Elevated Urinary IL-6 Predicts the Progression of IgA Nephropathy

Overview

Journal Kidney Int Rep

Publisher Elsevier

Specialty Nephrology

Date 2023 Mar 20

PMID 36938089

Authors

Wenjun Zhao

Shi Feng

Yucheng Wang

Cuili Wang

Pingping Ren

Junjun Zhang

Lei Yu

Chunjiang Zhang

Lihua Bai

Ying Chen

Qin Zhou

Lihui Qu

Jianghua Chen

Hong Jiang

Affiliations

Soon will be listed here.

Abstract

Introduction: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. However, biomarkers for predicting the progression or regression of IgAN remain a clinical challenge. In the present study, we aim to identify promising prognostic markers of IgAN.

Methods: Using the cytokine antibody array, we detected serum and urinary levels of 9 common cytokines selected from 23 IgAN-related biomarkers in 32 patients with IgAN and 16 healthy controls. The best biomarkers for distinguishing IgAN patients from healthy controls were identified and confirmed in a multicenter cohort with 222 patients with IgAN and 159 age- and sex-matched healthy controls. Their associations with IgAN progression were further explored in 762 patients with IgAN with a median follow-up of 65 months.

Results: Among the 9 candidate markers, urinary interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) levels were the best for distinguishing patients with IgAN from healthy controls. In the diagnostic cohort, both urinary IL-6 and TGF-β1 levels were elevated in patients with IgAN and showed good discriminatory power, with an area under curve (AUC) of 0.9725 (95% confidence interval: 0.9593-0.9858). Elevated urinary IL-6 level was independently and significantly correlated with the high risk of composite renal outcome (hazard ratio per log-transformed IL-6:1.420 [1.139-1.769]), but no statistical significance was observed between urinary TGF-β1 level and IgAN progression after adjusting for multiple confounders.

Conclusions: Elevated urinary IL-6 and TGF-β1 levels predict the progression of IgAN. Urinary IL-6 is an independent risk factor and a promising noninvasive predictor for IgAN progression.

Citing Articles

Targeting inerleukin-6 for renoprotection.

Gubernatorova E, Samsonov M, Drutskaya M, Lebedeva S, Bukhanova D, Materenchuk M Front Immunol. 2024; 15:1502299.

PMID: 39723211 PMC: 11668664. DOI: 10.3389/fimmu.2024.1502299.

An inflammatory cytokine signature predicts IgA nephropathy severity and progression.

Chen L, Chen X, Cai G, Jiang H, Chen X, Zhang M MedComm (2020). 2024; 5(11):e783.

PMID: 39492831 PMC: 11531656. DOI: 10.1002/mco2.783.

Blood and urine biomarkers of disease progression in IgA nephropathy.

Duan Z, Zhang C, Chen X, Cai G Biomark Res. 2024; 12(1):72.

PMID: 39075557 PMC: 11287988. DOI: 10.1186/s40364-024-00619-4.

Clinical significance of urinary inflammatory biomarkers in patients with IgA nephropathy.

Yoon S, Kim J, Jung S, Kim Y, Moon J, Lee S BMC Nephrol. 2024; 25(1):142.

PMID: 38649936 PMC: 11036669. DOI: 10.1186/s12882-024-03574-2.

References

Cai G, Chen X . Immunoglobulin A nephropathy in China: progress and challenges. Am J Nephrol. 2009; 30(3):268-73. DOI: 10.1159/000225563. View

Berthoux F, Mohey H, Laurent B, Mariat C, Afiani A, Thibaudin L . Predicting the risk for dialysis or death in IgA nephropathy. J Am Soc Nephrol. 2011; 22(4):752-61. PMC: 3065230. DOI: 10.1681/ASN.2010040355. View

Suzuki H, Raska M, Yamada K, Moldoveanu Z, Julian B, Wyatt R . Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes. J Biol Chem. 2014; 289(8):5330-9. PMC: 3931088. DOI: 10.1074/jbc.M113.512277. View

Reich H, Troyanov S, Scholey J, Cattran D . Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007; 18(12):3177-83. DOI: 10.1681/ASN.2007050526. View

Makita Y, Suzuki H, Kano T, Takahata A, Julian B, Novak J . TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy. Kidney Int. 2019; 97(2):340-349. PMC: 7372907. DOI: 10.1016/j.kint.2019.08.022. View

Lee H, Lee M, Lee S, Lee S, Lee E, Lee E . Histological grading of IgA nephropathy predicting renal outcome: revisiting H. S. Lee's glomerular grading system. Nephrol Dial Transplant. 2004; 20(2):342-8. DOI: 10.1093/ndt/gfh633. View

Rops A, Jansen E, van der Schaaf A, Pieterse E, Rother N, Hofstra J . Interleukin-6 is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice. Kidney Int. 2018; 93(6):1356-1366. DOI: 10.1016/j.kint.2018.01.005. View

Lv J, Zhang H, Wong M, Jardine M, Hladunewich M, Jha V . Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017; 318(5):432-442. PMC: 5817603. DOI: 10.1001/jama.2017.9362. View

Maixnerova D, Reily C, Bian Q, Neprasova M, Novak J, Tesar V . Markers for the progression of IgA nephropathy. J Nephrol. 2016; 29(4):535-41. PMC: 5548426. DOI: 10.1007/s40620-016-0299-0. View

10.

Zhao Y, Zhu L, Liu L, Shi S, Lv J, Zhang H . Measures of Urinary Protein and Albumin in the Prediction of Progression of IgA Nephropathy. Clin J Am Soc Nephrol. 2016; 11(6):947-955. PMC: 4891752. DOI: 10.2215/CJN.10150915. View

11.

Haramaki R, Tamaki K, Fujisawa M, Ikedo H, Haramaki N, Okuda S . Steroid therapy and urinary transforming growth factor-beta1 in IgA nephropathy. Am J Kidney Dis. 2001; 38(6):1191-8. DOI: 10.1053/ajkd.2001.29209. View

12.

Harada K, Akai Y, Kurumatani N, Iwano M, Saito Y . Prognostic value of urinary interleukin 6 in patients with IgA nephropathy: an 8-year follow-up study. Nephron. 2002; 92(4):824-6. DOI: 10.1159/000065465. View

13.

Sevillano A, Gutierrez E, Yuste C, Cavero T, Merida E, Rodriguez P . Remission of Hematuria Improves Renal Survival in IgA Nephropathy. J Am Soc Nephrol. 2017; 28(10):3089-3099. PMC: 5619972. DOI: 10.1681/ASN.2017010108. View

14.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

15.

Selvaskandan H, Shi S, Twaij S, Cheung C, Barratt J . Monitoring Immune Responses in IgA Nephropathy: Biomarkers to Guide Management. Front Immunol. 2020; 11:572754. PMC: 7572847. DOI: 10.3389/fimmu.2020.572754. View

16.

Barbour S, Coppo R, Zhang H, Liu Z, Suzuki Y, Matsuzaki K . Evaluating a New International Risk-Prediction Tool in IgA Nephropathy. JAMA Intern Med. 2019; 179(7):942-952. PMC: 6583088. DOI: 10.1001/jamainternmed.2019.0600. View

17.

Yu G, Guo L, Dong J, Shi S, Liu L, Wang J . Persistent Hematuria and Kidney Disease Progression in IgA Nephropathy: A Cohort Study. Am J Kidney Dis. 2020; 76(1):90-99. DOI: 10.1053/j.ajkd.2019.11.008. View

18.

Lim C, Yoon H, Kim Y, Ahn C, Han J, Kim S . Clinicopathological correlation of intrarenal cytokines and chemokines in IgA nephropathy. Nephrology (Carlton). 2004; 8(1):21-7. DOI: 10.1046/j.1440-1797.2003.00128.x. View

19.

Coppo R, Troyanov S, Bellur S, Cattran D, Cook H, Feehally J . Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments. Kidney Int. 2014; 86(4):828-36. PMC: 4184028. DOI: 10.1038/ki.2014.63. View

20.

Segarra-Medrano A, Carnicer-Caceres C, Valtierra-Carmeno N, Agraz-Pamplona I, Ramos-Terrades N, Escalante E . Value of urinary levels of interleukin-6, epidermal growth factor, monocyte chemoattractant protein type1 and transforming growth factor β1 in predicting the extent of fibrosis lesions in kidney biopsies of patients with IgA nephropathy. Nefrologia. 2017; 37(5):531-538. DOI: 10.1016/j.nefro.2016.11.017. View