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

doi:10.1136/lupus-2021-000576

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

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

20 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 language	English
Article number	e000576
Journal	Lupus Science and Medicine
Volume	9
Issue number	1
DOIs	https://doi.org/10.1136/lupus-2021-000576
State	Published - 7 Jan 2022

Bibliographical note

Publisher Copyright:
©

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.

Funders	Funder number
National Institutes of Health
National Cancer Institute	P30CA016087
National Institute of Arthritis and Musculoskeletal and Skin Diseases	SCR_018304, K23 AR068441
National Center for Advancing Translational Sciences	KL2 TR002558

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

autoimmunity
inflammation
lupus erythematosus
lupus nephritis
systemic

Access to Document

10.1136/lupus-2021-000576

Cite this

Wang, S., Wu, M., Chiriboga, L., Zeck, B., Goilav, B., Wang, S., Jimenez, A. L., Putterman, C., Schwartz, D., Pullman, J., Broder, A., & Belmont, H. M. (2022). Membrane attack complex (MAC) deposition in renal tubules is associated with interstitial fibrosis and tubular atrophy: A pilot study. Lupus Science and Medicine, 9(1), Article e000576. https://doi.org/10.1136/lupus-2021-000576

@article{8e2ec0ae602f46109327d8676dd2f5e7,

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

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.",

keywords = "autoimmunity, inflammation, lupus erythematosus, lupus nephritis, systemic",

author = "Shudan Wang and Ming Wu and Luis Chiriboga and Briana Zeck and Beatrice Goilav and Shuwei Wang and Jimenez, \{Alejandra Londono\} and Chaim Putterman and Daniel Schwartz and James Pullman and Anna Broder and Belmont, \{H. Michael\}",

note = "Publisher Copyright: {\textcopyright} ",

year = "2022",

month = jan,

day = "7",

doi = "10.1136/lupus-2021-000576",

language = "אנגלית",

volume = "9",

journal = "Lupus Science and Medicine",

issn = "2053-8790",

publisher = "BMJ Publishing Group",

number = "1",

}

Wang, S, Wu, M, Chiriboga, L, Zeck, B, Goilav, B, Wang, S, Jimenez, AL, Putterman, C, Schwartz, D, Pullman, J, Broder, A & Belmont, HM 2022, 'Membrane attack complex (MAC) deposition in renal tubules is associated with interstitial fibrosis and tubular atrophy: A pilot study', Lupus Science and Medicine, vol. 9, no. 1, e000576. https://doi.org/10.1136/lupus-2021-000576

TY - JOUR

T1 - Membrane attack complex (MAC) deposition in renal tubules is associated with interstitial fibrosis and tubular atrophy

T2 - A pilot study

AU - Wang, Shudan

AU - Wu, Ming

AU - Chiriboga, Luis

AU - Zeck, Briana

AU - Goilav, Beatrice

AU - Wang, Shuwei

AU - Jimenez, Alejandra Londono

AU - Putterman, Chaim

AU - Schwartz, Daniel

AU - Pullman, James

AU - Broder, Anna

AU - Belmont, H. Michael

PY - 2022/1/7

Y1 - 2022/1/7

N2 - 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.

AB - 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.

KW - autoimmunity

KW - inflammation

KW - lupus erythematosus

KW - lupus nephritis

KW - systemic

UR - https://www.scopus.com/pages/publications/85123071150

U2 - 10.1136/lupus-2021-000576

DO - 10.1136/lupus-2021-000576

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34996855

AN - SCOPUS:85123071150

SN - 2053-8790

VL - 9

JO - Lupus Science and Medicine

JF - Lupus Science and Medicine

IS - 1

M1 - e000576

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this