The association between TNF-receptors (TNFR1 and TNFR2) and mortality as well as kidney function decline in patients with chronic kidney disease
Abstract
Background: Higher circulating levels of tumor necrosis factor (TNF) alpha receptors 1 (TNFR1) and 2 (TNFR2) are associated with increased long-term mortality and impaired kidney function.
Aim: To study associations between levels of TNFR1 and TNFR2 and all-cause mortality as well as estimated glomerular filtration rate (eGFR) decline.
Population and methods: Patients with chronic kidney disease (CKD) stages 3–5 in the Salford Kidney Study were included. Associations between one standard deviation increase in plasma TNFR1 and TNFR2 and mortality were estimated by Cox regression models with hazard ratios (HRs) and 95% confidence intervals adjusted for age, sex, eGFR based on creatinine and cystatin C, urine-protein, C-reactive protin, cardiovascular comorbidity, smoking habits, and diabetes. Differences in eGFR decline in relation to plasma TNFR1 and TNFR2 were estimated by both linear and logistic regression models, with regression coefficients and odds ratios (ORs).
Results: Univariate models showed significant associations between TNFR1 (n = 985) and TNFR2 (n = 988) and all-cause mortality based on 7424 person-years at risk, but in the fully adjusted models with continuous variables significant only for TNFR2 HR 1.17 (1.03–1.34), but with a borderline value for TNFR1 HR 1.15 (1.00–1.31). For rapid decliners, that is, eGFR decline in highest TNFR-receptor quartile versus quartiles 1–3, the decline was 1.60% per month (interval 0.78–10.99). For eGFR decline in continuous models, the fully adjusted ORs were for TNFR1 1.29 (0.92–1.81) and for TNFR2 1.33 (0.90–1.98).
Conclusions: TNFR2 was associated with mortality, but TNFR1 was not, although showing a borderline value. Neither TNFR1 nor TNFR2 predicted decline in kidney function. TNFR1 and TNFR2 portray interesting aspects in patients with CKD, but the clinical utility seems limited.
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References
2. Carlsson AC, Juhlin CC, Larsson TE, Larsson A, Ingelsson E, Sundstrom J, et al. Soluble tumor necrosis factor receptor 1 (sTNFR1) is associated with increased total mortality due to cancer and cardiovascular causes – findings from two community based cohorts of elderly. Atherosclerosis. 2014;237(1):236–42. doi: 10.1016/j.atherosclerosis.2014.09.005
3. Carlsson AC, Ostgren CJ, Nystrom FH, Lanne T, Jennersjo P, Larsson A, et al. Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes. Cardiovasc Diabetol. 2016;15:40. doi: 10.1186/s12933-016-0359-8
4. Carlsson AC, Nordquist L, Larsson TE, Carrero JJ, Larsson A, Lind L, et al. Soluble tumor necrosis factor receptor 1 is associated with glomerular filtration rate progression and incidence of chronic kidney disease in two community-based cohorts of elderly individuals. Cardiorenal Med. 2015;5(4):278–88. doi: 10.1159/000435863
5. Carlsson AC, Larsson TE, Helmersson-Karlqvist J, Larsson A, Lind L, Arnlov J. Soluble TNF receptors and kidney dysfunction in the elderly. J Am Soc Nephrol. 2014;25(6):1313–20. doi: 10.1681/ASN.2013080860
6. Sedger LM, McDermott MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants – past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453–72. doi: 10.1016/j.cytogfr.2014.07.016
7. Speeckaert MM, Speeckaert R, Laute M, Vanholder R, Delanghe JR. Tumor necrosis factor receptors: biology and therapeutic potential in kidney diseases. Am J Nephrol. 2012;36(3):261–70. doi: 10.1159/000342333
8. Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech. 2000;50(3):184–95. doi: 10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H
9. Yang S, Wang J, Brand DD, Zheng SG. Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front Immunol. 2018;9:784. doi: 10.3389/fimmu.2018.00784
10. Cabal-Hierro L, Lazo PS. Signal transduction by tumor necrosis factor receptors. Cell Signal. 2012;24(6):1297–305. doi: 10.1016/j.cellsig.2012.02.006
11. Dempsey PW, Doyle SE, He JQ, Cheng G. The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev. 2003;14(3–4):193–209. doi: 10.1016/S1359-6101(03)00021-2
12. Gomez-Banoy N, Cuevas V, Higuita A, Aranzalez LH, Mockus I. Soluble tumor necrosis factor receptor 1 is associated with diminished estimated glomerular filtration rate in colombian patients with type 2 diabetes. J Diabetes Complications. 2016;30(5):852–7. doi: 10.1016/j.jdiacomp.2016.03.015
13. Tollitt J, Odudu A, Montaldi D, Kalra PA. Cognitive impairment in patients with moderate to severe chronic kidney disease: the Salford kidney cohort study. Clin Kidney J. 2021;14(6):1639–48.
14. Starmark JE, Stalhammar D, Holmgren E. The Reaction Level Scale (RLS85). Manual and guidelines. Acta Neurochir (Wien). 1988;91(1–2):12–20. doi: 10.1007/BF01400521
15. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.
16. Grubb A, Horio M, Hansson LO, Bjork J, Nyman U, Flodin M, et al. Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator. Clin Chem. 2014;60(7):974–86. doi: 10.1373/clinchem.2013.220707
17. Enoksen ITT, Rinde NB, Svistounov D, Norvik JV, Solbu MD, Eriksen BO, et al. Validation of eGFR for detecting associations between serum protein biomarkers and subsequent GFR decline. J Am Soc Nephrol. 2023; 34(8):1409–1420.
18. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51. doi: 10.1161/ATVBAHA.108.179705
19. Morange PE, Tregouet DA, Godefroy T, Saut N, Bickel C, Rupprecht HJ, et al. Polymorphisms of the tumor necrosis factor-alpha (TNF) and the TNF-alpha converting enzyme (TACE/ADAM17) genes in relation to cardiovascular mortality: the AtheroGene study. J Mol Med (Berl). 2008;86(10):1153–61.
20. Safranow K, Dziedziejko V, Rzeuski R, Czyzycka E, Wojtarowicz A, Binczak-Kuleta A, et al. Plasma concentrations of TNF-alpha and its soluble receptors sTNFR1 and sTNFR2 in patients with coronary artery disease. Tissue Antigens. 2009;74(5):386–92. doi: 10.1111/j.1399-0039.2009.01332.x
21. Marshall SM, Flyvbjerg A. Prevention and early detection of vascular complications of diabetes. BMJ. 2006;333(7566):475–80. doi: 10.1136/bmj.38922.650521.80
22. Fernandez-Real JM, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J, et al. Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes. 1998;47(11):1757–62. doi: 10.2337/diabetes.47.11.1757
23. Lee JE, Gohda T, Walker WH, Skupien J, Smiles AM, Holak RR, et al. Risk of ESRD and all cause mortality in type 2 diabetes according to circulating levels of FGF-23 and TNFR1. PLoS One. 2013;8(3):e58007. doi: 10.1371/journal.pone.0058007
24. Saulnier PJ, Gand E, Ragot S, Ducrocq G, Halimi JM, Hulin-Delmotte C, et al. Association of serum concentration of TNFR1 with all-cause mortality in patients with type 2 diabetes and chronic kidney disease: follow-up of the SURDIAGENE Cohort. Diabetes Care. 2014;37(5):1425–31. doi: 10.2337/dc13-2580
25. Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti F, et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol. 2012;23(3):507–15. doi: 10.1681/ASN.2011060627
26. Chinnadurai R, Flanagan E, Jayson GC, Kalra PA. Cancer patterns and association with mortality and renal outcomes in non-dialysis dependent chronic kidney disease: a matched cohort study. BMC Nephrol. 2019;20(1):380. doi: 10.1186/s12882-019-1578-5
27. Evans M, Grams ME, Sang Y, Astor BC, Blankestijn PJ, Brunskill NJ, et al. Risk factors for prognosis in patients with severely decreased GFR. Kidney Int Rep. 2018;3(3):625–37. doi: 10.1016/j.ekir.2018.01.002
28. Carlsson AC, Ingelsson E, Sundstrom J, Jesus Carrero J, Gustafsson S, Feldreich T, et al. Use of proteomics to investigate kidney function decline over 5 years. Clin J Am Soc Nephrol. 2017;12(8):1226–35. doi: 10.2215/CJN.08780816
29. Coresh J, Turin TC, Matsushita K, Sang Y, Ballew SH, Appel LJ, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 2014;311(24):2518–31. doi: 10.1001/jama.2014.6634
30. Premaratne E, Verma S, Ekinci EI, Theverkalam G, Jerums G, MacIsaac RJ. The impact of hyperfiltration on the diabetic kidney. Diabetes Metab. 2015;41(1):5–17. doi: 10.1016/j.diabet.2014.10.003
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