Transmembrane α-Klotho (TM-Klotho), expressed in renal tubules, is a cofactor for FGF23-receptor. Circulating soluble-α-Klotho (s-Klotho) results from TM-Klotho shedding and acts on Phosphate (P) and Calcium (Ca) tubular transport. Decreased TM-Klotho, described in experimental chronic kidney disease (CKD), prevents actions of FGF23 and lessens circulating s-Klotho. Thus, levels of s-Klotho could represent a marker of CKD-MBD. To evaluate the clinical significance of s-Klotho in CKD we assayed serum s-Klotho and serum FGF23 in 68 patients (age 58 ± 15; eGFR 45 ± 21 mL/min). s-Klotho was lower than normal (519 ± 183 versus 845 ± 330 pg/mL, P < .0001) in renal patients and its reduction was detectable since CKD stage 2 (P < .01). s-Klotho correlated positively with eGFR and serum calcium (Cas) and negatively with serum phosphate (Ps), PTH and FGF23. FGF23 was higher than normal (73 ± 51 versus 36 ± 11, P < .0002) with significantly increased levels since CKD stage 2 (P < .001). Our data indicate a negative effect of renal disease on circulating s-Klotho starting very early in CKD. Assuming that s-Klotho mirrors TM-Klotho synthesis, low circulating s-Klotho seems to reflect the ensuing of tubular resistance to FGF23, which, accordingly, is increased. We endorse s-Klotho as an early marker of CKD-MBD.

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BackgroundCalcifediol (25D) availability is crucial for calcitriol (1,25D) synthesis, but regulation of vitamin D hydroxylases is majorly responsible for 1,25D synthesis. The net efficiency of vitamin D hydroxylases might be informative. We assume that the ratio between calcitriol and calcifediol (25D/1,25D) serum concentrations could suggest the vitamin D hydroxylation efficiency.MethodsWe evaluated 25D/1,25D in different patient populations: hemodialysis (HD, n = 76), CKD stage 2–5 (n = 111), renal transplant (TX, n = 135), patients with no renal disease (No-CKD, n = 290), and primary hyperparathyroidism (PHP, n = 20).ResultsThe geometric mean of 1,25D/25D (pg/ng) averaged 1.11 (HD), 1.36 (CKD), 1.77 (TX), 2.22 (No-CKD), and 4.11 (PHP), with a progressive increment from HD to PHP (p-value for the trend <0.001). Each clinical condition elicited a significant effect on 25D/1,25D (p < 0.0001) and adjusted multivariate analysis indicated levels of Cas, Ps, PTH, and 25D as predictors of 25D/1,25D. Both in vitamin D deficient and replete subjects (25D< or ≥20 ng/ml) 25D/1,25D associated with each clinical condition (p < 0.0001) and mean values increased progressively from HD to PHP (p-values for the trend <0.0001). Regression analysis between 25D (substrate) and 25D/1,25D (efficiency) revealed an exponential negative correlation in No-CKD (r2Exp = 0.53, p < 0.001) with sharp increments of 25D/1,25D when 25D values are <20 ng/ml. At variance, in CKD (r2lin = 0.19) and in TX (r2lin = 0.32) the regression was linear as if, in case of deficit, some inhibition of the system were operating.Conclusion and General significanceIn conclusion 1,25D/25D can reflect the efficiency of vitamin D hydroxylases more than separate evaluation of 25D and 1,25D and can facilitate the therapeutic choices in different patient populations.

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Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone-vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease-mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases.

HD tissue hypoxia associates with organ dysfunctions. OER, the ratio between SaO2 and central-venous-oxygen-saturation, could estimate oxygen requirements during sessions, but no data are available. We evaluated OER behavior in 20 HD patients with permanent central venous catheter (CVC) as vascular access. Pre-HD OER (33.6 ± 1.4%; M ± SE) was higher than normal (range 20–30%). HD sessions increased OER to 39.2 ± 1.5% (M ± SE; p < 0.05) by 30′ and to 47.4 ± 1.5% (M ± SE; p < 0.001) by end of treatment (delta 40%). During HD sessions of the long and short interdialytic intervals, OER values overlapped, suggesting no influence of patient’s hydration status shifts. OER increased (p < 0.05) after 30′ of isolated HD (zero ultrafiltration), but not during isolated ultrafiltration (zero dialysate flow), suggesting a role for blood-membrane-dialysate interaction, independent of volume reduction. In ten patients, individual variability of pre-HD OER was low and repeatable (maximum calculated difference over time 6.6%), and negatively correlated with HD-induced OER increments (r = 0.860; p < 0.005), suggesting a decline in the adaptive response along with resting OER increments. In 30 prevalent patients, adjusted multivariate analysis showed that pre-HD OER (HR = 0.88, CI 0.79–0.99, p = 0.028) and percent HD-induced OER (HR = 1.04, CI 1.01–1.08, p = 0.015) were both associated with mortality, with threshold values respectively <32% and >40%. In HD patients with CVC as vascular access, OER is a cheap, easily measurable and repeatable parameter useful to assess intradialytic hypoxia, and a potential biomarker of HD related stress and morbidity, helpful to recognize patients at increased risk of mortality.

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