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Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis

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Abstract

Introduction/objective

Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare plasma and urine complement activation products between patients with active lupus nephritis (aLN) and those with acute TMA plus concomitant active LN (aTMA+aLN).

Methods

Plasma and urine samples were obtained from 20 patients with aTMA+aLN, 20 patients with aLN matched by the histological activity index, 5 patients with chronic TMA, 20 patients with inactive LN, and 10 kidney donors. Complement fragments C3a, C4a, C4d, Ba, C5a, C5bC9, and factor H were determined by ELISA; and kidney C4d deposition was detected by immunohistochemistry. Patients were followed for > 12 months and complement activation products re-measured after treatment in 10 aTMA+aLN patients.

Results

Both aTMA+aLN and aLN groups had increased circulating C3a, Ba, and C5bC9; and decreased circulating C3, C4, C4a, C4d, and factor H. Urinary C3a, C5a, Ba, and C5bC9 were higher in patients with aTMA+aLN than in aLN. After treatment, levels of circulating C3, C4, and factor H increased; while levels of urinary C3a, C5a, Ba, and C5bC9 decreased in patients with aTMA+aLN. These changes were observed at each aTMA episode in two patients studied during repeated TMA episodes. There was no difference in C4d deposition in glomerular capillaries, tubular basement membrane, peritubular capillaries, and arterioles between patients with aLN and those aTMA+aLN.

Conclusions

Circulating and urine complement activation products suggest that thrombotic microangiopathy associated with LN is mediated through activation of the alternative complement pathway.

Key Points

• Immune-complex kidney disease in systemic lupus erythematosus (SLE) is associated with activation of the classical, lectin, and alternative complement pathways

• Indirect evidence from measurement of circulating and urinary complement pathway activation products suggests that renal acute thrombotic microangiopathy in SLE is mediated by activation of the alternative complement pathway

• C4d kidney immunohistochemistry may be positive in both immune complex nephritis and thrombotic microangiopathy. Therefore, it is not a specific marker of renal thrombotic microangiopathy in SLE.

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Acknowledgments

This study was performed in partial fulfillment for the Doctorate Program in Medical Sciences of the Universidad Nacional Autónoma de México (UNAM). Juan M. Mejia-Vilet is a doctoral student from this program.

Funding

This work was supported by the Mexican National Council of Science and Technology (CONACYT), FOSSIS 2017-2-289663 grant to Juan M. Mejia-Vilet

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Authors and Affiliations

  1. Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez Sección XVI, Tlalpan, 14080, Mexico City, Mexico

    Juan M. Mejia-Vilet, Ismael A. Gómez-Ruiz, Cristino Cruz, R. Angélica Méndez-Pérez, Roque A. Comunidad-Bonilla & Luis E. Morales-Buenrostro

  2. Department of Pathology and Pathologic Anatomy, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Norma O. Uribe-Uribe

  3. Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Carlos A. Nuñez-Alvarez

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  1. Juan M. Mejia-Vilet
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  2. Ismael A. Gómez-Ruiz
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  3. Cristino Cruz
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  8. Luis E. Morales-Buenrostro
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Contributions

Conception and study design: JMMV, IGR, LEMB. Patient recruitment, sample and data acquisition, and management: JMMV, IGR, CC, RAMP, RACB, NOUU, CNA. Laboratory analyses: CC, NOUU, CNA. Analysis and interpretation of data: JMMV, IGR, LEMB. Drafting and revising of the manuscript: all authors.

Corresponding author

Correspondence to Luis E. Morales-Buenrostro.

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This research was conducted in compliance with the Helsinki declaration. The study was approved by the local research and ethics boards.

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Mejia-Vilet, J.M., Gómez-Ruiz, I.A., Cruz, C. et al. Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis. Clin Rheumatol 40, 2233–2242 (2021). https://doi.org/10.1007/s10067-020-05499-1

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