

Ineffective erythropoiesis is a predominant feature in β-thalassemia major (β-TM), causing marked erythroid expansion leading to highly raised levels of growth differentiation factor-15 (GDF-15), which, in turn, suppresses hepcidin production in liver resulting in increased iron absorption from gut. We aim to study the serum GDF-15 in polytransfused β-TM patients and its correlation with serum ferritin and serum hepcidin. Thirty-nine polytransfused β-TM children aged between 5 and 17 years and 33 age- and gender-matched healthy controls were enrolled in the study. Complete blood count, serum GDF-15, serum ferritin, and serum hepcidin were performed. The mean serum GDF-15, serum hepcidin, and serum ferritin levels were 638.65 ± 306.96 pg/ml, 108.21 ± 191.30 ng/ml, and 2274.60 ± 1216.08 ng/ml, respectively, which were significantly higher than control group (P < 0.001, P = 0.003, P < 0.001, respectively). There was significant positive correlation of GDF-15 with blood transfusions (r = 0.415, P = 0.009), positive correlation with serum ferritin (r = 0.653, P = 0), and significant negative correlation with serum hepcidin (r = -0.508, P = 0.001). The findings of the present study suggest that GDF-15 is an important regulator of hepcidin in β-TM patients. GDF-15 and serum hepcidin together can be used to monitor iron overload and its related complications in such patients.

Thrombospondin-2 as a potential noninvasive biomarker of hepatocyte injury but not liver fibrosis in children with MAFLD: A preliminary study.

Metabolic-associated fatty liver disease (MAFLD) requires close monitoring due to its increased incidence and progression to fibrosis, cirrhosis and even hepatocellular carcinoma. The search for non-invasive markers to diagnose liver fibrosis is ongoing. The aim of our study was to evaluate the serum levels of growth differentiation factor-15 (GDF-15), thrombospondin-2 (TSP2), pentraxin 3 (PTX3) and angiopoietin-like protein 8 (ANGPTL8) in children with MAFLD. Fifty-six overweight/obese children with suspected liver disease were included in this prospective study. MAFLD was diagnosed according to the latest consensus. Vibration-controlled transient elastography (TE) was performed to detect clinically significant liver fibrosis. Serum concentrations of GDF-15, TSP2, PTX3 and ANGPTL8 were measured by enzyme-linked immunosorbent assay (ELISA). Liver steatosis was diagnosed in abdominal ultrasound in 31 (55.36%) overweight/obese patients who were classified as the MAFLD group. Aspartate aminotransferase (AST)/platelet ratio (APRI) and liver stiffness measurement (LSM) values and TSP2 concentrations showed significantly higher values in patients in MAFLD than in the non-MAFLD group. TSP2 was significantly positively correlated with alanine transaminase (ALT), AST, γ-glutamyltransferase (GGT) and APRI in the study group. The receiver operating characteristics (ROC) analysis showed that the area under the curve (AUC) of LSM, APRI and serum TSP2 was significant for predicting MAFLD in obese children. In the multivariable regression model, LSM was the only significant parameter associated with the diagnosis of MAFLD in children. TSP2 may be a potential biomarker of hepatocyte injury in pediatric patients with MAFLD. None of the examined biomarkers were found to be effective non-invasive markers of liver fibrosis in children.

Iron status and anemia control are related to peritoneal membrane properties in peritoneally dialyzed patients.

Characteristics of peritoneal membrane is unique and individually different in peritoneal dialysis patients. Relationship between specific nature of peritoneal transport, anemia and inflammation has not yet been extensively studied. We attempted to outline the complex interplay of several biomarkers of iron status and their association with peritoneal transport, degree of inflammation and residual renal function. A total of 58 patients treated with peritoneal dialysis either CAPD or APD for at least 3 months were enrolled in this study. Full blood count, traditional markers of iron status (transferrin saturation-TSAT and ferritin), serum erythroferrone-ERFE, soluble transferrin receptor (sTfR), hepcidin, zonulin, growth differentiation factor -15 (GDF15), IL-16, hsCRP and hypoxia-inducible factor-α (HIF-1-α; in serum and dialysate) were measured using commercially available tests. We also performed Peritoneal Equilibrium Test and assessed GFR level. Hb levels above 10 g/dL was found in 74% of patients. Hb levels positively correlated with residual renal function and nutritional status. Adequate iron status was diagnosed in 69% of subjects, only in 9% of patients, criteria for absolute iron deficiency were met. Serum ERFE correlated inversely with hepcidin levels but was not associated with erythropoietin stimulating agent dose. Peritoneal transport had strong correlation with dialysate sTfR (p < 0.05), dialysate hepcidin (p < 0.05), dialysate GDF15 (p < 0.01) and dialysate zonulin (p < 0.001) levels, as well as serum IL6 (p = 0.03), serum hs-CRP (p = 0.04) and dialysate hs-CRP (p = 0.04). Residual kidney function contributes considerably to better control of anemia. Various degree of inflammation is inherent to PD patients. Additionally, fast-average peritoneal transport is associated with greater degree of inflammation and higher concentration of markers of iron status, GDF15 and zonulin in dialysate. This finding may indicate more effective clearance of higher-range middle molecules in fast-average transporters. The role of ERFE as a marker of erythropoiesis in PD patients requires further investigation.

Salivary growth differentiation factor-15 levels in oral leukoplakia and oral squamous cell carcinoma

Salivary growth differentiation factor-15 levels in oral leukoplakia and oral squamous cell carcinoma