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.

Kidney Damage in Long COVID: Studies in Experimental Mice

“…FGF23 expression is known to increase in response to inflammation and hypoxia, ultimately leading to chronic kidney disease (CKD) [43]. Notably, COVID-19-infected patients with a history of CKD exhibited elevated levels of FGF23 [44]. Our results demonstrate that there was no significant change in the mRNA expression of FGF-23 within the acutely infected group, as well as in the group treated with SPK (Figure 1C).…”

FGF7 enhances the expression of ACE2 in human islet organoids aggravating SARS-CoV-2 infection

“… 13 , 14 The most widely investigated plasma FGFs under SARS-CoV-2 infections are FGF2 (FGF basic), 13 , 14 FGF19, 15 FGF21 15 and FGF23. 15 , 16 However, the FGF7 levels in the circulation system under COVID-19 has not been investigated to date. Our clinical retrospective study found the higher serum FGF7 could serve as a promising biomarker for assessing COVID-19 severity in diabetes.…”

“… 10 However, in the context of COVID-19, proteases liberate ECM-bound FGFs to participate in the pathophysiological process associated with inflammation and angiogenesis-dependent diseases. 11 , 12 Recent studies have indicated that FGFs aggravate SARS-CoV-2 infection in host cells; 13 – 16 Inhibiting of FGFRs with dobesilate could improve the opacity of the hemithorax without the need for oxygen therapy in COVID-19 patients. 12 Additionally, a correlation between FGFs and ACE2 has been reported.…”

Serum fibroblast growth factor 23 concentration and the risk of mortality in patients undergoing peritoneal dialysis

“…Previous studies had shown that higher FGF23 concentration was significantly associated with increased risk of infections in patients with CKD 10 and undergoing HD. 34,35 There are several possible biologic mechanisms that may explain the relationship between a high FGF23 concentration and a greater risk of infection in PD patients. In mice with CKD, FGF23 was found to directly impair the recruitment of leukocytes to infected tissues and inhibit host defences.…”