Calciphylaxis is a rare, multifactorial disease characterised by painful skin lesions resulting from calcification and hyperplasia of the middle layer of arterioles and small arteries, leading to ischemia, necrosis, and tissue damage.1,2 It primarily develops in patients with advanced chronic kidney disease (CKD) (stage 4 or higher), including renal transplant recipients and patients on dialysis or pre-dialysis, when it is termed uremic calciphylaxis (UC). However, it has also been documented in patients with normal renal function or in the early stages of CKD, when it is termed nonuremic calciphylaxis (NUC).3–5

The pathogenesis, aetiology, and treatment of NUC are not well established.4 A better prognosis has been observed compared to patients with UC, with an annual mortality rate ranging from 25% to 45%, with sepsis being the leading cause of death.6,7 The optimal therapeutic approach includes pain management, lesion care, elimination of potential precipitating factors, and specific pharmacological treatment.2,3,7 Sodium thiosulfate (STS) is often used off-label to treat calciphylaxis, based on data obtained from retrospective studies of patients with UC.8–12 The mechanism of action of STS is unknown, although several pathways have been proposed to explain its effect, including the formation of soluble complexes with calcium, the restoration of endothelial function, the direct inhibition of calcification, and possible vasodilator and antioxidant effects.13 Adverse effects (AEs) include nausea and vomiting, headache, metabolic acidosis, hypernatremia, volume overload, hypotension, rhinorrhoea, headache, neurological effects (metallic taste, periorbital tingling, decreased hearing), weakness, and hypocalcaemia with a prolonged QT interval.8–10 There are no commercial presentations of intravenous STS in Spain. It is only available in its master formulation. Although there is no standardised intravenous dose of STS for treating calciphylaxis, the most commonly reported dosage guidelines in the literature range from 5 g to 25 g, administered 2–5 times per week.8–11,13

The primary objective of this study was to examine the effectiveness and safety outcomes of 25% STS administered intravenously in patients diagnosed with NUC. Secondary objectives were to identify and analyse potential predisposing factors for NUC and to determine the morbidity and mortality rates associated with the disease.

A total of 33 patients were included. Table 1 shows the demographic data and baseline characteristics of the patients. The lesion location pattern was distal in 90.9% of patients (n = 30) and proximal in 9.1% (n = 3). The diagnosis was confirmed by skin biopsy in all patients.

The most commonly used dose of 25% STS administered intravenously was 25 g (n = 26) per session, followed by 12.5 g (n = 5), and 20 g (n = 2). A total of 84.8% (n = 28) of patients received it 3 times per week, 9.1% (n = 3) once per week, and 6.1% (n = 2) twice per week. Median duration was 11.4 (IQR 5.7–18) weeks. Eleven patients received a combination of intravenous therapy and intralesional STS administration. Table 2 shows the complementary therapeutic measures used to promote lesion healing.

Table 3 shows the effectiveness and safety outcomes of STS treatment. Treatment was considered effective based on the clinical assessment of 78.8% (n = 26) of the patients. However, in 9 of these patients, STS was discontinued before complete healing of the lesions was achieved due to various circumstances: 15.4% (n = 4) died, 11.5% (n = 3) experienced adverse events, and 7.7% (n = 2) experienced events related to venous access. With one exception, all patients experienced AEs related to STS. The reasons for discontinuing STS were as follows: 51.5% (n = 17) lesion healing, 27.3% (n = 9) death, 15.2% (n = 5) AEs, and 6.1% (n = 2) events related to the route of administration (poor venous access and catheter-related bacteraemia leading to endocarditis). Of these patients, 9% (n = 3) required STS dose adjustment due to toxicity; treatment was permanently discontinued in 1 patient, while complete healing was achieved in the other 2 patients.

The following were identified as the most prominent possible predisposing factors in these patients: nonuremic CKD (81.8%), vitamin D or analogue supplementation (72.7%), hypoalbuminemia (66.7%), hyperparathyroidism (57%), diabetes mellitus (54.5%), use of vitamin K antagonists (54.5%), peripheral vasculopathy (51.5%), chronic corticoid therapy (48.5%), and obesity (42.4%). All patients had more than one concomitant factor.

The rate of significant morbidity was 69.7% (n = 23), with 6 patients experiencing more than 1 complication during the course of the disease. The most relevant complications were as follows: 57.6% (n = 19) lesion superinfection, 24.3% (n = 8) poor pain control, 9% (n = 3) sepsis, 6.1% (n = 2) lesion bleeding, and 3% (n = 1) bacteraemia due to long-term catheter use.

During the study period, total mortality was 66.7% (n = 22). The early mortality rate was 42.4% (n = 14). The NUC-related mortality rate was 39.4% (n = 13). This rate was subclassified into 2 categories: the rate directly attributable to NUC (9.1%, n = 3), caused mainly by sepsis of cutaneous origin; and the rate potentially attributable to NUC (30.3%, n = 10), corresponding to deaths occurring during hospital admission and associated with multiple factors, including deterioration of chronic diseases.

The present study showed that STS in combination with other complementary measures was effective in most patients (78.8%), resulting in complete healing or improvement of lesions, as determined by clinical assessment. However, there are no randomised clinical trials evaluating the efficacy of STS in patients with NUC. Available trials have been conducted exclusively in patients with UC, and their results have not yet been published (NCT03150420, NCT03146793, NCT03319914, NCT05018221). A systematic review by Peng et al. included 358 patients with UC treated with STS. They found an effectiveness rate of 70.1%, defined as an improvement in healing or pain control without associated mortality.15 Nigwekar et al. analysed 172 patients with UC. Of these, 85% completed treatment with STS. Response to treatment was evaluated in 53 patients using a questionnaire sent to treating physicians. A favourable response was observed in 73.6% of patients, broken down as complete healing (26.4%), significant improvement (18.9%) and partial improvement (28.3%).10

However, these results only refer to the use of STS in patients with UC. The available evidence on the use of STS in NUC is limited to isolated cases, case series, or systematic reviews describing its empirical use.4,5,12,16,17 A review by Bajaj et al. included 107 patients with calciphylaxis and normal renal function. No significant association was found between the use of intravenous STS and improvement of skin lesions (hazard ratio [HR] 1.1; 95% confidence interval [CI] 0.6–2.02), or with overall survival (HR 1.01; 95%CI 0.6–1.7).4 However, Altman et al. described a survival rate of 75% in a retrospective analysis of 16 patients with NUC. Patients survived for between 1 and 14 years after diagnosis. The authors attributed this high survival rate to the frequent use of STS in 63% of cases (n = 10).14

In terms of AEs, STS exhibited a safety profile similar to that reported in the literature for both UC and NUC.9 As metabolic acidosis and nausea and vomiting were the predominant AEs, it is important to perform regular laboratory monitoring during treatment and to assess appropriate antiemetic prophylaxis. Reducing the dose or changing the frequency of STS administration could be an option to reduce toxicity. However, in our study, we were unable to determine the optimal strategy for achieving an adequate risk–benefit ratio.

Although current evidence on the treatment of NUC is limited, the use of various strategies has been observed to improve disease progression.2,18 The main complementary measures implemented were topical lesion care and the elimination of precipitating factors. We also employed calcification reduction treatments (bisphosphonates and cinacalcet) and techniques to promote lesion healing (negative pressure therapy and hyperbaric oxygen therapy). In the present study, it was not possible to assess the impact of each of the measures due to the sample size. Bajaj et al. found no association between any combination of medical or surgical interventions (i.e. multimodal treatment) and lesion improvement or survival.4 In contrast, McCarthy et al. found that surgical debridement had a statistically significant benefit in terms of overall mortality.12 Although the magnitude of the effect of the different strategies could not be determined, and despite NUC being a multifactorial condition, the therapeutic management of patients with NUC should be based on applying all available interventions whenever possible.

Nonuremic calciphylaxis was more prevalent among elderly Caucasian women. The predominant characteristics observed in the analysed patient sample correspond to the risk factors for calciphylaxis described in other studies,7 as well as those specifically on NUC.3,4,6,14 However, the conclusions cannot be extrapolated due to the non-population-based design of the study. We draw attention to the normal phosphorus-calcium metabolism, suggesting that mineral abnormalities are not the main aetiological mechanism in NUC. Modifiable etiological factors, such as vitamin D supplements or vitamin K antagonists, should be taken into account. Therefore, when diagnosing patients, it is important to review their pharmacotherapeutic history to evaluate possible alternatives.

The morbidity of NUC was mainly associated with lesion superinfection, poor pain management, and bleeding. Sepsis was the most severe complication. The observed overall NUC-related mortality rate (39.4%) was lower than the rate (52%) reported by Nigwekar et al. in a systematic review of 36 patients with NUC.6 The early mortality rate (41.4%) was also lower than the rate (57.3%) described in the review by McCarthy et al., taking into account that their study also included UC patients.12 As the authors suggested, there appears to be a trend towards longer survival in patients with NUC. They attributed the higher mortality rates among patients with UC to the added risk posed by CKD itself, as well as to the possibility of different risk factors between UC and NUC.12

This study is limited by its retrospective design and heterogeneity in the clinical management of these patients, making it difficult to extrapolate the results. However, to our knowledge, this is one of the longest series published to date in patients with NUC.

In conclusion, the results suggest that STS is of benefit for lesion healing in patients with NUC, and has a similar safety profile to that reported in studies on UC, given the high morbidity and mortality rates associated with the disease. A multimodal treatment approach appears to be a reasonable strategy for NUC. However, further studies are needed to better understand the aetiology of the disease and thus determine the efficacy of the different therapeutic measures used.

Nonuremic calciphylaxis is a rare disease, many aspects of which remain unknown, and for which there is little scientific evidence. This study provides real-life data on the effectiveness and safety of using STS off-label to treat NUC.

The results obtained in this multicentre study demonstrate the usefulness of intravenous STS for patients with NUC. They provide relevant information on managing this disease and contribute to optimising the clinical approach.

Laura Cardona-Roca: Writing – review & editing, Writing – original draft, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. Laura Borràs Trias: Writing – review & editing, Validation, Supervision, Methodology, Formal analysis, Conceptualization. Rosario Bueno Uceda: Writing – review & editing, Validation, Data curation. Adrià Siles: Writing – review & editing, Validation, Data curation. Adrián Vilariño Seijas: Writing – review & editing, Validation, Data curation. Nuria Rudi Sola: Writing – review & editing, Validation, Supervision, Methodology, Data curation, Conceptualization. Carlos Seguí-Solanes: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Formal analysis, Conceptualization.

None declared.