Nephrogenic Calciphylaxis Arising after Bariatric Surgery: A Case Series.

Nephrogenic calciphylaxis is associated with multiple risk factors including long-term dialysis dependence, hyperphosphatemia, hypercalcemia, parathyroid hormone derangements, vitamin K deficiency, obesity, diabetes mellitus, warfarin use, and female sex. Bariatric surgery is known to cause altered absorption, leading to mineral and hormonal abnormalities in addition to nutritional deficiency. Prior case reports on calciphylaxis development following bariatric surgery have been published, though are limited in number. We report a case series of five bariatric patients from a single institution who developed nephrogenic calciphylaxis between 2012 and 2018. These patients had a history of bariatric surgery, and at the time of calciphylaxis diagnosis, demonstrated laboratory abnormalities associated with surgery including hypercalcemia (n = 3), hyperparathyroidism (n = 2), hypoalbuminemia (n = 5), and vitamin D deficiency (n = 5), in addition to other medication exposures such as vitamin D supplementation (n = 2), calcium supplementation (n = 4), warfarin (n = 2), and intravenous iron (n = 1). Despite the multifactorial etiology of calciphylaxis and the many risk factors present in the subjects of this case series, we submit that bariatric surgery represents an additional potential risk factor for calciphylaxis directly stemming from the adverse impact of malabsorption and overuse of therapeutic supplementation. We draw attention to this phenomenon to encourage early consideration of calciphylaxis in the differential for painful skin lesions arising after bariatric surgery as swift intervention is essential for these high-risk patients.

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.

The application of MDT model for calciphylaxis management in patients with end-stage renal disease.

This study focuses on the application of nurse-led multidisciplinary collaborative therapy (MDT) management model for calciphylaxis prevention of patients with terminal renal disease. Through the establishment of a multidisciplinary management team spanning nephrology department, blood purification center, dermatology department, burn and plastic surgery department, infection department, stem cell platform, nutrition department, pain department, cardiology department, hydrotherapy group, dermatology group, and outpatient treatment room, the distribution of duties among team members were clarified to bring out the best advantages of a multidisciplinary teamwork during treatment and nursing. For patients with calciphylaxis symptoms in terminal renal disease, a case-by-case management model was carried out with the focus on personalised problem. We emphasised on personalised wound care, precise medication care, active pain management, psychological intervention and palliative care, the amelioration of calcium and phosphorus metabolism disorder, nutritional supplementation, and the therapeutic intervention based on human amniotic mesenchymal stem cell regeneration. The MDT model effectively compensates for traditional nursing mode and could serve as a novel clinical management modality for calciphylaxis prevention in patients with terminal renal disease.

The Multifactorial Pathogenesis of Calciphylaxis: A Case Report.

BACKGROUND Calciphylaxis is a rare and lifethreatening syndrome characterized by small vascular calcifications, which lead to the occlusion of blood vessels and painful skin lesions with tissue necrosis. Although the disease can develop in a population without kidney failure, it is typically detected in patients receiving dialysis, with an increasing frequency ranging from 1% to 4%. Therefore, the disease is also known as calcific uremic arteriolopathy. The prognosis in patients with coexisting chronic kidney disease is very poor, with a 1-year mortality rate of up to 80%. Numerous risk factors for calciphylaxis have been described, such as obesity, diabetes mellitus, female sex, White race, overuse of calcium and vitamin D supplements, and vitamin K deficiency. The disease is often accompanied by disorders such as hyperphosphatemia, elevated parathyroid hormone level, and a deficiency of natural calcification inhibitors, such as fetuin-A and matrix Gla protein. However, not all patients with calciphylaxis have the abnormalities described above, suggesting that the pathogenesis of calciphylaxis is multifactorial and unfortunately still uncertain. CASE REPORT We report a case of calciphylaxis in a 52-year-old White woman with multiple comorbidities and on chronic hemodialysis treatment, who presented with severe subcutaneous painful nodules and necrotic ulcers on both legs. CONCLUSIONS Although the prognosis of this rare and underrecognized disease is poor, an early diagnosis and interdisciplinary treatment including pain relief, wound care, appropriate nutritional support, correction of mineral parameters, administration of sodium thiosulphate, and adequate hemodialysis therapy can improve patient quality of life.

[Iatrogenic non uremic calciphylaxis: A case report]. / Calciphylaxie non urémique iatrogène : une nouvelle observation.

Calciphylaxis is a rare and severe condition, characterized by calcification and thrombosis of small vessels, mainly affecting the skin. It is most often described in patients with end-stage renal disease on dialysis. Rarer cases of non-uremic calciphylaxis are reported. The prognosis is grim and the treatment is not well codified. Sodium thiosulfate has been used for more than a decade in the treatment of uremic calciphylaxis and has been shown to be effective. Its use in non-uremic cases has been reported in a few rare observations. Rheopheresis is a technique very recently used as an adjuvant treatment in uremic calciphylaxis. We describe a case of non-uremic calciphylaxis in a patient with normal renal function and with calcium supplementation. Sodium thiosulfate was introduced, then discontinued due to the patient's poor tolerance for this treatment. Rheopheresis was then used and allowed the acceleration of healing process and a significant reduction in pain. These two treatments are promising, larger studies are needed to establish their effectiveness in non-uremic calciphylaxis.

ARTERIAL INSUFFICIENCIES: Hyperbaric Oxygen Therapy for Selected Problem Wounds.

The use of hyperbaric oxygen (HBO2) for the treatment of selected problem wounds has focused almost entirely on the diabetic foot ulcer (DFU) in recent years. The prevalence of DFUs in today's patient population and the reimbursement available for the treatment of DFUs have given it priority status in discussions about problem wounds, but there are sound fundamental reasons why additional oxygen may have benefits in the treatment of non-DFU wounds.

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.

Hyperbaric oxygen therapy in patients suffering from wounds in calciphylaxis: a narrative review.

Background: Calcific uremic arteriolopathy (calciphylaxis) is a rare and highly lethal vascular disease. Vascular calcification with calcium depositions lead to ischemic ulcers associated with gangrene, severe pain and poor healing. Although hyperbaric oxygen (HBO2) therapy has been used in the treatment of calciphylaxis, evidence of its effectiveness is limited. Objective: To determine whether HBO2 therapy has a beneficial effect in the healing of calciphylaxis ulcers. Methods: A search was made in PubMed using a comprehensive strategy to identify the effect of HBO2 on calciphylaxis wounds. Included in the analysis were studies published up to October 2018 involving a minimum of four patients receiving HBO2 therapy. Results: Ten retrospective (case) series were included. This review included a total of 131 patients with calciphylaxis who were treated with HBO2 therapy; of these, 58 patients (45%) had full response on HBO2 with complete wound closure. Regarding partial response, 17 of the patients (13%) experienced substantial wound improvement on different wound scale scores. Conclusion: Patients with calcific uremic arteriolopathy can benefit from HBO2. More research is needed using standardized wound scores. Outcomes related to quality of life and pain relief should also be assessed.

[Primary hyperoxaluria: case report and therapeutic perspectives].

Primary hyperoxaluria (PH) is a rare genetic disorder with autosomal recessive transmission, characterized by high endogenous production and markedly excessive urinary excretion of oxalate (Ox). It causes the accumulation of calcium oxide crystals in organs and tissues including bones, heart, arteries, skin and kidneys, where it may cause oxalo-calcic nephrolithiasis, nephrocalcinosis and chronic renal failure. Some forms are secondary to enteric diseases, drugs or dietetic substances, while three primitive forms, caused by various enzymatic defects, are currently known: PH1, PH2 and PH3. An early diagnosis, with the aid of biochemical and genetic investigations, helps prevent complications and establish a therapeutic strategy that often includes liver and liver-kidney transplantation, improving the prognosis of these patients. In this work we describe the clinical case of a patient with PH1 undergoing extracorporeal hemodialysis treatment and we report the latest research results that could change the life of patients with PH.

Calcific uremic arteriolopathy (calciphylaxis) calls into question the validity of guidelines of diagnosis and treatment.

Background: Calciphylaxis is associated with end-stage renal failure or kidney transplant, although, cases of non-uremic calciphylaxis have been reported. It is a rare disorder, with high mortality, characterized by vascular calcification within cutaneous vessels; vascular calcification can occur in other organs, besides skin, like heart, lung, or pancreas, which is named visceral calciphylaxis.Objective: The purpose was to review current knowledge regarding diagnosis and therapeutic approach to cutaneous calciphylaxis.Methods: A literature review has been conducted associated to word "calciphylaxis".Results: The diagnosis is based mainly on clinical features and histologic findings. Therapeutic options are still controversial.Conclusions: Cutaneous calciphylaxis is a puzzling disease, with a challenging diagnosis, and a complex treatment, which requires a multidisciplinary team and expertise.

Phenprocoumon based anticoagulation is an underestimated factor in the pathogenesis of calciphylaxis.

BACKGROUND: Calciphylaxis is a life threatening complication in renal patients. Of great importance is the identification of concomitant factors for calciphylaxis. Due to the variability of clinical presentation the evaluation of such factors may be obscured when calciphylaxis diagnosis is based just on clinical features. We aimed to characterize associated factors only in patients with calciphylaxis proven by histomorphological parameters in addition to clinical presentation. METHODS: In a single center retrospective study we analyzed 15 patients in an 8 year period from 2008 to 2016. Only patients with clinical features and histomorphological proof of calciphylaxis were included. Criteria for histological diagnosis of calciphylaxis were intimal hyperplasia, micro thrombi or von Kossa stain positive media calcification. RESULTS: The mean age of patients was 64.8 years. Nine patients (60%) were female; 12 (80%) were obese with a Body-Mass-Index (BMI) > 30 kg/m2; 3 (20%) had no renal disease; 12 (80%) had CKD 4 or 5 and 10 (66.7%) had end-stage renal disease (ESRD). One-year mortality in the entire cohort was 73.3%. With respect to medication history, the majority of patients (n = 13 (86.7%)) received vitamin K antagonists (VKA); 10 (66.7%) were treated with vitamin D; 6 (40%) had oral calcium supplementation; 5 (33.3%) had been treated with corticosteroids; 12 (80%) were on proton pump inhibitors (PPI); 13 (86.7%) patients had a clinical proven hyperparathyroidism. Ten (66.7%) patients presented with hypoalbuminemia at diagnosis. CONCLUSIONS: The evaluation of biopsy proven calciphylaxis demonstrates that especially treatment with vitamin K antagonists and liver dysfunction are most important concomitant factors in development of calciphylaxis. As progression and development of calciphylaxis are chronic rather than acute processes, early use of DOACs instead of VKA might be beneficial and reduce the incidence of calciphylaxis.

Calciphylaxis in a renal transplant recipient with normal graft function: A case report and review of literature.

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare, life-threatening complication of end-stage renal disease. However, it may also occur in patients without renal failure, the nonuremic calciphylaxis. Most patients present with painful skin ulcers. Delayed diagnosis can lead to sepsis-related morbidity and mortality. Aberrations in calcium, phosphate, and parathyroid hormone physiology are common and biopsy is diagnostic. Early diagnosis and correction of vascular and metabolic aberrations may assist in healing as may the use of sodium thiosulfate and hyperbaric oxygen therapy. We report on successful treatment of a case of calciphylaxis in a renal transplant recipient with normal allograft function.

Calciphylaxis-as a drug induced adverse event.

INTRODUCTION: Calciphylaxis is a rare but devastating disease with a mortality rate up to 50% in 1 year. It is characterized by profoundly painful ischemic skin lesions and vascular calcification that affects predominantly patients with end stage renal disease. The use of certain medications is an important modifiable risk factor in calciphylaxis and discontinuation of these is a mainstay of treatment. AREAS COVERED: This review will provide an overview of calciphylaxis and will focus on how certain therapeutic agents can affect the risk of calcification and associated thrombosis, key processes involved in the development of calciphylaxis. EXPERT OPINION: Calciphylaxis treatment requires a multi-modal approach including prevention, risk factor management, wound care, reperfusion, and use of fibrinolytics and antioxidants. Patients with end stage renal disease represent the most affected population. This population often has multiple medications prescribed, some worth reconsidering before starting or continuing them. When possible, we recommend stopping all potentially contributing medications in patients with calciphylaxis, including warfarin, active vitamin D, calcium supplements, and iron.

[Hyperthyroidism-induced calciphylaxis: A case report]. / Calciphylaxie dans un contexte de maladie de Basedow : à propos d'un cas.

BACKGROUND: Calciphylaxis or calcific uremic arteriolopathy (CUA) is a cutaneous disease with ulcerations secondary to calcification of cutaneous and subcutaneous small arteries and arterioles. It is a rare but severe disease with significant morbidity and mortality affecting 1 to 4% of dialysis patients. The circumstances of occurrence are multiple. CASE: We report the case of a severe bilateral lower limb calciphylaxis in a 69-year-old, obese, hemodialysis patient with a recent diagnosis of Graves' disease complicated with hypercalcemia and cardiac arrhythmia requiring the use of vitamin K antagonist. Complex and multidisciplinary therapeutic management (daily hemodialysis, sodium thiosulfate therapy, treatment of hypercalcemia by denosumab, hyperbaric oxygen therapy, meshed skin autograft) allowed complete healing of the lesions. CONCLUSION: This is the first description of AUC secondary to hyperthyroidism in a dialysis patient. Multidisciplinary care is essential to achieve clinical improvement in those critical situations.

Calciphylaxis after parathyroidectomy.

A 60-year-old African American man with end stage renal disease on hemodialysis (HD) for the past 2.5 years developed severe hyperparathyroidism. Other past medical history included atrial fibrillation, type II diabetes mellitus, hypertension, gout, pericardial effusion needing pericardial window, deep vein thrombosis, mitral insufficiency, and cardiomyopathy with implantable cardioversion device placement. His parathyroid hormone (PTH) level peaked at 4,191 pg/mL despite being on cinacalcet, sevelamer, and paricalcitol. He underwent a subtotal parathyroidectomy in January 2015, after which his PTH levels dropped to 184 pg/mL. Approximately 4 weeks later he developed extensive, painful necrotic skin lesions in both his lower extremities and buttocks, suggestive of calciphylaxis which was confirmed by tissue biopsy. The patient was treated with elaborate wound care, wound debridements, increased dialysis dose, and IV sodium thiosulfate (STS) during hemodialysis. Besides STS, he was treated with narcotics, gabapentin, topical lidocaine on intact skin, and oral steroids for pain control. Even though his lesions improved initially, he deteriorated due to recurrent sepsis, respiratory failure, and prolonged hospitalization which culminated in stopping dialysis before he passed away. Calciphylaxis, or calcific uremic arteriolopathy, is a life-threatening complication of end stage renal disease. Treatment of this condition is multidisciplinary which includes elaborate wound care, increasing dialysis dose, and discontinuing vitamin D supplements and calcium containing phosphate binders. Even though STS has been recommended off-label, several studies have shown promising results with resolution of lesions. Thus, sodium thiosulfate has become the mainstay of treatment. Parathyroidectomy is a recommended modality of treatment in those with high PTH levels. Our case was unique in that calciphylaxis developed after subtotal parathyroidectomy. We believe that this is due to a decreased PTH level and decreasing bone turnover which resulted in more circulating calcium facilitating vascular and soft tissue calcification. The exact mechanism of developing calciphylaxis after parathyroidectomy is unknown. Even though parathyroidectomy is an effective treatment for calciphylaxis, clinicians should be aware that it can rarely present after parathyroidectomy.

Parathyroidectomy in Hyperparathyroidism-Associated Calciphylaxis in End-Stage Renal Disease Should be Prompt and Radical - a Case Report with Two Original Therapeutic Modifications and Successful Outcome.

We present a case of severe calciphylaxis in both thighs and calves in a patient with end-stage renal disease and advanced secondary hyperparathyroidism with successful outcome after modified therapeutic approach. The cause of calciphylaxis is multifactorial. In our case, not only severe hyperparathyroidism and mediocalcinosis, but also medication (warfarin, calcium and active vitamin D) was involved. Because the initial conservative therapy was not successful, we indicated parathyroidectomy. However, we were not able to localize parathyroid glands and we contraindicated bilateral neck exploration due to the patient's critical status. Therefore, we decided for total thyroidectomy with total parathyroidectomy. Surgery was uncomplicated and histology confirmed that all four parathyroid glands were removed. The expected post-operative hypocalcaemia was asymptomatic and we did not use any calcium supplementation or vitamin D. Thyroid hormone replacement was easy. After surgery, the large and multiple subcutaneous defects started to heal. We achieved complete healing within several months of continuing dedicated care. There is no recurrence after three years. Prompt and radical surgical parathyroidectomy was extremely useful in our patient.

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.

Calciphylaxis: Beyond CKD-MBD. / Calcifilaxis: más allá de CKD-MBD.

INTRODUCTION: Calcific uraemic arteriolopathy (CUA), also called calciphylaxis, is a rare but potentially fatal vascular disorder that almost exclusively affects patients with chronic renal failure. The objective of this study was to analyse various risk factors for developing CUA and its subsequent clinical course according to the treatment received. MATERIALS AND METHODS: A retrospective study that included patients diagnosed with CUA from December 1999 to December 2015. Various risk factors, clinical course and treatment options were analysed. RESULTS: A total of 28 patients (53.6% females) with a mean age of 67.2±11.8 (38-88) years were included. At the time of diagnosis, 53.6% were on haemodialysis, 25% were kidney transplant patients and 21.4% had normal renal function. The use of steroids (100%, P=.001) was the main risk factor in renal transplant patients. Skin lesions resolved in 60.7% (especially in those receiving multitargeted therapy). Patient survival at 12 months was 29% in transplant patients, 57% in haemodialysis patients and 100% in normal renal function patients (log-rank 6.88, P=.032). Chronic renal failure (P=.03) and hypoalbuminaemia (P=.02) were the main risk factor for CUA mortality. CONCLUSIONS: Although the incidence of CUA remains low, CUA mortality is very high, Special attention to its occurrence in kidney transplant patients and «non-renal¼ CUA forms is required. Oral anticoagulants and steroids appear to be the main risk factors, CUA is a challenge; a registry of patients and determining standard therapy are required.