Calciphylaxis Clinical Presentation
- Author: Julia R Nunley, MD; Chief Editor: Dirk M Elston, MD more...
Most patients with calciphylaxis have a long-standing history of chronic renal failure and renal replacement therapy. On rare occasions, calciphylaxis may occur in a patient with chronic renal failure prior to the initiation of replacement therapy. Very rarely, it may occur in an individual without a history of chronic renal failure.
Many persons who develop calciphylaxis have undergone renal allograft transplantation. The allograft may still be functional when calciphylaxis develops. Frequently, patients have been noncompliant with dietary, medical, and/or dialysis prescriptions prior to the onset of calciphylaxis.
Lesions of calciphylaxis typically develop suddenly and progress rapidly. Lesions may be singular or numerous, and they generally occur on the lower extremities (see image below); however, lesions also may develop on the hands and torso. Intense pain is a constant finding.
The patient's history may reveal an event that is a suspected trigger or risk factor for the development of calciphylaxis. These triggers include the following[5, 8, 7, 19, 20, 21, 22, 23, 24] :
Recent and sudden weight loss
Infusion of medications such as iron dextran
Remote and/or recent use of immunosuppressive agents, especially corticosteroids
Diabetes mellitus and insulin injections
Use of vitamin D and calcium-based phosphate binders
Elevated aluminum levels
Concomitant vascular disease
Concurrent use of warfarin anticoagulation: Current data suggest that warfarin therapy may lower protein C concentrations, leading to a procoagulant condition in the calcified vessel. Warfarin may also inhibit carboxylation of matrix Gla protein, an important inhibitor of calcification, thus promoting calcification
Review of the patient's medical record usually reveals a history of hyperphosphatemia with hyperparathyroidism and hypoalbuminemia. Patients with nonuremic calciphylaxis frequently have a history of primary hyperparathyroidism, malignancy, alcoholic liver disease, or underlying connective-tissue disease or pro-inflammatory condition.[19, 20, 25, 26, 27]
Early lesions of calciphylaxis manifest as nonspecific violaceous mottling; as livedo reticularis; or as erythematous papules, plaques, or nodules. More developed lesions have a stellate purpuric configuration with central cutaneous necrosis (see the image below).
Multiple lesions of variable age may be present, following the path of the vasculature. Less commonly, lesions may manifest as either bullae (see the image below) or distinct subcutaneous, erythematous nodules suggestive of erythema nodosum. Lesions are excruciatingly tender and extremely firm.
The distribution of the lesions may be characterized as proximal or distal. Ninety percent of lesions of calciphylaxis occur on the lower extremities. Distal lesions are those that occur below the knee; proximal lesions occur on the thighs or the trunk. Proximally distributed lesions occur in 44-68% of patients, with lesions developing predominantly on the thighs, the buttocks, and the lower part of the abdomen. Distal and visceral involvement are not uncommon.
An intact peripheral pulse helps to distinguish acral calciphylaxis from atherosclerotic peripheral vascular disease. Ulceration is considered a late finding and is associated with a higher mortality rate.
Disorders associated with the development of calciphylaxis include the following[2, 5, 20, 21, 22] :
Common associations include chronic renal failure, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, and vascular calcification.
Speculative associations include aluminum toxicity, coagulation abnormalities, and iron dextran infusion.
Associations suggested from clinical observations include renal transplantation, immunosuppressive agents, corticosteroid use, and obesity.
Systemic inflammation appears to be a predisposing factor. [11, 12]
The cause of calciphylaxis remains obscure. Most cases occur in the setting of chronic renal failure, abnormal calcium-phosphate homeostasis, and hyperparathyroidism. Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.
Case reports exist of calciphylaxis occurring in primary hyperparathyroidism, cirrhosis, Crohn disease, malignancy, and rheumatoid arthritis, without renal disease. The pathogenesis of calciphylaxis in these cases is uncertain.[19, 20, 25, 26] The exact role of PTH is uncertain because calciphylaxis may occur after total parathyroidectomy, in the absence of measurable PTH levels.
Patients at an increased risk appear to be those who are obese and those who have been exposed to immunosuppressive agents, including glucocorticoids. Calciphylaxis occurs more frequently in areas where body fat is most abundant, such as the thighs, the buttocks, and the lower part of the abdomen.[21, 22] Fatty areas may be at higher risk for thrombosis, owing to lower blood flow or the increased potential for vascular kinking.
Persons with diabetes mellitus may also be at an increased risk;[20, 21, 22] insulin injections may be an independent risk due to trauma to the subcutis.
The clinical appearance of the lesions of calciphylaxis (livedo reticularis and stellate purpura) suggests that the common endpoint of the process is small vessel occlusion. Indeed, microthrombi are found in most cases.
Hypercoagulable conditions, including protein C and protein S deficiencies, and the presence of a circulating anticoagulant have been described in a number of patients.[28, 29, 30, 31, 32] However, conditions of hypercoagulability are not found uniformly. If they do exist, they could possibly precipitate or exacerbate calciphylaxis in a predisposed patient.
Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, various pathologic roles may be attributed to this vascular calcification. First, calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability. Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion. Finally, data suggest that the uremic milieu may promote calcification through inhibition of various endogenous inhibitors of calcification such as alpha2-Heremans-Schmid glycoprotein/fetuin A (AHSG), osteopontin, and matrix Gla protein. These theories remain speculative.[7, 10]
Selye H. Calciphylaxis. Chicago, Ill: University of Chicago Press; 1962.
Gipstein RM, Coburn JW, Adams DA, et al. Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med. 1976 Nov. 136(11):1273-80. [Medline].
Zhou Q, Neubauer J, Kern JS, Grotz W, Walz G, Huber TB. Calciphylaxis. Lancet. 2014 Mar 22. 383(9922):1067. [Medline].
Selye H, Gabbiani G, Strebel R. Sensitization to calciphylaxis by endogenous parathyroid hormone. Endocrinology. 1962 Oct. 71:554-8. [Medline].
Lal G, Nowell AG, Liao J, Sugg SL, Weigel RJ, Howe JR. Determinants of survival in patients with calciphylaxis: a multivariate analysis. Surgery. 2009 Dec. 146(6):1028-34. [Medline].
Haas M, Leko-Mohr Z, Roschger P, et al. Osteoprotegerin and parathyroid hormone as markers of high-turnover osteodystrophy and decreased bone mineralization in hemodialysis patients. Am J Kidney Dis. 2002 Mar. 39(3):580-6. [Medline].
Schlieper G, Brandenburg V, Ketteler M, Floege J. Sodium thiosulfate in the treatment of calcific uremic arteriolopathy. Nat Rev Nephrol. 2009 Sep. 5(9):539-43. [Medline].
Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007 Apr. 56(4):569-79. [Medline].
Amuluru L, High W, Hiatt KM, Ranville J, Shah SV, Malik B. Metal deposition in calcific uremic arteriolopathy. J Am Acad Dermatol. 2009 Jul. 61(1):73-9. [Medline].
Rogers NM, Teubner DJ, Coates PT. Calcific uremic arteriolopathy: advances in pathogenesis and treatment. Semin Dial. 2007 Mar-Apr. 20(2):150-7. [Medline].
Slough S, Servilla KS, Harford AM, Konstantinov KN, Harris A, Tzamaloukas AH. Association between calciphylaxis and inflammation in two patients on chronic dialysis. Adv Perit Dial. 2006. 22:171-4. [Medline].
Swanson AM, Desai SR, Jackson JD, Andea AA, Hughey LC. Calciphylaxis associated with chronic inflammatory conditions, immunosuppression therapy, and normal renal function: a report of 2 cases. Arch Dermatol. 2009 Jun. 145(6):723-5. [Medline].
Kramann R, Brandenburg VM, Schurgers LJ, et al. Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy. Nephrol Dial Transplant. 2012 Dec 6. [Medline].
el-Azhary RA, Arthur AK, Davis MD, McEvoy MT, Gibson LE, Weaver AL, et al. Retrospective analysis of tissue plasminogen activator as an adjuvant treatment for calciphylaxis. JAMA Dermatol. 2013 Jan. 149 (1):63-7. [Medline].
Zembowicz A, Navarro P, Walters S, Lyle SR, Moschella SL, Miller D. Subcutaneous thrombotic vasculopathy syndrome: an ominous condition reminiscent of calciphylaxis: calciphylaxis sine calcifications?. Am J Dermatopathol. 2011 Dec. 33 (8):796-802. [Medline].
Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol. 2012 Dec. 67 (6):e253-60. [Medline].
Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997 Dec. 122(6):1083-9; discussion 1089-90. [Medline].
Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002 May-Jun. 15(3):172-86. [Medline].
Ortiz A, Ceccato F, Roverano S, Albertengo A, Paira S. Calciphylaxis associated with rheumatoid arthritis: communication of the second case. Clin Rheumatol. 2009 Jun. 28 Suppl 1:S65-8. [Medline].
Baig MA, Aksoy T, McClain D, Fomberstein B. Calciphylaxis in a hemodialysis patient on corticosteroids and etanercept for psoriatic arthritis. J Clin Rheumatol. 2010 Mar. 16(2):92-3. [Medline].
Hussein MR, Ali HO, Abdulwahed SR, Argoby Y, Tobeigei FH. Calciphylaxis cutis: a case report and review of literature. Exp Mol Pathol. 2009 Apr. 86(2):134-5. [Medline].
Aabed G, Al Furayh O, Al-Lehbi A, Al Mana H, Al Ghamedi A, Helmy A. Calciphylaxis-associated second renal graft failure and patient loss: a case report and review of the literature. Exp Clin Transplant. 2008 Dec. 6(4):287-93. [Medline].
Friedman SG. Leg revascularization in patients with calciphylaxis. Am Surg. 2002 Jul. 68(7):591-2. [Medline].
Rudwaleit M, Schwarz A, Trautmann C, Offermann G, Distler A. Severe calciphylaxis in a renal patient on long-term oral anticoagulant therapy. Am J Nephrol. 1996. 16(4):344-8. [Medline].
Kalajian AH, Malhotra PS, Callen JP, Parker LP. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol. 2009 Apr. 145(4):451-8. [Medline].
James LR, Lajoie G, Prajapati D, Gan BS, Bargman JM. Calciphylaxis precipitated by ultraviolet light in a patient with end-stage renal disease secondary to systemic lupus erythematosus. Am J Kidney Dis. 1999 Nov. 34(5):932-6. [Medline].
Sankarasubbaiyan S, Scott G, Holley JL. Cryofibrinogenemia: an addition to the differential diagnosis of calciphylaxis in end-stage renal disease. Am J Kidney Dis. 1998 Sep. 32(3):494-8. [Medline].
Mehta RL, Scott G, Sloand JA, Francis CW. Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med. 1990 Mar. 88(3):252-7. [Medline].
Perez-Mijares R, Payan-Lopez J, Guzman-Zamudio JL, et al. Free protein S deficiency in hemodialysis patients due to vascular calcifications?. Nephron. 1996. 74(2):356-60. [Medline].
Rostaing L, el Feki S, Delisle MB, et al. Calciphylaxis in a chronic hemodialysis patient with protein S deficiency. Am J Nephrol. 1995. 15(6):524-7. [Medline].
Goldsmith DJ. Calciphylaxis, thrombotic diathesis and defects in coagulation regulation. Nephrol Dial Transplant. 1997 May. 12(5):1082-3. [Medline].
Shmidt E, Murthy NS, Knudsen JM, et al. Net-like pattern of calcification on plain soft-tissue radiographs in patients with calciphylaxis. J Am Acad Dermatol. 2012 Dec. 67(6):1296-301. [Medline].
Norris B, Vaysman V, Line BR. Bone scintigraphy of calciphylaxis: a syndrome of vascular calcification and skin necrosis. Clin Nucl Med. 2005 Nov. 30(11):725-7. [Medline].
Cosmin A, Soudry G. A case of severe calciphylaxis seen on three-phase bone scan. Clin Nucl Med. 2005 Nov. 30(11):765-6. [Medline].
Soni S, Leslie WD. Bone scan findings in metastatic calcification from calciphylaxis. Clin Nucl Med. 2008 Jul. 33(7):502-4. [Medline].
Goldsmith DJ. Calcifying panniculitis or 'simple' inflammation? Biopsy is better than a bone scan. Nephrol Dial Transplant. 1997 Nov. 12(11):2463-4. [Medline].
Naik BJ, Lynch DJ, Slavcheva EG, Beissner RS. Calciphylaxis: medical and surgical management of chronic extensive wounds in a renal dialysis population. Plast Reconstr Surg. 2004 Jan. 113(1):304-12. [Medline].
Don BR, Chin AI. A strategy for the treatment of calcific uremic arteriolopathy (calciphylaxis) employing a combination of therapies. Clin Nephrol. 2003 Jun. 59(6):463-70. [Medline].
Zitt E, König M, Vychytil A, et al. Use of sodium thiosulphate in a multi-interventional setting for the treatment of calciphylaxis in dialysis patients. Nephrol Dial Transplant. 2013 Jan 4. [Medline].
Malbos S, Ureña-Torres P, Bardin T, Ea HK. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine. 2015 Oct 19. [Medline].
Lipsker D, Chosidow O, Martinez F, Challier E, Francès C. Low-calcium dialysis in calciphylaxis. Arch Dermatol. 1997 Jun. 133(6):798-9. [Medline].
Moe SM, Reslerova M, Ketteler M, et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int. 2005 Jun. 67(6):2295-304. [Medline].
Wang HY, Yu CC, Huang CC. Successful treatment of severe calciphylaxis in a hemodialysis patient using low-calcium dialysate and medical parathyroidectomy: case report and literature review. Ren Fail. 2004 Jan. 26(1):77-82. [Medline].
Barman Balfour JA, Scott LJ. Cinacalcet hydrochloride. Drugs. 2005. 65(2):271-81. [Medline].
Robinson MR, Augustine JJ, Korman NJ. Cinacalcet for the treatment of calciphylaxis. Arch Dermatol. 2007 Feb. 143(2):152-4. [Medline].
Velasco N, MacGregor MS, Innes A, MacKay IG. Successful treatment of calciphylaxis with cinacalcet-an alternative to parathyroidectomy?. Nephrol Dial Transplant. 2006 Jul. 21(7):1999-2004. [Medline].
Raymond CB, Wazny LD. Sodium thiosulfate, bisphosphonates, and cinacalcet for treatment of calciphylaxis. Am J Health Syst Pharm. 2008 Aug 1. 65(15):1419-29. [Medline].
Sharma A, Burkitt-Wright E, Rustom R. Cinacalcet as an adjunct in the successful treatment of calciphylaxis. Br J Dermatol. 2006 Dec. 155(6):1295-7. [Medline].
Monney P, Nguyen QV, Perroud H, Descombes E. Rapid improvement of calciphylaxis after intravenous pamidronate therapy in a patient with chronic renal failure. Nephrol Dial Transplant. 2004 Aug. 19(8):2130-2. [Medline].
Schliep S, Schuler G, Kiesewetter F. Successful treatment of calciphylaxis with pamidronate. Eur J Dermatol. 2008 Sep-Oct. 18(5):554-6. [Medline].
Shiraishi N, Kitamura K, Miyoshi T, et al. Successful treatment of a patient with severe calcific uremic arteriolopathy (calciphylaxis) by etidronate disodium. Am J Kidney Dis. 2006 Jul. 48(1):151-4. [Medline].
Hanafusa T, Yamaguchi Y, Tani M, Umegaki N, Nishimura Y, Katayama I. Intractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates. J Am Acad Dermatol. 2007 Dec. 57(6):1021-5. [Medline].
Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol. 2001 May. 21(5):817-24. [Medline].
Torregrosa JV, Durán CE, Barros X, Blasco M, Arias M, Cases A, et al. Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia. 2012 May 14. 32(3):329-34. [Medline].
Hackett BC, McAleer MA, Sheehan G, Powell FC, O'Donnell BF. Calciphylaxis in a patient with normal renal function: response to treatment with sodium thiosulfate. Clin Exp Dermatol. 2009 Jan. 34(1):39-42. [Medline].
Hayden MR, Goldsmith D, Sowers JR, Khanna R. Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate. Int Urol Nephrol. 2008. 40(2):443-51. [Medline].
Baker BL, Fitzgibbons CA, Buescher LS. Calciphylaxis responding to sodium thiosulfate therapy. Arch Dermatol. 2007 Feb. 143(2):269-70. [Medline].
Musso CG, Enz P, Vidal F, et al. Oral sodium thiosulfate solution as a secondary preventive treatment for calciphylaxis in dialysis patients. Saudi J Kidney Dis Transpl. 2008 Sep. 19(5):820-1. [Medline].
Cicone JS, Petronis JB, Embert CD, Spector DA. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis. 2004 Jun. 43(6):1104-8. [Medline].
Mataic D, Bastani B. Intraperitoneal sodium thiosulfate for the treatment of calciphylaxis. Ren Fail. 2006. 28(4):361-3. [Medline].
Meissner M, Kaufmann R, Gille J. Sodium thiosulphate: a new way of treatment for calciphylaxis?. Dermatology. 2007. 214(4):278-82. [Medline].
Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. 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. 2005 Mar 18. 4(1):4. [Medline]. [Full Text].
Guerra G, Shah RC, Ross EA. Rapid resolution of calciphylaxis with intravenous sodium thiosulfate and continuous venovenous haemofiltration using low calcium replacement fluid: case report. Nephrol Dial Transplant. 2005 Jun. 20(6):1260-2. [Medline].
Fernandes C, Maynard B, Hanna D. Successful treatment of calciphylaxis with intravenous sodium thiosulfate in a nonuremic patient: case report and review of therapy side effects. J Cutan Med Surg. 2014. 18:1-5. [Medline].
Noureddine L, Landis M, Patel N, Moe SM. Efficacy of sodium thiosulfate for the treatment for calciphylaxis. Clin Nephrol. 2011 Jun. 75(6):485-90. [Medline].
Smith VM, Oliphant T, Shareef M, Merchant W, Wilkinson SM. Calciphylaxis with normal renal function: treated with intravenous sodium thiosulfate. Clin Exp Dermatol. 2012 Dec. 37(8):874-8. [Medline].
Salmhofer H, Franzen M, Hitzl W, et al. Multi-modal treatment of calciphylaxis with sodium-thiosulfate, cinacalcet and sevelamer including long-term data. Kidney Blood Press Res. 2013. 37(4-5):346-59. [Medline].
Strazzula L, Nigwekar SU, Steele D, et al. Intralesional sodium thiosulfate for the treatment of calciphylaxis. JAMA Dermatol. 2013 Aug. 149(8):946-9. [Medline].
Biedunkiewicz B, Tylicki L, Lichodziejewska-Niemierko M, Liberek T, Rutkowski B. Ozonetherapy in a dialyzed patient with calcific uremic arteriolopathy. Kidney Int. 2003 Jul. 64(1):367-8. [Medline].
Vassa N, Twardowski ZJ, Campbell J. Hyperbaric oxygen therapy in calciphylaxis-induced skin necrosis in a peritoneal dialysis patient. Am J Kidney Dis. 1994 Jun. 23(6):878-81. [Medline].
Kerk N, Meyer V, Goerge T. Calciphylaxis induced by acquired protein S deficiency in a patient with multiple myeloma - effective treatment with low-molecular-weight heparin. J Dtsch Dermatol Ges. 2012 Jul. 10(7):518-9. [Medline].
Sewell LD, Weenig RH, Davis MD, McEvoy MT, Pittelkow MR. Low-dose tissue plasminogen activator for calciphylaxis. Arch Dermatol. 2004 Sep. 140(9):1045-8. [Medline].
Leblanc M, Roy LF, Legault L, Dufresne LR, Morin C, Thuot C. Severe skin necrosis associated with heparin in hemodialysis. Nephron. 1994. 68(1):133-7. [Medline].
Huang YC, Chou CY, Sue YM, Hu CH. Warfarin-induced calciphylaxis in a chronic hypercalcemic patient. Indian J Dermatol Venereol Leprol. 2013 Jan. 79(1):135. [Medline].
Polizzotto MN, Bryan T, Ashby MA, Martin P. Symptomatic management of calciphylaxis: a case series and review of the literature. J Pain Symptom Manage. Aug 2006. 32(2):186-90. [Medline].
Emohare O, Kowal-Vern A, Wiley D, Latenser BA. Vacuum-assisted closure use in calciphylaxis. J Burn Care Rehabil. 2004 Mar-Apr. 25(2):161-4. [Medline].
Dereure O, Leray H, Barneon G, Canaud B, Mion C, Guilhou JJ. Extensive necrotizing livedo reticularis in a patient with chronic renal failure, hyperparathyroidism and coagulation disorder: regression after subtotal parathyroidectomy. Dermatology. 1996. 192(2):167-70. [Medline].
Massry SG, Gordon A, Coburn JW, et al. Vascular calcification and peripheral necrosis in a renal transplant recipient. Reversal of lesions following subtotal parathyroidectomy. Am J Med. 1970 Sep. 49(3):416-22. [Medline].
Arch-Ferrer JE, Beenken SW, Rue LW, Bland KI, Diethelm AG. Therapy for calciphylaxis: an outcome analysis. Surgery. 2003 Dec. 134(6):941-4; discussion 944-5. [Medline].