Reliable markers for the rapid discrimination of severe renal damage remain a vital concern for lupus nephritis (LN). To determine a better tool for kidney damage detection, the present study compared the evaluation ability of novel urinary cytokines and chemokines (namely urinary monocyte chemoattractant protein 1 (uMCP-1), tumor necrosis factor-like weak inducer of apoptosis (uTWEAK)) with traditional serum or urinary markers (namely urinary alpha 1-microgrobulin (uα1-MG), beta 2-microglobulin (uβ2-MG) and serum complement C3 (C3), complement C4 (C4), creatinine (Cr), blood urea nitrogen (BUN) and cystatin C (Cys C)) in discriminating LN renal damage. Correlations between markers with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) renal SLEDAI scores, biopsy activity index (BAI) and biopsy chronicity index (BCI) scores were evaluated. Receiver operating characteristic (ROC) curves were generated to evaluate a single or combined model in discriminating active renal involvement (rSLEDAI scores > 0) and patients with poor pathological outcome (BAI scores ≥ 7). uMCP-1 and uTWEAK possess higher correlation coefficients with renal damage and larger areas under ROC curves (AUCs) than other markers. A combined model of uMCP-1 and uTWEAK showed an AUC of 0.887, sensitivity of 86.67% and specificity of 80.00% to discriminate active LN, and an AUC of 0.778, sensitivity of 75.00% and specificity of 81.82% to discriminate LN with poor outcome, which are better than the utility of any markers individually.
CostenbaderKHDesaiAAlarcónGSet al.Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006. Arthritis Rheum2011; 63: 1681–1688.
2.
CameronJS. Lupus nephritis. J Am Soc Nephrol1999; 10: 413–424.
3.
ChoeJYParkSHKimSK. Urine beta 2-microglobulin is associated with clinical disease activity and renal involvement in female patients with systemic lupus erythematosus. Lupus2014; 23: 1486–1493.
4.
RovinBHBirminghamDJNagarajaHNYuCYHebertLA. Biomarker discovery in human SLE nephritis. Bull NYU Hosp Jt Dis2007; 65: 187–193.
5.
WuHZengJYinJPengQZhaoMLuQ. Organ-specific biomarkers in lupus. Autoimmun Rev2017; 16: 391–397.
6.
MisraRGuptaR. Biomarkers in lupus nephritis. Int J Rheum Dis2015; 18: 219–232.
7.
MalafrontePVieiraJMJrPereiraACKriegerJEBarrosRTWoronikV. Association of the MCP-1 –2518 A/G polymorphism and no association of its receptor CCR2 –64 V/I polymorphism with lupus nephritis. J Rheumatol2010; 37: 776–782.
8.
AbulabanKMSongHZhangXet al.Predicting decline of kidney function in lupus nephritis using urine biomarkers. Lupus2016; 25: 1012–1018.
9.
HasegawaHKohnoMSasakiMet al.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.
10.
WolfBJSpainhourJCArthurJMJanechMGPetriMOatesJC. Development of biomarker models to predict outcomes in lupus nephritis. Arthritis Rheum2016; 68: 1955–1963.
TeschGH. MCP-1/CCL2: A new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol2008; 294: F697–F701.
13.
SchwartzNMichaelsonJSPuttermanC. Lipocalin-2, TWEAK, and other cytokines as urinary biomarkers for lupus nephritis. Ann N Y Acad Sci2007; 1109: 265–274.
14.
XuXZhengMLiuB. Urinary TWEAK/Fn14 mRNA as a biomarker of lupus nephritis activity. Int J Clin Exp Med2016; 9: 11236–11243.
15.
SchwartzNSuLBurklyLCet al.Urinary TWEAK and the activity of lupus nephritis. J Autoimmun2006; 27: 242–250.
16.
MichaelsonJSWisniackiNBurklyLCPuttermanC. Role of TWEAK in lupus nephritis: A bench-to-bedside review. J Autoimmun2012; 39: 130–142.
17.
CaderMZFilerAHazlehurstJde PabloPBuckleyCDRazaK. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: Comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis2011; 70: 949–955.
AbujamBCheekatlaSSAggarwalA. Urinary CXCL-10/IP-10 and MCP-1 as markers to assess activity of lupus nephritis. Lupus2013; 22: 614–623.
20.
WeeningJJD'AgatiVDSchwartzMMet al.The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol2004; 15: 241–250.
21.
AustinHA3rdMuenzLRJoyceKMAntonovychTTBalowJE. Diffuse proliferative lupus nephritis: Identification of specific pathologic features affecting renal outcome. Kidney Int1984; 25: 689–695.
22.
BrunnerHIBennettMRMinaRet al.Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum2012; 64: 2687–2697.
23.
Cortés-HernándezJOrdi-RosJLabradorMet al.Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone. Lupus2003; 12: 287–296.
24.
ZappitelliMDuffyCBernardCet al.Clinicopathological study of the WHO classification in childhood lupus nephritis. Pediatr Nephrol2004; 19: 503–510.
SchwartzNRubinsteinTBurklyLCet al.Urinary TWEAK as a biomarker of lupus nephritis: A multicenter cohort study. Arthritis Res Ther2009; 11: R143.
27.
RosaRFTakeiKAraújoNCLoducaSMSzajubokJCChahadeWH. Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients. J Rheumatol2012; 39: 1948–1954.
28.
FogazziGBGarigaliG. The clinical art and science of urine microscopy. Curr Opin Nephrol Hypertens2003; 12: 625–632.
29.
DingJYIbañezDGladmanDDUrowitzMB. Isolated hematuria and sterile pyuria may indicate systemic lupus erythematosus activity. J Rheumatol2015; 42: 437–440.
30.
AppenzellerSClarkAPineauCVasilevskyMBernatskyS. Isolated pyuria in systemic lupus erythematosus. Lupus2010; 19: 793–796.
31.
RahmanPGladmanDDIbañezDUrowitzMB. Significance of isolated hematuria and isolated pyuria in systemic lupus erythematosus. Lupus2001; 10: 418–423.
32.
ZhangXLJinMWuHFet al.Biomarkers of lupus nephritis determined by serial urine proteomics. Kidney Int2008; 74: 799–807.
33.
RovinBHSongHBirminghamDJHebertLAYuCYNagarajaHN. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J Am Soc Nephrol2005; 16: 467–473.
34.
SanzABSanchez-NiñoMDOrtizA. TWEAK, a multifunctional cytokine in kidney injury. Kidney Int2011; 80: 708–718.
35.
ZhuXJTanJZLiJXuXQYuanSGLiuFY. Urinary TWEAK level as a marker of lupus nephritis activity in 46 cases. J Biomed Biotechnol2012; 2012: 359647.
36.
HershAOvon SchevenEYazdanyJet al.Differences in long-term disease activity and treatment of adult patients with childhood- and adult-onset systemic lupus erythematosus. Arthritis Rheum2009; 61: 13–20.
37.
DavisLSHutchesonJMohanC. The role of cytokines in the pathogenesis and treatment of systemic lupus erythematosus. J Interf Cytok Res2011; 31: 781–789.
38.
TucciMBarnesEVSobelESet al.Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis. Arthritis Rheum2004; 50: 1842–1849.
González-SánchezDAÁlvarezCMVásquezGGómez-PuertaJA. Role of TWEAK/Fn14 signalling pathway in lupus nephritis and other clinical settings. Nefrologia2017; 37: 118–125.
41.
JulkunenHEkblom-KullbergSMiettinenA. Nonrenal and renal activity of systemic lupus erythematosus: A comparison of two anti-C1q and five anti-dsDNA assays and complement C3 and C4. Rheumatol Int2012; 32: 2445–2451.
42.
MoroniGQuagliniSRadiceAet al.The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. J Immunol Res2015; 2015: 106904.
43.
EsdaileJMAbrahamowiczMJosephLMacKenzieTLiYDanoffD. Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus. Why some tests fail. Arthritis Rheum1996; 39: 370–378.
44.
RibichiniFGrazianiMGambaroGet al.Early creatinine shifts predict contrast-induced nephropathy and persistent renal damage after angiography. Am J Med2010; 123: 755–763.
45.
BriscoMACocaSGChenJet al.Blood urea nitrogen/creatinine ratio identifies a high-risk but potentially reversible form of renal dysfunction in patients with decompensated heart failure. Circ Heart Fail2013; 6: 233–239.
46.
OhMYLeeHKimJSet al.Cystatin C, a novel indicator of renal function, reflects severity of cerebral microbleeds. BMC Neurol2014; 14: 127.
47.
ZhengJYaoYHanLXiaoY. Renal function and injury in infants and young children with congenital heart disease. Pediatr Nephrol2013; 28: 99–104.
48.
JiangXZhangQWangHBCuiXFLiuR. Associations of urinary, glomerular, and tubular markers with the development of diabetic kidney disease in type 2 diabetes patients. J Clin Lab Anal2018, pp. 32.
49.
MasudaTAkimotoTAndoYet al.Changes in the urinary excretion of beta2-microglobulin (beta 2MG) and N-acetyl-beta-D-glucosaminidase (NAG) during treatment for lupus nephritis. Intern Med2008; 47: 287–290.
50.
ChoeJYKimSK. Serum TWEAK as a biomarker for disease activity of systemic lupus erythematosus. Inflamm Res2016; 65: 479–488.
WorawichawongSWorawichawongSRadinahamedPet al.Urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratio as biomarkers for interstitial fibrosis and tubular atrophy in primary glomerulonephritis. Kidney Blood Press Res2016; 41: 997–1007.
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