Skip to main content
SpringerLink
Log in

Clinicopathological factors for tubulointerstitial injury in lupus nephritis

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

To investigate the incidence of tubulointerstitial injury in lupus nephritis (LN) and to examine clinicopathological factors that could indicate the presence of tubulointerstitial injury.

Methods

This study included 98 patients with LN. Clinical data and the pathological results of the initial renal biopsy were collected.

Results

The frequency of each tubulointerstitial injury parameter was over 50%, except for the interstitial edema, in the 98 patients investigated in this study. The most frequently detected tubulointerstitial injury parameter was tubular atrophy in this study. Neutrophil infiltration/karyorrhexis, wire loop lesion, and arteriosclerosis were observed frequently in patients with tubulointerstitial injuries. High serum creatinine and blood urea nitrogen (BUN) were observed more frequently in patients with tubulointerstitial injuries except tubular degeneration. The multivariable regression analysis showed a relationship between neutrophil infiltration/karyorrhexis and interstitial fibrosis/tubular degeneration, a relationship between wire loop lesion and tubulointerstitial inflammation/edema, and a relationship between arteriosclerosis and tubulointerstitial injuries (except interstitial edema). Patients with tubular degeneration had lower D-Dimer levels compared with those without. Patients with interstitial fibrosis had higher blood leukocyte counts than those without. The rate of low response to therapy was 13% among those without tubulointerstitial inflammation, but 35% in those with interstitial inflammation (P = 0.03).

Conclusion

Acute and chronic renal tubulointerstitial lesions are often found along with glomerular and vascular lesions. Immune and vascular factors are probably involved in tubulointerstitial injuries. Tubulointerstitial inflammation may be the initiator of chronic renal injury and may predict response to therapy.

Key Points

 

•To provide a theoretical basis for tubulointerstitial injury in LN.

 

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pokroy-Shapira E, Gelernter I, Molad Y (2014) Evolution of chronic kidney disease in patients with systemic lupus erythematosus over a long-period follow-up: a single-center inception cohort study. Clin Rheumatol 33(5):649–657. https://doi.org/10.1007/s10067-014-2527-0

    Article  PubMed  Google Scholar 

  2. Lewis EJ, Schwartz MM (2010) Lupus nephritis. Oxford University Press, Oxford

    Book  Google Scholar 

  3. Anders HJ, Rovin B (2016) A pathophysiology-based approach to the diagnosis and treatment of lupus nephritis. Kidney Int 90(3):493–501. https://doi.org/10.1016/j.kint.2016.05.017

    Article  CAS  PubMed  Google Scholar 

  4. Shao SJ, Hou JH, Xie GT, Sun W, Liang DD, Zeng CH, Zhu HX, Liu ZH (2019) Improvement of outcomes in patients with lupus nephritis: management evolution in Chinese patients from 1994 to 2010. J Rheumatol. https://doi.org/10.3899/jrheum.180145

  5. Weening JJ, D'Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M, International Society of Nephrology Working Group on the Classification of Lupus N, Renal Pathology Society Working Group on the Classification of Lupus N (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 65 (2):521–530. doi:https://doi.org/10.1111/j.1523-1755.2004.00443.x

  6. Parikh SV, Alvarado A, Malvar A, Rovin BH (2015) The kidney biopsy in lupus nephritis: past, present, and future. Semin Nephrol 35(5):465–477. https://doi.org/10.1016/j.semnephrol.2015.08.008

    Article  PubMed  Google Scholar 

  7. Hsieh C, Chang A, Brandt D, Guttikonda R, Utset TO, Clark MR (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 63(6):865–874. https://doi.org/10.1002/acr.20441

    Article  Google Scholar 

  8. Alsuwaida AO (2013) Interstitial inflammation and long-term renal outcomes in lupus nephritis. Lupus 22(14):1446–1454. https://doi.org/10.1177/0961203313507986

    Article  CAS  PubMed  Google Scholar 

  9. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang WK, Qu Z, Chen MH, Gao JJ, Li ZY, Zheng X, Ao J, Zhu SN, Wang SX, Zhao MH, Zou WZ, Liu G (2010) Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int 77(9):820–829. https://doi.org/10.1038/ki.2010.13

    Article  PubMed  Google Scholar 

  10. Pagni F, Galimberti S, Galbiati E, Rebora P, Pietropaolo V, Pieruzzi F, Smith AJ, Ferrario F (2016) Tubulointerstitial lesions in lupus nephritis: international multicentre study in a large cohort of patients with repeat biopsy. Nephrology (Carlton) 21(1):35–45. https://doi.org/10.1111/nep.12555

    Article  Google Scholar 

  11. Yu F, Haas M, Glassock R, Zhao MH (2017) Redefining lupus nephritis: clinical implications of pathophysiologic subtypes. Nat Rev Nephrol 13(8):483–495. https://doi.org/10.1038/nrneph.2017.85

    Article  PubMed  Google Scholar 

  12. Clark MR, Trotter K, Chang A (2015) The pathogenesis and therapeutic implications of tubulointerstitial inflammation in human lupus nephritis. Semin Nephrol 35(5):455–464. https://doi.org/10.1016/j.semnephrol.2015.08.007

    Article  PubMed  PubMed Central  Google Scholar 

  13. Trotter K, Clark MR, Liarski VM (2016) Overview of pathophysiology and treatment of human lupus nephritis. Curr Opin Rheumatol 28(5):460–467. https://doi.org/10.1097/BOR.0000000000000319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Davidson A, Aranow C (2010) Lupus nephritis: lessons from murine models. Nat Rev Rheumatol 6(1):13–20. https://doi.org/10.1038/nrrheum.2009.240

    Article  CAS  PubMed  Google Scholar 

  15. Yung S, Chan TM (2017) Molecular and immunological basis of tubulo-interstitial injury in lupus nephritis: a comprehensive review. Clin Rev Allergy Immunol 52(2):149–163. https://doi.org/10.1007/s12016-016-8533-z

    Article  CAS  PubMed  Google Scholar 

  16. Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dorner T, Doria A, Ferrario F, Floege J, Houssiau FA, Ioannidis JP, Isenberg DA, Kallenberg CG, Lightstone L, Marks SD, Martini A, Moroni G, Neumann I, Praga M, Schneider M, Starra A, Tesar V, Vasconcelos C, van Vollenhoven RF, Zakharova H, Haubitz M, Gordon C, Jayne D, Boumpas DT, European League Against R, European Renal Association-European D, Transplant A (2012) Joint European League Against rheumatism and European renal association-European Dialysis and Transplant association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 71(11):1771–1782. https://doi.org/10.1136/annrheumdis-2012-201940

    Article  CAS  PubMed  Google Scholar 

  17. Krishnan MR, Wang C, Marion TN (2012) Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice. Kidney Int 82(2):184–192. https://doi.org/10.1038/ki.2011.484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yung S, Zhang Q, Chau MK, Chan TM (2015) Distinct effects of mycophenolate mofetil and cyclophosphamide on renal fibrosis in NZBWF1/J mice. Autoimmunity 48(7):471–487. https://doi.org/10.3109/08916934.2015.1054027

    Article  CAS  PubMed  Google Scholar 

  19. Yung S, Zhang Q, Zhang CZ, Chan KW, Lui SL, Chan TM (2009) Anti-DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic acid. Arthritis Rheum 60(7):2071–2082. https://doi.org/10.1002/art.24573

    Article  CAS  PubMed  Google Scholar 

  20. Baelde HJ, Eikmans M, van Vliet AI, Bergijk EC, de Heer E, Bruijn JA (2004) Alternatively spliced isoforms of fibronectin in immune-mediated glomerulosclerosis: the role of TGFbeta and IL-4. J Pathol 204(3):248–257. https://doi.org/10.1002/path.1653

    Article  CAS  PubMed  Google Scholar 

  21. van Vliet AI, van Alderwegen IE, Baelde HJ, de Heer E, Bruijn JA (2002) Fibronectin accumulation in glomerulosclerotic lesions: self-assembly sites and the heparin II binding domain. Kidney Int 61(2):481–489. https://doi.org/10.1046/j.1523-1755.2002.00159.x

    Article  PubMed  Google Scholar 

  22. Bergijk EC, Baelde HJ, De Heer E, Killen PD, Bruijn JA (1995) Specific accumulation of exogenous fibronectin in experimental glomerulosclerosis. J Pathol 176(2):191–199. https://doi.org/10.1002/path.1711760213

    Article  CAS  PubMed  Google Scholar 

  23. Yung S, Ng CY, Ho SK, Cheung KF, Chan KW, Zhang Q, Chau MK, Chan TM (2015) Anti-dsDNA antibody induces soluble fibronectin secretion by proximal renal tubular epithelial cells and downstream increase of TGF-beta1 and collagen synthesis. J Autoimmun 58:111–122. https://doi.org/10.1016/j.jaut.2015.01.008

    Article  CAS  PubMed  Google Scholar 

  24. Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont MC, Ranchin B, Fabien N, Cochat P, Pouteil-Noble C, Trolliet P, Durieu I, Tebib J, Kassai B, Ansieau S, Puisieux A, Eliaou JF, Bonnefoy-Berard N (2009) Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol 10(7):778–785. https://doi.org/10.1038/ni.1741

    Article  CAS  PubMed  Google Scholar 

  25. Ramanujam M, Wang X, Huang W, Liu Z, Schiffer L, Tao H, Frank D, Rice J, Diamond B, Yu KO, Porcelli S, Davidson A (2006) Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest 116(3):724–734. https://doi.org/10.1172/JCI26385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gilliet M, Cao W, Liu YJ (2008) Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 8(8):594–606. https://doi.org/10.1038/nri2358

    Article  CAS  PubMed  Google Scholar 

  27. Chaturvedi A, Dorward D, Pierce SK (2008) The B cell receptor governs the subcellular location of toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity 28(6):799–809. https://doi.org/10.1016/j.immuni.2008.03.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Christensen SR, Shlomchik MJ (2007) Regulation of lupus-related autoantibody production and clinical disease by toll-like receptors. Semin Immunol 19(1):11–23. https://doi.org/10.1016/j.smim.2006.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN (2000) Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou nephrology study group. N Engl J Med 343(16):1156–1162. https://doi.org/10.1056/NEJM200010193431604

    Article  CAS  PubMed  Google Scholar 

  30. Chan TM, Tse KC, Tang CS, Mok MY, Li FK, Hong Kong Nephrology Study G (2005) Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 16(4):1076–1084. https://doi.org/10.1681/ASN.2004080686

    Article  CAS  Google Scholar 

  31. Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, Petri M, Gilkeson GS, Wallace DJ, Weisman MH, Appel GB (2005) Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353(21):2219–2228. https://doi.org/10.1056/NEJMoa043731

    Article  CAS  PubMed  Google Scholar 

  32. Zappitelli M, Duffy CM, Bernard C, Gupta IR (2008) Evaluation of activity, chronicity and tubulointerstitial indices for childhood lupus nephritis. Pediatr Nephrol 23(1):83–91. https://doi.org/10.1007/s00467-007-0619-7

    Article  PubMed  Google Scholar 

  33. Wang Y, Chang J, Yao B, Niu A, Kelly E, Breeggemann MC, Abboud Werner SL, Harris RC, Zhang MZ (2015) Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury. Kidney Int 88(6):1274–1282. https://doi.org/10.1038/ki.2015.295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baek JH, Zeng R, Weinmann-Menke J, Valerius MT, Wada Y, Ajay AK, Colonna M, Kelley VR (2015) IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease. J Clin Invest 125(8):3198–3214. https://doi.org/10.1172/JCI81166

    Article  PubMed  PubMed Central  Google Scholar 

  35. Edeling M, Ragi G, Huang S, Pavenstadt H, Susztak K (2016) Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol 12(7):426–439. https://doi.org/10.1038/nrneph.2016.54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tan RJ, Zhou D, Zhou L (2011) Liu Y (2014) Wnt/beta-catenin signaling and kidney fibrosis. Kidney Int Suppl 4(1):84–90. https://doi.org/10.1038/kisup.2014.16

    Article  CAS  Google Scholar 

  37. Chung AC, Lan HY (2011) Chemokines in renal injury. J Am Soc Nephrol 22(5):802–809. https://doi.org/10.1681/ASN.2010050510

    Article  CAS  PubMed  Google Scholar 

  38. Hill GS, Delahousse M, Nochy D, Mandet C, Bariety J (2001) Proteinuria and tubulointerstitial lesions in lupus nephritis. Kidney Int 60(5):1893–1903. https://doi.org/10.1046/j.1523-1755.2001.00017.x

    Article  CAS  PubMed  Google Scholar 

  39. Wu W, Liu C, Farrar CA, Ma L, Dong X, Sacks SH, Li K, Zhou W (2018) Collectin-11 promotes the development of renal tubulointerstitial fibrosis. J Am Soc Nephrol 29(1):168–181. https://doi.org/10.1681/ASN.2017050544

    Article  CAS  PubMed  Google Scholar 

  40. Tanaka K, Tanabe K, Nishii N, Takiue K, Sugiyama H, Wada J (2017) Sustained tubulointerstitial inflammation in kidney with severe leptospirosis. Intern Med 56(10):1179–1184. https://doi.org/10.2169/internalmedicine.56.8084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Joyce E, Glasner P, Ranganathan S, Swiatecka-Urban A (2017) Tubulointerstitial nephritis: diagnosis, treatment, and monitoring. Pediatr Nephrol 32(4):577–587. https://doi.org/10.1007/s00467-016-3394-5

    Article  PubMed  Google Scholar 

  42. Rankin AJ, Kipgen D, Geddes CC, Fox JG, Milne G, Mackinnon B, McQuarrie EP (2019) Assessment of active tubulointerstitial nephritis in non-scarred renal cortex improves prediction of renal outcomes in patients with IgA nephropathy. Clin Kidney J 12(3):348–354. https://doi.org/10.1093/ckj/sfy093

    Article  PubMed  Google Scholar 

Download references

Funding

This work was sponsored by the Youth Innovation Fund of Fujian Science and Technology Department (2015J05141).

Author information

Authors and Affiliations

  1. Department of Blood Purification, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China

    Huang Lan-ting, Chen You-ming & Zheng Xiao-yan

  2. Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China

    Wei Li-xin

  3. Department of Pathology, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China

    Wang Chen & He Hong-yan

Authors
  1. Huang Lan-ting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen You-ming
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Li-xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng Xiao-yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. He Hong-yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chen You-ming or Wei Li-xin.

Ethics declarations

Disclosures

None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number K2018-03-003) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lan-ting, H., You-ming, C., Li-xin, W. et al. Clinicopathological factors for tubulointerstitial injury in lupus nephritis. Clin Rheumatol 39, 1617–1626 (2020). https://doi.org/10.1007/s10067-019-04909-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04909-3

Keywords

Search

Navigation