C3 Glomerulopathy and Related Disorders in Children

Wong, Edwin K.S.; Marchbank, Kevin J.; Lomax-Browne, Hannah J.; Pappworth, Isabel Y.; Denton, Harriet; Cooke, Katie; Ward, Sophie; McLoughlin, Amy-Claire; Richardson, G. O.; Wilson, Valerie; Harris, Claire L.; Morgan, B. Paul; Hakobyan, Svetlana; McAlinden, Paul; Gale, Daniel; Maxwell, Heather; Christian, Martin; Malcomson, Roger D. G.; Goodship, Timothy H.J.; Marks, Stephen D.; Pickering, Matthew C.; Kavanagh, David; Cook, H. Terence; Johnson, Sally

doi:10.2215/cjn.00320121

Cited by 22 publications

(16 citation statements)

References 46 publications

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“…Just as prognostication approaches incorporating genetic factors have been identified and validated in ADPKD [21-23], these are now gaining more context [24 ] and being further added to for atypical ADPKD [13 & ] whilst also emerging for ADTKD [19,20,25]. Whilst a modest minority of cases have a monogenic cause, similar cohort findings have been reported for C3 glomerulopathy [26], which aids in a pragmatic genetic approach for such conditions with mixed or complex aetiological underpinnings. Together, this emerging evidence is increasingly indicating that a genetic or genomic result for an individual can have prognostic applications, and this may be a relative or potentially absolute indication for genomic testing in some instances of CKD.…”

Section: New Indications For Genomic Testingmentioning

confidence: 84%

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

Mallett

2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewThis review will summarize and synthesize recent findings in regard to monogenic kidney disorders, including how that evidence is being translated into practice. It will add to existing key knowledge to provide context for clinicians in consolidating existing practice and approaches.Recent findingsWhilst there are long established factors, which indicate increased likelihood of identifying a monogenic cause for kidney disease, these can now be framed in terms of the identification of new genes, new indications for genomic testing and new evidence for clinical utility of genomic testing in nephrology. Further, inherent in the use of genomics in nephrology are key concepts including robust informed consent, variant interpretation and return of results. Recent findings of variants in genes related to complex or broader kidney phenotypes are emerging in addition to understanding of de novo variants. Phenocopy phenomena are indicating a more pragmatic use of broader gene panels whilst evidence is emerging of a role in unexplained kidney disease. Clinical utility is evolving but is being successfully demonstrated across multiple domains of outcome and practice.SummaryWe provide an updated framework of evidence to guide application of genomic testing in chronic kidney disease (CKD), building upon existing principles and knowledge to indicate how the practice and implementation of this can be applied today. There are clearly established roles for genomic testing for some patients with CKD, largely those with suspected heritable forms, with these continuing to expand as new evidence emerges.

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Section: New Indications For Genomic Testingmentioning

confidence: 84%

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

Mallett

2022

Current Opinion in Nephrology &Amp; Hypertension

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“…118/287 included, had undergone central histopathology review for a recent pediatric-specific observational study. 17 Patients with a known paraprotein were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…These include baseline eGFR along with renal biopsy findings of interstitial fibrosis and tubular atrophy, crescents and segmental sclerosis. 12,[16][17][18][19] Literature regarding baseline proteinuria is more conflicting: in a study of 156 patients with C3G or IC-MPGN baseline proteinuria >2g per day was independently associated with the composite outcome of doubling of serum creatinine or KF 18 .…”

Section: Introductionmentioning

confidence: 99%

Clinical Predictors of Long-term Outcomes in C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis within the UK RaDaR Registry

Masoud,

Wong,

Downward

et al. 2024

Preprint

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Background C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare disorders that often result in kidney failure over the long-term. While there is much interest in the therapeutic potential of complement inhibition, the limited duration and necessarily small size of controlled trials, means there is a need to define how well short-term changes in eGFR and proteinuria predict clinically important outcomes such as kidney failure. We aimed to address this using longitudinal data from the UK National Registry of Rare Kidney Diseases (RaDaR). Methods 287 patients with biopsy-proven C3G (135, 47%) or IC-MPGN (152, 53%) were included. Analyses of kidney survival were conducted using Kaplan Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope. Results 85/135 (63%) C3G and 107/152 (70%) IC-MPGN patients reached kidney failure over follow-up after a median of 9.7 years (95% CI 7.6-12.4). Median time to first allograft loss following transplantation was 4.9 years (95% CI 1.7-6.5). Kidney survival was strongly associated with eGFR at baseline and 12-month timepoints (p<0.001). Proteinuria at diagnosis, although high, was not associated with long-term kidney failure risk. In contrast, both a time averaged 0.44g/g (50mg/mmol) and 50% reduction in UPCR at 12 months (from either diagnosis or 6 months) was strongly associated with a lower risk of kidney failure (≤0.002). Most notably those with a UPCR <0.88g/g (<100mg/mmol) at 12 months had a substantially lower rate of progression to kidney failure (HR adjusted for eGFR 0.13 (95% CI 0.03-0.56), p=0.007). Conclusions We quantified the relationships between early changes in both eGFR and proteinuria with long-term kidney survival. We demonstrate that proteinuria a short time after diagnosis is a strong predictor of long-term outcomes and that a UPCR <0.88g/g (<100mg/mol) at 1 year is associated with a substantially lower kidney failure risk.

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“… 43 In a recent study of C3G and related disorders in children, a significant proportion had antibodies to individual complement components, FH, FB, and C3b. 44 …”

Section: Nephritic Factors (Nef)mentioning

confidence: 99%

“… 47 Early work had shown them to be induced by injection of bacteria, presumably reacting to complement fixed on bacteria. This led Coombs and Coombs 1953 44 to suggest that immunoconglutinins should be regarded as “physiogenic” autoantibodies because they have the potential of enhancing bacterial opsonization. Lachmann (1966), 48 using a sensitive test for immunoconglutinins, found that no human sera tested entirely negative suggesting a degree of complement fixation was the normal state of affairs, an early premonition of the tickover hypothesis.…”

Section: Nephritic Factors and Immunoconglutininsmentioning

confidence: 99%

Physiology and pathology of the C3 amplification cycle: A retrospective

Peters

2022

Immunological Reviews

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In the Spring of 1970, a few months after I had started as a Lecturer in Renal Medicine at the Royal Postgraduate Medical School (RPMS) at Hammersmith Hospital in London, I arranged to meet Peter Lachmann, then in Cambridge, to set up a program studying the metabolism of complement proteins in patients with immunological disease. I was fortunate that he was enthusiastic about the idea but doubly so because the following year he accepted the Foundation Chair of Immunology at the RPMS, where we established a close collaboration and a lifetime friendship. Peter had worked with Henry Kunkel at the Rockefeller and was imbued with Henry's philosophy of combining information gleaned from patients with molecular analysis in the laboratory, a perfect fit for the RPMS, an institution which attached the highest priority to clinical research. Peter spent 1971-6 at the Hammersmith before returning to Cambridge, but more than half a century later related research is flourishing at the Hammersmith, driven first by his graduate student Mark Walport and subsequently by Marina Botto and MatthewPickering-I refer to their work later. I feel greatly privileged to be asked to contribute this review and I want to take the opportunity to illustrate the many clues to complement physiology, its role in disease, and ideas for therapy that arose from the detailed study (in the Kunkel tradition) of a small number of patients with exceptionally rare diseases. In the 1970s, complement was not even considered a mainstream aspect of immunology, and international meetings were easily accommodated in coastal resort hotels. The complement world was transformed with the discovery of its potential role in age-related macular degeneration (AMD) in 2005. Peter had a long-term belief in complement therapeutics based on his ideas of modulating the physiology of the C3 feedback cycle. These eventually materialized in his 80 s with the formation in 2014 of Gyroscope Therapeutics, a gene therapy company.

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C3 Glomerulopathy and Related Disorders in Children

Cited by 22 publications

References 46 publications

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

Clinical Predictors of Long-term Outcomes in C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis within the UK RaDaR Registry

Physiology and pathology of the C3 amplification cycle: A retrospective

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