Evaluating the clinical utility of measuring levels of factor H and the related proteins

Banerjee, Pratiti; Veuskens, Bert; Jorge, Elena Goicoechea de; Józsi, Mihály; Baeumner, Antje J.; Steiner, Mark‐Steven; Pouw, Richard B.; Toonen, Erik J. M.; Pauly, Diana; Poppelaars, Felix

doi:10.1016/j.molimm.2022.08.010

Cited by 8 publications

(11 citation statements)

References 193 publications

(271 reference statements)

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“…Ideally, the genetic analysis should thus be combined with additional tools such as plasma complement measurements and molecular imaging. 65,66 Altogether, this could enable an individualized approach to help select individuals that would benefit from complement inhibition and help determine the timing, dosing, duration, and type of complement blocker needed.…”

Section: Discussionmentioning

confidence: 99%

Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

Poppelaars,

Gaya da Costa,

Faria

et al. 2023

Preprint

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Background: Genetic analysis in transplantation offers potential for personalized medicine. Given the crucial role of the complement system in renal allograft injury, we investigated in kidney transplant pairs the impact of complement polymorphisms on long-term outcomes. Methods: In this observational cohort study, we analyzed polymorphisms in C3 (C3R102G), factor B (CFBR32Q), and factor H (CFHV62I) genes of 1,271 donor-recipient kidney transplant pairs and assessed their association with 15-year death-censored allograft survival. Results: Individually, only the presence of the CFB32Q variant in the donor and the combined presence in donor-recipient pairs were associated with better graft survival (P=0.027 and P=0.045, respectively). In the combined analysis, the C3R102G, CFBR32Q, and CFHV62I variants in the donor independently associated with the risk of graft loss (HR 1.32; 95%-CI, 1.08-1.58; P=0.005). Thus, donor kidneys carrying the genetic variants that promote the highest complement activity exhibited the worst graft survival, whereas those with the genetic variants causing the lowest complement activity showed the best graft survival (15-year death-censored allograft survival: 48.8% vs 87.8%, P=0.001). Conclusion: Our study demonstrates that the combination of complement polymorphisms in the donor strongly associates with long-term allograft survival following kidney transplantation. These findings hold significance for therapeutic strategies involving complement inhibition in kidney transplantation.

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Section: Discussionmentioning

confidence: 99%

Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

Poppelaars,

Gaya da Costa,

Faria

et al. 2023

Preprint

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“…FH and FHRs could be targets for therapeutic approaches (reviewed by [19] ). However, due to the structural complexity of FH, its recombinant production is far from trivial [20] , [21] .…”

Section: Introductionmentioning

confidence: 99%

Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into their in-vivo functions

Ruiz-Molina

Parsons

Decker

et al. 2023

Computational and Structural Biotechnology Journal

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“…15,16 Humans possess five genes adjacent to the complement factor H gene ( CFH ) that code for the factor H-related proteins (FHRs). 16,17 The FHRs also consist of CCP domains and share structural similarities with the factor H domains involved in ligand and surface binding, but lack the regulatory domains. 18 For example, domains 1 to 3 of FHR-3 share 91%, 85%, and 62% similarity with domains 6 to 8 in factor H, while domains 4 and 5 of FHR-3 exhibit 64% and 37% similarity to domains 19 and 20 of factor H. 18 The current belief is that FHRs antagonize Factor H’s complement regulatory ability by competing for the binding to specific surfaces, leading to further complement activation due to their lack of regulatory capacity.…”

Section: Introductionmentioning

confidence: 99%

“…Noteworthy, a major limitation has been the lack of specific monoclonal antibodies (mAb) that discriminate between the various FHRs and Factor H. 16,17 Recently, a novel mAb against FHR-3 was described (RETC-2), showing promise for local and systemic detection without cross-reactivity with other FHRs or factor H. 21 The average serum levels of FHR-3 are much lower than factor H, making it unlikely for any physiologically relevant competition to occur in the circulation between FHR-3 and the more abundant factor H, and instead suggesting a more plausible local role for FHR-3. 16,17,21,22 . The current study aims to investigate FHR-3 deposition in the kidneys during kidney transplantation settings characterized by complement activation, such as in deceased donors prior to transplantation and in transplanted kidneys with acute tubular necrosis and various forms of rejection.…”

Section: Introductionmentioning

confidence: 99%

Factor H-related protein 3 (FHR-3) deposition in kidney allografts – localization and correlation with complement activation

Poppelaars,

Schäfer,

Meter-Arkema

et al. 2023

Preprint

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Introduction: Factor H-related proteins (FHRs) have emerged as novel players in complement-mediated diseases, as they exhibit structural resemblances to factor H but lack the regulatory domains, enabling them to antagonize factor H and increase complement activation through several activities. Despite the widely importance of the complement system in kidney transplantation, FHRs have not been studied in this context. Utilizing a novel monoclonal antibody, we investigated the presence of FHR-3 in kidney allografts. Methods: The RTEC-2 monoclonal antibody was validated using immunohistochemistry, Western Blot analysis, and immunoprecipitation combined with mass spectrometry. FHR-3 deposition, localization, and the relationships to complement activation were analyzed in human kidney biopsies obtained pre-transplantation from living and deceased donors, and post-transplantation in cases with acute tubular necrosis, acute cellular and vascular rejection, or chronic rejection. Results: Glomerular FHR-3 deposition was detected in kidneys from deceased, but not living, donors before transplantation. Additionally, we observed FHR-3 deposition in post-transplant settings, both in cases of rejection and non-rejection. While tubular and vascular deposition of FHR-3 was observed in some cases, FHR-3 was predominantly seen in the glomeruli, where it was primarily localized to podocytes. Moreover, co-localization of FHR-3 and C3d was rarely detected, with most cases exhibiting separate and non-overlapping staining patterns for both antigens, However, there was a moderate correlation between the staining intensity of the FHR-3 and C3d in the kidney biopsies (r=0.38, P=0.01). Conclusion: We detected FHR-3 deposition in kidney allografts under inflammatory conditions, primarily colocalizing with podocytes in both the presence and absence of complement activation.

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Evaluating the clinical utility of measuring levels of factor H and the related proteins

Cited by 8 publications

References 193 publications

Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into their in-vivo functions

Factor H-related protein 3 (FHR-3) deposition in kidney allografts – localization and correlation with complement activation

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