Serum Klotho: Relation to Fibroblast Growth Factor-23 and Other Regulators of Phosphate Metabolism in Children with Chronic Kidney Disease

Abstract

FGF23 and Klotho synergize to regulate phosphate homeostasis by promoting renal phosphate excretion. Chronic kidney disease (CKD) may be viewed as a state of FGF23 resistance caused by Klotho deficiency. This viewpoint explains several observations on phosphate metabolism in CKD that lack mechanistic insights. Our objectives were to correlate serum klotho and FGF-23 with other variables that regulate phosphate metabolism. We studied 40 patients with CKD on conservative treatment (group A), 44 patients with end-stage renal disease (ESRD) on regular hemodialysis (group B), 40 kidney transplant recipients (KTR) (group C) and 40 healthy controls for measuring serum klotho and FGF-23. Blood samples were withdrawn for measuring the levels of serum Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), 1,25 (OH)₂ D₃, intact parathyroid hormone (PTH), FGF-23 and α klotho. The mean levels of FGF-23 and α klotho in control group were 225.78 ± 111.05 pg/ml (range: 102.4, 418.5) and 6.78 ± 1.90 ng/ml (range: 4, 11), respectively. The mean levels of FGF-23 in the 3 studied groups were 1,034.2 ± 84.6, 1,288.7 ± 131.4 and 1,008.7 ± 117.6 pg/ml, respectively. The median levels of s-klotho in the 3 studied groups were 3.15, 2.3 and 2.95, respectively. It was found that FGF-23 was significantly increased and α klotho was significantly decreased in all patients when compared with those in the control group (p < 0.001, <0.001, respectively). We found that there was a significant inverse correlation between serum Ca and α klotho in the studied groups. There was no significant correlation between FGF-23 and α klotho in the studied groups (p > 0.05).We have shown that circulating s-klotho was not related to FGF-23 in CKD, dialysis and KTR patients. In addition, we demonstrated a novel association between serum Ca and s-klotho that needs to be further studied.

αKlotho and Chronic Kidney Disease

“…Correspondingly, circulating serum αKlotho levels were progressively lower with each CKD stage when compared to healthy controls (Pavik et al, 2013). This was also observed in kidney transplant recipients vs healthy controls (Sawires, Essam, Morgan, & Mahmoud, 2015). Furthermore, adjusted mean serum αKlotho decrease was 3.2 pg/mL for each 1 mL/min eGFR decrease in adult CKD patients (Pavik et al, 2013).…”

“…High levels of FGF23 have been found to be associated with high mortality and morbidity in CKD (Arnlov et al, 2013; Desjardins et al, 2012; Faul et al, 2011; Fliser et al, 2007; Grabner et al, 2015; Greenhill, 2011; Guo & Yuan, 2015; Hanks, Casazza, Judd, Jenny, & Gutierrez, 2015; Hasegawa et al, 2010; Krupp & Madhivanan, 2014; Mencke et al, 2015; Mirza, Larsson, Melhus, Lind, & Larsson, 2009; Razzaque, 2009a, 2009b; Rotondi et al, 2015; Sawires et al, 2015; Silswal et al, 2014; Silver, Rodriguez, & Slatopolsky, 2012; Sinha et al, 2015; Wolf, 2010; Wright et al, 2014; Zhang, Yan, Zhu, & Ni, 2015; Zhang, Yang, et al, 2015). Given that administration of exogenous αKlotho has a favorable effect on CKD animals in terms of improvement of renal function, better maintenance of phosphate homeostasis, and attenuation of vascular calcification and cardiac hypertrophy, whether synergistic utilization of FGF23 antagonist or inhibitor and αKlotho can enhance αKlotho therapeutic efficacy needs to be tested.…”

Study of Serum Soluble Klotho in Egyptian Hemodialysis Patients

“…This is consistent with many studies in CKD patients [19,22] Limitations of our study are several. First, the number of evaluated patients is rather low.…”

Deviations from the expected relationship between serum FGF23 and other markers in children with CKD: a cross-sectional study

“…[12] Both FGF23 and CysC are low molecular weight proteins (LMWPs) that accumulate with worsening GFR. It is not yet clear whether higher FGF23 levels occur as a: (i) compensatory response to decreased renal capacity to excrete phosphate [13–15]; (ii) result of the use of calcium-based phosphate binders [16]; (iii) result of decreased 1,25 vitamin D3 levels; (iv) result of secondary hyperparathyroidism [17]; (v) or whether this is related to the disease process of CKD alone, as LMWP blood concentrations are greatly influenced by the GFR. [12, 18, 19] Furthermore, nutritional factors and uremic toxins may also increase FGF23-concentrations.…”