Membrane attack complex (MAC) deposition in renal tubules is associated with interstitial fibrosis and tubular atrophy: A pilot study

Shudan Wang, Ming Wu, Luis Chiriboga, Briana Zeck, Beatrice Goilav, Shuwei Wang, Alejandra Londono Jimenez, Chaim Putterman, Daniel Schwartz, James Pullman, Anna Broder, H. Michael Belmont

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9 Scopus citations

Abstract

Introduction Treatment failures for lupus nephritis (LN) are high with 10%-30% of patients progressing to end-stage renal disease (ESRD) within 10 years. Interstitial fibrosis/tubular atrophy (IFTA) is a predictor of progression to ESRD. Prior studies suggest that tubulointerstitial injury secondary to proteinuria in LN is mediated by complement activation in the tubules, specifically through the membrane attack complex (MAC). This study aimed to investigate the associations between tubular MAC deposition with IFTA and proteinuria. Methods In this cross-sectional study, LN kidney biopsies were assessed for MAC deposition by staining for Complement C9, a component of the MAC. Chromogenic immunohistochemistry was performed on paraffin-embedded human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197). Tubular C9 staining intensity was analysed as present versus absent. IFTA was defined as minimal (<10%), mild (10%-24%), moderate (25%-50%) and severe (>50%). Results Renal biopsies from 30 patients with LN were studied. There were 24 (80%) female sex, mean age (SD) was 33 (12) years old and 23 (77%) had pure/mixed proliferative LN. Tubular C9 staining was present in 7 (23%) biopsies. 27 patients had minimal-To-mild IFTA and 3 patients had moderate IFTA. Among the C9 + patients, 3 (43%) had moderate IFTA as compared with none in the C9-group, p=0.009. C9 + patients had higher median (IQR) proteinuria as compared with C9-patients: 6.2 g (3.3-13.1) vs 2.4 g (1.3-4.6), p=0.001 at the time of biopsy. There was no difference in estimated glomerular filtration rate (eGFR) between the C9 + and C9-groups. Conclusion This study demonstrated that tubular MAC deposition is associated with higher degree of IFTA and proteinuria, which are predictors of progression to ESRD. These results suggest that tubular MAC deposition may be useful in classification of LN. Understanding the role of complement in tubulointerstitial injury will also identify new avenues for LN treatment.

Original languageEnglish
Article numbere000576
JournalLupus Science and Medicine
Volume9
Issue number1
DOIs
StatePublished - 7 Jan 2022

Bibliographical note

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Funding

Funding All individuals with direct involvement of this study are listed as authors. This research was supported by NIH/National Center for Advancing Translational Science (NCATS) Einstein – Montefiore CTSA Grant Number KL2 TR002558 (Shudan Wang) and supported by NIH/NIAMS K23 AR068441 (Anna Broder). The NIH provide K grants to support Drs Wang and Broder in their career development and is not involved in study design, data analysis and writing of this manuscript. The NYULH Center for Biospecimen Research and Development, Histology and Immunohistochemistry Laboratory (RRID:SCR_018304), is supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant; NIH/NCI P30CA016087 (Luis Chiriboga). Competing interests None declared. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research. Patient consent for publication Not applicable. Ethics approval This study was approved by the New York University (NYU) Institutional Review Board and was performed in accordance with the ethical standards of the Declaration of Helsinki. The manuscript adheres to the ‘Strengthening the Reporting of Observational Studies in Epidemiology’ (STROBE) guidelines for cross-sectional study. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available upon reasonable request. Data are available on reasonable request. Data are from deidentified patients who had their kidney biopsy done either Tisch Hospital (NYU) or Bellevue Hospital.

FundersFunder number
National Institutes of Health
National Cancer InstituteP30CA016087
National Institute of Arthritis and Musculoskeletal and Skin DiseasesSCR_018304, K23 AR068441
National Center for Advancing Translational SciencesKL2 TR002558

    Keywords

    • autoimmunity
    • inflammation
    • lupus erythematosus
    • lupus nephritis
    • systemic

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