A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death

Abstract

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes. Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes. Acute kidney injury (AKI) reflects an abrupt decline in kidney function that occurs frequently among hospitalized adults and has been reported to be associated with excess risks of death, kidney disease progression, and cardiovascular events.1Mehta R. Pascual M. Soroko S. et al.Spectrum of acute renal failure in the intensive care unit: the PICARD experience.Kidney Int. 2004; 66: 1613-1621Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar, 2Palevsky P.M. Zhang J.H. O'Connor T.Z. et al.Intensity of renal support in critically ill patients with acute kidney injury.N Engl J Med. 2008; 359: 7-20Crossref PubMed Scopus (1442) Google Scholar, 3Bellomo R. Cass A. Cole L. et al.Intensity of continuous renal-replacement therapy in critically ill patients.N Engl J Med. 2009; 361: 1627-1638Crossref PubMed Scopus (1184) Google Scholar, 4Chawla L.S. Amdur R.L. Shaw A.D. et al.Association between AKI and long-term renal and cardiovascular outcomes in United States veterans.Clin J Am Soc Nephrol. 2014; 9: 448-456Crossref PubMed Scopus (260) Google Scholar, 5James M.T. Ghali W.A. Knudtson M.L. et al.Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography.Circulation. 2011; 123: 409-416Crossref PubMed Scopus (305) Google Scholar, 6Forman D.E. Butler J. Wang Y. et al.Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure.J Am Coll Cardiol. 2004; 43: 61-67Crossref PubMed Scopus (791) Google Scholar, 7Go A.S. Hsu C.Y. Yang J. et al.Acute kidney injury and risk of heart failure and atherosclerotic events.Clin J Am Soc Nephrol. 2018; 13: 833-841Crossref PubMed Scopus (103) Google Scholar, 8Chalikias G. Serif L. Kikas P. et al.Long-term impact of acute kidney injury on prognosis in patients with acute myocardial infarction.Int J Cardiol. 2019; 283: 48-54Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The potential importance of AKI has been further highlighted during the coronavirus disease 2019 pandemic.9Batlle D. Soler M.J. Sparks M.A. et al.Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology.J Am Soc Nephrol. 2020; 31: 1380-1383Crossref PubMed Scopus (413) Google Scholar However, there are important limitations of many existing studies examining clinical complications after AKI. These include primarily retrospective designs that are susceptible to multiple biases, lack of systematic assessment of kidney function before and after the AKI episode, use of varying definitions of AKI, lack of adjudication of potential cardiovascular events, and inclusion of study populations with limited demographic diversity. In addition, hospitalized patients, who may be at increased risk for these events, are not always compared with similar hospitalized patients without AKI. Furthermore, the limited number of existing prospective studies have primarily focused on selected populations (e.g., coronary angiography,10James M.T. Samuel S.M. Manning M.A. et al.Contrast-induced acute kidney injury and risk of adverse clinical outcomes after coronary angiography: a systematic review and meta-analysis.Circ Cardiovasc Interv. 2013; 6: 37-43Crossref PubMed Scopus (233) Google Scholar cardiac surgery,11Hansen M.K. Gammelager H. Jacobsen C.J. et al.Acute kidney injury and long-term risk of cardiovascular events after cardiac surgery: a population-based cohort study.J Cardiothorac Vasc Anesth. 2015; 29: 617-625Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 12Hansen M.K. Gammelager H. Mikkelsen M.M. et al.Post-operative acute kidney injury and five-year risk of death, myocardial infarction, and stroke among elective cardiac surgical patients: a cohort study.Crit Care. 2013; 17: R292Crossref PubMed Scopus (78) Google Scholar, 13Olsson D. Sartipy U. Braunschweig F. et al.Acute kidney injury following coronary artery bypass surgery and long-term risk of heart failure.Circ Heart Fail. 2013; 6: 83-90Crossref PubMed Scopus (68) Google Scholar or myocardial infarction14Parikh C.R. Coca S.G. Wang Y. et al.Long-term prognosis of acute kidney injury after acute myocardial infarction.Arch Intern Med. 2008; 168: 987-995Crossref PubMed Scopus (276) Google Scholar) and have not examined heart failure separately with atherosclerotic cardiovascular events. Given the global burden of AKI and the need for additional evidence-based clinical guidance, we addressed these issues by prospectively examining the associations among AKI with subsequent kidney-related consequences, heart failure, major atherosclerotic cardiovascular events (MACE), and death among matched adults surviving a hospitalization with or without AKI. We hypothesized AKI would be independently associated with higher risks of each of these events in the presence or absence of preexisting chronic kidney disease (CKD). We enrolled and individually matched 769 adults with AKI and 769 adults without AKI, with 39.8% having preexisting CKD (Supplementary Appendix S1 and Figure 1). The distribution of matched pairs enrolled by center was 156 (20.3%) from Kaiser Permanente Northern California, 251 (32.6%) from Vanderbilt University, 154 (20.0%) from the Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury (TRIBE-AKI) Consortium, and 208 (27.1%) from the University of Washington. Among participants with AKI, 561 (73%), 111 (14%), and 97 (13%) had stages 1, 2, and 3 AKI, respectively, with only 26 (1.7%) of participants with AKI who were receiving acute renal replacement therapy. Furthermore, 48% of AKI episodes were of brief duration, 22% were of medium duration, 12% were of long duration, and 18% were of very long duration. Regardless of CKD status, compared with participants classified as non-AKI, those with AKI were modestly younger, had slightly lower preadmission estimated glomerular filtration rate (eGFR), and were more likely to have prior cardiovascular disease, have diabetes, receive care in an intensive care unit, be diagnosed with sepsis during the index hospitalization, and have higher baseline study visit levels of plasma cystatin C and proteinuria. In contrast, there were no significant differences in Hispanic ethnicity, smoking status, or baseline study visit measures of body mass index or systolic or diastolic blood pressure (Table 1). Among participants without preexisting the of was lower in those with AKI, there was no significant in In participants with preexisting there was no significant in between those with AKI were likely to be (Table of adults with and without AKI, by the presence or absence of CKD at study preexisting AKI AKI cardiovascular diabetes in during index during index baseline mass blood blood cystatin acute kidney chronic kidney glomerular filtration intensive care are or in a AKI, acute kidney chronic kidney glomerular filtration intensive care are or follow-up was with follow-up of in participants with AKI and in participants classified as participants with AKI and who were non-AKI from the CKD was in participants with AKI compared with in matched adults who were non-AKI In participants with preexisting the rate of those CKD progression was in participants with AKI compared with in matched participants who were non-AKI In multivariable analysis among matched participants without preexisting AKI was associated with a higher adjusted rate of incident CKD 1, for additional demographic sepsis during the index and diabetes status, and body mass index at the baseline visit the (adjusted hazard ratio 95% confidence interval 2, AKI was associated with a higher adjusted rate of CKD progression in matched participants 1, and the with CKD progression increased after for additional potential (adjusted 95% 2, incident and there was a significant for with more and longer AKI in multivariable (Supplementary and In a analysis among participants with AKI and those who were non-AKI matched on each were similar to the (Supplementary Appendix of AKI with of incident CKD and progression of of AKI no AKI on kidney clinical center, age, estimated glomerular filtration diabetes status, prior cardiovascular disease, and intensive care unit during index sepsis during index baseline visit smoking status, diabetes status, and body mass acute kidney confidence chronic kidney hazard clinical center, age, estimated glomerular filtration diabetes status, prior cardiovascular disease, and intensive care unit during index in a AKI, acute kidney confidence chronic kidney hazard Among matched participants without prior the of hospitalization for heart failure was higher in those with in those without AKI The was similar in those with preexisting with a higher in those with in those without AKI In multivariable analysis among matched AKI was associated with a higher adjusted rate of heart failure events 1, 3) that was attenuated after additional for potential (adjusted 95% 2, However, further for cystatin and proteinuria at the baseline visit attenuated the of AKI with subsequent heart failure hospitalization that was no longer significant The of was in those with in those without preexisting the with multivariable were similar (Table of AKI with subsequent heart failure, and death, and by preexisting of AKI no from preexisting preexisting preexisting clinical center, age, estimated glomerular filtration diabetes status, prior cardiovascular disease, and intensive care unit during index sepsis during index admission, baseline visit smoking status, diabetes status, and body mass baseline visit estimated glomerular filtration plasma cystatin and acute kidney confidence chronic kidney hazard major atherosclerotic cardiovascular clinical center, age, estimated glomerular filtration diabetes status, prior cardiovascular disease, and intensive care unit during index in a AKI, acute kidney confidence chronic kidney hazard major atherosclerotic cardiovascular In addition, after accounting for and potential there was a significant of more AKI with heart failure hospitalization in those without preexisting CKD for not in those with preexisting CKD for The in those without preexisting CKD was attenuated and no longer significant after further for baseline visit measures of kidney function and proteinuria (Supplementary Appendix AKI was associated with higher adjusted rate of heart failure hospitalization in a adjusted (Supplementary Appendix In a analysis of matched participants with AKI and without AKI, were similar to the analysis that there a higher adjusted risk of heart failure events associated with AKI and no preexisting after accounting for measures of kidney function and proteinuria (Supplementary Appendix In those without the of was in participants with AKI compared with in matched participants classified as non-AKI was no significant in between those with CKD with AKI and those without AKI were in multivariable (Table was no significant between AKI and (Supplementary Appendix were similar to the analysis in a analysis among the of and were matched on (Supplementary Appendix was higher in those with in those without AKI and in the presence or absence of preexisting CKD After accounting for and additional AKI was associated with a higher rate of death 2, 3) that was attenuated and no longer significant after further accounting for degree of renal recovery and proteinuria status at 3 months were similar in adjusted of the presence of preexisting CKD (Table was a significant of more AKI with excess that was attenuated and no longer significant after for kidney function and longer AKI was independently associated with higher (Supplementary and In in the of and were matched on were similar to the that AKI was independently associated with a higher rate of death in those with preexisting CKD after additional for kidney function and proteinuria (Supplementary Appendix In a prospective cohort of matched AKI was independently associated with higher subsequent risks of incident CKD and In the matched AKI was associated with excess risks of heart failure hospitalization and all-cause of the presence or absence of preexisting these associations were attenuated and no longer significant after accounting for kidney function and proteinuria 3 months after In adjusted by preexisting CKD status, we that AKI associated with an excess risk of heart failure events in patients without preexisting there was a higher risk of all-cause death in those with preexisting However, AKI was not associated with or in those with or without preexisting The and of Acute Kidney Injury study as the prospective cohort study of a of matched adults who months after to examine the of AKI with kidney and cardiovascular events a long follow-up as an that in the of AKI additional of compared with previous studies are the of a hospitalization to before and of a study visit as The hospitalization to AKI and with clinical for Acute Kidney Full Text Full Text PDF Scopus Google Scholar The systematic of plasma cystatin and proteinuria at 3 months was as we that the associations of AKI with excess risks of heart failure and death were attenuated after accounting for kidney function and has significant clinical of kidney function and proteinuria 3 months after discharge, be through would important long-term prognostic study had additional the prospective and among a matched cohort that many that retrospective We had long-term follow-up of kidney function and and of heart failure events and cohort a of patients from intensive care unit and hospitalized study has limitations. was not on the presence and of proteinuria before the index hospitalization. were on preadmission as as of the AKI episode, although we there no to the of H. et of of acute kidney from the Nephrol. 2014; PubMed Scopus Google Scholar on preadmission blood pressure was Given cohort was based in clinical centers and with patients cardiac surgery or in an may not to hospitalized patients, or an we between an of AKI and subsequent clinical as we or The of of AKI in with the number of patients sepsis or cardiovascular heart C.Y. the in kidney Am Soc Nephrol. PubMed Scopus Google P. A. et disease and stroke a from the Heart 2019; PubMed Scopus Google Scholar that AKI, may to long-term adverse outcomes have important D.E. Butler J. Wang Y. et al.Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure.J Am Coll Cardiol. 2004; 43: 61-67Crossref PubMed Scopus (791) Google et of renal and impact on in patients hospitalized with acute heart a from the Fail. 13: Full Text Full Text PDF PubMed Scopus Google et for in heart and PubMed Scopus Google Scholar previous studies have examined the of AKI on kidney and cardiac complications in hospitalized patients, many from limitations. studies were retrospective in with biases, and only on to AKI status preadmission and study on a prospective study of adults cardiac surgery that that AKI was associated with a higher adjusted rate of the of death or hospitalization for acute coronary heart failure, or of coronary C.R. J. et of kidney injury with long-term cardiovascular outcomes after cardiac Am Soc Nephrol. PubMed Scopus Google Scholar by AKI and progression of as as excess heart failure are not L.S. et al.Acute kidney injury and chronic kidney disease as Engl J Med. 2014; PubMed Scopus Google Scholar AKI associated with increased levels of et al.Acute renal failure after associated with Am Soc Nephrol. PubMed Scopus Google Scholar D. et analysis of during from AKI for and as of J PubMed Scopus Google Scholar in M. et levels after acute kidney Int. 2013; Full Text Full Text PDF PubMed Scopus Google D.E. M. et in patients with acute kidney injury and risk of adverse 2013; PubMed Scopus Google Scholar and myocardial D. A. et in acute kidney Fail. PubMed Scopus Google Scholar risk among AKI, and cardiovascular disease (e.g., age, diabetes, and lack of studies have a between AKI and adverse L.S. et al.Acute kidney injury and chronic kidney disease as Engl J Med. 2014; PubMed Scopus Google Scholar potential that the kidney a in and subsequent status and blood pressure injury during AKI, in to that to during L.S. et al.Acute kidney injury and chronic kidney disease as Engl J Med. 2014; PubMed Scopus Google D. et injury in to and long-term J PubMed Scopus Google Scholar, D. et on long-term function of and following renal J PubMed Scopus Google Scholar, H. et from renal injury associated with renal pressure and J 2009; PubMed Scopus Google Scholar in in on may to a of AKI heart failure, and In we that AKI independently associated with higher rates of incident and as as subsequent heart failure events and death among of a hospitalization. However, after accounting for degree of renal recovery and proteinuria status 3 months after discharge, the associations of AKI with heart failure and death were not significant. and longer AKI may be associated with clinical outcomes. study provides to support of kidney function recovery and proteinuria 3 months after an of AKI to prognostic information that may clinical Furthermore, evidence to to AKI or in the of AKI the risks of adverse renal and cardiovascular L.S. et al.Acute kidney injury and chronic kidney disease as Engl J Med. 2014; PubMed Scopus Google Scholar The by the of and Kidney of the of a matched cohort study of hospitalized who or not an of AKI and to an baseline study visit 3 months after of the and have been A.S. C.R. et and subsequent of acute kidney injury and Nephrol. 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C.R. et and subsequent of acute kidney injury and Nephrol. PubMed Scopus Google Scholar and Appendix the inclusion to and having a baseline before to acute multiple or significant heart death, receiving chronic or before the baseline or enrolled in an study at the baseline study or of months of by a study The study was in a clinical All the study participants were the study participants the were in the of study and or assessment of the to in the The study was by review of the and was from of the study be with study the baseline we information on and complications during the index and and and A.S. C.R. et and subsequent of acute kidney injury and Nephrol. PubMed Scopus Google Scholar In addition, blood and heart rate were A.S. C.R. et and subsequent of acute kidney injury and Nephrol. PubMed Scopus Google Scholar for and plasma were a proteinuria and was follow-up visit was months after the index hospitalization and annually of with at A.S. 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