High Plasma Levels of Fibroblast Growth Factor 23 Are Associated with Increased Risk of COVID-19 in End-Stage Renal Disease Patients on Hemodialysis: Results of a Prospective Cohort

Abstract

End-stage renal disease (ESRD) patients are a population with high rates of COVID-19 and mortality. These patients present a low response to anti-SARS-CoV-2 immunization, which is associated with immune dysfunction. ESRD patients also present high plasma titers of Fibroblast Growth Factor 23 (FGF23), a protein hormone that reduces immune response in vivo and in vitro. Increased FGF23 levels associate with higher infection-related hospitalizations and adverse infectious outcomes. Thus, we evaluated whether ESRD patients with high FGF23 titers have an increased rate of SARS-CoV-2 infection. Methods: We performed a prospective cohort of ESRD patients in hemodialysis who had measurements of plasma intact FGF23 in 2019. We determined COVID-19 infections, hospitalizations, and mortality between January 2020 and December 2021. Results: We evaluated 243 patients. Age: 60.4 ± 10.8 years. Female: 120 (49.3%), diabetes: 110 (45.2%). During follow-up, 45 patients developed COVID-19 (18.5%), 35 patients were hospitalized, and 12 patients died (mortality rate: 26.6%). We found that patients with higher FGF23 levels (defined as equal or above median) had a higher rate of SARS-CoV-2 infection versus those with lower levels (18.8% versus 9.9%; Hazard ratio: 1.92 [1.03–3.56], p = 0.039). Multivariate analysis showed that increased plasma FGF23 was independently associated with SARS-CoV-2 infection and severe COVID-19. Discussion: Our results suggest that high plasma FGF23 levels are a risk factor for developing COVID-19 in ESRD patients. These data support the potential immunosuppressive effects of high circulating FGF23 as a factor implicated in the association with worse clinical outcomes. Further data are needed to confirm this hypothesis.

Full text

Citation: Toro, L.; Michea, L.;
Parra-Lucares, A.; Mendez-Valdes,
G.; Villa, E.; Bravo, I.; Pumarino, C.;
Ayala, P.; Sanhueza, M.E.; Torres, R.;
et al. High Plasma Levels of
Fibroblast Growth Factor 23 Are
Associated with Increased Risk of
COVID-19 in End-Stage Renal
Disease Patients on Hemodialysis:
Results of a Prospective Cohort.
Toxins 2023,15, 97. https://doi.org/
10.3390/toxins15020097
Received: 24 October 2022
Revised: 20 December 2022
Accepted: 6 January 2023
Published: 19 January 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
toxins
Article
High Plasma Levels of Fibroblast Growth Factor 23 Are
Associated with Increased Risk of COVID-19 in End-Stage
Renal Disease Patients on Hemodialysis: Results of a
Prospective Cohort
Luis Toro 1,2,3,*, Luis Michea 1,4, Alfredo Parra-Lucares 5,6, Gabriel Mendez-Valdes 7, Eduardo Villa 7,
Ignacio Bravo 7, Catalina Pumarino 7, Patricia Ayala 2, María Eugenia Sanhueza 1,3, Ruben Torres 1,3,
Leticia Elgueta 1,3, Sebastian Chavez 8, Veronica Rojas 2,5 and Miriam Alvo 1
1Division of Nephrology, Department of Medicine, Hospital Clinico Universidad de Chile,
Santiago 8380456, Chile
2Centro de Investigación Clínica Avanzada, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile
3Fuerza de Trabajo Anti-COVID-19 (FUTAC Team), Sociedad Chilena de Nefrología, Santiago 7500781, Chile
4Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile,
Santiago 8380453, Chile
5Division of Critical Care Medicine, Department of Medicine, Hospital Clinico Universidad de Chile,
Santiago 8380456, Chile
6MD PhD Degree Program, Faculty of Medicine, Universidad de Chile, Santiago 8380456, Chile
7School of Medicine, Faculty of Medicine, Universidad de Chile, Santiago 8380456, Chile
8Division of Internal Medicine, Department of Medicine, Hospital Clinico Universidad de Chile,
Santiago 8380456, Chile
*Correspondence: ltoro@med.uchile.cl; Tel.: +56-2-29788423
Abstract:
End-stage renal disease (ESRD) patients are a population with high rates of COVID-19
and mortality. These patients present a low response to anti-SARS-CoV-2 immunization, which is
associated with immune dysfunction. ESRD patients also present high plasma titers of Fibroblast
Growth Factor 23 (FGF23), a protein hormone that reduces immune response
in vivo
and
in vitro
.
Increased FGF23 levels associate with higher infection-related hospitalizations and adverse infectious
outcomes. Thus, we evaluated whether ESRD patients with high FGF23 titers have an increased
rate of SARS-CoV-2 infection. Methods: We performed a prospective cohort of ESRD patients in
hemodialysis who had measurements of plasma intact FGF23 in 2019. We determined COVID-19
infections, hospitalizations, and mortality between January 2020 and December 2021. Results: We
evaluated 243 patients. Age: 60.4
±
10.8 years. Female: 120 (49.3%), diabetes: 110 (45.2%). During
follow-up, 45 patients developed COVID-19 (18.5%), 35 patients were hospitalized, and 12 patients
died (mortality rate: 26.6%). We found that patients with higher FGF23 levels (defined as equal or
above median) had a higher rate of SARS-CoV-2 infection versus those with lower levels (18.8% versus
9.9%; Hazard ratio: 1.92 [1.03–3.56], p= 0.039). Multivariate analysis showed that increased plasma
FGF23 was independently associated with SARS-CoV-2 infection and severe COVID-19. Discussion:
Our results suggest that high plasma FGF23 levels are a risk factor for developing COVID-19 in ESRD
patients. These data support the potential immunosuppressive effects of high circulating FGF23 as a
factor implicated in the association with worse clinical outcomes. Further data are needed to confirm
this hypothesis.
Keywords:
end-stage renal disease; hemodialysis; FGF23; COVID-19; SARS-CoV-2; immune response;
mortality
Key Contribution:
In end-stage renal disease patients on hemodialysis, high plasma levels of Fibrob-
last Growth Factor 23 (FGF23) is a risk factor for SARS-CoV-2 infection and severe COVID-19.
Toxins 2023,15, 97. https://doi.org/10.3390/toxins15020097 https://www.mdpi.com/journal/toxins

Toxins 2023,15, 97 2 of 13
1. Introduction
The SARS-CoV-2 pandemic has had a massive impact worldwide over the past two
years, with over 620,000,000 infections and over 6,500,000 deaths as of October 2022 [
1
].
Patients with end-stage renal disease (ESRD) in renal replacement therapy, such as renal
transplantation, peritoneal dialysis, and hemodialysis, are a population with higher infec-
tion rates and adverse outcomes, including hospitalizations, requirements of mechanical
ventilation and deaths, compared to the general population [2–5].
ESRD patients develop an immune dysfunction that includes impairment in both
innate and adaptive immune response [
6
], including decreased neutrophil bacterial activity,
monocyte hypoactivity, impaired activity of T lymphocytes, and a decreased number of B
lymphocytes [
6
]. This immune impairment is associated with a higher rate of infections
and up to 100-fold higher infection-related mortality than the general population [
7
].
ESRD patients also present a high failure rate of immunization against viruses such as
influenza, despite appropriate vaccination [
6
], and immunization against SARS-CoV-2
produced a lower humoral response in ESRD patients versus control subjects [
7
]. Patients
on hemodialysis who were vaccinated with mRNA vaccines induce anti-SARS-CoV-2
antibodies [
8
], although at lower concentrations than healthy volunteers [
9
]. In addition,
they have an early decrease in antibody titers compared to the general
population [10–12]
.
The causal mechanisms leading to the immune impairment of ESRD patients are not
entirely understood.
ESRD patients present high plasma levels of Fibroblast Growth Factor 23 (FGF23), a
protein hormone involved in the regulation of vitamin D and phosphate metabolism [
13
].
In addition to its role in mineral homeostasis, recent evidence shows that FGF23 acts as
an immunomodulatory hormone, affecting the immune response due to indirect actions
on non-immune tissues and direct actions on immune cells, including macrophages and
polymorphonuclear neutrophils. Elevated titers of FGF23 are associated with increased
inflammation in patients [
14
], and increased levels of FGF23 induce immune dysfunction in
experimental murine models and human white blood cells
in vitro
[
15
]. In addition, clinical
studies in ESRD patients [
16
] and non-ESRD chronic kidney disease patients [
17
] show that
high plasma levels of FGF23 are associated with an increased infection rate compared to
patients with lower titers.
We propose that high baseline plasma levels of FGF23 are associated with increased
risk and severity of SARS-CoV-2 infection in the ESRD population. Therefore, we evaluated
a multicenter prospective cohort of adult ESRD patients in chronic hemodialysis to deter-
mine the association between high FGF23 titers and the incidence of SARS-CoV-2 infection
and COVID-related adverse clinical outcomes.
2. Results
2.1. Baseline Characteristics
We evaluated 243 end-stage renal disease patients on chronic hemodialysis for the
study. Table 1presents the baseline characteristics of these patients. Age:
60.4 ±10.8 years
.
Patients over 60 years: 132 (54.3%). Female: 120 (49.3%). Diabetes: 110 (45.2%), hemodialy-
sis vintage: 25 [15–40] months. Baseline intact FGF23 levels: 319 [204–600] pg/mL.
2.2. COVID-19-Related Events and Predictors of SARS-CoV-2 Infection
During follow-up (January 2020–December 2021), 45 patients (18.5%) had SARS-CoV-2
infection, and 35 patients (14.4%) presented COVID-related hospitalizations. Regarding
mortality, 32 patients (13.1%) died during follow-up: 12 patients (4.9%) had COVID-related
deaths, and 20 (8.2%) died of other causes, where cardiovascular diseases were the most
frequent causes. Regarding the period of COVID-19 events, 40/45 of total SARS-CoV-2
infections (88.9%) and 10/12 of total COVID-related deaths (83.3%) occurred before the
initiation of the vaccination campaign in hemodialysis patients (initiated in February 2021
in Chile).

Toxins 2023,15, 97 3 of 13
Table 1. Baseline characteristics of patients. Information on the total cohort and stratification by the
presence of SARS-CoV-2 infection are presented. Data are expressed as number (N) and percentage
(%) for categorical variables and as mean
±
standard deviation or median [p25–p75] for continuous
variables. The p-values of patients who presented SARS-CoV-2 infection vs. those without SARS-
CoV-2 infection are detailed.
Characteristics Total Cohort Patients without
SARS-CoV-2 Infection
Patients with
SARS-CoV-2 Infection pValue
N % N % N %
Total 243 100% 198 81.48% 45 18.52% -
Sex
Female (%) 120 49.38% 102 51.52% 18 40.00%
0.163
Male (%) 123 50.62% 96 48.48% 27 60.00%
Age group
18–39 years (%) 8 3.29% 8 4.04% 0 0.00%
0.024
40–49 years (%) 37 15.23% 35 17.68% 2 4.44%
50–59 years (%) 66 27.16% 56 28.28% 10 22.22%
60–69 years (%) 95 39.09% 73 36.87% 22 48.89%
70–79 years (%) 31 12.76% 23 11.62% 8 17.78%
≥80 years (%) 6 2.47% 3 1.52% 3 6.67%
Comorbidities
Diabetes (%) 110 45.27% 83 41.92% 27 60.00% 0.028
Hypertension (%) 218 89.71% 177 89.39% 41 91.11% 0.732
Heart failure (%) 40 16.46% 31 15.66% 9 20.00% 0.478
Vascular access Arteriovenous fistula (%) 140 57.61% 111 56.06% 29 64.44% 0.304
Hemodialysis catheter (%) 103 42.39% 87 43.94% 16 35.56%
Hemodialysis
parameters
Residual diuresis (%) 80 32.92% 67 33.84% 13 28.89% 0.524
Hemodialysis vintage
(months) 25 [15–40] 25 [15–39] 26 [18–45] 0.481
Dry weight (kg) 70.20 ±7.66 70.54 ±7.45 68.71 ±8.44 0.148
Single pool Kt/V (spKt/V) 1.31 ±0.20 1.31 ±0.21 1.34 ±0.22 0.413
Medications
Angiotensin receptor
blockers (%) 175 72.02% 142 71.72% 33 73.33% 0.827
Calcium channel blockers
(%) 178 73.25% 147 74.24% 31 68.89% 0.464
Loop diuretics (%) 46 18.93% 35 17.68% 11 24.44% 0.296
Vitamin D analogs (%) 56 23.05% 46 23.23% 10 22.22% 0.885
Phosphate binders (%) 209 86.01% 170 85.86% 39 86.67% 0.888
Calcimimetics (%) 48 19.75% 40 20.20% 8 17.78% 0.712
Erythropoietic stimulating
agents (%) 203 83.54% 166 83.84% 37 82.22% 0.792
Laboratory
parameters
Blood ureic nitrogen
(mg/dL) 64.06 ±12.70 64.56 ±12.31 61.86 ±14.25 0.199
Intact parathormone
(pg/mL) 565 [284–884] 572 [275–888] 511 [293–795] 0.433
25-OH vitamin D (ng/mL) 19.05 ±8.53 19.31 ±8.57 17.93 ±8.36 0.328
Serum phosphate (mg/dL) 5.15 ±1.08 5.16 ±1.12 5.08 ±8.78 0.664
Total serum calcium
(mg/dL) 8.22 ±0.98 8.21 ±0.98 8.26 ±1.01 0.785
Ferritin (ng/mL) 467.72 ±168.45 464.82 ±170.17 480.51 ±161.89 0.573
Hemoglobin (g/dL) 9.45 ±1.33 9.42 ±1.36 9.61 ±1.20 0.379
Intact fibroblast growth
factor 23 (pg/mL) 319 [204–600] 288 [195–580] 436 [269–669] 0.026

Toxins 2023,15, 97 4 of 13
When comparing patients who developed SARS-CoV-2 infection versus those with-
out infection (Table 1), infected patients were older (66.2
±
9.3 versus 59.1
±
10.7 years,
p< 0.001
) and had a higher rate of diabetes (60.0 vs. 41.9%, p= 0.028). Concerning ad-
ditional baseline variables before the SARS-CoV-2 infection, the only parameter which
differed between both groups was plasma FGF23 which was higher in those who devel-
oped COVID-19 (436 [269–669] vs. 288 [195–580] pg/mL, p= 0.026). This association was
sustained after statistical adjustment for age and other comorbidities.
2.3. Relation between Plasma FGF23 Levels and COVID-19-Related Events
When comparing according to their baseline plasma FGF23 levels (Table 2), patients
who had higher plasma FGF23 levels (equal to or above p50 of the total sample) had lower
single-pool Kt/V (1.27
±
0.20 versus 1.35
±
0.21 years, p= 0.003), higher use of recombinant
erythropoietin (88.5 vs. 78.5%, p= 0.035) and increased parathormone (PTH) levels (598
[465–703] vs. 204 [160–267] pg/mL, p< 0.001). In addition, people who had higher FGF23
titers had increased infection rates (23.7 vs. 13.2%, p= 0.034; Figure 1) and increased rates
of severe COVID-19 (patients with COVID-related hospitalizations and deaths) (19.6 vs.
9.9%, p= 0.032; Figure 2).
Table 2.
Comparison of patients according to plasma FGF23 levels. Information on the total cohort
and stratification by baseline plasma intact FGF23 levels are presented. Data are expressed as number
(N) and percentage (%) for categorical variables and as mean
±
standard deviation or median
[p25–p75] for continuous variables. p-values of low FGF23 vs. high FGF23 are detailed.
Characteristics Total Cohort Patients with Low
FGF23 Levels (<p50)
Patients with High
FGF23 Levels (≥p50) p-Value
N % N % N %
Total 243 100% 121 49.79% 122 50.21% -
Sex
Female (%) 120 49.38% 57 47.11% 63 51.64%
0.480
Male (%) 123 50.62% 64 52.89% 59 48.36%
Age group
18–39 years (%) 8 3.29% 6 4.96% 2 1.64%
0.236
40–49 years (%) 37 15.23% 22 18.18% 15 12.30%
50–59 years (%) 66 27.16% 29 23.97% 37 30.33%
60–69 years (%) 95 39.09% 50 41.32% 45 36.89%
70–79 years (%) 31 12.76% 12 9.92% 19 15.57%
≥80 years (%) 6 2.47% 2 1.65% 4 3.28%
Comorbidities
Diabetes (%) 110 45.27% 49 40.50% 61 50.00% 0.137
Hypertension (%) 218 89.71% 109 90.08% 109 89.34% 0.850
Heart failure (%) 40 16.46% 19 15.70% 21 17.21% 0.751
Vascular access Arteriovenous fistula (%) 140 57.61% 74 61.16% 66 54.10% 0.266
Hemodialysis catheter (%) 103 42.39% 47 38.84% 56 45.90%
Hemodialysis
parameters
Residual diuresis (%) 80 32.92% 42 34.71% 38 31.15% 0.555
Hemodialysis vintage (months) 25 [15–40] 27 [16–42] 23 [14–39] 0.128
Dry weight (kg) 70.20 ±7.66 70.47 ±7.74 69.92 ±7.60 0.574
Single pool Kt/V (spKt/V) 1.31 ±0.20 1.35 ±0.21 1.27 ±0.20 0.003
Medications
Angiotensin receptor blockers (%) 175 72.02% 92 76.03% 83 68.03% 0.165
Calcium channel blockers (%) 178 73.25% 91 75.21% 87 71.31% 0.493
Loop diuretics (%) 46 18.93% 23 19.01% 23 18.85% 0.975
Vitamin D analogs (%) 56 23.05% 29 23.97% 27 22.13% 0.734
Phosphate binders (%) 209 86.01% 107 88.43% 102 83.61% 0.279
Calcimimetics (%) 48 19.75% 23 19.01% 25 20.49% 0.771
Erythropoietic stimulating agents (%) 203 83.54% 95 78.51% 108 88.52% 0.035

Toxins 2023,15, 97 5 of 13
Table 2. Cont.
Characteristics Total Cohort Patients with Low
FGF23 Levels (<p50)
Patients with High
FGF23 Levels (≥p50) p-Value
N % N % N %
Laboratory
parameters
Blood ureic nitrogen (mg/dL) 64.06 ±12.70 62.86 ±13.56 65.24 ±11.73 0.145
Intact parathormone (pg/mL) 565 [284–884] 379 [233–710] 697 [479–918] 0.001
25-OH vitamin D (ng/mL) 19.05 ±8.53 19.14 ±8.12 18.96 ±8.96 0.868
Serum phosphate (mg/dL) 5.15 ±1.08 5.17 ±1.13 5.12 ±1.03 0.725
Total serum calcium (mg/dL) 8.22 ±0.98 8.24 ±1.05 8.19 ±0.92 0.668
Ferritin (ng/mL) 467.72 ±168.45 472.89 ±167.94 462.60 ±169.49 0.635
Hemoglobin (g/dL) 9.45 ±1.33 9.36 ±1.35 9.55 ±1.31 0.263
Intact fibroblast growth factor 23
(pg/mL) 319 [204–600] 204 [160–267] 598 [465–703] <0.001
Clinical
outcomes
SARS-CoV-2 infection (%) 45 18.52% 16 13.22% 29 23.77% 0.034
COVID-19-related hospitalization (%)
35 14.40% 12 9.92% 23 18.85% 0.047
COVID-19-related death (%) 12 4.94% 4 3.31% 8 6.56% 0.242
COVID-19-non-related death (%) 20 8.23% 8 6.61% 12 9.84% 0.360
COVID-19-related hospitalization or
death (%) 36 14.81% 12 9.92% 24 19.67% 0.032
Multivariate analysis indicates that SARS-CoV-2 infection predictors (Table 3) included
age above 60 years (HR: 2.63 [1.35–5.11], p= 0.004), presence of diabetes (HR: 1.92 [1.05–3.48],
p= 0.033) and high plasma FGF23 levels (HR: 1.92 [1.03–3.56], p= 0.039). No association
was detected with another baseline clinical and laboratory variables. Finally, multivariate
analysis indicates that the predictors of severe COVID-19 (Table 4) also included age above
60 years (HR: 2.65 [1.22–5.77], p= 0.014), presence of diabetes (HR: 2.52 [1.25–5.06],
p= 0.009
)
and high plasma FGF23 levels (HR: 2.12 [1.04–4.28], p= 0.036).
Toxins 2023, 15, x FOR PEER REVIEW 5 of 12
Loop diuretics (%) 46 18.93% 23 19.01% 23 18.85% 0.975
Vitamin D analogs (%) 56 23.05% 29 23.97% 27 22.13% 0.734
Phosphate binders (%) 209 86.01% 107 88.43% 102 83.61% 0.279
Calcimimetics (%) 48 19.75% 23 19.01% 25 20.49% 0.771
Erythropoietic stimulating agents (%) 203 83.54% 95 78.51% 108 88.52% 0.035
Laboratory
parameters
Blood ureic nitrogen (mg/dL) 64.06 ± 12.70 62.86 ± 13.56 65.24 ± 11.73 0.145
Intact parathormone (pg/mL) 565 [284–884] 379 [233–710] 697 [479–918] 0.001
25-OH vitamin D (ng/mL) 19.05 ± 8.53 19.14 ± 8.12 18.96 ± 8.96 0.868
Serum phosphate (mg/dL) 5.15 ± 1.08 5.17 ± 1.13 5.12 ± 1.03 0.725
Total serum calcium (mg/dL) 8.22 ± 0.98 8.24 ± 1.05 8.19 ± 0.92 0.668
Ferritin (ng/mL) 467.72 ± 168.45 472.89 ± 167.94 462.60 ± 169.49 0.635
Hemoglobin (g/dL) 9.45 ± 1.33 9.36 ± 1.35 9.55 ± 1.31 0.263
Intact fibroblast growth factor 23 (pg/mL) 319 [204–600] 204 [160–267] 598 [465–703] < 0.001
Clinical out-
comes
SARS-CoV-2 infection (%) 45 18.52% 16 13.22% 29 23.77% 0.034
COVID-19-related hospitalization (%) 35 14.40% 12 9.92% 23 18.85% 0.047
COVID-19-related death (%) 12 4.94% 4 3.31% 8 6.56% 0.242
COVID-19-non-related death (%) 20 8.23% 8 6.61% 12 9.84% 0.360
COVID-19-related hospitalization or death
(%) 36 14.81% 12 9.92% 24 19.67% 0.032
Figure 1. Infection rate of SARS-CoV-2 during follow-up, stratified by baseline plasma FGF23 levels.
Cumulative incidence rate of SARS-CoV-2 infection in end-stage renal disease patients in hemodi-
alysis. Patients were classified according to baseline plasma intact FGF23 levels: low FGF23 (n =
121—blue line) and high FGF23 (n = 122—red line).
Figure 1.
Infection rate of SARS-CoV-2 during follow-up, stratified by baseline plasma FGF23
levels. Cumulative incidence rate of SARS-CoV-2 infection in end-stage renal disease patients in
hemodialysis. Patients were classified according to baseline plasma intact FGF23 levels: low FGF23
(n = 121—blue line) and high FGF23 (n = 122—red line).

Toxins 2023,15, 97 6 of 13
Toxins 2023, 15, x FOR PEER REVIEW 6 of 12
Figure 2. Severe COVID-19 rate during follow-up, according to baseline plasma FGF23 levels. Cu-
mulative incidence of severe COVID-19 in end-stage renal disease patients in hemodialysis. Severe
COVID-19 is defined as the requirements for hospitalizations or COVID-related deaths. Patients
were classified according to baseline plasma intact FGF23 levels: low FGF23 (n = 121—blue line) and
high FGF23 (n = 122—red line).
Multivariate analysis indicates that SARS-CoV-2 infection predictors (Table 3) in-
cluded age above 60 years (HR: 2.63 [1.35–5.11], p = 0.004), presence of diabetes (HR: 1.92
[1.05–3.48], p = 0.033) and high plasma FGF23 levels (HR: 1.92 [1.03–3.56], p = 0.039). No
association was detected with another baseline clinical and laboratory variables. Finally,
multivariate analysis indicates that the predictors of severe COVID-19 (Table 4) also in-
cluded age above 60 years (HR: 2.65 [1.22–5.77], p = 0.014), presence of diabetes (HR: 2.52
[1.25–5.06], p = 0.009) and high plasma FGF23 levels (HR: 2.12 [1.04–4.28], p = 0.036).
Table 3. Determination of predictors of SARS-CoV-2 infection during a 2-year follow-up. We pre-
sent a univariate and multivariate logistic regression of several clinical, demographic, and labora-
tory parameters of patients. The variables which were included in the multivariate model were
those which had a p-value below 0.2 in the univariate analysis. Variables that were considered pre-
dictors of SARS-CoV-2 infection were those with a p-value below 0.05 in the final model. Hazard
ratios, the 95% confidence interval (95%CI), and the p-value are detailed.
Univariate Analysis Multivariate Analysis
Variable Hazard ratio 95% CI p-Value Hazard ratio 95% CI p-Value
Male 1.551 0.854 2.816 0.149 1.597 0.875 2.915 0.127
Age >60 years 2.634 1.360 5.101 0.004 2.630 1.352 5.118 0.004
Diabetes 1.909 1.051 3.465 0.034 1.916 1.053 3.485 0.033
Hypertension 1.192 0.427 3.328 0.737
Heart failure 1.315 0.634 2.731 0.462
Vascular access (fistula) 1.415 0.768 2.604 0.265
Residual diuresis 0.819 0.430 1.561 0.545
Hemodialysis vintage 1.004 0.991 1.017 0.568
Dry weight 0.973 0.938 1.008 0.128 0.981 0.946 1.017 0.301
spKt/V 1.904 0.469 7.738 0.368
Use of ARBs 1.076 0.556 2.083 0.829
Use of CCBs 0.798 0.424 1.500 0.483
Figure 2.
Severe COVID-19 rate during follow-up, according to baseline plasma FGF23 levels.
Cumulative incidence of severe COVID-19 in end-stage renal disease patients in hemodialysis. Severe
COVID-19 is defined as the requirements for hospitalizations or COVID-related deaths. Patients were
classified according to baseline plasma intact FGF23 levels: low FGF23 (n = 121—blue line) and high
FGF23 (n = 122—red line).
Table 3.
Determination of predictors of SARS-CoV-2 infection during a 2-year follow-up. We present
a univariate and multivariate logistic regression of several clinical, demographic, and laboratory
parameters of patients. The variables which were included in the multivariate model were those
which had a p-value below 0.2 in the univariate analysis. Variables that were considered predictors of
SARS-CoV-2 infection were those with a p-value below 0.05 in the final model. Hazard ratios, the 95%
confidence interval (95%CI), and the p-value are detailed.
Univariate Analysis Multivariate Analysis
Variable Hazard
Ratio 95% CI p-Value Hazard
Ratio 95% CI p-Value
Male 1.551 0.854 2.816 0.149 1.597 0.875 2.915 0.127
Age > 60 years 2.634 1.360 5.101 0.004 2.630 1.352 5.118 0.004
Diabetes 1.909 1.051 3.465 0.034 1.916 1.053 3.485 0.033
Hypertension 1.192 0.427 3.328 0.737
Heart failure 1.315 0.634 2.731 0.462
Vascular access
(fistula) 1.415 0.768 2.604 0.265
Residual diuresis
0.819 0.430 1.561 0.545
Hemodialysis
vintage 1.004 0.991 1.017 0.568
Dry weight 0.973 0.938 1.008 0.128 0.981 0.946 1.017 0.301
spKt/V 1.904 0.469 7.738 0.368
Use of ARBs 1.076 0.556 2.083 0.829
Use of CCBs 0.798 0.424 1.500 0.483
Use of loop
diuretics 1.387 0.702 2.737 0.346

Toxins 2023,15, 97 7 of 13
Table 3. Cont.
Univariate Analysis Multivariate Analysis
Variable Hazard
Ratio 95% CI p-Value Hazard
Ratio 95% CI p-Value
Use of vitamin D
analogs 0.959 0.475 1.938 0.908
Use of phosphate
binders 1.073 0.454 2.534 0.873
Use of
calcimimetics 0.899 0.419 1.931 0.786
Use of ESAs 0.840 0.391 1.803 0.654
Blood ureic
nitrogen 0.987 0.963 1.010 0.261
Intact PTH 1.000 0.999 1.000 0.420
25-OH vitamin D
0.982 0.948 1.016 0.295
Serum
phosphate 0.941 0.722 1.226 0.654
Total serum
calcium 1.060 0.789 1.425 0.697
Ferritin 1.000 0.999 1.002 0.580
Hemoglobin 1.091 0.884 1.347 0.418
Intact FGF23
(>p50) 1.917 1.041 3.530 0.037 1.920 1.035 3.562 0.039
Table 4.
Determination of predictors of severe COVID-19 during a 2-year follow-up. We present
a univariate and multivariate logistic regression of several clinical, demographic, and laboratory
variables of patients. Severe COVID-19 is defined as the requirements for hospitalizations or COVID-
related deaths. The variables which were included in the multivariate model were those which had
ap-value below 0.2 in the univariate analysis. Variables that were considered predictors of severe
COVID-19 were those which had a p-value below 0.05 in the final model. Hazard ratios, the 95%
confidence interval (95%CI), and the p-value are detailed.
Univariate Analysis Multivariate Analysis
Variable Hazard
Ratio 95% CI p-Value Hazard
Ratio 95% CI p-Value
Male 1.823 0.923 3.600 0.084 1.913 0.963 3.800 0.064
Age > 60 years 2.841 1.336 6.043 0.007 2.655 1.221 5.776 0.014
Diabetes 2.546 1.273 5.091 0.008 2.526 1.259 5.066 0.009
Hypertension 0.913 0.323 2.583 0.865
Heart failure 1.749 0.822 3.719 0.147 1.433 0.660 3.110 0.363
Vascular access
(fistula) 1.223 0.626 2.390 0.556
Residual diuresis
0.668 0.314 1.420 0.294
Hemodialysis
vintage 1.005 0.991 1.019 0.496
Dry weight 0.970 0.932 1.010 0.139 0.979 0.940 1.020 0.319
spKt/V 2.258 0.472 10.809 0.308

Toxins 2023,15, 97 8 of 13
Table 4. Cont.
Univariate Analysis Multivariate Analysis
Variable Hazard
Ratio 95% CI p-Value Hazard
Ratio 95% CI p-Value
Use of ARBs 0.879 0.432 1.786 0.721
Use of CCBs 0.718 0.359 1.435 0.348
Use of loop
diuretics 1.242 0.566 2.725 0.589
Use of vitamin D
analogs 1.111 0.523 2.363 0.784
Use of phosphate
binders 1.017 0.395 2.615 0.972
Use of
calcimimetics 1.021 0.447 2.330 0.961
Use of ESAs 0.755 0.331 1.724 0.505
Blood ureic
nitrogen 0.984 0.959 1.011 0.239
Intact PTH 1.000 0.999 1.001 0.866
25-OH vitamin D
0.982 0.945 1.021 0.363
Serum
phosphate 0.869 0.645 1.171 0.356
Total serum
calcium 1.125 0.807 1.568 0.487
Ferritin 1.001 0.999 1.003 0.558
Hemoglobin 1.034 0.813 1.315 0.783
Intact FGF23
(>p50) 2.116 1.058 4.232 0.034 2.121 1.049 4.287 0.036
3. Discussion
3.1. Association between Plasma Levels of FGF23 and COVID-19-Related Outcomes
This multicenter observational study showed that patients with end-stage renal disease
in chronic hemodialysis who presented high baseline plasma levels of FGF23 had a higher
rate of SARS-CoV-2 infection and severe COVID-19, including hospitalizations and deaths.
In addition, this risk factor was independent of other variables associated with increased
infections, such as age and diabetes. This study is one of the first clinical studies that
evaluated the association between plasma FGF23 levels and COVID-19 in patients on renal
replacement therapy. Currently, most studies evaluating the association between plasma
FGF23 levels and infectious morbidity were performed before the SARS-CoV-2 pandemic
and evaluated other infection-related hospitalizations caused by severe bacterial and viral
infections [
16
,
17
]. A recent study determined that patients with asymptomatic SARS-CoV-2
infection had higher values of fibroblast growth factors (including FGF19, FGF21, and
FGF23) compared to those with mild symptomatic COVID-19 [18].
3.2. Association between High Baseline FGF23 Levels and Development of Severe Infections
in Humans
A posthoc analysis of the Hemodialysis Study (HEMO study) in ESRD patients on
hemodialysis found that patients with high baseline FGF23 levels had an increased rate of a
combined outcome of first infectious hospitalization or infectious death in a median follow-
up of three years [
16
]. This association was independent of other associated variables.
In addition, a posthoc analysis of the Chronic Kidney Insufficiency Cohort Study (CRIC

Toxins 2023,15, 97 9 of 13
study) in non-terminal chronic kidney disease (CKD) patients found that patients who
had high baseline plasma titers of C-terminal FGF23 had an increased risk of first-time
hospitalization with a severe infection, including pneumonia, urinary tract infection, and
septicemia [
17
]. This association was independent of other inflammatory and bone mineral
metabolism parameters. In addition, a post hoc analysis of the Cardiovascular Health Study
(CHS study) in community-dwelling adults over 65 years (with or without CKD) found that
those with high FGF23 levels had a higher rate of first infection-related hospitalization [
19
].
This association was observed in both patients with CKD and without CKD. These results,
including our data, support the potential role of increased baseline FGF23 levels as a risk
factor for severe infections.
3.3. High FGF23 Levels and Severe Infections: Correlation or Causality?
Previous data have shown that high FGF23 titers are associated with increased rates
of cardiovascular events in CKD patients [
13
,
20
,
21
] and the general population [
22
]. FGF23
has deleterious cardiovascular effects, including cardiac hypertrophy [
23
–
25
], arterial wall
calcification, and alteration of intracellular calcium and smooth muscle cell contractility [
26
].
There is currently limited evidence concerning the potential mechanisms related to the
association of high baseline FGF23 levels and increased risk of severe infections. FGF23
is a negative modulator of the 1-alpha hydroxylase, the enzyme responsible for active
vitamin D synthesis (1,25 dihydroxy vitamin D), both in renal [
27
,
28
] and extrarenal tissue,
including monocytes [
29
]. Vitamin D is a hormone that modules immune response [
30
],
and low vitamin D levels plus high FGF23 levels (a common condition in ESRD patients)
are associated with adverse infectious outcomes [16]. A translational study demonstrated
that FGF23 per se causes an immune dysfunction in experimental murine models and white
blood cells obtained from healthy volunteers [
15
,
31
]. These effects include decreased neu-
trophil selectin-mediated rolling and chemokine-induced recruitment
in vitro
. In addition,
in experimental models of bacterial pneumonia in CKD mice, the administration of FGF23
exacerbated disease activity and decreased murine survival [
15
]. Moreover, pharmacolog-
ical blockage of FGF23 using specific anti-FGF23 antibodies [
15
] and short-acting small
molecules reversibly inhibiting FGF23 [
30
,
32
] prevent cardiac and immune effects
in vitro
and in CKD mice. The mechanisms have not been clarified yet. It has been proposed
that FGF23 may activate the FGFR2 receptor in neutrophil cells and cause indirect effects
mediated by the FGFR receptors in other cells of the inflammatory milieu [30].
3.4. Limitations and Strengths of the Study
Concerning the strengths of this work is the prospective design, which evaluated
this group of patients before and during the first two years of the SARS-CoV-2 pandemic,
including relevant demographic, clinical, and laboratory baseline data, that was associated
with clinical outcomes in ESRD patients. In addition, we had detailed data on COVID-19-
related events obtained by direct information from hemodialysis centers and the national
COVID-19 database, with follow-up data of all patients during the study period.
In relation to the limitations of this study, its (non-interventional) observational design
has biases, as some potential influencing variables are difficult to isolate. For example,
people who had a higher incidence of COVID-19, besides higher levels of plasma FGF23,
also were older and had increased rates of diabetes, known risk factors for COVID-19 in the
general population and ESRD patients [
5
,
33
], which may have influenced the differences
in clinical outcomes. Additionally, patients with high FGF23 levels also had high PTH
levels. PTH is modulated by FGF23 [
13
], and low PTH levels have been associated with
increased infection rates in ESRD patients [
34
,
35
]. To decrease this bias, we used statistical
adjustments, including potential confounding variables, such as multivariate regressions,
to evaluate the association of FGF23 levels and adverse clinical outcomes regardless of other
demographical and clinical variables. Another limitation is the lack of data on C-terminal
FGF23 levels in these patients. Similar to intact FGF23, high C-terminal FGF23 is associated
with worse clinical outcomes and increased mortality [
13
,
14
] and has been associated with

Toxins 2023,15, 97 10 of 13
increased rates of severe infections [
17
]. Currently, no published data compares intact
versus C-terminal FGF23 and its association with severe infections, including COVID-19.
4. Conclusions
Our results suggest that high baseline plasma FGF23 levels in end-stage renal disease
patients on chronic hemodialysis are associated with an increased risk for SARS-CoV-2
infection and severe COVID-19, including hospitalization and death. This is one of the first
reports that evaluate the relationship between FGF23 and COVID-19 in this population.
These data support the potential immunosuppressive effects of high circulating FGF23 as a
factor associated with worse clinical outcomes in ESRD and non-ESRD patients. Further
data from translational research and clinical studies with larger populations are needed to
confirm this hypothesis.
5. Materials and Methods
5.1. Study Design
The CATALINA-HD study is a multicenter observational cohort of end-stage renal
disease patients on chronic hemodialysis performed in Chile. The study was initiated in
2018 to evaluate the association of FGF23 with clinical outcomes, including hospitalizations,
major cardiovascular events, infectious events, and death. The information included demo-
graphic, laboratory, and clinical data, which were collected from patients. Measurements
of plasma FGF23 were performed in 2019. We evaluated the association of plasma FGF23
levels before the SARS-CoV-2 pandemic with clinical outcomes, including SARS-CoV-2
infection and severe COVID-19, including COVID-related hospitalizations and deaths. The
study was approved by the local Institutional Ethics Committee.
5.2. Inclusion and Exclusion Criteria
We included people older than 18 years with a previous diagnosis of end-stage renal
disease who were on chronic hemodialysis before 1 January 2020 and had measurements
of plasma FGF23 levels during 2019. The analysis included the final measurement if a
patient had more than one measurement. We excluded: terminal patients with palliative
management, pregnancy or breastfeeding women, and patients with incomplete data.
5.3. Evaluation of Patients
Determination of plasma levels of intact FGF23 was performed using an enzyme-
linked immunosorbent assay (ELISA) technique (human iFGF23: cat#60–6600, Quidel, San
Diego, CA, USA). Blood samples were collected during the hemodialysis session, before
the initiation of hemodialysis, by the puncture of the vascular access (arteriovenous fistula
or central venous catheter) using a 4-mL EDTA tube. Samples were centrifugated, and
plasma was extracted and then used for measurements. Patients were classified according
to their plasma FGF23 levels, as low level (FGF23 below p50 of the whole sample) and high
level (FGF23 greater than or equal to p50 of the whole sample).
Patient follow-up was carried out between 1 January 2020 and 31 December 2021.
SARS-CoV-2 infection was confirmed by a polymerase chain reaction (PCR) test. This infor-
mation was reported on the Epivigila platform (the method used by the Chilean Ministry of
Health to perform patient follow-ups) [
36
]. We evaluated patients who had COVID-related
hospitalization or COVID-related death with PCR confirmation, corresponding to the U07.1
code in the International Classification of Diseases, 10th Revision [37].
5.4. Statistical Analysis
Continuous variables are expressed as arithmetic mean
±
standard deviation or
median [percentile 25—percentile 75], and discrete variables are expressed as absolute
values (percentages). To compare baseline data between groups, we used the chi-square
test for discrete variables or the Student t-test for paired or unpaired groups. In addition,
calculations of Hazard Ratios and their 95% confidence intervals (95% CI), Kaplan-Meier

Toxins 2023,15, 97 11 of 13
analysis, and Cox proportional tests were performed for survival analysis. Finally, we
performed a multivariate analysis using logistic regression to evaluate predictors of SARS-
CoV-2 infection or severe COVID-19, evaluating several clinical, demographical, and
laboratory variables. In those models, we included variables that had a p-value below 0.20
in univariate analysis. Data analysis was executed using GraphPad Prism v.6.0 (GraphPad
Software, La Jolla, CA, USA) and Stata/SE v.17.0 (Stata Software, College Station, TX, USA).
All the analyses were two-tailed, and we considered a statistically significant difference
with a p-value below 5% (p< 0.05).
Author Contributions:
L.T. performed patient recruitment, clinical follow-up, and data analysis.
L.M., M.A., M.E.S., R.T., L.E., S.C., V.R. and R.T. recruited patients and collected clinical data. P.A.
performed ELISA measurements. A.P.-L., G.M.-V., E.V., C.P. and I.B. collected clinical data related to
COVID-19 infection and mortality. L.T. and A.P.-L. created the figures. L.T. and L.M. designed the
clinical study and drafted the manuscript, which was revised by all authors. All authors have read
and agreed to the published version of the manuscript.
Funding:
This research was funded by FONDECYT de Iniciacion 11171141 (L.T.) and FONDECYT
Regular 1221571 (L.T.) of the Agencia Nacional de Investigacion y Desarrollo (ANID). This institution
did not participate in the study design, data analysis, or writing of the manuscript.
Institutional Review Board Statement:
The study was performed in accordance with the Declaration
of Helsinki and approved by the Ethics Committee of Universidad de Chile (protocol code N
◦
033/16
approved in August 2016).
Informed Consent Statement:
We obtained informed consent from all the patients who participated
in the study.
Data Availability Statement:
The information that supports the findings of our study is available
upon reasonable request to the corresponding author, L.T. This information is not publicly available
because it contains data that may compromise the privacy of the research participants and third-
party restrictions.
Acknowledgments:
We thank all the members of the FUTAC-RENAL group Team and the Chilean
Society of Nephrology.
Conflicts of Interest: The authors declare no conflict of interest.
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