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Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment.
Kidney Int Rep 2019; 4(10):1387-1400KI

Abstract

Introduction

Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H-related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome.

Methods

We developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort.

Results

Glomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) (P = 0.04, difference of medians 19.7 ml/min per 1.73 m2; 95% confidence interval [CI] 1.1-43.0) and positively with a membranoproliferative glomerulonephritis pattern at diagnostic biopsy (odds ratio 18; 95% CI 1.6-201; P = 0.049). Glomerular FHR5 staining intensity positively correlated with glomerular complement C3b/iC3b/C3c (Pearson's correlation coefficient [R] = 0.59; P = 0.0008), C3dg (R = 0.47; P = 0.02) and C5b9 (R = 0.44, P = 0.02).

Conclusions

Glomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents.

Authors+Show Affiliations

Centre for Inflammatory Disease, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, UK.Centre for Inflammatory Disease, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, UK.Centre for Inflammatory Disease, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, UK.Centre for Inflammatory Disease, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, UK.Renal and Transplant Centre, Imperial College Healthcare NHS Trust, UK.Centre for Inflammatory Disease, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, UK.Centre for Inflammatory Disease, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31701048

Citation

Medjeral-Thomas, Nicholas R., et al. "Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment." Kidney International Reports, vol. 4, no. 10, 2019, pp. 1387-1400.
Medjeral-Thomas NR, Moffitt H, Lomax-Browne HJ, et al. Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment. Kidney Int Rep. 2019;4(10):1387-1400.
Medjeral-Thomas, N. R., Moffitt, H., Lomax-Browne, H. J., Constantinou, N., Cairns, T., Cook, H. T., & Pickering, M. C. (2019). Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment. Kidney International Reports, 4(10), pp. 1387-1400. doi:10.1016/j.ekir.2019.06.008.
Medjeral-Thomas NR, et al. Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment. Kidney Int Rep. 2019;4(10):1387-1400. PubMed PMID: 31701048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment. AU - Medjeral-Thomas,Nicholas R, AU - Moffitt,Hilary, AU - Lomax-Browne,Hannah J, AU - Constantinou,Nicholas, AU - Cairns,Tom, AU - Cook,H Terence, AU - Pickering,Matthew C, Y1 - 2019/06/19/ PY - 2019/03/25/received PY - 2019/05/30/revised PY - 2019/06/10/accepted PY - 2019/11/9/entrez PY - 2019/11/9/pubmed PY - 2019/11/9/medline KW - C3 glomerulopathy KW - complement KW - glomerulonephritis SP - 1387 EP - 1400 JF - Kidney international reports JO - Kidney Int Rep VL - 4 IS - 10 N2 - Introduction: Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H-related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome. Methods: We developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort. Results: Glomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) (P = 0.04, difference of medians 19.7 ml/min per 1.73 m2; 95% confidence interval [CI] 1.1-43.0) and positively with a membranoproliferative glomerulonephritis pattern at diagnostic biopsy (odds ratio 18; 95% CI 1.6-201; P = 0.049). Glomerular FHR5 staining intensity positively correlated with glomerular complement C3b/iC3b/C3c (Pearson's correlation coefficient [R] = 0.59; P = 0.0008), C3dg (R = 0.47; P = 0.02) and C5b9 (R = 0.44, P = 0.02). Conclusions: Glomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents. SN - 2468-0249 UR - https://www.unboundmedicine.com/medline/citation/31701048/Glomerular_Complement_Factor_H-Related_Protein_5_(FHR5)_Is_Highly_Prevalent_in_C3_Glomerulopathy_and_Associated_With_Renal_Impairment L2 - https://linkinghub.elsevier.com/retrieve/pii/S2468-0249(19)31386-5 DB - PRIME DP - Unbound Medicine ER -