Abstract
The use of sodium thiosulfate has emerged as a promising treatment for calciphylaxis, albeit inconclusively in terms of efficacy and variable outcomes. Research in this field has been limited by a paucity of samples due to the rarity of the disease. We herein discuss eight calciphylaxis patients' responses to STS, the potential predictive factors affecting outcomes and compare our results with previously published literature. We are able to show that lesion severity, concomitant drugs, and dialysis duration may be predictive factors of outcomes. Further, improvement of the wound site may be a clinically relevant prognostic determinant.
Keywords: Calciphylaxis, sodium thiosulfate, outcome
Calciphylaxis is a rare but catastrophic condition chiefly observed in dialysis patients.1 In current practice, a gold standard and recommended approach are still to be established. Despite a multi-interventional approach, the mortality rate remains high. In a search for a cure, sodium thiosulfate (STS) has been in the spotlight. A proposed action is through reversing calcium phosphate deposition.2 However, because of limited case reports and small case series, the clinical outcome of STS is still inconclusive. In this report, we discuss our patients' responses to STS and the potential predictive factors affecting outcomes and compare our results with those in the previously published literature.
Medical records of patients who received STS between January 2013 and December 2018 at King Chulalongkorn Memorial Hospital in Bangkok, Thailand were reviewed retrospectively. Patients who received STS for indications other than calciphylaxis were excluded. The diagnosis of calciphylaxis was confirmed by histology and/or radiography reports. A total of eight patients were included for analysis and were categorized as responders and non-responders, respectively, where responders were those whose wound sites showed improvement.
Demographics, clinical features, treatment modalities, and outcomes are listed in Table 1. All patients received STS at a dosage of 12.5g to 25g three times weekly. Of the eight patients, four (50%) were classified as responders. The responder and non-responder groups differed in terms of the cumulative dose (1611.3±560.8 g vs. 456.3±280.9 g) and duration of STS (22.3±6.1 weeks vs. 6.0±3.5 weeks), with both being higher/longer in the responder group. Thus, we believe that STS may influence positive outcomes, although determining the optimal dosage and duration is challenging. The earliest positive response that we observed was as late as eight weeks after the treatment was initiated.
TABLE 1.
Demographics, clinical features, treatment modalities, and outcomes
| PATIENT CHARACTERISTICS | RESPONDERS | MEAN±SD | NON-RESPONDERS | MEAN±SD | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |||
| Age, years | 47 | 51 | 66 | 69 | 58.3 ± 10.9 | 52 | 60 | 43 | 53 | 52.0 ± 7.0 |
| Sex | F | F | F | F | M | F | F | F | ||
| Dialysis modalities | HD | HD | HD | HD | HD | PD | HD | HD | ||
| Vintage, years | 14 | 0 | 6 | 3 | 5.8 ± 6.0 | 9 | 7 | 5 | 4 | 6.3 ± 2.2 |
| Comorbidities | DM, HTN, PAD, tertiary hyperparathyroidism | AKI, hypercalcemia (PTH independent) | DM,HTN | CA rectum, CA corpus, tertiary hyperparathyroidism | DM, CAD, AF, ITP | HTN, CA bladder, gastritis, tertiary hyperparathyroidism | SLE with LN class IV, AIHA, IE | DM, HTN, secondary hyperparathyroidism | ||
| Concomitant agents | VDA | - | - | - | Warfarin, CS, VDA | C-P binder, VDA | Warfarin, CS | VDA | ||
| Serum calcium, mg/dL | 11.1 | 18 | n/a | 7.6 | 12.2 ± 5.3 | 10.5 | 11.3 | 9.5 | 9.6 | 10.2 ± 0.8 |
| Serum phosphorus, mg/dL | 1.7 | 5.3 | n/a | 4.4 | 3.8 ± 1.9 | 8.7 | 8 | 5 | 5.5 | 6.8 ± 1.8 |
| Serum iPTH, pg/mL | 853.4 | 12.8 | n/a | 4629 | 853.4 (433.1-2741.2)b | 293.1 | 2738 | 73.5 | 1711 | 1203.9 (238.2-1967.8)b |
| Location of skin lesions | Distal LE | All extremities, trunk | Proximal and distal LE, trunk | Trunk | Distal LE | Proximal LE | Distal LE | Distal LE | ||
| Lesion characteristics | Gangrene | Ulcer with skin necrosis | n/a | Necrosis | Necrosis | Necrosis | Necrosis | Necrotic eschar | ||
| No. of weeks before STS | 18 | 4 | 4 | 8 | 8.5 ± 6.6 | 12 | 3 | 5 | 7 | 6.8 ± 3.9 |
| Time from STS to initial improvement, weeks | 30 | 19 | 24 | 8 | 20.3 ± 9.3 | - | - | - | - | - |
| Total duration of STS, weeks | 30 | 19 | 24 | 16 | 22.3 ± 6.1 | 5 | 3 | 3 | 11 | 6.0 ± 3.5 |
| Cumulative dose, g | 1,125 | 2,320 | 1,800 | 1,575 | 1,611.3 ± 560.8 | 475 | 150 | 375 | 825 | 456.3 ± 280.9 |
| 12-month mortality | No | No | No | No | Yes | No | Yes | Yes | ||
| Time to death’, weeks | 129 | - | - | - | 5 | - | 5 | 11 | ||
| Additional treatments | DB, angioplasty with stent | DB, HBO (2 sessions), B | DB | Cinacalcet, parathyroidectomy | DB | Cinacalcet, parathyroidectomy | - | DB, parathyroidectomy | ||
F, female; M, male; HD, hemodialysis; PD, peritoneal dialysis; DM, diabetes mellitus; HTN, hypertension; PAD, peripheral artery disease; AKI, acute kidney injury; PTH, parathyroid hormone; CAD, coronary artery disease; AF, atrial fibrillation; ITP, idiopathic thrombocytopenic purpura; SLE, systemic lupus erythematosus; LN, lupus nephritis; AIHA, autoimmune hemolytic anemia; VDA, vitamin D analog; CP binder, calcium-based phosphate binder; CS, corticosteroid; iPTH, intact parathyroid hormone; STS, sodium thiosulfate; LE, lower extremities; DB, debridement; B, bisphosphonate; HBO, hyperbaric oxygen therapy.
aTime measured from date of STS initiation.
bExpressed as median and interquartile range values.
Compared to other published reports, fewer positive outcomes were achieved in this series (Table 2). All of the patients in this study presented with ulcer and necrosis, which were moderate to highly severe, according to the previously defined staging system.3 Two of the non-responders were unable to discontinue warfarin and corticosteroid treatment because of comorbidities. Further, the mean dialysis vintage in this series was longer than that of the others. It is important to note that the non-responders also showed longer dialysis vintage than the responders did (6.3 ± 2.2 years vs. 5.8 ± 6.0 years). It is also possible that these long-standing processes may be associated with poorer wound healing and survival.
TABLE 2.
Comparison among case series reporting the use of sodium thiosulfate in calciphylaxis
| OUR SERIES | NIGWEKAR ET AL6 | ZITT ET AL3 | NOUREDDINE ET AL7 | BALDWIN ET AL8 | BOURGEOIS ET AL9 | SOOD ET AL10 | SALMHOFER ET AL11 | ROSSO ET AL12 | |
|---|---|---|---|---|---|---|---|---|---|
| Patients (n) | 8 | 172 | 27 | 14 | 7 | 8 | 6 | 5 | 5 |
| Age (years) | 55.1±9.1 | 55±13 | 68±12 | 49.3±11.8 | 65.1±12.2 | 72.9±9.6 | 49.7±12.3 | 61.2±2.9 | 60.2±15.3 |
| Female (%) | 87.5 | 73.8 | 66.7 | 71.4 | 85.7 | 75 | 83.3 | 20 | 80 |
| BMI (kg/m2) | 23.9±6.8 | N/A | 29.5±9.1 | 29+9 | N/A | N/A | N/A | 33.5±9.4 | N/A |
| HD (%) | 87.5 | 100 | 85 | 57.1 | 14.3 | 37.5 | 33.3 | 100 | 100 |
| PD (%) | 12.5 | 0 | 15 | 42.9 | 71.4 | 0 | 66.7 | 0 | 0 |
| Vintage (years) | 6±4.2 | 3.1a (1.2,6.2) | 1.0a (0.3, 6.9) | 4.5±4.2 | 3.0±1.6 | N/A | 4.5±2.9 | 2.5±2.5 | 4.2±2.3 |
| DM (%) | 50 | 55.2 | 48 | 35.7 | 57.1 | 50 | 50 | 40 | 40 |
| Ulcer/necrosis lesions (%) | 100 | N/A | 88.9 | 57.1 | 42.9 | ≥75 | 83.3 | 80 | 100 |
| Diagnosis | Biopsy (62.5%), radiography (87.5%) | Clinical, biopsy (n=25) | Clinical, biopsy (52%) | Clinical, biopsy (71.4%) | Biopsy (100%) | Biopsy (100%) | Clinical, biopsy (33%), bone scan (83%) | Clinical, biopsy (60%) | Clinical, biopsy (40%) |
| Trigger agents | |||||||||
| Warfarin (%) | 25 | N/A | 30 | 21.4 | 42.9 | 25 | 33.3 | 80 | 60 |
| C-P binder (%) | 12.5 | N/A | 56 | N/A | 29 | 12.5 | 50 | 60 | 60 |
| Vitamin D analogues (%) | 50 | N/A | 63 | N/A | 57.1 | 25 | 66.7 | 40 | 100 |
| Laboratory values | |||||||||
| Serum calcium (mg/dl) | 11.1±3.3 | 8.7±0.8 | 9.6±1.1 | 8.3±0.6 | 9.0±1.3 | N/A | 10.4±0.5 | 9.2±1.6 | 10.2±0.6 |
| Serum phosphorus (mg/dl) | 5.5±2.3 | 5.8±1.5 | 5.1±1.8 | 5.6±2.8 | 5.3±1.8 | N/A | 6.5±1.0 | 5.6±1.2 | 4.9±1.0 |
| Serum albumin (g/dl) | 3.3±0.5 | 3.5±0.5 | 3.3±0.9 | N/A | N/A | N/A | 2.1±0.5 | N/A | N/A |
| Serum iPTH (pg/ml) | 853.4a (183.3, 2,224.5) | 332a (170, 654) | 362±298 | 849±1,647 | 466±353 | N/A | 321±430 | 515±525 | 1186±296 |
| Treatment modalities | |||||||||
| STS Duration (weeks) | 14.8±10.1 | 13.1a | 13.7 (7.7, 19) | N/A | 8.0±3.7 | 10.5±9.8 | 10.8±3.7 | 80±72.4 | 82.8 |
| Cumulative dose (g) | 1080.6±764.9 | 950a | 1268±1555 | 850±1648 | N/A | 862.5±945.2 | 770.8±253.2 | 7872±9588 | N/A |
| HBO (%) | 12.5 | N/A | 4 | 14.3 | 85.7 | 0 | 0 | 0 | 0 |
| Parathyroidectomy (%) | 37.5 | 15 | 4 | 14.3 | 14.3 | 0 | 33.3 | 40 | 0 |
| Cinacalcet (%) | 25 | 57 | 37 | 57.1 | 57.1 | 25 | 33.3 | 100 | 100 |
| Bisphosphonate (%) | 12.5 | N/A | N/A | 21.4 | N/A | 25 | 83.3 | 20 | N/A |
| Debridement/ wound care (%) | 62.5 | 34 | 22 | N/A | 100 | 100 | 83.3 | N/A | 100 |
| Outcome | |||||||||
| Improved (%) | 50 | 73.6 (n=53) | 70 | 71.4 | 100 | 75 | 66.7 | 100 | 80 |
| Not improved (%) | 50 | 5.7 (20.8% n/a) | 30 | 21.4 (7.1% n/a) | 0 | 25 | 33.3 | 0 | 20 |
| Death (%) (overall) | 50 | 42 | 52 | 71 | 28.6 | 50 | 50 | 100 | 0 |
Unless otherwise noted, values are mean+SD.; body mass index (BMI); hemodialysis (HD); peritoneal dialysis (PD); diabetes mellitus (DM); calcium-based phosphate binder (C-P binder); intact parathyroid hormone (iPTH); expressed as median and interquartile range (a).
Factors reported to have a hand in predicting poor survival were female sex, higher weight, severe cutaneous lesions, and proximal lesions.3,4 Interestingly, all non-survivors in our series exhibited distal calciphylaxis. Thus, the proximal type might not necessarily dictate such poor outcomes as previously reported. An additional finding observed in this series was that the improvement of the wound sites might be a clinically relevant prognostic determinant. The mortality rate in the responder group at 12 months was 0%, while that of the nonresponders was 75%.
Given the small number of study participants, the fact that not all cases had a histologically confirmed diagnosis, and the difference in clinical evaluation times across the studies, determining the clinical outcome of STS is especially challenging. Further studies are warranted which, in the long run, should be beneficial to those who suffer from this deadly disease.
We propose that lesion severity, concomitant drugs, and dialysis duration might be predictive factors of outcomes. In addition, improvement of the wound site may be a clinically relevant prognostic determinant. Given the proposed action of STS, it may take some time before positive responses are observed. Meanwhile, providing specific treatments such as calcimimetics and parathyroidectomy may lower the rates of wound deterioration and mortality for those with tertiary hyperthyroidism.5
ACKNOWLEDGMENTS
The authors thank the Skin and Allergy Research Unit at Chulalongkorn University for its support.
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