Prognostic stratification in a diabetic kidney disease trial using plasma concentrations of soluble tumor necrosis factor receptor 1

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Korean J Nephrol. 2026;.j.krcp.25.198

Publication date (electronic) : 2026 August 4

doi : https://doi.org/10.23876/j.krcp.25.198

Vladimir Petrovic^,1, Vladislav A. Malkov¹, Andrew N. Billin¹, Uptal D. Patel², Pablo E. Pergola³, Glenn M. Chertow⁴, Jan Skupien⁵, Andrzej S. Krolewski⁵

¹Gilead Biosciences, Foster City, CA, USA

²Department of Medicine, Duke University, Durham, NC, USA

³Renal Associates PA, San Antonio, TX, USA

⁴Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA

⁵Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA, USA

Correspondence: Vladimir Petrovic Gilead Biosciences, 310 Lakeside Dr., Foster City, CA 94404, USA. E-mail: vladimir.petrovic@gilead.com

Received 2025 June 24; Revised 2025 October 24; Accepted 2025 November 28.

Abstract

Introduction

Diabetic kidney disease (DKD) is among the most common chronic disorders globally, affecting up to 40% of patients with type 2 diabetes mellitus (T2DM) [1]. It is characterized by a progressive and highly variable decline of kidney function, with about 20% of patients exhibiting a rapid decline in estimated glomerular filtration rate (eGFR) of at least 3 mL/min/1.73 m² per year [2]. Many phase 3 clinical trials in patients with DKD rely on traditional event-driven endpoints, including a sizeable relative decline in kidney function (e.g., ≥40% or 50% decline in eGFR) or progression to end-stage kidney disease (ESKD), and often require large cohorts with extended follow-up to demonstrate efficacy. The ability to enrich clinical trials with participants more likely to experience a rapid decline in kidney function has the potential to accelerate the development of novel therapeutics.

Elevated concentration of circulating soluble tumor necrosis factor receptor 1 (sTNFR1) in patients with T2DM has been associated with progression to ESKD in cohort studies [3]. sTNFR1 is a soluble form of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) receptor, readily detectable in blood samples from healthy persons and elevated in patients with inflammatory diseases, including DKD. However, the prognostic utility of sTNFR1 plasma concentrations in clinical trials has not been demonstrated.

The Joslin cohort investigated the natural history of the DKD progression in patients with T2DM and impaired kidney function (chronic kidney disease [CKD] stages 3 or 4) followed for a period of 4 to 15 years. Data from this cohort were used to derive a prognostic criterion for patient stratification based on sTNFR1 plasma concentrations and to define the corresponding cutpoint of 4.3 ng/mL [4]. GS-US-223-1015 was a double-blind, placebo-controlled, dose-finding, 48-week phase 2 trial that enrolled 334 patients with T2DM and DKD, selected for high rates of progression based on eGFR and urine albumin-to-creatinine ratio [5]. The trial evaluated the safety and efficacy of three doses of selonsertib, a small molecule that selectively inhibits apoptosis signal-regulating kinase 1 (ASK1), a ubiquitously expressed serine/threonine kinase activated by oxidative stress that promotes inflammation, apoptosis, and fibrosis. In preclinical models of DKD/CKD, ASK1 inhibition reduced kidney injury, inflammation, and fibrosis, prevented podocyte loss, improved overall kidney function, and attenuated GFR decline [6]. A nominally significant reduction in the decline of chronic eGFR slope (rate of decline from week 4 to 48 that followed an acute decrease in eGFR during the first 4 weeks) was observed with 18-mg once daily selonsertib relative to placebo [5]. The previously proposed sTNFR1 cutpoint of 4.3 ng/mL was based on large longitudinal cohorts of DKD patients. We evaluated the prognostic utility of sTNFR1 in a highly selected clinical trial population in direct comparison to a cohort study used to derive the cutpoint to determine if it is useful in a setting of clinical trial setting. Additionally, a hypothesis that baseline sTNFR1 concentrations could have predictive utility for clinical benefit in patients treated with selonsertib was generated based on numerical trends observed.

Short methods

Seventy-six sites across the United States and four sites across Canada—representing hospitals, outpatient clinics, academic centers, and private research sites—conducted the double-blind, placebo-controlled, dose-finding phase 2 trial (ClinicalTrials.gov identifier NCT02177786) between 06/01/2014 and 07/01/2016 in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines for Good Clinical Practice (GCP).

RESULTS

Most baseline demographic characteristics were similar for the Joslin T2DM and selonsertib trial populations (Table 1); however, the trial population had a higher mean baseline sTNFR1 than the Joslin cohort (Table 1).

Table 1.

Basic demographics comparison between Joslin and trial cohorts

We correlated the sTNFR1 plasma concentration and eGFR in the selonsertib trial and Joslin cohort for each individual subject (Fig. 1). We used data generated from the Joslin cohort and compared it to the selonsertib trial cohort at baseline or 48-week time point. We observed high inverse correlation at baseline in both datasets (r = –0.68 [95% confidence interval (CI), –0.75 to –0.60], p < 0.001; r = –0.74 [95% CI, –0.79 to –0.68], p < 0.001).

Figure 1.

Inverse correlation between plasma sTNFR1 and eGFR at baseline.

Relationship between plasma sTNFR1 concentration and eGFR in the Joslin cohort (A) and in the clinical trial cohort (B). Each data point represents an individual participant. The dashed vertical line indicates the prespecified cutpoint of 4.3 ng/mL used to stratify low and high sTNFR1 groups. Spearman rank correlation coefficients were calculated.

sTNFR1, soluble tumor necrosis factor receptor 1; eGFR, estimated glomerular filtration rate.

Participants in the two study cohorts were then stratified by baseline sTNFR1 plasma concentrations into two groups, high and low, with plasma sTNFR1 >4.3 ng/mL and ≤4.3 ng/mL, respectively, based on previously published data [4]. Clinical events, consisting of death, progression to ESKD, or ≥40% reduction in eGFR were counted during the follow-up, and a Cox proportional hazards model was utilized to determine the risk of experiencing such an event. Results were represented as a probability of event-free survival over time (Fig. 2). Even though a relatively small number of clinical events was detected in the clinical study cohort due to a modest cohort size and a relatively short follow-up time, we found a significantly higher probability of experiencing an event in high sTNFR1 subgroups in each of the cohorts, with comparable hazard ratios of 2.58 and 2.22 for Joslin and trial cohorts respectively.

Figure 2.

Kaplan–Meier estimates of kidney-related events (end-stage renal disease, >40% loss of eGFR from baseline, or death).

(A) GS-US-223-1015 trial cohort. Patients with sTNFR1 >4.3 ng/mL (yellow) had a significantly higher risk of end-stage renal disease, >40% loss of estimated glomerular filtration rate from baseline, or death compared with those with sTNFR1 ≤4.3 ng/mL (blue) (Cox proportional hazard ratio [HR], 2.22; 95% confidence interval [CI], 1.13–4.36; p = 0.02). (B) Joslin type 2 diabetes mellitus cohort. Patients with sTNFR1 >4.3 ng/mL (yellow) had a significantly higher risk of kidney events compared with those with sTNFR1 ≤4.3 ng/mL (blue) (Cox proportional HR, 2.58; 95% CI, 1.71–3.89; p = 6.06e–06).

sTNFR1, soluble tumor necrosis factor receptor 1; eGFR, estimated glomerular filtration rate.

We utilized eGFR slope as a proxy for the rate of kidney functional decline [8]. When placebo and the 18 mg selonsertib GS-US-223-1015 study arms were compared, we found a significant reduction in eGFR slope decline in both high- and low-sTNFR1 groups but with a numerically greater reduction in the high sTNFR1 subgroup (Fig. 3). This indicates a potential utility for baseline sTNFR1 as a predictive marker of selonsertib treatment benefit in DKD patients, a hypothesis that we plan to address prospectively in an ongoing clinical study.

Figure 3.

eGFR slope in different subject subgroups.

(A) Placebo- or selonsertib (SEL) 18 mg-treated trial patients stratified into two groups based on plasma soluble tumor necrosis factor receptor 1 (sTNFR1) levels (≤4.3 ng/mL and >4.3 ng/mL), as described previously. The estimated eGFR slope between week 4 and week 48 is shown, and the Wilcoxon test was applied to determine the statistical significance of the difference between the placebo and SEL 18 mg-treated groups. (B) Joslin cohort subjects stratified by plasma sTNFR1 levels (≤4.3 ng/mL and >4.3 ng/mL). The annual eGFR slope is shown, and the Wilcoxon test was applied to assess the difference between the high and low sTNFR1 groups.

eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes.

Discussion

We found that plasma concentrations of circulating sTNFR1 were prognostic in identifying individuals with DKD at high risk of progressive kidney function decline who were enrolled in a clinical trial. These findings build upon similar evidence previously reported in a cohort study [4]. We analyzed data from two cohorts of individuals with T2DM and with advanced DKD; one comprised of individuals with T2DM participating in a long-term observational cohort study representing the natural history of DKD from a referral center (Joslin), and the other comprised of individuals enrolled in a 48-week trial based on representative inclusion criteria. Our analyses suggest that in independent cohorts, sTNFR1 concentrations are inversely correlated with creatinine-based estimated GFR, and higher concentrations of sTNFR1 are associated with greater risks of experiencing a discrete composite endpoint of ≥40% decline in eGFR or kidney failure. We found a high degree of concordance between the two cohorts suggesting that the prognostic performance of sTNR1 was maintained regardless of patient inclusion criteria and the distribution of the baseline sTNFR1 concentrations. The eGFR slope was attenuated by selonsertib exposure in both low- and high sTNFR1 groups, with a tendency towards greater effect in the high sTNFR1 group suggesting a potentially enhanced treatment benefit.

Even though the prognostic utility of plasma concentration of sTNFR1 in DKD has been demonstrated, the biological processes leading to increased concentration of sTNFR1 during the onset and progression of DKD, as well as response to selonsertib or other therapies, is largely unknown. ASK1 has been shown to be a mediator of TNF-α–induced apoptosis of kidney cells [9]. ASK1 inhibitors are efficacious in animal models of CKD where TNF-α is upregulated [6,10], and post-hoc analyses of this phase 2 trial in DKD patients indicated that 18-mg selonsertib may reduce the rate of decline in eGFR. Preclinical analyses demonstrate downregulation of sTNFR1 following selonsertib exposure and support ASK1 inhibition as a therapeutic strategy in progressive kidney diseases, and further studies are underway to better understand this interaction [6,11]. A prospective analysis in further trials of selonsertib in DKD is required to formally test whether any sTNFR1 plasma concentration cut point identifies a group of patients who respond better to selonsertib. Our findings confirm the prognostic utility of plasma sTNFR1 concentration in patients with DKD and the potential for enriching clinical trials with participants who are more likely to experience clinical kidney-related events.

The sTNFR1 has shown prognostic utility in observational studies in patients with DKD, but the prognostic performance of sTNFR1 plasma concentrations in DKD clinical trials has not been tested. We applied a predefined sTNFR1 cutpoint to risk-stratify patients in a phase 2 clinical trial of selonsertib and compared it with an observational cohort used to derive the cutpoint. We observed a higher probability of experiencing a clinical event and elevated hazard ratios in individuals with sTNFR1 plasma concentrations above the established cutpoint supporting its potential prognostic utility in DKD clinical trials.

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