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Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation.
As with progressive chronic disease of native kidneys, chronic graft failure results in end-stage renal disease (ESRD) with the need for kidney replacement therapy in the form of dialysis or repeat transplantation. Pathological processes that characterize the late course of graft failure are loss of nephrons, glomerulosclerosis of the remaining nephrons, and interstitial fibrosis and tubular atrophy (
Loss of viable nephrons is reflected in a reduced glomerular filtration rate (GFR), therefore late kidney graft failure is inevitably preceded by a decline in GFR. Notably, the annual rate of eGFR decline in incident dialysis patients with graft failure is higher than in transplant-naïve incident dialysis patients (
The present article provides an overview of primary endpoints used in clinical trials involving CKD, including a contemporary perspective on endpoints for assessing graft dysfunction after kidney transplantation. Biomarkers that have meaningful associations with graft failure are discussed.
The guideline EMA/CHMP/500825/2016 ( • Kidney function at different timepoints (e.g., 6, 12, and 24 months; 3 and 5 years) • Proteinuria incidence or worsening • Time to reach different CKD stages (representing progression of renal damage).
Notably, for primary prevention studies (defined as CKD prevention in patients without any sign of kidney damage), the European Medicines Agency (EMA) recommends using a clinically meaningful and stable GFR loss rate (measured either via slope or time-to-event analyses) as the primary endpoint (
As initial decline in kidney function is asymptomatic, and clinical manifestations of renal insufficiency occur late in the disease course, general definitions of kidney disease focus on measures of function (e.g., GFR) or damage (e.g., proteinuria, morphological abnormalities). Several CKD biomarkers indicate levels of kidney damage (e.g., active urinary sediment, presence of proteinuria or albuminuria, leakage markers) or functional status (e.g., failure to filtrate plasma or endogenous substances, absorb primary urine, secrete hydrogen ions, or contribute to endocrine function) (
Filtration reflects the main function of the kidneys, and GFR is also used as an indicator of kidney function in grafts. Markers for calculating measured (m)GFR must be freely filtered in the glomeruli and not reabsorbed, secreted, or metabolized by renal cells. Although exogenous substances including inulin and iothalamate fulfill these criteria, their analysis requires intravenous infusion; methods to measure their concentrations are costly and are not universally available nor necessarily error free.
Creatinine and cystatin C measurements are widely used to assess GFR in clinical or research settings, in every relevant patient population (including kidney transplant recipients). Creatinine is a breakdown product of creatine from muscle cells and is largely removed from the blood by glomerular filtration. Therefore, the serum creatinine level, which is easily measured, is a useful reflection of GFR and is traditionally analyzed as an indicator of kidney function. Several decades ago, cystatin C — released by all nucleated cells — was also shown to be a reasonable marker of kidney function. Importantly, however, neither creatinine nor cystatin C meet the requirements of an ideal filtration marker (
Creatinine clearance over a 24-h period can be used as a surrogate marker of GFR. However, creatinine is also secreted, which leads to GFR overestimation. Moreover, 24-h urine collection is burdensome, and inaccuracies in collection cause discrepancies between creatinine clearance and GFR. To overcome such limitations, equations have been developed to calculate eGFR (
In kidney transplantation populations, the use of formulas such as MDRD and CKD-EPI to calculate eGFR (
For accurate assessment of kidney function at a given time point in an individual, mGFR is undoubtedly the best available method (
When selecting an outcome measure of kidney function for clinical research, it is important to know the strength of the relationship between each measure and the occurrence of hard endpoints such as ESRD. No studies show that one-time determination of mGFR is more strongly associated with future ESRD than eGFR, and mGFR has potential limitations, such as the complexity of evaluating large trials. Another major drawback of mGFR evaluation is the impossibility of calculating slopes over time (see below), which requires many repeated measurements.
There is limited agreement between decline in mGFR and eGFR. The Chronic Renal Insufficiency Cohort (CRIC) study compared associations between longitudinal changes (two measurements in 24 months) in eGFR and mGFR (urinary iothalamate clearance) with ESRD risk (
Proteinuria is generally measured as the albumin or total protein concentration in a spot sample or in urine collected during a specified time period (e.g., 24 h); in the latter case, the excretion rate of albumin or protein can be calculated. Consequently, EMA/CHMP guidelines state that proteinuria should be assessed quantitatively, using a timed or untimed (spot) urine collection (
Since collection of timed urine samples is inconvenient and error prone, use of spot samples has gained popularity. Studies in people with diabetes mellitus, immunoglobulin (Ig) A nephropathy, and a mixed cohort of patients with CKD show that measuring ACR in a morning spot sample is at least equal to measuring 24-h albumin or protein excretion for predicting CKD progression (
Generally, EMA/CHMP guidelines prefer ACR to PCR, especially at low levels of proteinuria, acknowledging that PCR may be the best way to characterize kidney injury (e.g., diabetic nephropathy). Timed urine collection and testing is required after any positive ACR/PCR result to confirm the findings, although repeat ACR/PCR could also be considered. EMA/CHMP guidelines also state that timed urine sample testing would be necessary to assess therapeutic efficacy during a clinical study (
As mentioned above, progressive decline in kidney graft function in many aspects resembles the course of dysfunction in native kidney disease. However, compared with CKD, it must be realized that after kidney transplantation the course of kidney function is more subject to acute events such as infection and rejection, as well as to changes in immunosuppressive therapy. Literature on kidney endpoints has largely focused on CKD, but data for transplant recipients are available. Data on kidney function endpoints post transplantation were extracted from 213 reports from randomized controlled trials (RCTs) published between 2010 and 2014, comparing immunosuppressive interventions (
RCTs in kidney transplantation with renal function as primary endpoint, published after 2014 (
Study | Population | Intervention/control | Duration | Renal endpoint | Finding | Comments |
---|---|---|---|---|---|---|
APOLLO ( |
|
I: conversion from CNI to EVR | 12 months | eGFR: Nankivell | NSD | Premature termination due to slow recruitment. Higher eGFR — MDRD in EVR group |
C: continuation of CNI | ||||||
CENTRAL ( |
|
I: conversion from CsA to EVR | 3 years | Change in measured GFR by iohexol or51Cr-EDTA clearance from randomization to 36 months | NSD | High rate of study withdrawals. Benefit in renal function in EVR group in on-treatment analysis |
C: continuation of CsA | ||||||
SPIESSER( |
|
I: SRL | 12 months | eGFR: Nankivell | NSD | Benefit in renal function in EVR group in on-treatment analysis |
C: CsA | ||||||
Tedesco-Silva et al. ( |
|
I: conversion from TAC to SRL | 24 months | eGFR: MDRD change >5 ml/1.73 m2 in on-therapy population ( |
NSD | High discontinuation rate in SLR group |
C: continuation of TAC | ||||||
Knoll et al. ( |
|
I: ramipril | 48 months | Composite endpoint: doubling of sCr, ESRD, or death | NSD | Small numbers per group |
C: placebo | ||||||
ELEVATE ( |
|
I: conversion from CNI to EVR | 24 months | Change in eGFR — MDRD from randomization to 12 m | NSD | Significantly higher eGFR in EVR group vs CsA subgroup |
C: continuation of CNI | ||||||
ADHERE ( |
|
I: TAC (8–12 ng/ml until Day 41 and then 6–10 ng/ml) + SRL | 12 months | mGFR by iohexol clearance | NSD | High withdrawal rate in the intervention group |
C: continuation of TAC (8–12 ng/ml) + MMF | ||||||
3C STUDY ( |
|
I: conversion from TAC to SRL | 18 months | eGFR—MDRD | NSD | Significantly better renal function in SRL group in on-treatment analysis |
C: continuation of TAC | ||||||
BORTEJECT ( |
|
I: bortezomib | 24 months | Slope of eGFR—Mayo equation | NSD | Small sample size |
C: placebo | ||||||
TRANSFORM ( |
|
I: EVR + reduced-dose CNI | 24 months | Composite of treated BPAR or eGFR—MDRD <50 ml/min/1.73 m2 at 12 months | NSD | No difference in eGFR |
C: MPA + standard-dose CNI |
AMR, antibody-mediated rejection; C, control group; CNI, calcineurin inhibitor; CsA, cyclosporine; dn,
Doubling of the serum creatinine level is commonly an endpoint in clinical studies of kidney disease, including transplantation: it is considered analogous to a prespecified reduction in eGFR, and is often part of a composite outcome together with initiation of kidney replacement therapy and death from a renal cause (
Consistent with findings observed in CKD (
The Clinical Trials in Organ Transplantation consortium showed that a 20–40% decline in eGFR at 3–24 or 6–24 months post transplantation was significantly associated with graft loss at 2–5 years, and with absolute eGFR at 5 years (
In some circumstances eGFR may not be a valid surrogate endpoint, although potential solutions for some situations have been formulated (
Several RCTs involving kidney transplant recipients have used eGFR, or a change in eGFR, as a single primary endpoint (
Therefore, in most circumstances, post-transplantation eGFR seems to be an appropriate endpoint for evaluating graft dysfunction. A systematic review concluded that post-transplantation eGFR (at 12 months) is associated with risk for overall or death-censored graft loss, and all-cause mortality, in univariate and multivariate analyses (
Clinical studies in diabetic nephropathy, hypertension and CKD, and polycystic kidney disease use the eGFR slope to evaluate the efficacy of interventions that aim to slow progression of kidney insufficiency (
In 2017, the KDIGO conference
In March 2018, several meta-analyses based on individual patient data were conducted in preparation for the workshop
A theoretical advantage of using the eGFR slope as the endpoint, rather than a time-to-event endpoint (e.g., ESRD), is that the decision to initiate dialysis or (re)transplantation can be affected by factors other than GFR. The effect of an intervention on the eGFR slope may therefore better reflect the true effect on kidney graft function.
Importantly, suitability of the eGFR slope as surrogate endpoint depends on patterns of acute and chronic phases of the slope, in the context of the specific disease and potential pharmacodynamic impact of the investigational compound on the slope. The total eGFR slope reflects the slope from time of randomization, i.e., across the entire study period; the chronic slope calculation starts later and is less affected by acute changes in eGFR during the initial phase post randomization. In this respect, transplant recipients likely differ from patients with native CKD. The chance of a non-linear decline in eGFR is probably higher in kidney transplant recipients as a result of acute events such as infection, rejection and initiation or withdrawal of drugs that have acute effects on kidney function, including immunosuppressive agents. This can also impact the number of eGFR measurements needed to calculate the eGFR slope. Such information should be available to evaluate the usefulness of eGFR slope after kidney transplantation and to judge the validity of the chronic slope, versus the total slope. The EMA has indicated that the total slope is generally favored over the chronic slope, because the total slope minimizes possible biases introduced when post-randomization events (e.g., death) or acute changes in eGFR on investigational drug initiation are not considered (
The only study in kidney transplant recipients to use the eGFR slope as the primary outcome measure was a clinical trial of bortezomib in late antibody-mediated rejection (AMR) (
Few RCTs in kidney transplantation have used a change in mGFR as the primary endpoint; mGFR assessment was based on iohexol or 51Cr-EDTA clearance (
While proteinuria can be considered as a surrogate marker for severity of glomerular damage, proteinuria can also directly contribute to kidney injury and decline in kidney function (
In a large cohort (31,372 individuals from a general population; two or more ACR measurements in 2 years), a fourfold increase in ACR was associated with a threefold heightened risk of ESRD during a median 3 years of follow-up (
In IgA nephropathy, proteinuria is the most widely recognized risk factor for progression to ESRD. Analysis of 13 controlled intervention trials in IgA nephropathy showed an association between treatment effects on percentage reduction of proteinuria, and on a composite of time to doubling of serum creatinine, ESRD, or death (
Unlike specific diseases in native kidneys, causes of proteinuria after kidney transplantation are diverse. During the early months after transplantation there may be some contribution from proteinuric native kidneys, but major causes of proteinuria are chronic rejection, recurrence of proteinuric disease, or
In contrast to studies investigating chronic disease in native kidneys, no studies in kidney transplantation have demonstrated a beneficial effect of proteinuria reduction on progression to ESRD. A clinical trial of ramipril versus placebo in 213 kidney transplant recipients with (mean proteinuria ≥0.2 g/day) showed no difference in the primary outcome (a composite of doubling of serum creatinine, ESRD or death), despite some reduction in mean proteinuria (
The KDIGO 2012 guidelines updated the classification system for CKD to include albuminuria, stating that, for the general population, risk of adverse outcomes (mortality, progression to ESRD) at a given eGFR increases with higher levels of albuminuria.
Although studies indicate its promise (
The interaction between eGFR and proteinuria — as demonstrated in participants with diabetes in the ADVANCE study — was also observed in kidney transplant recipients. An analysis of linked databases in Canada (
Finally, the causes of long-term graft failure are complex, and there are good arguments to capture this heterogeneity in more integrated composite scoring systems. For this, we refer to the paper in this supplement on surrogate endpoints (
• Chronic renal graft dysfunction resembles CKD of native kidneys in many aspects: ○ Loss of nephrons, glomerulosclerosis, interstitial fibrosis, and tubular atrophy are pathological hallmarks of both. ○ Dysfunction is reflected as GFR loss, with or without proteinuria, ultimately leading to ESRD; however, ESRD is typically a late event and its use as an endpoint in clinical trials requires very large numbers of patients and prolonged follow-up. • The EMA 2016 guideline recommended the time to a predefined and justified loss in GFR, such as 50%, as an endpoint in secondary prevention trials. • Since the guideline was released, additional literature has been published on the choice of endpoints in CKD, and various endpoints have been used in clinical trials. ○ Many studies in CKD and kidney transplantation show that a change in eGFR (MDRD or CKD-EPI formulas) is strongly associated with ESRD. ○ It is increasingly advocated to use eGFR trajectories as endpoints in intervention trials in CKD. A caveat is the occurrence of an acute treatment effect that hampers use of the GFR trajectory; therefore, in kidney transplantation, special consideration should be given to studies including initiation or discontinuation of calcineurin inhibitors. ○ No studies convincingly demonstrate that measured GFR is a better predictor of ESRD than eGFR. • In studies including patients with advanced-stage graft dysfunction (eGFR <45 ml/min/1.73 m2) and/or rapid decline of GFR (>5 ml/min/1.73 m2 per year), a composite endpoint consisting of a 30%–40% decline in eGFR or ESRD occurrence is both robust and feasible. • In studies aimed at improving the lifespan of a transplanted kidney with more conserved renal function (eGFR >45 ml/min/1.73 m2), eGFR time course (expressed as slope) should be accepted as surrogate endpoint, provided that the following limitations are considered: ○ Use of the chronic eGFR slope is inappropriate when a treatment has acute effects on GFR that are relatively large compared with expected chronic effects. In such cases, use of the total eGFR slope is generally favored. ○ Creatinine-based formulas to estimate GFR can be imprecise when there are non-GFR determinants of the creatinine concentration, such as use of drugs that inhibit tubular secretion [trimethoprim] or changes in muscle mass due to corticosteroid treatment. ○ Accuracy of cystatin C-based formulas to estimate eGFR can be influenced by corticosteroid use. • While proteinuria/albuminuria appears to be a useful surrogate endpoint for CKD progression, especially in diabetes and IgA nephropathy, more research must be undertaken before proteinuria (or the combination of eGFR and proteinuria) can be advocated as an endpoint in studies in kidney transplant recipients.
This paper provides a contemporary discussion of graft functional parameters as primary endpoints in clinical trials as endpoints for clinical trials in kidney transplantation. ESOT has come to the following conclusions:
• The CHMP agreed that endpoints to assess efficacy of medicinal products to slow progression of chronic renal insufficiency ( ○ These include hard clinical endpoints (incidence of ESRD and renal/overall survival), proportional decrease in eGFR, and annual decrease in eGFR (slope). • The CHMP agreed that conceptual approaches used to assess efficacy endpoints for dysfunction can be extrapolated to kidney transplantation, as far as the concomitant medications and diseases are comparable: ○ The impact of additional nephrotoxicity (e.g., in cases of CNI or viral nephropathy due to over-immunosuppression) should be delineated from lower potential to preserve functional efficacy. • The CHMP stated that multiple definitions of efficacy endpoints using GFR have been proposed: the most conservative of these is the 57% reduction in GFR, reflecting doubling of serum creatinine; more recently, lesser degrees of proportional reduction in GFR have been proposed. • The CHMP agreed that several publications advocate use of eGFR slope as a surrogate for clinical outcome in kidney disease trials, with the following notes: ○ eGFR slope should not replace any of the aforementioned GFR-based surrogate endpoints, but should rather be understood as an additional tool to estimate renal benefit; choice of GFR-based endpoint will depend on baseline rate of GFR decline, feasibility issues (e.g., disease prevalence, estimated efficacy of the medicinal product); GFR-based endpoints could also be used to address efficacy in trials of renal transplantation. ○ Annualized loss of GFR does not meet all criteria for a valid surrogate endpoint, but (properly defined) is considered as a valuable measure of efficacy in addition to the currently accepted hard clinical endpoints (incidence of ESRD and renal/overall survival). Loss of GFR is most often assessed through serial estimates of GFR (eGFR) but can also be assessed as proportional reduction in GFR (30%–57%). ○ The main purpose for a slope-based endpoint in the assessment of therapy in CKD is when feasibility is an issue using standard endpoints, as might be the case in studies of rare and/or early kidney disease. In addition, the value of GFR slope in assessing a medicinal product may be evident during early clinical stages, i.e., in exploratory studies. ○ Several issues should be addressed before determining the acceptability of GFR slope as an efficacy assessment in phase III studies to support market access authorization. The main prerequisites are: – Low prevalence of the condition as reflected in the target population. It may not be feasible to determine efficacy using standard endpoints in rare diseases or in subpopulations of more common diseases. – Slow rate of progression of the kidney disease in the target population. Obviously, assessment of efficacy using standard endpoints may be feasible if rate of progression is rapid. ○ Other important considerations: – Linearity of the slope. A final decision cannot be made without detailed understanding of nature and patterns of acute and chronic phases of the GFR slope in the context of the specific kidney disease and the pharmacological actions of the investigational compound [see ( – Suitability of GFR slope as the primary endpoint should be determined on a case-by-case basis. This includes the assessment of how best to analyse efficacy based on eGFR slopes, especially in the context of issues around a possible acute drug effect and linearity assumptions of the GFR measurements. – Intercurrent events and confounding. As for any endpoint assessment, development should consider clear definitions of intercurrent events (e.g., death, concomitant medication, treatment discontinuation) and missing data, and a clear understanding of how to handle these issues on a case-by-case basis. – Clinically relevant magnitude of effect size. Clinical significance of the proposed difference in slope progressions between treatment arms (active or placebo) should be defined for the specific development. An annual difference of 1 ml/min/1.73 m2 for 2 years has been proposed as a clinically significant difference compared with placebo ( – Efficacy should be supported by other clinical measures, e.g. a second study or other endpoints, most often the standard renal endpoints. The benefit as assessed by these endpoints should be in the same direction as that of the GFR slope. • The CHMP agreed that proteinuria/albuminuria is of limited value as an endpoint in kidney transplantation.
This article was developed from the Broad Scientific Advice request submitted to the EMA/CHMP by ESOT in 2020: interactions between EMA and ESOT regarding this request began in 2016. For the present article, through virtual and face-to-face discussions, the working group on functional endpoints in kidney transplantation developed the ESOT position on the core question “Does the CHMP agree with the proposed definitions of graft (dys)function in kidney transplantation, and the recommendations for parameters that could be used as primary endpoints in clinical trial settings”. The Centre for Evidence in Transplantation (CET) supported specific data extraction requests: these literature searches formed the basis of evidence used in the advice request and the present article. Input into the working group's output was provided from all ESOT members involved in the advice request process. The present article was adapted by LH and MN from the final Broad Scientific Advice request submission (June 2020), presentation documents and minutes of the meeting between ESOT and the CHMP Scientific Advice Working Party (SAWP) (September 2020), and the final response from the SAWP (December 2020). The revised draft was reviewed, finalized, and approved by all co-authors before submission.
This work was supported by the European Society for Organ Transplantation.
LH reports speaker fees from Astellas, consultancy and research support from Chiesi, consultancy for Novartis, and research support from Sandoz. KB has received honoraria and/or research funding from Alexion, Astellas, Bristol Myers Squibb, Chiesi, Fresenius, Hansa, Hexal, Merck, Novartis, Otsuka, Pfizer, Roche, Sandoz, Siemens, and Veloxis. LF has received honoraria and/or research funding from Astellas, Chiesi, Hansa, and Novartis. JG consults for Sanofi. UH has received grants/research support from Baxter, Chiesi, and Neovii; speakers' bureaux/honoraria from Chiesi and Hansa; and consulting fees from Astellas, Hansa, Neovii, Novartis, and Teva. DH has received lecture fees and consulting fees from Astellas, Chiesi, MedinCell, Novartis, and Vifor; and grant support (paid to institution) from Astellas, Bristol Myers Squibb, and Chiesi. RO has received grants/research support from Amgen, Astellas, and Chiesi; and speakers' bureaux/honoraria from Amgen, Astellas, Chiesi, Hansa, Neovii, Novartis, and Teva. MR has received lecture fees from Astellas and Chiesi; and research grant support (paid to institution) from Astellas and Chiesi for investigator initiated studies. SS has received grants/research support from Bridge to Life, Chiesi, Neovii, Novartis, Organ Recovery Systems, and Sandoz; speakers' bureaux/honoraria from Astellas, BMS, Chiesi, Novartis, OrganOx, and Sanofi; and consulting fees from Astellas, Atara, Merck, NefroHealth, Novartis, Sandoz, and Teva.
The remaining authors declare that the work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors thank the experts involved with the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) who participated in the Broad Scientific Advice request. The published information is based on EMA feedback received during the Broad Scientific Advice request. EMA/CHMP have not been involved in the drafting or review of the manuscript to be published. This publication does not constitute a formal EMA/CHMP endorsement of the manuscript. Medical writing support was provided by Linda Edmondson, independent medical writer, funded by ESOT.