Objective: Circulating soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) are associated with chronic kidney disease (CKD) progression in patients with CKD or diabetes, and with higher mortality. However, data in patients with end-stage renal disease are scarce. Therefore, we analyzed serum levels of sTNFR1 and sTNFR2 and investigated their association with inflammatory markers and mortality in dialysis patients. Research Design and Methods: This was a longitudinal cohort study of 207 prevalent patients (median age 66 years, 56% men) undergoing hemodialysis in Stockholm, Sweden. Demographics, clinical characteristics, including comorbidities and laboratory data, were obtained at baseline, together with prospective follow-up for mortality. Results: The median sTNFR1 and sTNFR2 levels were 17,680 ng/l [95% confidence interval (CI) 17,023-18,337] and 24,450 ng/l (95% CI 23,721-25,179), respectively. During a follow-up of 31 months (interquartile range, 21-38), 77 patients died. There was no association between the levels of sTNFRs and mortality in Cox regression models, and no consistent trend towards higher or lower mortality was seen in Laplace regression models. sTNFR1 and sTNFR2 levels were highly associated with other inflammatory markers including interleukin-6, pentraxin 3 and TNF-α. Conclusions: Prevalent hemodialysis patients have several-fold higher levels of sTNFRs compared to previous studies in CKD stage 4 patients. As no consistent association between TNFR and mortality was observed, clinical implications of measuring these receptors to predict outcome end-stage renal disease patients provide limited results.

Keywords:
Tumor necrosis factor, Laplace regression, Mortality, Inflammation
1.
Stenvinkel P: Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010;268:456-467.
2.
Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimburger O, Massy Z: Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle? Clin J Am Soc Nephrol 2008;3:505-521.
3.
Hasegawa G, Nakano K, Sawada M, Uno K, Shibayama Y, Ienaga K, Kondo M: Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int 1991;40:1007-1012.
4.
Lopes-Virella MF, Baker NL, Hunt KJ, Cleary PA, Klein R, Virella G: Baseline markers of inflammation are associated with progression to macroalbuminuria in type 1 diabetic subjects. Diabetes Care 2013;36:2317-2323.
5.
Krolewski AS, Niewczas MA, Skupien J, Gohda T, Smiles A, Eckfeldt JH, Doria A, Warram JH: Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care 2014;37:226-234.
6.
Niewczas MA, Ficociello LH, Johnson AC, Walker W, Rosolowsky ET, Roshan B, Warram JH, Krolewski AS: Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol 2009;4:62-70.
7.
Gohda T, Niewczas MA, Ficociello LH, Walker WH, Skupien J, Rosetti F, Cullere X, Johnson AC, Crabtree G, Smiles AM, Mayadas TN, Warram JH, Krolewski AS: Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol 2012;23:516-524.
8.
Luna JM, Moon Y, Liu K, Spitalnik S, Paik M, Sacco R, Elkind MS: Tumour necrosis factor receptor 1 and mortality in a multi-ethnic cohort: the Northern Manhattan Study. Age Ageing 2013;42:385-390.
9.
Mattey DL, Glossop JR, Nixon NB, Dawes PT: Circulating levels of tumor necrosis factor receptors are highly predictive of mortality in patients with rheumatoid arthritis. Arthritis Rheum 2007;56:3940-3948.
10.
Saulnier PJ, Gand E, Ragot S, Ducrocq G, Halimi JM, Hulin-Delmotte C, Llaty P, Montaigne D, Rigalleau V, Roussel R, Velho G, Sosner P, Zaoui P, Hadjadj S; Surdiagene Study Group: 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;37:1425-1431.
11.
Miyazawa I, Araki S, Obata T, Yoshizaki T, Morino K, Kadota A, Ugi S, Kawai H, Uzu T, Nishio Y, Koya D, Haneda M, Kashiwagi A, Maegawa H: Association between serum soluble TNFα receptors and renal dysfunction in type 2 diabetic patients without proteinuria. Diabetes Res Clin Pract 2011;92:174-180.
12.
Carrero JJ, Qureshi AR, Axelsson J, Avesani CM, Suliman ME, Kato S, Barany P, Snaedal-Jonsdottir S, Alvestrand A, Heimburger O, Lindholm B, Stenvinkel P: Comparison of nutritional and inflammatory markers in dialysis patients with reduced appetite. Am J Clin Nutr 2007;85:695-701.
13.
Snaedal S, Heimburger O, Qureshi AR, Danielsson A, Wikstrom B, Fellstrom B, Fehrman-Ekholm I, Carrero JJ, Alvestrand A, Stenvinkel P, Barany P: Comorbidity and acute clinical events as determinants of C-reactive protein variation in hemodialysis patients: implications for patient survival. Am J Kidney Dis 2009;53:1024-1033.
14.
Bottai M, Zhang J: Laplace regression with censored data. Biom J 2010;52:487-503.
15.
Gonzalez-Clemente JM, Mauricio D, Richart C, Broch M, Caixas A, Megia A, Gimenez-Palop O, Simon I, Martinez-Riquelme A, Gimenez-Perez G, Vendrell J: Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus. Clin Endocrinol 2005;63:525-529.
16.
Pitsiou G, Kyriazis G, Hatzizisi O, Argyropoulou P, Mavrofridis E, Patakas D: Tumor necrosis factor-alpha serum levels, weight loss and tissue oxygenation in chronic obstructive pulmonary disease. Respir Med 2002;96:594-598.
17.
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;25:1313-1320.
18.
Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002;106:2067-2072.
19.
Evans JL, Goldfine ID, Maddux BA, Grodsky GM: Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002;23:599-622.
20.
Fernandez-Real JM, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J, Richart C: Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes 1998;47:1757-1762.
21.
Elmarakby AA, Quigley JE, Pollock DM, Imig JD: Tumor necrosis factor alpha blockade increases renal CYP2c23 expression and slows the progression of renal damage in salt-sensitive hypertension. Hypertension 2006;47:557-562.
22.
Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C, Kreuzer J, Heidecke H, Haller H, Zenke M, Luft FC: Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol 2002;161:1679-1693.
23.
Don BR, Kim K, Li J, Dwyer T, Alexander F, Kaysen GA: The effect of etanercept on suppression of the systemic inflammatory response in chronic hemodialysis patients. Clin Nephrol 2010;73:431-438.
© 2015 S. Karger AG, Basel
2015
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