[Update on the pathogenesis and possible therapeutic approach to vascular calcifications in patients with chronic renal failure]. / Update sulla patogenesi e sul possibile approccio terapeutico alle calcificazioni vascolari nel paziente con insufficienza renale.

Chronic renal failure is a well-known risk condition for cardiovascular disease and in particular vascular calcifications. In fact, with respect to the normal population, where only ''classic'' risk factors have been described, kidney patients also have non-classic risk conditions. Among these, alterations in divalent ions, parathyroid hormone and vitamin D are of utmost importance. Further, several substances are recognized to have inhibitory or inductive effects in the pathogenesis of vascular calcifications, affecting either the calcium salts precipitation phenomenon or the phenotypic transformation of vascular smooth muscle cells into osteoblast-like cells (the latter phenomenon being regarded as a determinant of calcification of the tunica media). Given that vascular calcifications are irreversible, therapeutic strategies are aimed at preventing their formation or at blunting their progression (which is especially accelerated in renal patients). For this purpose it is essential to pursue optimal biochemical control of secondary hyperparathyroidism, but we must consider that in the individual patient the choice of drugs and their dosage can be essential for the development of calcifications. Given the physiological importance of inhibitory substances, we can hypothesize their future use in this setting. Finally, we must consider that by administering drugs known to interfere with inhibitors (like warfarin) or with the normal process of mineralization (like bisphosphonates), we can hypothetically favor or respectively prevent vascular calcifications.

The bone and the kidney.

Renal tubular diseases may present with osteopenia, osteoporosis or osteomalacia, as a result of significant derangements in body electrolytes. In case of insufficient synthesis of calcitriol, as in renal failure, the more complex picture of renal osteodystrophy may develop. Hypothetically, also disturbed renal production of BMP-7 and Klotho could cause bone disease. However, the acknowledgment that osteocytes are capable of producing FGF23, a phosphaturic hormone at the same time modulating renal synthesis of calcitriol, indicates that it is also bone that can influence renal function. Importantly, a feed-back mechanism exists between FGF23 and calcitriol synthesis, while Klotho, produced by the kidney, determines activity and selectivity of FGF23. Identification of human diseases linked to disturbed production of FGF23 and Klotho underlines the importance of this new bone-kidney axis. Kidney and bone communicate reciprocally to regulate the sophisticated machinery responsible for divalent ions homeostasis and for osseous or extraosseous mineralisation processes.

Distinct impact of vitamin D insufficiency on calcitriol levels in chronic renal failure and renal transplant patients: a role for FGF23.

INTRODUCTION: Vitamin D insufficiency contributes to calcitriol (1,25D) reduction in chronic kidney disease (CKD). Since CKD patients on conservative therapy (CRF) mostly develop, whereas transplant (TX) patients possibly recover from, secondary hyperparathyroidism (SH), we hypothesized a different efficiency of vitamin D hydroxylation in these 2 clinical conditions. METHODS: We compared the impact of reduced 25-hydroxyvitamin D (25D) on circulating 1,25D in 111 CRF (mean age 63 ± 15 years; estimated glomerular filtration rate [eGFR] 36.4 ± 22.0 ml/min) and in 136 TX patients (mean age 50 ± 11 years; eGFR 47 ± 19.0 ml/min). RESULTS: Vitamin D insufficient patients (69.1% in TX vs. 82% in CRF; p<0.005), compared with those without insufficiency, had lower values of 1,25D in CRF (24.5 ± 17.4 vs 35.8 ± 17.8 pg/mL; p<0.01) but not in TX (42.7 ± 23.8 vs. 50.1 ± 25.4 pg/mL; p=n.s.). Serum 25D and 1,25D were correlated in both CRF (r=0.387, p<0.0001) and TX (r=0.240, p0<.005) groups, but 1,25D values were higher in the TX group in any of the 4 ranges for 25D considered. Serum calcitriol correlated with eGFR (CRF: r=0.641, p<0.0001; TX: r=0.426, p<0.0001), but again with higher values in the TX group, in any of the CKD stages considered, except stage 2. In both conditions, the most predictive parameter of 1,25D levels was eGFR, together with phosphate and 25D in the CRF group (r2=0.545; p<0.0001), and with Ca and 25D in the TX group (r2=0.345; p<0.0001). In 2 subgroups, comparable for eGFR and 25D, levels of FGF23 were lower in the TX group, in agreement with higher values of 1,25D. CONCLUSIONS: A 25D deficit more significantly affects calcitriol concentrations in CRF as compared with TX. Efficiency of vitamin D hydroxylation should be considered when planning vitamin D replacement strategies.