A retrospective review of outcomes after hyperbaric oxygen therapy for the treatment of calciphylaxis.

BACKGROUND: Calciphylaxis is a thrombotic vasculopathy characterized by painful necrotic ulcerations. There are no Food and Drug Administration approved therapies despite high mortality. OBJECTIVE: To compare mortality and wound healing outcomes in patients treated with hyperbaric oxygen therapy (HBOT) in addition to intravenous sodium thiosulfate (IV STS) versus patients who received IV STS only. Findings were stratified by dialysis status and modality. METHODS: 93 patients were included, with 57 patients in the control group (IV STS) and 36 patients in the treatment group (HBOT + IV STS). Mortality data were analyzed with traditional survival analyses and Cox proportional hazard models. Longitudinal wound outcomes were analyzed with mixed effects modeling. RESULTS: Univariate survival analyses showed that full HBOT treatment was associated with significantly (P = .016) longer survival time. Increasing number of HBOT sessions was associated with improved mortality outcomes, with 1, 5, 10 and 20 sessions yielding decreasing hazard ratios. There was also a significant (P = .042) positive association between increasing number of HBOT sessions and increased wound score. LIMITATIONS: Data collection was retrospective. CONCLUSION: HBOT may have a role in the treatment of calciphylaxis with benefits demonstrated in both mortality and wound healing. Larger prospective studies are needed to identify which patients would most benefit from this intervention.

Topical cannabis-based medicines - A novel paradigm and treatment for non-uremic calciphylaxis leg ulcers: An open label trial.

Non-Uremic Calciphylaxis (NUC) is a rare condition that often manifests as intractable and painful integumentary wounds, afflicting patients with a high burden of co-morbidity. The Endocannabinoid System (ECS) is a ubiquitous signalling system that is theorised to be dysregulated within wound beds and associated peri-wound tissues. Preclinical research has shown that the dominant chemical classes derived from the cannabis plant, cannabinoids, terpenes, and flavonoids, interact with the integumentary ECS to promote wound closure and analgesia. This is a prospective open label cohort study involving two elderly Caucasian females with recalcitrant NUC leg ulcers of greater than 6 months duration. Topical Cannabis-Based Medicines (TCBM) composed of cannabinoids, terpenes, and flavonoids were applied daily to both the wound bed and peri-wound tissues until complete wound closure was achieved. Wounds were photographed regularly, and the digital images were subjected to planimetric analysis to objectively quantify the degree of granulation and epithelization. Analgesic utilisation, as a surrogate/proxy for pain scores, was also tracked. The cohort had a mean M3 multimorbidity index score of 3.31. Complete wound closure was achieved in a mean of 76.3 days. Additionally, no analgesics were required after a mean of 63 days. The treatments were well tolerated with no adverse reactions. The positive results demonstrated in very challenging wounds such as NUC, among highly complex patients, suggest that TCBM may have an even broader role within integumentary and wound management. This treatment paradigm warrants being trialled in other wound types and classes, and ultimately should be subjected to randomised controlled trials.

Direct oral anticoagulant medications in calciphylaxis.

BACKGROUND: Recent studies suggest that calciphylaxis is a thrombotic condition in which arteriolar thrombosis leads to painful skin infarcts and consequent morbidity and mortality. Paradoxically, warfarin is implicated as a risk factor for calciphylaxis. Our objective is to report the use of oral direct thrombin and factor Xa inhibitors (termed direct oral anticoagulants [DOACs]) in patients with calciphylaxis. METHODS: We retrospectively reviewed records of 16 patients with calciphylaxis who received concomitant administration of novel anticoagulants. Patient data, including demographics, comorbidities, other treatments, and adverse events, were abstracted from the health records. RESULTS: Eleven patients (69%) had chronic kidney disease (stage ≥3A), and eight (50%) received dialysis. Apixaban was the most frequently used agent (n = 11 [69%]). Dabigatran (n = 4 [25%]) and rivaroxaban (n = 2 [13%]) were reserved for patients with mild renal impairment (stage ≤2). One clinically relevant but nonmajor bleeding event occurred. There were no major bleeding events. Nine patients (56%) were alive at last follow-up, and five (31%) had complete resolution of their calciphylaxis (mean follow-up, 523 days; range, 26-1884 days). CONCLUSION: DOACs were safe and well tolerated in patients with calciphylaxis, in this initial experience. Several patients had improvement or resolution of calciphylaxis in response to therapy that included DOACs. The degree of renal impairment should guide DOAC choice. Randomized trials are required to determine treatment efficacy.

A novel pharmacodynamic assay to evaluate the effects of crystallization inhibitors on calcium phosphate crystallization in human plasma.

Cardiovascular calcification (CVC) is a progressive complication of chronic kidney disease and a predictor of CV events and mortality. The use of biomarkers to predict CV risk and activities of potential or current treatment drugs in these patients could have a crucial impact on therapeutic approaches. Our aim was to develop a novel assay for measurement of the rate of calcium phosphate crystallization in human plasma and provide a tool to evaluate the effects of crystallization inhibitors. The efficacy of inhibitors was determined by adding inhibitory compounds (polyphosphates, fetuin-A, sodium thiosulfate or citrate) to control samples. The assay was additionally validated for SNF472, an experimental formulation of phytate being developed for the treatment of calciphylaxis and CVC in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). The method was repeatable and reproducible. The plasma crystallization rate was reduced up to 80% in a concentration-dependent manner following treatment with inhibitors in vitro, among which SNF472 was the most potent. This method appears beneficial in evaluating and discriminating between inhibitory activities of compounds such as polyphosphates on calcium phosphate crystallization, which present a novel therapeutic approach to treat CVC in ESRD patients.

Calcinosis Cutis and Calciphylaxis.

Calcinosis cutis (CC) is defined as the deposition of calcium salts in the skin. The condition is divided into 5 types: calciphylaxis and dystrophic, metastatic, idiopathic, and iatrogenic CC. Dystrophic CC is the most common form and usually occurs in association with autoimmune diseases. CC can be treated surgically or with the use of drugs such as diltiazem, bisphosphonates, warfarin, ceftriaxone, probenecid, minocycline, or aluminum hydroxide. Calciphylaxis is defined as calcification of the media of small- and medium-sized blood vessels in the dermis and subcutaneous tissue. Clinically, calciphylaxis causes livedo racemosa, which progresses to retiform purpura and skin necrosis. First-line treatment is with sodium thiosulfate. We present a review of the calcifying disorders of the skin, focusing on their diagnosis and treatment.

Calciphylaxis: a devastating complication of derangements of calcium-phosphorus metabolism--a case report and review of the literature.

Calciphylaxis is a rare and potentially devastating condition also referred to as uremic gangrene syndrome, calcific uremic arteriolopathy, metastatic calcification, and uremic small-vessel disease that can present in patients with end stage renal disease. This article reports a case of a 38-year-old African-American female on peritoneal dialysis for six years with a known history of non-adherence with diet, medications, and prescribed peritoneal dialysis treatment regimen. At her monthly clinic visit, the patient complained of burning sensation in the fingers of both hands with limited fine motor movement due to edema and severe pain. A presumptive diagnosis of calciphylaxis led to hospital admission with confirmation by X-ray of her hands. The patient was switched to hemodialysis with low calcium dialysate, aggressive reduction in phosphorus, diet counseling, use of cinacalcet, and six weeks of intravenous sodium thiosulfate infusion with hemodialysis treatments. The patient's condition improved with resolution of symptoms. This case was chosen based on the rarity of a calciphylaxis presentation and paucity of knowledge regarding diagnosis and treatment.

Retrospective analysis of tissue plasminogen activator as an adjuvant treatment for calciphylaxis.

OBJECTIVE: To report our experience with low-dose tissue plasminogen activator in the treatment of calciphylaxis, a rare, usually fatal thrombotic condition that results in ischemia, necrosis, and infarction of adipose and cutaneous tissue. DESIGN: Retrospective chart review. SETTING: Tertiary care academic medical center. PATIENTS: Fifteen patients (4 men and 11 women) with calciphylaxis, treated from January 1, 2002, through December 31, 2010. INTERVENTION: Treatment with tissue plasminogen activator, concomitant wound care, and management of calcium-phosphate status. MAIN OUTCOME MEASURES: Short-term ulcer healing, long-term survival. RESULTS: Patients received daily low-dose infusions of tissue plasminogen activator (mean treatment duration, 11 days). Six patients had no adverse reactions, 3 had minor bleeding, 6 required blood transfusions, and 3 had life-threatening bleeding. No patients died of treatment-related complications. Ten patients died (median time to death, 3.6 months; range, 23 days to 4.2 years). Of the remaining 5 patients, the median duration of follow-up was 36.8 months (range, 70 days to 4.3 years). Patients treated with tissue plasminogen activator had approximately 30% greater survival than controls, but the difference was not significant (P= .14). Our results were limited by the use of concomitant therapies, referral bias for advanced disease, and retrospective case-series design. CONCLUSIONS: Thrombolytic tissue plasminogen activator may be a useful adjunctive treatment in the management of patients with calciphylaxis. However, a multidisciplinary approach that includes aggressive wound care, débridement, thrombolytic therapy, restoration of tissue oxygenation, avoidance of infection, and control of calcium-phosphate homeostasis also is essential.

Calciphylaxis with normal renal function: treated with intravenous sodium thiosulfate.

Calciphylaxis is a rare and potentially life-threatening condition. It is thought to result from arterial calcification causing complete vascular occlusion and subsequent cutaneous infarction. Most often, it is a complication of end-stage renal failure or hyperparathyroidism; without either of these associated conditions, it is extremely rare. We report a case of calciphylaxis in a 58-year-old white British man, who had received long-term oral prednisolone for asthma control, with prophylactic calcium supplementation. There was no history of renal failure, and the patient's parathyroid function was normal. He was found to be heterozygous for the Factor V Leiden mutation. The acute presentation was seemingly precipitated by an episode of trauma and subsequent compression bandaging. The patient responded promptly to intravenous sodium thiosulfate. To our knowledge, this is the first case with no history of renal failure and normal parathyroid function, precipitated by compression bandaging and with an associated Factor V Leiden mutation.

Penile calciphylaxis: a life-threatening condition successfully treated with sodium thiosulfate.

Calciphylaxis or calcific uremic arteriolopathy is a life-threatening condition that predominantly affects patients with end-stage renal disease on hemodialysis. A prevalence of up to 4% and a 6-month mortality rate of up to 80% have been reported in those with proximal disease (thighs, abdomen wall, and buttocks). Penile calciphylaxis is very rare but has a mortality rate of 69% within 6 months. Its treatment is controversial. For small lesions, conservative treatment with local wound care and debridement may suffice. Partial or complete penectomy may be needed for more extensive lesions, and especially those associated with signs of local infection. In addition to surgical intervention, as with any other case of calcific uremic arteriolopathy, the cornerstones of therapy should be to keep serum phosphorus <6 mg/dL, and a Ca × P product <55 mg²/dL². We report here the first case of penile calciphylaxis whereby intravenous sodium thiosulfate was used in addition to the standard medical and surgical therapy. Two months after surgery, the patient's wound completely healed and he has experienced no new lesions over the past 11 months.

Calciphylaxis: no therapeutic concepts for a poorly understood syndrome?

Calciphylaxis is a very uncommon and severe disease which mainly appears in patients with chronic renal insufficiency. It presents with ischemia and necrosis of the skin, subcutaneous adipose tissue, muscles and rarely viscera. The pathogenetic mechanisms inducing calciphylaxis are for the most part unknown. The mortality rate of 80% in the first year is very high. Patients experience marked pain, recurrent infections and the constant risk of secondary sepsis. Even multidisciplinary therapeutic strategies are limited, although there are recent case reports providing promising new therapeutic options including sodium thiosulfate and cinacalcet. This review summarizes the important aspects of diagnosis, pathogenesis, prevention and the possible therapeutic strategies of this intriguing, rare and often fatal disease.

Calcifilaxis en un paciente con niveles de calcio, fósforo, parathormona y función renal normales / Calciphylaxis in a patient with normal levels of calcium, phosphorus, parathormone and renal function

Llamamos calcifilaxis al depósito de sales cálcicas en la capa media de pequeñas y medianas arterias que induce una necrosis de los tejidos suprayacentes. Fue descrita de forma experimental por Selye en 1962 y clínicamente se caracteriza por la formación de úlceras de gran profundidad, en general localizadas en abdomen y muslos. La mayoría de los casos se relacionan con alteraciones del metabolismo fosfocálcico, con niveles de calcio, fósforo y parathormona elevados, por ello se da con mayor frecuencia en los enfermos con insuficiencia renal crónica. En algunos pacientes se ha descrito asociada a déficit de proteínas C y/o S, y en casos excepcionales con metabolismo fosfocálcico normal. Llamamos calcifilaxis al depósito de sales cálcicas en la capa media de pequeñas y medianas arterias que induce una necrosis de los tejidos suprayacentes. Fue descrita de forma experimental por Selye en 1962 y clínicamente se caracteriza por la formación de úlceras de gran profundidad, en general localizadas en abdomen y muslos. La mayoría de los casos se relacionan con alteraciones del metabolismo fosfocálcico, con niveles de calcio, fósforo y parathormona elevados, por ello se da con mayor frecuencia en los enfermos con insuficiencia renal crónica. En algunos pacientes se ha descrito asociada a déficit de proteínas C y/o S, y en casos excepcionales con metabolismo fosfocálcico normal. Presentamos el caso de una enferma diabética de 53 años que consultó por úlceras y lesiones induradas en abdomen y muslos de 10 meses de evolución, con niveles de calcio, fósforo, paratormona y proteínas C y S normales. Los hallazgos histopatológicos fueron diagnósticos de calcifilaxis y presentó positividad en una determinación de anticuerpos antifosfolípidos. Fue tratada con anticoagulantes y corticoides con buena evolución del cuadro, a pesar de lo cual desarrolló posteriormente una gangrena acral progresiva de evolución fatal. Este cuadro es excepcional en enfermos con metabolsimo fosfocálcico normal y la presencia de anticuerpos antifosfolípidos apoya que los factores locales pueden ser determinantes para el desarrollo de calcifilaxis en algunos enfermos (AU)