How to cite:
Harun Harnavi, Febrianti Ika Kurnia, Kam Alexander. (2022).
Correlation of Serum Fibroblast Growth Factor 23 With Left
Ventricular Diastolic Function in Chronic Kidney Patients. Journal of
Eduvest. Vol 2(9): Page 1894-1904
E-ISSN:
2775-3727
Published by:
https://greenpublisher.id/
Eduvest – Journal of Universal Studies
Volume 2 Number 9, September, 2022
p- ISSN 2775-3735 - e-ISSN 2775-3727
CORRELATION OF SERUM FIBROBLAST GROWTH
FACTOR 23 WITH LEFT VENTRICULAR DIASTOLIC
FUNCTION IN CHRONIC KIDNEY PATIENTS
Harun Harnavi
1
, Febrianti Ika Kurnia
2
, Kam Alexander
3
Andalas University, Padang-West Sumatera, Indonesia
1
, Hospital of Lubuk
Basung, District Agam-West Sumatera, Indonesia
2
Dr. M Djamil General Hospital,
Padang-West Sumatera, Indonesia
3
Email: [email protected]; [email protected]
1
,
[email protected]
2
, [email protected]
3
ABSTRACT
Chronic Kidney Disease (CKD) is one of most common
world’s health problems with constantly increasing
prevalence and many complications, and cardiovascular is
one of them. The earliest cardiovascular damage that can be
seen is left ventricular diastolic dysfunction. In patients with
CKD, there will be mineral metabolism disorders, including
phosphate. Persistently increased phosphate in CKD will
cause rising in Fibroblast Growth Factor 23 (FGF23) that
regulates phosphate in the circulation. High level of FGF23
will directly damage the heart and stimulates cardiac
remodeling that will result in cardiomyocyte damage,
atherosclerosis and intramyocardial cells fibrosis. This will
cause myocardial stiffness and diastolic dysfunction. The
purpose of the study is to discover correlation between
Fibroblast Growth Factor 23 (FGF23) serum and left
ventricle diastolic function in patients with chronic kidney
disease. This is an observational study with cross-sectional
methods. The sample is 30 patients diagnosed with chronic
kidney disease (CKD). Patients are evaluated for Fibroblast
Growth Factor 23 (FGF23) level in their serum, assessed the
left ventricle diastolic function by measuring early diastolic
velocity of the left ventricle (lateral e’) using
echocardiography.There is significantly increased of FGF23
serum levels and decreased of lateral e’ value in chronic
kidney disease case. There’s also a strong correlation
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between FGF23 serum and filtration glomerulus rate (LFG)
(p<0.05), and a strong correlation between FGF23 serum
level with lateral e’ as a component of left ventricle diastolic
function. There’s a strong correlation between FGF23 with
left ventricle diastolic function in patients with CKD.
KEYWORDS
Chronic kidney disease, Fibroblast Growth Factor 23
(FGF23), left ventricle diastolic function, lateral e’
This work is licensed under a Creative Commons
Attribution-ShareAlike 4.0 International
INTRODUCTION
Chronic kidney disease is defined by Kidney Disease Improving Global
Outcomes (KDIGO) 2012 as abnormalities of kidney structure or function,
present for >3 months, with implications for health and marked with one or more
signs of kidney damage (Kdigo, 2012). Kidney is the main organ that controls
homeostasis of extracellular phosphate (Yan & Bowman, 2014), (Levin et al.,
n.d.) The main hormones that modulate phosphate in the kidney is parathyroid
hormone (PTH) that produced by parathyroid glands, and FGF23 which
synthesized and secreted by osteocytes and osteoblasts in the skeleton (Bergwitz
& Jüppner, 2010). The change in phosphate metabolism is a consequences of
CKD. Along with the decreased of LFG, there’s a raise in urine fractional
excretion of phosphate as a compensation to maintain normal phosphate serum
level (Heron, 2018).
Fibroblast Growth Factor 23 can directly affect the left ventricle by
changes in gene expression that is similar with those caused by chronic pressure
overload, so there will be pathological Left Ventricular Hypertrophy (LVH) (Faul
et al., 2011). LVH is an important mechanism of cardiovascular disease in CKD.
Elevated levels of FGF23 are associated with higher risk of LVH and mortality in
patients with CKD. in their study with mice as the test animals has found FGF23
expression in cardiac fibroblasts, cardiac myocytes hypertrophy that leads to LVH
and diastolic dysfunction (Yan & Bowman, 2014).
RESEARCH METHOD
This is an observational study with cross-sectional methods. The study
was conducted in Outpatient and Inpatient setting of Internal Medicine
Department in Dr. M. Djamil Public Hospital of Padang along with other private
hospitals in Padang in 6 months course. Population in this study is patients with
CKD that came to polyclinic and those who had been admitted to Internal
Medicine Department in Dr. M. Djamil Public Hospital of Padang and other
private hospitals in Padang. The sample of this study is all patients with CKD in
stage 3 to 5 that meet Kidney Disease Improving Global Outcomes (KDIGO)
criteria and passed the exclusion criteria that were taken by consecutive sampling.
The initial screening was done on the potential subjects and they were explained
about the protocols of the study and already gave informed consent. The total of
the sample in this study is 30 subjects. This study already got permission from the
Research Ethics Committee in Medical Faculty of Andalas University.
Harun Harnavi, Febrianti Ika Kurnia, Kam Alexander
1896
Statistical analysis was done by using SPSS 22.0 version. Absolute
correlation will give value of r = 1, very strong relationship (0.8-1.0), strong
relationship (0.6-0.799), moderate relationship (0.4-0.599), weak relationship
(0.0-0.399). Correlation is considered significant if p < 0.05.
RESULTS AND DISCUSSION
This study involved 30 patients with CKD with the characteristics that can
be seen from Table 1. The mean FGF 23 serum in this study is 599.19 (579.27)
pg/dl (normal valuea <90 pg/dl.) FGF 23 serum levels in this study is 304.75
pg/dl, with the lowest score 39.56 pg/dl and the highest score 1,777 pg/dl. The
result of Shapiro-Wilk normality test showed FGF23 serum levels in this study is
not normally distributed. Table 2 presents median score for FGF 23 serum level.
On this study, there is 30 samples that were obtained after performing
echocardiography and the mean lateral e’ is 9.83 (2.32) and septal e’ is 7.39 (2.55)
cm/s.
Table 1: Characteristics of the samples in the study
Characteristics
n (%)
Mean (SD)
Gender
Male
Female
17 (56.67%)
13 (43.33%)
Age (year old)
44.07 (13.81)
SBP (mmHg)
127.67
(13.82)
DBP (mmHg)
78.33 (12.06)
BMI (kg/m
2
)
22.96 (3.41)
Urea (mg/dl)
81.93 (42.63)
Creatinine (mg/dl)
3.01 (1.71)
FBG (gr/dl)
86.87 (8.36)
2HPPG (gr/dl)
172.27
(22.46)
GFR (ml/min/1.73 m
2
)
27.83 (12.71)
Total cholesterol (mg/dl)
170.40
(26.64)
LDL (mg/dl)
108.83
(27.88)
HDL (mg/dl)
33.43 (7.04)
Triglycerides (mg/dl)
148.63
(20.33)
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Table 2: FGF 23 Levels in Patients with Chronic Kidney Disease
Variable
N
Median (Min-
Max)
FGF23 (pg/dl)
30
304.75 (39.56-
1,777.0)
Table 3: Lateral e’ Value in Patients with Chronic Kidney Disease
Variable
N
Mean (SD)
Lateral e’ (cm/s)
30
9.83 (2.32)
Table 4: Septal e’ Value in Patients with Chronic Kidney Disease
Variable
N
Mean (SD)
Septal e’ (cm/s)
30
7.39 (2.55)
Figure 1. Correlation between FGF23 serum and lateral e’
Harun Harnavi, Febrianti Ika Kurnia, Kam Alexander
1898
Figure 2. Correlation between FGF23 serum and septal e’
Figure 1 and 2 showed the correlation between FGF23 serum levels and
left ventricle diastolic function in patients with CKD. Correlation analysis is done
by using Spearman correlation test and we got p value <0.05. Analysis result
showed that there is significant correlation between FGF23 serum levels with
each lateral e’ and septal e’ (p<0.05) with direction of negative correlation and
strong relationship (correlation coefficient lateral e’ r = -0.65 and septal e’ r = -
0.69).
Figure 3. Correlation between FGF23 Serum with Glomerulus Filtration
Rate in Patients with Chronic Kidney Disease
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Figure 3 showed correlation between FGF23 serum levels with GFR in
patients with CKD. Correlation analysis that’s used is Spearman correlation test
with confidence degree p<0.05. Analysis result showed there is significant
correlation between FGF23 serum levels with GFR with direction of negative
correlation and strong relationship (correlation coefficient r = -0.733).
From 30 subjects with CKD, 17 (56.67%) of them were males and 13
(43.33%) of them were females. This supports the study by Fliser D et al in 2007
at Germany’s cohort study that include 227 nondiabetic patients with CKD stage
2-5 where there are 67.84% males and 32.16% females (Fliser et al., 2007). Based
on Chathoth S et al in 2016 in Arab Saudi, males percentage is also higher
(70.8%) than the females (29.21%) (Chathoth et al., 2016).
Contrary from the study by Tjekyan RMS in 2012 at Palembang, where
female patients is higher than male patients with ratio of 56.3% : 43.7%. This
study didn’t find the significant correlation between CKD based on gender.
Gender isn’t the main risk factor of chronic kidney disease because this also
associated with genetic and environmental factors (Tjekyan, 2014).
This study found the mean age of patients with CKD is 44.07±13.81-year-
old, with the youngest is 17-year-old and the oldest one is 60-year-old. The
similar result is also found from the study by Fliser D et al in nondiabetic patients
with CKD stage 2-5 in Germany which is 46.57 year old (Fliser et al., 2007).
Chathoth S et al in 2016 got the mean age for patients with CKD stage 3-5 is
42.6±15.6-year-old (Chathoth et al., 2016).
A study by Park M et al in 2012 at California showed that the mean age of
patients with CKD is 59±11-year-old with mostly CKD stage 5 (Tjekyan, 2014).
The mean age differences that has been found is may be caused by characteristics
differences from the studied subjects. Krol GD in 2011 also said that CKD can
occur in all age groups and gender and influenced by dietary and lifestyle
(Bergwitz & Jüppner, 2010).
Mean body mass index or BMI in patients from this study is 22.96±3.41
kg/m
2
. This result is similar with study by Chathoth S et al in 2016 at Arab Saudi
with mean BMI 27.7±6.7 kg/m (Tonelli, Wanner, & Members*, 2014).
While Park M et al in 2012 got the mean BMI of 32 kg/m
2
with metabolic
syndrome presents in most patients Park et al., (2012) In patients with CKD there
might be changes in calories and proteins intake. Reduction in GFR will also
reduce the protein and calory intake because of raised uremic toxin accumulation
that leads to dietary habit and anorexia. But, patients with CKD only show the
symptoms in end stage of kidney disease, so the low BMI with malnutrition is
commonly found in CKD patients that already undergo hemodyalisis.
The mean systolic blood pressure (SBP) in the patients is 127.67±13.82
mmHg, and the mean diastolic blood pressure (DBP) is 78.33±112.06 mmHg.
Patients who has history of hypertension is excluded from this study. Similar
result is found in the study by Fliser et al., (2007) in Germany, from 227 patients
with CKD and haven’t been on hemodialysis yet, the mean SBP is 137.4 mmHg
and DBP is 87 mmHg. The blood pressure in this study by Fliser can be
Harun Harnavi, Febrianti Ika Kurnia, Kam Alexander
1900
considered in control because the subjects are given antihypertensive drugs and
the blood pressure was monitored. The study by Chathoth et al in 2016 shows
mean SBP 146.3±22.4 mmHg, DBP 78.3±13.5 mmHg. In this study, patient with
uncontrolled hypertension is still included.
Blood pressure in CKD patients tend to rise, especially in end stage renal
disease, the blood pressure is significantly increased. Hypertension in CKD
patients may be the result from vascular that happen because of the renal
dysfunction (Ramadhan, n.d.). The mean fasting blood glucose of the patients in
this study is 86.87±8.36 gr/dl and the 2 hour post prandial glucose is 172.27 gr/dl.
This is similar to the criteria of the study where patient with history of diabetes
mellitus is excluded from this patient.
Mean total cholesterol level of the patients is 170.40±26.64 mg/dl, mean
LDL level is 108.33±27.88 mg/dl, mean HDL level is 33.43±7.04 mg/dl, and
mean triglycerides level is 148.63±20.30 mg/dl. This result is similar with the
study by Park M et al in 2012 at California, with mean LDL level is 100.25
(15.75) mg/dl, mean HDL level is 48.25(15.75) mg/dl, mean triglycerides level is
155.75(104.75) mg/dl and mean total cholesterol is 183.25 (44.25) mg/dl.
Patients with CKD also experience dyslipidemia. The abnormal lipid and
lipoproteins in renal disease is varied, which include hypertriglyceridemia,
hypercholesterolemia, elevation of LDL and low HDL level. Abnormality of lipid
metabolism is caused by proteinuria that will increase 3-hydroxy-3-methylglutaryl
CoA reductase level resulting in hypercholesterolemia (Tonelli et al., 2014).
The mean urea level in patients is 81.93±42.63 mg/dl and creatinine
3.01±1.71 mg/dl. This result is not much different from the study by Fliser D in
2007 on nondiabetic patients with CKD stage 2-5 with mean serum creatinine
level 2.155.
(Fliser et al., 2007).
Mean glomerulus filtration rate (GFR) in the patients is 27.83±12.71
ml/min/1.73 m
2
, where the mean stage of CKD patients in is stage 4. This result is
similar with Chathoth S et al in 2016, where the GFR is 24.44±4.73
ml/min/1.73m
2
(CKD stage 4).
8
Fliser D et al in 2017 stated that mean GFR in
their study is 64.25 ml/min/1.73m
2
(CKD stage 3) (Fliser et al., 2007).
Fibroblast Growth Factor 23 (FGF23) is the most important phosphaturic
hormone. FGF23 is secreted by osteocytes and osteoblasts.
14
The main organ
target of FGF23 is the renal. Fibroblast Growth Factor 23 inhibits phosphate
reabsorption by suppresses sodium phosphate cotransporter 2a and 2c in proximal
tubules (Heron, 2018), (Shimada et al., 2004), (Kdigo, 2012). High level of
FGF23 in chronic kidney disease is stimulated by persistent hyperphosphatemia,
resulting in high plasma FGF23 concentrations and lead to target organ damage,
including cardiovascular system (Scialla & Wolf, 2014).
Mean FGF23 in this study is 518.66 mg/dl. The median FGF23 serum is
304.75 mg/dl, with minimum level is 39.56 pg/dl and maximum 1,777 pg/dl. This
study shows wide range FGF23 value that similar with study by Chathoth in 2016
that stated FGF23 level is volatile and has wide range (Chathoth et al., 2016)
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Sakan H et al in 2014 conducted study with 236 CKD patients and showed
that FGF23 serum is increased significantly in the early and intermediate CKD
with p<0.005.
19
Negishi K et al in 2010 stated that mean FGF23 serum in patients
who routinely had hemodialysis is 1,171±553 pg/ml (r=0.433, P=0.0001)
(Bergwitz & Jüppner, 2010)
Chathoth et al in 2016 got mean FGF23 serum in stage 3 CKD patients as
61.2±14.1 pg/dl, while in stage 4 CKD patients 118.5±62.3 pg/dl and patients in
stage 5 CKD is 1,526±1,456 pg/dl. This study showed that there is elevation in
FGF23 on stage 3 CKD patients and it skyrocketed in stage 5 patients.
A prospective study by Titan et al in 2009 in patients with early to
moderate CKD shows that there is elevation in plasma FGF23 level, and this
event will accelerate worsening the CKD.
21
Juppner in 2011 also found
unreasonable FGF23 elevation in patients with stage 3-5 CKD where serum levels
may increase to more than 1000 times (Bergwitz & Jüppner, 2010).
Systolic dysfunction represents abnormality of the left ventricle that
includes decreased of distensibility, impaired relaxation and abnormal filling that
may be found symptomatic or asymptomatic (Ito et al., 2005), (Faul et al., 2011).
Diastolic dysfunction of the left ventricle is the early stage of heart failure that can
occur without any sign of heart failure, but there is already abnormality in the
structure. Examination of e’ from Tissue Doppler imaging (TDI)
echocardiography is the first test that performed to assess the flow of left ventricle
tissues in the early mitral flow (Sanderson, 2007).
In this study we got mean septal e’ level 7.93 (2.55) cm/s (normal septal e’
≥8 cm/s) and lateral e’ 9.83 (2.32) cm/s (normal lateral e’ ≥10 cm/s). This study
result is similar with the study by Seifert. ME et al in 2014 at America that
observed 31 patients with 3 stage CKD and got the mean lateral e’ 8 cm/s, it also
showed that there is left ventricular diastolic dysfunction in 15 subjects from 48
subjects with p=1.00 (Zile et al., 2011).
In the study by Okamoto Y in Japan on patients with increased FGF23
level, it was found that the median e’ for diastolic dysfunction in 5 (4,3-6,5) cm/s
and p<0.05. Zoccali et al in 2004 stated that there is cardiovascular complications
in CKD patients that may cause diastolic dysfunction (Zoccali et al., 2004).
The result of correlation test between FGF233 serum with lateral e’ and
septal e’ as a component of left ventricle diastolic function from this study shows
that it’s statistically significant (p<0.05) with direction of negative correlation and
strong relationship (correlation coefficient septal e’ r=0.69 and lateral e’ r=0.65).
This study also found there’s strong relationship between FGF23 serum and septal
e’ also lateral e’, what we can conclude is the higher FGF23 serum level, the
lower e’ value that represents the left ventricle tissues and the poorer elasticity the
left ventricle tissues have, and it also represents that the left ventricular diastolic
dysfunction in chronic kidney disease patient is already happened.
We haven’t found another study investigating relationship between FGF23
serum with septal and lateral e’ that also evaluate left ventricle diastolic function
in patients with CKD. Faul et al in 2011 had already done it in animals, where the
Harun Harnavi, Febrianti Ika Kurnia, Kam Alexander
1902
result show increased in FGF23 level will stimulate myocytes hypertrophy of the
left ventricle and activated gene transcription that involved in cardiomyocytes
hypertrophy. The high FGF23 level is independently associated with left ventricle
hypertrophy and diastolic dysfunction.
While the study by Park M et al in 2012 shows reduced in GFR in patients
with CKD associated with LVH and left ventricular mass index (LVMI).
Okamoto Y et al in 2016 also found that FGF23 is associated with cardiac
hypertrophy and reduced ejection fraction of the ventricle. As much as 269
patients (69 females, 200 males) with ejection fraction >50% were studied. This
study shows insignificant relationship between FGF23 and left ventricular
diastolic dysfunction, where only 30 (11.2%) from 269 patients that experience
diastolic dysfunction.
28
It also happens in the study by Negishi K et al in 2010 in
patients who routinely undergo hemodialysis, only LVMI is significantly
correlated to FGF23 with r=0.268 and p=0.039.
Spearman test result between GFR and FGF23 serum level in this study
shows statistically significant result (p<0.05) with direction of negative
correlation and moderate relationship (correlation coefficient r= -0.733).
Correlation between GFR and FGF23 serum level will be higher. From this study
we can see that the poorer renal function is, the higher phosphate retention that
happen and it represented from increased of FGF23 serum.
According to Fliser D et al in 2007 in nondiabetic patients with stage 3-5
CKD it found that there’s negative correlation (r= -0.6) between GFE and FGF23
with p<0.001. In this study we get independent predictor factor that significantly
has a role in the progressivity of CKD, which is GFR (p<0.001), FGF23
(p=0.005).
69
Another study by Orlando Gutierrez et al in 2002 also found there’s
significant correlation between FGF23 and GFR with r
2
=0.44 and p=0.001. The
lower GFR represents poorer renal function that will increase phosphate retention
and lead to FGF23 elevation. Elevation of FGF23 will also worsen the damage in
the kidney and it can affect remodeling of the heart (Faul et al., 2011). Limitation
of this study is there may be genetic factors that can affect FGF23 level and the
diastolic function was not evaluated
CONCLUSION
There is increased in FGF23 serum in patients with CKD. There is
reduction in the lateral e’ value as a component of diastolic function in patients
with CKD. There is strong correlation between FGF23 serum with lateral e’ as a
component of diastolic function in patients with CKD with the direction of
negative correlation. There is strong correlation between FGF23 serum level with
GFR in patients with CKD and negative correlation direction.
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