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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2019  |  Volume : 30  |  Issue : 5  |  Page : 1044-1051
Prediction of mortality and need for renal replacement therapy in patients of acute kidney injury using fibroblast growth factor 23


1 Department of Internal Medicine, Nephrology Unit, Kasr Al Aini School of Medicine, Cairo University, Cairo, Egypt
2 Department of Critical Care, Kasr El Aini School of Medicine, Cairo University, Cairo, Egypt

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Date of Submission09-Jun-2018
Date of Decision16-Jul-2018
Date of Acceptance18-Jul-2018
Date of Web Publication4-Nov-2019
 

   Abstract 


Acute kidney injury (AKI) occurs in up to 50% of patients admitted to the intensive care units. Fibroblast growth factor 23 (FGF23), which plays an important role in regulating phosphate, rises early in AKI. Few studies were conducted to correlate the level of FGF23 and adverse outcomes in AKI. The study was conducted on 30 participants with AKI, which was defined according to AKI network criteria, admitted to the Critical Care Department, Kasr El Aini Hospital, Cairo University between July 2016 and May 2017, and serum FGF23 was measured within 24 h of AKI onset to correlate the level of FGF23 with mortality and need for renal replacement therapy (RRT). Enrollment FGF23 levels were significantly higher among patients who died than in the survival group (mean level: 544.2 vs. 59.3 pg/mL, P = 0.004). Furthermore, FGF23 levels were significantly higher in patients who needed RRT than in other participants (mean level: 529.5 vs. 285.11 pg/mL, P = 0.04). There was a statistically significant positive relationship between FGF23 level and sequential organ failure assessment score (P = 0.03). In patients with AKI, higher FGF23 levels are associated with increased risk of mortality and need for RRT.

How to cite this article:
Fayed A, Radwan WA, Amin M, Gamal A. Prediction of mortality and need for renal replacement therapy in patients of acute kidney injury using fibroblast growth factor 23. Saudi J Kidney Dis Transpl 2019;30:1044-51

How to cite this URL:
Fayed A, Radwan WA, Amin M, Gamal A. Prediction of mortality and need for renal replacement therapy in patients of acute kidney injury using fibroblast growth factor 23. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 20];30:1044-51. Available from: http://www.sjkdt.org/text.asp?2019/30/5/1044/270259



   Introduction Top


Acute kidney injury (AKI) is a syndrome characterized by a rapid (hours to days) deterioration of kidney function. It is often diagnosed in the context of other acute illnesses and and is particularly common in critically ill patients. The clinical consequences of AKI include the accumulation of waste products, electrolytes, and fluid, but also less obvious effects, including reduced immunity and dysfunction of nonrenal organs (organ cross-talk).[1] Fibroblast growth factor 23 (FGF23) which is produced in bone participates in the maintenance of phosphate metabolism and serves as a biomarker for adverse cardiovascular outcomes in patients with chronic kidney disease and end-stage renal disease.[2],[3],[4],[5],[6] Circulating FGF23 rapidly increases after AKI, preceding other known markers such as neutrophil gelatinase-associated lipocalin and serum creatinine. A limited number of studies correlated high FGF23 levels in AKI with adverse outcomes.[6],[7],[8],[9],[10] We aimed to investigate the value of serum FGF23 in the prediction of mortality in patients of AKI and to evaluate the role of FGF23 in predicting the need for renal replacement therapy (RRT) in patients with AKI.


   Patients and Methods Top


The current study was conducted as a prospective, cohort, single-center study on 30 patients who developed AKI at the Critical Care Department, Kasr El Aini Hospital, Cairo University between July 2016 and May 2017. We included all patients developed AKI which was defined according to criteria established by the AKI network, and they are aged 18 years or older. We excluded patients with CKD, patients on therapy with elemental Vitamin D or phosphate binders, and patients with a history of parathyroid diseases. All the patients were subjected to full medical history, full physical examination, admission laboratory tests including sodium, potassium, complete blood count, liver function tests, kidney function tests, calcium, phosphorus, and magnesium with daily urea, creatinine, and daily blood gases. Peripheral blood samples were obtained by routine venipuncture within 24 h of established diagnosis of AKI, and serum samples were processed, and FGF23 levels were determined by enzyme-linked immunosorbent assay (ELISA) technique. The serum level of intact FGF23 was determined using a two-site (NH2-terminal/C-terminal) ELISA (Immutopics, San Clemente, CA, USA). According to the instructions of the manufacturer, samples were collected in the morning after 12 h fasting. The collected samples were centrifuged, and the plasma was separated from the cells. Samples were assayed immediately or stored at −70°C or below.

Sequential organ failure assessment (SOFA) score was calculated for all patients on days 1, 3, and 5. The SOFA score is used to predict mortality in intensive care unit (ICU) patients based on the degree of dysfunction of six organs (respiratory, coagulation, cardiovascular, hepatic, central nervous system, and renal) depending on either maximum score or the trend of the score either increasing, not changing or declining. Acute physiology and chronic health evaluation II (APACHE II) score which depends on different clinical and laboratory variables was calculated on the day of ICU admission using the worst value in the first 24 h mainly to predict the mortality.

Abdominal ultrasound was done for patients to determine the size of kidneys degree of nephropathy and to rule out obstruction and postrenal AKI. Echocardiography was done to all patients to determine the left ventricular (LV) systolic function and any detected calcifications.


   Statistical Methods Top


Data were statistically described in terms of mean ± standard deviation, median and range, or frequencies (number of cases) and percentages when appropriate. A comparison of numerical variables between the study groups was done using Student’s t-test for independent samples in comparing two groups when normally distributed and Mann-Whitney U-test for independent samples. The correlation between various variables was done using the Pearson moment correlation equation for linear relation in normally distributed variables and Spearman rank correlation equation for nonnormal variables/nonlinear monotonic. Receiver operating characteristic curve was used to detect the cutoff value. P <0.05 was considered statistically significant.


   Results Top


A total of 30 patients were enrolled in our study. They included 17 males (56.7%) and 13 females (43.3%). ICU stay in the study population was 10.5 ± 5.7 days (3–22 days). Serum FGF 23 levels in the population study was 350.27 ± 629.93 pg/mL (12–2415 pg/mL). Among the patients included in our study, abdominal and pelvic U/S could be done in 22 patients [Table 1]. Among a total of 30 patients developed AKI, 22 patients (73.3%) had sepsis, 20 patients (66.7%) were shocked, and vasopressors were initiated to support hemodynamics [Table 2].
Table 1: Baseline patients' characteristics, chemical parameters, abdominal ultrasound, and echocardiography on the day of ICU admission.

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Table 2: Probable etiology of acute kidney injury.

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Outcomes

Mortality: Among the 30 patients included in the study 18 patients (60%) died while 12 patients (40%) survived.

1. RRT: According to the need for RRT patients are divided into two groups :

  1. Patients required RRT: Eight patients (26.7%)
  2. Patients did not require RRT: Twenty-two patients (73.3%).


There was statistically significant relationship between FGF23 level and SOFA score (P = 0.034). There was no statistically significant association between serum FGF23 level and serum calcium level (P = 0.178) and serum phosphorus level (P= 0.109) [Table 3].
Table 3: The association between FGF23 level and different parameters.

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Multinomial regression analysis was performed to create a model to predict mortality and the participants who needed RRT. There was a significant statistical relationship between serum FGF23 level and mortality (P = 0.004). Our study suggests a cutoff value of 48 pg/mL as a potential predictor for mortality with sensitivity 0.775 and specificity of 0.25 [Figure 1]. Serum FGF23 level was significantly higher in the participants who needed RRT compared to patients who did not need RRT (P = 0.04). Our study suggests a cutoff value of (131 pg/mL) as a potential predictor for the need for RRT with sensitivity 0.75 and specificity 0.727 [Figure 2].
Figure 1: ROC curve showing cutoff value of FGF23 level for prediction of mortality.
ROC curve: Receiver operating characteristic curve, FGF23: Fibroblast growth factor 23.


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Figure 2: ROC curve showing cutoff value of FGF23 level for prediction of need for RRT.
ROC curve: Receiver operating characteristic curve, FGF23: Fibroblast growth factor 23, RRT: Renal replacement therapy.


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   Discussion Top


This study was intended to investigate the role of serum FGF23 in the prediction of mortality and need for renal replacement therapy in patients who develop AKI. Our study showed a statistically significant relationship between FGF23 levels and mortality (P = 0.004). The study suggests a cutoff value of 48 pg/mL as a potential predictor for mortality in patients with AKI.

In concordance with our study, Leaf et al studied the role of FGF23 as a predictor for adverse outcomes in AKI and they found that enrollment FGF23 levels were significantly higher among those participants who died compared with those participants who survived.[6] Similarly, in another study, conducted by Zhang et al, on 12 patients with AKI and eight controls and measured serum FGF23 level and parathyroid hormone level for participants, they demonstrated that FGF23 levels were significantly higher in nonsurvivors than survivors.[5] In agreement with our results, a study conducted by Zeid et al to assess the association of FGF23, parathyroid hormone, and Vitamin D with AKI and revealed that FGF23 level was significantly higher in the mortality group than the survival group.[8] In 2016, Leaf et al performed a prospective cohort study on 250 patients who underwent cardiac surgery using FGF23 to predict the development of AKI following surgery and adverse outcomes and found a significant independent association between serum FGF23 level and mortality.[8] Furthermore, Speer et al, who performed their study on 859 patients undergoing elective cardiac surgery, found a strong correlation between high FGF23 levels and mortality in both postoperative periods and during the follow-up.[9] However, contrary to our results, Zeid et al suggested a cutoff value of 280 pg/dL as a predictor of mortality, but in their study, they used C-terminal FGF23 not iFGF23.[8]

Our results also revealed a statistically significant association between serum FGF23 level and need for RRT (P = 0.04). These results were found to be similar to those reported by Leaf et al, in 2012, who demonstrated that FGF23 levels were significantly higher among those participants who required RRT compared with patients who did not need RRT.[6] This is in agreement with the results obtained by Leaf et al, in 2016, on patients who underwent cardiac surgery that showed higher FGF23 levels were significantly associated with need for RRT.[7]

Our study also showed a significant relationship between serum FGF23 level and SOFA score on the day of ICU admission (P = 0.034). This is in agreement with the results obtained by Zeid et al who found a statistically significant positive correlation on day 1 between FGF23 and SOFA score.[8]

Our study showed higher serum FGF23 levels in oliguric patients compared to nonoliguric patients but the differences did not reach statistical significance (P = 0.94). In concordance with our results, Leaf et al demonstrated a trend toward higher levels of FG23 among participants with oliguric compared with nonoliguric AKI; however, the differences did not reach significance.[6]

Our study revealed no statistically significant relationship between FGF23 level and APACHE II score on the day of ICU admission (P = 0.33). In agreement with our results, Zhang et al found no statistically significant correlation between FGF23 level and APACHE II score.[5] These results differ from those demonstrated by Zeid et al who conducted their study on 30 patients of AKI from the general medical wards and ICUs and 30 control participants and showed a significant association between FGF23 level and APACHE II score.[8] In their study design, APACHE II score was calculated on the same day of the development of AKI and taking samples to measure FGF23 level, and the study included patients from general wards and ICUs. In our study, all patients were admitted to ICU, and APACHE II score was calculated on the day of ICU admission.

As regard length of stay, our study showed no significant association between FGF23 level and length of stay (P = 0.59). These results were different from results of Leaf et al and Speer et al that showed evidence of statistically significant relationship between FGF23 level and length of stay, this difference could be due to smaller sample size in our study.[7],[9]

Our results go with those published by Speer et al who performed their study on 859 patients undergoing elective cardiac surgery and measured the FGF23 level before the operation and found no statistically significant association between FGF23 level and the LV systolic function.[9] However, these results are different from results of Shibata et al who performed their study on 100 patients to evaluate the association between circulating FGF23, a-Klotho, and the LV ejection fraction and LV mass in cardiology inpatients and demonstrated a statistically significant association between high serum FGF23 levels and reduced LVEF after adjustment for other calcium-phosphate metabolism-related parameters. However, this study was conducted on patients admitted to wards, and the study included patients with various cardiovascular diseases not in the settings of AKI.[11]

Our data revealed higher FGF23 levels in shocked patients who needed vasopressors to support hemodynamics without reaching a statistical significance (P = 0.19). These results differ from that reported by Leaf et al that showed a statistically significant association between higher preoperative FGF23 levels and postoperative need for vasopressors in cardiac surgery patients. Small sample size in our study may be a contributing factor for this difference.[7]

Our study showed no significant association between FGF23 level and serum creatinine (P = 0.267). In contrary to our results, Speer et al showed a statistically significant association between the FGF23 level and serum creatinine, but this difference could be due to the small sample size in our study.[9]

Our study showed no statistically significant association between FGF23 level and serum phosphorus level (P = 0.109). These results are supported by the results published by Zhang et al that revealed no significant correlation between FGF23 level and serum phosphorus level.[5] n addition, Zeid et al showed no statistically significant relationship between FGF23 level and serum phosphorus level.[8] In contrary to these results, Leaf et al showed a statistically significant correlation between enrollment FGF23 level and phosphorus level and this relationship was not significant on day 5.[6]

Our results revealed no statistically significant association between FGF23 level and serum calcium level (P = 0.178). In concordance with our results, studies performed by Leaf et al and Zeid et al showed no significant correlation between enrollment FGF23 level and serum calcium level.[6],[8]

More studies will be needed to define the biologic role of FGF23 in AKI. Our results suggest that FGF23 could have a role as a biomarker of adverse outcomes among patients with established AKI. Our data raise important questions about the potential mechanisms that may underlie our observations of FGF23 in AKI. Whether elevated FGF23 levels may be directly toxic to target organs, such as the cardiovascular, skeletal, and endocrine systems, and thereby, contribute directly to adverse outcomes in AKI is a possibility that will require additional study.


   Conclusion Top


Our study showed that serum FGF23 level is a good prognostic marker and predictor of adverse outcomes (mortality/need for RRT) in patients with AKI, and FGF23 can play an important role in understanding more about the pathophysiology of AKI syndrome.


   Ethical Committee Approval Top


The Local Ethical Committee of the Critical Care Department, School of Medicine, Cairo University, approved this work.

Human and Animal Rights: All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent: Informed consent was obtained from all individual participants included in the study.

Conflict of interest: None declare.



 
   References Top

1.
Singbartl K, Joannidis M. Short-term effects of acute kidney injury. Crit Care Clin 2015;31: 751-62.  Back to cited text no. 1
    
2.
Gattineni J, Bates c, Twombley K, et al. FGF23 decreases renal naPi-2a and naPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009;297:F282-91.  Back to cited text no. 2
    
3.
Ichikawa S, Sorenson AH, Austin AM, et al. Ablation of the galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased fgf23 expression. Endocrinology 2009;150:2543-50.  Back to cited text no. 3
    
4.
Leaf DE, Wolf M, Stern L. Elevated FGF-23 in a patient with rhabdomyolysis-induced acute kidney injury. Nephrol Dial Transplant 2010; 25:1335-7.  Back to cited text no. 4
    
5.
Zhang M, Hsu R, Hsu CY, et al. FGF-23 and PTH levels in patients with acute kidney injury: A cross-sectional case series study. Ann Intensive Care 2011;1:21.  Back to cited text no. 5
    
6.
Leaf DE, Wolf M, Waikar SS, et al. FGF-23 levels in patients with AKI and risk of adverse outcomes. Clin J Am Soc Nephrol 2012;7:1217-23.  Back to cited text no. 6
    
7.
Leaf DE, Christov M, Jüppner H, et al. Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery. Kidney Int 2016;89:939-48.  Back to cited text no. 7
    
8.
Zeid M, Deghady AM, Elsaygh H, El Shaer H GR. Association of fibroblast growth factor 23, parathyroid hormone and Vitamin D with acute kidney injury. Egypt J Obes Diabet Endocrinol 2016;2:88-94.  Back to cited text no. 8
    
9.
Speer T, Groesdonk HV, Zapf B, et al. A single preoperative FGF23 measurement is a strong predictor of outcome in patients undergoing elective cardiac surgery: A prospective observational study. Crit Care 2015;19:190.  Back to cited text no. 9
    
10.
Christov M. Fibroblast growth factor 23 in acute kidney injury. Curr Opin Nephrol Hypertens 2014;23:340-5.  Back to cited text no. 10
    
11.
Shibata K, Fujita S, Morita H, et al. Association between circulating fibroblast growth factor 23, α-klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLoS One 2013;8:e73184.  Back to cited text no. 11
    

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Correspondence Address:
Ahmed Fayed
Department of Internal Medicine, Nephrology Unit, Kasr Al Aini School of Medicine, Cairo University, Cairo
Egypt
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DOI: 10.4103/1319-2442.270259

PMID: 31696842

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