Background: Patients on chronic hemodialysis or peritoneal dialysis often develop an inflammatory state that causes morbidity and mortality. Cross-sectional studies of dialysis patients have determined that C-reactive protein (CRP) is a predictor of morbidity. Little is known as to whether CRP, cytokines, such as IL-6 and IL-1β that stimulate the synthesis of CRP, or matrix metalloproteinases (MMPs) are markers of inflammation in patients on dialysis. Methods: We assayed by ELISA serum levels of MMP-2, MMP-3, IL-6 and CRP in healthy individuals and in patients with pre-end-stage renal disease (pESRD, n = 10), peritoneal dialysis (PD, n = 11), hemodialysis (HD, n = 17) and renal transplant (TX, n = 10). Results: MMP-2 was significantly elevated before dialysis, perhaps indicative of progressive chronic renal sclerosis. MMP-3 was markedly elevated in hemodialysis patients but not in pESRD or PD patients, and may be related to the hemodialysis process and/or accelerated atherogenesis in these patients. IL-6 was significantly elevated in all patient groups, including pESRD patients. There were no statistically significant differences in CRP levels among the study groups. CRP correlated with IL-6, but not with MMP-2 or MMP-3. Conclusions: The data indicate that there are measurable differences in the expression of MMPs within the dialysis patient population. Because dialysis can be associated with local and systemic inflammation, increased levels of MMP-3 in the hemodialyis group may be a reflection of gene stimulation induced by inflammatory cytokines and should be considered as a marker of chronic, local inflammation.

Keywords:
C-reactive protein, Hemodialysis, Inflammation, Interleukin-6, Matrix metalloproteinases, Peritoneal dialysis
1.
Pannen BH, Robotham JL: The acute-phase response. New Horiz 1995;3:183–197.
2.
Kaysen GA, Stevenson FT, Depner TA: Determinants of albumin concentration in hemodialysis patients. Am J Kidney Dis 1997;29:658–668.
3.
Yeun JY, Kaysen GA: Acute phase proteins and peritoneal dialysate albumin loss are the main determinants of serum albumin in peritoneal dialysis patients. Am J Kidney Dis 1997;30:923–927.
4.
Owen WF, Lowrie EG: C-reactive protein as an outcome predictor for maintenance hemodialysis patients. Kidney Int 1998;54:627–636.
5.
Sharma AP, Gupta A, Sharma RK, Agarwal DK, Sural S, Wardhe DJ: Does serum albumin at start of continuous ambulatory peritoneal dialysis (CAPD) or its drop during CAPD determine patient outcome? [In process citation]. Adv Perit Dial 2000;16:119–122.
6.
Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648–658.
7.
Stahl WM: Acute phase protein response to tissue injury. Crit Care Med 1987;15:545–550.
8.
Dowton SB, Colten HR: Acute phase reactants in inflammation and infection. Semin Hematol 1988;25:84–90.
9.
Zhang D, Jiang SL, Rzewnicki D, Samols D, Kushner I: The effect of interleukin-1 on C-reactive protein expression in Hep3B cells is exerted at the transcriptional level. Biochem J 1995;310:143–148.
10.
Ito A, Itoh Y, Sasaguri Y, Morimatsu M, Mori Y: Effects of interleukin-6 on the metabolism of connective tissue components in rheumatoid synovial fibroblasts. Arthritis Rheum 1992;35:1197–1201.
11.
Nakamoto Y, Imai H, Yasuda T, Wakui H, Miura AB: A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. Nephrol Dial Transplant 1999;14:2370–2378.
12.
Kaul H, Girndt M, Sester U, Sester M, Kohler H: Initiation of hemodialysis treatment leads to improvement of T-cell activation in patients with end-stage renal disease. Am J Kidney Dis 2000;35:611–616.
13.
Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, Nakahata T, Kawai H, Tagoh H, Komori T et al: Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood 1989;74:1360–1367.
14.
Henderson LW: Symptomatic hypotension during hemodialysis. Kidney Int 1980;17:571–576.
15.
Wang P, Ba ZF, Cioffi WG, Bland KI, Chaudry IH: Hepatocellular dysfunction after severe hypotension in the absence of blood loss is associated with the increased IL-6 and PGE2. J Surg Res 1998;80:136–142.
16.
Borden P, Heller RA: Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases. Crit Rev Eukaryot Gene Expr 1997;7:159–178.
17.
Kossakowska AE, Edwards DR, Prusinkiewicz C, Zhang MC, Guo D, Urbanski SJ, Grogan T, Marquez LA, Janowska-Wieczorek A: Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin’s lymphomas. Blood 1999;94:2080–2089.
18.
Davies M, Martin J, Thomas GJ, Lovett DH: Proteinases and glomerular matrix turnover. Kidney Int 1992;41:671–678.
19.
Akiyama K, Shikata K, Sugimoto H, Matsuda M, Shikata Y, Fujimoto N, Obata K, Matsui H, Makino H: Changes in serum concentrations of matrix metalloproteinases, tissue inhibitors of metalloproteinases and type IV collagen in patients with various types of glomerulonephritis. Res Commun Mol Pathol Pharmacol 1997;95:115–128.
20.
Norman JT, Lewis MP: Matrix metalloproteinases (MMPs) in renal fibrosis. Kidney Int Suppl 1996;54:S61–63.
21.
Turck J, Pollock AS, Lovett DH: Gelatinase A is a glomerular mesangial cell growth and differentiation factor. Kidney Int 1997;51:1397–1400.
22.
Turck J, Pollock AS, Lee LK, Marti HP, Lovett DH: Matrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation. J Biol Chem 1996;271:15074–15083.
23.
Lovett DH, Johnson RJ, Marti HP, Martin J, Davies M, Couser WG: Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. Am J Pathol 1992;141:85–98.
24.
Kotajima L, Aotsuka S, Fujimani M, Okawa-Takatsuji M, Kinoshita M, Sumiya, M, Obata K: Increased levels of matrix metalloproteinase-3 in sera from patients with active lupus nephritis. Clin Exp Rheumatol 1998;16:409–415.
25.
Galis ZS, Sukhova GK, Lark MW, Libby P: Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994;94:2493–2503.
26.
Bini A, Itoh Y, Kudryk BJ, Nagase H: Degradation of cross-linked fibrin by matrix metalloproteinase 3 (stromelysin 1): Hydrolysis of the gamma Gly 404-Ala 405 peptide bond. Biochemistry 1996;35:13056–13063.
27.
Ye S, Humphries S, Henney A: Matrix metalloproteinases: Implication in vascular matrix remodelling during atherogenesis. Clin Sci (Colch) 1998;94:103–110.
28.
Shapiro SD: Matrix metalloproteinase degradation of extracellular matrix: Biological consequences. Curr Opin Cell Biol 1998;10:602–608.
29.
Ribbens C, Andre B, Jaspar JM, Kaye O, Kaiser MJ, De Groote D, Malaise MG: Matrix metalloproteinase-3 serum levels are correlated with disease activity and predict clinical response in rheumatoid arthritis. J Rheumatol 2000;27:888–893.
30.
Ribbens C, Martin Y, Porras M, Franchimont N, Kaiser MJ, Jaspar JM, Damas P, Houssiau FA, Malaise MG: Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: Relationship with synovitis and steroid treatment. Ann Rheum Dis 2002;61:161–166.
31.
Hanemaaijer R, Koolwijk P, le Clercq L, de Vree WJ, van Hinsbergh VW: Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells: Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. Biochem J 1993;296:803–809.
32.
McIntyre C, Harper I, Macdougall IC, Raine AE, Williams A, Baker LR: Serum C-reactive protein as a marker for infection and inflammation in regular dialysis patients. Clin Nephrol 1997;48:371–374.
33.
Solomon A, Li DQ, Lee SB, Tseng SC: Regulation of collagenase, stromelysin, and urokinase-type plasminogen activator in primary pterygium body fibroblasts by inflammatory cytokines. Invest Ophthalmol Vis Sci 2000;41:2154–2163.
34.
Zbroch E, Malyszko J, Wolczynski S, Hryszko T, Mysliwiec M: Concentration of leptin in patients on hemodialysis and peritoneal dialysis. Pol Arch Med Wewn 1999;101:503–508.
35.
Baumann H, Jahreis GP, Morella KK: Interaction of cytokine- and glucocorticoid-response elements of acute-phase plasma protein genes. Importance of glucocorticoid receptor level and cell type for regulation of the elements from rat alpha 1-acid glycoprotein and beta-fibrinogen genes. J Biol Chem 1990;265:22275–22281.
36.
Baumann H, Jahreis GP, Morella KK, Won KA, Pruitt SC, Jones VE, Prowse KR: Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB. J Biol Chem 1991;266:20390–20399.
37.
Szalai AJ, van Ginkel FW, Wang Y, McGhee JR, Volanakis JE: Complement-dependent acute-phase expression of C-reactive protein and serum amyloid P-component. J Immunol 2000;165:1030–1035.
38.
Lonnemann G: The quality of dialysate: An integrated approach. Kidney Int 2000;58 (suppl 76):S112–119.
39.
Rodrigo E, Lopez-Hoyos M, Escallada R, Fernandez-Fresnedo G, Ruiz JC, Pinera C, Cotorruelo, JG, Zubimendi, JA, de Francisco AL, Arias M: Circulating levels of matrix metalloproteinases MMP-3 and MMP-2 in renal transplant recipients with chronic transplant nephropathy. Nephrol Dial Transplant 2000;15:2041–2045.
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2002
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