Defining a minimal clinically meaningful difference in 12‐month estimated glomerular filtration rate for clinical trials in deceased donor kidney transplantation

Mayne, Tracy J.; Nordyke, Robert J.; Schold, Jesse D.; Weir, Matthew R.; Mohan, Sumit

doi:10.1111/ctr.14326

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…We conducted this study to elucidate whether early eGFR slopes, from 12 up to 24 months after biopsy, could serve as a surrogate for future allograft loss in patients diagnosed with late ABMR. The search for a “minimally clinically meaningful difference” with respect to eGFR slopes as an accepted trial endpoint in kidney transplantation is ongoing and several recent studies have addressed this issue ( 8 , 9 , 21 – 23 ). In trials studying chronic kidney disease, eGFR slopes were recently accepted as a surrogate endpoint by the FDA, but their value in late ABMR remains elusive ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection

et al. 2022

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BackgroundLate antibody-mediated rejection (ABMR) after kidney transplantation is a major cause of long-term allograft loss with currently no proven treatment strategy. Design for trials testing treatment for late ABMR poses a major challenge as hard clinical endpoints require large sample sizes. We performed a retrospective cohort study applying commonly used selection criteria to evaluate the slope of the estimated glomerular filtration rate (eGFR) within an early and short timeframe after biopsy as a surrogate of future allograft loss for clinical trials addressing late ABMR.MethodsStudy subjects were identified upon screening of the Vienna transplant biopsy database. Main inclusion criteria were (i) a solitary kidney transplant between 2000 and 2013, (ii) diagnosis of ABMR according to the Banff 2015 scheme at >12 months post-transplantation, (iii) age 15–75 years at ABMR diagnosis, (iv) an eGFR > 25 mL/min/1.73 m2 at ABMR diagnosis, and (v) a follow-up for at least 36 months after ABMR diagnosis. The primary outcome variable was death-censored graft survival. A mixed effects model with linear splines was used for eGFR slope modeling and association of graft failure and eGFR slope was assessed applying a multivariate competing risk analysis with landmarks set at 12 and 24 months after index biopsy.ResultsA total of 70 allografts from 68 patients were included. An eGFR loss of 1 ml/min/1.73 m2 per year significantly increased the risk for allograft failure, when eGFR slopes were modeled over 12 months [HR 1.1 (95% CI: 1.01–1.3), p = 0.020] or over 24 months [HR 1.3 (95% CI: 1.1–1.4), p = 0.001] after diagnosis of ABMR with landmarks set at both time points. Covariables influencing graft loss in all models were histologic evidence of glomerulonephritis concurring with ABMR as well as the administration of anti-thymocyte globulin (ATG) at the time of transplantation.ConclusionOur study supports the use of the eGFR slope modeled for at least 12 months after biopsy-proven diagnosis of late ABMR, as a surrogate parameter for future allograft loss. The simultaneous occurrence of glomerulonephritis together with ABMR at index biopsy and the use of ATG at the time of transplantation–likely representing a confounder in pre-sensitized recipients–were strongly associated with worse transplant outcomes.

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Section: Discussionmentioning

confidence: 99%

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection

et al. 2022

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“…27 At the mid-range, a change in at least five eGFR can represent a clinically meaningful difference in kidney function. 35 The individual fits showed major differences between models. Many kidney transplant patients have different eGFR growth and eGFR stable values, hitting a peak value and then losing some amount of function and stabilizing at a different value.…”

Section: Resultsmentioning

confidence: 99%

“…For example, an eGFR of 40 is indicative of reduced kidney function while an eGFR of 60 may be interpreted as acceptable function 27 . At the mid‐range, a change in at least five eGFR can represent a clinically meaningful difference in kidney function 35 …”

Section: Resultsmentioning

confidence: 99%

Longitudinal estimated glomerular filtration rate (eGFR) modeling in long‐term renal function to inform clinical trial design in kidney transplantation

Kosinski

Frey

Klein

et al. 2023

Clinical Translational Sci

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Kidney transplantation is the preferred treatment for individuals with end‐stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post‐transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post‐transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well‐known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post‐transplant. Our model is a nonlinear, mixed‐effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long‐term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long‐term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post‐transplant in various clinically relevant populations.

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“…Outcomes of interest included mean eGFR at prespecified time points throughout the trial and changes in eGFR from baseline through week 52. To further evaluate the impact of study treatment over time, a responder analysis was performed to determine the percentage of participants with a clinically meaningful change from baseline in eGFR (≥ 5 mL/min/1.73 m 2 ) [ 9 , 10 ] as well as a change from baseline ≥ 10 mL/min/1.73 m 2 at weeks 26 and 52. All renal outcome measures were assessed for the total trial population by randomized treatment allocation (palopegteriparatide and placebo/palopegteriparatide) and stratified by baseline renal function (eGFR < 60 and ≥ 60 mL/min/1.73 m 2 ).…”

Section: Methodsmentioning

confidence: 99%

Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial

Rejnmark,

Gosmanova,

Khan

et al. 2024

Adv Ther

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Introduction Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. Methods PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m 2 . Results At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m 2 from baseline ( P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m 2 . In participants with baseline eGFR < 60 mL/min/1.73 m 2 , 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m 2 ( P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. Conclusion In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted. Trial Registration ClinicalTrials.gov NCT04701203. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-024-02843-8.

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Defining a minimal clinically meaningful difference in 12‐month estimated glomerular filtration rate for clinical trials in deceased donor kidney transplantation

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 6 publications

References 34 publications

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection

Longitudinal estimated glomerular filtration rate (eGFR) modeling in long‐term renal function to inform clinical trial design in kidney transplantation

Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial

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