Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). Conventional biomarkers for assessing renal disease activity are imperfect in predicting clinical outcomes associated with LN. The aim of this study is to identify urinary protein biomarkers that reliably reflect the disease activity or predict clinical outcomes. A quantitative proteomic analysis was performed to identify protein biomarker candidates that can differentiate between SLE patients with and without LN. Selected biomarker candidates were further verified by enzyme-linked immunosorbent assay using urine samples from a larger cohort of SLE patients (n = 121) to investigate their predictive values for LN activity measure. Furthermore, the association between urinary levels of a selected panel of potential biomarkers and prognosis of LN was assessed with a four-year follow-up study of renal outcomes. Urinary vitamin D-binding protein (VDBP), transthyretin (TTR), retinol binding protein 4 (RBP4), and prostaglandin D synthase (PTGDS) were significantly elevated in SLE patients with LN, especially in patients with active LN (n = 21). Among them, VDBP well correlated with severity of proteinuria (rho = 0.661, p < 0.001) and renal SLE Disease Activity Index (renal SLEDAI) (rho = 0.520, p < 0.001). In the four-year follow-up, VDBP was a significant risk factor (hazard ratio 9.627, 95% confidence interval 1.698 to 54.571, p = 0.011) for the development of proteinuric flare in SLE patients without proteinuria (n = 100) after adjustments for multiple confounders. Urinary VDBP correlated with proteinuria and renal SLEDAI, and predicted the development of proteinuria.
OrtegaLMSchultzDRLenzOPardoVContrerasGN. Review: Lupus nephritis: Pathologic features, epidemiology and a guide to therapeutic decisions. Lupus2010; 19: 557–574.
2.
KorbetSMLewisEJSchwartzMMReichlinMEvansJRohdeRD. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis2000; 35: 904–914.
3.
HillGSDelahousseMNochyDet al.Outcome of relapse in lupus nephritis: Roles of reversal of renal fibrosis and response of inflammation to therapy. Kidney Int2002; 61: 2176–2186.
4.
FiehnCHaijarYMuellerKWaldherrRHoADAndrassyK. Improved clinical outcome of lupus nephritis during the past decade: Importance of early diagnosis and treatment. Ann Rheum Dis2003; 62: 435–439.
5.
FaurschouMStarklintHHalbergPJacobsenS. Prognostic factors in lupus nephritis: Diagnostic and therapeutic delay increases the risk of terminal renal failure. J Rheumatol2006; 33: 1563–1569.
6.
StilesKPYuanCMChungEMLyonRDLaneJDAbbottKC. Renal biopsy in high-risk patients with medical diseases of the kidney. Am J Kidney Dis2000; 36: 419–433.
7.
EiroMKatohTWatanabeT. Risk factors for bleeding complications in percutaneous renal biopsy. Clin Exp Nephrol2005; 9: 40–45.
8.
MoroniGRadiceAGiammarresiGet al.Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis. Ann Rheum Dis2009; 68: 234–237.
RubinsteinTPitashnyMLevineBet al.Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis. Rheumatology (Oxford)2010; 49: 960–971.
11.
Torres-SalidoMTCortés-HernándezJVidalXPedrosaAVilardell-TarrésMOrdi-RosJ. Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis. Nephrol Dial Transplant2014; 29: 1740–1749.
12.
RosaRFTakeiKAraújoNCLoducaSMSzajubokJCChahadeWH. Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients. J Rheumatol2012; 39: 1948–1954.
13.
SchwartzNRubinsteinTBurklyLCet al.Urinary TWEAK as a biomarker of lupus nephritis: A multicenter cohort study. Arthritis Res Ther2009; 11: R143.
14.
SomparnPHirankarnNLeelahavanichkulAKhovidhunkitWThongboonkerdVAvihingsanonY. Urinary proteomics revealed prostaglandin H(2)D-isomerase, not Zn-α2-glycoprotein, as a biomarker for active lupus nephritis. J Proteomics2012; 75: 3240–3247.
15.
GuptaRYadavAMisraRAggarwalA. Urinary prostaglandin D synthase as biomarker in lupus nephritis: A longitudinal study. Clin Exp Rheumatol2015; 33: 694–698.
16.
KorteEAGaffneyPMPowellDW. Contributions of mass spectrometry-based proteomics to defining cellular mechanisms and diagnostic markers for systemic lupus erythematosus. Arthritis Res Ther2012; 14: 204.
17.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725.
18.
WeeningJJD'AgatiVDSchwartzMMet al.The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol2004; 15: 241–250.
RovinBHFurieRLatinisKet al.Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum2012; 64: 1215–1226.
21.
HebertLADillonJJMiddendorfDFLewisEJPeterJB. Relationship between appearance of urinary red blood cell/white blood cell casts and the onset of renal relapse in systemic lupus erythematosus. Am J Kidney Dis1995; 26: 432–438.
22.
GordonCJayneDPuseyCet al.European consensus statement on the terminology used in the management of lupus glomerulonephritis. Lupus2009; 18: 257–263.
23.
AfkarianMBhasinMDillonSTet al.Optimizing a proteomics platform for urine biomarker discovery. Mol Cell Proteomics2010; 9: 2195–2204.
24.
ShevchenkoATomasHHavlisJOlsenJVMannM. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc2006; 1: 2856–2860.
25.
NesvizhskiiAIKellerAKolkerEAebersoldR. A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem2003; 75: 4646–4658.
26.
PavelkaNFournierMLSwansonSKet al.Statistical similarities between transcriptomics and quantitative shotgun proteomics data. Mol Cell Proteomics2008; 7: 631–644.
27.
WuTFuYBrekkenDet al.Urine proteome scans uncover total urinary protease, prostaglandin D synthase, serum amyloid P, and superoxide dismutase as potential markers of lupus nephritis. J Immunol2010; 184: 2183–2193.
28.
SuzukiMWiersKBrooksEBet al.Initial validation of a novel protein biomarker panel for active pediatric lupus nephritis. Pediatr Res2009; 65: 530–536.
29.
LeveyASBoschJPLewisJBGreeneTRogersNRothD. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med1999; 130: 461–470.
30.
RobinsonABThierry-PalmerMGibsonKLRabinovichCE. Disease activity, proteinuria, and vitamin D status in children with systemic lupus erythematosus and juvenile dermatomyositis. J Pediatr2012; 160: 297–302.
31.
VargheseSAPowellTBBudisavljevicMNet al.Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol2007; 18: 913–922.
32.
SessoRRettoriRNishidaSSatoEAjzenHPereiraAB. Assessment of lupus nephritis activity using urinary retinol-binding protein. Nephrol Dial Transplant1994; 9: 367–371.
33.
GuyJMBrammahTBHoltLet al.Urinary excretion of albumin and retinol binding protein in systemic lupus erythematosus. Ann Clin Biochem1997; 34: 668–674.
34.
OonkSSpitaliPHillerMet al.Comparative mass spectrometric and immunoassay-based proteome analysis in serum of Duchenne muscular dystrophy patients. Proteomics Clin Appl2016; 10: 290–299.
35.
ThrailkillKMJoCHCockrellGEMoreauCSFowlkesJL. Enhanced excretion of vitamin D binding protein in type 1 diabetes: A role in vitamin D deficiency?. J Clin Endocrinol Metab2011; 96: 142–149.
36.
TianXQZhaoLMGeJPZhangYXuYC. Elevated urinary level of vitamin D-binding protein as a novel biomarker for diabetic nephropathy. Exp Ther Med2014; 7: 411–416.
37.
MirkovićKDoorenbosCRDamWAet al.Urinary vitamin D binding protein: A potential novel marker of renal interstitial inflammation and fibrosis. PLoS One2013; 8: e55887.
38.
BrunnerHIBennettMRGulatiGet al.Urine biomarkers to predict response to lupus nephritis therapy in children and young adults. J Rheumatol2017; 44: 1239–1248.
39.
VerbovenCRabijnsADe MaeyerMVan BaelenHBouillonRDe RanterC. A structural basis for the unique binding features of the human vitamin D-binding protein. Nat Struct Biol2002; 9: 131–136.
40.
NykjaerADragunDWaltherDet al.An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell1999; 96: 507–515.
41.
SchifferLBethunaickanRRamanujamMet al.Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol2008; 180: 1938–1947.
42.
ChishimbaLThickettDRStockleyRAWoodAM. The vitamin D axis in the lung: A key role for vitamin D-binding protein. Thorax2010; 65: 456–462.
43.
SumethkulKBoonyaratavejSKitumnuaypongTet al.The predictive factors of low serum 25-hydroxyvitamin D and vitamin D deficiency in patients with systemic lupus erythematosus. Rheumatol Int2013; 33: 1461–1467.
44.
ChenSSimsGPChenXXGuYYChenSLipskyPE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol2007; 179: 1634–1647.
45.
DoorenbosCRde CubaMMVogtLet al.Antiproteinuric treatment reduces urinary loss of vitamin D-binding protein but does not affect vitamin D status in patients with chronic kidney disease. J Steroid Biochem Mol Biol2012; 128: 56–61.
46.
KazemipourNQazizadehHSepehrimaneshMSalimiS. Biomarkers identified from serum proteomic analysis for the differential diagnosis of systemic lupus erythematosus. Lupus2015; 24: 582–587.
47.
RocchettiMTCentraMPapaleMet al.Urine protein profile of IgA nephropathy patients may predict the response to ACE-inhibitor therapy. Proteomics2008; 8: 206–216.
48.
KirsztajnGMNishidaSKSilvaMSAjzenHMouraLAPereiraAB. Urinary retinol-binding protein as a prognostic marker in glomerulopathies. Nephron2002; 90: 424–431.
49.
SessoRSantosAPNishidaSKKlagMJCarvalhaesJTAjzenH. Prediction of steroid responsiveness in the idiopathic nephrotic syndrome using urinary retinol-binding protein and beta-2-microglobulin. Ann Intern Med1992; 116: 905–909.
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