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Calciphylaxis

BASICS

DESCRIPTION

- Complaints of exquisitely painful skin lesions in characteristic sites - Lesions develop rapidly, over course of weeks to months. - Lesions may have progressed from painful nodules to necrotic ulcers. - Occurs almost exclusively in ESRD - Occasionally seen in predialysis chronic kidney disease - Exceedingly rare in absence of renal disease

- Preulcerating lesions - Intensely painful, dense, indurated, subcutaneous plaques or nodules with distinctly demarcated boundaries - Superficial skin manifestations: erythema, violaceous mottling, fixed livedo reticularis (livedo racemosa) - Location - Distal: calves, 2 to 5 cm above Achilles tendon; often without proximal involvement; usually bilateral - Proximal: overlying thick adipose tissue (abdominal wall, medial thighs, buttocks, breasts)

- Ulcerating lesions - Evolve rapidly at both proximal and distal sites. - Intense erythema - Frank necrosis with ulceration and platelike eschar formation - Superinfection

- Tc-99m MDP bone scintigraphy - High sensitivity (97%) (1)[B] - Isotopic uptake corresponding to sites of clinical involvement - Application in tracking disease activity - Proposed utility in detecting preclinical disease

- IV sodium thiosulfate (off label) (3)[B] - 25 g diluted in 100 mL NS given over last 30 to 60 minutes of each dialysis session - Na/Ca exchange generates Ca thiosulfate, which is 500 to 100,000 times more soluble than Ca phosphate. - Thiosulfate excreted by biliary route or dialyzed off in subsequent dialysis session. - Reported pain improvement after only 2 weeks - Chronic therapy lasting ≥6 months to full resolution - Nonuremic calciphylaxis 12.5 or 25 gm IV 4 to 5 times per week (5)[C] - Common side effects: nausea, vomiting, hypotension, volume overload - Sulfate retention may precipitate anion gap acidosis; treat with high bicarbonate dialysate.

- Parathyroidectomy (4)[B] - Useful for poorly or uncontrolled hyperparathyroidism - Mechanisms of action - Suppression of PTH-mediated tissue calcification - Leeching of Ca and P from soft tissue into bone (hungry bone syndrome)

- Surgical d ©bridement - Controversial procedure - Must weigh increased risk of sepsis against benefit of necrotic tissue removal

- Dialysis revision - Low Ca bath - Establish optimal adequacy Kt/V >1.4.

- ~3 times mortality risk for ESRD with calciphylaxis compared to ESRD without - Early detection and new treatment strategies (cinacalcet hydrochloride, IV sodium thiosulfate) may improve modern-day prognosis. - Registry - Centralized, online registry compiles and analyzes clinical data on patients with calciphylaxis. - Characterization of natural history and treatment approaches presented at American Society of Nephrology - Registry Web site: http://www2.kumc.edu/calciphylaxisregistry/

  • Rare, highly morbid, obliterative vasculopathy, characterized by ischemic or necrotic skin lesions
  • Affects patients with end-stage renal disease (ESRD)-uremic calciphylaxis
  • Rarely in those without ESRD: nonuremic calciphylaxis
  • Skin lesionsEarly: extremely painful, dense, subcutaneous plaques or nodules; fixed livedo reticularis (racemosa)Late: nonhealing ulcers, necrosis, eschars, potentially causing sepsis and deathLocation: distal areas: most commonly isolated calf involvement; proximal areas overlying thick adipose tissue (thighs, buttocks, abdomen, breasts, penis)
  • Systemic deposition into other internal organ systems including GI tract, lungs, brain, muscle is rare but reported.
  • Pathogenesis involves medial calcification and intimal proliferation in subcutaneous vessels leading to ischemia.
  • As high as 85% mortality from secondary infections leading to sepsis
  • Synonym(s): calcific uremic arteriolopathy; uremic gangrene syndrome; calcifying panniculitis

EPIDEMIOLOGY

Incidence

1% of dialysis population

Prevalence

  • ~1-4% of the dialysis population
  • May be increasing due to increasing awareness

ETIOLOGY AND PATHOPHYSIOLOGY

  • Pathogenesis is a two-step process involving initial obliterative vascular lesions, followed by ischemic tissue necrosis.
  • Vascular lesionsCharacterized by arteriolar medial calcification, intimal proliferation, endovascular fibrosisMay involve capillaries, venules, and small arteries of both dermis and SC fat
  • Tissue lesionsIschemic infarction distal to damaged (obliterated, thrombosed) vesselsLocal trauma, hypotension, thrombosis, procoagulant states may trigger process.
  • ESRD patients commonly develop vascular calcification in absence of calciphylaxis. Mechanisms involveDeficiency in inhibitory factors of vascular calcificationMatrix G1a protein (inhibits vascular smooth muscle calcification; vitamin K-dependent , thus may be reduced by warfarin)Fetuin-A (clears serum of excess calcium [Ca] and phosphorus [P]; downregulated in inflammatory states)Phenotypic transformation of vascular smooth muscle cells into osteoblast-like cellsElevated P stimulates this transformation.Bone morphogenetic protein 2 (BMP-2)-potential stimuli for transformation
  • Disturbances in Ca/P/parathyroid hormone (PTH) homeostasis have been implicated but are inconclusive.Elevated Ca, P, and Ca — P product promote calcium/phosphate crystal growth.Animals sensitized with active vitamin D, Ca, P, and PTH develop lesions of calciphylaxis when challenged with inflammatory stimuli.Reports of clinical improvement following parathyroidectomyImprovement does not prove causality.Abrupt decline in PTH induces leeching of Ca and P back into bone (hungry bone syndrome).Disturbances in Ca, P, and PTH homeostasis are common in ESRD patients, most of whom donot develop calciphylaxis.
  • Obesity is an important etiologic factor.Skin lesions commonly occur in areas of greatest subcutaneous adipose thickness.Abdominal adipose tissue has diminished blood flow in obese versus nonobese patients; gravity-mediated tension promotes partial occlusion of adipose vessels.Vascular calcification may exacerbate already reduced blood flow to critically low levels.

RISK FACTORS

  • ESRD (<15 mL/min GFR)Managed by hemodialysis or peritoneal dialysisRenal transplant recipients
  • Female gender (female > male ratio = 5:1)
  • Obesity (mean weight of 21 calciphylaxis patients was 94 kg); derangements in Ca, P, PTH metabolismHyperphosphatemiaHypercalcemiaElevated Ca — P productHyperparathyroidism
  • Caucasian race
  • Diabetes mellitus
  • Treatment with warfarin, vitamin D analogs, calcitriol, Ca-based phosphate binders, systemic corticosteroids
  • Hypercoagulability states (protein C or S deficiency, antiphospholipid syndrome)
  • Protein malnutrition, hypoalbuminemia
  • Liver disease
  • Elevated serum aluminum
  • In patients without renal impairment: primary hyperparathyroidism, liver disease, malignancy, chronic inflammatory disease, autoimmune disorders
  • Statins may have protective effect.

DIAGNOSIS

  • Diagnosis is primarily clinical by characteristic skin findings in ESRD patients with risk factors.
  • Lab studies are not recommended for diagnostic use.
  • Imaging studies demonstrating tissue calcification can support diagnosis but are nondiagnostic.
  • Punch or incisional biopsy is often required to establish more definite diagnosis; carries small risk inducing ulceration at biopsy site

HISTORY

  • Complaints of exquisitely painful skin lesions in characteristic sites
  • Lesions develop rapidly, over course of weeks to months.
  • Lesions may have progressed from painful nodules to necrotic ulcers.
  • Occurs almost exclusively in ESRDOccasionally seen in predialysis chronic kidney diseaseExceedingly rare in absence of renal disease

PHYSICAL EXAM

  • Preulcerating lesionsIntensely painful, dense, indurated, subcutaneous plaques or nodules with distinctly demarcated boundariesSuperficial skin manifestations: erythema, violaceous mottling, fixed livedo reticularis (livedo racemosa)LocationDistal: calves, 2 to 5 cm above Achilles tendon; often without proximal involvement; usually bilateralProximal: overlying thick adipose tissue (abdominal wall, medial thighs, buttocks, breasts)
  • Ulcerating lesionsEvolve rapidly at both proximal and distal sites.Intense erythemaFrank necrosis with ulceration and platelike eschar formationSuperinfection

DIFFERENTIAL DIAGNOSIS

  • Cellulitis
  • Cholesterol emboli
  • Warfarin necrosis
  • Vasculitis
  • Purpura fulminans
  • Oxalate vasculopathy
  • Nephrogenic systemic fibrosis (NSF)
  • Cryoglobulinemia
  • Venous stasis ulcers
  • Peripheral vascular disease with distal ischemic ulceration

DIAGNOSTIC TESTS & INTERPRETATION

  • Lab tests can be useful in evaluating risk factors, such as Ca, P, PTH disturbances or progression.
  • Plain radiographs and high-resolution CTDiffuse, fine reticular, or coarse reticulonodular calcification patterns in affected tissue
  • MammographyMore sensitive than plain radiograph in identifying tissue calcification for breast calciphylaxisLimited by painful compression of tissue between plates
  • Tc-99m MDP bone scintigraphyHigh sensitivity (97%) (1)[B]Isotopic uptake corresponding to sites of clinical involvementApplication in tracking disease activityProposed utility in detecting preclinical disease

Diagnostic Procedures/Other

Skin biopsy

  • Reserved for diagnostic uncertainty following clinical exam and imaging studies or for ruling out a suspected alternative condition
  • Risk of inciting ulceration limits routine use.

Test Interpretation

Common histopathologic features

  • Calcification of arterioles (media), capillaries, venules, and small arteries of dermis and subcutaneous fat
  • Intimal proliferation, endovascular fibrosis
  • Endovascular thrombosis
  • Extravascular (luminal) calcification
  • Cutaneous necrosis at various levels (epidermis, dermis, pannicular)

TREATMENT

  • No FDA medications specifically approved for calciphylaxis
  • Aggressive control of Ca, P, and PTH (2)[B]
  • Pharmacologic mobilization/solubilization of Ca from involved tissue
  • Chelation of Ca and P by IV thiosulfate (emerging as a standard of care based on increasing clinical success) (3)[B]
  • Parathyroidectomy for refractory hyperparathyroidism or uncontrollable hyperphosphatemia (4)[B]
  • Pain control and comprehensive wound care

GENERAL MEASURES

  • Comprehensive wound care and analgesics for pain control
  • Avoidance of trauma to at-risk tissue
  • Avoidance of SC injections in areas most susceptible to skin lesions
  • Early and aggressive treatment of infections

MEDICATION

  • Non-Ca-based phosphate bindersSevelamer carbonate (FDA-approved for controlling P for CKD), lanthanum carbonate (FDA clinical trials for calciphylaxis)Target serum P 3.5 to 4.5 mg/dLTarget Ca — P product <55 (2)[B]
  • Cinacalcet hydrochloride 30 to 60 mg/dLAn oral calcimimetic (suppresses PTH)FDA-approved secondary hyperparathyroidismTarget intact PTH 150 to 300 pg/mL (5)[B]
  • IV sodium thiosulfate (off label) (3)[B]25 g diluted in 100 mL NS given over last 30 to 60 minutes of each dialysis sessionNa/Ca exchange generates Ca thiosulfate, which is 500 to 100,000 times more soluble than Ca phosphate.Thiosulfate excreted by biliary route or dialyzed off in subsequent dialysis session.Reported pain improvement after only 2 weeksChronic therapy lasting ≥6 months to full resolutionNonuremic calciphylaxis 12.5 or 25 gm IV 4 to 5 times per week (5)[C]Common side effects: nausea, vomiting, hypotension, volume overloadSulfate retention may precipitate anion gap acidosis; treat with high bicarbonate dialysate.
  • Drugs to avoidCa-based phosphate bindersVitamin D analogsWarfarin: reduces activity of matrix G1a protein, an inhibitor of vascular calcification (6)[B]

ADDITIONAL THERAPIES

Novel/experimental therapies include the following:

  • Bisphosphonates (off label)Prevent lesions in animal models of calciphylaxisScattered case reports in human disease
  • Hyperbaric oxygen (HBO) therapyResolution of necrotic lesions in 8 of 9 patients treated with forty, 90-minute sessions at 2.5 atm (7)[B]Limited availability, high cost
  • SNF 472: hexasodium phytate
  • Infusion of low dose of tissue plasminogen activator (tPA) (off label) (8)[B]Healing but bleeding complicationsSurvival advantage over historical controls
  • Intralesional Na thiosulfate (off label) (9)[B]Effective in localized diseaseFour case reports

SURGERY/OTHER PROCEDURES

  • Parathyroidectomy (4)[B]Useful for poorly or uncontrolled hyperparathyroidismMechanisms of actionSuppression of PTH-mediated tissue calcificationLeeching of Ca and P from soft tissue into bone (hungry bone syndrome)
  • Surgical d ©bridementControversial procedureMust weigh increased risk of sepsis against benefit of necrotic tissue removal
  • Dialysis revisionLow Ca bathEstablish optimal adequacy Kt/V >1.4.

ONGOING CARE

DIET

  • Weight reduction, optimize protein intake
  • A phosphorus-restricted diet

PROGNOSIS

  • High morbidity and mortalityInfectious morbidity within weeks of diagnosis and death within months are common.1-Year mortality 45-80%Higher mortality with ulcerative lesions (65-85%) than with plaque only (33% at 6 months)Better survival with distal versus proximal lesions
  • ~3 times mortality risk for ESRD with calciphylaxis compared to ESRD without
  • Early detection and new treatment strategies (cinacalcet hydrochloride, IV sodium thiosulfate) may improve modern-day prognosis.
  • RegistryCentralized, online registry compiles and analyzes clinical data on patients with calciphylaxis.Characterization of natural history and treatment approaches presented at American Society of NephrologyRegistry Web site: http://www2.kumc.edu/calciphylaxisregistry/

COMPLICATIONS

Superinfection of wound sites leading to sepsis

REFERENCES

11 Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61(6):2210-2217.22 Block GA. Prevalence and clinical consequences of elevated Ca — P product in hemodialysis patients. Clin Nephrol. 2000;54(4):318-324.33 Nigwekar SU, Brunelli SM, Meade D, et al. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8(7):1162-1170.44 Arch-Ferrer JE, Beenken SW, Rue LW, et al. Therapy for calciphylaxis: an outcome analysis. Surgery. 2003;134(6):941-945.55 Nigwekar SU, Kroshinsky D, Nazarian RM, et al. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015;66(1):133-146.66 Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation. 2014;129(11):1196-1203.77 Basile C, Montanaro A, Masi M, et al. Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series. J Nephrol. 2002;15(6):676-680.88 el-Azhary RA, Arthur AK, Davis MD, et al. Retrospective analysis of tissue plasminogen activator as an adjuvant treatment for calciphylaxis. JAMA Dermatol. 2013;149(1):63-67.99 Strazzula L, Nigwekar SU, Steele D, et al. Intralesional sodium thiosulfate for the treatment of calciphylaxis. JAMA Dermatol. 2013;149(8):946-949.

ADDITIONAL READING

  • Araya CE, Fennell RS, Neiberger RE, et al. Sodium thiosulfate treatment for calcific uremic arteriolopathy in children and young adults. Clin J Am Soc Nephrol. 2006;1(6):1161-1166.
  • Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol. 2004;15(12):2959-2964.
  • Hayashi M, Takamatsu I, Kanno Y, et al. A case-control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant. 2012;27(4):1580-1584.
  • Madden JJJr, Bailey A, Spear M. Calciphylaxis: a review. Plast Surg Nurs. 2010;30(3):195-197.
  • Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int. 2001;60(1):324-332.
  • Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3(4):1139-1143.
  • Norris B, Vaysman V, Line BR. Bone scintigraphy of calciphylaxis: a syndrome of vascular calcification and skin necrosis. Clin Nucl Med. 2005;30(11):725-727.
  • Ross EA. Evolution of treatment strategies for calciphylaxis. Am J Nephrol. 2011;34(5):460-467.
  • Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol. 2008;58(3):458-471.
  • Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56(4):569-579.
  • Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15(3):172-186.

CODES

ICD10

E83.59 Other disorders of calcium metabolism

ICD9

275.49 Other disorders of calcium metabolism

SNOMED

Calciphylaxis (disorder)

CLINICAL PEARLS

  • Calciphylaxis is a highly morbid systemic condition of uncertain pathogenesis, primarily affecting the skin that is almost unique to the ESRD population, often confused with ulcerative and necrotic vascular disease.
  • Diagnosis is primarily clinical, however, histology can provide clear diagnosis.
  • Primary cause of mortality is superinfection leading to sepsis.
  • Heightened awareness of the condition in the dialysis population can lead to prompt diagnosis and early treatment with promising modern-day strategies.