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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 3  |  Page : 531-539
Fibroblast growth factor-23 as a predictor biomarker of acute kidney injury after cardiac surgery


1 Department of Internal Medicine and Nephrology, Cairo University, Kaser Al Aini Hospital, Cairo, Egypt
2 Department of Cardiothoracic Surgery, Cairo University, Kaser Al Aini Hospital, Cairo, Egypt
3 Department of Clinical and Chemical Pathology, Cairo University, Kaser Al Aini Hospital, Cairo, Egypt

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Date of Submission01-Jun-2017
Date of Acceptance05-Jul-2017
Date of Web Publication28-Jun-2018
 

   Abstract 

Renal ischemia/reperfusion injury is a major cause of acute kidney injury (AKI). The lack of early biomarkers for predicting AKI has hampered our ability to initiate preventive and therapeutic measures in an opportune way. Fibroblast growth factor 23 (FGF-23) is elevated in chronic kidney disease, but data on FGF-23 in humans with AKI are limited. Herein, we tested whether FGF-23 levels rise early in the course of AKI following cardiac surgery. We prospectively evaluated eighty adult patients who underwent cardiac surgery. Patients were divided into two groups (AKI and non-AKI group) on the basis of whether they developed postoperative AKI within 24 h after surgery. Plasma FGF-23 levels were measured before surgery and 24 h after surgery. The primary outcome was AKI diagnosed using the AKI Network criteria. Forty-five patients (56.2.5%) developed AKI after surgery. Plasma FGF-23 increased significantly from a mean of 26.8 ± 2.47 ng/mL at baseline to 341.7 ± 38.1 ng/mL 24 h after cardiopulmonary bypass. Univariate analysis showed a significant correlation between AKI and the following: percent change in plasma FGF-23, postoperative serum level of creatinine, FGF-23, and neutrophil gelatinase-associated lipocalin. Receiver operating characteristic curve analysis revealed that, for percent change in plasma FGF-23 concentrations at 24 h, the area under the curve was 0.9, sensitivity was 100%, and specificity was 97.1%. Plasma FGF-23 percent change is more valid compared with FGF-23 before or after procedure in the prediction of AKI and represents a novel and highly predictive early biomarker for AKI after cardiac surgery.

How to cite this article:
Shaker AM, El Mohamed E, Samir HH, Elnokeety MM, Sayed HA, Ramzy TA. Fibroblast growth factor-23 as a predictor biomarker of acute kidney injury after cardiac surgery. Saudi J Kidney Dis Transpl 2018;29:531-9

How to cite this URL:
Shaker AM, El Mohamed E, Samir HH, Elnokeety MM, Sayed HA, Ramzy TA. Fibroblast growth factor-23 as a predictor biomarker of acute kidney injury after cardiac surgery. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2022 May 24];29:531-9. Available from: https://www.sjkdt.org/text.asp?2018/29/3/531/235180

   Introduction Top


Acute kidney injury (AKI) is one of the most common complications of cardiac surgery.[1] Novel markers of early AKI are needed to improve clinical outcomes after cardiac surgery.[2]

The mechanisms of cardiac surgery-associated AKI (CSA-AKI) include decreased renal perfusion, oxidative stress, hypothermia, atheroembolism, and inflammation.[3]

Although glomerular filtration rate (GFR) is the accepted indicator of renal function that depends on serum creatinine (Cr) and urine output, it does not help clinicians make an early diagnosis of AKI.[4]

Not too many studies exist on the role of fibroblast growth factor-23 (FGF-23) in AKI, but recent studies have revealed that FGF-23 is elevated in AKI.[4]


   Patients and Methods Top


The study population was chosen and data collection was performed between December 2015 and January 2017; 130 consecutive patients were screened for eligibility, and we prospectively enrolled a cohort of eighty adult patients undergoing cardiac surgery with the use of cardiopulmonary bypass (CPB) at Cairo University Hospital (Cairo, Egypt). Procedures included isolated coronary artery bypass grafting, isolated valve surgery, and simultaneous coronary artery bypass grafting and valve surgery. Exclusion criteria included emergency surgery (operation performed within 24 h after cardiac symptoms), presence of preexisting renal impairment, having undergone renal transplant, peripheral vascular disease, use of nephrotoxic drugs or contrast material before or during the study period, and age <18 years.

The study required no changes to standard clinical practice during operation and intensive care. The postoperative use of vasopressor agents, inotropic medications (dobutamine or milrinone), and furosemide was recorded hourly until patients were discharged from the Intensive Care Unit (ICU). Other variables obtained included age, sex, CPB time, aortic cross-clamp time (AXT), previous heart surgery, and urine output. The study protocol was approved by the Institutional Review Board of Cairo University. Written informed consent was obtained from each participant before enrollment.

Biochemical and biomarkers' measurements

Blood samples were collected at baseline and at frequent intervals for five days after CPB. We centrifuged samples at 2000 g for 5 min and stored the supernatants in equal volumes at -80°C. Serum Cr was measured at baseline and routinely monitored at least twice a day in the immediate postoperative period and at least daily after postoperative day-3. Baseline serum Cr was defined as the level obtained at hospital admission the day before surgery. Estimated GFR was estimated with the Modification of Diet in Renal Disease Study equation.

Neutrophil gelatinase-associated lipocalin (NGAL) was measured in serum samples (human lipocalin-2/NGAL ELISA; BioVendor, Brno, Czech Republic) 24 h after initiation of CPB using the sandwich enzyme immuno-assay method according to manufacturer's instructions. Concentrations of plasma FGF-23 were measured at baseline and 24 h after commencement of CPB. As the intact FGF-23 molecule was highly unstable (resulting in a decreased immunoreactivity over time), specimen collection and assay or storage procedures were conducted expeditiously. As recommended, samples were collected in the morning from patients. The collected samples were centrifuged, and the plasma or the media were separated from the cells. They were assayed immediately or stored at -70°C or below. The serum levels of intact FGF-23 molecules were measured using the two-site (NH2-terminal/C-terminal) enzyme-linked immunosorbent assay (Immutopics Inc., San Clemente, California, USA). To assay the sample in duplicate, 300 μL of plasma or culture media were collected. The human intact FGF-23 enzyme-linked immunosorbent assay (Immutopics Inc.) was carried out according to the manufacturer's guidelines.

Outcome measures

The primary outcome variable was the development of AKI, defined as an increase in serum Cr level by either more than 50% or more than 0.3 mg/dL (compared with preoperative values), during the first 48 h after surgery. Other outcomes included absolute and relative increase in serum Cr from baseline to peak value during the first five postoperative days, indicating severity of AKI, dose of furosemide to maintain urine output 0.5–1.0 mL/kg/h, requirement for renal replacement therapy, length of stay in the ICU and in hospital, and mortality (in-hospital and at 6 months postoperatively through information from the outpatient department).


   Statistical Analysis Top


Data were coded and entered using the using Statistical Package for the Social Sciences (SPSS) version 24.0 for Windows (SPSS Inc., Chicago, IL, USA). Data were summarized using mean, standard deviation, median, minimum, and maximum in quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables were made using unpaired t-test in normally distributed variables and the non-parametric Mann–Whitney test in data that is not normally distributed. For comparison of serial measurements within each patient, the nonparametric Wilcoxon signed-rank test was used. For comparing categorical data, Chi-square (χ2) test was performed. The exact test was used instead when the expected frequency is <5. Correlations between quantitative variables were done using Spearman's correlation coefficient. The receiver operating characteristic (ROC) curve was constructed with area under curve analysis performed to detect best cutoff values for the detection of AKI. Logistic regression was done to detect independent predictors of AKI. P < 0.05 was considered as statistically significant.


   Results Top


Forty-five patients (56.2.5%) developed AKI according to the AKI Network criteria. Patients who developed postoperative AKI were comparable to the non-AKI group with regard to age, sex, body mass index, preoperative serum Cr, estimated GFR, and left ventricular ejection fraction. However, patients who developed AKI showed longer CPB times and AXTs and received postoperative vasopressor/inotropic support more frequently than those without AKI [Table 1].
Table 1: Clinical and laboratory findings in the study patients before and after surgery.

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They also stayed longer in the ICU and hospital. Four patients in the AKI group required continuous renal replacement therapy. Two patients in the AKI group died in the hospital.

Serum creatinine after cardiac surgery

Preoperative, peak postoperative, and change in serum Cr levels after cardiac surgery were statistically different between patients with and without AKI. The percent change in serum Cr levels was statistically different (P = 0.001) between patients with and without AKI [Table 1].

Plasma Fibroblast growth factor-23 before and after cardiac surgery

Before surgery, the mean plasma FGF-23 level in all patients studied was 26.2 ± 2.24 pg/mL. Plasma FGF-23 level 24 h after surgery was significantly higher compared with preoperative values (26.2 ± 2.24 vs. 208.8 ± 157.2; p <0.0001, respectively) [Table 2] and [Figure 1].
Figure 1: Plasma FGF-23 levels before (pre-operative) and after (postoperative) cardiac surgery and postoperative change in plasma FGF-23 levels in all patients (mean+SD).
*P < 0.0001 compared with preoperative values. FGF-23: Fibroblast growth factor 23.


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Table 2: Plasma levels of fibroblast growth factor-23 in patients with and without acute kidney injury.

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Plasma Fibroblast growth factor-23 and acute kidney injury

Preoperative plasma FGF-23 levels were similar in patients who later developed AKI and patients without postoperative AKI (26.8 ± 2.4 vs. 25.6 ± 1.8 pg/mL; P= 0.015). Patients who subsequently developed AKI displayed a remarkable increase in plasma FGF-23 at 24 h (P <0.0001 vs. baseline; [Table 2] and [Figure 2].
Figure 2: Plasma FGF-23 levels before (pre-operative) and after (postoperative) cardiac surgery (24 h) and postoperative change in plasma FGF-23 levels in patients with and without AK) (mean ± SD).
*P <0.0003 compared with the non-AKI group. FGF-23: Fibroblast growth factor 23, AKI: Acute kidney injury.


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Patients who never developed AKI had a small insignificant increase in plasma FGF-23 24 h after CPB [Table 2] and [Figure 2]. The postoperative change in plasma FGF-23 levels was significantly different between the two groups (314.2 ± 38 vs. 15.2 ± 4.91 pg/mL; P = 0.0003). Moreover, the degree of change in FGF-23 was significantly greater in patients who developed AKI compared with patients without postoperative AKI (P <0.0001) [Table 2] and [Figure 3].
Figure 3: Percentage change in plasma FGF-23 levels after cardiac surgery (24 h) in patients with and without AKI (mean±SD).
FGF-23: Fibroblast growth factor 23, AKI: Acute kidney injury.


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In patients with AKI, univariate linear regression analysis showed that percent change of FGF-23 correlated positively with peak Cr (F = 0.025), change in Cr (P = 0.003), percent change in Cr (P = 0.0001), NGAL (P <0.0001), CPB time (P <0.0001), AXT (P <0.0001), duration of ICU stay (P <0.0001), and duration of hospital stay (P = 0.0005).

Multivariate logistic regression analysis did not show any variable as a significant independent predictor for AKI.

Receiver operating characteristic curves

ROC curves were generated to evaluate the ability of plasma FGF-23 to predict AKI. Area under the curves (AUCs) were low for the absolute FGF-23 levels preoperatively. AUC was highest for the postoperative FGF-23 level and percent of FGF-23 change 24 h after surgery. AUC of the ROC curve for serum NGAL to predict AKI was 1.00 [Table 3].
Table 3: Statistical analysis data of fibroblast growth factor-23 and neutrophil gelatinase-associated lipocalin in the study patients.

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   Discussion Top


FGF-23 is a bone-produced novel hormone that has excellent features to be considered a new and early biomarker for AKI. It is generated and secreted primarily in bones by osteoblasts and osteocytes.[5]

In this study, patients with AKI displayed a remarkable increase in plasma FGF-23 at 24 h after CPB, with a significantly different change in plasma FGF-23 levels between the two groups. Moreover, the percent change of FGF-23 was significantly greater in patients who developed AKI compared with patients with-out postoperative AKI.

These findings are consistent with a previous report in a murine model of AKI, in which they reported a similarly large magnitude of FGF-23 elevation beginning early in the course of AKI that occurred independent of changes in other mineral metabolites.[6]

We found that higher FGF-23 levels are independently associated with an increased risk for the development of AKI and other important postoperative complications including RRT/ death and longer length of hospital stay. These findings suggest that elevated FGF-23 levels may be an early and novel marker of AKI and other adverse clinical outcomes after cardiac surgery.

Interestingly, we found elevations in FGF-23 levels in both patients with and without AKI, although the magnitude of rise was greater in patients with AKI and even greater in patients with severe AKI. Furthermore, FGF-23 increased even in patients without AKI, suggesting that these patients may have experienced subclinical renal injury or FGF-23 may function as an acute-phase reactant after exposure to operative stress. The latter mechanism is consistent with elevated postoperative FGF-23 levels among patients undergoing hip arthroplasty (n = 55), which occurred independent of AKI status[7] and a recent report demonstrating that acute inflammation markedly increases FGF-23 levels in mice.[8]

The precise mechanism of the elevated FGF-23 levels has not yet been elucidated. Increased production rather than decreased elimination of FGF-23 contributes to elevated levels of FGF-23 in AKI, and hence impaired renal FGF-23 scavenging due to the reduction of the glomerular function units is not the major pathway for raising the FGF-23 levels.[9]

Furthermore, another pathway that can contribute to the elevation of serum FGF-23 may be deficiency of the important FGF23 co-receptor Klotho in the injured kidney.[10]

The Klotho deficiency leads to FGF-23 resistance resulting in raised serum FGF-23 levels. Besides, enhanced bone production of FGF-23 in AKI patients was demonstrated by immunohistochemical and Western blot analyses of the bones also as a mechanism contributing to elevated FGF-23 serum levels.[10]

Cardiac surgery with CPB is the most common surgical procedure that is associated with a high risk for AKI.[11] Renal injury is frequent after cardiac surgery because of renal hypoperfusion, reperfusion injury, and inflammatory responses. Unfortunately, the currently used marker of renal function (or dysfunction), serum Cr level, is an inappropriately insensitive and late marker of renal dysfunction. Consequently, by the time, renal dysfunction is indicated by an increase in serum Cr levels, adequate therapeutic intervention is not possible.[12]

In our study, we evaluated the performance of plasma FGF-23 as a biomarker for AKI in an adult postcardiac surgery cohort. The AUC-ROC value was highest for the percent of change of renalase at 24 h after surgery (AUC = 0.99, P <0.0001) with a sensitivity of 100% and specificity of 97%. We, therefore, propose that plasma FGF-23 level might be better to detect intraoperative renal injury early after cardiac surgery compared with serum Cr level or serum NGAL.

A meta-analysis evaluating the early postoperative diagnostic performance of biomarkers of CSA-AKI showed that urine bio-markers such as NGAL, kidney injury molecule 1, and L-FABP exhibited composite AUCs of 0.69–0.72; the composite AUCs for postoperative urine cystatin C, N-acetyl-β-d-glucosaminidase, and IL-18 were at least 0.70.[13] Similarly, the composite AUROCs for postoperative plasma NGAL and cystatin C were <0.75. The meta-analysis concluded that current biomarkers have generally poor and at best modest discrimination for AKI when measured within the first 24 h after cardiac surgery in adults.[14]

We acknowledge several limitations of this study including a single-center and observational design. Plasma FGF-23 and serum NGAL were measured at only single time point (24 h) after cardiac surgery. This time point might be relatively late for therapeutic intervention. Further studies with measurement at various time points after a renal insult (i.e., after initiation of CPB) are required to validate our findings. We did not measure all potentially relevant biomarkers such as soluble Klotho, Vitamin D–binding protein, and inflammatory biomarkers. We did not have access to data on urine output, which might have allowed earlier identification of AKI and would have been another clinical biomarker with which to compare FGF-23.

However, within these limitations, we believe our work will stimulate more research on this topic


   Conclusion Top


The currently used kidney injury biomarkers cannot detect AKI early and usually their concentrations start to rise when the injury process is in the late phase. Our hypothesis that FGF-23 might represent an early and a more sensitive biomarker of ischemic renal injury compared with serum Cr level or other biomarkers (NGAL) in patients undergoing cardiac surgery was confirmed in this study The goal of the new and early kidney injury biomarker is to predict and diagnose AKI with the aim to start the nephroprotective treatment before the damage occurs. FGF-23 could be a novel promising biomarker of AKI, especially in the complex perioperative period. However, additional research in the field is needed.

Conflicts of interest: None declared.

 
   References Top

1.
Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: A meta-analysis. Clin J Am Soc Nephrol 2013;8:1482-93.  Back to cited text no. 1
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2.
Loef BG, Epema AH, Smilde TD, et al. Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 2005;16:195-200.  Back to cited text no. 2
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Gaffney AM, Sladen RN. Acute kidney injury in cardiac surgery. Curr Opin Anaesthesiol 2015;28:50-9.  Back to cited text no. 3
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Sakan S, Bašić-Jukić N, Kes P, Jelaković B, Pavlović DB, Perić M. Significance of fibroblast growth factor 23 in acute kidney injury. Acta Clin Croat 2015;54:279-84.  Back to cited text no. 4
    
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Christov M, Waikar SS, Pereira RC, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int 2013;84:776-85.  Back to cited text no. 5
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Riminucci M, Collins MT, Fedarko NS, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003;112:683-92.  Back to cited text no. 6
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Goebel S, Lienau J, Rammoser U, et al. FGF23 is a putative marker for bone healing and regeneration. J Orthop Res 2009;27:1141-6.  Back to cited text no. 7
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David V, Martin A, Isakova T, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 2016;89:135-46.  Back to cited text no. 8
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Isakova T, Xie H, Barchi-Chung A, et al. Fibroblast growth factor 23 in patients undergoing peritoneal dialysis. Clin J Am Soc Nephrol 2011;6:2688-95.z  Back to cited text no. 9
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Koh N, Fujimori T, Nishiguchi S, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001;280:1015-20.  Back to cited text no. 10
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11.
Stubbs JR, He N, Idiculla A, et al. Longitudinal evaluation of FGF23 changes and mineral metabolism abnormalities in a mouse model of chronic kidney disease. J Bone Miner Res 2012;27:38-46.z  Back to cited text no. 11
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Haase-Fielitz A, Haase M, Bellomo R, et al. Decreased catecholamine degradation associates with shock and kidney injury after cardiac surgery. J Am Soc Nephrol 2009;20: 1393-403.  Back to cited text no. 12
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13.
Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 2004;15:1597-605.  Back to cited text no. 13
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Ho J, Tangri N, Komenda P, et al. Urinary, plasma, and serum biomarkers' utility for predicting acute kidney injury associated with cardiac surgery in adults: A Meta-analysis. Am J Kidney Dis 2015;66:993-1005.  Back to cited text no. 14
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Correspondence Address:
Dr. Amr M Shaker
Department of Internal Medicine and Nephrology, Cairo University, Kaser Al Aini Hospital, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.235180

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