Median Growth Differentiation Factor 15 Research Articles

High serum growth differentiation factor 15 is a risk factor for the occurrence of hepatocellular carcinoma in chronic hepatitisB patients treated with nucleos(t)ide analogs.

Patients with chronic hepatitisB (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitisB virus (HBV) RNA, hepatitis B core-related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitisC. We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB-4 index, alpha-fetoprotein and gamma-glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0ng/mL, gamma-glutamyl transpeptidase ≥22U/L, FIB-4 index≥1.93, and GDF-15≥1.17ng/mL groups. In patients with no or more than three of these five risk factors, the 10-year HCC cumulative incidence rates were 0% and 41.0%, respectively. High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs.

Diagnostic value of serum GDF-15 in patients with pseudomyxoma peritonei

Background and aimsPseudomyxoma peritonei (PMP) is a rare malignancy that lacks a highly sensitive and specific biomarker for its diagnosis. Identifying reliable serum markers is crucial for improving the diagnostic accuracy and management of PMP. This study aims to explore the diagnostic value of serum growth differentiation factor 15 (GDF-15) in patients with PMP. Material and methodsWe carried on a 1:1 matched case-control study. 44 patients with PMP hospitalized in Aerospace Center Hospital were recruited as cases, and 44 sex- and age-matched apparently healthy participants were selected as controls. The serum GDF-15 concentrations were tested using an ELISA method. The diagnostic value of GDF-15 in PMP patients was assessed by receiver operating characteristic (ROC) curve analysis. ResultsThe median serum GDF-15 level in PMP patients was 1192.77 (843.03–1879.06) pg/mL, notably higher than that in healthy controls [533.27 (410.46–641.47) pg/mL] (P<0.001). The area under the curve (AUC) of serum GDF-15 for PMP diagnosis was 0.907, the optimal diagnostic threshold value was 644.58 pg/mL, the sensitivity was 93.18 %, and the specificity was 77.27 %. The AUC of GDF-15 combined with carbohydrate antigen 125 (CA125) was larger than that of GDF-15 alone (P=0.027), and the sensitivity and specificity achieved 86.36 % and 95.45 %. GDF-15 levels showed a significant correlation with age (P=0.042), with younger PMP patients exhibiting notably lower concentrations of GDF-15 compared to older patients. ConclusionSerum GDF-15 could become a new marker for the PMP diagnosis. The combination of GDF-15 and CA125 demonstrated superior diagnostic performance for PMP compared to GDF-15 alone, achieving a sensitivity of 86.36% and a specificity of 95.45%.

Association between eating speed and atherosclerosis in relation to growth differentiation factor-15 levels in older individuals in a cross-sectional study

Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima–media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60–69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.

Is there any relationship of serum Growth Differentiation Factor 15 and Iron Profile with Age?

Objective: To compare growth differentiation Factor-15(GDF-15), iron and ferritin levels in younger and elderly patients suffering from end stage renal disease on hemodialysis and to determine is there any age-related change in these markers?.Methodology:This cross-sectional comparative study was conducted in the Nephrology Department of Sheikh Zayed Hospital Lahore from January 2018 to December 2018 after getting approval from Institutional Review Board of National Health Research Complex (NHRC) with vide no. F39/NHRC/Admin/IRB/372 Written consent was taken from patients.Group A has less than 60 years, while group B was with patients of greater than 60 years of age.Serum GDF-15, serum iron and ferritin of hemodialysis patients were determined by ELISA. Statistical analysis was done by SPSS 22.0 Results: The total number of patients was 140. Group A has 86 patients (40 male and 46 female). Group B had 54 patients(36 male and 17 female). Group A and Group B participants had serum median (IQR) GDF-15 levels 684(120-1604) and 2650(369-3625)pg/ml respectively, (P value 0.001) Conclusion: GDF-15 levels were significantly elevated in patients greater than 60 years of age and ferritin levels were similar in all age groups.

Prognostic significance of growth differentiation factor-15 across age in chronic heart failure.

Growth differentiation factor-15 (GDF15), a cytokine in the transforming growth factor family, is up-regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age-specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF). Serum levels of GDF15 were examinedin 942 hypertensive patients (median 68years) with CHF from the SUPPORT trial across the four age groups [under 50 (n=73), 51-59 (n=158), 60-69 (n=296), and 70-79years (n=415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all-cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50years to 855 in 51-59years, 1114 in 60-69years, and 1516 in 70-79years (trend P<0.001). Age, sex, systolic blood pressure, history of diabetes, ischaemic heart disease, left ventricular (LV) end-systolic dimension, LV ejection fraction, estimated glomerular filtration rate, haemoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin, C-reactive protein, and the use of angiotensin-converting enzyme inhibitors, diuretics, and statins were mutually selected as clinical covariates of GDF15. The LASSO regression analysis identified significant interactions between age and the history of diabetes and NT-proBNP, with particularly robust associations in patients aged between 60 and 70years. During the mean follow-up of 8.6years, 474 composite endpoints of HF hospitalization or death occurred. GDF15 was associated with a higher risk of HF hospitalization or all-cause death [adjusted hazard ratio 1.84 (95% confidence interval 1.45-2.33)], with a particularly heightened risk in patients aged around 70years (Pinteraction=0.0008). The model with GDF15 on top of other established risk factors yielded marginally higher C-statistics compared with the model without GDF15 (0.803 and 0.796, P=0.045). The additive value of GDF15 on top of other established risk factors appeared similar across ages. A universal cut-off value of 1400pg/mL performed well in discriminating between those with and without HF hospitalization or death. Some clinical correlates of GDF15 have an interaction with age. GDF15 is an important determinant of cardiovascular endpoints, particularly in patients aged around 70years. The additive value of GDF15 appeared consistent across ages, suggesting the use of a universal cut-off value.

Prognostic significance of growth differentiation factor-15 across the BMI spectrum in patients with chronic heart failure: Insights from the SUPPORT trial

Abstract Background Obesity is a risk factor for cardiovascular diseases including heart failure (HF), yet patients with obesity have better outcomes than their leaner counterparts in HF (i.e. the obesity paradox). We sought to investigate whether growth differentiation factor-15 (GDF15), an emerging biomarker in HF reflecting inflammation and oxidative stress, is a prognostic indicator across the body mass index (BMI) spectrum in chronic heart failure (CHF). Methods Serum levels of GDF15 and its prognostic significance across BMI were examined in a total of 1,040 Japanese patients with CHF enrolled in a randomized clinical trial of the SUPPORT trial (supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan) (mean age 66.0±9.9 years, 26% female). Patients were categorized into four groups: underweight (BMI &amp;lt;18.5 kg/m2; n = 56), normal (BMI 18.5-22.9; n = 304), overweight (BMI 23-24.9; n = 257), and obese (BMI ≥25; n = 423) defined based on the WHO recommendation for Asian-Pacific population. Results The underweight group consisted of older patients with a higher prevalence of NYHA class III and reduced left ventricular ejection fraction (LVEF) compared to obese patients (mean age 69.0 vs 64.7 years, NYHA class III 17.9 vs 5.9%, and mean LVEF 49.3 vs 55.5%; all p&amp;lt;0.05). Median GDF15 level in the underweight group was higher (1,864 pg/mL [IQR 1,070-2,626]) but was similar in overweight and obese groups (1,285 [953, 1772] and 1,220 [888-1,789], respectively) compared to normal BMI group (1,276 [879-2,018]). During follow-up (median 10.3 years), 540 composite events of HF hospitalization or all-cause death occurred. The risk was higher in the underweight group (adjusted HR 1.8, 95%CI [1.3-2.5]) and lower in the obesity group (adjusted HR 0.8 [95% CI 0.6-0.9]) compared to the normal BMI group. An increased GDF15 incurred a consistently higher risk from underweight to obese groups; per unit increase in logGDF15 (pg/mL) was associated with 4.1, 2.4, 1.7 and 2.4 times higher risk, respectively. The optimal cut-off point for discriminating those with and without the composite events was 1,343 pg/mL in overall patients. This cut-off value performed well as a prognostic indicator across the continuous BMI spectrum including those with higher BMI (Figure). Conclusions The prognostic significance of GDF15 persisted across the BMI spectrum in patients with CHF. GDF15 may be useful for providing prognostic information across patients with a diverse range of BMI even in those with modest outcomes.HF events in high GDF15 across BMI

The Novel Biomarker Growth Differentiation Factor-15 in Patients with Chronic Heart Failure at a Heart Failure Clinic in the Asia-Pacific Region: A Prospective Observational Study

Background: Growth differentiation factor-15 (GDF-15) is an emerging prognostic biomarker in heart failure (HF). However, there are limited data on its role in HF patients in southeast Asia. This prospective observational study investigated the association between GDF-15 and various clinical parameters, and its role in predicting all-cause mortality. Methods: 160 patients with chronic HF and reduced left ventricular ejection fraction (LVEF) enrolled between October 2020 and April 2021. At study entry, baseline GDF-15 and N-terminal pro B-type natriuretic peptide (NT-proBNP) were evaluated. Patients were followed up per clinical routine. Results: The median GDF-15 was 1,715 ng/l. Patients were divided into two groups: GDF-15 &lt;2,000 or ≥2,000 ng/l. This cut-off has been shown to represent prognostic threshold in previous studies. The GDF-15 ≥2,000 group was older, had more severe HF and higher comorbidity burden, and lower use of renin–angiotensin–aldosterone system inhibitors (RAASi). GDF-15 was positively correlated with a history of MI, diabetes, chronic kidney disease and use of loop diuretics, but negatively correlated with RAAsi use. GDF-15 ≥2,000 was not associated with all-cause mortality at 60 weeks. The pooled stratum of GDF-15 ≥2,000/NT-proBNP ≥1,000 pg/ml had significantly higher mortality than GDF-15 &lt;2,000/NT-proBNP &lt;1,000 pg/ml. NT-proBNP and the Meta-Analysis Global Group In Chronic risk score but not GDF-15, were independently predictive of all-cause mortality. Conclusion: In our cohort of chronic HF patients with reduced LVEF who were relatively younger than the cohorts studied in previous GDF-15 in HF trials, well-managed and largely asymptomatic, GDF-15 did not independently predict all-cause mortality. The prognostic cut-off of GDF-15 ≥2,000 ng/l was not significantly associated with higher all-cause mortality at 60 weeks.

Growth differentiation factor-15 and prediction of cancer-associated thrombosis and mortality: a prospective cohort study

BackgroundPatients with cancer are at increased risk of venous thromboembolism (VTE) and arterial thromboembolic/thrombotic events (ATEs). Growth differentiation factor-15 (GDF-15) improves cardiovascular risk assessment, but its predictive utility in patients with cancer remains undefined. ObjectivesTo investigate the association of GDF-15 with the risks of VTE, ATE, and mortality in patients with cancer and its predictive utility alongside established models. MethodsThe Vienna Cancer and Thrombosis Study (CATS)—a prospective, observational cohort study of patients with newly diagnosed or recurrent cancer—which was followed for 2 years, served as the study framework. Serum GDF-15 levels at study inclusion were measured, and any association with VTE, ATE, and death was determined using competing risk (VTE/ATE) or Cox regression (death) modeling. The added value of GDF-15 to established VTE risk prediction models was assessed using the Khorana and Vienna CATScore. ResultsAmong 1531 included patients with cancer (median age, 62 years; 53% men), median GDF-15 levels were 1004 ng/L (IQR, 654-1750). Increasing levels of GDF-15 were associated with the increased risks of VTE, ATE, and all-cause death ([subdistribution] hazard ratio per doubling, 1.16 [95% CI, 1.03-1.32], 1.30 [95% CI, 1.11-1.53], and 1.57 [95% CI, 1.46-1.69], respectively). After adjustment for clinically relevant covariates, the association only prevailed for all-cause death (hazard ratio, 1.21; 95% CI, 1.10-1.33) and GDF-15 did not improve the performance of the Khorana or Vienna CATScore. ConclusionGDF-15 is strongly associated with survival in patients with cancer, independent of the established risk factors. While an association with ATE and VTE was identified in univariable analysis, GDF-15 was not independently associated with these outcomes and failed to improve established VTE prediction models.

Abstract CT108: First-in-patient study of the GDF-15 inhibitor ponsegromab in patients with cancer and cachexia: Safety, tolerability, and exploratory measures of efficacy

Abstract Background: Cachexia is common in patients with advanced cancer and has been associated with elevated serum growth/differentiation factor 15 (GDF-15) concentrations. This first-in-patient, phase 1b, study assessed the use of ponsegromab, a monoclonal antibody against GDF-15, in participants with advanced cancer and cachexia. Methods: Adult participants (n = 10) with cachexia, advanced cancer (non-small cell lung, colorectal, or pancreatic), and elevated serum concentrations of GDF-15 received open-label subcutaneous ponsegromab every three weeks (Q3W) for 12 weeks in addition to standard of care anti-cancer treatment. Study endpoints included assessment of ponsegromab safety, tolerability, and pharmacokinetics. Serum GDF-15 concentrations and exploratory measures of efficacy were also assessed. Results: No treatment-related adverse events or injection site reactions were reported. No adverse trends in clinical laboratory tests, vital signs, or electrocardiogram parameters attributable to ponsegromab dosing were evident. Ninety-two adverse events deemed unrelated to treatment were reported; most were mild (Grade 1 = 58.7%) or moderate (Grade 2 = 28.3%) in severity. All participants were negative for anti-drug antibodies at baseline (n = 10) and after receiving 5 doses (Q3W) of ponsegromab (n = 9). Mean unbound ponsegromab Ctrough ranged from 4.041-4383 ng/mL between Days 22-106. An elevated GDF-15 concentration was required for inclusion in the study. Following initiation of study treatment, median unbound GDF-15 concentration was reduced to below the lower limit of quantification (0.0424 ng/mL) on day 1 and remained suppressed until week 15 (3 weeks after final dose). Increases in body weight were observed at all time points during the treatment (weeks 3, 6, 9, and 12) and follow-up (weeks 15, 18, and 24) periods. The mean (SD) body weight at baseline was 70.49 (16.97) kg. An LS mean (SE) increase of 4.63 kg (1.98) was observed at week 12 (end of treatment); representing an increase of approximately 6.5% relative to baseline. Improvements in actigraphy-based assessments of physical activity and in quality of life, including appetite, as assessed by Functional Assessment of Anorexia-Cachexia Therapy (FAACT) total and subscale scores, were also observed during the course of ponsegromab treatment. Conclusions: In participants with advanced cancer, cachexia, and elevated baseline GDF-15, ponsegromab was well tolerated and suppressed serum GDF-15 concentrations to below the median concentration seen in healthy subjects. Preliminary evidence of efficacy, including a mean observed weight gain of approximately 6.5% at 12 weeks, supports continued development of ponsegromab for the treatment of cancer cachexia. Funded by Pfizer. ClinicalTrials.gov: NCT04299048 Citation Format: Jeffrey Crawford, Roberto A. Calle, Susie M. Collins, Yan Weng, Shannon L. Lubaczewski, Clare Buckeridge, Ellen Q. Wang, Magdalena A. Harrington, Anil Tarachandani, Michelle I. Rossulek, James H. Revkin. First-in-patient study of the GDF-15 inhibitor ponsegromab in patients with cancer and cachexia: Safety, tolerability, and exploratory measures of efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT108.

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.

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.

Circulating cardiovascular biomarkers during and after preeclampsia: Crosstalk with placental function?

Cardiovascular disease (CVD) is the leading cause of death in women, yet sex-specific risk factors remain understudied. Preeclampsia and other adverse pregnancy outcomes imply an increased maternal cardiovascular risk. We hypothesized that cardiac troponin T (cTnT), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) are increased in such pregnancies and correlate with markers of placental dysfunction. We also investigated these cardiovascular biomarkers 1 or 3years postpartum. Prior to delivery, we included serum from 417 pregnant women: 55 early-onset preeclampsia (EO-PE), 63 late-onset preeclampsia (LO-PE), 30 gestational hypertension (GH) and 269 healthy controls. Postpartum, we included 341 women 1 or 3years after delivery: 26 EO-PE, 107 LO-PE, 61 GH, and 147 healthy pregnancies. Prior to delivery, median cTnT and NT-proBNP concentrations were higher in women with EO-PE, LO-PE, or GH than in controls. Median GDF-15 was higher in EO-PE and LO-PE compared to controls. Postpartum, GDF-15 was elevated in women with previous EO-PE. Markers of placental dysfunction correlated with CVD biomarkers in pregnancy, but not postpartum. Our findings underscore the cardiovascular burden of hypertensive disorders of pregnancy and the crosstalk with placental function. The upregulation of circulating GDF-15 following early-onset preeclampsia is in line with the epidemiological excessive risk of premature CVD in this group of women. GDF-15 may be explored for targeting postpartum women with most to gain from intensified preventive follow-up for CVD.

Abstract 14368: Growth Differentiation Factor-15 in Heart Failure Across Body Mass Index Categories: The PREHOSP-CHF Study

Introduction: Growth differentiation factor-15 (GDF-15), a stress-responsive member of the transforming growth factor ꞵ cytokine superfamily is an independent prognostic predictor in patients with heart failure (HF). GDF-15 has been also reported to be associated with cardiac cachexia and malnutrition. However the association of GDF-15 and prognosis in patients with HF according to body mass index (BMI) is unclear. Methods: The PREHOSP-CHF study is a multicenter prospective cohort study among patients with HF. A total of 1,024 patients (mean age, 75.5 years, 58.7% male) were included in the analyses. Serum levels of GDF-15, as well as N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin I (hs-cTnI), and high sensitivity C-reactive protein (hs-CRP), were measured. We divided the patients into 3 groups based on the tertile of BMI: low (≤19.9), middle (19.9&lt;, ≤23.4), and high (&gt;23.4). Results: The low BMI group were older, and had more female, HF with preserved ejection fraction (≥50%), and NYHA 3/4. NT-proBNP levels were higher in the low group, but hs-cTnI and hs-CRP were comparable between the 3 subgroups. Median GDF-15 levels in the low, middle and high groups were 2271, 2264, and 1888 pg/ml, respectively. During 2 years follow-up, all-cause death and major adverse cardiovascular events (MACE: cardiovascular death and HF hospitalization) occurred in 111 and 130 in the low group, 66 and 132 in the middle group, and 34 and 88 in the high group. After adjustment for clinical confounders and cardiac biomarkers, higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the entire cohort. BMI subgroup analysis revealed that higher GDF-15 was significantly associated with the incidence of all-caused death and MACE in the middle and high groups, but not in the low group (Figure). Conclusions: Among HF, higher GDF-15 was significantly associated with all-cause death and MACE especially in the middle and high BMI groups.

Growth Differentiation Factor 15: A Novel Growth Biomarker for Children With Congenital Heart Disease.

Failure to thrive (FTT), defined as weight or height less than the lowest 2.5 percentile for age, is prevalent in up to 66% of children with congenital heart disease (CHD). Risk stratification methods to identify those who would benefit from early intervention are currently lacking. We aimed to identify a novel growth biomarker to aid clinical decision-making in children with CHD. This is a cross-sectional study of patients 2 months to 10 years of age with any CHD undergoing cardiac surgery. Preoperative weight-for-age Z scores (WAZ) and height-for-age Z scores (HAZ) were calculated and assessed for association with preoperative plasma biomarkers: growth differentiation factor 15 (GDF-15), fibroblast growth factor 21, leptin, prealbumin, and C-reactive protein (CRP). Of the 238 patients included, approximately 70% of patients had WAZ/HAZ < 0 and 34% had FTT. There was a moderate correlation between GDF-15 and WAZ/HAZ. When stratified by age, the correlation of GDF-15 to WAZ and HAZ was strongest in children under 2 years of age and persisted in the setting of inflammation (CRP > 0.5 mg/dL). Diagnoses commonly associated with congestive heart failure had high proportions of FTT and median GDF-15 levels. Prealbumin was not correlated with WAZ or HAZ. GDF-15 represents an important growth biomarker in children with CHD, especially those under 2 years of age who have diagnoses commonly associated with CHF. Our data do not support prealbumin as a long-term growth biomarker.

Relationship between GDF-15, urinary sodium and markers of renal function in patients with chronic heart failure

Abstract Background Patients with heart failure (HF) often have altered renal function. Urinary sodium is a marker of diuretic resistance and is associated with a worse prognosis in HF. Growth differentiation factor-15 (GDF-15) is a marker of oxidative stress and inflammation and is a prognostic predictor in HF. Objectives We sought to assess the relationship of GDF-15 with renal function parameters and with urinary sodium in patients with chronic HF. Methods We undertook a cross-sectional study of patients with HF from specialized outpatient clinic. Patients with signs and symptoms of HF and LVEF &amp;lt;50% were included. An echocardiogram was performed and blood samples were collected, which were frozen for the final study, where the performance of GDF-15 in the prediction of renal outcomes in HF will be evaluated. The dosage of NT-proBNP was performed using the Elecsys® system (Roche, Basel, Switzerland) and GDF-15 by the sandwich immunoassay method with monoclonal antibodies (Elecsys®, Roche, Basel, Switzerland). Analysis of the relationship between GDF-15 and baseline renal parameters was performed. Correlation analysis was performed between GDF-15 and continuous variables, using the Spearman method. Results Sixty-seven patients were included. The etiologies of HF were hypertension, diabetes mellitus, alcoholic cardiomyopathy and idiopathic cardiomyopathy. Forty-one (61.2%) individuals were male, with a mean age of 61±13 years. Median GDF-15 values were 1413 pg/mL (interquartile range 1044–2554). Patients with GDF-15 values above the median had lower urinary sodium values (88 mEq/L [53–121] vs 112 [76–171], p=0.06), lower glomerular filtration rate (GFR) (63.9±29.1 vs 91.2±25 mL/min/1.73 m2, p=0.001) and higher creatinine levels (1.32 mg/dL [0.85–1.71] vs 0.91 [0.78–1.08], p&amp;lt;0.001). There was no significant difference in relation to urinary albumin (21 mg/L [7–126] vs 15.1 [5.8–41], p=0.30). The urinary albumin/creatinine ratio was higher in the group above the median, but did not reach statistical significance (38 mg/g [11–110] vs 12.5 [4.9–29], p=0.13). There was a direct correlation between GDF-15 and creatinine (r=0.56, p&amp;lt;0.001) and an inverse correlation with urinary sodium (r=−0.39, p=0.005) and with GFR (r=−0.55, p&amp;lt;0.001). Conclusion GDF-15 correlated with lower urinary sodium levels and worse kidney function in patients with chronic HF. Future studies should address whether GDF-15 is a predictor of worsening renal function overtime. Funding Acknowledgement Type of funding sources: None.

Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children.

BackgroundPrimary mitochondrial disorders (PMDs) are a diagnostic challenge for paediatricians, and identification of reliable and easily measurable biomarkers has become a high priority. This study aimed to investigate the role of serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) in children with PMDs.MethodsWe analysed serum FGF21 and GDF15 concentrations by enzyme-linked immunosorbent assay (ELISA) in children with PMDs, patients with non-mitochondrial neuromuscular disorders (NMDs), and aged-matched healthy children, and compared them with serum lactate and ratio of lactate and pyruvate (L/P). We also evaluated correlations between these biomarkers and the phenotype, genotype, and severity of PMDs.ResultsThe median serum GDF15 and FGF21 concentrations were significantly elevated in fifty-one patients with PMDs (919.46 pg/ml and 281.3 pg/ml) compared with those of thirty patients with NMDs (294.86 pg/ml and 140.51 pg/ml, both P < 0.05) and fifty healthy controls (221.21 pg/ml and 85.02 pg/ml, both P < 0.05). The area under the curve of GDF15 for the diagnosis of PMDs was 0.891, which was higher than that of the other biomarkers, including FGF21 (0.814), lactate (0.863) and L/P ratio (0.671). Calculated by the maximum Youden index, the critical value of GDF15 was 606.369 pg/ml, and corresponding sensitivity and specificity were 74.5and 100%. In the PMD group, FGF21 was significantly correlated with International Paediatric Mitochondrial Disease Scale (IPMDS) score. The levels of GDF15 and FGF21 were positively correlated with age, critical illness condition, and multisystem involvement but were not correlated with syndromic/non-syndromic PMDs, different mitochondrial syndromes, nuclear DNA/mitochondrial DNA pathogenic variants, gene functions, or different organ/system involvement.ConclusionRegardless of clinical phenotype and genotype, circulating GDF15 and FGF21 are reliable biomarkers for children with PMDs. GDF15 can serve as a screening biomarker for diagnosis, and FGF21 can serve as a severity biomarker for monitoring.

The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker)

BackgroundPlasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients.MethodsThis Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed.ResultsA total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918–1720) pg/mL with empagliflozin, and 1299 (952–1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03–1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = – 0.23, p = 0.031), and end-diastolic volume (R = – 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86–1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97–1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01.ConclusionEmpagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP.Trial registration: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.

Growth Differentiation Factor 15 Is Superior to Troponin I in the Evaluation of Kidney Transplant Candidates

Introduction: Pretransplant cardiac troponin I (cTNI) has demonstrated its predicting value in survival after kidney transplant. Growth differentiation factor 15 (GDF-15) is a biomarker currently studied as a predictor of mortality and cardiovascular events (CVE) in different scenarios. The aim of this study was to compare the utility of these two biomarkers in the prediction of events after kidney transplant. Methods: We included 359 kidney transplants performed in our center between 2005 and 2015. cTNI and GDF-15 were measured on stored serum samples obtained pretransplant. Results: Median GDF-15 was 5,346.4 pg/mL, and cTNI was 5.6 ng/L. After follow-up, 77 (21.5%) patients died, and the incidence of cerebrovascular accident (CVA), acute coronary syndrome (ACS), and major adverse CVEs (MACE) was 6.38%, 12.68%, and 20.56%, respectively. Patients were stratified in tertiles according to GDF-15 and cTNT levels. By multivariate cox regression analysis including both biomarkers and different clinical characteristics, we found a significant relation between GDF-15 and mortality, CVAs, and MACE (highest tertile hazard ratio [HR] 2.2 95% confidence interval [CI] [1.2–4.1], p = 0.01, HR 9.7 CI 95% [2.2–43.1], p = 0.003 and HR 2.7 CI 95% [1.4–5.1], p = 0.002). On the contrary, posttransplant ACS was related to cTNI (highest cTNI tertile HR 3.2 CI 95% [1.5–7.3], p = 0.003). Discussion: Our study indicates the potential utility of GDF-15 as a mortality and CVE predictor after kidney transplant and its superiority compared to cTNI. By contrast, probably due to its tissue specificity, cardiac troponin showed a stronger correlation with acute coronary events. Although more studies are needed to confirm our findings, these two molecules could be used in conjunction with other tools to predict adverse events after transplant and ideally find strategies to minimize them.

Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C.

In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV). Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2-4 as "possible" MD. Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression. Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06-25.92] for FGF21 and 3.5 (95%CI: 1.19-10.25) for GDF15. Relationships persisted after covariate adjustments. FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.

FGF21 outperforms GDF15 as a diagnostic biomarker of mitochondrial disease in children

Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD.