Warfarin-Associated Nonuremic Calciphylaxis

Abstract

IMPORTANCE Classic calciphylaxis associated with renal failure is a life-threatening disease. Warfarin-associated calciphylaxis without renal injury has been described, but whether it is a subset of classic calciphylaxis or a different entity remains unknown. We describe 1 case of warfarin-associated calciphylaxis, present data from 2 others from our institution, and review all cases of warfarin-associated calciphylaxis available in the literature. Our review indicates that warfarin-associated calciphylaxis is clinically and pathophysiologically distinct from classic calciphylaxis. OBJECTIVE To review warfarin-associated calciphylaxis and determine its relationship to classic calciphylaxis. DESIGN, SETTING, AND PARTICIPANTSWe searched MEDLINE and Ovid without language or date restrictions for case reports of calciphylaxis from the inpatient setting using the terms "calciphylaxis and warfarin," "non-uremic calciphylaxis," and "nonuremic calciphylaxis." We defined nonuremic calciphylaxis as a histopathologic diagnosis of calciphylaxis without severe kidney disease (serum creatinine level >3 mg/dL; glomerular filtration rate <15 mL/min; acute kidney injury requiring dialysis; and renal transplantation).EXPOSURES Each patient had been exposed to warfarin before the onset of calciphylaxis.MAIN OUTCOMES AND MEASURES Patient data were abstracted from published reports. Original patient medical records were requested and reviewed when possible. RESULTSWe identified 18 patients with nonuremic calciphylaxis, 15 from the literature, and 3 from our institution. Patients were predominantly female (15 of 18 [83%]) with ages ranging from 19 to 86 years. Duration of warfarin therapy prior to calciphylaxis onset averaged 32 months. Lesions were usually located below the knees (in 12 of 18 [67%]). No cases reported elevated calcium-phosphate products (0 of 17 [0%]). Calcifications were most often noted in the tunica media (n = 8 [44%]) or in the vessel lumen and tunica intima (n = 7 [39%]). The most common treatments included substitution of heparin or low-molecular weight heparin for warfarin (n = 13 [72%]), intravenous sodium thiosulfate (n = 9 [50%]), and hyperbaric oxygen (n = 3 [17%]). The survival rate on hospital discharge was remarkably high, with 15 cases (83%) reporting full recovery and 3 cases ending in death. CONCLUSIONS AND RELEVANCEWarfarin-associated calciphylaxis is distinct from classic calciphylaxis in pathogenesis, course, and, particularly, outcome. This finding should influence clinical management of the disease and informs targeted treatment of the disease.

Evaluating the validity of subclassifying warfarin‐associated nonuremic calciphylaxis: a retrospective cohort study

“…Of our recently reported cohort of 101 calciphylaxis patients, 20% had nonuremic calciphylaxis. As noted by Yu et al ,. survival of the nonuremic patients tends to be better than those with uremic calciphylaxis.…”

“…A recent article by Yu et al . regarding warfarin‐associated nonuremic calciphylaxis evaluated three patients who developed nonuremic calciphylaxis while on warfarin therapy and summarized an additional 15 affected patients from the literature. Patients had been taking warfarin for variable time duration (range: 1 month–168 months; not recorded for 4 patients) prior to the onset of calciphylaxis, and discontinuation of warfarin yielded mixed outcomes.…”

Calciphylaxis

“…Calciphylaxis, although largely described in patients with ESRD, is not exclusive to the patients with ESRD and has been described in patients with normal kidney function and in those with less advanced chronic kidney disease [10–12]. In the German Calciphylaxis Registry, 10% of the total patients with calciphylaxis had either normal kidney function or had CKD not requiring renal replacement therapy [7 ■■ ].…”

“…Other reported risk associations include female sex, white race, diabetes mellitus, obesity, autoimmune diseases, thrombophilic disorders, liver disease, hypoalbuminemia, and increased serum aluminium levels, hypercalcemia, hyperphosphatemia, hyperparathyrodism, and adynamic bone disease, increased dialysis vintage, unmet dialysis adequacy parameters, high dialysate calcium bath, vitamin K antagonist (warfarin) therapy, malabsorption disorders, calcium supplements, calcium-based phosphate binders, vitamin D analogues, iron therapy, corticosteroids, subcutaneous injections, teriparatide, and a syndrome referred to as polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome [2,3,10,12, 14,20–25]. It is important to emphasize that most of these associations are derived from individual case reports or from small retrospective studies and associations in epidemiological studies do not confirm causality.…”

Calcinosis cutis: a rock and a hard place

“…Calcinosis cutis is seen in the setting of connective tissue disease, where chronic inflammation and relative tissue hypoxia are believed to be a nidus for ectopic calcification, while calciphylaxis typically occurs in advanced chronic kidney disease due to a complex interplay between intravascular calcium and phosphorus deposition in vessel walls and alteration of vascular smooth muscle cells coupled with hypercoaguability and proinflammatory cytokines . Reported triggers of nonuremic calciphylaxis include prednisone, warfarin, obesity, hyperparathyroidism, liver disease and malignancy …”