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JAMA Netw Open. 2023 Apr 3;6(4):e2310068.
Intravenous Sodium Thiosulphate for Calciphylaxis of Chronic Kidney Disease: A Systematic Review and Meta-analysis
Wen Wen, Ignacio Portales-Castillo , Rituvanthikaa Seethapathy, Olivia Durant, Beza Mengesha Scott Krinsky, Daniela Kroshinsky, Sahir Kalim, Jeremy Goverman, Rosalynn M Nazarian, Vipul Chitalia, Rajeev Malhotra, Rafael Kramann, Cindy K Malhotra, Sagar U Nigwekar
PMID: 37099293
Introduction
Calciphylaxis, more accurately now called calcific uremic arteriolopathy (CUA), is characterized by vascular calcification of the microvessels in subcutaneous adipose tissue and dermis that results in intensely painful, ischemic skin lesions (Nigwekar et al, NEJM 2018). The term “calciphylaxis” is derived from ‘calci’ meaning ‘calcium’ and ‘phulaksis’ from Greek meaning ‘a watching or guarding’ implying a ‘protection from calcium’. Though recognized first by Bryant and White in 1898 in a 6 month old child, the term was first coined in 1961 after finding calcifications in rat skin (Seyle et al, Science 1961).
In a large nationwide study, the incidence rate of calciphylaxis was found to be 3.49 per 1000 patients per year in patients undergoing regular maintenance HD. In a single center study, the incidence of calciphylaxis in patients receiving dialysis was 4.5% per year with a 6-month mortality rate of 33% in patients presenting with plaques only, but surged above 80% if ulceration was present (Fine and Zacharias, Kidney Int 2022). Repeated hospitalizations, sepsis, poor nutrition, and chronic pain are major morbidities that contribute to a poor quality of life in patients with CUA (Chang JJ, Adv Skin Wd Care 2019). Some details about the risk factors for calciphylaxis can be seen in the following infographic.
Adapted from Chang JJ, Adv Skin Wd Care, 2019
Read more on the pathology of CUA (NephJC summary by Vandana Dua Niyyar) and the role of image guided core needle biopsy for the diagnosis of cutaneous calciphylaxis (NephJC summary by Itunu Owoyemi). The following figure also depicts the possible pathogenesis of calciphylaxis.
Figure depicting the proposed pathogenesis of calciphylaxis from Nigwekar et al, NEJM 2018
The treatment of calciphylaxis is challenging, and there is no approved or one-size fits all therapy. The main goals of treatment are to relieve pain, promote wound healing, and prevent infection. Management often involves a multidisciplinary approach. The following strategies have been described for management of patients with calciphylaxis (Chang JJ, Adv Skin Wd Care, 2019):
Table adapted from Chang JJ, Adv Skin Wd Care, 2019
Sodium thiosulphate (STS) chelates calcium salts and is also an antioxidant agent. STS reduces intravascular and extravascular calcifications by forming a more soluble product, calcium thiosulfate. This effectively attenuates the burden of calcification in adipocytes and vascular smooth muscle cells. The possible mechanism of STS on the vascular wall can be seen in the following figure (Hyden et al, Semin Dial 2010).
Figure from Hyden et al, Semin Dial 2010
Since 2004, STS has been used as an off-label medication in patients with calciphylaxis to relieve pain and promote wound healing (Cicone et al, AJKD 2004). Since that time, there have been published reports, but notably no clinical trials, regarding the benefit of STS for treatment of calciphylaxis. Many of these observational studies lacked a comparator arm limiting their interpretation. This systematic review aimed to overcome this by including all retrospective studies that compared calciphylaxis treated with (intervention) and without (comparator) intravenous STS.
The Study
Question: Does intravenous sodium thiosulphate improve skin lesions and survival in patients with CKD experiencing calciphylaxis?
Methods
Design
A systematic review and meta-analysis of retrospective cohort studies
The controlled vocabulary terms and synonyms of calciphylaxis were used to search from 4 databases (PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov)
All the publications of clinical trials or cohort studies with no language restriction published before August 31, 2021 were included
Eligible studies were identified by two authors according to inclusion and exclusion criteria by using Endnote X9 (Clarivate). Discrepancies were reevaluated by the third author and consensus discussion was done for final decision.
Inclusion Criteria
Cohort studies with participants aged 18 years or older, who were diagnosed with CKD (eGFR <60 ml/min/1.73m2 for at least 3 month)
With focus on calciphylaxis as the main complication studied and it being the primary indication for STS treatment. (It is useful to check out the vocabulary terms and synonyms mentioned in the supplement for search- ‘vascular calcification’, ‘cardiovascular calcification’, ‘calciphylaxis’, ‘calcification of joints and arteries’, ‘calcification of aortic valve’, ‘calcific uremic arteriolopathy’, ‘calci-’, ‘microcalci-’)
Having both intervention (STS) and comparator (no STS) arms affording adequate chance for comparison
Exclusion Criteria
Outcomes were reported for non-intravenous STS treatment arm only (oral, intraperitoneal, intralesional)
Studies which did not provide data on skin lesions and survival outcomes
Studies reporting calcinosis or other calcifications not belonging to vascular calcification
Reviews, letters, and other literature in which the information of patients are not extractable
Case reports and case series
Population
Patients with CKD experiencing calciphylaxis
Intervention
Intravenous infusion of Sodium thiosulphate at the end of dialysis
Comparator(s)/control
Placebo or usual care (without intravenous STS)
Outcomes
Comparative outcomes between intravenous STS groups and other treatments group (comparators)
Survival Benefit between STS and comparators groups
Skin lesion Improvement between STS and comparators groups
Statistics
A random-effects empirical Bayes model was used to quantify skin lesion improvement and survival.
Log risk ratio (RR) or log hazard ratio was used to analyze categorical data.
The impact from publication year on treatment- related effect sizes were examined by using Meta-regression.
The publication bias was measured by using the Funnel plot and the Egger test.
An I2 index was used to assess heterogeneity and obvious heterogeneity was defined if I2 index >50%.
Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) was used to grade the risk of bias in the studies.
Sensitivity analyses were run to test effect size measurements and single studies.
Statistical analysis was done by Static version 16 (StataCorp).
The latest update of analysis was done on February 6, 2023.
Funding
Funding was from The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Heart, Lung, and Blood Institute (NHLBI), the American Heart Association (AHA), the Wild Family Foundation, the National Institute of Biomedical Imaging and Bioengineering (NIBIB). The funders had no role in the study process.
Results
From the targeted databases, 5601 publications were identified. After removing duplicated studies and applying inclusion and exclusion criteria, 19 retrospective cohort studies were eligible for systematic review and meta-analysis. In particular among the exclusions were 353 case reports. Details can be seen in figure 1.
Figure 1. Flowchart of Study (Wen W et al, JAMA Netw Open 2023)
A total of 422 patients with CKD experiencing calciphylaxis from nineteen retrospective cohort studies were included. Among them, more than half of patients received intravenous STS (233, 55.2%) and most patients were dialysis dependent (347, 82%). Of these 347, studies only mentioned 23 patients specifically using peritoneal dialysis (PD). Mean age was 57 years and a slight majority were women (62.7%). Eleven studies involved less than 10 participants per study. The longest follow up was > 9 years and the shortest was 14 weeks, but some studies could not provide follow up duration. Most of the patients were given intravenous STS between 5 to 25 grams, dosed at the end of the dialysis. Details can be seen in the following table 1.
Table 1. Summary of 19 Retrospective Cohort Studies for Calciphylaxis (Wen W et al, JAMA Netw Open 2023)
Skin Lesion Improvement Outcome
Twelve studies (110 patients) reported on skin lesion improvement and did not report a significant difference between STS and comparator groups with a RR 1.23 (95% CI, 0.85-1.78).
Figure 2A. No association of STS with lesion improvement (Wen W et al, JAMA Netw Open 2023)
Survival Benefit Outcome
Survival benefit over comparator groups was also not shown in the included 158 patients from 15 studies with an RR 0.88 (95% CI, 0.70-1.10).
Figure 2B. No association of STS with improved survival among patients with calciphylaxis (Wen W et al, JAMA Netw Open 2023)
Time to Event death
A total of three studies (269 patients) reported Time-to-Event death data, again with no significant benefit seen with a hazard ratio of 0.82 (95% CI, 0.57-1.18).
Figure 2C. No association of STS with overall survival among patients with calciphylaxis (Wen W et al, JAMA Netw Open 2023)
Metaregression and Sensitivity analyses
The correlation analysis between publication year and log effect size estimates using z test based on random-effects model have shown a negative correlation between STS groups' skin lesion improvement and the publication year (coefficient = −0.14; P = .008) suggesting a lower benefit of STS in recent studies. This effect was not seen for the other two outcomes.
Table 2. Meta-regression for the association of publication year with calciphylaxis outcomes (Wen W et al, JAMA Netw Open 2023)
In sensitivity analysis for effect size measurements and single studies, lesion improvement and mortality had larger 95% CIs, but no significant differences were observed during comparing RR and overall odd ratios (ORs). Details can be seen in the following figure.
The researchers also performed sensitivity analysis by removing single studies. When removing Omer et al, lesion improvement was favored for using STS with RR of 1.64 (95% CI, 1.17-2.29) but removing An et al, it was turned favored for comparison groups with RR to 0.99 (95% CI, 0.59-1.67)
eFigure 2: Sensitivity analysis by removing single studies.
However, all-cause death and overall survival were not different in sensitivity analysis no matter which study was removed from the original analyses.
No significant difference for skin lesion improvement and survival benefit were found in analysis between small studies and large studies (sample size >10 patients and <10 patients).
Sensitivity analysis was also undergone in studies only involving dialysis patients and it showed comparator groups had non-significant favorable effects for skin lesion improvement and all-cause death in relative risk reduction (RR).
eFigure 4: Sensitivity analysis for studies only included dialysis patients.
Heterogeneity was assessed using the I2 test and there was no obvious or high heterogeneity. Risk-of-bias assessment of the 19 cohort studies using ROBINS-I tool does show a moderate to a critical risk of bias.
Discussion
Many observational studies reporting the effectiveness of STS in patients with calciphylaxis lack a comparator arm, thus limiting the interpretation of their findings. This meta-analysis was performed with the intention to overcome this limitation. Due to the lack of clinical trials in this area, it is limited to retrospective cohort studies. To its credit, this meta-analysis is the largest to date on this topic, comparing patients with CKD and calciphylaxis treated with STS and those without. A total of 422 patients with CKD experiencing calciphylaxis from 19 retrospective cohort studies were included. Among them 233 (55.2%) patients were involved in intravenous STS groups and 347 (82%) patients were dialysis dependent However, no significant improvement was observed in skin lesions or overall survival with STS use.
The current study encompassed a larger number of recently published studies and included a greater pool of patients compared to the previous analysis. Sensitivity analysis and meta-regression techniques were employed to investigate how various study characteristics may have influenced the results. Notably, worse outcomes were observed in studies only focusing on dialysis patients. Furthermore, a negative correlation was observed between improvement in skin lesions and the publication year, suggesting a publication bias where successful STS treatments were more likely to be published in the past, while recent publications have also included reports of non-responders. The other possible hypothesis is improvement in overall care for calciphylaxis, thus reducing the importance of STS.
The first reported use of STS in calc was in 2004 (Cicone et al, AJKD 2004). This was following the reports of successful treatment of tumoral calcification, a complication of ESRD similar to calciphylaxis, in hemodialysis patients with IV STS. There has been no data available from a clinical trial to inform its efficacy and safety. A previous meta-analysis of 6 studies among hemodialysis patients, concluded that intravenous STS could attenuate the progression of macrovascular calcification among hemodialysis patients and help ameliorate arterial stiffness in hemodialysis patients (Wen et al, NDT 2022).
On the other hand, the case reports and uncontrolled studies paint the picture of “knight in the shining armor” for STS with the effective rates for STS treatment between 67% and 84.4% in a systematic review of case reports and multi-case reports (Peng et al, Nephrology 2017).
The present study underscores the importance of having a control group while interpreting efficacy of an intervention.
Similar results were also reported in another meta-analysis which included controlled studies and explored the benefits of 5 treatment modalities for calcific uremic arteriolopathy or calciphylaxis in patients focussing on 2 clinical outcomes: wound healing and mortality (Udomkarnjananun et al, KI Reports, 2019). For mortality among patients who received STS, the RR was 0.89 (95% CI 0.71–1.12).
No difference was reported also the risk of amputation, worsening of lesions, and death between patients treated with and without STS. The common side effects reported included nausea and vomiting, high anion gap metabolic acidosis, and hypernatremia.
Although the present meta-analysis is the largest till date, a significant limitation was the lack of available treatment details concerning STS in most of the studies. The majority of the studies were small in scale, and several had no occurrences of the events of interest. There were imbalances in preexisting conditions and important confounding factors, such as age, sex, and therapies like hyperbaric oxygen therapy, between the two groups. Additionally, the assessment of lesion improvement varied across the studies, lacking uniformity. Pain intensity improvement, another significant outcome, could not be analyzed consistently due to inconsistent reporting.
Calciphylaxis is one of the less understood but most dreaded conditions in Nephrology. Early and accurate diagnosis of calciphylaxis is important, and clinical mimickers (Gabel CK et al, JAAD 2021) may contribute to delayed or misdiagnosis of this condition and unnecessary measures. Early diagnosis and prompt treatment may be crucial (Rrapi R et al, JAAD 2021) for improving outcomes, but the overall prognosis remains guarded, with a high mortality rate (McCarthy et al, Mayo Clin Proc. 2016) with an estimated six month survival of 50%. Death usually is due to sepsis and multi-organ failure. In a matched case-control study (Nigwekar et al, JASN 2016) using data from a large dialysis organization consisting of 1030 HD patients with newly diagnosed CUA, mortality rates were 27% at 6 months and 45% at 12 months after CUA diagnosis.
Thus, well-designed randomized controlled trials are warranted to establish the effect of STS on calciphylaxis. However, recruitment of patients remains a challenge since calciphylaxis is a rare disease with life-threatening nature. The CALISTA trial, a phase 3 trial designed to examine the effect of IV STS on acute calciphylaxis-associated pain was terminated early due to inability to accrue subjects that met the exclusion criterion “Any prior (within the past 30 days) or current STS treatment”. An ongoing trial, BEAT-CALCI is currently comparing STS, magnesium, and vitamin K treatments for patients with calciphylaxis.
Table : Current and Recent Randomized Controlled Trials for Treatment of Calciphylaxis Indexed at ClinicalTrials.gov (from Marin et al. AJKD 2023)
Calciphylaxis registries such as The Partners Calciphylaxis Biorepository (PCB) and European Calciphylaxis Registry Network (EuCalNet) also aim to address these gaps within calciphylaxis research.
Conclusion
Calciphylaxis, the dreaded bête noire of patients and nephrologists alike, continues to challenge the medical community. It would be unjust to write-off STS as a “fond illusion” in the absence of a single prospective clinical trial in this domain. STS seems to be a glimmer of hope still in alleviating the suffering associated with this devastating condition even as the equipoise in evidence continues.
Summary by
Nyi Min Han
Consultant Nephrologist
No (2) DSGH, Nay Pyi Taw, Myanmar
And
Anitha Swamy,
Assistant Professor,
All India Institute of Medical Sciences,
Hyderabad, India
NSMC Interns, Class of 2023
Reviewed by Sayali Thakare, Husam Alzayer, Jade Teakell, and Swapnil Hiremath
Header Image created by AI, based on prompts by Evan Zeitler