Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery
Authors: Steven Menez, Dennis G. Moledina, Amit X. Garg, Heather Thiessen-Philbrook, Eric McArthur, Yaqi Jia, Caroline Liu, Wassim Obeid, Sherry G. Mansour, Jay L. Koyner, Michael G. Shlipak, Francis P. Wilson, Steven G. Coca, Chirag R. Parikh
Journal: Kidney International (2020)

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 during follow-up or unable to link to follow-up data (17.2%), the analytical population consisted of 613 patients in the primary cohort (Figure 1). There were no significant differences in baseline characteristics in those with versus without follow-up serum creatinine values available (Supplementary Table S1). Table 1 outlines the baseline characteristics of participants by composite primary outcome in the primary cohort.11Fernandez F.G. Falcoz P.E. Kozower B.D. et al.The Society of Thoracic Surgeons and the European Society of Thoracic Surgeons general thoracic surgery databases: joint standardization of variable definitions and terminology.Ann Thorac Surg. 2015; 99: 368-376Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar The mean age of patients at the time of surgery was 71.0 ± 8.8 years, and 168 patients (27%) were female. The mean baseline eGFR was 71.0 ± 18.2 ml/min per 1.73 m2, and there were no significant differences in baseline eGFR between participants who developed the primary outcome and those who did not. Similarly, there were no significant differences in baseline hypertension, congestive heart failure, and prior myocardial infarction or differences in surgery type and indication.Table 1Baseline demographic characteristics of the primary cohortVariableAll (N = 613)No primary outcome (n = 441)Developed primary outcome (n = 172)PAge at the time of surgery, yr70.97 ± 8.8470.68 ± 9.1471.70 ± 8.010.20Sex, female168 (27.4)113 (25.6)55 (32.0)0.11Race, White589 (96.1)427 (96.8)162 (94.2)0.13Diabetes256 (41.8)173 (39.2)83 (48.3)0.03Hypertension484 (79.0)345 (78.2)139 (80.8)0.20Congestive heart failure62 (10.1)40 (9.1)22 (12.8)0.11Left ventricular ejection fraction <40%48 (7.8)29 (6.6)19 (11.0)0.048Previous myocardial infarction173 (28.2)123 (27.9)50 (29.1)0.26eGFR, ml/min per 1.73 m271.00 ± 18.2370.79 ± 19.3271.55 ± 15.120.64eGFR, ml/min per 1.73 m2 >60447 (72.9)301 (68.3)146 (84.9)<0.001 <60165 (26.9)140 (31.7)25 (14.4)Serum creatinine, mg/dl1.03 ± 0.311.04 ± 0.311.01 ± 0.320.25Urine microalbumin, preoperative, >30 mg/g365 (59.5)248 (56.2)117 (68.0)0.027STS score11Fernandez F.G. Falcoz P.E. Kozower B.D. et al.The Society of Thoracic Surgeons and the European Society of Thoracic Surgeons general thoracic surgery databases: joint standardization of variable definitions and terminology.Ann Thorac Surg. 2015; 99: 368-376Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar9.08 ± 3.498.99 ± 3.529.33 ± 3.400.27Elective surgery561 (91.5)404 (91.6)157 (91.3)0.28Isolated CABG or valve surgery480 (78.3)347 (78.7)133 (77.3)0.75Off-pump69 (11.3)53 (12.0)16 (9.3)0.20Reoperation6 (1.0)———Perfusion time, min107.12 ± 57.93106.93 ± 57.57107.63 ± 59.020.89Cross-clamp time, min71.59 ± 43.8671.89 ± 43.4870.80 ± 44.970.78AKIN stage 0403 (65.7)307 (69.6)96 (55.8)0.001 1186 (30.3)122 (27.7)64 (37.2) 2 or 324 (3.9)12 (2.7)12 (7.0)AKI duration, d 1–2143 (23.3)94 (21.3)49 (28.5)0.015 3–650 (8.2)31 (7.0)19 (11.0) >616 (2.6)9 (2.0)7 (4.1)Last serum creatinine before discharge1.03 ± 0.451.01 ± 0.311.07 ± 0.670.15AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CABG, coronary artery bypass graft; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; STS, Society of Thoracic Surgeons.Data are expressed as mean ± SD and n (%) for the continuous and categorical variables, respectively.Dash indicates small cell counts that cannot be presented because of privacy concerns.The primary outcome was a composite of CKD incidence or progression: CKD incidence (preoperative eGFR ≥60 ml/min per 1.73 m2): 25% reduction in eGFR and a fall below 60 ml/min per 1.73 m2; CKD progression (preoperative eGFR <60 ml/min per 1.73 m2): 50% reduction in eGFR or a fall below 15 ml/min per 1.73 m2. Open table in a new tab AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CABG, coronary artery bypass graft; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; STS, Society of Thoracic Surgeons. Data are expressed as mean ± SD and n (%) for the continuous and categorical variables, respectively. Dash indicates small cell counts that cannot be presented because of privacy concerns. The primary outcome was a composite of CKD incidence or progression: CKD incidence (preoperative eGFR ≥60 ml/min per 1.73 m2): 25% reduction in eGFR and a fall below 60 ml/min per 1.73 m2; CKD progression (preoperative eGFR <60 ml/min per 1.73 m2): 50% reduction in eGFR or a fall below 15 ml/min per 1.73 m2. Over a median follow-up of 5.6 years (interquartile range, 4.3–8.6 years), 172 patients (28%) developed the primary outcome of CKD incidence or progression at a rate of 53.2 per 1000 person-years on the basis of at least 1 follow-up serum creatinine measurement. We noted a higher rate of the primary outcome in patients with increasing AKI stage, from 96 patients without inhospital AKI developing the primary outcome (23.8%) to 24 patients with stage 2 or 3 AKI developing the primary outcome (50%). Of the 172 patients who developed the primary outcome, 144 patients (84%) had at least 2 serum creatinine measurements during follow-up spaced ≥90 days apart. In total, a median of 21 (interquartile range, 12–34) serum creatinine values were measured per patient over the course of follow-up, with those who developed AKI stages 2 or 3 having notably more follow-up creatinine values (31; interquartile range, 13–34). Forty blood and urine biomarkers were analyzed for the association with the primary outcome. In unadjusted analyses after natural log transformation, higher postoperative values of blood basic fibroblast growth factor (bFGF), interleukin-2, interleukin-10, kidney injury molecule-1 (KIM-1), N-terminal pro–B-type natriuretic peptide (NT-proBNP), tumor necrosis factor receptor 1 (TNF-r1), vascular endothelial growth factor receptor 1, and YKL-40 were significantly associated with the primary outcome (Table 2). After adjustment for age, sex, AKI stage, preoperative albuminuria, preoperative serum creatinine, and discharge serum creatinine, the levels of biomarkers bFGF, NT pro-BNP, and TNF-r1 remained significantly associated with an increased risk of the CKD incidence or progression (Table 2). Additionally, KIM-1 was associated with an increased risk of CKD incidence or progression that was approaching statistical significance (adjusted hazard ratio, 1.51; 95% confidence interval, 0.98–2.32; P = 0.07). The association of these 4 postoperative biomarkers with the primary outcome was then evaluated by tertiles, with the first tertile serving as the reference group. In categorical analysis, only participants in the highest tertile of bFGF had a significantly higher risk of the primary outcome than did those in the lowest tertile (hazard ratio, 1.89; 95% confidence interval, 1.26–2.82) (Supplementary Table S2). Adjustment for preoperative biomarker levels yielded similar point estimates for bFGF, KIM-1, NT pro-BNP, and TNF-r1, but with wider confidence intervals such that NT-proBNP no longer reached statistical significance (Supplementary Table S3).Table 2Risk of CKD incidence or progression by postoperative biomarker levelBlood biomarkers (natural log transformed)nUnadjusted HR (95% CI)Adjusted HR (95% CI)bFGF6121.50 (1.20–1.87)1.52 (1.19–1.93)aP < 0.05.KIM-16121.55 (1.14–2.10)1.51 (0.98–2.32)bP ≤ 0.07.NT-pro-BNP3871.21 (1.05–1.39)1.19 (1.01–1.41)aP < 0.05.TNF-r16121.77 (1.26–1.49)1.75 (1.18–2.59)aP < 0.05.IL-106121.14 (1.01–1.29)1.11 (0.98–1.27)IL-26121.19 (1.01–1.40)1.08 (0.91–1.28)VEGFr16121.31 (1.08–1.59)1.21 (0.98–1.49)YKL-406121.27 (1.03–1.56)1.10 (0.88–1.38)bFGF, basic fibroblast growth factor; CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; IL-2, interleukin-2; IL-10, interleukin-10; KIM-1, kidney injury molecule-1; NT-proBNP, N-terminal pro–B-type natriuretic peptide; TNF-r1, tumor necrosis factor receptor 1; VEGFr1, vascular endothelial growth factor receptor 1.Adjusted for age, sex, acute chronic injury stage, preoperative albuminuria, preoperative serum creatinine, and discharge serum creatinine.a P < 0.05.b P ≤ 0.07. Open table in a new tab bFGF, basic fibroblast growth factor; CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; IL-2, interleukin-2; IL-10, interleukin-10; KIM-1, kidney injury molecule-1; NT-proBNP, N-terminal pro–B-type natriuretic peptide; TNF-r1, tumor necrosis factor receptor 1; VEGFr1, vascular endothelial growth factor receptor 1. Adjusted for age, sex, acute chronic injury stage, preoperative albuminuria, preoperative serum creatinine, and discharge serum creatinine. Supplementary Table S4 lists the baseline characteristics of the replication cohort, on the basis of data from the largest US center, in the Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury cohort. Over a median follow-up of 6.5 years (interquartile range, 4.2–8.6 years), 60 patients (19%) developed the primary outcome of CKD incidence or progression at a rate of 61.3 per 1000 person-years on the basis of at least 1 follow-up serum creatinine measurement. In addition to bFGF, NT pro-BNP, and TNF-r1, we evaluated the associations between KIM-1 and our primary outcome in the replication cohort, given its established association with kidney injury from prior literature and the strength of association relative to other biomarkers. Similar to the primary cohort, higher postoperative blood levels of bFGF, KIM-1, and NT pro-BNP remained significantly associated with the primary kidney outcome after adjustment in the replication cohort (Supplementary Table S5). Increases in postoperative TNF-r1 concentration were not significantly associated with an increased risk of CKD incidence or progression (hazard ratio, 1.73; 95% confidence interval, 0.94–3.18). Patients in the third tertile of all 3 biomarkers had a significantly higher risk than did those in the first tertile (Supplementary Table S5). In a meta-analysis of both cohorts, after natural log transformation, the pooled hazard ratios for all 4 biomarkers were significantly associated with our primary outcome (Figure 2). There were a total of 78 deaths (12.7%) in the primary cohort and 31 deaths (10%) in the replication cohort. We performed a competing risk analysis of death in the primary cohort. There was no significant difference in the primary outcome after accounting for competing risk of death using the Fine and Gray subdistribution model (Supplementary Table S6). We performed interaction testing to evaluate the effect of clinical AKI. There was no significant interaction between the biomarker level and our primary outcome by AKI status in continuous analysis. However, in categorical analysis, patients without clinical AKI in the highest tertile of bFGF, KIM-1, and TNF-r1 had similar or higher rates of the primary outcome than did patients with clinical AKI in the lowest tertiles (Figure 3). We additionally evaluated for interaction by preoperative CKD status and did not find any significant difference in outcome for any of the 4 biomarkers (Supplementary Table S7). Notably, the analysis of TNF-r1 produced wide confidence intervals, though the interaction P value was not significant, likely as a result of limited power for this analysis. Within each cohort, we examined model performance by calculating the net reclassification index for models with biomarker measurements added to a base model with clinical parameters alone (Supplementary Table S8). In sensitivity analysis, we additionally examined the association between the peak postoperative biomarker level (Supplementary Table S9) and the mean postoperative biomarker level (Supplementary Table S10) with CKD incidence or progression. We found generally similar results to our primary analysis using first postoperative biomarker levels. In this prospective cohort study of adults undergoing cardiac surgery, we evaluated 40 blood and urine biomarkers and found that elevated postoperative levels of blood bFGF, KIM-1, NT pro-BNP, and TNF-r1 were independently associated with an increased risk of CKD incidence or progression regardless of AKI status after surgery. It is well established that patients who develop AKI are at a higher risk of long-term adverse outcomes including mortality and cardiovascular disease than those who do not.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,12Coca S.G. Outcomes and renal function trajectory after acute kidney injury: the narrow road to perdition.Kidney Int. 2017; 92: 288-291Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,13See 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 (99) Google Scholar In recent years, several 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 creatinine.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,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 Elevations in biomarkers of injury, inflammation, and repair have been associated with the long-term risk of overall mortality and cardiovascular disease.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,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,14Parikh C.R. Coca S.G. Thiessen-Philbrook H. et al.Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery.J Am Soc Nephrol. 2011; 22: 1748-1757Crossref PubMed Scopus (367) Google Scholar,15Zhang W.R. Garg A.X. Coca S.G. et al.Plasma IL-6 and IL-10 concentrations predict AKI and long-term mortality in adults after cardiac surgery.J Am Soc Nephrol. 2015; 26: 3123-3132Crossref PubMed Scopus (90) Google Scholar This is the first study to evaluate a large number of blood and urine biomarkers establish their association with the increased risk of CKD incidence or progression in a cardiac surgery cohort. There are a number of plausible mechanisms by which levels of bFGF, KIM-1, NT pro-BNP, and TNF-r1 can associate with CKD incidence or progression. bFGF, also referred to as FGF2, is a member of the fibroblast growth factor family distinct from FGF-21 and FGF-23. Similar to other members of the FGF family, bFGF serves multiple roles in cellular differentiation and function through various signaling pathways, several of which include inhibition of bone mineralization, angiogenesis, and cell proliferation.16Kang W. Liang Q. Du L. et al.Sequential application of bFGF and BMP-2 facilitates osteogenic differentiation of human periodontal ligament stem cells.J Periodontal Res. 2019; 54: 424-434Crossref PubMed Scopus (25) Google Scholar bFGF has been implicated in the response to inflammation by upregulation of endothelial cell adhesion molecules as well, with chronic inflammation being a known factor in CKD progression.17Zittermann S.I. Issekutz A.C. Basic fibroblast growth factor (bFGF, FGF-2) potentiates leukocyte recruitment to inflammation by enhancing endothelial adhesion molecule expression.Am J Pathol. 2006; 168: 835-846Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar KIM-1 is a transmembrane protein located in the proximal tubule of the kidney, and its expression is significantly upregulated in the setting of proximal tubular injury.18Han W.K. Bailly V. Abichandani R. et al.Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.Kidney Int. 2002; 62: 237-244Abstract Full Text Full Text PDF PubMed Scopus (1170) Google Scholar,19Ichimura T. Bonventre J.V. Bailly V. et al.Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.J Biol Chem. 1998; 273: 4135-4142Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar Urinary KIM-1 has been shown to be a robust marker for acute tubular injury, with localization to the proximal tubule, in both animal and human studies.18Han W.K. Bailly V. Abichandani R. et al.Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.Kidney Int. 2002; 62: 237-244Abstract Full Text Full Text PDF PubMed Scopus (1170) Google Scholar, 19Ichimura T. Bonventre J.V. Bailly V. et al.Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.J Biol Chem. 1998; 273: 4135-4142Abstract Full Text Full Text PDF PubMed Scopus (874) Google Scholar, 20Parikh C.R. Thiessen-Philbrook H. Garg A.X. et al.Performance of kidney injury molecule-1 and liver fatty acid-binding protein and combined biomarkers of AKI after cardiac surgery.Clin J Am Soc Nephrol. 2013; 8: 1079-1088Crossref PubMed Scopus (144) Google Scholar However, elevated blood levels of KIM-1 have been associated with the progression to CKD in patients with type 1 diabetes mellitus and even in healthy adults.21Schulz C.A. Engstrom G. Nilsson J. et al.Plasma kidney injury molecule-1 (p-KIM-1) levels and deterioration of kidney function over 16 years.Nephrol Dial Transplant. 2020; 35: 265-273Crossref PubMed Scopus (15) Google Scholar,22Nowak N. Skupien J. Niewczas M.A. et al.Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes.Kidney Int. 2016; 89: 459-467Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar NT pro-BNP has also been independently associated with the progression of CKD.23Kim Y. Matsushita K. Sang Y. et al.Association of high-sensitivity cardiac troponin T and natriuretic peptide with incident ESRD: the Atherosclerosis Risk in Communities (ARIC) study.Am J Kidney Dis. 2015; 65: 550-558Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Elevations in NT pro-BNP may help distinguish patients at increased risk of a cardiorenal phenotype of CKD.24Choudhary R. Gopal D. Kipper B.A. et al.Cardiorenal biomarkers in acute heart failure.J Geriatr Cardiol. 2012; 9: 292-304Crossref PubMed Scopus (13) Google Scholar One study in patients with type 2 diabetes demonstrated the association between both TNF-r1 and NT pro-BNP with the progression of CKD.25Bansal N. Hyre Anderson A. Yang W. et al.High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study.J Am Soc Nephrol. 2015; 26: 946-956Crossref PubMed Scopus (72) Google Scholar These findings are consistent with these prior studies supporting the association between elevated levels of these markers with kidney function decline. TNF-r1 serves as a cell membrane receptor that binds TNF-α and accentuates endothelial inflammation. TNF-r1 has been associated with the progression to end-stage kidney disease and mortality in patients with type 1 and type 2 diabetes mellitus beyond establ