A 56-year-old female patient presented after a fall, with worsening lower extremity edema. She was found to have acute-on-chronic kidney injury (7.46 mg/dL on baseline creatinine of 2.42 mg/dL). Past medical history was significant for diabetes mellitus type II and diabetic neuropathy, morbid obesity (body mass index = 48 kg/m2), deep venous thrombosis, and pulmonary embolism, receiving warfarin for 2 years and 9 months, dyslipidemia, hypertension, chronic kidney disease stage I V, and peripheral vascular disease status post-amputation of the left toe 5 months earlier. Workup for acute kidney injury (AKI) was conducted, excluding post obstructive, prerenal, vasculitis, and multiple myeloma. The patient had a drop in hemoglobin; warfarin was withheld for 4 days on suspicion of blood loss and then restarted on day 6 (international normalized ratio [INR] = 1.6 reaching 1.3) after placement of an Ash catheter and initiation of dialysis with INR target in the range of 2-3, which was maintained throughout the entire hospital stay.
The patient developed a right foot blister on day 7 and bilateral thigh blisters on day 10 (Figure 4) that were attributed initially to volume overload. Laboratory values were as follows: serum calcium (Ca) 7.4 mg/dL, albumin 2.9 g/dL, inorganic phosphorus 10.3 mg/dL, creatinine 7.68 mg/dL, blood urea nitrogen (BUN) 98 mg/dL, erythrocyte sedimentation rate (ESR) 122 mm/hr, intact parathyroid hormone (PTH) 368 pg/mL, glucose 109 mg/dL. The patient had significant proteinuria of 8,456 mg/g, attributed to diabetic nephropathy (glycated hemoglobin [HbA1c] 5.2%). Total bilirubin was 0.5 mg/dL, alkaline phosphatase was 65 IU/L, aspartate aminotransferase (AST) was 15 IU/L, and alanine aminotransferase (ALT) was 24 IU/L.
The skin became mottled and the lesions worsened progressively over 3 days to become necrotic eschars (Figure 5). Similar lesions developed over the lower extremities, flanks, and lower abdomen (Figure 6). Extended workup for vasculitis, autoimmune disorders, and coagulopathies was conducted and all were negative: anti-nuclear antibodies (ANA), anti-smith antibodies, anti-double-stranded DNA (dsDNA), anti-ribonucleoprotein (RNP) antibody, anti-neutrophil cytoplasmic antibodies (ANCA) (proteinase-3 AB and myeloperoxidase AB), Sjogren A and Sjogren B antibodies, C3 and C4 complement level, immunoglobulin (Ig)G anti-platelet factor (PF)-4, lupus anticoagulant, anti-cardiolipin IgG and IgM, anti-phospholipid IgM IgG antibodies, beta2 glycoprotein I IgG IgM IgA antibodies, hepatitis serologies for hepatitis C and B virus, and workup for multiple myeloma. Protein C function was 33%, expected secondary to Coumadin therapy. Protein S activity, antithrombin III, IgA-IgM-IgG levels were all normal.
The patient became septic, with persistent leukocytosis and low-grade fever, along with worsening of skin lesions (Figure 7), with white blood count of 26 TH/mm3, platelet count of 264 TH/mm3, albumin of 1 g/dL, AST of 38 IU/L, ALT of 37 IU/L, total bilirubin (Tbil) of 0.5 mg/dL, and alkaline phosphatase of 124 IU/L.
The patient had eschar lesions on the right lower extremity (75 x 20 cm), the left lower extremity (75 x 20 cm), and an abdominal lesion (10 x 5 x 5 cm) (Figure 8). The burn specialist provided care and the patient underwent skin debridement and wound care; however, all resuscitation efforts failed on day 42.
A skin biopsy was performed and showed a portion of skin and subcutaneous tissue with diffuse necrosis and focal acute inflammation as well as multiple small arteries showing calcification of the tunica media. This pattern is strongly suggestive of calciphylaxis (Figure 1). Autopsy confirmed our diagnosis, with diffuse calcification of the splanchnic and renal arteries media.
WISN usually appears 3-10 days after starting warfarin, but can occur after many months to 15 years. WISN and calciphylaxis shares similar clinical findings and only biopsy of the skin can differentiate between the two conditions, showing a thrombotic occlusion in dermal, subcutaneous vasculature with hemorrhage. WISN lesions predominate in areas where there is relatively greater adipose tissue, for example, the breasts, thighs, hips, and buttock region.
All workup for AKI and skin necrosis was conducted and vasculitis, multiple myeloma, coagulation disorder, heparin-induced thrombocytopenia, and cryoglobulinemia were excluded. The skin biopsy confirmed our diagnosis and excluded disseminated intravascular coagulation and other microthrombotic etiologies.
The pathogenesis of calciphylaxis is not well-known. It is related to many conditions such as malignancies, cirrhosis, primary hyperparathyroidism, and secondary hyperparathyroidism as a result of short-bowel syndrome and Crohn's disease. Previous observational studies have suggested several risk factors, including hyperphosphatemia, hypercalcemia, low serum albumin levels, female gender, obesity, diabetes mellitus, calcium content of the skin, warfarin therapy, systemic corticosteroid use, and elevation in alkaline phosphatase. Clarifying the causality relationship of many coexistent conditions in end-stage renal disease is challenging.
Hayashi et al conducted a multivariate analysis and found that there was a 10.1-fold higher risk of calciphylaxis with warfarin therapy.
Cases of calciphylaxis have been reported as occurring in the absence of hyperparathyroidism and renal failure. These findings support the view of calciphylaxis as a final common endpoint of an independent pathway. Calciphylaxis is believed to occur as a product of culminating conditions and stimuli via a final common pathway involving the nuclear factor kappa-beta activation, leading to vascular calcification.
Descriptive cross-sectional data in humans as well as experimental data in rodents report a positive correlation of vitamin K antagonists and vascular calcification, leading to wide concern regarding the use of warfarin in cardiovasculopathic patients, and the viewing of this disease as partly iatrogenic when it is not a well-known natural sequel of chronic kidney disease (such as renal bone disease or renal hypertension or renal anemia).
Warfarin therapy provokes an unbalanced pro- and anti-calcification factors, by inhibiting a matrix G1A protein responsible for inhibiting the mineralization of tissues. Matrix G1A protein is an 84 amino acid vitamin K dependent that is activated by carboxylation of glutamate residues. In rat models, the disruption of this protein led to extensive vascular calcification, and this possibly occurs in patients receiving long-term warfarin therapy. Retrospectively, vitamin K supplementation can lead to suppression of the calcification tendency.
There are two subtypes of vitamin K: vitamin K1 is the most important for the activation of hepatic clotting factors, and vitamin K2 is involved in the inhibition of calcium deposition in the vasculature. Genetic variation and differential gamma-carboxylation at the glutamate residues is thought to be responsible for the varying phenotypes and susceptibility to vascular calcification.
As this is a multifactorial disease, multifactorial treatment may be a successful intervention tool.
Supportive treatment includes wound and pain management. Some success has been achieved with hyperbaric oxygen and intravenous sodium thiosulfate therapy. Correction of hypercalcemia and hyperphosphatemia is essential for treatment. Parathyroidectomy may benefit patients with refractory hyperphosphatemia.
We hypothesize that the reintroduction of warfarin creates an imbalance favoring calcification in the vessels in previously sensitized conditions, which set our patient up for a catastrophic acceleration of vascular calcification.
Understanding the pathophysiology of this process will certainly enhance our treatment approach and reduce the morbidity and mortality of this devastating condition.