CalciphylaxisCalciphylaxisAM reportAM report

Lisa Rose-Jones, MDLisa Rose-Jones, MD

May 2, 2009May 2, 2009

Pathology of “Calcific Pathology of “Calcific Uremic Arteriolopathy”Uremic Arteriolopathy”

Poorly understoodPoorly understood Systemic medial calcification of arteries Systemic medial calcification of arteries

that lead to ischemiathat lead to ischemia Histologically see 1)small vessel mural Histologically see 1)small vessel mural

calcification w or w/o fibrosis (absence calcification w or w/o fibrosis (absence vasculitic changes) 2) extravascular vasculitic changes) 2) extravascular calcification 3) vascular thrombosiscalcification 3) vascular thrombosis

Calcium deposition.Calcium deposition. (A) Hematoxylin-and-eosin staining shows calcifications (purple color) in the walls of arterioles and inflammatory changes in the adipose (A) Hematoxylin-and-eosin staining shows calcifications (purple color) in the walls of arterioles and inflammatory changes in the adipose tissue as a result of ischemia. (B) Calcium deposits can be confirmed by von Kossa's staining, which reveals calcium (black color) in the intima of small- and tissue as a result of ischemia. (B) Calcium deposits can be confirmed by von Kossa's staining, which reveals calcium (black color) in the intima of small- and medium-sized arterioles. medium-sized arterioles.

Demonstrated here is the characteristic circumferential medial calcific deposit in an arteriole with subintimal edema.

EpidemiologyEpidemiology

11stst described in rats 1962 described in rats 1962 Most commonly affects those w/ Stage 5 Most commonly affects those w/ Stage 5

CKD who are on HD and those recently CKD who are on HD and those recently who have recv’d renal transplantwho have recv’d renal transplant

Other reported case reports w/ Other reported case reports w/ occurrence in Breast Ca, Alcoholic Liver occurrence in Breast Ca, Alcoholic Liver dz, Chron’s, RA, SLE, Primary dz, Chron’s, RA, SLE, Primary HyperparathyroidHyperparathyroid

Epi continued……Epi continued……

True incidence not known, believed to True incidence not known, believed to affect 1-4% of pts w/ ESRDaffect 1-4% of pts w/ ESRD

Affects Caucasians >> African AmericansAffects Caucasians >> African Americans 3 Females :1 Male3 Females :1 Male One study suggested seen in younger One study suggested seen in younger

patients w/ history of long duration of HDpatients w/ history of long duration of HD

Why An Association with Why An Association with ESRD ESRD

?Role of PTH – suggested by beneficial ?Role of PTH – suggested by beneficial effect of parathyroidectomy = transient effect of parathyroidectomy = transient uptake of Ca,P (hungry bone) and lower uptake of Ca,P (hungry bone) and lower Ca XP productCa XP product

High doses Vit D induces this in animal High doses Vit D induces this in animal models, interesting since analogs like models, interesting since analogs like Calcitriol administered to tx 2ndary Calcitriol administered to tx 2ndary Hyperparathryoidism in ESRD ptsHyperparathryoidism in ESRD pts

Other triggers?Other triggers?

Long-term obesity Long-term obesity Recent and sudden weight loss Recent and sudden weight loss Malnutrition Malnutrition Infusion of medications such as iron dextran Infusion of medications such as iron dextran Remote and/or recent use of immunosuppressive agents, Remote and/or recent use of immunosuppressive agents,

especially corticosteroids especially corticosteroids Liver disease Liver disease Diabetes mellitus and insulin injections Diabetes mellitus and insulin injections Use of vitamin D and calcium-based phosphate binders Use of vitamin D and calcium-based phosphate binders Concurrent use of warfarin anticoagulation: Current data Concurrent use of warfarin anticoagulation: Current data

suggest that warfarin therapy may lower protein C suggest that warfarin therapy may lower protein C concentrations, leading to a procoagulant condition in the concentrations, leading to a procoagulant condition in the calcified vessel.  Warfarin may also inhibit carboxylation of calcified vessel.  Warfarin may also inhibit carboxylation of matrix Gla protein, an important inhibitor of calcification, thus matrix Gla protein, an important inhibitor of calcification, thus promoting calcificationpromoting calcification

Clinical Manifestations:Clinical Manifestations:

From ischemia one then develops livedo From ischemia one then develops livedo reticularis and/or violaceous painful plaque reticularis and/or violaceous painful plaque like subcutaneous nodules where there is like subcutaneous nodules where there is most abundant adipose (trunk, buttocks, most abundant adipose (trunk, buttocks, and proximal extremities)and proximal extremities)

. .

The patient in Panel A suffers from end-stage renal disease and has been treated with hemodialysis for more than 4 years. She has had ischemic, nonhealing necrotic ulcerations on her calves for more than 4 months. The patient in Panel B, who was on peritoneal dialysis, presented with a 2-month duration of well-demarcated erythema, hemorrhagic bullae, ulcers, and ecchymoses surrounded by skin thickening and tender subcutaneous indurations.

Clinical Manifestations:Clinical Manifestations:

Ulceration is considered a late finding and is associated with a higher mortality rate

Multiple lesions of variable age may be present, following the path of the vasculature.

Less commonly, lesions may manifest as either bullae or distinct subcutaneous, erythematous nodules.

Diagnosis:Diagnosis:

Plain films reveal vascular calcifications w/in Plain films reveal vascular calcifications w/in dermis or subQ tissue (non-specific). ?dermis or subQ tissue (non-specific). ?mammographymammography

Bone Scan can reveal abnormal uptakeBone Scan can reveal abnormal uptake Deep Incisional Biopsy** riskyDeep Incisional Biopsy** risky Rule out HyperCoag states and Rule out HyperCoag states and

CryoglbulinemiaCryoglbulinemia~There is no threshold of levels for PTH, Ca, or ~There is no threshold of levels for PTH, Ca, or

Phos to exclude/estb this diagnosisPhos to exclude/estb this diagnosis

Treatment:Treatment:

Lower Ca x P product to < 55 w/ non-Lower Ca x P product to < 55 w/ non-calcium containing Phosphate binders calcium containing Phosphate binders such as Sevelamer or Lanthanumsuch as Sevelamer or Lanthanum

Cinacalcet (increases Ca receptor Cinacalcet (increases Ca receptor sensitivity to Ca thus normalizing PTH sensitivity to Ca thus normalizing PTH secretion) secretion)

BisphosphonatesBisphosphonates ? Role of urgent parathryoidectomy? Role of urgent parathryoidectomy

Pain Management is extremely ImportantPain Management is extremely Important Surgical c/s for wound care & debridementSurgical c/s for wound care & debridement Hyperbaric Oxygen therapy has proven Hyperbaric Oxygen therapy has proven

successful in several casessuccessful in several cases

Sodium Thiosulfate – a Novel therapy? – a Novel therapy?

A potent antioxidant that increases A potent antioxidant that increases solubility of calcium depositssolubility of calcium deposits

IV use for calciphylaxis is off-labelIV use for calciphylaxis is off-label Generally well tolerated, but must watch Generally well tolerated, but must watch

for Anion Gap metabolic Acidosisfor Anion Gap metabolic Acidosis

~Prognosis~Prognosis

Mortality rate as high as 60-80% in pts w/ Mortality rate as high as 60-80% in pts w/ ulcerative diseaseulcerative disease

Most patients succumb to sepsis from Most patients succumb to sepsis from their wound infections or organ failure their wound infections or organ failure from internal involvement (stone heart)from internal involvement (stone heart)

Location of skin lesions helps predict Location of skin lesions helps predict outcomes: those proximal to outcomes: those proximal to elbows/knees (63%) vs distal (23%)elbows/knees (63%) vs distal (23%)

References:References:

UptodateUptodate

Cicone JS, Petronis JB, Embert CD, Spector D. Successful treatment of calciphylaxis with Cicone JS, Petronis JB, Embert CD, Spector D. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J. Kidney Dis. Jun 2004; 43(6)1104-8.intravenous sodium thiosulfate. Am J. Kidney Dis. Jun 2004; 43(6)1104-8.

Don BR, Chin AI. A strategy for the treatment of calcific uremic arteriolopathy (calciphylaxis) Don BR, Chin AI. A strategy for the treatment of calcific uremic arteriolopathy (calciphylaxis) employing a combination of therapies. employing a combination of therapies. Clin NephrolClin Nephrol. 2003;59:463-470.. 2003;59:463-470.

Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. outcome. J Am AcadJ Am Acad Dermatol. 2007;56:569-579. Dermatol. 2007;56:569-579.