Download PDF
Aktuelle Rheumatologie 2019; 44(02): 121-127
DOI: 10.1055/s-0043-121629
Originalarbeit
Georg Thieme Verlag KG Stuttgart · New York

Progranulin and insulin-like Growth Factor Binding Protein-2 as Biomarkers of Disease Activity and Pathological Changes in Lupus Nephritis

Progranulin und Insulin-ähnliches Wachstumsfaktor-bindendes Protein-2 als Biomarker für Krankheitsaktivität und pathologische Veränderungen bei Lupusnephritis
Samar H. Goma
1   Department of Rheumatology, Rehabilitation, and Physical Medicine, Assiut University Hospital, Assiut, Egypt
,
Marwa Mahmoud Abdelaziz
1   Department of Rheumatology, Rehabilitation, and Physical Medicine, Assiut University Hospital, Assiut, Egypt
,
Eman H. El-Hakeim
1   Department of Rheumatology, Rehabilitation, and Physical Medicine, Assiut University Hospital, Assiut, Egypt
,
Mona H. El Zohri
2   Department of Internal Medicine, Rheumatology Unit, Assiut University Hospital, Assiut, Egypt
,
Sohair K. Sayed
3   Department of Clinical Pathology, Assiut University Hospital, Assiut, Egypt
› Author Affiliations
Further Information

Publication History

Publication Date:
27 November 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease, characterised by the production of auto-antibodies and the formation of immune complexes due to the polyclonal activation of T and B lymphocytes, which results in tissue and organ damage. During inflammation, neutrophils and macrophages release serine proteases to cleave progranulin (PGRN) into granulin, which exerts its pro-inflammatory effects that counteract the anti-inflammatory effects of intact PGRN. It is suggested that insulin-like growth factor binding protein-2 (IGFBP-2) is a dependable biomarker of renal deterioration but it is still unclear if it has high sensitivity and specificity for discriminating SLE-caused kidney disease from other-cause kidney disease.

This study aimed to investigate the diagnostic value of PGRN and ILGFBP-2 in patients with lupus nephritis (LN) and the correlation of these biomarkers with disease activity and renal biopsy pathology.

Patients and methods Patients with SLE (n=25) and chronic kidney disease (CKD) (n=25), and age- and sex-matched controls (n=25) were enrolled in the study. Serum PGRN and ILGFBP-2 levels were measured for each group.

Results Disease duration was 4.78±4.26 years in the SLE patients. The mean SLE Disease Activity Index score was 15.04±7.54. All renal biopsy results were class 2, 3, and 5 with a percentage of 32, 24, and 44% respectively. PGRN and ILGFBP-2 were significantly higher in SLE patients (p<0.001 all) than in the CKD and control groups. All patients with high levels of biomarkers showed higher values of SLE disease activity. No significant difference was noted between active and inactive LN or classes of renal biopsy with PGRN and ILGFBP-2.

Conclusion PGRN and ILGFBP-2 are significantly elevated in SLE compared to CKD and the general population and were associated with the SLE Disease Activity Index but not with active LN or classes of renal biopsy.

Zusammenfassung

Hintergrund Der systemische Lupus erythematodes (SLE) ist eine chronische Autoimmunerkrankung, die durch die Produktion von Autoantikörpern und die Bildung von Immunkomplexen aufgrund der polyklonalen Aktivierung von T- und B-Lymphozyten gekennzeichnet ist, die zu Gewebs- und Organschäden führen. Während der Entzündung können Neutrophile und Makrophagen Serin-Proteasen freisetzen, um Progranulin (PGRN) in Granulin zu spalten, das seine entzündungsfördernden Wirkungen ausübt, die den entzündungshemmenden Wirkungen von intaktem PGRN entgegenwirken. Es wird vorgeschlagen, dass das Insulin-ähnliche Wachstumsfaktor-Bindungsprotein-2 (IGFBP-2) ein verlässlicher Biomarker für die renale Verschlechterung ist, aber es ist immer noch unklar, ob es eine hohe Sensitivität und Spezifität für die Diskriminierung von SLE-verursachter Nierenerkrankung hat. Ziel dieser Studie war es, den diagnostischen Wert von PGRN und ILGFBP-2 bei Patienten mit Lupusnephritis (LN) und die Korrelation dieser Biomarker mit Krankheitsaktivität und Nierenbiopsie-Pathologie zu untersuchen.

Patienten und Methoden In die Studie wurden Patienten mit SLE (n = 25) und chronischer Nierenerkrankung (CKD) (n = 25), Kontroll- und Geschlechtskontrollen (n = 25) eingeschlossen. Die Serum-PGRN- und ILGFBP-2-Spiegel wurden für jede Gruppe gemessen.

Ergebnisse Die Krankheitsdauer betrug bei den SLE-Patienten 4,78 ± 4,26 Jahre. Die mittlere SLEDisease Activity Index erzielte 15,04 ± 7,54. Alle Nierenbiopsieergebnisse waren Klasse 2, 3 und 5 mit einem Prozentsatz von 32%, 24% bzw. 44%. PGRN und ILGFBP-2 waren signifikant höher bei SLE-Patienten (p<0,001all) als in der CKD und Kontrollgruppen. Alle Patienten mit hohen Biomarkern wiesen höhere SLE-Werte auf. Es wurde kein signifikanter Unterschied zwischen aktivem und inaktivem LN oder Klassen der Nierenbiopsie mit PGRN und ILGFBP-2 festgestellt.

Schlussfolgerung PGRN und ILGFBP-2 sind im Vergleich zu CKD und der Allgemeinbevölkerung signifikant erhöht und mit dem SLEDisease-Aktivitätsindex assoziiert, jedoch nicht mit aktiven LN oder Klassen von Nierenbiopsien.

Key words

progranulin (PGRN) - insulin-like growth factor binding protein (IGFBP-2) - lupus nephritis - pathology

Schlüsselwörter

progranulin (PGRN) - Insulin-ähnliches Wachstumsfaktorbindungsprotein (IGFBP-2) - lupus nephritis - Pathologie
 

  • References

  • 1 Rahman A, Isenberg DA. Systemic lupus erythematous. N Engl J Med 2008; 358: 929-939
    CrossrefPubMedGoogle Scholar
  • 2 Kotzin BI. Systemic lupus erythematosus. Cell 1996; 85: 303-306
    CrossrefPubMedGoogle Scholar
  • 3 Stohl W. Future prospects in biologic therapy for systemic lupus erythematosus. Nat Rev Rheumatol 2013; 9: 705-720
    CrossrefPubMedGoogle Scholar
  • 4 Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus. Medicine 2006; 85: 147-156
    PubMedGoogle Scholar
  • 5 Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J BoimedBiotechnol 2010; 2010: 638413
    PubMedGoogle Scholar
  • 6 Ortega LM, Schultz DR, Lenz O. et al. Review: Lupus nephritis: pathologic features, epidemiology and a guide to therapeutic decisions. Lupus 2010; 19: 557-574
    CrossrefPubMedGoogle Scholar
  • 7 Manger K, Manger B, Repp R. et al. Definition of risk factors for death, end stage renal disease and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus. Ann Rheum Dis 2002; 61: 1065-1070
    CrossrefPubMedGoogle Scholar
  • 8 Cervera R, Khamashta MA, Font J. et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 2003; 82: 299-308
    PubMedGoogle Scholar
  • 9 Borchers AT, Leibushor N, Naguwa SM. et al. Lupus nephritis: a critical review. Autoimmun Rev 2012; 12: 174-194
    CrossrefPubMedGoogle Scholar
  • 10 Ding H, Kharboutli M, Saxena R. et al. Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis. Clinical and Experimental Immunology 2016; 184: 11-18
    CrossrefPubMedGoogle Scholar
  • 11 Liu CJ. Progranulin: a promising therapeutic target for rheumatoid arthritis. FEBS Lett 2011; 585: 3675-3680
    CrossrefPubMedGoogle Scholar
  • 12 Park B, Buti L, Lee S. et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011; 34: 505-513
    CrossrefPubMedGoogle Scholar
  • 13 Tanaka A, Tsukamoto H, Mitoma H. et al. Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity. Arthritis Res Ther. 2012; 14: R244
    CrossrefPubMedGoogle Scholar
  • 14 Wu J, Wei L, Wang W. et al. Diagnostic value of progranulin in patients with lupus nephritis and its correlation with disease activity. Rheumatol Int 2016; 36: 759-767
    CrossrefPubMedGoogle Scholar
  • 15 Bruchim I, Werner H. Targeting IGF-1 signaling pathways in gynecologic malignancies. Expert OpinTher Targets 2013; 17: 307-320
    PubMedGoogle Scholar
  • 16 Forbes BE, McCarthy P, Norton RS. Norton. Insulin-like growth factor binding proteins: a structural perspective. Front Endocrinol (Lausanne) 2012; 3: 38
    PubMedGoogle Scholar
  • 17 Petri M, Orbai AM, Alacon GS. et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677-2668
    CrossrefPubMedGoogle Scholar
  • 18 Bombardier C, Gladman DD, Urowitz MB. et al. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arhritis Rheum 1992; 35: 630-640
    PubMedGoogle Scholar
  • 19 Petri M, Genovese M, Engle E. et al. Definition, incidence and clinical description of flare in systemic lupus erythematosus. Arthritis Rheum 1991; 8: 937-944
    PubMedGoogle Scholar
  • 20 Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002; 29: 288-291
    Google Scholar
  • 21 Weening JJ, D’Agati VD, Schwartz MM. etal. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65: 521-530
    CrossrefPubMedGoogle Scholar
  • 22 Rock RC, Walker WG, Jennings CD. Nitrogen metabolites and renal function.In fundamentals of clinical chemistry. editor Tiez NW. 3rd edition W.B. Saunders Company; 1987: 669-704
    Google Scholar
  • 23 Rovin BH, Zhang X. Biomarkers for lupus nephritis: the quest continues. Clin J Am ScoNephrol 2009; 4: 1858-1865
    PubMedGoogle Scholar
  • 24 Frieri M, Samih MA, Dzhindzhikhashvili M. et al. Toll-like receptor 9 and vascular endothelial growth factor levels in human kidneys from lupus nephritis patients. J Nephrol 2012; 25: 1041
    CrossrefPubMedGoogle Scholar
  • 25 Panda AK, Parida JR, Tripathy R. et al. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther 2012; 14: R218
    CrossrefPubMedGoogle Scholar
  • 26 Rosa RF, Takei K, Araújo NC. et al. Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients. J Rheumatol 2012; 39: 1948-1954
    PubMedGoogle Scholar
  • 27 Kirsztajn G. Serum beta 2-microglobulin/ cystatin C index: a useful biomarker in lupus nephritis. Nephron Extra 2012; 2: 169-176
    CrossrefPubMedGoogle Scholar
  • 28 Singh S, Wu T, Xie C. et al. Urine VCAc of renal pathology activity index in lupus nephritis. Arthritis Res Ther 2012; 14: R164
    CrossrefPubMedGoogle Scholar
  • 29 Treamtrakanpon W, Tantivitayakul P, Benjachat T. et al. APRIL, a proliferation-inducing ligand, as a potential marker of lupus nephritis. Arthritis Res Ther 2012; 14: R252
    CrossrefPubMedGoogle Scholar
  • 30 Badot V, Luijten RK, van Roon JA. et al. Serum soluble interlukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus. Ann Rheum Dis 2013; 72: 453-456
    CrossrefPubMedGoogle Scholar
  • 31 Wu T, Du Y, Han J. et al. Urinary angiotensin- a novel putative marker of renal pathology chronicity in lupus nephritis. Mol Cell Proteomics. 2013; 12: 1170-1179
    CrossrefPubMedGoogle Scholar
  • 32 Mok CC, Ding H, Kharboutli M. et al. Axl, ferritin, insulin-like growth factor binding protein 2, and tumour necrosis factor receptor type II as biomarkers in systemic lupus erythematosus. Arthritis care and research 2016; 68: 1303-1309
    PubMedGoogle Scholar
  • 33 Bagavant H, Fu SM. Pathogenesis of kidney disease in systemic lupus erythematosus. CurrOpinRheumatol 2009; 21: 489-494
    PubMedGoogle Scholar
  • 34 Qiu F, Song L, Ding F. et al. Expression level of the growth factor progranulin is related with development of systemic lupus erythematosus. Diagnostic Pathology 2013; 8: 88
    PubMedGoogle Scholar
  • 35 Lech M, Anders HJ. The pathogenesis of lupus nephritis. J Am SocNephrol 2013; 24: 1357-1366
    PubMedGoogle Scholar
  • 36 Lorenzo G, Desai J, Anders HJ. Lupus nephritis: update on mechanisms of systemic autoimmunity and Kidney immunopathology. CurrOpinNephrolHypertens 2014; 23: 211-217
    PubMedGoogle Scholar
  • 37 Neidel J. Changes in systemic levels of insulin-like growth factors and their binding proteins in patients with rheumatoid arthritis. Clin and ExperRheumatol 2001; 1: 81-84
    PubMedGoogle Scholar
  • 38 Fled SM, Hirschberg R. Insulin-like growth factor-1 and insulin-like growth factor-binding proteins in the nephrotic syndrome. PediatrNephrol 1996; 10: 355-358
    PubMedGoogle Scholar
  • 39 Narayanan RP, Fu B, Heald AH. et al. ILGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes. Endocr Connect 2012; 1: 95-102
    CrossrefPubMedGoogle Scholar
  • 40 Daniel R, He Z, Carmichael KP. et al. Cellular localization of gene expression for progranulin. J HistochemCytochem 2000; 48: 999-1009
    PubMedGoogle Scholar
  • 41 He Z, Ong CH, Halper J. et al. Progranulin is a mediator of the wound response. Nat Med 2003; 9: 225-229
    CrossrefPubMedGoogle Scholar
  • 42 Bateman A, Bennett HP. The granulin gene family: from cancer to dementia. Bioessays 2009; 31: 1245-1254
    CrossrefPubMedGoogle Scholar
  • 43 Van Damme P, Van Hoecke A, Lambrechts D. et al. Progranulin functions as a neurotropic factor to regulate neurite outgrowth and enhanve neuronal survival. J Cell Biol 2008; 181: 37-41
    CrossrefPubMedGoogle Scholar