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. 2022 Jul 8:9:904963.
doi: 10.3389/fmed.2022.904963. eCollection 2022.

Low Klotho/Fibroblast Growth Factor 23 Ratio Is an Independent Risk Factor for Renal Progression in Chronic Kidney Disease: Finding From KNOW-CKD

Hyo Jin Kim  1   2 , Yunmi Kim  3 , Minjung Kang  4 , Seonmi Kim  4 , Sue Kyung Park  5 , Suah Sung  6 , Young Youl Hyun  7 , Ji Yong Jung  8 , Curie Ahn  9 , Kook-Hwan Oh  4   10
Affiliations

Low Klotho/Fibroblast Growth Factor 23 Ratio Is an Independent Risk Factor for Renal Progression in Chronic Kidney Disease: Finding From KNOW-CKD

Hyo Jin Kim et al. Front Med (Lausanne). .

Abstract

Background: We aimed to evaluate soluble Klotho and circulating fibroblast growth factor 23 (FGF23) ratio as a risk factor for renal progression, cardiovascular (CV) events, and mortality in chronic kidney disease (CKD).

Methods: We analyzed 2,099 subjects from a CKD cohort whose soluble Klotho and C-terminal FGF23 levels were measured at enrollment. The Klotho to FGF23 ratio was calculated as Klotho values divided by FGF23 values + 1 (hereinafter called the Klotho/FGF23 ratio). Participants were categorized into quartiles according to Klotho/FGF23 ratio. The primary outcome was renal events, defined as the doubling of serum creatinine, 50% reduction of estimated glomerular filtration rate from the baseline values, or development of end-stage kidney disease. The secondary outcomes consisted of CV events and death. Changes in CV parameters at the time of enrollment and during follow-up according to the Klotho/FGF23 ratio were also examined.

Results: During the follow-up period of 64.0 ± 28.2 months, 735 (35.1%) and 273 (13.0%) subjects developed renal events and composite outcomes of CV events and death, respectively. After adjustment, the first (HR: 1.36; 95% CI: 1.08-1.72, P = 0.010) and second (HR: 1.45; 95% CI: 1.15-1.83, P = 0.002) quartiles with regard to the Klotho/FGF23 ratio showed elevated risk of renal events as compared to the fourth quartile group. There was no significant association between Klotho/FGF23 ratio and the composite outcome of CV events and death. The prevalence of left ventricular hypertrophy and vascular calcification was higher in the low Klotho/FGF23 ratio quartiles at baseline and at the fourth-year follow-up.

Conclusions: Low Klotho/FGF23 ratio was significantly associated with increased renal events in the cohort of Korean predialysis CKD patients.

Keywords: Klotho; chronic kidney disease; fibroblast growth factor 23; mortality; renal progression.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Event rates for renal events and composites of death and CV events according to Klotho/FGF23 ratio. The first quartile of the Klotho/FGF23 ratio group was at a greater risk of developing renal events compared to the other quartile groups (P < 0.001). Composites of death and CV events were not significantly different according to Klotho/FGF23 ratio groups (P = 0.153). FGF23, fibroblast growth factor 23; CV, cardiovascular.
Figure 2
Figure 2
Renal events according to Klotho/FGF23 ratio. The Kaplan-Meier curves show that the low Klotho/FGF23 ratio group had a significantly higher cumulative incidence of renal events (P < 0.001). FGF23, fibroblast growth factor 23.
Figure 3
Figure 3
The eGFR slope and rapid decline of eGFR according to Klotho/FGF23 ratio. (A) The eGFR slope according to Klotho/FGF23 ratio; (B) rapid decline of eGFR according to Klotho/FGF23 ratio. The eGFR slope was analyzed in 1,851 patients for whom eGFR was measured more than three times during the follow-up period. The eGFR slope was lower in the low Klotho/FGF23 ratio group (P < 0.001; A). The rapid decline of kidney function was defined as an estimated glomerular filtration rate (eGFR) <-3 ml/min/1.73 m2/year. The proportion of patients exhibiting a rapid decline of eGFR was higher in the first quartile of Klotho/FGF23 ratio group (P < 0.001; B). eGFR, estimated glomerular filtration rate by CKD-EPI creatinine equation; FGF23, fibroblast growth factor 23.
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