Vascular calcification in ESRD: Another cloud appears in the perfect storm—but highlights a silver lining?
Authors: Dwight A. Towler
Journal: Kidney International (2004)

The horrendous cardiovascular consequences of end-stage renal disease (ESRD) are multifactorial; metabolic, hypertensive, inflammatory, and electrolyte abnormalities that drive macrovascular disease processes result in the 20% annual mortality in our patients afflicted with ESRD1Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Google Scholar. Severe vascular calcification is highly characteristic of ESRD, a process that alters vascular compliance and inhibits physiologic regulation of blood flow and coagulation. At least four histoanatomic variants of macrovascular calcification—intimal, medial, valvular, and vascular tissue calciphylaxis—have emerged2Vattikuti R. Towler D.A. Osteogenic regulation of vascular calcification: An early perspective.Am J Physiol Endocrinol Metab. 2004; 286: E686-696Google Scholar. Once thought benign, the deleterious consequences of vascular calcification have become clear3Abedin M. Tintut Y. Demer L.L. Vascular calcification: Mechanisms and clinical ramifications.Arterioscler Thromb Vasc Biol. 2004; 24: 1161-1170Google Scholar. In the setting of diabetes, medial calcification portends increased cardiovascular mortality and risk of lower extremity amputation4Lehto S. Niskanen L. Suhonen M. et al.Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus.Arterioscler Thromb Vasc Biol. 1996; 16: 978-983Google Scholar. Aortic valve calcium content is the single best predictor of clinical progression in extant asymptomatic aortic stenosis5Rosenhek R. Binder T. Porenta G. et al.Predictors of outcome in severe, asymptomatic aortic stenosis.N Engl J Med. 2000; 343: 611-617Google Scholar. In patients with ESRD, London et al6London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Google Scholar have convincingly demonstrated that both medial and intimal calcification portend mortality risk. Molecular and histologic features of vascular osteogenesis are evident in the first three variants listed above2Vattikuti R. Towler D.A. Osteogenic regulation of vascular calcification: An early perspective.Am J Physiol Endocrinol Metab. 2004; 286: E686-696Google Scholar. Recapitulating features of bone marrow stromal cell physiology, vascular myofibroblasts contribute to cardiovascular calcification; along with dystrophic calcium deposition in dying cells and lipoprotein deposits, active endochondral and intramembranous ossification processes contribute to vascular calcium load. Mural myofibroblasts and Sca1+ progenitors—arising from medial and adventitial venues—are recruited in response to oxidized lipids, inflammation, and mechanical injury2Vattikuti R. Towler D.A. Osteogenic regulation of vascular calcification: An early perspective.Am J Physiol Endocrinol Metab. 2004; 286: E686-696Google Scholar. Paracrine vascular signals provided by bone morphogenetic protein-2, Wnts, parathyroid hormone–related polypeptide, osteopontin, osteoprotegerin, and fetuin complexes control calcium deposition, and are entrained to endocrine, metabolic, inflammatory, and mechanical cues2Vattikuti R. Towler D.A. Osteogenic regulation of vascular calcification: An early perspective.Am J Physiol Endocrinol Metab. 2004; 286: E686-696Google Scholar. In ESRD, a “perfect storm” of vascular calcification arises, with hyperglycemia, hyperphosphatemia, hypercholesterolemia, hypertension, parathyroid hormone resistance, and iatrogenic calcitriol excess contributing to severe calcific vasculopathy7Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Google Scholar. In this issue of Kidney International, Giachelli et al8Yang Y. Curinga G. Giachelli C.M. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.Kidney Int. 2004; 66: 2293-2299Google Scholar identify yet another metabolic parameter—serum calcium concentration—that now must be independently considered in the pathobiology and clinical management of vascular calcification. At first glance, this may seem trivial, and, of course, clinical guidelines already address this parameter. However, in a series of carefully performed experiments, calcium is shown to promote cell-mediated matrix calcification at any given phosphate concentration; they demonstrate that elevated extracellular calcium ion promotes the active, cell-mediated calcification processes of vascular smooth muscle cells8Yang Y. Curinga G. Giachelli C.M. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.Kidney Int. 2004; 66: 2293-2299Google Scholar. This may occur in part via up-regulation of the type III Na/Pi cotransporter (also known as Pit-1, Glvr-1, SCL20A1); indeed, inhibition of cellular phosphate uptake with foscarnet inhibits calcium-induced VSMC calcification8Yang Y. Curinga G. Giachelli C.M. Elevated extracellular calcium levels induce smooth muscle cell matrix mineralization in vitro.Kidney Int. 2004; 66: 2293-2299Google Scholar. The Giachelli lab has previously shown that inorganic phosphate (Pi) signaling via Pit-1 enhances expression of Runx2/Cbfa19Jono S. MckEE M.D. Murry C.E. et al.Phosphate regulation of vascular smooth muscle cell calcification.Circ Res. 2000; 87: E10-E17Google Scholar, a chondro-osteogenic transcription factor that participates in neovascularization, matrix synthesis, and mineralization in bone. Of note, Runx2/Cbfa1 appears to be a general vascular “stress-responsive” gene, inducible by mechanical injury10Geary R.L. Wong J.M. Rossini A. et al.Expression profiling identifies 147 genes contributing to a unique primate neointimal smooth muscle cell phenotype.Arterioscler Thromb Vasc Biol. 2002; 22: 2010-2016Google Scholar and uremia11Moe S.M. Duan D. Doehle B.P. et al.Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels.Kidney Int. 2003; 63: 1003-1011Google Scholar. Whether these latter stressors also signal via Pit-1 to up-regulate vascular Runx2/Cbfa1 is as yet unknown. Nevertheless, the observation that hypercalcemia up-regulates Pit-1—the phosphate transporter that conveys procalcific osteogenic cellular responses to hyperphosphatemia12Giachelli C.M. Vascular calcification: In vitro evidence for the role of inorganic phosphate.J Am Soc Nephrol. 2003; 14: S300-304Google Scholar—highlights the importance of this arterial vascular smooth muscle cell signaling cascade to uremic vascular disease. In the future, it should be possible, using either genetically lesioned or pharmacologically manipulated mice, to assess whether strategies that alter Pit-1 activities regulate vascular calcification responses in vivo as observed in vitro. If so, pharmacologic manipulation of vascular phosphate transporters, coupled with assiduous metabolic control13Chertow G.M. Dillon M. Burke S.K. et al.A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium. Strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients.Clin Nephrol. 1999; 51: 18-26Google Scholar and endocrine strategies that normalize vascular and skeletal calcium flux14Shao J.S. Cheng S.L. Charlton-Kachigian N. et al.Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice.J Biol Chem. 2003; 278: 50195-50202Google Scholar , 15London 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: 1943-1951Google Scholar, may help our patients to better weather the vasculopathy of ESRD. This paper was supported by NIH grants HL69229, AR43731, and the Barnes-Jewish Research Foundation.