Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Thompson, Aliza; Carroll, Kevin; Inker, Lesley A.; Floege, Jürgen; Perkovic, Vlado; Boyer‐Suavet, Sonia; Major, Rupert; Schimpf, Judith; Barratt, Jonathan; Cattran, Daniel C.; Gillespie, Barbara S.; Kausz, Annamaria T.; Mercer, Alex; Reich, Heather N.; Rovin, Brad H.; West, Melissa; Nachman, Patrick H.

doi:10.2215/cjn.08600718

Cited by 173 publications

(145 citation statements)

References 53 publications

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“…These results complement ongoing efforts to define clinical end points for RCTs in membranous nephropathy and focal and segmental glomerulosclerosis with nephrotic syndrome or in immunoglobulin A nephropathy. [52][53][54][55] We do not propose that the current results replace these initiatives. In less common diseases, the large sample size needed to reliably assess treatment effects on albuminuria may not be available.…”

Section: Resultsmentioning

confidence: 87%

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

Levey

Gansevoort

Coresh

et al. 2020

American Journal of Kidney Diseases

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376

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The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R 2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR > 30 mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0 mL/min/1.73 m 2 per year were associated with an HR of w0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings. Complete author and article information provided before references.

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Section: Resultsmentioning

confidence: 87%

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

Levey

Gansevoort

Coresh

et al. 2020

American Journal of Kidney Diseases

Self Cite

376

353

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“…Thompson et al [48], in a very relevant study, analyzed 13 controlled trials (doubling serum Cr, ESKD, or death). Following this analysis, the sustained reduction in proteinuria <0.5 g/day emerges as the most related factor with the best kidney outcome.…”

Section: Clinical Presentationmentioning

confidence: 99%

“…The goal of treatment should be to maintain a proteinuria below 0.5–0.75 g/day and a BP lower than 125/75 mm Hg. A controversial issue has been the definition of the “ point of no return ,” and following the results of different studies (especially VALIGA) [48, 63], we consider that the lower level of eGFR acceptable for initiation of therapy could be around 20–25 mL/min/1.73 m 2 . It is probably necessary to stratify the risk of patients.…”

Section: Treatmentmentioning

confidence: 99%

A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges

Gutiérrez

Carvaca-Fontán

Luzardo

et al. 2020

Nephron

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IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world among patients undergoing renal biopsy. Approximately 30% of patients with IgAN develop end-stage kidney disease 20 years after renal biopsy. It is a glomerulopathy with a very broad clinical presentation, making it difficult to stratify and treat. IgAN is characterized by dysregulation of the immune system, which causes an abnormal synthesis of IgA1 that is deglycosylated causing its mesangial deposition. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. On the other hand, the renal-gut connection can also play an important role in the pathogenesis of IgAN with possible therapeutic implications. In order to standardize the histological findings, the Oxford Classification has allowed clarifying renal lesions that confer potential risk of progression. Currently, except for the blockade of the renin-angiotensin-aldosterone system, no other therapies are available in clinical setting for the treatment of IgAN, although the range of new drugs under investigation is extensive. The incorporation in the next trials of clinical parameters such as the amount of hematuria and histological lesions may allow more personalized therapeutic approaches. To summarize, in recent years, several important efforts have taken place in the understanding of IgAN, but still, further studies are warranted to elucidate the best therapeutic strategies according to the risk to improve the prognosis of this entity.

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“…An early reduction in proteinuria with a range of interventions has been associated with improved long term kidney survival in IgAN ( 86 , 90 ). In 2019, the FDA (Food and Drug Administration) accepted an early change in proteinuria as a reasonably likely surrogate end point for a treatment’s effect on progression to ESKD in IgAN.…”

Section: Traditional Biomarkers Currently Used In the Management Of Imentioning

confidence: 99%

Monitoring Immune Responses in IgA Nephropathy: Biomarkers to Guide Management

et al. 2020

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IgA nephropathy (IgAN) is the commonest biopsy-reported primary glomerulonephritis worldwide. It has an incidence which peaks among young adults, and 30 to 40% of patients’ progress to end stage kidney disease within twenty years of diagnosis. Ten-year kidney survival rates have been reported to be as low as 35% in some parts of the world. The successful management of IgAN is limited by an incomplete understanding of the pathophysiology of IgAN and a poor understanding of how pathophysiology may vary both from patient to patient and between patient groups, particularly across races. This is compounded by a lack of rigorously designed and delivered clinical trials in IgAN. This is slowly changing, with a number of Phase 2 and 3 clinical trials of novel therapies targeting a number of different putative pathogenic pathways in IgAN due to report in the next 5 years. From our current, albeit limited, understanding of the pathophysiology of IgAN it is unlikely a single therapy will be effective in all patients with IgAN. The successful management of IgAN in the future is, therefore, likely to be reliant on targeted therapies, carefully selected based on an individualized understanding of a patient’s risk of progression and underlying pathophysiology. The potential role of biomarkers to facilitate personalization of prognostication and treatment of IgAN is immense. Here we review the progress made over the past decade in identifying and validating new biomarkers, with a particular focus on those that reflect immunological responses in IgAN.

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Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Cited by 173 publications

References 53 publications

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges

Monitoring Immune Responses in IgA Nephropathy: Biomarkers to Guide Management

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