Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery

Abstract

Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort –TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m2, we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m2, we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro–B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery. Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort –TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m2, we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m2, we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro–B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery. More than 1 million cardiac surgeries are performed annually worldwide.1Rosner M.H. Okusa M.D. Acute kidney injury associated with cardiac surgery.Clin J Am Soc Nephrol. 2006; 1: 19-32Crossref PubMed Scopus (755) Google Scholar,2Vervoort D. Meuris B. Meyns B. et al.Global cardiac surgery: access to cardiac surgical care around the world.J Thorac Cardiovasc Surg. 2020; 159: 987-996Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Patients receiving cardiac surgery undergo intense physiological stress and are at increased risk of adverse outcomes. Acute kidney injury (AKI) is a frequent complication after cardiac surgery, affecting up to 30% of patients.1Rosner M.H. Okusa M.D. Acute kidney injury associated with cardiac surgery.Clin J Am Soc Nephrol. 2006; 1: 19-32Crossref PubMed Scopus (755) Google Scholar It is well known that AKI is associated with an increased risk of all-cause mortality as well as adverse cardiovascular outcomes after cardiac surgery.3Coca S.G. Yusuf B. Shlipak M.G. et al.Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis.Am J Kidney Dis. 2009; 53: 961-973Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, 4Coca S.G. Garg A.X. Thiessen-Philbrook H. et al.Urinary biomarkers of AKI and mortality 3 years after cardiac surgery.J Am Soc Nephrol. 2014; 25: 1063-1071Crossref PubMed Scopus (100) Google Scholar, 5Parikh C.R. Puthumana J. Shlipak M.G. et al.Relationship of kidney injury biomarkers with long-term cardiovascular outcomes after cardiac surgery.J Am Soc Nephrol. 2017; 28: 3699-3707Crossref PubMed Scopus (34) Google Scholar AKI has also been increasingly recognized as a major risk factor for chronic kidney disease (CKD).6Chawla 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 (495) Google Scholar Notably, however, only a fraction of patients who develop AKI progress to CKD whereas some patients who do not develop AKI subsequently develop CKD.6Chawla 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 (495) Google Scholar It remains unclear how to identify patients at the highest risk of CKD after surgery. The use of serum creatinine–based definitions of AKI has a number of important limitations when evaluating a long-term outcome such as CKD, particularly in the inpatient setting. Acute changes in serum creatinine may not accurately reflect the severity or nature of kidney injury because of the influence of factors such as age, sex, muscle mass, nutritional status, medication effects on creatinine kinetics, i.v. fluid administration, and hemodynamic changes with subsequent oxygen supply-demand mismatch.7Bullen A. Liu Z.Z. Hepokoski M. et al.Renal oxygenation and hemodynamics in kidney injury.Nephron. 2017; 137: 260-263Crossref PubMed Scopus (12) Google Scholar Therefore, serum creatinine measured in the hospital setting can vary significantly and unpredictably. Furthermore, elevations in serum creatinine are known to occur 48 to 72 hours after the episode of kidney injury.8Parikh C.R. Mishra J. Thiessen-Philbrook H. et al.Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.Kidney Int. 2006; 70: 199-203Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar Previous research has demonstrated that patients with subclinical AKI, namely, those without AKI by serum creatinine but with elevated levels of kidney injury biomarkers, show clear structural kidney injury on histology.9Moledina D.G. Hall I.E. Thiessen-Philbrook H. et al.Performance of serum creatinine and kidney injury biomarkers for diagnosing histologic acute tubular injury.Am J Kidney Dis. 2017; 70: 807-816Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Patients with subclinical AKI have higher long-term morbidity and mortality risk than do individuals with biomarker levels in the normal range.4Coca S.G. Garg A.X. Thiessen-Philbrook H. et al.Urinary biomarkers of AKI and mortality 3 years after cardiac surgery.J Am Soc Nephrol. 2014; 25: 1063-1071Crossref PubMed Scopus (100) Google Scholar,10Haase M. Kellum J.A. Ronco C. Subclinical AKI—an emerging syndrome with important consequences.Nat Rev Nephrol. 2012; 8: 735-739Crossref PubMed Scopus (135) Google Scholar A number of blood and urine biomarkers reflecting hemodynamic and cardiac function, as well as markers for structural injury, inflammation, and repair, have been investigated previously with long-term cardiovascular outcomes and mortality.5Parikh C.R. Puthumana J. Shlipak M.G. et al.Relationship of kidney injury biomarkers with long-term cardiovascular outcomes after cardiac surgery.J Am Soc Nephrol. 2017; 28: 3699-3707Crossref PubMed Scopus (34) Google Scholar To our knowledge, no studies have investigated the relationship between blood and urine biomarkers of injury, inflammation, or repair with CKD independent of serum creatinine in the setting of cardiac surgery. Therefore, in this study, we aimed to examine the independent associations of biomarkers specific for structural injury, inflammation, and repair with long-term CKD in patients after either coronary artery bypass grafting or valvular cardiac surgery. We hypothesized that kidney injury and repair biomarkers would be associated with either incident CKD in patients with estimated glomerular filtration rate (eGFR) ≥60 ml/min per 1.73 m2 or progression of CKD in patients with GFR <60 ml/min per 1.73 m2 whereas cardiac biomarkers would not have any significant independent associations with the primary outcome. After excluding 127 participants with missing data follow-up or to to follow-up data the of 613 patients in the primary cohort were no significant in baseline in those with without follow-up serum creatinine 1 the baseline of participants by composite primary outcome in the primary et of and the of surgery of definitions and Thorac Surg. Full Text Full Text PDF PubMed Scopus Google Scholar The of patients at the of surgery was years, and patients were The baseline eGFR was ml/min per 1.73 and there were no significant in baseline eGFR between participants who developed the primary outcome and those who there were no significant in baseline and or in surgery and demographic of the primary primary outcome primary outcome at the of surgery, fraction ml/min per 1.73 ml/min per 1.73 m2 creatinine, et of and the of surgery of definitions and Thorac Surg. Full Text Full Text PDF PubMed Scopus Google or or serum creatinine acute kidney Acute Kidney Injury coronary artery bypass CKD, chronic kidney estimated glomerular filtration of are as and for the continuous and that be because of primary outcome was a composite of CKD incidence or CKD incidence eGFR ≥60 ml/min per 1.73 25% reduction in eGFR and a 60 ml/min per 1.73 CKD progression eGFR <60 ml/min per 1.73 50% reduction in eGFR or a ml/min per 1.73 in a AKI, acute kidney Acute Kidney Injury coronary artery bypass CKD, chronic kidney estimated glomerular filtration of are as and for the continuous and that be because of The primary outcome was a composite of CKD incidence or CKD incidence eGFR ≥60 ml/min per 1.73 25% reduction in eGFR and a 60 ml/min per 1.73 CKD progression eGFR <60 ml/min per 1.73 50% reduction in eGFR or a ml/min per 1.73 Over a median follow-up of 5.6 years 172 patients developed the primary outcome of CKD incidence or progression at a rate of per on the of at 1 follow-up serum creatinine We noted a higher rate of the primary outcome in patients with AKI from patients without AKI the primary outcome to patients with or 3 AKI the primary outcome the 172 patients who developed the primary patients at serum creatinine follow-up In a median of serum creatinine were measured per over the of with those who developed AKI or 3 follow-up creatinine blood and urine biomarkers were for the association with the primary outcome. In after log higher of blood basic fibroblast growth factor kidney injury N-terminal pro–B-type natriuretic peptide tumor necrosis factor receptor 1 growth factor receptor and were significantly associated with the primary outcome After adjustment for age, sex, AKI serum creatinine, and serum creatinine, the levels of biomarkers and significantly associated with an increased risk of the CKD incidence or progression was associated with an increased risk of CKD incidence or progression that was (adjusted hazard confidence The association of biomarkers with the primary outcome was evaluated by with the as the In analysis, only participants in the highest of a significantly higher risk of the primary outcome than those in the confidence for biomarker levels for and but with confidence such that no of CKD incidence or progression by biomarker biomarkers log basic fibroblast growth confidence CKD, chronic kidney hazard kidney injury N-terminal pro–B-type natriuretic tumor necrosis factor receptor growth factor receptor for age, sex, acute chronic injury serum creatinine, and serum in a basic fibroblast growth confidence CKD, chronic kidney hazard kidney injury N-terminal pro–B-type natriuretic tumor necrosis factor receptor growth factor receptor for age, sex, acute chronic injury serum creatinine, and serum the baseline of the replication on the of data from the in the in Acute Kidney Injury cohort. Over a median follow-up of years 60 patients developed the primary outcome of CKD incidence or progression at a rate of per on the of at 1 follow-up serum creatinine In to and we evaluated the associations between and our primary outcome in the replication association with kidney injury from and the of association to other Similar to the primary higher blood levels of and significantly associated with the primary kidney outcome after adjustment in the replication cohort in were not significantly associated with an increased risk of CKD incidence or progression confidence Patients in the of 3 biomarkers a significantly higher risk than those in the In a of after log the hazard for biomarkers were significantly associated with our primary outcome were a of in the primary cohort and in the replication cohort. We performed a risk analysis of in the primary cohort. was no significant in the primary outcome after for risk of the and We performed interaction to the of clinical was no significant interaction between the biomarker and our primary outcome by AKI in continuous in analysis, patients without clinical AKI in the highest of and or higher of the primary outcome than patients with clinical AKI in the We evaluated for interaction by CKD and not any significant in outcome for any of the biomarkers Notably, the analysis of confidence the interaction value was not as a of for this we by the for with biomarker to a with clinical In analysis, we the association between the biomarker and the biomarker with CKD incidence or progression. We results to our primary analysis biomarker In this prospective cohort study of undergoing cardiac surgery, we evaluated 40 blood and urine biomarkers and that elevated levels of blood and were independently associated with an increased risk of CKD incidence or progression of AKI after surgery. It is well that patients who develop AKI are at a higher risk of long-term adverse outcomes mortality and cardiovascular disease than those who do 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 (495) Google S.G. and after acute kidney injury: the to Int. 2017; Full Text Full Text PDF PubMed Scopus Google et al.Long-term risk of adverse outcomes after acute kidney injury: a systematic review and of cohort studies definitions of Int. Full Text Full Text PDF PubMed Scopus Google Scholar In years, studies have evaluated the risk of cardiovascular outcomes after subclinical AKI, with elevated levels of kidney injury or repair biomarkers in the setting of normal serum D.G. Hall I.E. Thiessen-Philbrook H. et al.Performance of serum creatinine and kidney injury biomarkers for diagnosing histologic acute tubular injury.Am J Kidney Dis. 2017; 70: 807-816Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar,10Haase M. Kellum J.A. Ronco C. Subclinical AKI—an emerging syndrome with important consequences.Nat Rev Nephrol. 2012; 8: 735-739Crossref PubMed Scopus (135) Google Scholar in biomarkers of injury, inflammation, and repair have been associated with the long-term risk of mortality and cardiovascular S.G. Yusuf B. Shlipak M.G. et al.Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis.Am J Kidney Dis. 2009; 53: 961-973Abstract Full Text Full Text PDF PubMed Scopus (727) Google C.R. Puthumana J. Shlipak M.G. et al.Relationship of kidney injury biomarkers with long-term cardiovascular outcomes after cardiac surgery.J Am Soc Nephrol. 2017; 28: 3699-3707Crossref PubMed Scopus (34) Google C.R. S.G. Thiessen-Philbrook H. et biomarkers acute kidney injury and outcomes after adult cardiac surgery.J Am Soc Nephrol. PubMed Scopus Google Garg A.X. S.G. et and AKI and long-term mortality in after cardiac surgery.J Am Soc Nephrol. 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The results of this research may have in follow-up care after hospital Patients at a higher risk of CKD incidence or progression be with on other known risk factors for CKD. Furthermore, patients a of individuals with a known risk of CKD and be in clinical to to or CKD. study has a number of the use of with follow-up after from surgery, we were to from the primary cohort. 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S.G. Thiessen-Philbrook H. et biomarkers acute kidney injury and outcomes after adult cardiac surgery.J Am Soc Nephrol. PubMed Scopus Google Scholar The study was by the review of and was from undergoing cardiac surgery, either coronary artery bypass grafting or valvular surgery, at a risk of AKI were between and C.R. S.G. Thiessen-Philbrook H. et biomarkers acute kidney injury and outcomes after adult cardiac surgery.J Am Soc Nephrol. PubMed Scopus Google S.G. D. et association of markers with acute kidney injury and mortality after cardiac J Kidney Dis. Full Text Full Text PDF PubMed Scopus Google Scholar from the in Canada were for our primary analysis, the and of data to other Patients in the who to with data for long-term follow-up and at 1 follow-up serum creatinine after were in the primary cohort. cohort follow-up of patients because of care from 1 was with data for of and have been C.R. S.G. Thiessen-Philbrook H. et biomarkers acute kidney injury and outcomes after adult cardiac surgery.J Am Soc Nephrol. PubMed Scopus Google Scholar and blood were and for up to after cardiac surgery. urine and blood were hours of the of the surgery. Blood were in to and subsequently at urine biomarkers and blood biomarkers were measured as previously C.R. S.G. Thiessen-Philbrook H. et biomarkers acute kidney injury and outcomes after adult cardiac surgery.J Am Soc Nephrol. PubMed Scopus Google S.G. D. et association of markers with acute kidney injury and mortality after cardiac J Kidney Dis. Full Text Full Text PDF PubMed Scopus Google Scholar, Garg A.X. Shlipak M.G. et al.Urinary and acute kidney injury after cardiac J Kidney Dis. Full Text Full Text PDF PubMed Scopus Google Scholar, D.G. et is associated with acute kidney injury and after cardiac Thorac Surg. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar for the study use the biomarker to biomarkers that were in subsequent In the primary AKI was not for 1 for and serum creatinine for AKI was defined as an increase of or in serum creatinine the with serum creatinine as serum creatinine were measured surgery. creatinine were clinical care for the eGFR was estimated the Kidney et to glomerular filtration 2009; PubMed Scopus Google Scholar The severity of AKI was the Acute Kidney Injury on the of the serum creatinine the Kellum J.A. et Kidney Injury of an to outcomes in acute kidney PubMed Scopus Google Scholar The of risk were on the of and demographic surgical and on et of and the of surgery of definitions and Thorac Surg. Full Text Full Text PDF PubMed Scopus Google Scholar The primary outcome of the study was a composite of CKD incidence or progression. In those individuals with eGFR ≥60 ml/min per 1.73 m2 CKD incidence was defined as a 25% reduction in eGFR and a 60 ml/min per 1.73 In those individuals with eGFR <60 ml/min per 1.73 m2 CKD progression was defined as a 50% reduction in eGFR or a ml/min per 1.73 These definitions were on as by the and of Acute Kidney Injury C.R. et and of Acute Kidney Injury and Nephrol. 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Thiessen-Philbrook H. et in may to in the development of biomarker for acute kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar We estimated hazard the and hazard for the risk of We performed additional analysis evaluating the interaction between AKI and our primary outcome as well as between CKD and our primary outcome. 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