Skip to main content

Advertisement

SpringerLink
Log in

Calciphylaxis: from the disease to the diseased

  • Review
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Calciphylaxis, or calcific uremic arteriolopathy, is a vascular ossification–calcification disease involving cutaneous or visceral arterioles, with ischemic damage of the surrounding tissues, usually in the setting of chronic kidney disease. Pathogenesis is still unclear and probably comprises the participation of vascular smooth muscle cells, endothelial cells and macrophages surrounded by a uremic and/or pro-calcifying environment. According to the original concept of calcific uremic arteriolopathy coined by Hans Selye, risk factors may be divided into sensitizers and challengers and their knowledge is useful in clinical practice to pre-emptively identify both uremic and non-uremic ‘at risk’ patients and guide treatment. Systemic calcific uremic arteriolopathy is a rarity. Cutaneous calcific uremic arteriolopathy is more frequent and clinically presents as a first phase of cutaneous hardening and erythema, followed by a second phase of ulcerations and scars; these two phases are probably associated with the initial development of arteriolar lesion and tissue ischemic damage, respectively. Clinical history, physical examination, laboratory analysis, histology and imaging are the main tools to exclude important differential diagnoses and obtain a definitive diagnosis. Treatment is generally unrewarding and consists of rigorous control of comorbid conditions, anti-oxidant, anti-inflammatory and antithrombotic strategies, avoidance of iatrogeny and wound and pain management. Prognosis remains poor in terms of morbidity and mortality. Efforts should be made towards a greater awareness of calcific uremic arteriolopathy, development of better therapies and improvement of clinical outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Prabahar MR et al (2006) Severe extraosseous calcification in chronic kidney disease. Dial Transplant 35(12):772–776

    Article  Google Scholar 

  2. Hayden M et al (2005) Vascular ossification—calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis—calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol 4(1):4

    Article  PubMed Central  PubMed  Google Scholar 

  3. Demer LL, Tintut Y (2008) Vascular calcification: pathobiology of a multifaceted disease. Circulation 117(22):2938–2948

    Article  PubMed Central  PubMed  Google Scholar 

  4. Kalajian AH et al (2009) Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol 145(4):451–458

    Article  PubMed  Google Scholar 

  5. Kramann R et al (2013) Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy. Nephrol Dial Transplant 28(4):856–868

    Article  CAS  PubMed  Google Scholar 

  6. Ng AT, Peng DH (2011) Calciphylaxis. Dermatol Ther 24(2):256–262

    Article  PubMed  Google Scholar 

  7. Hafner J et al (1995) Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 33(6):954–962

    Article  CAS  PubMed  Google Scholar 

  8. Reiter N et al (2011) Calcinosis cutis: part I. Diagnostic pathway. J Am Acad Dermatol 65(1):1–12 (quiz 13–14)

    Article  CAS  PubMed  Google Scholar 

  9. Rogers NM, Teubner DJ, Coates PT (2007) Calcific uremic arteriolopathy: advances in pathogenesis and treatment. Semin Dial 20(2):150–157

    Article  PubMed  Google Scholar 

  10. Wollina U (2013) Update on cutaneous calciphylaxis. Indian J Dermatol 58(2):87–92

    Article  PubMed Central  PubMed  Google Scholar 

  11. Magro CM, Simman R, Jackson S (2010) Calciphylaxis: a review. J Am Col Certif Wound Spec 2(4):66–72

    PubMed Central  PubMed  Google Scholar 

  12. Bhambri A, Del Rosso JQ (2008) Calciphylaxis: a review. J Clin Aesthet Dermatol 1(2):38–41

    PubMed Central  PubMed  Google Scholar 

  13. Sowers KM, Hayden MR (2010) Calcific uremic arteriolopathy: pathophysiology, reactive oxygen species and therapeutic approaches. Oxid Med Cell Longev 3(2):109–121

    Article  PubMed Central  PubMed  Google Scholar 

  14. Giachelli CM (2003) Vascular calcification. in vitro evidence for the role of inorganic phosphate. J Am Soc Nephrol 14(suppl 4):S300–S304

    Article  CAS  PubMed  Google Scholar 

  15. Weenig RH (2008) Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol 58(3):458–471

    Article  PubMed  Google Scholar 

  16. Shroff RC et al (2008) Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation 118(17):1748–1757

    Article  CAS  PubMed  Google Scholar 

  17. Mathur RV, Shortland JR, El Nahas AM (2001) Calciphylaxis. Postgrad Med J 77(911):557–561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Heiss A et al (2003) Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 278(15):13333–13341

    Article  CAS  PubMed  Google Scholar 

  19. Ketteler M et al (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361(9360):827–833

    Article  CAS  PubMed  Google Scholar 

  20. Brandenburg VM et al (2014) Calcific uraemic arteriolopathy: a rare disease with a potentially high impact on chronic kidney disease-mineral and bone disorder. Pediatr Nephrol 29:2289–2298

    Article  PubMed  Google Scholar 

  21. Brandenburg VM et al (2012) Calciphylaxis in CKD and beyond. Nephrol Dial Transplant 27(4):1314–1318

    Article  PubMed  Google Scholar 

  22. Bostrom K et al (2001) Matrix GLA protein modulates differentiation induced by bone morphogenetic protein-2 in C3H10T1/2 cells. J Biol Chem 276(17):14044–14052

    CAS  PubMed  Google Scholar 

  23. Schurgers LJ, Cranenburg EC, Vermeer C (2008) Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost 100(4):593–603

    CAS  PubMed  Google Scholar 

  24. Cranenburg ECM et al (2008) The circulating inactive form of matrix Gla protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res 45(5):427–436

    Article  CAS  PubMed  Google Scholar 

  25. Shroff RC et al (2010) Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol 21(1):103–112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Giachelli CM (2009) The emerging role of phosphate in vascular calcification. Kidney Int 75(9):890–897

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Thompson B, Towler DA (2012) Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol 8(9):529–543

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Jablonski KL, Chonchol M (2013) Vascular calcification in end-stage renal disease. Hemodial Int 17:S17–S21

    Article  PubMed  Google Scholar 

  29. Kapustin AN, Shanahan CM (2012) Calcium regulation of vascular smooth muscle cell-derived matrix vesicles. Trends Cardiovasc Med 22(5):133–137

    Article  CAS  PubMed  Google Scholar 

  30. Proudfoot D, Shanahan CM (2011) Nanocrystals seed calcification in more ways than one. Kidney Int 79(4):379–382

    Article  PubMed  Google Scholar 

  31. Ahmed S et al (2001) Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 37(6):1267–1276

    Article  CAS  PubMed  Google Scholar 

  32. Sage AP et al (2011) Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int 79(4):414–422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Anderson D, Stewart W, Piercy D (1968) Calcifying panniculitis with fat and skin necrosis in a case of uraemia with autonomous hyperparathyroidism. Lancet 292(7563):323–325

    Article  Google Scholar 

  34. Richens G, Piepkorn MW, Krueger GG (1982) Calcifying panniculitis associated with renal failure. A case of Selye’s calciphylaxis in man. J Am Acad Dermatol 6(4 Pt 1):537–539

    Article  CAS  PubMed  Google Scholar 

  35. Edwards RB et al (2000) Calciphylaxis: a rare limb and life threatening cause of ischaemic skin necrosis and ulceration. Br J Plast Surg 53(3):253–255

    Article  CAS  PubMed  Google Scholar 

  36. Dauden E, Onate MJ (2008) Calciphylaxis. Dermatol Clin 26(4):557–568, ix

    Article  PubMed  Google Scholar 

  37. Weenig RH et al (2007) Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 56(4):569–579

    Article  PubMed  Google Scholar 

  38. Budisavljevic MN, Cheek D, Ploth DW (1996) Calciphylaxis in chronic renal failure. J Am Soc Nephrol 7(7):978–982

    CAS  PubMed  Google Scholar 

  39. Brandenburg VM, Cozzolino M, Ketteler M (2011) Calciphylaxis: a still unmet challenge. J Nephrol 24(2):142–148

    Article  PubMed  Google Scholar 

  40. Hayashi M et al (2012) A case–control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant 27(4):1580–1584

    Article  CAS  PubMed  Google Scholar 

  41. Nigwekar SU et al (2013) Statin use and calcific uremic arteriolopathy: a matched case–control study. Am J Nephrol 37(4):325–332

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Zacharias J, Fontaine B, Fine A (1999) Calcium use increases risk of calciphylaxis: a case–control study. Perit Dial Int 19(3):248–252

    CAS  PubMed  Google Scholar 

  43. Bleyer AJ et al (1998) A case control study of proximal calciphylaxis. Am J Kidney Dis 32(3):376–383

    Article  CAS  PubMed  Google Scholar 

  44. Wilmer WA, Magro CM (2002) Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial 15(3):172–186

    Article  PubMed  Google Scholar 

  45. Rezaie W et al (2009) Calciphylaxis in chronic renal failure: an approach to risk factors. Indian J Nephrol 19(3):115–118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Vedvyas C, Winterfield LS, Vleugels RA (2012) Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol 67(6):e253–e260

    Article  PubMed  Google Scholar 

  47. Lee JL et al (2008) Recognizing calcific uremic arteriolopathy in autoimmune disease: an emerging mimicker of vasculitis. Autoimmun Rev 7(8):638–643

    Article  CAS  PubMed  Google Scholar 

  48. Slough S et al (2006) Association between calciphylaxis and inflammation in two patients on chronic dialysis. Adv Perit Dial 22:171–174

    PubMed  Google Scholar 

  49. Harris RJ, Cropley TG (2011) Possible role of hypercoagulability in calciphylaxis: review of the literature. J Am Acad Dermatol 64(2):405–412

    Article  PubMed  Google Scholar 

  50. Rogers NM, Coates PT (2008) Calcific uraemic arteriolopathy: an update. Curr Opin Nephrol Hypertens 17(6):629–634

    Article  PubMed  Google Scholar 

  51. Nichols B, Saadat P, Vadmal MS (2011) Fatal systemic nonuremic calciphylaxis in a patient with primary autoimmune myelofibrosis. Int J Dermatol 50(7):870–874

    Article  PubMed  Google Scholar 

  52. Kim NR et al (2012) Pulmonary calciphylaxis associated with acute respiratory and renal failure due to cryptogenic hypercalcemia: an autopsy case report. Korean J Pathol 46(6):601–605

    Article  PubMed Central  PubMed  Google Scholar 

  53. Li YJ et al (2006) Fulminant pulmonary calciphylaxis and metastatic calcification causing acute respiratory failure in a uremic patient. Am J Kidney Dis 47(4):e47–e53

    Article  PubMed  Google Scholar 

  54. Brown DF, Denney CF, Burns DK (1998) Systemic calciphylaxis associated with massive gastrointestinal hemorrhage. Arch Pathol Lab Med 122(7):656–659

    CAS  PubMed  Google Scholar 

  55. Andersen LK, Lehman JS, Davis MD (2014) Calciphylaxis is a cutaneous process without involvement of internal organs in a retrospective study of postmortem findings in three patients. Acta Derm Venereol 94(3):298–302

    Article  PubMed  Google Scholar 

  56. Tsolakidis S et al (2013) Calciphylaxis—a challenging and solvable task for plastic surgery? A case report. BMC Dermatol 13:1

    Article  PubMed Central  PubMed  Google Scholar 

  57. Smith JR et al (2012) The role of sodium thiosulphate in the treatment of calciphylaxis. Port J Nephrol Hypertens 26:245–254

    Google Scholar 

  58. Bleibel W, Hazar B, Herman R (2006) A case report comparing various radiological tests in the diagnosis of calcific uremic arteriolopathy. Am J Kidney Dis 48(4):659–661

    Article  PubMed  Google Scholar 

  59. Kyttaris VC et al (2007) Calciphylaxis: a pseudo-vasculitis syndrome. Semin Arthritis Rheum 36(4):264–267

    Article  PubMed  Google Scholar 

  60. Kumar VA (2011) Calcific uremic arteriolopathy: an underrecognized entity. Perm J 15(2):85–87

    PubMed Central  PubMed  Google Scholar 

  61. Shmidt E et al (2012) Net-like pattern of calcification on plain soft-tissue radiographs in patients with calciphylaxis. J Am Acad Dermatol 67(6):1296–1301

    Article  PubMed  Google Scholar 

  62. Khalpey Z et al (2010) The importance of prevention of calciphylaxis in patients who are at risk and the potential fallibility of calcimimetics in the treatment of calciphylaxis for patients with secondary hyperparathyroidism. NDT Plus 3(1):68–70

    PubMed Central  PubMed  Google Scholar 

  63. Torregrosa JV et al (2012) Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia 32(3):329–334

    PubMed  Google Scholar 

  64. Floege J et al (2014) The effect of cinacalcet on calciphylaxis events in haemodialysis patients in the EVOLVE Clinical Trial. American Society of Nephrology Kidney Week 2014, Philadelphia

  65. Coates T et al (1998) Cutaneous necrosis from calcific uremic arteriolopathy. Am J Kidney Dis 32(3):384–391

    Article  CAS  PubMed  Google Scholar 

  66. Kang AS et al (2000) Is calciphylaxis best treated surgically or medically? Surgery 128(6):967–971 (discussion 971–972)

    Article  CAS  PubMed  Google Scholar 

  67. O’Neill WC (2013) Sodium thiosulfate: mythical treatment for a mysterious disease? Clin J Am Soc Nephrol 8(7):1068–1069

    Article  PubMed  Google Scholar 

  68. Cicone JS et al (2004) Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis 43(6):1104–1108

    Article  PubMed  Google Scholar 

  69. Monney P et al (2004) Rapid improvement of calciphylaxis after intravenous pamidronate therapy in a patient with chronic renal failure. Nephrol Dial Transplant 19(8):2130–2132

    Article  PubMed  Google Scholar 

  70. Rogers NM et al (2008) Hyperbaric oxygen as effective adjuvant therapy in the treatment of distal calcific uraemic arteriolopathy. NDT Plus 1(4):244–249

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

This article does not contain any studies with human participants or animals performed by any of the authors.

Author information

Authors and Affiliations

  1. School of Medicine of Porto University, Porto, Portugal

    Tiago M. Oliveira

  2. Department of Renal, Urologic and Infectious Diseases, School of Medicine of Porto University, Porto, Portugal

    João M. Frazão

  3. Department of Nephrology, São João Hospital Centre, EPE, Porto, Portugal

    João M. Frazão

  4. Nephrology and Infectiology Research and Development Group, INEB, Porto, Portugal

    João M. Frazão

Authors
  1. Tiago M. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. João M. Frazão
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to João M. Frazão.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oliveira, T.M., Frazão, J.M. Calciphylaxis: from the disease to the diseased. J Nephrol 28, 531–540 (2015). https://doi.org/10.1007/s40620-015-0192-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-015-0192-2

Keywords

Search

Navigation