【Abstract】Objective To investigate the serum growth differentiation factor-15 (GDF-15) level in patients with different types of renal diseases and its correlation with renal function. Methods We recruited 122 patients with different types of nephropathy treated in the Department of Nephrology, Shandong Provincial Hospital from December 2019 to August 2020 in this study, and 15 healthy people from physical examination center as the control group. Serum GDF-15 was detected by ELISA. Clinical data and laboratory parameters were collected, and analyzed in association with serum GDF-15 and other factors. Results Serum GDF-15
was significantly higher in patients with diabetic nephropathy than that in control group (t=6.522, P＜0.001), IgA nephropathy (t=4.322, P=0.004) and lupus nephritis patients (t=3.884, P=0.001). Serum GDF-15 was significantly higher in multiple myeloma patients than in control group (t=5.678, P＜0.001), IgA nephropathy (t=4.532, P=0.004) and lupus nephritis patients (t=4.244, P=0.008). Age (r=0.395, P<0.001), abnormal immunofixation electrophoresis (r=0.251, P=0.003), blood glucose (r=0.205, P= 0.016), CRP (r=0.178, P=0.038), free light chain ratio (r=0.324, P<0.001), and MM (r=0.225, P=0.008) were positively correlated with serum GDF-15 level. Linear regression analysis showed that serum GDF-15 level was significantly associated with age (β= 0.395, P<0.001), elevated CRP (β=0.175, P=0.040), MM (β=0.192, P=0.025), abnormal immunofixation electrophoresis (β=0.251, P=0.003), and abnormal free light chain ratio (β=0.299, P<0.001). Conclusions Serum GDF-15 level varied in different renal diseases and was correlated with age, blood glucose, CRP,MM, free light chain ratio and abnormal immunofixation electrophoresis. Serum GDF-15 level is a useful index reflecting the extent of kidney injury.
1. Arkoumani M, N Papadopoulou-Marketou, NC Nicolaides, et al. The clinical impact of growth differentiation factor-15 in heart disease: A 2019 update[J]. Crit Rev Clin Lab Sci, 2020, 57(2):114-125.
2. Fang L, F LiC Gu. GDF-15: A Multifunctional Modulator and Potential Therapeutic Target in Cancer[J]. Curr Pharm Des, 2019, 25(6):654-662.
3. Liu DDYA Mei. [Effects of growth differentiation factor-15 (GDF-15) on neurological systems, cardiovascular diseases, and cancer progression][J]. Sheng Li Xue Bao, 2017, 69(1):109-121.
4. Widera C, E Giannitsis, T Kempf, et al. Identification of follistatin-like 1 by expression cloning as an activator of the growth differentiation factor 15 gene and a prognostic biomarker in acute coronary syndrome[J]. Clin Chem, 2012, 58(8):1233-41.
5. Frank D, C Kuhn, B Brors, et al. Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program[J]. Hypertension, 2008, 51(2):309-18.
6. Clerk A, TJ Kemp, G Zoumpoulidou, et al. Cardiac myocyte gene expression profiling during H2O2-induced apoptosis[J]. Physiol Genomics, 2007, 29(2):118-27.
7. Schlittenhardt D, A Schober, J Strelau, et al. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions[J]. Cell Tissue Res, 2004, 318(2):325-33.
8. Bermúdez B, S López, YM Pacheco, et al. Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery[J]. Cardiovasc Res, 2008, 79(2):294-303.
9. Nickel N, D Jonigk, T Kempf, et al. GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells[J]. Respir Res, 2011, 12(1):62.
10. Bao X, Y Borné, IF Muhammad, et al. Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malm? Diet and Cancer-Cardiovascular Cohort[J]. Diabetologia, 2019, 62(1):78-86.
11. Nair V, C Robinson-Cohen, MR Smith, et al. Growth Differentiation Factor-15 and Risk of CKD Progression[J]. J Am Soc Nephrol, 2017, 28(7):2233-2240.
12. Breit SN, JJ Carrero, VW Tsai, et al. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease[J]. Nephrol Dial Transplant, 2012, 27(1):70-5.
13. Mazagova M, H Buikema, A van Buiten, et al. Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes[J]. Am J Physiol Renal Physiol, 2013, 305(9):F1249-64.
14. Kastritis E, I Papassotiriou, G Merlini, et al. Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis[J]. Blood, 2018, 131(14):1568-1575.
15. Hellemons ME, M Mazagova, RT Gansevoort, et al. Growth-differentiation factor 15 predicts worsening of albuminuria in patients with type 2 diabetes[J]. Diabetes Care, 2012, 35(11):2340-6.
16. Teng J, EA Turbat-HerreraGA Herrera. An animal model of glomerular light-chain-associated amyloidogenesis depicts the crucial role of lysosomes[J]. Kidney Int, 2014, 86(4):738-46.
17. Tanno T, Y Lim, Q Wang, et al. Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells[J]. Blood, 2014, 123(5):725-33.
18. Preusch MR, M Baeuerle, C Albrecht, et al. GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis[J]. Eur J Med Res, 2013, 18(1):19.
19. Bootcov MR, AR Bauskin, SM Valenzuela, et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily[J]. Proc Natl Acad Sci U S A, 1997, 94(21):11514-9.
20. Unsicker K, B SpittauK Krieglstein. The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1[J]. Cytokine Growth Factor Rev, 2013, 24(4):373-84.
21. Johnen H, S Lin, T Kuffner, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1[J]. Nat Med, 2007, 13(11):1333-40.
22. Hong JH, HK Chung, HY Park, et al. GDF15 Is a Novel Biomarker for Impaired Fasting Glucose[J]. Diabetes Metab J, 2014, 38(6):472-9.
23. Sarkar D, IV Lebedeva, L Emdad, et al. Human polynucleotide phosphorylase (hPNPaseold-35): a potential link between aging and inflammation[J]. Cancer Res, 2004, 64(20):7473-8.
24. Sarkar DPB Fisher. Molecular mechanisms of aging-associated inflammation[J]. Cancer Lett, 2006, 236(1):13-23.
25. Bouabdallaoui N, B Claggett, MR Zile, et al. Growth differentiation factor-15 is not modified by sacubitril/valsartan and is an independent marker of risk in patients with heart failure and reduced ejection fraction: the PARADIGM-HF trial[J]. Eur J Heart Fail, 2018, 20(12):1701-1709.
26. Macia L, VW Tsai, AD Nguyen, et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets[J]. PLoS One, 2012, 7(4):e34868.
27. Wang X, K Chrysovergis, J Kosak, et al. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling[J]. Aging (Albany NY), 2014, 6(8):690-704.
28. Li J, L Yang, W Qin, et al. Adaptive induction of growth differentiation factor 15 attenuates endothelial cell apoptosis in response to high glucose stimulus[J]. PLoS One, 2013, 8(6):e65549.
29. Retnakaran R. Novel Biomarkers for Predicting Cardiovascular Disease in Patients With Diabetes[J]. Can J Cardiol, 2018, 34(5):624-631.
30. Carlsson AC, C Nowak, L Lind, et al. Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach[J]. Ups J Med Sci, 2020, 125(1):37-43.
31. Mimeault MSK Batra. Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer[J]. J Cell Physiol, 2010, 224(3):626-35.
32. Kyle RASV Rajkumar. Epidemiology of the plasma-cell disorders[J]. Best Pract Res Clin Haematol, 2007, 20(4):637-64.
33. Guan J, S Mishra, J Shi, et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity[J]. Basic Res Cardiol, 2013, 108(5):378.
34. Diomede L, P Rognoni, F Lavatelli, et al. A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis[J]. Blood, 2014, 123(23):3543-52.
35. Migrino RQ, S Truran, DD Gutterman, et al. Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins[J]. Am J Physiol Heart Circ Physiol, 2011, 301(6):H2305-12.
36. Kempf T, R Horn-Wichmann, G Brabant, et al. Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay[J]. Clin Chem, 2007, 53(2):284-91.
37. Martini S, V Nair, BJ Keller, et al. Integrative biology identifies shared transcriptional networks in CKD[J]. J Am Soc Nephrol, 2014, 25(11):2559-72.
38. Dutta S, MD Karol, T Cohen, et al. Effect of dexmedetomidine on propofol requirements in healthy subjects[J]. J Pharm Sci, 2001, 90(2):172-81.
