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

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 (p≤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. ### Competing Interest Statement CP and NW are employees and shareholders of Novartis AG who part funded the analysis. EKSW declares receiving fees for consulting and presenting from Novartis, Apellis, Alexion, Arrowhead and Biocryst. DPG declares support for the current manuscript from St Peter’s Trust for Kidney Bladder and Prostate Research, Novartis AG, Medical Research Council, Kidney Research UK, Kidney Care UK, and Polycystic Kidney Disease Charity (payments to institution), chairs the Rare Diseases Committee of the UKKA and has received fees for consulting and presenting from Novartis, Alexion, Calliditas, Sanofi, Britannia and Travere. All other authors declare no competing interests as they relate to the current manuscript. ### Funding Statement RaDaR has received funding from The UK Medical Research Council, Kidney Research UK, Kidney Care UK and the Polycystic Kidney Disease Charity. The analysis of this study was part funded by Novartis AG ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Research Ethics committee of NHS South-West-Central Bristol gave ethical approval for this work (14/SW/1088) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes