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Metabolismo calcio-fosforo / nefrolitiasi

SOLUBLE ALPHA-KLOTHO SERUM LEVELS IN CHRONIC KIDNEY DISEASE (CKD)

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Introduction

  • 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.

Methods

  • 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

Results

  • 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.
release  1
pubblicata il  25 settembre 2012 
da PASQUALI M., ROTONDI S., TARTAGLIONE L., PIRRO' G., MUCI M.L., LEONANGELI C., MAZZAFERRO S.
(Department of Cardiovascular, Respiratory, Nephrologic and Geriatric Sciences, Sapienza University of Rome )
Parole chiave: metabolismo minerale
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