GFR Decline as an End Point for Clinical Trials in CKD: A Scientific Workshop Sponsored by the National Kidney Foundation and the US Food and Drug Administration

doi:10.1053/j.ajkd.2014.07.030

American Journal of Kidney Diseases

Volume 64, Issue 6, December 2014, Pages 821-835

https://doi.org/10.1053/j.ajkd.2014.07.030 Get rights and content

The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.

Section snippets

Kidney Disease Outcomes and Measures

The prevalence of CKD is increasing in the United States and worldwide, with high cost and poor outcomes, especially for patients with kidney failure.⁶ There are few proven therapies to slow the progression of CKD. However, despite the availability of simple laboratory tests to identify people with earlier stages of CKD, fewer clinical trials have been performed for kidney disease than for other common diseases.7, 8 It is widely acknowledged that the lack of specific symptoms prior to the stage

Methods, Results, and Interpretation

In this section, we summarize methods, results, and interpretation of analyses reported elsewhere in more detail.2, 3, 4, 5 We begin with a definition of established and alternative surrogate end points, then discuss the general framework for analysis of observational studies (cohorts), clinical trials, and simulations, including strengths and limitations of each source of data. Next, we discuss the sources of data, then the main results and interpretation for each analysis.

The Proposal

Based on these results, the planning committee and analytic group proposed and the workshop participants agreed that under some circumstances, a GFR decline of 30% could be a valid and useful surrogate end point for progression to kidney failure in clinical trials of CKD (Table 4). Evidence was stronger for a GFR decline of 40% as the end point, which represents a more cautious approach and is likely to be more widely applicable (Fig 4). Using the CKD-EPI 2009 creatinine equation, a 30% and 40%

Conclusion

In summary, our results support the use of alternative eGFR-based end points as a surrogate for kidney failure in clinical trials. We have analyzed a large number of cohorts and clinical trials and developed a tool to simulate outcomes for alternative eGFR-based end points based on participant clinical characteristics and trial design. We have proposed eGFR decline of 30% as an alternative surrogate end point in trials of CKD, with stronger evidence for a 40% eGFR decline. We have considered

Acknowledgements

The workshop planning committee comprised Andrew S. Levey, MD (chair), Aliza M. Thompson, MD (FDA; co-chair), Josef Coresh, MD, PhD, Kerry Willis, PhD (NKF), Norman Stockbridge, MD, PhD (FDA), Edmund Lewis, MD, Dick de Zeeuw, MD, PhD, and Alfred K. Cheung, MD. The analytical group was chaired by Josef Coresh, MD, PhD, and comprised the observational studies subgroup (Kunihiro Matsushita, MD, PhD [lead], Josef Coresh, MD, PhD, Mark Woodward, PhD, Morgan Grams, MD, MS, Yingying Sang, MS, and

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Effect of Tyrosine Kinase Inhibitor Therapy on Estimated Glomerular Filtration Rate in Patients with Chronic Myeloid Leukemia
2024, Clinical Lymphoma, Myeloma and Leukemia
The advent of tyrosine kinase inhibitors (TKIs) was revolutionary in the management of chronic myeloid leukemia (CML). Although TKIs were generally considered to be safe, they can be associated with renal injury. We evaluated the effect of TKIs on renal functions in a cohort of patients with long-term follow-up.
We retrospectively examined patients with chronic phase CML treated with TKIs. We analyzed the estimated glomerular filtration rate (eGFR) of patients from the initiation of TKI to the last follow-up. eGFR values of CML patients were compared to those of patients with stage 1 or 2 chronic kidney disease (CKD).
A total of 195 patients with CML and 138 patients with CKD were examined. eGFR decline was 1.556 ml/min/1.73m²/year for patients with CML (P = .221). Patients receiving second-generation TKIs (2GTKI) were estimated to have 0.583 ml/min/1.73m² higher eGFR value than that of the imatinib group, but it was not significant (P = .871). eGFR of patients who had used bosutinib had a downward trend. Duration of TKI therapy, age, and hypertension were found to be significant factors in eGFR decline for CML patients. Lower baseline GFR was associated with an increased risk of CKD development.
Imatinib could result in a decline in eGFR which was clinically similar to early-stage CKD patients. We did not observe significant kidney function deterioration in patients receiving 2GTKIs including dasatinib and nilotinib. We recommend close renal function monitoring in patients receiving imatinib, especially for elderly patients with lower baseline eGFR and hypertension.
Impact of Thyroid Status on Incident Kidney Dysfunction and Chronic Kidney Disease Progression in a Nationally Representative Cohort
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To examine the relationship between thyroid status and incident kidney dysfunction/chronic kidney disease (CKD) progression.
We examined incident thyroid status, ascertained by serum thyrotropin (TSH) levels measured from January 1, 2007, through December 31, 2018, among 4,152,830 patients from the Optum Labs Data Warehouse, containing deidentified retrospective administrative claims data from a large national health insurance plan and electronic health record data from a nationwide network of provider groups. Associations of thyroid status, categorized as hypothyroidism, euthyroidism, or hyperthyroidism (TSH levels >5.0, 0.5-5.0, and <0.5 mIU/L, respectively), with the composite end point of incident kidney dysfunction in patients without baseline kidney dysfunction and CKD progression in those with baseline CKD were examined using Cox models.
Patients with hypothyroidism and hyperthyroidism had higher risk of incident kidney dysfunction/CKD progression in expanded case-mix analyses (reference: euthyroidism): adjusted hazard ratios (aHRs) (95% CIs) were 1.37 (1.34 to 1.40) and 1.42 (1.39 to 1.45), respectively. Incrementally higher TSH levels in the upper reference range and TSH ranges for subclinical, mild overt, and overt hypothyroidism (≥3.0-5.0, >5.0-10.0, >10.0-20.0, and >20.0 mIU/L, respectively) were associated with increasingly higher risk of the composite end point (reference: TSH level, 0.5 to <3.0 mIU/L): aHRs (95% CIs) were 1.10 (1.09 to 1.11), 1.37 (1.34 to 1.40), 1.70 (1.59 to 1.83), and 1.70 (1.50 to 1.93), respectively. Incrementally lower TSH levels in the subclinical (<0.5 mIU/L) and overt (<0.1 mIU/L) hyperthyroid ranges were also associated with the composite end point: aHRs (95% CIs) were 1.44 (1.41 to 1.47) and 1.48 (1.39 to 1.59), respectively.
In a national cohort, TSH levels in the upper reference range or higher (≥3.0 mIU/L) and below the reference range (<0.5 mIU/L) were associated with incident kidney dysfunction/CKD progression.
Empagliflozin in chronic kidney disease: nephroprotection is independent of albuminuria, primary kidney disease, and baseline eGFR
2024, The Lancet Diabetes and Endocrinology
Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial
2024, The Lancet Diabetes and Endocrinology
Sodium–glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.
EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m², or with an eGFR of 45 to less than 90 mL/min per 1·73 m² with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.
Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m², 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m², and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m² or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m² (95% CI 1·83–2·41) reduction in eGFR, equivalent to a 6% (5–6) dip in the first 2 months. After this, it halved the chronic slope from –2·75 to –1·37 mL/min per 1·73 m² per year (relative difference 50%, 95% CI 42–58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36–136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19–38] reduction for those with baseline uACR ≥2000 mg/g; p_trend<0·0001).
Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.
Boehringer Ingelheim and Eli Lilly.
Circulating tumor necrosis factor-related biomarkers predict kidney function decline in Japanese patients with diabetes: An observational cohort study
2023, Diabetes Research and Clinical Practice
Tumor necrosis factor (TNF) receptors (TNFRs: TNFR1 and, TNFR2) are reportedly associated with chronic kidney disease (CKD) progression chiefly in Caucasian patients with diabetes. We assessed the prognostic value of TNF-related biomarkers for CKD progression in Japanese patients with diabetes.
We estimated TNF-related biomarkers using an enzyme-linked immunosorbent assay in 640 patients with diabetes. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) per one standard deviation (SD) increase in a log-transformed biomarker. The kidney and the composite outcome were defined as a 30% reduction in estimated glomerular filtration rate (eGFR) from baseline, and kidney outcome plus death before kidney outcome, respectively.
During the median follow-up of 5.4 years, 75 (11.7%) patients reached the kidney outcome and 37 (5.8%) died before reaching the kidney outcome. Each SD increase in baseline circulating TNFR1, TNFR2, and ephrin type-A receptor 2 (EphA2) was associated with a higher risk of the kidney outcome independently from baseline eGFR and urine albumin-to-creatinine ratio. However, circulating osteoprotegerin was associated with the composite outcome only.
Elevated TNFR1, TNFR2, and EphA2 were associated with both kidney and composite outcomes in Japanese patients with diabetes.
The Association of Intravitreal Anti-VEGF Injections With Kidney Function in Diabetic Retinopathy
2023, Ophthalmology Science
To examine whether patients with diabetic retinopathy receiving intravitreal anti-VEGF injections are at increased risk of kidney function decline.
Retrospective cohort study.
Included 187 patients who received intravitreal anti-VEGF injections for proliferative diabetic retinopathy (PDR) and/or diabetic macular edema (DME), and 929 controls with non-PDR who did not receive injections, at a large tertiary care center in Chicago, Illinois.
We queried our institutional enterprise data warehouse to identify patients with diabetic retinopathy, determined whether they received intravitreal anti-VEGF injections, and followed kidney function for all patients over time.
We assessed time to sustained 40% decline in estimated glomerular filtration rate (eGFR) from baseline in patients receiving intravitreal anti-VEGF injections and compared it with controls using Kaplan-Meier and multivariable adjusted Cox proportional hazards regression models.
This study included 1116 patients (565 female [50.6%]; mean [standard deviation {SD}] age, 57.3 [13.6] years; mean [SD] eGFR, 65.3 [32.1] ml/min/1.73 m²). Of these, 187 patients received ≥ 1 intravitreal anti-VEGF injection (mean [SD], 11.4 [13.1] injections) for PDR and/or DME, and 929 controls with non-PDR received no injections. Intravitreal anti-VEGF injection use was not associated with an increased risk of kidney function decline (hazard ratio [HR], 1.44; 95% confidence interval [CI], 0.97–2.15). Subgroup analyses revealed that use of intravitreal anti-VEGF injections was associated with increased risk of kidney function decline in male patients (HR, 1.87; 95% CI, 1.11–3.14) but not female patients (HR, 0.97; 95% CI, 0.50–1.89). Intravitreal anti-VEGF injection use was also associated with an increased risk of kidney function decline in patients with baseline eGFR > 30 ml/min/1.73 m² (HR, 1.86; 95% CI, 1.15–3.01), but not in individuals with baseline eGFR ≤ 30 ml/min/1.73 m² (HR, 0.97; 95% CI, 0.45–2.10). Among patients who received injections, receiving ≥ 12 injections was not associated with risk of kidney function decline (HR, 1.13; 95% CI, 0.52–2.49).
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Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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: Because an author of this article is an editor for AJKD, the peer-review and decision-making processes were handled entirely by an Associate Editor (Mark M. Mitsnefes, MD) who served as Acting Editor-in-Chief. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Editorial Policies.

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Special Section: GFR Decline as an End Point for Clinical Trials in CKDSpecial ReportGFR Decline as an End Point for Clinical Trials in CKD: A Scientific Workshop Sponsored by the National Kidney Foundation and the US Food and Drug Administration

Section snippets

Kidney Disease Outcomes and Measures

Methods, Results, and Interpretation

The Proposal

Conclusion

Acknowledgements

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Am J Kidney Dis

Lancet

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Kidney Int

Kidney Int

Lancet

Lancet

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality

JAMA

US Renal Data System 2012 annual data report

Am J Kidney Dis

Special Section: GFR Decline as an End Point for Clinical Trials in CKD
Special Report
GFR Decline as an End Point for Clinical Trials in CKD: A Scientific Workshop Sponsored by the National Kidney Foundation and the US Food and Drug Administration