IP-10 and MCP-1 are pro-inflammatory chemokines which are involved in the immunopathogenesis of lupus nephritis and may thus be useful biomarkers.
Methods
SLE patients fulfilling ACR 1997 criteria were included. SLEDAI was calculated and blood and urine samples collected. Active lupus was defined as SLEDAI ≥4. Active patients were divided into active renal (proteinuria ≥ 500 mg/day or active sediment in urine) and active non-renal lupus. Patients with active renal lupus were followed until the nephritis became inactive, when a second sample was collected. Serum and urinary levels of MCP-1 and IP-10 (pg/ml) were measured by ELISA. Urinary values were normalized for urinary spot creatinine (in mg/dL. Thus the values were expressed as pg/mg creatinine × 100 creatinine).
Results
A total of 136 patients with SLE including 78 active (46 active renal and 32 active non-renal) were included. Median age was 25 (10–55) years and SLE duration was 23 (six to 48) months. Both serum (data not shown) and urinary levels of MCP-1 (35.2 (12.7–71.7), 9.4 (4.4–17), p < 0.001) and IP-10 (9.5 (4.4–17.9), 3.9 (1.9–9.3), p < 0.001) were higher in active compared to inactive SLE. However, in active renal compared to active non-renal SLE, there was no difference in serum levels; only urinary levels of MCP-1 (46.2 (19.9–125), 12.7 (5.8–43.9), p < 0.001) and IP-10 (12.5 (5.6–22.7), 5.2 (2.3–12.2), p < 0.05) were higher. On longitudinal follow-up of active renal patients (n = 24), there was a decrease in urinary levels of MCP-1 and IP-10 (p = 0.005). On ROC analysis, urinary MCP-1 outperformed C4 and urinary IP-10, but was similar to dsDNA and C3 in differentiating active renal from non-renal SLE.
Conclusions
Urinary and serum IP-10 and MCP-1 are potentially useful markers of lupus activity; however, only the urinary levels are indicative of renal activity. However, on ROC analysis, they are not better than conventional markers.
PeschkenCAKatzSJSilvermanE. The 1000 Canadian faces of lupus: Determinants of disease outcome in a large multiethnic cohort. J Rheumatol2009; 36: 1200–1208.
2.
ChambersSAAllenERahmanAIsenbergD. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford)2009; 48: 673–675.
3.
CrocaSCRodriguesTIsenbergDA. Assessment of a lupus nephritis cohort over a 30-year period. Rheumatology (Oxford)2011; 50: 1424–1430.
4.
EsdaileJMJosephLMacKenzieTKashgarianMHayslettJP. The benefit of early treatment with immunosuppressive agents in lupus nephritis. J Rheumatol1994; 21: 2046–2051.
5.
FaurschouMStarklintHHalbergPJacobsenS. Prognostic factors in lupus nephritis: Diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol2006; 33: 1563–1569.
6.
RovinBHBirminghamDJNagarajaHNYuCYHebertLA. Biomarker discovery in human SLE nephritis. Bull NYU Hosp Jt Dis2007; 65: 187–193.
VargheseSAPowellTBBudisavljevicMN. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol2007; 18: 913–922.
9.
LiYTucciMNarainS. Urinary biomarkers in lupus nephritis. Autoimmun Rev2006; 5: 383–388.
10.
BrunnerHIMuellerMRutherfordC. Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum2006; 54: 2577–2582.
11.
ChanRWLaiFMLiEK. Intrarenal cytokine gene expression in lupus nephritis. Ann Rheum Dis2007; 66: 886–892.
12.
HasegawaHKohnoMSasakiM. Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice. Arthritis Rheum2003; 48: 2555–2566.
DaiCLiuZZhouHLiL. Monocyte chemoattractant protein-1 expression in renal tissue is associated with monocyte recruitment and tubulo-interstitial lesions in patients with lupus nephritis. Chin Med J (Engl)2001; 114: 864–868.
15.
NevilleLFMathiakGBagasraO. The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): A novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev1997; 8: 207–219.
16.
ShiozawaFKasamaTYajimaN. Enhanced expression of interferon-inducible protein 10 associated with Th1 profiles of chemokine receptor in autoimmune pulmonary inflammation of MRL/lpr mice. Arthritis Res Ther2004; 6: R78–R86.
17.
SegererSBanasBWörnleM. CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Am J Pathol2004; 164: 635–649.
18.
ErikssonCEneslättKIvanoffJRantapää-DahlqvistSSundqvistKG. Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus. Lupus2003; 12: 766–774.
19.
NarumiSTakeuchiTKobayashiYKonishiK. Serum levels of IFN-inducible protein-10 relating to the activity of systemic lupus erythematosus. Cytokine2000; 12: 1561–1565.
20.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1732.
21.
PetriMKimMYKalunianKC. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med2005; 353: 2550–2558.
22.
PitashnyMSchwartzNQingX. Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum2007; 56: 1894–1903.
23.
RomagnaniPLazzeriELasagniL. IP-10 and Mig production by glomerular cells in human proliferative glomerulonephritis and regulation by nitric oxide. J Am Soc Nephrol2002; 13: 53–64.
24.
PanzerUSteinmetzOMReinkingRR. Compartment-specific expression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascular injury. J Am Soc Nephrol2006; 17: 454–464.
25.
AvihingsanonYPhumesinPBenjachatT. Measurement of urinary chemokine and growth factor messenger RNAs: A noninvasive monitoring in lupus nephritis. Kidney Int2006; 69: 747–753.
26.
WatsonLMidgleyAPilkingtonC. Urinary monocyte chemoattractant protein 1 and alpha 1 acid glycoprotein as biomarkers of renal disease activity in juvenile-onset systemic lupus erythematosus. Lupus2012; 21: 496–501.
27.
FuQChenXCuiH. Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients. Arthritis Res Ther2008; 10: R112–R112.
28.
LitLCWongCKTamLSLiEKLamCWK. Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus. Ann Rheum Dis2006; 65: 209–215.
29.
KongKOTanAWThongBY. Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus. Clin Exp Immunol2009; 156: 134–140.
30.
MellerSWinterbergFGillietM. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum2005; 52: 1504–1516.
31.
ZojaCLiuXHDonadelliR. Renal expression of monocyte chemoattractant protein-1 in lupus autoimmune mice. J Am Soc Nephrol1997; 8: 720–729.
32.
Wagrowska-DanilewiczMStasikowskaODanilewiczM. Correlative insights into immunoexpression of monocyte chemoattractant protein-1, transforming growth factor beta-1 and CD68+ cells in lupus nephritis. Pol J Pathol2005; 56: 115–120.
33.
MarksSDWilliamsSJTullusKSebireNJ. Glomerular expression of monocyte chemoattractant protein-1 is predictive of poor renal prognosis in pediatric lupus nephritis. Nephrol Dial Transplant2008; 23: 3521–3526.
34.
TucciMCalvaniNRichardsHBQatarCSilvestrisF. The interplay of chemokines and dendritic cells in the pathogenesis of lupus nephritis. Ann N Y Acad Sci2005; 1051: 421–432.
35.
TamFWSandersJSGeorgeA. Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis. Nephrol Dial Transplant2004; 19: 2761–2768.
36.
WadaTFuruichiKSegawa-TakaedaC. MIP-1alpha and MCP-1 contribute to crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int1999; 56: 995–1003.
37.
KianiANJohnsonKChenC. Urine osteoprotegerin and monocyte chemoattractant protein-1 in lupus nephritis. J Rheumatol2009; 36: 2224–2240.
38.
RovinBHSongHBirminghamDJHebertLAYuCYNagarajaHN. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J Am Soc Nephrol2005; 16: 467–473.
39.
AlzawawyAZoharyMAblordinyMEldalieM. Estimation of monocyte-chemoattractantprotein-1 (Mcp-1) level in patients with lupus nephritis. Int J Rheum Dis2009; 12: 311–318.
40.
El-ShehabyADarweeshHEl-KhatibM. Correlations of urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and IL-8 with lupus nephritis. J Clin Immunol2011; 31: 848–856.
41.
RosaRFTakeiKAraújoNCLoducaSMSzajubokJCChahadeWH. Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients. J Rheumatol2012; 39: 1948–1954.
42.
NorisMBernasconiSCasiraghiF. Monocyte chemoattractant protein-1 is excreted in excessive amounts in the urine of patients with lupus nephritis. Lab Invest1995; 73: 804–809.
43.
TianSLiJWangL. Urinary level of RANTES and M-CSF are predictors of lupus nephritis flare. Inflamm Res2007; 56: 304–310.
44.
SchwartzNRubinsteinTBurklyLC. Urinary TWEAK as a biomarker of lupus nephritis: A multicenter cohort study. Arthritis Res Ther2009; 11: R143–R143.
45.
RovinBHZhangX. Biomarkers for lupus nephritis: The quest continues. Clin J Am Soc Nephrol2009; 4: 1858–1865.
46.
WuTXieCWangHW. Elevated urinary VAM-1, P-selectin, soluble TNF receptor-1, and CXC chemokine ligand 16 in multiple murine lupus strains and human lupus nephritis. J Immunol2007; 179: 7166–7175.
47.
TsaiCYWuTHYuCLLuJYTsaiYY. Increased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein. Nephron2000; 85: 207–214.
48.
BrunnerHIBennettMRMinaR. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum2012; 64: 2687–2697.
