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Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical ch

Marina Wainstein , Samual MacDonald, Daniel Fryer,Kyle Young, Valeria Balan, Husna Begum, Aidan Burrell, Barbara WanjiruCitarella, J. Perren Cobb, Sadie Kelly, KalynnKennon, James Lee, Laura Merson

Abstract

Background

Acute kidney injury (AKI) is one of the most common and significant problems in patients with Coronavirus Disease 2019 (COVID-19). However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional Kidney Disease Improving Global Outcomes (KDIGO) definition can fail to identify patients for whom hospitalisation coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesised that an extended KDIGO (eKDIGO) definition, adapted from the International Society of Nephrology (ISN) 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI (CA-AKI) with similarly poor outcomes as previously reported in this population.

Introduction

Acute kidney injury (AKI) has been identified as one of most common and significant problems in hospitalised patients with Coronavirus Disease 2019 (COVID-19) [1–3]. Observational studies have consistently shown that patients who develop AKI are more likely to be admitted to an intensive care unit (ICU), require invasive mechanical ventilation, have longer lengths of stay (LOS) and increased mortality [1,2,4]. Autopsy studies point to several potential pathophysiological pathways for AKI including acute tubular injury from hemodynamic shifts, local inflammatory and microvascular thrombotic changes from immune dysregulation as well as direct viral invasion through the angiotensin converting enzyme 2 (ACE2) receptor [5].

Methods

Study design

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)–World Health Organization (WHO) Clinical Characterisation Protocol (CCP) for Severe Emerging Infections provided a framework for prospective, observational data collection on hospitalised patients affected by pathogens of public health interest. The protocol, case report forms (CRFs), and study information are available online (https://isaric.org/research/covid-19-clinical-research-resources), of which only the core CRF was used in this study [12]. These CRFs were developed to standardise clinical data collection on patients admitted with suspected or confirmed COVID-19 and have been widely used since the start of the pandemic [13,14]. Collection of sCr measurements across all sites was not time standardised, and the frequency of collection was left to the discretion of each site.

Results

From February 15, 2020 to February 1, 2021, data were collected for 418,111 individuals admitted to hospital with clinically suspected or laboratory confirmed SARS-COV-2 infection from 1,609 sites and 54 countries. Of these, 75,670 were used as the analysis cohort (Fig 1). The median length of admission was 12 days (IQR 7, 20 days). Missing data were less than 10% for most variables—although averaging 20% for symptoms on admission—and distributed evenly between groups for those with higher missingness levels (S3 Table).

Discussion

In the largest, multinational cohort of hospitalised patients with COVID-19, it was found that an extended KDIGO criteria for the diagnosis of AKI, which includes a fall in sCr during admission, identified almost twice as many cases of AKI than the traditional KDIGO definition. The majority of these additional cases were stage 1 AKI, occurring early in the admission, supporting the hypothesis that they may represent recovering CA-AKI. This group had comparatively worse outcomes than patients without AKI, making their identification and exploration in future studies enormously important.

Acknowledgments

In the UK, this work used data provided by patients and collected by the NHS as part of their care and support #Data Saves Lives. We are extremely grateful to the 2,648 frontline NHS clinical and research staff and volunteer medical students who collected these data in challenging circumstances and the generosity of the patients and their families for their individual contributions in these difficult times. We also acknowledge the support of Jeremy J Farrar and NahokoShindo; the coordination in Canada by Sunnybrook Research Institute; endorsement of the Irish Critical Care- Clinical Trials Group, coordination in Ireland by the Irish Critical Care-Clinical Trials Network at University College Dublin; the COVID clinical management team, AIIMS, Rishikesh, India; Cambridge NIHR Biomedical Research Centre; the dedication and hard work of the Groote Schuur Hospital Covid ICU Team; support by the Groote Schuur nursing and University of Cape Town registrar bodies coordinated by the Division of Critical Care at the University of Cape Town; the dedication and hard work of the Norwegian SARS-CoV-2 study team; Imperial NIHR Biomedical Research Centre; the Firland Foundation, Shoreline, Washington, USA; and the preparedness work conducted by the Short Period Incidence Study of Severe Acute Respiratory Infection

Citation: Wainstein M, MacDonald S, Fryer D, Young K, Balan V, Begum H, et al. (2022) Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical characterisation protocol. PLoS Med 19(4): e1003969. https://doi.org/10.1371/journal.pmed.1003969

Academic Editor: Giuseppe Remuzzi, Istituto Di RicercheFarmacologiche Mario Negri, ITALY

Received: November 24, 2021; Accepted: March 24, 2022; Published: April 20, 2022

Copyright: © 2022 Wainstein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The data that underpin this analysis are highly detailed clinical data on individuals hospitalised with COVID-19. Due to the sensitive nature of these data and the associated privacy concerns, they are available via a governed data access mechanism following review of a data access committee. Data can be requested via the IDDO COVID-19 Data Sharing Platform (www.iddo.org/covid-19). The Data Access Application, Terms of Access and details of the Data Access Committee are available on the website. Briefly, the requirements for access are a request from a qualified researcher working with a legal entity who have a health and/or research remit; a scientifically valid reason for data access which adheres to appropriate ethical principles. The full terms are at https://www.iddo.org/document/covid-19-data-access-guidelines. A small subset of sites who contributed data to this analysis have not agreed to pooled data sharing as above. In the case of requiring access to these data, please contact the ISARIC team at ncov@isaric.org in the first instance who will look to facilitate access.

Funding: In the UK this work was supported by grants from: the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; grant MC_PC_19059), the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z), Bill & Melinda Gates Foundation (OPP1209135). Internationally this work has been supported by the CIHR Coronavirus Rapid Research Funding Opportunity OV2170359, funding by the Health Research Board of Ireland [CTN-2014-12]; the Rapid European COVID-19 Emergency Response research (RECOVER) [H2020 project 101003589] and European Clinical Research Alliance on Infectious Diseases (ECRAID) [965313], the Research Council of Norway grant no 312780, and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner; Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115523 COMBACTE, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013) and EFPIA companies, in-kind contribution; is sponsored by INSERM and funded by the REACTing (REsearch&ACtionemergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n°20-0424); StiftungsfondszurFörderung der Bekämpfung der Tuberkulose und andererLungenkrankheiten of the City of Vienna, Project Number: APCOV22BGM; Italian Ministry of Health “FondiRicercacorrente–L1P6” to IRCCS OspedaleSacroCuore–Don Calabria; grants from Instituto de Salud Carlos III, Ministerio de Ciencia, Spain; Brazil, National Council for Scientific and Technological Development Scholarship number 303953/2018-7. MW declared funding from the University of Queensland’s Research and Training Scholarship. SM, DF, KY and SS declared funding from Artificial Intelligence for Pandemics (A14PAN) at University of Queensland. SM & SS declared funding from The Australian Research Council Centre of Excellence for Engineered Quantum Systems (EQUS, CE170100009). AN declared funding from The Health Research Board of Ireland. JL reports grants from European Commission RECOVER Grant Agreement No 101003589 and European Commission ECRAID-Base Grant Agreement 965313. JPC declared funding from US Center for Disease Control and Prevention Foundation (site PI, SCCM Discovery-PREP Covid-19 and influenza), Herrick Medical LLC (industry-sponsored RCT of iv tubing modification for air-in-line evacuation, ClinicalTrials.gov NCT04851782. SK declared funding from Wellcome (222410/Z/21/Z). MGS reports grants from National Institute of Health Research UK, Medical Research Council UK, Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. LM declared funding from the University of Oxford’s COVID-19 Research Response Fund. SM declared funding from Canadian Institutes of Health Research. SS declared funding from the University of Queensland Strategic funding and University of Queensland Gender Equity Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All other authors declared no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations:: ACE2, angiotensin converting enzyme 2; ACEi, ACE inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; CA-AKI, community-acquired AKI; CCP, Clinical Characterisation Protocol; CKD, chronic kidney disease; COVID-19, Coronavirus Disease 2019; CRF, case report form; eGFR, estimated glomerular filtration rate; eKDIGO, extended KDIGO; HIC, high income; ICU, intensive care unit; IQR, interquartile range; ISARIC, International Severe Acute Respiratory and Emerging Infection Consortium; ISN, International Society of Nephrology; KDIGO, Kidney Disease Improving Global Outcomes; LLMIC, low and low middle-income countries; LOS, length of stay; MICE, Multiple Imputation by Chained Equations; RAS, renin–angiotensin system; RRT, renal replacement therapy; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; sCr, serum creatinine; STROBE, STrengthening the Reporting of OBservational studies in Epidemiology; UMIC, upper middle income; WHO, World Health Organization

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