Limited Significance of Antifactor H Antibodies in Patients with Membranous Nephropathy

Sethi, Amit; Miao, Jing; Willrich, Maria Alice V.; Frinack, Jody L.; Cattran, Daniel C.; Fervenza, Fernando C.; Investigators, Mentor study

doi:10.2215/cjn.16631020

Cited by 5 publications

(6 citation statements)

References 5 publications

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“…It has also been posited that FHAA, which have been reported in a small subset of patients with primary MN, 190,191 may contribute to the activation of the AP. However, these antibodies were not identified in all the MN cohorts tested, and their presence did not correlate with worse disease outcome 190,192 . Thus, even when FHAA are produced in patients with primary MN, they are unlikely to play a significant role in the development of severe forms of the disease.…”

Section: Other Kidney Diseases Associated With Alternative Complement...mentioning

confidence: 99%

“…In particular, the loss of heparan sulfate chains from the glomerular basal membrane, which has been observed in human and experimental MN, 183 , 188 , 189 could lead to impaired recruitment of factor H, the major inhibitor of the AP in plasma. It has also been posited that FHAA, which have been reported in a small subset of patients with primary MN, 190 , 191 may contribute to the activation of the AP. However, these antibodies were not identified in all the MN cohorts tested, and their presence did not correlate with worse disease outcome.…”

Section: Other Kidney Diseases Associated With Alternative Complement...mentioning

confidence: 99%

“…However, these antibodies were not identified in all the MN cohorts tested, and their presence did not correlate with worse disease outcome. 190 , 192 Thus, even when FHAA are produced in patients with primary MN, they are unlikely to play a significant role in the development of severe forms of the disease.…”

Section: Other Kidney Diseases Associated With Alternative Complement...mentioning

confidence: 99%

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Kidney diseases

Daina

Cortinovis

2022

Immunological Reviews

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The complement system, a central part of the innate immunity that serves as a first line of defense against foreign and altered host cells, is an extremely effective cell-killing and inflammation-provoking pathway. However, complement activation is a double-edged sword because uncontrolled stimulation can be highly detrimental to host tissues. [1][2][3] In order to avoid self-damage, a plethora of inhibitory mechanisms are known to prevent overwhelming activation at all stages of the complement cascade. The alternative pathway (AP) of complement is particularly significant for survival against invading pathogens and can be triggered by several other conditions, such as trauma, surgery, or pregnancy. Inappropriate AP activation may be

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Section: Other Kidney Diseases Associated With Alternative Complement...mentioning

confidence: 99%

Section: Other Kidney Diseases Associated With Alternative Complement...mentioning

confidence: 99%

Section: Other Kidney Diseases Associated With Alternative Complement...mentioning

confidence: 99%

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Kidney diseases

Daina

Cortinovis

2022

Immunological Reviews

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“…Several reports further suggested that anti-complement factor H (anti-CFH) antibodies may be expressed in MN, although the evidence is conflicting. An initial case series reported that anti-CFH antibodies were possibly tied with deterioration in renal function in spite of anti-PLA2R antibody seroconversion, but this was not validated in larger studies, including retrospective analyses of the MENTOR trial cohort ( 73 , 74 ). Conversely, a Japanese study showed a high degree of seropositivity for anti-CFH antibodies among patients with MN (up to 77.8% of patients), and that this was associated with renal failure progression but not the degree of proteinuria ( 75 ).…”

Section: Evidence Of Complement Pathway Activation In Membranous Neph...mentioning

confidence: 99%

The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets

Chan

Yap

et al. 2022

Front. Immunol.

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Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in the adult population. Although the discovery of different autoantibodies against glomerular/podocytic antigens have highlighted the role of B cells in the pathogenesis of MN, suboptimal response or even resistance to B cell-directed therapies occurs, suggesting that other pathophysiological mechanisms are involved in mediating podocyte injury. The complement system plays an important role in the innate immune response to infection, and dysregulation of the complement system has been observed in various kidney diseases. There is compelling evidence of complement cascade activation in primary MN, with the mannose-binding lectin (MBL) and alternative pathways particularly implicated. With appropriate validation, assays of complements and associated activation products could hold promise as adjunctive tools for non-invasive disease monitoring and prognostication. While there is growing interest to target the complement system in MN, there is concern regarding the risk of infection due to encapsulated organisms and high treatment costs, highlighting the need for clinical trials to identify patients most likely to benefit from complement-directed therapies.

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“…However, the mechanism of alternative pathway activation in PMN without initial activation of the lectin pathway remains unclear though one could postulate the role of traditional activators of the alternative pathway such as infection, which increase C3a levels and subsequent overexpression of PLA2R on podocytes that predisposes to autoimmunity. Anti-CFH autoantibodies are an unlikely mechanism of alternative pathway activation, detected in only 3% of patients with PMN ( 145 ). CFH also binds to human glomeruli via interaction with heparan sulfate, which is downregulated in PMN, AHN and PHN though whether this results in alternative pathway activation remains unproven ( 146 – 149 ).…”

Section: The Complement System and Other Mechanisms Of Glomerular Inj...mentioning

confidence: 99%

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment

et al. 2022

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Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.

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Limited Significance of Antifactor H Antibodies in Patients with Membranous Nephropathy

Cited by 5 publications

References 5 publications

Kidney diseases

Kidney diseases

The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment

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