Floege, Jürgen

ABSTRACT Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past 10 years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids and avacopan, and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates.

Significance Statement Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. Background Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. Methods Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. Results Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were −0.41 (95% Bayesian Credible Interval, −0.64 to −0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and −0.06 (95% Bayesian Credible Interval, −0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. Conclusions In Phase 2 trials of CKD with sample sizes of 100–200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

Background and objectives Outcomes reported in trials in adults with glomerular disease are often selected with minimal patient input, are heterogeneous, and may not be relevant for clinical decision making. The Standardized Outcomes in Nephrology–Glomerular Disease (SONG-GD) initiative aimed to establish a core outcome set to help ensure that outcomes of critical importance to patients, care partners, and clinicians are consistently reported. Design, setting, participants, and measurements We convened two 1.5-hour workshops in Melbourne, Australia, and Washington, DC, United States. Attendees were identified purposively with 50 patients/care partners and 88 health professionals from 19 countries; 51% were female. Patients and care partners were from the United States, Australia, and Canada, and had experience of a glomerular disease with systemic features ( n =9), kidney-limited nephrotic disease ( n =9), or other kidney-limited glomerular disease ( n =8). Attendees reviewed the results of the SONG-GD Delphi survey and aims of the workshop and then discussed potential core outcomes and their implementation in trials among moderated breakout groups of eight to 12 people from diverse backgrounds. Transcripts of discussions were analyzed thematically. Results Three themes were identified that supported the proposed core outcomes: limiting disease progression, stability and control, and ensuring universal relevance ( i.e. , applicable across diverse populations and settings). The fourth theme, preparedness for implementation, included engaging with funders and regulators, establishing reliable and validated measures, and leveraging existing endorsements for patient-reported outcomes. Conclusions Workshop themes demonstrated support for kidney function, disease activity, death, life participation, and cardiovascular disease, and these were established as the core outcomes for trials in adults with glomerular disease. Future work is needed to establish the core measures for each domain, with funders and regulators central to the uptake of the core outcome set in trials.

Background Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. Methods To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. Results The mean acute effect across all studies was −0.21 ml/min per 1.73 m 2 (95% confidence interval, −0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, −2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. Conclusion The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Background and objectives Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices. Design, setting, participants, & measurements We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically. Results Across 16 focus groups, 134 participants (range, 19–85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family. Conclusions Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.