Calciphylaxis

BASICS

DESCRIPTION

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 lesions
- Early: extremely painful, dense, subcutaneous plaques or nodules; fixed livedo reticularis (racemosa)
- Late: nonhealing ulcers, necrosis, eschars, potentially causing sepsis and death
- Location: 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 lesions
- Characterized by arteriolar medial calcification, intimal proliferation, endovascular fibrosis
- May involve capillaries, venules, and small arteries of both dermis and SC fat
Tissue lesions
- Ischemic infarction distal to damaged (obliterated, thrombosed) vessels
- Local trauma, hypotension, thrombosis, procoagulant states may trigger process.
ESRD patients commonly develop vascular calcification in absence of calciphylaxis. Mechanisms involve
- Deficiency in inhibitory factors of vascular calcification
  - Matrix 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 cells
  - Elevated 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 parathyroidectomy
  - Improvement 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 dialysis
- Renal transplant recipients
Female gender (female > male ratio = 5:1)
Obesity (mean weight of 21 calciphylaxis patients was 94 kg); derangements in Ca, P, PTH metabolism
- Hyperphosphatemia
- Hypercalcemia
- Elevated Ca — P product
- Hyperparathyroidism
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 ESRD
- Occasionally seen in predialysis chronic kidney disease
- Exceedingly rare in absence of renal disease

PHYSICAL EXAM

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

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 CT
- Diffuse, fine reticular, or coarse reticulonodular calcification patterns in affected tissue
Mammography
- More sensitive than plain radiograph in identifying tissue calcification for breast calciphylaxis
- Limited by painful compression of tissue between plates
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

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 binders
- Sevelamer carbonate (FDA-approved for controlling P for CKD), lanthanum carbonate (FDA clinical trials for calciphylaxis)
- Target serum P 3.5 to 4.5 mg/dL
- Target Ca — P product <55 (2)[B]
Cinacalcet hydrochloride 30 to 60 mg/dL
- An oral calcimimetic (suppresses PTH)
- FDA-approved secondary hyperparathyroidism
- Target 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 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.
Drugs to avoid
- Ca-based phosphate binders
- Vitamin D analogs
- Warfarin: 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 calciphylaxis
- Scattered case reports in human disease
Hyperbaric oxygen (HBO) therapy
- Resolution 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
- In FDA clinical trials
Infusion of low dose of tissue plasminogen activator (tPA) (off label) (8)[B]
- Healing but bleeding complications
- Survival advantage over historical controls
Intralesional Na thiosulfate (off label) (9)[B]
- Effective in localized disease
- Four case reports

SURGERY/OTHER PROCEDURES

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.

ONGOING CARE

DIET

Weight reduction, optimize protein intake
A phosphorus-restricted diet

PROGNOSIS

High morbidity and mortality
- Infectious 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.
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/

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.

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