- α-Klotho is a transmembrane protein expressed in renal distal tubules where it is a co-factor for the phosphaturic hormone FGF23 (Figura 1). Thus a decrease in α-Klotho may prevent the actions of FGF23.
- Soluble, circulating α-Klotho (s-Klotho), resulting from shedding of the α-Klotho transmembrane extracellular domain, acts as a humoral factor regulating phosphaturia, calciuria and other cell functions (Figura 1). Circulating levels of s-Klotho could reflect possible changes of membrane α-Klotho expression (Figura 1).
- CKD is a clinical condition with low α-Klotho and with a possible tubular resistance to FGF23 (Figura 1).
- Clinical significance of s-Klotho in CKD is still a matter of debate.
Aim of the study
- To evaluate, in CKD patients , the circulating levels of s-Klotho.
- To consider its potential clinical and pathophysiological significance.
- We assayed circulating s-Klotho, FGF23, vitamin D and standard parameters of mineral metabolism in 70 CKD pts (59±16 y.o.) with eGFR 45±22 ml/min (stage 2 to 4 ).
- 10 normal subjects (34±12 y.o.; eGFR 95± 19 ml/min) were the control for s-Klotho and FGF23
- With mild vitamin D insufficiency (25D: 23±11, ng/ml), patients had 1,25D levels at the lower limit of normality, mild increment of PTH, and normal values of serum Ca (Cas), serum P (Ps) and bone AP (BALP) (Figura 2).
- Circulating levels of s-Klotho were significantly lower in CKD than in normal (Figura 2). This difference was evident since CKD stage 2 (Figura 3).
- In patients, serum levels of FGF23 were increased as compared to normal (Figura 2). This difference was statistically evident since CKD stage 3 (Figura 3).
- s-Klotho correlated positively with renal function (r=.43; p<.001) (Figura 4) but not with age (r=.15; p: n.s). A negative relationship was evident with FGF23 (r=-.33; p<.01) (Figura 4) and Ps (r=-.25; p<.05) (Figura 5). At variance with FGF23 which correlated with fractional excretion of P (FE-PO4, r=.47; r<.001) (Figura 5), s-Klotho did not (r=.16 p: n.s) (Figura 6). Finally s-Klotho showed a positive relationship with serum Ca (r=.30; p<.01) (Figura 6)
Discussion and Conclusions
- Our data indicate a significant negative effect of decreased renal function on circulating levels of s-Klotho, which seems to start very early in the course of the disease.
- The progressive reduction in s-Klotho is accompanied by a parallel increment of FGF23, thus linking the two analytes.
- The negative correlation of s-Klotho with FGF23 and serum P indicates its involvement with derangements of PO4 metabolism in CRF. However, s-Klotho did not correlate with FE-PO4, suggesting no direct phosphaturic effect in this clinical context. Our data are in agreement with the hypothesis that early reduction in α-Klotho is responsible for tubular resistance to FGF23. Increments of FGF23 can be considered as an effort to overcome the ongoing resistance. The observed reduction of s-Klotho seems to reflect the behaviour of transmembrane α-Klotho.
- As for Ca homeostasis, s-Klotho, even though reduced, seems to preserve its direct action on serum Ca.
- In summary, s-Klotho drops early in the course of renal insufficiency and is involved with derangements of serum PO4 and Ca, thus representing a potential marker of transmembrane α-Klotho.