Impact of random variation in albuminuria and estimated glomerular filtration rate on patient enrolment and duration of clinical trials in nephrology

Aim To test whether a screening approach with more flexible urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) thresholds would decrease screen failure rate without negatively impacting on the event rate and overall study duration. Methods We performed a post-hoc analysis of the ALTITUDE trial. We selected participants randomized to placebo with a UACR of >300 mg/g and an eGFR between 30 mL/min/1.73 m(2) and 60 mL/min/1.73 m(2) at the first visit (pre-screening) for the trial. We then used less stringent lower UACR and higher eGFR thresholds for the following qualifying visit. For each scenario we calculated the number of eligible participants, the number of renal and cardiovascular endpoints, and the event rates. Based on this, we performed simulations for a future trial and estimated the duration of enrolment and total duration of this trial. Results The base scenario consisted of 848 participants (median UACR 1239 mg/g; median eGFR 44 mL/min/1.73 m(2)). Lowering the UACR and/or raising eGFR qualification thresholds increased the number of eligible participants, decreased screen failures and resulted in only a modest decrease in renal and cardiovascular event rates. For example, relaxing the UACR criterion from 300 mg/g to 210 mg/g at the qualifying visit, increased the number of eligible patients from 848 to 923, and increased the number of renal events from 117 to 122 events. The event rate showed a moderate decrease from 5.6 (4.6-6.7) events per 100 patient-years to 5.3 (4.4-6.4) events per 100 patient-years. In simulations, lowering the UACR and raising eGFR thresholds for inclusion accelerated patient enrolment and did not increase in the overall trial duration. Conclusion More flexible albuminuria and eGFR-based inclusion criteria, in participants who met the inclusion criteria of a trial based on pre-screening values prior to the clinical trial, decreases screen failure rates and accelerated patient enrolment leading to more efficient trial conduct without impacting the overall trial duration

Short-Term Changes in Albuminuria and Risk of Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus:A Post Hoc Analysis of the EMPA-REG OUTCOME Trial

Background Early reduction in albuminuria with an SGLT2 (sodium-glucose cotransporter 2) inhibitor may be a positive indicator of long-term cardiovascular and renal benefits. We assessed changes in albuminuria during the first 12 weeks of treatment and subsequent long-term cardiovascular and renal risks associated with the SGLT2 inhibitor, empagliflozin, in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) trial. Methods and Results We calculated the percentage urinary albumin creatinine ratio (UACR) change from baseline to week 12 in 6820 participants who did not experience a cardiovascular outcome (including 3-point major cardiovascular events and cardiovascular death or hospitalization for heart failure) or renal outcome (defined as 40% decline in estimated glomerular filtration rate from baseline, estimated glomerular filtration rate 30% reduction in UACR (odds ratio, 1.42; 95% CI, 1.27-1.58; P<0.001). During 3.0 years of follow-up, 704 major cardiovascular events, 440 cardiovascular deaths/hospitalizations for heart failure, and 168 renal outcomes were observed. Each 30% decrease in UACR during the first 12 weeks was statistically significantly associated with a lower hazard for major cardiovascular events (HR, 0.96; 95% CI, 0.93-0.99; P=0.012), cardiovascular deaths/hospitalizations for heart failure (HR, 0.94; 95% CI, 0.91-0.98; P=0.003), and renal outcomes (HR, 0.83; 95% CI, 0.78-0.89; P<0.001). Conclusions Short-term reduction in UACR was more common with empagliflozin and was statistically significantly associated with a decreased risk of long-term cardiovascular and renal outcomes. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676

Association between TNF Receptors and KIM-1 with Kidney Outcomes in Early-Stage Diabetic Kidney Disease

Background and objectives: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. Tumor Necrosis Factor Receptor (TNFR)-1, TNFR-2 and Kidney Injury Marker (KIM)-1 are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNFR-1, TNFR-2 and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. Design, setting, participants and measurements: TNFR-1, TNFR-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the CANVAS trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome and stratified the population by the 4th quartile of each biomarker distribution and assessed the number of events and event rates. Results: In patients with normoalbuminuria (N=2,553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (IQR 5.8 to 6.4) years (event rate 3.5 [95%CI 2.6-4.6] per 1,000-patient-years). Each doubling of baseline TNFR-1 (HR 4.16; 95%CI 1.80-9.61) and TNFR-2 (HR 2.35; 95%CI 1.51-3.63) was associated with a higher risk for the kidney outcome. Baseline KIM-1, UACR and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of the TNFR-1 (≥2,992 ng/ml) or TNFR-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000-patient-years compared to 2.4 and 2.8 in the lower three quartiles. Conclusion: TNFR-1 and TNFR-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria

Change in albuminuria as a surrogate endpoint

Purpose of review Chronic kidney disease is a global health problem with few effective therapies available that slow the progression to end-stage renal disease. The established clinical endpoints for renal trials; doubling of serum creatinine or end-stage renal disease, are late manifestations of CKD. This leads to large trials enrolling preferably patients with advanced stages of CKD. The use of valid surrogate biomarkers that substitute a clinical endpoint (surrogate endpoints), can lead to trials of shorter duration that can be performed at earlier stages of CKD. Change in albuminuria has been proposed as surrogate endpoint in CKD. Yet, although albuminuria is a strong risk factor for CKD progression, there is persistent uncertainty about its validity to substitute clinical endpoints. Recent findings New observational studies have demonstrated robust associations between changes in albuminuria and risk of end-stage renal disease. In addition, a meta-analysis of observational studies confirmed the strong association between change in albuminuria and end-stage renal disease. Another meta-analysis of clinical trials showed moderately strong associations between treatment effects on albuminuria and treatment effects on clinical endpoints. These new data support a role for change in albuminuria as surrogate endpoint for clinical trials of progression of CKD. There is increasing evidence that change in albuminuria is a valid surrogate endpoint for CKD. Implementing albuminuria as surrogate requires proper understanding of the settings in which the surrogate works well

Impact of random variation in albuminuria and estimated glomerular filtration rate on patient enrolment and duration of clinical trials in nephrology

Aim: To test whether a screening approach with more flexible urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) thresholds would decrease screen failure rate without negatively impacting on the event rate and overall study duration. Methods: We performed a post-hoc analysis of the ALTITUDE trial. We selected participants randomized to placebo with a UACR of &gt;300 mg/g and an eGFR between 30 mL/min/1.73 m2 and 60 mL/min/1.73 m2 at the first visit (pre-screening) for the trial. We then used less stringent lower UACR and higher eGFR thresholds for the following qualifying visit. For each scenario we calculated the number of eligible participants, the number of renal and cardiovascular endpoints, and the event rates. Based on this, we performed simulations for a future trial and estimated the duration of enrolment and total duration of this trial. Results: The base scenario consisted of 848 participants (median UACR 1239 mg/g; median eGFR 44 mL/min/1.73 m2). Lowering the UACR and/or raising eGFR qualification thresholds increased the number of eligible participants, decreased screen failures and resulted in only a modest decrease in renal and cardiovascular event rates. For example, relaxing the UACR criterion from 300 mg/g to 210 mg/g at the qualifying visit, increased the number of eligible patients from 848 to 923, and increased the number of renal events from 117 to 122 events. The event rate showed a moderate decrease from 5.6 (4.6-6.7) events per 100 patient-years to 5.3 (4.4-6.4) events per 100 patient-years. In simulations, lowering the UACR and raising eGFR thresholds for inclusion accelerated patient enrolment and did not increase in the overall trial duration. Conclusion: More flexible albuminuria and eGFR-based inclusion criteria, in participants who met the inclusion criteria of a trial based on pre-screening values prior to the clinical trial, decreases screen failure rates and accelerated patient enrolment leading to more efficient trial conduct without impacting the overall trial duration.Pattern Recognition and Bioinformatic

The effect of atrasentan on kidney and heart failure outcomes by baseline albuminuria and kidney function: a post hoc analysis of the SONAR randomized trial

Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failure events according to baseline eGFR and urinary albumin-creatinine ratio (UACR) in a analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial. The effect of atrasentan versus placebo in 3668 patients with type 2 diabetes and CKD with elevated albuminuria was examined in the SONAR trial. We used Cox proportional hazards regression analysis to study effects on the primary kidney outcome (composite of doubling of serum creatinine, kidney failure, or kidney death) and heart failure hospitalization across subgroups of eGFR (&lt;30, ≥30-45, and ≥45 ml/min per 1.73 m ) and UACR (&lt;1000, ≥1000-3000, and ≥3000 mg/g). Atrasentan reduced the relative risk of the primary kidney outcome (hazard ratio, 0.71; 95% confidence interval, 0.58 to 0.88) consistently across all subgroups of baseline eGFR and UACR (all interaction &gt;0.21). Patients in the highest UACR and lowest eGFR subgroups, in whom rates of the primary kidney outcome were highest, showed the largest absolute benefit (all interaction &lt;0.01). The risk of heart failure hospitalization was higher in the atrasentan group (hazard ratio, 1.39; 95% confidence interval, 0.97 to 1.99) and was consistent across subgroups, with no evidence that relative or absolute risks differed across eGFR or UACR subgroups (all interaction &gt;0.09). Atrasentan reduced the relative risk of the primary kidney outcome consistently across baseline UACR and eGFR subgroups. The absolute risk reduction was greater among patients in the lowest eGFR and highest albuminuria category who were at highest baseline risk. Conversely, the relative and absolute risks of heart failure hospitalization were similar across baseline UACR and eGFR subgroups. Study of Diabetic Nephropathy with Atrasentan (SONAR), NCT01858532. [Abstract copyright: Copyright © 2021 by the American Society of Nephrology.

Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial

Aims/hypothesis: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories. Methods: DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25–75 ml min−1 [1.73 m]−2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and &lt;565.0 mg/mmol (200–5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories. Results: Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction &gt;0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories. Conclusion/interpretations: The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity. Trial registration: ClinicalTrials.gov NCT03036150

Critical Role of TLR7 Signaling in the Priming of Cross-Protective Cytotoxic T Lymphocyte Responses by a Whole Inactivated Influenza Virus Vaccine

<p>Current influenza vaccines fail to induce protection against antigenically distinct virus strains. Accordingly, there is a need for the development of cross-protective vaccines. Previously, we and others have shown that vaccination with whole inactivated virus (WIV) induces cross-protective cellular immunity in mice. To probe the mechanistic basis for this finding, we investigated the role of TLR7, a receptor for single-stranded RNA, in induction of cross-protection. Vaccination of TLR7-/- mice with influenza WIV failed to protect against a lethal heterosubtypic challenge; in contrast, wild-type mice were fully protected. The lack of protection in TLR7-/- mice was associated with high viral load and a relative paucity of influenza-specific CD8+ cytotoxic T lymphocyte (CTL) responses. Dendritic cells (DCs) from TLR7-/- mice were unable to cross-present WIV-derived antigen to influenza-specific CTLs in vitro. Similarly, TLR7-/- DCs failed to mature and become activated in response to WIV, as determined by the assessment of surface marker expression and cytokine production. Plasmacytoid DCs (pDCs) derived from wild-type mice responded directly to WIV while purified conventional DCs (cDCs) did not respond to WIV in isolation, but were responsive in mixed pDC/cDC cultures. Depletion of pDCs prior to and during WIV immunization resulted in reduced numbers of influenza-specific CTLs and impaired protection from heterosubtypic challenge. Thus, TLR7 plays a critical role in the induction of cross-protective immunity upon vaccination with WIV. The initial target cells for WIV appear to be pDCs which by direct or indirect mechanisms promote activation of robust CTL responses against conserved influenza epitopes.</p>