The ASSESS-AKI Study found urinary epidermal growth factor is associated with reduced risk of major adverse kidney events

Abstract

Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients. Biomarkers of tubular function such as epidermal growth factor (EGF) may improve prognostication of participants at highest risk for chronic kidney disease (CKD) after hospitalization. To examine this, we measured urinary EGF (uEGF) from samples collected in the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study, a multi-center, prospective, observational cohort of hospitalized participants with and without AKI. Cox proportional hazards regression was used to investigate the association of uEGF/Cr at hospitalization, three months post-discharge, and the change between these time points with major adverse kidney events (MAKE): CKD incidence, progression, or development of kidney failure. Clinical findings were paired with mechanistic studies comparing relative Egf expression in mouse models of kidney atrophy or repair after ischemia-reperfusion injury. MAKE was observed in 20% of 1,509 participants over 4.3 years of follow-up. Each 2-fold higher level of uEGF/Cr at three months was associated with decreased risk of MAKE (adjusted hazards ratio 0.46, 95% confidence interval: 0.39-0.55). Participants with the highest increase in uEGF/Cr from hospitalization to three-month follow-up had a lower risk of MAKE (adjusted hazards ratio 0.52; 95% confidence interval: 0.36-0.74) compared to those with the least change in uEGF/Cr. A model using uEGF/Cr at three months combined with clinical variables yielded moderate discrimination for MAKE (area under the curve 0.73; 95% confidence interval: 0.69-0.77) and strong discrimination for kidney failure at four years (area under the curve 0.96; 95% confidence interval: 0.92-1.00). Accelerated restoration of Egf expression in mice was seen in the model of adaptive repair after injury, compared to a model of progressive atrophy. Thus, urinary EGF/Cr may be a biomarker of distal tubular health, with higher concentrations and increased uEGF/Cr post-discharge independently associated with reduced risk of MAKE in hospitalized patients. Lay SummaryUrinary epidermal growth factor (uEGF) is a protein expressed in the distal nephron, with previous studies demonstrating that higher levels of uEGF normalized to urinary creatinine concentration (uEGF/Cr) associated with lower risk of adverse kidney outcomes after acute kidney injury. In this study, we discovered that among hospitalized adult patients, higher uEGF/Cr measured at hospitalization, higher uEGF/Cr measured at 3-month postdischarge follow-up, and an increase in uEGF/Cr between these time points were all independently associated with lower risk of major adverse kidney events (MAKEs), including chronic kidney disease incidence and progression. In prediction modeling, uEGF/Cr provided moderate discrimination to predict MAKEs and strong discrimination for end-stage kidney disease over time. Urinary epidermal growth factor (uEGF) is a protein expressed in the distal nephron, with previous studies demonstrating that higher levels of uEGF normalized to urinary creatinine concentration (uEGF/Cr) associated with lower risk of adverse kidney outcomes after acute kidney injury. In this study, we discovered that among hospitalized adult patients, higher uEGF/Cr measured at hospitalization, higher uEGF/Cr measured at 3-month postdischarge follow-up, and an increase in uEGF/Cr between these time points were all independently associated with lower risk of major adverse kidney events (MAKEs), including chronic kidney disease incidence and progression. In prediction modeling, uEGF/Cr provided moderate discrimination to predict MAKEs and strong discrimination for end-stage kidney disease over time. Evaluation of long-term health risks after an acute insult or injury remains a significant problem. Several studies have investigated the risk of long-term decline in kidney function, and the development of chronic kidney disease (CKD), after acute kidney injury (AKI).1Chawla L.S. Kimmel P.L. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.Kidney Int. 2012; 82: 516-524Abstract Full Text Full Text PDF PubMed Scopus (621) Google Scholar, 2See E.J. Jayasinghe K. Glassford N. et al.Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure.Kidney Int. 2019; 95: 160-172Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 3Horne K.L. Shardlow A. Taal M.W. et al.Long term outcomes after acute kidney injury: lessons from the ARID study.Nephron. 2015; 131: 102-106Crossref PubMed Scopus (11) Google Scholar However, clinical AKI, a known risk factor for progression to CKD,4Ikizler T.A. Parikh C.R. Himmelfarb J. et al.A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death.Kidney Int. 2021; 99: 456-465Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar relies by definition on serum creatinine concentration (sCr) and urine output, which are both limited with regard to accuracy, timeliness, and precision in determining type and severity of injury.5Delanaye P. Cavalier E. Pottel H. Serum creatinine: not so simple.Nephron. 2017; 136: 302-308Crossref PubMed Scopus (188) Google Scholar Biomarkers of kidney injury, inflammation, and repair have therefore been increasingly investigated toward improving the accuracy and precision in the diagnosis of kidney disease.6Haase M. Kellum J.A. Ronco C. Subclinical AKI--an emerging syndrome with important consequences.Nat Rev Nephrol. 2012; 8: 735-739Crossref PubMed Scopus (177) Google Scholar,7Ronco C. Kellum J.A. Haase M. Subclinical AKI is still AKI.Crit Care. 2012; 16: 313Crossref PubMed Scopus (51) Google Scholar Similarly, biomarkers have been explored for their prognostic potential of short- and long-term adverse kidney outcomes in an episode of AKI.8Menez S. Moledina D.G. Garg A.X. et al.Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac Int. 2021; 99: Full Text Full Text PDF PubMed Scopus Google Scholar, S. et EGF and and risk of CKD after cardiac 2021; Google Scholar, S. Moledina D.G. H. et of urinary biomarkers in hospitalized with Kidney Full Text Full Text PDF PubMed Scopus Google Scholar, et as prognostic for kidney disease and failure events after acute kidney Nephrol. PubMed Scopus Google Scholar, M. H. et from AKI and prediction of long-term in Kidney Full Text Full Text PDF PubMed Scopus Google Scholar, J. 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To is the study to that in uEGF/Cr from hospitalization to a postdischarge time are associated with long-term adverse kidney EGF is a that as a growth factor in repair after for epidermal growth factor in the Kidney Full Text PDF PubMed Scopus Google Scholar have that EGF is expressed in of the distal and that is EGF expression in the of AKI compared with S. et EGF and and risk of CKD after cardiac 2021; Google Scholar study this for Egf expression after AKI, with expression in the and distal at a in a repair model of compared with atrophy reduced uEGF/Cr levels an AKI may distal tubular injury in the with in uEGF/Cr at postdischarge follow-up of adaptive or of change in uEGF/Cr postdischarge may repair or injury, at higher risk for long-term adverse kidney for uEGF/Cr levels or from the time of hospitalization to postdischarge follow-up follow-up with a higher of kidney function be a from in a clinical the study AKI are not for follow-up, and among those seen in postdischarge follow-up, long-term kidney outcomes is consensus to which the follow-up. associations of uEGF/Cr with MAKEs at time points and after hospitalization, and the of uEGF/Cr from hospitalization to follow-up, this as a potential prognostic model discrimination for the of MAKEs was with uEGF/Cr combined models of clinical variables uEGF/Cr and biomarkers measured at months for the of models of clinical variables and uEGF/Cr without of is to these findings to uEGF/Cr as a strong of after hospitalization, after which such a model may be used for in clinical or of to follow-up. in this study, we that the associations of uEGF/Cr with MAKEs are of and development of clinical AKI. with in biomarkers of kidney injury without associated in the of with M. Kellum J.A. Ronco C. Subclinical AKI--an emerging syndrome with important consequences.Nat Rev Nephrol. 2012; 8: 735-739Crossref PubMed Scopus (177) Google Scholar have been to be at risk for adverse kidney outcomes compared with without in biomarker of S. Moledina D.G. Garg A.X. et al.Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac Int. 2021; 99: Full Text Full Text PDF PubMed Scopus Google J. H. et of and repair in kidney disease 2021; PubMed Scopus Google Scholar with lower uEGF/Cr measured at time hospitalization or in the postdischarge of clinical AKI may have distal tubular function with repair and be at higher risk for adverse study previous studies uEGF/Cr with long-term kidney outcomes in clinical the was to as a of AKI in hospitalized patients. the of this study the of uEGF/Cr as a biomarker of CKD progression measured both in the and after study important this study with AKI in a hospitalized the of AKI was not by AKI CKD was by not which may have a of from the CKD for in including cardiovascular and hospitalization, not for such as and were not to as of this study, as with study such as in the Acute Kidney Injury in Study, not have samples collected K.L. Shardlow A. Taal M.W. et al.Long term outcomes after acute kidney injury: lessons from the ARID study.Nephron. 2015; 131: 102-106Crossref PubMed Scopus (11) Google Scholar a be of uEGF/Cr clinical which is the of this we were to clinical findings with and in a model of we were not to clinical to kidney for mechanistic as paired in clinical and after an episode of AKI are However, we have explored from in the Kidney a significant in EGF expression at the time of S. et EGF and and risk of CKD after cardiac 2021; Google Scholar In higher uEGF/Cr levels measured after and hospitalization are associated with lower risk of as is the change in uEGF/Cr between these time findings uEGF/Cr as a of distal tubular with for long-term kidney and as of the of and in and are on a and for of Acute from and in the from for and of Kidney the A be the of and and Kidney at to all of the Assessment, Serial Evaluation, and Subsequent Sequelae Acute Kidney Injury (ASSESS-AKI) Study and for this study Study was by from the of and and Kidney and from of and expressed in this are not those of the the the of and and the of the from the of and and Kidney and from from of and from from from and

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