Treatment of vascular calcification
2008; Elsevier BV; Volume: 74; Issue: 11 Linguagem: Inglês
10.1038/ki.2008.502
ISSN1523-1755
Autores Tópico(s)Dermatological and Skeletal Disorders
ResumoA variety of potential therapies for vascular calcification, based either on the underlying biology or physical chemistry or solely on empiric observations in patients, may be effective but lack rigorous testing. Pasch et al. provide convincing evidence that sodium thiosulfate prevents medial vascular calcification in uremic rats. Although this provides some scientific basis for the clinical use of thiosulfate, uncertainty about mechanism of action and safety still remains. A variety of potential therapies for vascular calcification, based either on the underlying biology or physical chemistry or solely on empiric observations in patients, may be effective but lack rigorous testing. Pasch et al. provide convincing evidence that sodium thiosulfate prevents medial vascular calcification in uremic rats. Although this provides some scientific basis for the clinical use of thiosulfate, uncertainty about mechanism of action and safety still remains. One manifestation of the accelerated vascular disease in chronic kidney disease (CKD) is calcification of the medial (muscular) layer of large and small arteries. This should be distinguished from intimal calcification, which is associated with atherosclerosis and occurs in both the absence and the presence of CKD. Medial calcification occurs on elastic fibers between the layers of smooth muscle and cannot be ascribed solely to hyperphosphatemia, since it occurs in the absence of hyperphosphatemia in aging and diabetes. The etiology is almost certainly multifactorial, involving changes in smooth muscle factors that both inhibit and promote calcification, as well as ambient calcium and phosphate levels. The first consideration in treating medial calcification is whether it is harmful. Humans lacking an enzyme that synthesizes extracellular pyrophosphate, a potent calcification inhibitor, develop severe medial calcification that causes death at a very young age unless treated.1.Rutsch F. Vaingankar S. Johnson K. et al.PC-1 nucleotide triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.Am J Pathol. 2001; 158: 543-554Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar Abundant data demonstrate that vascular calcification is associated with poorer outcomes in CKD and end-stage renal disease, and the reduction in vascular calcification with sevelamer compared with calcium-containing phosphate binders is associated with reduced mortality.2.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar Unfortunately, the imaging techniques used cannot distinguish between intimal and medial calcification. Despite this limitation, these data strongly suggest that treatment or prevention of medial calcification is beneficial, and it is difficult to imagine otherwise. Treatment of medial calcification has generally been limited to optimizing the management of mineral metabolism and metabolic bone disease, to which it is inextricably linked. However, several factors probably limit the effectiveness of this approach. First, most phosphate binders provide a significant calcium load. Second, calcitriol and calcitriol analogues may increase medial calcification, either through direct actions on vascular smooth muscle or by raising circulating calcium levels. Lastly, smooth muscle-specific factors that promote and inhibit calcification are not addressed by this strategy. Another approach is to directly interfere with the calcification process (Figure 1). A seemingly safe way to do this would be to use calcification inhibitors normally present in vascular smooth muscle, of which pyrophosphate is the most feasible. Although pyrophosphate prevents medial calcification in vitamin D-toxic rats,3.Schibler D. Russell G.G. Fleisch H. Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats.Clin Sci. 1968; 35: 363-372PubMed Google Scholar very high doses are required because of rapid hydrolysis to orthophosphate. To circumvent this problem, bisphosphonates were developed in the 1960s as non-hydrolyzable analogues of pyrophosphate and have proven to be potent inhibitors of medial calcification in uremic rats.4.Price P.A. Faus S.A. Williamson M.K. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption.Arterioscler Thromb Vasc Biol. 2001; 21: 817-824Crossref PubMed Scopus (268) Google Scholar An alternative approach to raising pyrophosphate levels is to inhibit tissue-nonspecific alkaline phosphatase (TNAP), an ectoenzyme that hydrolyzes pyrophosphate. This is particularly attractive because TNAP is upregulated in uremic arteries.5.Lomashvili K.A. Garg P. Narisawa S. et al.Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: potential mechanism for uremic vascular calcification.Kidney Int. 2008; 73: 1024-1030Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Potent specific inhibitors of TNAP have recently been developed and inhibit smooth muscle calcification in vitro.6.Narisawa S. Harmey D. Yadav M.C. et al.Novel inhibitors of alkaline phosphatase suppress vascular smooth muscle cell calcification.J Bone Miner Res. 2007; 22: 1700-1710Crossref PubMed Scopus (177) Google Scholar Magnesium also inhibits hydroxyapatite formation and could be an effective substitute for calcium in phosphate binders. Clinical efficacy has not been proven for any of these agents, and there are significant concerns about safety. In 1985, Yatzidis first proposed the use of sodium thiosulfate to prevent kidney stones,7.Yatzidis H. Successful sodium thiosulfate treatment for recurrent calcium urolithiasis.Clin Nephrol. 1985; 23: 63-67PubMed Google Scholar and Yatzidis and Agroyannis subsequently used it to treat tumoral calcifications in renal failure.8.Yatzidis H. Agroyannis B. Sodium thiosulfate treatment of soft-tissue calcifications in patients with end-stage renal disease.Perit Dial Int. 1987; 7: 250-252Google Scholar The first reports of thiosulfate to treat calcific uremic arteriolopathy (CUA; formerly known as calciphylaxis) appeared four years ago, and it is now commonly used to treat CUA despite the lack of any clinical or basic studies demonstrating whether it works, how it works, and, most importantly, whether it is safe. This has been possible because sodium thiosulfate is already approved for clinical use in the treatment of cyanide toxicity. It is this uncertainty that forms the backdrop for the important new contribution of Pasch et al.9.Pasch A. Schaffner T. Huynh-Do U. et al.Sodium thiosulfate prevents vascular calcifications in uremic rats.Kidney Int. 2008; 74: 1444-1453Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar (this issue). These authors used a model of renal failure based on addition of adenine to the diet, which produces severe interstitial nephritis and uremia, with medial vascular calcification developing within 4 weeks. Thiosulfate completely prevented calcification in this model at a dose and interval comparable to those used in humans with CUA, thus providing a scientific basis for its clinical use. However, this is a model of large-artery calcification, not CUA, and the pathogenesis may not be the same. Also, this model of renal failure is associated with marked polyuria and salt wasting rather than the oliguria and sodium retention in dialysis patients, which could differentially affect thiosulfate levels and calcium balance. Despite careful measurement of multiple biochemical parameters by the authors, the mechanism by which calcification was prevented remains unclear. Notably, there were no significant changes in serum calcium, phosphate, or parathyroid hormone levels. However, the serum calcium level was adjusted for albumin concentration, and this adjustment could be altered by thiosulfate. Recognizing this, the authors performed short-term measurements of ionized calcium and parathyroid hormone immediately after administration of thiosulfate. There was a transient decrease in ionized calcium, which the authors suggest could represent an interaction between calcium ions and thiosulfate ions but could just as easily have been dilutional. There was a delayed increase in total serum calcium that was accompanied by an increase in ionized calcium. Although the former might have been proportionally greater than the latter, suggesting binding by thiosulfate, the effect is quite small and the delay is not consistent with a chemical interaction. The most striking biochemical finding was a marked increase in calcium excretion in the urine, which was also seen in non-uremic rats. Possible explanations for this are the renal excretion of large amounts of the poorly reabsorbed thiosulfate anion and a large distal sodium delivery. However, calcium excretion does not increase in humans treated with thiosulfate,7.Yatzidis H. Successful sodium thiosulfate treatment for recurrent calcium urolithiasis.Clin Nephrol. 1985; 23: 63-67PubMed Google Scholar suggesting that the hypercalciuria is peculiar to this model. The hypercalciuria could be preventing vascular calcification through negative calcium balance, but this is unlikely without a long-term reduction in serum calcium or increase in parathyroid hormone. Not surprisingly, the serum anion gap increased with a drop in bicarbonate concentration and pH. Since sodium thiosulfate is not an acid, the drop in serum bicarbonate is merely dilutional, leading to an expansion acidosis. This is consistent with the fact that no decrease in pH was observed when sodium thiosulfate was added to blood in vitro. Nevertheless, hydroxyapatite formation and vascular calcification are pH-dependent,10.Lomashvili K. Garg P. O’Neill W.C. Chemical and hormonal determinants of vascular calcification in vitro.Kidney Int. 2006; 69: 1464-1470Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar and metabolic acidosis can reduce aortic calcification in uremic rats.11.Mendoza F.J. Lopez I. Montes de Oca A. et al.Metabolic acidosis inhibits soft tissue calcification in uremic rats.Kidney Int. 2008; 73: 407-414Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar However, it is unlikely that the small changes in pH noted after thiosulfate administration can explain the complete prevention of aortic calcification. Because only one dose of thiosulfate was tested, it is not possible to correlate inhibition of vascular calcification with the other effects of thiosulfate. So, how is thiosulfate working? The answer probably lies in the ionic interaction between thiosulfate and calcium ions and the solubility of the undissociated Ca2∣S2O32– ion pair. Although some authors refer to this as chelation, that term is reserved for compounds that bind an ion at two or more sites, as if being gripped by a claw (the Greek word from which ‘chelate’ was derived). Ion pairing can be either tight or loose, depending on whether there are intervening solvent molecules. Measurements of CaS2O3 association constants have indicated that as much as 10% of the thiosulfate in biological fluids may be in the form of soluble Ca2+∣S2O32– ion pairs.12.Gimblett F.G.R. Monk C.B. Spectrophotometric studies of electrolytic dissociation. I. Some thiosulfates in water.Trans Faraday Soc. 1955; 51: 793-802Crossref Google Scholar Thus, at the concentrations of thiosulfate achieved in plasma in this study and in humans (5 mM or more), there would be up to 0.5 mM of this ion pair. However, no such increase in total calcium was observed by Pasch et al.,9.Pasch A. Schaffner T. Huynh-Do U. et al.Sodium thiosulfate prevents vascular calcifications in uremic rats.Kidney Int. 2008; 74: 1444-1453Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar there were no signs of hypocalcemia, and the changes in ionized calcium levels produced by thiosulfate in vitro were much less than predicted by this degree of ion pairing. This discrepancy between the extent of ion pairing and the minimal effects on total and ionized calcium levels suggests that the Ca2+∣S2O32– ion pairing is quite loose, which is consistent with the greater attraction of calcium ions to water molecules than to thiosulfate ions. A decrease in ionized calcium was observed in the urine of humans treated with thiosulfate,7.Yatzidis H. Successful sodium thiosulfate treatment for recurrent calcium urolithiasis.Clin Nephrol. 1985; 23: 63-67PubMed Google Scholar but this may be explained by the lower pH affecting the hydration of calcium ions. It is important to note that Pasch et al.9.Pasch A. Schaffner T. Huynh-Do U. et al.Sodium thiosulfate prevents vascular calcifications in uremic rats.Kidney Int. 2008; 74: 1444-1453Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar demonstrate prevention of medial calcification rather than reversal. The loose ion pairing of calcium and thiosulfate ions is probably sufficient to interfere with CaHPO4 formation but not strong enough to mobilize calcium from calcifications (W.C.O., unpublished data). The decrease in calcium deposits noted in case reports could be due to the combination of inhibition of further calcification and concurrent measures to reduce calcium load. Thiosulfate is also an antioxidant, and an effect related to this cannot be ruled out. Before we jump in and treat vascular calcification with direct inhibitors, it is important to realize that they could also inhibit hydroxyapatite formation in bone. Doses of bisphosphonates that inhibit vascular calcification can also reduce bone mineralization (K. Lomashvili et al., unpublished data), and the finding of decreased bone strength by Pasch et al.9.Pasch A. Schaffner T. Huynh-Do U. et al.Sodium thiosulfate prevents vascular calcifications in uremic rats.Kidney Int. 2008; 74: 1444-1453Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar raises the same concern with thiosulfate. Although some humans have been treated with thiosulfate for several years,7.Yatzidis H. Successful sodium thiosulfate treatment for recurrent calcium urolithiasis.Clin Nephrol. 1985; 23: 63-67PubMed Google Scholar they did not have renal failure, and bone was not examined. Bisphosphonates are retained in renal failure and can be incorporated into bone, which might also occur with thiosulfate. The results of Pasch et al.9.Pasch A. Schaffner T. Huynh-Do U. et al.Sodium thiosulfate prevents vascular calcifications in uremic rats.Kidney Int. 2008; 74: 1444-1453Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar are an important step in establishing the clinical utility of thiosulfate in treating vascular calcification, but subsequent studies will need to address mechanisms of action and the therapeutic window. The author declared no competing interests. The author thanks Kenneth Hardcastle (Department of Chemistry, Emory University) for helpful discussions. Support for work from the author's laboratory has come from grant DK069681 from the National Institutes of Health, a grant from the Genzyme Renal Innovations Program, and grants from Baxter Healthcare and Amgen.
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