When attempting to rank which chronic kidney disease (CKD)-related research issues should receive most attention, the fibroblast growth factor-23 (FGF-23)/Klotho axis would no doubt cover one of the top positions. The insights that FGF-23 may appear to be the master regulator of phosphate homeostasis, the key suppressor of renal 1α-hydroxylase activity and, as such, the initial inducer of pathomechanisms subsequently leading to secondary hyperparathyroidism (sHPT) seems to change paradigms concerning CKD-mineral and bone disorders (CKD-MBD) more substantially than any experimental and clinical research finding in the last 10–20 years [ 1 ]. In this context, the membrane-bound co-receptor Klotho plays a pivotal role because the renal FGF-23 actions are absolutely dependent on the presence of Klotho as an indispensable part of a dimeric FGF-23 receptor.

More recently, it became evident that circulating soluble Klotho (sKlotho) has the potential to mimick the CKD-MBD-related FGF-23 actions on phosphaturia and calcitriol synthesis, respectively [ 2 ]. Therefore, the question is whether sKlotho must be regarded as another phosphoregulatory hormone and, if the answer is yes, how its power may be related to those of FGF-23, became the focus of many researchers and clinicians in the field.

In this issue, Komaba et al. [ 3 ] report on the effects of cinacalcet treatment on circulating sKlotho levels in patients with CKD receiving haemodialysis therapy. In a multicentre, open label single-arm treatment trial lasting 52 weeks, they observed a significant but modest and reversible decrease of sKlotho blood levels associated with calcimimetic therapy. Despite its formal statistical significance, the magnitude of the effect (<5% decline), however, certainly justifies the question, whether this might cause any biological effect at all. Moreover, they found no association of sKlotho with parameters that play an important role in CKD-MBD, such as parathyroid hormone (PTH) or FGF-23.

What can we deduct from these data? As the authors correctly pointed out, further studies are clearly needed to determine the source and metabolism of sKlotho in CKD patients. Only very recently, enzyme-linked immunosorbent assay (ELISA)-based quantification of sKlotho has been established, and first human data on plasma sKlotho were reported from healthy volunteers [ 4 ]. In this study, higher sKlotho levels were found in children compared to adults, and in the overall data analyses, sKlotho was correlated with age, serum phosphate, FGF-23 and serum creatinine. However, exclusion of children from the analysis substantially weakened these associations, and accordingly, they disappeared after adjustment for age and other confounders. So far, sKlotho levels in CKD patients are not available, but data from animal experiments suggest a progressive decline of sKlotho with decreasing kidney function, as a down-regulation of membrane-bound Klotho is also observed with progressive CKD [ 5 ]. However, in a large cohort of CKD patients Stages 2–4, we did not find a noteworthy change of sKlotho across these CKD stages, despite anticipated changes in other CKD-MBD parameters, i.e. significant increase in PTH and FGF-23 levels [ 6 ]. Of note, we used the same ELISA as in the study by Komaba et al. [ 3 ]. Moreover, we found no correlation between sKlotho and serum FGF-23 and PTH levels nor with the fractional urine phosphate excretion ( Table 1 ). Moreover, in an elegant experimental study, Olauson et al. [ 7 ] used mice with a targeted deletion of parathyroid Type 1 membrane-bound α-Klotho and found that lack of this molecule does not cause evident abnormalities in mineral metabolism. When challenged with a low calcium diet, these mice had a non-significant trend towards lower PTH levels as compared to controls, but serum calcium, phosphate and FGF-23 remained normal. They concluded that Klotho is unlikely to play a primary pathogenic role in the development of sHPT [ 7 ]. Last but not least, our preliminary results indicate that FGF-23, but not sKlotho, is significantly correlated with outcome during a follow-up of 1.4 ± 0.7 years [ 6 ], highlighting the mounting importance of FGF-23 as a valuable biomarker for assessment of cardiovascular risk and progression in CKD patients [ 8–11 ]. Taken together, in CKD patients, changes in FGF-23 blood levels are obviously not parallelled by changes in sKlotho, and it has to be clarified whether other sources than kidney tissue contributes to circulating sKlotho levels. In addition, the data available so far permit the conclusion that sKlotho is not related to outcome in CKD patients and does not respond in a similar way to intervention with cinacalcet as do other parameters of CKD-MBD.

Table 1.

Correlation between sKlotho and parameters of calcium–phosphate metabolism in 312 patients with CKD Stage 1–4 [ 6 ] a

 sKlotho (pg/mL)   
PTH (pg/mL) r = 0.05, P = 0.374  PTH (pg/mL)  
FePi (%) r = 0.05, P = 0.392  r = 0.52, P < 0.001  FePi (%) 
FGF-23 (rU/mL) r = −0.03, P = 0.652  r = 0.34, P < 0.001  r = 0.38, P < 0.001  
 sKlotho (pg/mL)   
PTH (pg/mL) r = 0.05, P = 0.374  PTH (pg/mL)  
FePi (%) r = 0.05, P = 0.392  r = 0.52, P < 0.001  FePi (%) 
FGF-23 (rU/mL) r = −0.03, P = 0.652  r = 0.34, P < 0.001  r = 0.38, P < 0.001  
a

Indicated are correlations coefficients ( r ) and levels of significance (P). PTH, parathyroid hormone; FePi, urinary fractional phosphate excretion.

It is often hypothesized that a deranged calcium–phosphate metabolism contributes to the tremendous burden of cardiovascular morbidity and mortality in patients with CKD—particularly those with Stage 5D. In numerous cohort studies, hyperphosphataemia, sHPT and hypovitaminosis D were identified as adverse outcome predictors [ 12–14 ]. In the past, the primary derangement in the mineral and bone disorders in CKD patients was thought to be hypovitaminosis D resulting from reduced activity of renal 1α-hydroxylase that accompanies the progressive loss of renal mass. Together with the accompanying renal phosphate retention, it contributes to the development of sHPT. As already stated above, however, this vitamin D centred view was recently challenged in clinical trials identifying elevated FGF-23 levels as the earliest biological markers of a deranged calcium–phosphate metabolism in the course of CKD [ 6 , 15 , 16 ]. Renal FGF-23 signalling requires the expression of the trans-membrane protein Klotho on target cells [ 17 ], and reduced levels of plasma and urinary Klotho were reported in mice with incipient CKD [ 5 ], which might require a compensatory increase in serum levels of FGF-23. Therefore, a partial deficiency of Klotho has been postulated as the initial inducer of hyper-FGF-23-aemia in early CKD [ 18 ]. It has further been hypothesized that sKlotho might exert diverse vasculoprotective functions after its release from the cell membrane into blood, however, an idea that is not supported by recent clinical data [ 3 , 6 ].

Finally, we recently learnt that FGF-23 may not just be a risk-predicting biomarker, but a direct and deleterious pathomechanistic link potentially causing morbidity and mortality by inducing left ventricular hypertrophy and dysfunction [ 19 ]. Although we currently have no data on sKlotho's effects on myocardial structures, the recent publication by Faul et al. [ 19 ] excluded the involvement of membrane-bound Klotho in FGF23-induced myocardial damage. In the CKD-MBD context, both this study by Komaba et al. [ 3 ] as well as our own data do not support a major role of sKlotho as an endogenous regulatory hormone and thus as an emerging biomarker in CKD when compared to the data available on FGF-23 [ 3 , 6 ]. Consequently, at the moment, FGF-23 rather than sKlotho appears to be the appropriate risk marker and potential therapeutic target for future interventional trials in CKD patients.

Conflict of interest statement . None declared.

(See related article by Komaba et al. Effects of cinacalcet treatment on serum soluble Klotho levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2012; 27: 1967–1969 .)

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