Elevated Fibroblast Growth Factor 23 and Decreased Klotho Levels Are Associated With Diastolic Dysfunction in CKD G4-5D Patients.

To the Editor:

In a recent study, Sharma et al. reported an association between higher levels of fibroblast growth factor 23 (FGF-23) and left ventricular (LV) diastolic dysfunction in 47 end-stage renal disease (ESRD) patients receiving hemodialysis. Fibroblast growth factor 23 requires Klotho protein as a co-receptor to bind FGF receptors and to exert its biological effects. Moreover, Klotho deficiency contributes to chronic kidney disease (CKD) progression and development of cardiovascular diseases in patients with advanced CKD.

We studied an association of FGF-23 and Klotho levels with LV hypertrophy and diastolic function in 51 patients with CKD G4-5D patients (median age, 48 years; 27 male patients). In all, 26 patients were treated with hemodialysis. Serum FGF-23 and Klotho levels were measured by enzyme-linked immunosorbent assay. Left ventricular diastolic function was evaluated using Doppler echocardiographic analysis.

Characteristics of the study cohort stratified by quartiles of FGF-23 levels are shown in Table 1. As expected, serum Klotho levels were decreased in patients with higher FGF-23 levels. Serum FGF-23 and Klotho levels significantly correlated with LV diastolic dysfunction (r = 0.469, P = 0.002, and r = −0.501, P = 0.001, respectively). According to multivariate analysis, Klotho but not FGF-23 level was independently associated with diastolic dysfunction (R = 0.152; 95% confidence interval for slope, 0.993−0.999; P = 0.01).

Table 1

Main characteristics stratified by quartiles of FGF-23 levels

Parameter	All patients	Serum FGF-23 level (pg/ml)				P
		Quartile 170.0 (44.5–92.0)	Quartile 2189.0 (127.2–273.8)	Quartile 3638.5 (529.8–783.0)	Quartile 43270 (1813.0–5115.5)
Patients, n	51	10	14	12	15
Age, yr	48 (18–65)	49 (21–59)	47 (19–65)	50 (20–63)	48 (19–64)	0.248
Serum phosphate, mmol/l	1.52 (1.29–1.87)	1.30 (1.16–1.42)	1.44 (1.22–1.58)	1.54 (1.23–1.72)	1.82 (1.54–2.10)	0.020
EF >50%, n (%)	40 (78.4)	10 (100)	14 (100)	8 (66.7)	8 (53.33)	0.025
LV hypertrophy, n (%)	35 (68.6)	3 (30)	6 (42.8)	11 (91.7)	15 (100)	0.001
E/A ratio	1.3 (0.73–2.2)	0.9 (0.76–1.45)	1.1 (0.80–1.54)	1.3 (0.87–2.1)	1.6 (0.98–2.4)	0.029
LV diastolic dysfunction, n (%)	33 (64.7)	3 (28)	6 (45)	10 (83.3)	14 (93.3)	0.002
Klotho, pg/ml	410.5 (312.5–470.0)	542.0 (515.0–603.5)	454.0 (421.0–461.0)	364.0 (330.0–399.0)	267.0 (145.5–288.5)	0.010

E/A ratio, transmitral early filling velocity/transmitral late filling velocity; EF, ejection fraction; FGF-23, fibroblast growth factor 23; LV, left ventricular.

Data are expressed as a median (interquartile range) or as frequency (percentage), as appropriate.

Our findings support the results of Sharma et al., who showed an adverse effect of FGF-23 on LV diastolic function in ESRD patients receiving hemodialysis. However, our data suggest that Klotho may play a more important role in the development of LV diastolic dysfunction in patients with advanced CKD.