Overcoming barriers in the design and implementation of clinical trials for acute kidney injury: a report from the 2020 Kidney Disease Clinical Trialists meeting

Lazzareschi, Daniel; Mehta, Ravindra L.; Dember, Laura M.; Bernholz, Juliane; Turan, Alparslan; Sharma, Amit; Kheterpal, Sachin; Parikh, Chirag R.; Farouk, Omar; Schulman, Ivonne H; Ryan, Abigail; Feng, Jean; Simon, Noah; Pirracchio, Romain; Rossignol, Patrick; Legrand, Matthieu

doi:10.1093/ndt/gfac003

Cited by 19 publications

(14 citation statements)

References 68 publications

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“…We speculate that uncharacterized clinically and physiologically distinct substages exist within critically ill children with AKI and that they are associated with differences in the risk of adverse outcomes. Moreover, because of the inherent heterogeneity of AKI in its etiology and pathophysiology, human studies investigating the prevention and treatment of AKI remain largely inconclusive [ 43 , 44 ]. The identification of AKI subphenotypes linked to underlying pathophysiologic processes may parse the heterogeneity in the AKI phenotype and identify treatment-responsive AKI subtypes [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

The outcome of acute kidney injury substages based on urinary cystatin C in critically ill children

Chen

Jiang

Huang

et al. 2023

Ann. Intensive Care

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Background The concept of acute kidney injury (AKI) substages has been recommended to better phenotype AKI and identify high-risk patient groups and therefore improve the diagnostic accuracy of AKI. However, there remains a gap between the recommendation and the clinical application. The study aimed to explore the incidence of AKI substages based on a sensitive AKI biomarker of urinary cystatin C (uCysC), and to determine whether AKI substages were relevant with respect to outcome in critically ill children. Results The multicenter cohort study enrolled 793 children in pediatric intensive care unit (PICU) of four tertiary hospitals in China. Children were classified as non-AKI, sub-AKI and AKI substages A and B according to uCysC level at PICU admission. Sub-AKI was defined by admission uCysC level ≥ 1.26 mg/g uCr in children not meeting the KDIGO criteria of AKI. In children who fulfilled KDIGO criteria, those with uCysC < 1.26 was defined as AKI substage A, and with ≥ 1.26 defined as AKI substage B. The associations of AKI substages with 30-day PICU mortality were assessed. 15.6% (124/793) of patients met the definition of sub-AKI. Of 180 (22.7%) patients with AKI, 90 (50%) had uCysC-positive AKI substage B and were more likely to have classical AKI stage 3, compared to substage A. Compared to non-AKI, sub-AKI and AKI substages A and B were risk factors significantly associated with mortality, and the association of sub-AKI (adjusted hazard ratio HR = 2.42) and AKI substage B (adjusted HR = 2.83) with mortality remained significant after adjustment for confounders. Moreover, AKI substage B had increased risks of death as compared with sub-AKI (HR = 3.10) and AKI substage A (HR = 3.19). Conclusions Sub-AKI defined/based on uCysC occurred in 20.2% of patients without AKI and was associated with a risk of death close to patients with AKI substage A. Urinary CysC-positive AKI substage B occurred in 50% of AKI patients and was more likely to have classical AKI stage 3 and was associated with the highest risk of mortality.

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Section: Discussionmentioning

confidence: 99%

The outcome of acute kidney injury substages based on urinary cystatin C in critically ill children

Chen

Jiang

Huang

et al. 2023

Ann. Intensive Care

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“…For instance, human recombinant alkaline phosphatase is an endogenous detoxification enzyme with anti-inflammatory effects. In a phase II trial of patients with sepsis-related AKI, it significantly improved long-term renal function and reduced mortality ( Lazzareschi et al, 2022 ). Moreover, Sirtuin 1 (SIRT1) can inhibit the expression of inflammatory genes and reduce inflammatory tissue injury ( Fan et al, 2013 ).…”

Section: The Treatment Of Oxidative Stress Regulation For Akimentioning

confidence: 99%

Nanosystems for oxidative stress regulation in the anti-inflammatory therapy of acute kidney injury

Wang

Jiang

Zhang

et al. 2023

Front. Bioeng. Biotechnol.

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Acute kidney injury (AKI) is a clinical syndrome that results from a rapid decline in renal structure or renal functional impairment with the main pathological feature of sublethal and lethal damage to renal tubular cells. However, many potential therapeutic agents cannot achieve the desired therapeutic effect because of their poor pharmacokinetics and short retention time in the kidneys. With the recent emergence and progress of nanotechnology, nanodrugs with unique physicochemical properties could prolong circulation time, enhance efficient targeted delivery, and elevate the accumulation of therapeutics that can cross the glomerular filtration barrier and indicate comprehensive application prospects in the prevention and treatment of AKI. In this review, various types of nanosystems (such as liposomes, polymeric nanosystems, inorganic nanoparticles and cell-derived extracellular vesicles) are designed and applied to improve the pharmacokinetics of drug formation, which could further relieve the burden on the kidneys caused by the final cumulative dose of drugs in conventional treatments. Moreover, the passive or active targeting effect of nanosystems can also reduce the total therapeutic dose and off-target adverse effects on other organs. Nanodelivery systems for treating AKI that alleviate oxidative stress-induced renal cell damage and regulate the inflammatory kidney microenvironment are summarized.

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“…Randomized controlled trials reported in the literature are often affected by poor generalizability, and pragmatic trials have become an increasingly utilized workaround approach to overcome logistical limitations and explore routine interventions demonstrating equipoise in clinical practice 1 . Intravenous albumin, for example, is commonly administered in the perioperative setting despite lacking supportive evidence.…”

Section: Introductionmentioning

confidence: 99%

Leveraging observational data to identify targeted patient populations for future randomized trials

Lazzareschi

Fong

Pirracchio

et al. 2023

Preprint

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Randomized controlled trials reported in the literature are often affected by poor generalizability, and pragmatic trials have become an increasingly utilized workaround approach to overcome logistical limitations and explore routine interventions demonstrating equipoise in clinical practice. Intravenous albumin, for example, is commonly administered in the perioperative setting despite lacking supportive evidence. Given concerns for cost, safety, and efficacy, randomized trials are needed to explore the clinical equipoise of albumin therapy in this setting, and we therefore present an approach to identifying populations exposed to perioperative albumin to encourage clinical equipoise in patient selection and optimize study design for clinical trials.

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Overcoming barriers in the design and implementation of clinical trials for acute kidney injury: a report from the 2020 Kidney Disease Clinical Trialists meeting

Cited by 19 publications

References 68 publications

The outcome of acute kidney injury substages based on urinary cystatin C in critically ill children

The outcome of acute kidney injury substages based on urinary cystatin C in critically ill children

Nanosystems for oxidative stress regulation in the anti-inflammatory therapy of acute kidney injury

Leveraging observational data to identify targeted patient populations for future randomized trials

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