Lupus nephritis (LN) is an ominous manifestation of systemic lupus erythematosus (SLE). Clinical renal affection is present in about 70% of lupus patients, and more patients have histological evidence of renal involvement without clinical manifestations. This study aimed to investigate the potential role of serum interleukin-34 (IL-34) as an early marker for the detection of silent LN.
Methods
Thirty-three lupus patients with silent LN (group I), 37 patients with clinical LN (group II) and 20 controls were included. The SLE Disease Activity Index (SLEDAI), IL-34, anti-dsDNA antibodies and renal biopsy were assessed in all patients.
Results
Serum IL-34 levels were significantly higher in all lupus patients compared to healthy controls (p < 0.001) and showed a significant positive correlation with SLEDAI score. SLE patients with positive anti-dsDNA antibodies had more active disease according to SLEDAI and higher levels of IL-34 than those with negative anti-dsDNA antibodies. In both studied groups, serum IL-34 levels were significantly higher in patients with proliferative LN (class III and class IV) than those with non-proliferative lupus (class II and class V) and controls. Yet, in both groups, IL-34 was not useful in differentiating active from chronic renal affection.
Conclusion
In lupus patients with insignificant proteinuria, serum levels of IL-34 distinguished the different histological classes of subclinical LN. Serum IL-34 may be used as a surrogate marker for early renal affection in silent LN, especially the proliferative type.
BombackASAppelGB.Updates on the treatment of lupus nephritis. J Am Soc Nephrol2010;
21: 2028–2035.
2.
WaldmanMMadaioMP.Pathogenic autoantibodies in lupus nephritis. Lupus2005;
14: 19–24.
3.
NowlingTKGilkesonGS.Mechanisms of tissue injury in lupus nephritis. Arthritis Res Ther2011;
13: 250.
4.
DavisLSHutchesonJMohanC.The role of cytokines in the pathogenesis and treatment of systemic lupus erythematosus. J Interferon Cytokine Res2011;
31: 781–789.
5.
GiganteAGasperiniMLAfeltraA, et al.
Cytokines expression in SLE nephritis.Eur Rev Med Pharmacol Sci2011;
15: 15–24.
GuillonneauCBézieSAnegonI.Immunoregulatory properties of the cytokine IL-34. Cell Mol Life Sci2017;
74: 2569–2586.
8.
LinHLeeEHestirK, et al.
Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science2008;
320: 807–811.
9.
DroinNSolaryE.CSF1R, CSF‐1, and IL‐34, a ‘ménage à trois’ conserved across vertebrates. J Leukoc Biol2010;
87: 745–747.
10.
EdaHZhangJKeithRHMichenerMBeidlerDRMonahanJB.Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood. Cytokine2010;
52: 215–220.
11.
ZhouRPWuXSXieYY, et al.
Functions of interleukin‐34 and its emerging association with rheumatoid arthritis. Immunology2016;
149: 362–373.
12.
CicciaFAlessandroRRodolicoV, et al.
IL-34 is overexpressed in the inflamed salivary glands of patients with Sjögren’s syndrome and is associated with the local expansion of pro-inflammatory CD14(bright)CD16+ monocytes. Rheumatology2013;
52: 1009–1017.
13.
TanidaSOzekiKMizoshitaT, et al.
Managing refractory Crohn’s disease: challenges and solutions.Clin Exp Gastroenterol2015;
8: 131–140.
14.
CashHRelleMMenkeJ, et al.
Interleukin 6 (IL-6) deficiency delays lupus nephritis in MRL-Faslpr mice: the IL-6 pathway as a new therapeutic target in treatment of autoimmune kidney disease in systemic lupus erythematosus. J Rheumatol2010;
37: 60–70.
15.
El-GoharyAHegazyAAbbasMKamelNNasefSI.Serum and urinary interferon‐gamma‐inducible protein 10 in lupus nephritis. J Clin Lab Anal2016;
30: 1135–1138.
16.
KimHLLeeDSYangSH, et al.
The polymorphism of monocyte chemoattractant protein-1 is associated with the renal disease of SLE. Am J Kidney Dis2002;
40: 1146–1152.
17.
BethunaickanRBerthierCCZhangWKretzlerMDavidsonA.Comparative transcriptional profiling of 3 murine models of SLE nephritis reveals both unique and shared regulatory networks. PLoS One2013;
8: e77489.
18.
MokCC.Understanding lupus nephritis: diagnosis, management, and treatment options. Int J Womens Health2012;
4: 213–222.
19.
Christopher-StineLSiednerMLinJ, et al.
Renal biopsy in lupus patients with low levels of proteinuria.J Rheumatol2007;
34: 332–335.
20.
PetriMOrbaiAMAlarcónGS, et al.
Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum2012;
64: 2677–2686.
21.
MarkowitzGSD’AgatiVD.The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int2007;
71: 491–495.
22.
MokCC.Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol2010;
2010: 638413.
23.
HochbergMC.Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997;
40: 1725.
24.
Zabaleta-LanzMEMuñozLETapanesFJ, et al.
Further description of early clinically silent lupus nephritis. Lupus2006;
15: 845–851.
WeeningJJD’AgatiVDSchwartzMM, et al.
The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int2004;
65: 521–530.
27.
AustinIII HAMuenzLRJoyceKM, et al.
Prognostic factors in lupus nephritis: contribution of renal histologic data. Am J Med1983;
75: 382–391.
28.
WangHCaoJLaiX.Serum interleukin-34 levels are elevated in patients with systemic lupus erythematosus. Molecules2016;
22: 35.
29.
MetoniABalanescuPDimaA, et al.
Interleukin-17-association to silent lupus nephritis and disease activity. J Transl Med Res2015;
20: 71–75.
30.
BrugosBVinczeZSipkaSSzegediGZeherM.Serum and urinary cytokine levels of SLE patients. Pharmazie2012;
67: 411–413.
31.
XieHHShenHZhangLCuiMYXiaLPLuJ.Elevated serum interleukin-34 level in patients with systemic lupus erythematosus is associated with disease activity.Sci Rep2018;
8: 3462.
32.
FoucherEDBlanchardSPreisserL, et al.
IL‐34‐ and M‐CSF‐induced macrophages switch memory T cells into Th17 cells via membrane IL‐1α. Eur J Immunol2015;
45: 1092–1102.
33.
CornecDCornec-LeGESegalenZ, et al.
Which autoantibodies announce that lupus nephritis is on the way?Int J Clin Rheumatol2009;
4: 287–295.
34.
YungSChanTM.Mechanisms of kidney injury in lupus nephritis – the role of anti-dsDNA antibodies. Front Immunol2015;
6: 475.
35.
Zabaleta-LanzMVargas-ArenasRETápanesFDaboinIAtahualpa PintoJBiancoNE.Silent nephritis in systemic lupus erythematosus. Lupus2003;
12: 26–30.
36.
Al-HefnyAMEl-BakrySAMobasherSANadaOHAbazaN.Renal biopsy findings in lupus patient with insignificant proteinuria: relation to disease activity and clinical manifestations. Life Sci J2013;
10: 1872–1879.
37.
El BakrySAEl DinABAl HusseinM, et al.
Anti-nucleosome antibodies: a potential surrogate marker for renal affection in lupus patients with insignificant proteinuria. Egypt Rheumatol2014;
36: 79–84.
38.
WakasugiDGonoTKawaguchiY, et al.
Frequency of class III and IV nephritis in systemic lupus erythematosus without clinical renal involvement: an analysis of predictive measures. J Rheumatol2012;
39: 79–85.
39.
FanQYanXZhangH, et al.
IL-34 is associated with the presence and severity of renal dysfunction and coronary artery disease in patients with heart failure. Sci Rep2016;
6: 39324.
40.
EdaHShimadaHBeidlerDRMonahanJB.Proinflammatory cytokines, IL-1β and TNF-α, induce expression of interleukin-34 mRNA via JNK- and p44/42 MAPK-NF-κB pathway but not p38 pathway in osteoblasts. Rheumatol Int2011;
31: 1525–1530.
41.
MastellerELWongBR.Targeting IL-34 in chronic inflammation. Drug Discov Today2014;
19: 1212–1216.
ApostolidisSACrispínJCTsokosGC.IL-17-producing T cells in lupus nephritis. Lupus2011;
20: 120–124.
44.
MendeRVincentFBKandane-RathnayakeR, et al.
Analysis of serum interleukin (IL)-1β and IL-18 in systemic lupus erythematosus. Front Immunol2018;
9: 1250.
45.
YangXWengQHuL, et al.
Increased interleukin-22 levels in lupus nephritis and its association with disease severity: a study in both patients and lupus-like mice model. Clin Exp Rheumatol2019;
37: 400–407.
46.
ChenDYChenYMWenMCHsiehTYHungWTLanJL.The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis. Lupus2012;
21: 1385–1396.
47.
ElewaEAZakariaOMohamedEIBoghdadiG.The role of interleukins 4, 17 and interferon gamma as biomarkers in patients with systemic lupus erythematosus and their correlation with disease activity. Egypt Rheumatol2014;
36: 21–27.
