Treatment Of Calcific Uremic Arteriolopathy Research Articles

Hexasodium fytate for the treatment of calciphylaxis: a randomised, double-blind, phase 3, placebo-controlled trial with an open-label extension

In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)],-5.3 [5.2] versus-6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI):-2.5, 3.0]; p=0.88) and Pain VAS (mean [SD],-19.5 [26.9] versus-32.2 [38.5]; least squares mean difference, 11.5 [96% CI:-4.8, 27.8]; p=0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group. Funded by Sanifit, a CSL Vifor company.

Sodium thiosulfate in the treatment of calcific uremic arteriolopathy (calciphylaxis)

Sodium thiosulfate in the treatment of calcific uremic arteriolopathy (calciphylaxis)

Multimodal treatment of calcific uraemic arteriolopathy (calciphylaxis): a case series.

BackgroundThis is an incident series of five dialysis patients with late-diagnosed calcific uraemic arteriolophathy (CUA), severe uncontrolled hyperparathyroidism and infected skin ulcerations.MethodsA multimodal intervention was based on wound care, antibiotics, surgical debridement, sodium thiosulphate and cinacalcet and associated with regression of skin disease in four cases after varying treatment time periods ranging from 4 to 33 months.ResultsMultimodal treatment including sodium thiosulphate and cinacalcet was associated with very favourable local outcomes and survival. This series further confirms that the diagnosis of CUA is rarely made at the nodular, non-ulcerative phase of the disease.ConclusionsThis series contributes to the build-up of case series reporting on the treatment of CUA, and will hopefully serve as a basis of well-conceived comparative effectiveness studies investigating the value of the combined interventions applied so far in this severe condition.

Hyperbaric oxygen in the treatment of calciphylaxis: A case series and literature review.

Calcific uraemic arteriolopathy (CUA) or calciphylaxis is most commonly seen in end-stage renal disease and is associated with significant morbidity and mortality. The aim of this study was to determine whether hyperbaric oxygen therapy (HBOT) is effective in healing calciphylaxis lesions and to determine if there are any patient factors that can predict wound healing and patient survival. We identified by retrospective review all cases of CUA referred to our institution for treatment with HBOT. We documented the clinical and biochemical parameters of this patient population, the size and distribution of the lesions as well as wound outcomes and patient survival following treatment. A total 46 patients were identified with CUA associated with renal failure. Of the 46 patients, only 34 received a full course of HBOT. The balance was deemed unsuitable for treatment or was unable to tolerate treatment and was palliated. Of the 34 patients that received a full course of HBOT, 58% showed improvement in their wound scores, with more than half of these patients having complete healing of their wounds. The balance did not benefit from the therapy and had a very poor prognosis. Those that benefited from HBOT survived on average for more than 3 years. The only factor significantly associated with improved wound healing and survival was diabetes. This retrospective analysis suggests a role for HBOT in the treatment of CUA with more than half of the treated patients benefiting and surviving for an average of more than 3 years.

Successfully treated calcific uremic arteriolopathy: two cases of a high anion gap metabolic acidosis with intravenous sodium thiosulfate.

Calcific uremic arteriolopathy (CUA) is a rare and potentially fatal disorder of calcification involving subcutaneous small vessels and fat in patients with renal insufficiency. We describe the successful use of intravenous sodium thiosulfate (STS) for the treatment of CUA in two patients. The first case was complicated by the development of a severe anion gap metabolic acidosis, which was accompanied by a seizure. Both patients had complete wound healing within five months. Although STS should be considered in the treatment of CUA, little is known about pharmacokinetics and additional studies are required to determine dosing strategies to minimize severe potential side effects.

Maximal conservative therapy of calcific uremic ateriolopathy

We present the case of a 61-year- old female patient in long-term hemodialysis who developed calcific uremic arteriolopathy (CUA) upon administration of the oral calcimimetic agent cinacalcet for treatment of secondary hyperparathyroidism. In May 2009, the baseline serum values were parathormone (PTH) 310 pg/ml, calcium 9.1 mg/dl and phosphorous 6.9 mg/dl. Necrotic wounds in the suprapubic fat tissue were successfully treated first, by correcting the calcium phosphorous product; second, through treatment with sodium thiosulfate and third, through intensive wound care with hyperbaric oxygen therapy and vacuum-assisted closure therapy, with no need for parathyroidectomy. Multiple factors have been described to play a role in the development of CUA. Based on the findings of this case, the treatment of CUA should be aimed at correcting different causes simultaneously.

Successful treatment of calcific uraemic arteriolopathy with bisphosphonates.

Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition that almost exclusively affects patients with chronic kidney disease. Several therapies have been employed to treat this disease but with irregular results. We report a prospective case series of eight patients diagnosed with CUA in our unit between 2002 and 2010. The series consisted of eight patients with CUA (including 4 men, 5 dialysis patients and 3 with functioning allografts) who were treated with bisphosphonates. The diagnosis was by clinical suspicion and a confirmatory biopsy. Five patients had a previous history of high calcium-phosphorus product, 6 had a history of high parathyroid hormone levels (>800pg/ml), 4 had undergone parathyroidectomy, 5 had a history of high cumulative doses of steroids, and 6 patients were under dicoumarin treatment. None of the patients were obese or had diabetes mellitus. In all patients, progression of skin lesions stopped between 2 to 4 weeks after starting bisphosphonate therapy, with no changes in blood levels of calcium and phosphate. Improvement in pain and lesions was faster in patients receiving intravenous ibandronate. All of these patients remained on bisphosphonate treatment for at least 6 months until the wounds healed completely. No recurrences have been observed after follow-up periods between 1 and 9 years. Renal function remained stable in transplant recipients. The treatment was well tolerated and no adverse effects were observed. Bisphosphonates could be a new and attractive alternative to treat CUA.

Successful Treatment of Calcific Uremic Arteriolopathy with Sodium Thiosulfate in a Renal Transplant Recipient

Calcific uremic arteriolopathy (CUA) is a rare but life-threatening disorder of arteriolar calcification. It frequently leads to severe ischemia, intense pain, and tissue necrosis with non-healing skin ulcerations. CUA usually occurs in patients with chronic kidney disease (CKD), especially those on dialysis, and its occurrence is rare in kidney transplant recipients. The treatment of this disorder is not clearly defined, and no randomized prospective trials are available. Treatment has focused on optimizing dialysis treatment, control of bone mineral parameters, wound care, experimental anticalcification therapies—using bisphosphonates, cinacalcet, parathyroidectomy, and hyperbaric oxygen. Such treatments are based on the pathophysiological considerations and evidences from case reports or series. Recently, several cases have reported about the emerging benefits of intravenous sodium thiosulfate (STS) in the treatment of CUA. STS has resulted in rapid pain relief, wound healing, and prevention of death. We report a case of CUA in a 63-year-old Caucasian man with a functioning renal allograft. In this patient, intravenous STS was administered for 8 months, which was the principal therapy, which resulted in complete resolution of the CUA and skin healing.

Calcific Uremic Arteriolopathy in Peritoneal Dialysis Populations

Calciphylaxis or calcific uremic arteriolopathy is an infrequent complication of end stage kidney disease. It is characterized by arteriolar medial calcification, thrombotic cutaneous ischemia, tissue necrosis often leading to ulceration, secondary infection and increased mortality rates. Current, multimodality treatment involves local wound care, well-controlled calcium, phosphate and parathyroid hormone levels and combination therapy with sodium thiosulfate and hyperbaric oxygen therapy. This combination therapy may be changing the historically poor prognosis of calcific uremic arteriolopathy reported in the literature. Peritoneal dialysis is considered a risk factor based on limited publications, however this remains to be proven. Clinical presentation, diagnosis, pathogenesis and treatment of calcific uremic arteriolopathy in these patients are no different from other patients manifesting with this condition.

Calciphylaxis in the current era: emerging 'ironic' features?

Calcific uraemic arteriolopathy (CUA), previously known as calciphylaxis, is a condition of microvascular calcification and thrombosis with resultant tissue necrosis. Due to the rarity of this disease, our understanding of its pathogenesis remains speculative. Iron has emerged as a potential pathogenic contributor to the development of CUA, but investigation into this link is lacking. The purpose of our study was to explore the clinical characteristics of patients diagnosed with CUA at our institution to allow for comparison to available literature. In addition, we wanted to pursue the possibility of iron being a pathogenic contributor to CUA development. We hypothesized that iron would have to be present in areas of microvascular calcification in order to play a contributing pathogenic role and, therefore, wished to establish whether iron deposition was present within available diagnostic CUA skin biopsy specimens. This study included all patients diagnosed with CUA at our institution between 1997 and 2009 whose tissue was available for further analysis. All available diagnostic skin biopsy specimens were reviewed and further analysed by a dermatopathologist. As the goal was to explore the potential pathogenic role of iron, staining for iron deposition within biopsy specimens was undertaken. All available medical and biochemical information about patients was also collated for analytic purposes and related to the biopsy specimen findings. Tissue blocks from 12 patients diagnosed with CUA at our institution were available for further analysis. In this CUA cohort, the average age at diagnosis was 61 years (range, 36-83 years), with six (50%) patients being female. Of these patients, 8 (67%) had diabetes, 8 (67%) had coronary artery disease and 10 (83%) had dyslipidaemia. At the time of diagnosis, eight (67%) were on peritoneal dialysis, two (17%) on haemodialysis and two (17%) were pre-dialysis. Our patients had short dialysis vintage times prior to diagnosis (average, 2.1 years). Iron deposition was detected in areas of microvascular calcification in all diagnostic specimens and was absent in unaffected microvasculature within the same biopsy specimens. The findings of iron deposition in affected microvasculature lend support to the potential role of iron in the complex pathophysiologic cascade of CUA. The implications for iron therapy in high-risk patients and the possible rationale for the use of sodium thiosulphate, a metal chelator, in the treatment of CUA are explored.

Successful treatment of calcific uremic arteriolopathy in a pediatric dialysis patient

Calcific uremic arteriolopathy (CUA) is a rare, life-threatening disease, typically affecting patients with end-stage renal disease. It is characterized by widespread vascular calcification, endothelial fibrosis and end-organ ischemia. The mortality rate is high with infection and sepsis being the most common causes of death. Common therapies include restoration of calcium and phosphorous homeostasis, wound care and pain control. Although soft tissue calcification is a known complication in children with advanced renal disease, the incidence of CUA in pediatrics remains unknown. Additionally, current literature regarding its management in pediatric patients is lacking. We report the case of a 17-year-old African–American male patient with end-stage renal disease secondary to Wegener’s granulomatosis who developed CUA after 3 years on peritoneal dialysis. Treatment with sodium thiosulfate (STS) and hyperbaric oxygen (HBO) therapy alone was ineffective, forcing the patient to undergo bilateral below the-knee-amputation (BKA) 5 months after presentation. It was not until peritoneal dialysis had been changed to daily hemodialysis, while continuing STS and HBO therapy, that the patient demonstrated complete resolution of CUA on repeat bone scan. Based on these findings, and the extremely high mortality rate associated with this disease, CUA management requires early and aggressive intervention with multi-faceted therapy, including prompt conversion from peritoneal dialysis to hemodialysis, STS infusions and hyperbaric oxygen therapy.

Sodium thiosulfate in the treatment of calcific uremic arteriolopathy

Calcific uremic arteriolopathy (CUA; also known as calciphylaxis) is a life-threatening condition observed mostly in patients on dialysis. The key histopathologic features of CUA include media calcification of small arteries, associated with endovascular fibrosis and thrombosis. Several risk factors for CUA are related to disturbances in bone and mineral metabolism; current treatments largely aim to normalize these disturbances by lowering serum calcium phosphate concentration and thereby preventing, or even reversing, calcium phosphate oversaturation, precipitation and, finally, calcification. Administration of sodium thiosulfate, which sequesters calcium ions to form highly soluble calcium thiosulfate complexes, can prevent calcium phosphate precipitation. As randomized controlled studies on sodium thiosulfate are lacking, this Perspectives article focuses on case reports and case series; in these reports the compound seemed to be effective and was not associated with serious short-term adverse events. Large clinical trials to evaluate the efficacy and long-term safety of sodium thiosulfate are clearly warranted.

Pivotal Role of Paricalcitol in the Treatment of Calcific Uremic Arteriolopathy in the Presence of a Parathyroid Adenoma

Calcific uremic arteriolopathy, or calciphylaxis, is a serious and life-threatening complication of end-stage renal disease. Its pathogenesis is not yet fully elucidated and treatment is controversial. In the presence of severe hyperparathyroidism, parathyroidectomy should be considered. We report a case of a woman on maintenance hemodialysis therapy with calciphylaxis and parathyroid adenoma who refused to undergo parathyroidectomy. She was treated successfully with a combination of noncalcium phosphate binders, cinacalcet, and paricalcitol. Subcutaneous plaques disappeared, and the necrotic lesion was healed. Discontinuation of paricalcitol led to an increase in serum parathyroid hormone levels and reappearance of the patient's symptoms, whereas its reintroduction resulted in complete remission of the clinical picture. Paricalcitol, a less calcemic vitamin D analogue, is also a selective vitamin D receptor activator with a number of nonclassic actions (such as inhibition of inflammation and ossification-calcification) that could prove beneficial in cases of calciphylaxis.

Hyperbaric oxygen as effective adjuvant therapy in the treatmentof distal calcific uraemic arteriolopathy.

Calcific uraemic arteriolopathy (CUA), calciphylaxis or uraemia of small-vessel disease is a rare life-threatening complication predominantly affecting patients with end-stage renal disease (ESRD) [1]. It typically occurs in those with secondary hyperparathyroidism and is associated with deranged calcium and phosphate metabolism. Other factors, such as malnutrition, obesity, diabetes mellitus, warfarin therapy and female gender, have been implicated as additional risk factors [2]. CUA presents as severely painful ulcers, usually occurring in the lower limbs. The mechanism of injury appears to be calcification of subcutaneous tissues and small arterioles. At a molecular level, derangement of vascular smooth muscle cell function leading to osteogenic differentiation in conjunction with endothelial cell dysfunction appears to be important [3]. The lesions are slow to heal, with superimposed bacterial infection leading to sepsis, the most common cause of death (in up to 80% of patients). The first case series of CUA was published in 1976 [4]. Subsequently, the incidence of CUA in patients with ESRD has increased markedly [3]. Reports to the Australia and New Zealand Dialysis and Transplantation Registry (ANZDATA) demonstrate that CUA had been identified as a comorbidity or cause of death in 171 patients, from its first documentation in 1985 until March 2005 (Figure ​(Figure1).1). Despite an increasing awareness of this disease and a better understanding of its aetiology, an effective form of treatment remains elusive. Most therapeutic regimens include aggressive wound care, ensuring adequate nutrition, improving calcium–phosphate balance and correcting secondary hyperparathyroidism. The use of bisphosphonates [5], low-molecular weight heparin [1] or sodium thiosulfate [6] has been met with success in a few patients. Fig. 1 The number of patients with ESRD and CUA as a comorbidity or cause of death reported to ANZDATA between 1985 and 2005. Hyperbaric oxygen (HBO) involves breathing 100% oxygen within a pressurized environment. It is first-line therapy for a number of medical conditions, namely decompression sickness and carbon monoxide poisoning [7]. Most recently, HBO has been shown to be of benefit in advancing wound healing, including lesions due to CUA [8]. It is proposed to work by increasing oxygen tension in the ischaemic tissue, although the primary initiating factor of vascular calcification is not altered. We report our experience with the treatment of CUA with HBO, which appears to be well tolerated. We describe the largest, single-centre case series of patients with CUA successfully treated with a combination of therapies including HBO.

Calcific Uremic Arteriolopathy (Calciphylaxis)

We present 3 cases of calciphylaxis, better termed calcific uremic arteriolopathy (CUA), which illustrate typical and atypical presentations of this disorder to discuss its classification, pathophysiology, and treatment based on a review of the literature. Of the 3 patients presenting with biopsy-proven CUA, 1 patient with proximal lesions expired in the setting of upper gastrointestinal bleeding and superinfection of ulcers, a second patient had an extensive distal ulcerative lesion that failed to heal and necessitated lower-extremity amputation, and a third patient with multiple small distal lesions experienced complete resolution of the ulcers. The classification, pathophysiology, and treatment of CUA are detailed here. CUA is a heterogeneous syndrome which typically follows a progressive course leading to loss of life or limb. Diagnosis requires a high index of suspicion and low threshold for biopsy in at-risk patients. Parathyroidectomy is appropriate to rapidly lower the calcium-phosphorus product in the setting of marked hyperparathyroidism; additional therapy includes the avoidance of purported precipitants, medical lowering of the serum calcium and phosphorus, and promotion of wound healing with hyperbaric oxygen therapy.

Successful treatment of calcific uraemic arteriolopathy with wide local excision

Successful treatment of calcific uraemic arteriolopathy with wide local excision