Immunoglobulin A-nephropathy in Russian population: clinical and morphological presentation and long-term prognosis

 AIM. The analysis of incidence, clinical and morphological manifestations, and the prognosis of IgA nephropathy in the Russian population.

PATIENTS AND METHODS. Six hundred cases with primary IgA nephropathy (IgAN) from 1999 to 2019 were enrolled in the single-center retrospective study. Demographic and clinical parameters, morphrology data, and the treatment were analyzed. Three hundred forty seven patients were included in follow-up study. The following outcomes were evaluated: the occurrence of complete (PR) or partial remission (CR), death from all causes, the need for renal replacement therapy (RRT). The composite endpoint (RRT or eGFR decrease ≥ 50 % from the time of biopsy) was used to evaluate the risk of IgAN progression and associated factors.

RESULTS. The period-average incidence of IgAN cases was 20.5 % of all indication biopsies and 31.7 % of primary immune glomerulopathies (with gradual increase to 41,5 % in last 5 years). At the time of the kidney biopsy, the proteinuria was 2.20 (1.10; 4.40) g/24h, eGFR – 69 ± 32 ml / min / 1.73 m2. Proportions of cases with arterial hypertension and with eGFR <60 ml / min / 1.73 m2 were 75 % and 36 %, respectively. The prevalence of histological changes in accordance with the MEST-C classification was as follows: M1 – 40.5 %, E1 -22.9 %, S1-70.2 %, T1-22 %, T2 – 9 %, C1-16.7 %, C2 – 4.4 %. Combined deposits of IgA and IgM (71.1 % of cases) were more frequent compared to IgA and IgG (9,6 %). In the followup period (27 (11; 61) month), 6 deaths from all causes were registered (1.7 %). The 10-year cumulative renal survival was 75 % (by dialysis) and 55 % (by composite endpoint). PR registered in 26 % of cases, CR – 24 %. PR / CR was more frequent in patients who received immunosuppression compared with patients on renin-angiotensin system blockers only (60 % vs. 40 %, p = 0.001). In multivariable Cox regression the independent factors associated with the risk of IgAN progression were: male gender, a younger age, higher blood pressure and hematuria, lower eGFR, interstitial fibrosis/ tubular atrophy (≥50 %), peritubular capillaritis and the presence of any crescents. Compared to the cohorts of other ethnic or geographical affiliation, analyzed IgAN cases were found to have more severe clinical and morphological presentations and faster progression rate.

CONCLUSION. While being the most common glomerulopathy, IgAN in the Russian population has more pronounced clinical and morphological presentations and an unfavorable prognosis.

1. Schena FP, Nistor I. Epidemiology of IgA Nephropathy: A Global Perspective. Semin Nephrol 2018;38:435–442. doi: 10.1016/j.semnephrol.2018.05.013

2. Reily C, Ueda H, Huang ZQ et al. Cellular Signaling and Production of Galactose-Deficient IgA1 in IgA Nephropathy, an Autoimmune Disease. Journal of Immunology Research 2014. doi: 10.1155/2014/197548

3. Hiki Y, Odani H, Takahashi M et al. Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int 2001;59(3):1077–1085. doi: 10.1046/j.15231755.2001.0590031077.x

4. Tomana M, Novak J, Julian B et al. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactosedeficient hinge region and antiglycan antibodies. J Clin Invest 1999;104(1):73–81. doi: 10.1172/JCI5535

5. Boyaka PN. Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems. J Immunol 2017;199:9–16. doi: 10.4049/jimmunol.1601775

6. Muto M, Manfroi B, Suzuki H et al. Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy. J Am Soc Nephrol 2017;28(4):1227–1238. doi: 10.1681/ASN.2016050496

7. Robert T, Berthelot L, Cambier A et al. Molecular Insights into the Pathogenesis of IgA Nephropathy. Trend Mol Med 2015;12:762–775. doi: 10.1016/j.molmed.2015.10.003

8. Ben Mkaddem S, Benhamou M, Monteiro RC. Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools. Front Immunol 2019; 10: 1–12. doi: 10.3389/fimmu.2019.00811

9. Novak J, Julian BA, Tomana M et al. IgA Glycosylation and IgA Immune Complexes in the Pathogenesis of IgA Nephropathy. Semin Nephrol 2008;28(1):78–87. doi: 10.1016/j.semnephrol.2007.10.009

10. Wyatt RJ, Julian BA. IgA Nephropathy. N Engl J Med 2013; 368:2402–2414. doi: 10.1056/NEJMra1206793

11. Novak J, Tomana M, Matousovic K et al. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int 2005;67:504–513. doi: 10.1111/j.1523-1755.2005.67107.x

12. Kiryluk K, Li Y, Sanna-Cherchi S et al. Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis. PLoS Genet 8(6):e1002765. doi: 10.1371/journal.pgen.1002765

13. Moriyama T, Tanaka K, Iwasaki C et al. Prognosis in IgA Nephropathy: 30-Year Analysis of 1,012 Patients at a Single Center in Japan. PLOS ONE 2014;9(3). doi: 10.1371/journal.pone.0091756

14. Lee H, Kim DK, Oh KH et al. Mortality of IgA Nephropathy Patients: A Single Center in Korea. Experience over 30 Years. PLoS ONE 7(12):e51225. doi: 10.1371/journal.pone.0051225

15. Le W, Liang S, Hu Y et al. Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population. Nephrol Dial Transplant 2012;27:1479–1485. doi: 10.1093/ndt/gfr527

16. Coppo R, Troyanov S, Bellur S et al. Validation of the Oxford classification of IgA-nephropathy in cohorts with different presentations and treatments. Kidney Int 2014;86:828–836. doi: 10.1038/ki.2014.63

17. Roberts IS. Pathology of IgA nephropathy. Nat Rev Nephrol 2014;10:445–454. doi: 10.1038/nrneph.2014.92

18. Cattran DC, Coppo R, Cook HT et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. A Working Group of the International IgA Nephropathy Network and the Renal Pathology Society. Kidney Int 2009;76(5): 534–545. doi: 10.1038/ki.2014.63

19. Trimarchi H, Barratt J, Cattran DC et al. IgAN Classification Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Conference Participants. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int 2017;91(5):1014–1021. doi: 10.1016/j.kint.2017.02.003.

20. Shilov EM, Bobkova IN, Kolina IB, Kamyshova ES. Klinicheskie rekomendacii po diagnostike i lecheniyu IgA-nefropatii. Nefrologiya. Klinicheskie rekomendacii pod red. SHilov EM, Smirnov AV, Kozlovsky NL. GEOTAR-Media, M., 2019;175–190. (In Russ.)

21. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Сhapter 10: Immunoglobulin A nephropathy. Kidney Int Suppl 2012;2:209–217. doi: 10.1038/kisup.2012.23

22. Dadyk EA, Dadyk AI, Vasilenko IV. IgA-nefropatiya: morfologicheskaya harakteristika, osobennosti klinicheskogo techeniya i prognoz. Vestnik neotlozhnoj i vosstanovitel'noj mediciny 2008. (In Russ.)

23. Vozrastnye osobennosti morfometricheskih pokazatelej u bol'nyh s IgAnefropatiej. Klinicheskaya gerontologiya 2010. (In Russ.)

24. Ryabova TS, Rakityanskaya IA. Ekspressiya IL-10 v pochechnoj tkani i kliniko-morfologicheskaya kartina zabolevaniya u bol'nyh s IgA-nefropatiej. Profilakticheskaya i klinicheskaya medicina 2012. (In Russ.)

25. Yeo SC, Goh SM, Barratt J. Is immunoglobulin A nephropathy different in different ethnic populations? Nephrology (Carlton) 2019;24(9):885–895. doi: 10.1111/nep.13592

26. Chang JH, Kim DK, Kim HW et al. Changing prevalence of glomerular diseases in Korean adults: a review of 20 years of experience. Nephrol Dial Transplant 2009;24(8):2406–2410. doi: 10.1093/ndt/gfp091

27. Coppo R. The Gut-Renal Connection in IgA Nephropathy. Semin Nephrol 2018;38(5):504–512. doi: 10.1016/j.semnephrol.2018.05.020

28. Zhu TT, Wang L, Wang HL et al. Helicobacter pylori participates in the pathogenesis of IgA nephropathy. Ren Fail 2016;38(9):1398–1404. doi: 10.1080/0886022X.2016.1216713

29. Floege J, Feehally J. The mucosa-kidney axis in IgA nephropathy. Nat Rev Nephrol 2016;12(3):147–156. doi: 10.1038/nrneph.2015.208

30. Heybeli C, Oktan MA et al. Clinical significance of mesangial IgM deposition in patients with IgA nephropathy. Clinical and Experimental Nephrology 2018;23(3):371–379. doi: 10.1007/s10157-018-1651-6

31. Dong J, Peng T, Gao J et al. A pilot and comparative study between pathological and serological levels of immunoglobulin and complement among three kinds of primary Glomerulonephritis. BMC Immunology 2018;19:18. doi: 10.1186/s12865-018-0254-z

32. Dobronravov VA, Smirnov AV. Etiology and clinic-morphological presentation of membranoproliferative glomerulonephritis in Russian population. Ter arh 2018;12:39–47. (In Russ.) doi: 10.26442/00403660.2018.12.000007

33. Alvarado AS, Andeen NK, Brodsky S et al. Location of glomerular immune deposits, not codeposition of immunoglobulin G, influences definitive renal outcomes in immunoglobulin A nephropathy. Nephrol Dial Transplant 2018;33:1168–1175. doi: 10.1093/ndt/gfx238

34. Akio Koyama, Masaki Kobayashi. Treatment of IgA Nephropathy: Present and Future. Nephrology 1997;3:633–799

35. Zeng CH, Le W, Ni Z et al. A Multicenter Application and Evaluation of the Oxford Classification of IgA Nephropathy in Adult Chinese Patients. Am J Kidney Dis 2012;60:812–820. doi: 10.1053/j.ajkd.2012.06.011

36. Li M, Yu X. Genetic study of immunoglobulin A nephropathy: From research to clinical application. Nephrology (Carlton) 2018;23:26–31. doi: 10.1111/nep.13470

37. Feehally J, Barratt J. The Genetics of IgA Nephropathy: An Overview from Western Countries. Kidney Dis (Basel) 2015;1:33– 41. doi: 10.1159/000381738

38. Berthoux F, Mohey H, Laurent B et al. Predicting the Risk for Dialysis or Death in IgA Nephropathy. J Am Soc Nephrol 2011;22:752–761. doi: 10.1681/ASN.2010040355

39. Reich HN, Troyanov S, Scholey JW et al. Remission of Proteinuria Improves Prognosis in IgA Nephropathy. J Am Soc Nephrol 2007;18:3177–3183. doi: 10.1681/ASN.2007050526

40. Shi SF, Wang SX, Jiang L et al. Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification. Clin J Am Soc Nephrol 2011; 6(9): 2175–2184. doi: 10.2215/CJN.11521210

41. Liu LJ, Li GT, Zhou Y et al. Clinicopathologic Features and Outcomes in Endocapillary Proliferative IgA Nephropathy. Nephron Clin Pract 2010;115:161–167. doi: 10.1159/000312880

42. Sevillano AM, Gutiйrrez E, Yuste C et al. Remission of Hematuria Improves Renal Survival in IgA Nephropathy J Am Soc Nephrol 2017;28(10):3089–3099. doi: 10.1681/ASN.2017010108.

43. Alamartine E, Sauron C, Laurent B et al. The Use of the Oxford Classification of IgA Nephropathy to Predict Renal Survival. Clin J Am Soc Nephrol 2011;6:2384–2388. doi: 10.2215/CJN.01170211

44. Yau T, Korbet SM, Schwartz MM et al. The Oxford Classification of IgA Nephropathy: A Retrospective Analysis. Am J Nephrol 2011;34:435–444. doi: 10.1159/000332223

45. Lee H, Sul Hee Yi, Mi Seon Seo et al. Validation of the Oxford Classification of IgA Nephropathy: A Single-Center Study in Korean Adults. Korean J Intern Med 2012;27:293–300. doi: 10.3904/kjim.2012.27.3.293

46. Tanaka S, Ninomiya T, Katafuchi R et al. Development and Validation of a Prediction Rule Using the Oxford Classification in IgA Nephropathy. Clin J Am Soc Nephrol 2013;8:2082–2090. doi: 10.2215/CJN.03480413

47. Kang SH, Choi SR, Park HS et al. The Oxford classification as a predictor of prognosis in patients with IgA nephropathy. Nephrol Dial Transplant 2012;27:252–258. doi: 10.1093/ndt/gfr295.

48. Bellur SS, Roberts ISD, Troyanov S et al. Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the Validation of IGA study cohort. Nephrol Dial Transplant 2019;34(10):1681–1690. doi: 10.1093/ndt/gfy337

49. Rankin AJ, Kipgen D, Geddes CC et al. Assessment of active tubulointerstitial nephritis in non-scarred renal cortex improves prediction of renal outcomes in patients with IgA nephropathy. Clin Kidney J 2018;12:348–354. doi: 10.1093/ckj/sfy093

50. Sato R, Joh K, Komatsuda A et al. Validation of the Japanese histologic classification 2013 of immunoglobulin A nephropathy for prediction of long-term prognosis in a Japanese single-center cohort. Clin Exp Nephrol 2015;19:411–418. doi: 10.1007/s10157-014-1004-z

51. Okonogi H, Kawamura T, Joh K et al. A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity. Clin Exp Nephrol 2019;23:16–25. doi: 10.1007/s10157018-1657-0

52. Katafuchi R, Ninomiya T, Nagata M et al. Validation Study of Oxford Classification of IgA Nephropathy: The Significance of Extracapillary Proliferation. Clin J Am Soc Nephrol 2011;6:2806– 2813. doi: 10.2215/CJN.02890311

53. Barbour SJ, Coppo R, Zhang H et al. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy. JAMA Intern Med 2019;179:942–952. doi: 10.1001/jamainternmed.2019.0600.

54. Chen T, Li X, Li Y et al. Prediction and Risk Stratification of Kidney Outcomes in IgA Nephropathy. Am J Kidney Dis 2019;74:300–309. doi: 10.1053/j.ajkd.2019.02.016.

55. Xie J, Kiryluk K, Wang W et al. Predicting Progression of IgA Nephropathy: New Clinical Progression Risk Score. PLoS ONE 2012;7:e38904. doi: 10.1371/journal.pone.0038904

56. Goto M, Wakai K, Kawamura T et al. A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transplant 2009;24:3068– 3074. doi: 10.1093/ndt/gfp273

57. Bartosik LP, Lajoie G, Sugar L et al. Predicting progression in IgA nephropathy. Am J Kidney Dis 2001;38:728–735. doi: 10.1053/ajkd.2001.27689

58. Soares MFS, Roberts ISD. Histologic Classification of IgA Nephropathy: Past, Present, and Future. Seminars in Nephrology 2018;38:477–484. doi: 10.1016/j.semnephrol.2018.05.017

59. Coppo R. Treatment of IgA nephropathy: Recent advances and prospects. Nephrol Ther 2018;1:13–21. doi: 10.1016/j.nephro.2018.02.010

60. Hotta O, Furuta T, Chiba S et al. Regression of IgA nephropathy: a repeat biopsy study. Am J Kidney Dis 2002;39:493–502. doi: 10.1053/ajkd.2002.31399

61. Tumlin JA, Lohavichan V, Hennigar R. Crescentic, proliferative IgA nephropathy: clinical and histological response to methylprednisolone and intravenous cyclophosphamide. Nephrol Dial Transplant 2003;18:1321–1329. doi: 10.1093/ndt/gfg081

62. McIntyre CW, Fluck RJ, Lambie SH. Steroid and cyclophosphamide therapy for IgA nephropathy associated with crescentic change: an effective treatment. Clin Nephrol 2001;56:193–198

63. Tan L, Tang Y, Peng W et al. Combined Immunosuppressive Treatment May Improve Short-Term Renal Outcomes in Chinese Patients with Advanced IgA Nephropathy. Kidney Blood Press Res 2018;43:1333–1343. doi: 10.1159/000492592

64. Lv J, Zhang H, Wong MG et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy The TESTING Randomized Clinical Trial. JAMA 2017;318:432–442. doi: 10.1001/jama.2017.9362

65. Yang YZ, Chen P, Liu LJ et al. Comparison of the effects of hydroxychloroquine and corticosteroid treatment on proteinuria in IgA nephropathy: a case-control study. BMC Nephrology 2019;20:297. doi: 10.1186/s12882-019-1488-6

66. Rauen T, Fitzner C, Eitner F et al. Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy. J Am Soc Nephrol 2018;29:317–325. doi: 10.1159/000489580

67. Hou JH, Le WB, Chen N et al. Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial. Am J Kidney Dis 2017;69:788–795. doi: 10.1053/j.ajkd.2016.11.027

68. Chen S, Qing Yin, Song Ren et al. A comparison of the effectiveness of cyclophosphamide, leflunomide, corticosteroids, or conservative management alone in patients with IgA nephropathy: a retrospective observational study. Scientific Reports 2018;8:13663. doi: 10.1038/s41598-018-31727-5

69. Tatematsu M, Yasuda Y, Morita Y et al. Complete remission within 2 years predicts a good prognosis after methylprednisolone pulse therapy in patients with IgA nephropathy. Clin Exp Nephrol 2012;16:883–891. doi: 10.1007/s10157-012-0644-0