Metabolic acidosis and vascular calcification: Using blueprints from bone to map a new venue for vascular research
2008; Elsevier BV; Volume: 73; Issue: 4 Linguagem: Inglês
10.1038/sj.ki.5002738
ISSN1523-1755
Autores Tópico(s)Renal function and acid-base balance
ResumoVascular calcification is an important problem in patients with chronic kidney disease. The pathobiology of vascular calcification is complex and is intricately related to bone remodeling. Mendoza et al. report that experimental metabolic acidosis prevents calcitriol-induced vascular calcification in uremic animals. To fully understand the effect of acidosis on the vasculature, a comprehensive and integrated approach that simultaneously examines the effect of metabolic acidosis on bone and vasculature is needed. Vascular calcification is an important problem in patients with chronic kidney disease. The pathobiology of vascular calcification is complex and is intricately related to bone remodeling. Mendoza et al. report that experimental metabolic acidosis prevents calcitriol-induced vascular calcification in uremic animals. To fully understand the effect of acidosis on the vasculature, a comprehensive and integrated approach that simultaneously examines the effect of metabolic acidosis on bone and vasculature is needed. Extraosseous or extraskeletal calcification, mainly vascular calcification, is being increasingly recognized as an important problem in patients with chronic kidney disease, diabetes mellitus, and chronic inflammatory conditions.1.Al-Aly Z. Medial vascular calcification in diabetes mellitus and chronic kidney disease: the role of inflammation.Cardiovasc Hematol Disord Drug Targets. 2007; 7: 1-6Crossref PubMed Scopus (38) Google Scholar The pathobiology of extraskeletal calcification is complex and involves a variety of factors, including derangements in calcium and phosphorus homeostasis, increased proinflammatory cytokines, increased levels of procalcific moieties, and decreased levels of calcification inhibitors. Vascular calcification appears to be a highly regulated process that is also associated with increased morbidity and mortality. Metabolic acidosis is highly prevalent in patients with kidney disease.2.Widmer B. Gerhardt R.E. Harrington J.T. et al.Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure.Arch Intern Med. 1979; 139: 1099-1102Crossref PubMed Scopus (122) Google Scholar,3.Wallia R. Greenberg A. Piraino B. et al.Serum electrolyte patterns in end-stage renal disease.Am J Kidney Dis. 1986; 8: 98-104Abstract Full Text PDF PubMed Scopus (67) Google Scholar Although the effect of metabolic acidosis on bone has been investigated, its effect on extraosseous calcification and mainly vascular calcification is largely unknown. Mendoza and collaborators4.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 (78) Google Scholar (this issue) now show that experimentally induced metabolic acidosis prevents extraosseous calcification in a uremic animal model of calcification. These findings are important and highlight the need for an integrated approach to evaluate the effect of metabolic acidosis on bone mineralization and extraskeletal calcification. The bony skeleton as an organ system contains large amounts of alkaline salts, and, in response to chronic metabolic acidosis, bone buffers hydrogen ions with carbonate, subsequently maintaining systemic pH at the expense of liberating bone minerals. As a result, chronic metabolic acidosis induces net calcium efflux from bone and a decrease in bone mineral content. Chronic metabolic acidosis is also associated with a significant increase in urinary calcium and phosphorus excretion and significant reduction in proximal tubule synthesis of 1,25(OH)2D3, thus limiting intestinal calcium absorption and subsequently resulting in a negative balance of these divalent ions. Metabolic acidosis induces a net bone mineral loss both in vitro and in vivo. This happens via two mechanisms, one that involves physicochemical mineral dissolution and another that involves cellular protein and gene regulation. Metabolic acidosis affects a repertoire of genes and protein expression, leading to enhanced osteoclast-mediated bone resorption and decreased osteoblast-mediated matrix protein synthesis and alkaline phosphatase activity. Metabolic acidosis induces cyclooxygenase-2 mRNA and protein in osteoblasts, leading to increased production of prostaglandins with a resultant increase in the osteoblastic receptor activator of nuclear factor-κB ligand (RANKL), which stimulates further osteoclast activity. There is also evidence to suggest that chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells.5.Disthabanchong S. Radinahamed P. Stitchantrakul W. et al.Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells.Kidney Int. 2007; 71: 201-209Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Some studies in patients have suggested that correction of acidosis may prevent the progression of secondary hyperparathyroidism. A small prospective study examined the effect of dialysate bicarbonate concentration on the progression of renal osteodystrophy in 21 patients on chronic maintenance dialysis. Patients were randomized to receive dialysis with either conventional bicarbonate dialysate (33 ± 2 mmol per liter) or dialysate containing additional amounts of bicarbonate (7–15 mmol per liter) to obtain a predialysis bicarbonate concentration of 24 mequiv. per liter. Whereas patients assigned to the conventional dialysate bicarbonate concentration had an average predialysis plasma bicarbonate level of 15.6 mequiv. per liter, patients assigned to the higher dialysate bicarbonate had a predialysis bicarbonate level of 24.0 mequiv. per liter. The study showed that after 18 months of follow-up, the group of patients assigned to the conventional dialysate bicarbonate concentration had progression of secondary hyperparathyroidism as evidenced by worsening of bone histomorphometry parameters and increased plasma intact parathyroid hormone, whereas those assigned to higher bicarbonate dialysate experienced no significant worsening in renal osteodystrophy.6.Lefebvre A. de Vernejoul M.C. Gueris J. et al.Optimal correction of acidosis changes progression of dialysis osteodystrophy.Kidney Int. 1989; 36: 1112-1118Abstract Full Text PDF PubMed Scopus (150) Google Scholar A cross-sectional retrospective study on 76 patients with varying degrees of chronic kidney disease showed that 10 patients (13%) had normal bone histology and bone histomorphometry and that those patients had on average a higher serum bicarbonate (23 mmol per liter) than patients with mild or advanced mixed osteodystrophy, who had serum bicarbonate levels below 20 mmol per liter.7.Coen G. Mazzaferro S. Ballanti P. et al.Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study.Nephrol Dial Transplant. 1996; 11: 813-819Crossref PubMed Scopus (125) Google Scholar Another retrospective study of 24 patients showed that patients with metabolic acidosis often have osteomalacia in pure or mixed form and that they may be relatively resistant to active vitamin D treatment.8.Coen G. Manni M. Addari O. et al.Metabolic acidosis and osteodystrophic bone disease in predialysis chronic renal failure: effect of calcitriol treatment.Miner Electrolyte Metab. 1995; 21: 375-382PubMed Google Scholar Mendoza and collaborators4.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 (78) Google Scholar examine the effect of metabolic acidosis on extraosseous calcification in five-sixths-nephrectomized rats treated with calcitriol to induce calcification. The authors show that the addition of NH4Cl to drinking water prevents aortic calcium and phosphorus accumulation. They make an attempt to examine the mechanism of the protective effect conferred by metabolic acidosis and show that gene expression of the sodium-dependent phosphate cotransporter Pit-1 is increased and that the addition of NH4Cl to drinking water abrogates this effect significantly. There is growing epidemiologic evidence to suggest that there is an inverse relationship between bone mass and vascular calcification. Hak et al.9.Hak A.E. Pols H.A. van Hemert A.M. et al.Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study.Arterioscler Thromb Vasc Biol. 2000; 20: 1926-1931Crossref PubMed Scopus (315) Google Scholar examined the association between the extent of aortic calcification and metacarpal bone mass and density in a cross-sectional study of 720 postmenopausal women and found a graded inverse association. The investigators in this same study also reported on a cohort of 236 women who were followed longitudinally for 9 years and found that 25% of them had progression of aortic calcification and that the loss in metacarpal bone mass and density was significantly more pronounced in women with progression of aortic calcification.9.Hak A.E. Pols H.A. van Hemert A.M. et al.Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study.Arterioscler Thromb Vasc Biol. 2000; 20: 1926-1931Crossref PubMed Scopus (315) Google Scholar These findings were echoed in multiple other studies that showed an inverse correlation between the severity of calcification and bone mineral density and, in patients followed longitudinally over time, a strong graded association between the progression of vascular calcification and bone loss.10.Schulz E. Arfai K. Liu X. et al.Aortic calcification and the risk of osteoporosis and fractures.J Clin Endocrinol Metab. 2004; 89: 4246-4253Crossref PubMed Scopus (351) Google Scholar,11.Bagger Y.Z. Tanko L.B. Alexandersen P. et al.Radiographic measure of aorta calcification is a site-specific predictor of bone loss and fracture risk at the hip.J Intern Med. 2006; 259: 598-605Crossref PubMed Scopus (147) Google Scholar Similar to findings in postmenopausal women, there seems to be an intimate relationship between vascular calcium content and bone mineral content in patients with kidney disease. In dialysis patients an inverse relationship between arterial calcification and bone density has been documented. Furthermore, a high arterial calcification score is associated with bone histomorphometry suggestive of low bone activity and adynamic bone disease.12.London G.M. Marty C. Marchais S.J. et al.Arterial calcifications and bone histomorphometry in end-stage renal disease.J Am Soc Nephrol. 2004; 15: 1943-1951Crossref PubMed Scopus (487) Google Scholar Recent experimental evidence suggests that the bisphosphonates ibandronate and etidronate, which inhibit bone resorption, prevented medial artery calcification in uremic rats.13.Price P.A. Roublick A.M. Williamson M.K. Artery calcification in uremic rats is increased by a low protein diet and prevented by treatment with ibandronate.Kidney Int. 2006; 70: 1577-1583Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar These findings lend further support to a possible link between vascular calcification and bone remodeling.14.Persy V. De Broe M. Ketteler M. Bisphosphonates prevent experimental vascular calcification: treat the bone to cure the vessels?.Kidney Int. 2006; 70: 1537-1538Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The prevailing thinking, although not rigorously tested, is that minerals leached out of bones, particularly in the uremic setting, find their way to extraskeletal sites including the vasculature. Whereas the effect of metabolic acidosis on bone biology is fairly well established, the effect of metabolic acidosis on extraskeletal calcification has not been previously investigated. Drawing from the observations that there is an inverse relationship between bone mineral content and extent of calcification, it would be plausible to hypothesize that metabolic acidosis, which contributes to decreased mineral bone content, may lead to worsening vascular calcification. Mendoza and collaborators4.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 (78) Google Scholar take a different approach in constructing their a priori hypothesis. The hypothesis tested by Mendoza et al.4.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 (78) Google Scholar rests on the assumption that since the molecular fingerprints of calcified vascular tissue share a striking resemblance to those of bone tissue, and since the process of vascular calcification seems to recapitulate osteogenic bone formation, the response of extraosseous calcification to metabolic acidosis may be similar to that of bone, and, given that metabolic acidosis impairs bone mineralization, it is likely to attenuate the calcification process in extraskeletal sites. The fundamental problem in this hypothetical framework is that it does not account for the fate of calcium efflux from bone in metabolic acidosis. In models previously tested, metabolic acidosis induces a net calcium efflux from bone that is accompanied by a significant increase in urinary calcium excretion and a net negative balance of calcium. In the uremic animal model used by the investigators, renal handling of calcium could be significantly impaired. How does the system deal with this calcium load? How is it ‘buffered’? Is it just increased solubility of minerals in an acidotic environment? How does the vascular tissue become immune or resistant to calcification? What are the molecular mechanisms underpinning this behavior? What is the effect of metabolic acidosis on bone in experimental uremia? How does the addition of active vitamin D modulate the relationship? The study by Mendoza and collaborators4.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 (78) Google Scholar ushers a new venue for research in the field of vascular calcification and highlights the need for more studies to provide a cohesive understanding of the effect of metabolic acidosis on the biology of calcification and the interplay between bone and vasculature and its effect on health and disease.
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