Sodium Thiosulfate for Calciphylaxis Treatment in Patients on Peritoneal Dialysis: A Systematic Review

Limited data are available on the utilization of sodium thiosulfate (STS) treatment for calciphylaxis in peritoneal dialysis (PD) patients, while it is well-studied in hemodialysis (HD) patients. A systematic literature search was conducted using Ovid MEDLINE, EBM Reviews—Cochrane Central Register of Controlled Trials, and EBM Reviews—Cochrane Database of Systematic Reviews to identify reported cases of PD patients with calciphylaxis who received STS. The search covered the inception of the databases through August 2022. Across 19 articles, this review identified 30 PD patients with calciphylaxis who received STS. These included 15 case reports, 2 case series, and 2 cohort studies. The administration routes and doses varied depending on the study. For intravenous (IV) administration (n = 18), STS doses ranged from 3.2 g twice daily to 25 g three times weekly for 5 weeks to 8 months. Outcomes included 44% of patients experiencing successful wound healing, 6% discontinuing STS due to adverse effects, 67% transitioning to HD, and 50% dying from calciphylaxis complications. For intraperitoneal (IP) administration (n = 5), STS doses ranged from 12.5 to 25 g three to four times weekly for 12 h to 3 months. Results showed 80% of patients achieving successful wound healing, 80% discontinuing STS due to adverse effects, 40% transitioning to HD, and 20% dying from IP STS-related chemical peritonitis. In cases where patients switched from IV to IP STS (n = 3), doses ranged from 12.5 to 25 g two to three times weekly for 2.5 to 5 months. Among them, 67% experienced successful wound healing, while 33% died from sepsis. Two cases utilized oral STS at a dose of 1500 mg twice daily for 6 and 11 months, resulting in successful wound healing without adverse effects or need for HD. However, one patient (50%) died due to small bowel obstruction. This systematic review provides an overview of STS treatment for PD patients with calciphylaxis. Although successful treatment cases exist, adverse effects were significant. Further research, including larger clinical studies and pharmacokinetic data, is necessary to establish the optimal route, dose, and efficacy of STS in PD patients.


Introduction
Calciphylaxis, also known as calcific uremic arteriolopathy (CUA) or uremic smallvessel disease, is an infrequent yet serious complication that can develop in patients with end-stage kidney disease (ESKD) [1][2][3]. The condition arises due to the deposition of calcium in the small blood vessels of the skin and other organs, resulting in painful tissue necrosis and skin ulcers [4][5][6]. While the exact cause of calciphylaxis remains unknown, an

Ovid MEDLINE Search
In Ovid MEDLINE, a combination of MeSH terms and keywords were employed to identify relevant studies. The MeSH terms used were "calciphylaxis", "peritoneal dialysis", and "sodium thiosulfate". Additionally, keywords were used to expand the search, including "calcific uremic arteriolopathy", "peritoneal dialysis", and "sodium thiosulfate". The MeSH terms and keywords were combined using the Boolean operator "AND".

EMBASE Search
For EMBASE, a similar strategy was applied. Emtree terms (equivalent to MeSH terms in MEDLINE) such as "calciphylaxis", "peritoneal dialysis", and "sodium thiosulfate" were used. In addition, keywords similar to those used in MEDLINE, including "calcific uremic arteriolopathy", "peritoneal dialysis", and "sodium thiosulfate" were used. The terms were combined using the Boolean operator "AND".

Cochrane CENTRAL and Database of Systematic Reviews Searches
In both Cochrane CENTRAL and Cochrane Database of Systematic Reviews, similar search strategies were employed. The MeSH terms used were "calciphylaxis", "peritoneal dialysis", and "sodium thiosulfate". Free text search terms were also utilized to capture any relevant studies not indexed by MeSH terms. The terms were combined with the Boolean operator "AND".
The search was performed from the inception of the databases through August 2022. No restrictions were placed on publication date or language. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) [39] statement (online Supplementary Materials) guided the study's execution. The study provides access to the data supporting its findings via the Open Science Framework (https://osf.io/2jvgf/ accessed: 7 September 2022).

Selection Criteria
The inclusion and exclusion criteria were pre-established to ensure the selection of relevant studies. Studies were included if they reported on PD patients with calciphylaxis who received STS treatment. Case reports, case series, and cohort studies were considered eligible. Studies that did not provide information on STS treatment or did not focus on PD patients were excluded. The screening of titles, abstracts, and full-text articles was performed independently by two reviewers. Any disagreements were resolved through discussion or consultation with a third reviewer.

Data Abstraction
Data extraction was carried out by trained reviewers using a standardized data abstraction form. The form captured relevant information from the included studies, including patient demographics, STS administration route and dosage, treatment outcomes, adverse effects, need for hemodialysis transition, and complications or deaths associated with calciphylaxis or STS treatment. Data abstraction was conducted independently by two reviewers, and any discrepancies were resolved through consensus or consultation with a third reviewer.

Evaluation of Bias Risk
Two independent reviewers performed the bias risk evaluation using various standardized tools suitable for each type of study incorporated. Any disagreements that arose were managed through discussion or by involving a third reviewer.
When analyzing case reports, the JBI Critical Appraisal Checklist for Case Reports was applied [40]. This checklist uses eight specific criteria to determine the quality of case reports, such as patient demographics clarity, diagnosis accuracy, outcome measurement appropriateness, and the impartiality of the intervention and outcome description.
The NIH Quality Assessment Tool for Case Series Studies was utilized for case series [41]. This tool scrutinizes the bias risk across nine domains, encompassing the research question's clarity, the comprehensiveness of the case series, the uniformity of data collection, and the validity of the statistical analysis.
For cohort studies, we implemented the ROBINS-I tool [42]. This tool reviews seven bias domains: confounding elements, participant selection, intervention classification, deviations from planned interventions, missing data, outcome measurement, and result reporting. All studies underwent bias risk evaluation and received a classification of "low", "moderate", "serious", or "critical" risk of bias based on the combined scores across relevant domains.

Statistical Analysis
Due to the heterogeneity of the included studies and the lack of raw data, a formal statistical analysis was not performed. Instead, a descriptive analysis was conducted to summarize the findings. The extracted data were presented as frequencies and percentages for categorical variables, and ranges for continuous variables, when applicable. This approach allowed for a comprehensive summary of the treatment outcomes and adverse effects reported in the included studies.

Results
The flow diagram shown in Figure 1 outlines the process of article selection and screening conducted for this research study. Initially, a total of 116 articles from Embase, Ovid MEDLINE, EBM Reviews-Cochrane Central Register of Controlled Trials, and EBM Reviews-Cochrane Database of Systematic Reviews were considered. Title and abstract screening resulted in the exclusion of five articles that were in vitro or animal studies. Additionally, 19 duplicate articles were identified and removed. Out of the remaining 92 articles, which underwent full-length article review, 73 were excluded as they were either review articles or not relevant to peritoneal dialysis patients. Finally, 19 articles met the inclusion criteria and were selected for systematic reviews.
Across the 19 articles, this review identified 30 PD patients with calciphylaxis who received STS ( Figure 2). These included 15 case reports, 2 case series, and 2 cohort studies ( Table 1). The presented table offers a comprehensive overview of numerous studies and case reports investigating the treatment and outcomes of calciphylaxis, with a specific emphasis on the utilization of sodium thiosulfate. The studies, conducted over a span of nearly two decades from 2004 to 2022, provide a broad view of the varied cases of calciphylaxis, with differences in the types, locations, and severities of skin lesions. The age of the patients in the examined studies spans a broad spectrum from 17 to 85 years (Table 2), with a noteworthy female preponderance representing 63% of the total patient pool. The duration of PD administration exhibits substantial variation, ranging from as short as 3 months to as long as 10 years. Data on the adequacy of dialysis, quantified by kt/v values, are unfortunately sparse; nonetheless, where reported, these values oscillate between 1.2 and greater than 2.1. A heterogeneous patient demographic is reflected in the ethnicity/race information, encompassing a variety of racial/ethnic groups such as Caucasian, African American, Asian American, Latina, Black, White, and Chinese. Among those with a specified ethnicity/race, Caucasian patients constitute the majority, comprising approximately 50% of these particular cases. Comorbidity profiles of these patients illustrate a diverse array of health conditions, with hypertension emerging as the most prevalent. Other frequently encountered comorbidities include various cardiovascular conditions and diabetes, Across the 19 articles, this review identified 30 PD patients with calciphylaxis who received STS ( Figure 2).  These included 15 case reports, 2 case series, and 2 cohort studies ( Table 1). The presented table offers a comprehensive overview of numerous studies and case reports investigating the treatment and outcomes of calciphylaxis, with a specific emphasis on the utilization of sodium thiosulfate. The studies, conducted over a span of nearly two decades from 2004 to 2022, provide a broad view of the varied cases of calciphylaxis, with differences in the types, locations, and severities of skin lesions. The age of the patients in the examined studies spans a broad spectrum from 17 to 85 years (Table 2), with a noteworthy female preponderance representing 63% of the total patient pool. The duration of PD administration exhibits substantial variation, ranging from as short as 3 months to as long as 10 years. Data on the adequacy of dialysis, quantified by kt/v values, are unfortunately sparse; nonetheless, where reported, these values oscillate between 1.2 and greater than 2.1. A heterogeneous patient demographic is reflected in the ethnicity/race information, encompassing a variety of racial/ethnic groups such as Caucasian, African American, Asian American, Latina, Black, White, and Chinese. Among those with a specified ethnicity/race, Caucasian patients constitute the majority, comprising approximately 50% of these particular cases. Comorbidity profiles of these patients illustrate a diverse array of health conditions, with hypertension emerging as the most prevalent. Other frequently encountered comorbidities include various cardiovascular conditions and diabetes, indicating a multifaceted health profile prevalent within this PD patient population with calciphylaxis.
Treatment durations for sodium thiosulfate, commonly administered intravenously, ranged from several weeks to multiple months. Together with sodium thiosulfate, various Treatment durations for sodium thiosulfate, commonly administered intravenously, ranged from several weeks to multiple months. Together with sodium thiosulfate, various supplementary treatments were used, including changes in diet, the cessation of certain medications, the introduction of noncalcium binders, opioids, and specialized wound care. Additionally, surgical methods such as parathyroidectomy were employed in some cases.
The efficacy of sodium thiosulfate treatment, as evidenced by these studies, exhibits a wide range. There were instances where patients showed notable improvement. New et al. (2011) [17] noted that the administration of sodium thiosulfate resulted in wound resolution in four out of five patients, although one patient unfortunately succumbed to sepsis. Gupta [36] discontinued sodium thiosulfate due to severe nausea, but significant pain reduction and partial wound healing were achieved through the use of low-calcium dialysate. These findings collectively underscore the variable response exhibited by patients to sodium thiosulfate and emphasize the necessity for tailored treatment approaches that consider individual patient characteristics and adherence to the prescribed regimen.
Another notable case study conducted by Danijela Mataic and Bahar Bastani (2006) [36] highlighted the initial improvement of wounds in a patient presenting multiple calciphylaxis lesions following sodium thiosulfate administration. However, recurrence of the condition and sepsis occurred due to poor compliance and the introduction of intraperitoneal (IP) sodium thiosulfate. Conversely, Dethloff (2012) [45] successfully demonstrated complete wound healing through the application of sodium thiosulfate treatment in a single case study. Furthermore, Janom et al. (2021) [46] achieved favorable outcomes by employing sodium thiosulfate in conjunction with peritoneal dialysis and subtotal parathyroidectomy for the treatment of calciphylaxis. In contrast, Zhang et al. (2016) [11] reported wound improvement with intravenous (IV) sodium thiosulfate; nevertheless, 75% of the patients eventually transitioned to hemodialysis and encountered a one-year mortality rate due to sepsis. Sood et al. (2011) [47] presented mixed results, with some patients experiencing an exacerbation of wound intensity while others displayed wound reduction; unfortunately, two patients succumbed to sepsis within one year. Finch et al. (2010) [48] documented complete wound resolution following IV sodium thiosulfate treatment. Overall, these findings underscore the inherent variability in patients' responses to sodium thiosulfate therapy and emphasize the crucial role of individual patient characteristics and compliance with treatment protocols in achieving favorable outcomes.
The administration routes and doses varied depending on the study ( Figure 3). For intravenous (IV) administration (n = 18), STS doses ranged from 3.2 g twice daily to 25 g three times weekly for 5 weeks to 8 months. Outcomes included 44% of patients experiencing successful wound healing, 6% discontinuing STS due to adverse effects, 67% transitioning to HD, and 50% dying from calciphylaxis complications.
For intraperitoneal (IP) administration (n = 5), STS doses ranged from 12.5 to 25 g three to four times weekly for 12 h to 3 months. Results showed 80% of patients achieving successful wound healing, 80% discontinuing STS due to adverse effects, 40% transitioning to HD, and 20% dying from IP STS-related chemical peritonitis.
In cases where patients switched from IV to IP STS (n = 3), doses ranged from 12.5 to 25 g two to three times weekly for 2.5 to 5 months. Among them, 67% experienced successful wound healing, while 33% died from sepsis.
Two cases utilized oral STS at a dose of 1500 mg twice daily for 6 and 11 months, resulting in successful wound healing without adverse effects or the need for HD. However, one patient (50%) died due to small bowel obstruction.
The outcomes varied depending on the route of STS administration ( Figure 4), with both successful wound healing and adverse effects observed across the different routes. The highest success rates were seen with IP administration, while the highest mortality rates were observed with IV administration and IP STS-related chemical peritonitis.  The administration routes and doses varied depending on the study (Figure intravenous (IV) administration (n = 18), STS doses ranged from 3.2 g twice daily three times weekly for 5 weeks to 8 months. Outcomes included 44% of patients encing successful wound healing, 6% discontinuing STS due to adverse effects, 67 sitioning to HD, and 50% dying from calciphylaxis complications. For intraperitoneal (IP) administration (n = 5), STS doses ranged from 12.5 three to four times weekly for 12 h to 3 months. Results showed 80% of patients ac successful wound healing, 80% discontinuing STS due to adverse effects, 40% tra ing to HD, and 20% dying from IP STS-related chemical peritonitis.
In cases where patients switched from IV to IP STS (n = 3), doses ranged from 25 g two to three times weekly for 2.5 to 5 months. Among them, 67% experienc cessful wound healing, while 33% died from sepsis.
Two cases utilized oral STS at a dose of 1500 mg twice daily for 6 and 11 m resulting in successful wound healing without adverse effects or the need for HD ever, one patient (50%) died due to small bowel obstruction.
The outcomes varied depending on the route of STS administration (Figure 4 both successful wound healing and adverse effects observed across the different The highest success rates were seen with IP administration, while the highest m rates were observed with IV administration and IP STS-related chemical peritonit

Risk of Bias Assessment
To evaluate bias in the case reports, the JBI Critical Appraisal Checklist for Ca ports was employed [40]. This tool scrutinizes various aspects of the study, such appropriateness of the study design, the clarity of the research objectives and que the adequacy of data collection methods, the consideration of ethical issues, the tra ency of data analysis, and the validity of the conclusions drawn. The assessment iden one case report [26] with a high risk of bias, indicating potential limitations in the design, data collection, or analysis that may affect the reliability of the findings. An case report [36] demonstrated a moderate risk of bias, implying some shortcomin not to the extent of the high-risk study. The remaining case reports were deemed to a low risk of bias, indicating a higher level of methodological rigor.
For the case series studies, the NIH Quality Assessment Tool for Case Series S was employed [41]. This tool evaluates various aspects of study design, data colle and analysis, including the clarity of the case series objectives, the appropriateness o selection and data sources, the completeness of data collection, the consideration o founding factors, and the reporting of outcomes. Among the case series studies, one [17] exhibited a moderate risk of bias, suggesting potential limitations in the study d

Risk of Bias Assessment
To evaluate bias in the case reports, the JBI Critical Appraisal Checklist for Case Reports was employed [40]. This tool scrutinizes various aspects of the study, such as the appropriateness of the study design, the clarity of the research objectives and questions, the adequacy of data collection methods, the consideration of ethical issues, the transparency of data analysis, and the validity of the conclusions drawn. The assessment identified one case report [26] with a high risk of bias, indicating potential limitations in the study design, data collection, or analysis that may affect the reliability of the findings. Another case report [36] demonstrated a moderate risk of bias, implying some shortcomings but not to the extent of the high-risk study. The remaining case reports were deemed to have a low risk of bias, indicating a higher level of methodological rigor.
For the case series studies, the NIH Quality Assessment Tool for Case Series Studies was employed [41]. This tool evaluates various aspects of study design, data collection, and analysis, including the clarity of the case series objectives, the appropriateness of case selection and data sources, the completeness of data collection, the consideration of confounding factors, and the reporting of outcomes. Among the case series studies, one study [17] exhibited a moderate risk of bias, suggesting potential limitations in the study design or analysis that may impact the validity of the results. On the other hand, the other case series study [47] demonstrated a low risk of bias, indicating a higher level of methodological rigor and fewer potential sources of bias.
The risk bias assessment for the cohort studies utilized the ROBINS-I tool [43], which examines the risk of bias across several domains, including confounding, participant selection, intervention classification, deviations from intended interventions, missing data, outcome measurement, and selection of reported results. Among the cohort studies, one study [11] displayed a moderate risk of bias, suggesting potential limitations that may impact the internal validity of the study. However, none of the included cohort studies were reported to have a high risk of bias, indicating a relatively stronger methodological quality in terms of minimizing potential biases.
Overall, the risk bias assessments provide valuable insights into the methodological quality and potential biases present in the included studies. They emphasize the importance of interpreting the study findings cautiously, taking into account the limitations introduced by the identified risks of bias. These assessments underscore the significance of critically appraising the included studies to evaluate their methodological rigor and potential sources of bias. Moreover, they highlight the need for further high-quality studies with robust methodologies to strengthen the evidence base regarding the treatment and outcomes of calciphylaxis and the utilization of sodium thiosulfate.

Discussion
Calciphylaxis, a rare and severe condition characterized by the calcification and ischemic necrosis of small-to-medium-sized blood vessels in the skin and subcutaneous tissues, primarily affects ESKD patients undergoing dialysis, particularly those on PD [13,17,18,20]. STS has been utilized as a treatment option for calciphylaxis; however, its effectiveness and usage in PD patients have been less studied compared to patients undergoing HD. This systematic review aimed to explore the existing literature on the use of STS in PD patients with calciphylaxis.
The review identified 30 PD patients from 19 articles who received STS for treating calciphylaxis. The administration routes and doses of STS varied across the studies, indicating the absence of standardized protocols for PD patients. The most commonly reported method was IV administration, with doses ranging from 3.2 g twice daily to 25 g three times weekly for durations of 5 weeks to 8 months [17,56,57]. IP administration was used in a smaller subset of patients, with doses ranging from 12.5 to 25 g three to four times weekly for 12 h to 3 months [17]. In a few cases, patients switched from IV to IP administration, and oral STS was used in two instances.
The outcomes of STS treatment varied, with some patients experiencing successful wound healing, while others had to discontinue treatment due to adverse effects or experienced more severe complications. For IV administration, 44% of patients achieved successful wound healing, but 6% had to discontinue STS due to adverse effects. Additionally, 67% of patients transitioned to HD, and 50% of patients died from calciphylaxis-related complications. The outcomes were somewhat different for IP administration, with 80% of patients achieving successful wound healing but 80% discontinuing STS due to adverse effects. Among the patients who switched from IV to IP administration, 67% experienced successful wound healing, but 33% died from sepsis. The two cases involving oral STS demonstrated successful wound healing without adverse effects, but one patient died due to small bowel obstruction.
These findings emphasize the potential benefits of STS treatment in PD patients with calciphylaxis, particularly regarding wound healing. However, it is important to note that adverse effects were significant, leading to treatment discontinuation in a considerable number of cases. The adverse effects associated with STS use, such as chemical peritonitis with IP administration and sepsis in patients switching from IV to IP administration, underscore the necessity for careful monitoring and personalized dosing regimens [38,43,58,59]. The high mortality rate observed in this review also highlights the severity and complexity of calciphylaxis in PD patients [2,11,17,60].
Moreover, transitioning from PD to HD has been commonly recommended for better management of hyperphosphatemia and hyperparathyroidism, which are key factors contributing to the development and progression of calciphylaxis [61,62]. HD allows more efficient removal of phosphate and improved control of mineral and bone disorders. Consequently, the administration of STS during hemodialysis sessions has become a common practice in treating calciphylaxis [63]. This approach capitalizes on the dialysis session to deliver STS directly into the bloodstream, potentially enhancing its therapeutic effectiveness. While the reviewed studies primarily focused on STS administration in PD patients, a significant proportion of cases involved transitioning to HD [11,17]. This suggests that clinicians switch to HD to optimize calciphylaxis management and enhance patient outcomes. The transition to HD allows for more precise control of STS dosing and better monitoring of treatment response. Furthermore, HD offers the advantage of regular s-essions with close clinical supervision, facilitating the identification and management of potential adverse effects associated with STS therapy. The use of STS during hemodialysis provides a targeted treatment approach by infusing it directly into the bloodstream, enabling precise dosing and reducing the risk of complications associated with IP administration. Close monitoring during HD sessions allows for prompt identification and management of adverse effects, potentially improving the safety profile of STS therapy. Overall, transitioning from PD to HD, coupled with STS administration during hemodialysis, appears to be a prevalent strategy in calciphylaxis management. This integrated approach addresses the underlying pathophysiology, including the control of mineral and bone disorders, while also leveraging the benefits of STS therapy. However, it is crucial to consider individual patient factors such as comorbidities, vascular access, and dialysis adequacy when making treatment decisions and determining the most appropriate dialysis modality and STS administration route.
Nevertheless, it is important to acknowledge that transitioning from PD to HD may not always be feasible or recommended. Some PD patients with calciphylaxis may have limitations that prevent them from switching to HD. Hemodynamic instability can be a significant concern in certain patients, making them unsuitable candidates for hemodialysis due to underlying cardiovascular conditions or compromised hemodynamic stability. Additionally, challenging vascular access can impede the transition to HD, as some patients may have exhausted their options for vascular access due to repeated failures or complications. Limited or compromised vascular access can make hemodialysis difficult or even impossible, necessitating the continuation of PD as the primary dialysis modality. Patient preferences and autonomy also play a crucial role in treatment decisions. Despite understanding the risks and benefits associated with transitioning to hemodialysis, some patients may refuse to switch due to personal reasons, fear of change, or lifestyle considerations. In such cases, healthcare providers should respect patient autonomy and collaborate to explore alternative treatment options and optimize PD care for effective calciphylaxis management.
In clinical practice, healthcare professionals often encounter situations where calciphylaxis patients cannot be transitioned to hemodialysis due to hemodynamic instability, challenging vascular access, or patient refusal. These cases present unique challenges, requiring tailored treatment strategies to address individual patient needs and circumstances. Alternative approaches, including optimizing PD techniques, adjunctive therapies, wound care management, and supportive measures, may be employed to meet the specific requirements of these patients and improve their outcomes while on PD.
The limitations of this review include the scarcity of data on STS treatment specifically in PD patients with calciphylaxis and the heterogeneity of the included studies in terms of study design, sample size, and dosing regimens. The absence of standardized protocols and the retrospective nature of most studies hindered definitive conclusions regarding the optimal use of STS in this patient population. In order to address the existing limitations in the current literature and enhance the management of calciphylaxis, future studies in this field should focus on a range of areas. It is crucial to conduct well-designed prospective studies that can evaluate the effectiveness and safety of STS in patients undergoing PD, with particular attention to optimizing the timing, dosage, and duration of treatment. Furthermore, comparative investigations that directly compare PD and HD patients would provide valuable insights for treatment decision-making. Exploring alternative treatment modalities, such as calcimimetics, intravenous administration of tissue plasminogen activation" and hyperbaric oxygen therapy, is also warranted. Efforts should be made to develop strategies that can mitigate adverse effects, establish standardized protocols, and evaluate long-term outcomes and cost-effectiveness. Additionally, the identification of biomarkers and imaging techniques for early diagnosis and monitoring would significantly contribute to the advancement of calciphylaxis management. By undertaking research in these areas, future studies will facilitate the development of evidence-based strategies for the effective care of patients affected by calciphylaxis.

Conclusions
This systematic review provides an overview of the utilization of STS in PD patients with calciphylaxis. While some patients achieved successful wound healing with STS treatment, adverse effects were significant, and mortality rates were high. Further research, including well-designed prospective studies, is necessary to establish standardized protocols, determine optimal dosing regimens, and assess the long-term efficacy and safety of STS in PD patients with calciphylaxis. Additionally, comparative investigations on the outcomes of STS treatment in PD and HD patients would be valuable for informing clinical decision-making and improving the management of this challenging condition.