Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression

Neuen, Brendon L.; Tighiouart, Hocine; Heerspink, Hiddo J L; Vonesh, Edward F.; Chaudhari, Juhi; Miao, Shiyuan; Chan, Tak Mao; Fervenza, Fernando C.; Floege, Jürgen; Goicoechea, Marián; Herrington, William G.; Imai, Enyu; Jafar, Tazeen H.; Lewis, Julia B.; Li, Philip Kam-Tao; Locatelli, Francesco; Maes, Bart; Perrone, Ronald D.; Praga, Manuel; Perna, Annalisa; Schena, Francesco Paolo; Wanner, Christoph; Wetzels, Jack F.M.; Woodward, Mark; Xie, Di; Greene, Tom; Inker, Lesley A.

doi:10.1681/asn.2021070948

Cited by 11 publications

(6 citation statements)

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“…Reducing glomerular hyperfiltration with dietary or pharmacological interventions can result in a negative acute effect on GFR in the short term, but in the long term, such interventions can stabilize GFR, as reflected by the chronic slope. 2,18,[20][21][22][23] This mechanism may lead to a negative correlation between the effect on the acute GFR slope and the effect on the chronic slope, in which case the clinical benefit of slowing decline in the chronic slope may be partially offset by the clinical implications of greater acute declines in GFR. Some have suggested that the inverse association between acute and chronic effects may be stronger for patients with more advanced disease.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD

Collier

Inker

Haaland

et al. 2023

CJASN

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Background The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope.Methods We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m 2 /yr) and those of the clinical end point (doubling of serum creatinine, GFR ,15 ml/min per 1.73 m 2 , or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m 2 , baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m 2 /yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero. ResultsThere was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [20.05 to 0.03]; baseline UACR [20.02 to 0.04]; CKD progression rate [20.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11]; baseline UACR [20.11 to 20.02]; CKD progression rate [0.01 to 0.15]).Conclusions These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD

Collier

Inker

Haaland

et al. 2023

CJASN

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“…Our acute studies in a 5/6 Nx model further showed that selonsertib does not acutely change GFR, renal blood flow, BP, or heart rate. Of note, both ACEI and sodium-glucose cotransporter-2 inhibitors are known to cause acute decreases in eGFR ("eGFR dip") due to acute lowering of systemic and/or glomerular hemodynamics, whereas selonsertib has also been shown to cause acute decreases in eGFR that are attributed to the inhibition of the tubular creatinine transporters MATE1/2K (22,23). Although these transporters do not have a prominent role in regulating plasma creatinine in rodents (24), this study and previously published studies demonstrating no effect on hemodynamics with selonsertib or ASK1 inhibition are consistent with the blockade of creatinine secretion as a cause for eGFR changes; however, more clinical studies are needed to fully address this.…”

Section: Discussionmentioning

confidence: 99%

Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model

Badal

Tuhaifi

et al. 2022

Kidney360

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Background: Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with chronic kidney disease (CKD), there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the non-diabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril. Methods: Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib+enalapril), and untreated controls. Serum creatinine, systolic blood pressure (SBP) and urinary albumin were measured at intervals. Animals were sacrificed at week 12 for histological, biochemical, and molecular analyses. Results: All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8-12 reduced SBP versus controls, decreased albuminuria and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, while selonsertib treatment reduced apoptosis and podocyte loss. RNA-Seq revealed that combined treatment impacted pathways related to extracellular matrix and wound-healing. Conclusions: Selonsertib targets a novel, non-hemodynamic pathway in CKD. Our data suggest that ASK1 inhibition when combined with ACEI has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.

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“…Patterns of change in GFR (GFR slope) after initiation of an intervention are often nonlinear, with possibly differing direction and rates of changes in early follow-up (herein called acute slope) versus longer-term follow-up (herein called chronic slope) 39 . The average rate of decline from the beginning to the end of the study incorporates both elements (herein called total slope).…”

Section: Treatment Effects On the Gfr Slope And The Clinical Endpointmentioning

confidence: 99%

A meta-analysis of GFR slope as a surrogate endpoint for kidney failure

Inker,

Collier,

Greene

et al. 2023

Nat Med

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studies in diabetes, CKD and GN, but not for CVD, there was an average benefit of the active treatments on the 3-year total slope and on the chronic slope compared to the control arms under a random-effects meta-analysis (Fig. 1 and Extended Data Table 2).Across the 66 studies, the median follow-up for the clinical endpoint was 35 months (25th to 75th percentile, 22-52 months), with shorter follow-up for studies with CVD compared to the three other disease groups (Extended Data Table 3). Over the full study duration, a total of 11,396 (6.1%) patients reached the primary clinical endpoint, defined as the composite of kidney failure with replacement therapy (KFRT) (initiation of chronic treatment with dialysis or kidney transplantation); sustained GFR < 15 ml min −1 per 1.73 m 2 ; or doubling of serum creatinine (equivalent to 57% decline in GFR). A benefit on the clinical endpoint was indicated by a hazard ratio (HR) less than 1, estimated within each study using Cox regression. Across all of the studies, as well as for studies in diabetes, CKD and GN, but not for CVD, an average benefit of treatment was observed (Fig. 1 and Extended Data Table 3). We also evaluated the treatment effect on the secondary clinical endpoint, defined as the composite of KFRT or sustained GFR < 15 ml min −1 per 1.73 m 2 . In the overall set of studies, as well as for studies in diabetes, CKD, GN and CVD, an average benefit of treatment was observed (Extended Data Table 3).Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression

Cited by 11 publications

References 79 publications

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD

Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD Model

A meta-analysis of GFR slope as a surrogate endpoint for kidney failure

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