Compressing Calciphylaxis

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The Pre-brief

Calciphylaxis, or calcific uremic arteriolopathy, is a rare but life-threatening disease state most commonly but not exclusively occurring in end-stage renal disease (ESRD) patients and characterized by calcification of small to medium blood vessels.  Clinically, patients have tremendously painful skin ulceration which can progress to local necrosis and gangrene.  Overall, the rarity of cases limits the supporting evidence for the constellation of therapies used for calciphylaxis.  Therapies include sodium thiosulfate, surgical parathyroidectomy, cinacalcet, and bisphosphonates.  Among these therapies, hyperbaric oxygen therapy (HBOT) can also be considered as an adjunct.

Background

Calciphylaxis occurs primarily in patients with ESRD and in this population has a reported prevalence of 1-4%.  Of important note though, there are rarer cases of non-uremic calciphylaxis which can occur outside of patients on dialysis.  Aside from ESRD, underlying comorbidities associated with the disease include lesser degrees of chronic kidney disease (CKD), diabetes mellitus, and autoimmune diseases.  According to a single-center retrospective review from the Mayo Clinic, it is more common in female patients (80%) and obese patients (68%). In all patients, two-year mortality is reported as high as 60-80% and is usually secondary to wound infection and sepsis.  The pathophysiology of this disease is unclear but ultimately leads to arteriolar calcium deposition which leads to compromised vascularity and soft tissue necrosis downstream.  

The lower extremities are most commonly but not exclusively affected.  Cases are also reported of localized penile calciphylaxis.  While these are typically not fatal if the disease remains local, outcomes as far as tissue salvage are typically poor.  Diagnosis of calciphylaxis is confirmed histologically via biopsy demonstrating calcium deposits in the vascular intima.  In more advanced cases, calcific deposits in soft tissue can even be seen on plain radiography.    Vascular calcifications distinct from atherosclerosis can also occur in organs such as the heart or lungs in a separate disease state termed visceral calciphylaxis.    

Treatment options

Sodium thiosulfate (STS): Though considered off-label, STS is the most commonly used treatment for calciphylaxis.  Per a recent meta-analysis on the treatment of calciphylaxis, STS was used in 50% of cases.  There are multiple mechanisms by which STS is thought to be of benefit in patients with calciphylaxis.  STS is proposed to replace calcium in vascular deposits to form calcium thiosulfate.  Calcium thiosulfate is subsequently then excreted by the kidneys or in most of these cases removed during dialysis.  Some also argue for STS’s use given activity as a vasodilator and antioxidant.  

Dosing of STS is recommended to start at 25g IV to be given during each dialysis session and continued for 8-24 weeks.  Dose can be halved for patients less than 60kg or for patients who are not tolerating initial dose due to gastrointestinal side effects. 

Surgical parathyroidectomy, cinacalcet, bisphosphonates: Globally, control of calcium-phosphate metabolism is important in treating calciphylaxis.  On a case-by-case basis, treatment of any cause of hyperparathyroidism should be addressed and can include surgical parathyroidectomy, cinacalcet, and/or bisphosphonates.  Obviously, a continuation of regular dialysis is also required for maintenance of calcium-phosphate metabolism in the majority of patients with calciphylaxis.

HBOT: Hypovascularity and hypoxic tissue injury are central to the pathophysiology of calciphylaxis.  The hyperoxia inherent to HBOT can help with this disease process in multiple ways.  First and most apparent, hyperoxia during treatments can transiently relieve hypoxic stress in injured tissues.  Second and more importantly for long-term healing, HBOT induces neovascularization via stem cell mobilization and local collagen deposition. 

Case series and retrospective reviews do suggest some improvement in healing and survival when HBOT is employed early on as an adjunct for the treatment of calciphylaxis.  A recent systematic review of 131 patients with calciphylaxis who were treated with HBOT reported 45% healing to complete wound closure with 13% experiencing partial healing.  Interestingly, select reports suggest better outcomes when STS and HBOT are used concurrently.  Better outcomes are also reported when patients receive 20 or more HBOT sessions. 

Glucocorticoids: Systemic glucocorticoids are argued to potentially reduce skin ulceration in calciphylaxis though support in the literature is limited.  

Surgical:  Surgical debridement of necrotic tissue is an area of debate regarding the treatment of calciphylaxis.  One school of thought is that the surgical insult can induce worsening and further skin ulceration whereas the contrary school of thought is that surgical debridement of necrotic tissue is similar to that employed in a disease process such as necrotizing fasciitis can help prevent terminal infections.  

The Debrief

  • Calciphylaxis is a rare but life-threatening disease occurring most commonly in dialysis patients
  • The primary pathophysiologic mechanism of calciphylaxis is arteriolar calcium deposition which leads to local soft tissue hypervascularity and soft tissue necrosis
  • Treatment options include sodium thiosulfate, surgical parathyroidectomy, cinacalcet, bisphosphonates, and HBOT
  • Supporting mechanisms for the rationale for use of HBOT include reversal of local tissue hypoxia acutely, and neovascularization and collagen deposition in the long term
  • Partially attributable to how rare the disease is, data are limited in support of the above-listed treatment options.

References 

  1. An J, Devaney B, Ooi KY, Ford S, Frawley G, Menahem S. Hyperbaric oxygen in the treatment of calciphylaxis: A case series and literature review. Nephrology (Carlton). 2015 Jul;20(7):444-50. doi: 10.1111/nep.12433. PMID: 25707425.
  2. Chiriac A, Grosu OM, Terinte C, Perţea M. Calcific uremic arteriolopathy (calciphylaxis) calls into question the validity of guidelines of diagnosis and treatment. J Dermatolog Treat. 2020 Aug;31(5):545-548. doi: 10.1080/09546634.2019.1618435. Epub 2019 May 31. PMID: 31075991.
  3. Charaghvandi DA, Teguh DN, van Hulst RA. Hyperbaric oxygen therapy in patients suffering from wounds in calciphylaxis: a narrative review. Undersea Hyperb Med. 2020 First-Quarter;47(1):111-123. doi: 10.22462/01.03.2020.12. PMID: 32176952.
  4. Lipinski M, Sahu N. Hyperbaric Oxygen Therapy Improving Penile Calciphylaxis. Cureus. 2020 Jul 14;12(7):e9190. doi: 10.7759/cureus.9190. PMID: 32818121; PMCID: PMC7426662.
  5. McCarthy JT, El-Azhary RA, Patzelt MT, Weaver AL, Albright RC, Bridges AD, Claus PL, Davis MD, Dillon JJ, El-Zoghby ZM, Hickson LJ, Kumar R, McBane RD, McCarthy-Fruin KA, McEvoy MT, Pittelkow MR, Wetter DA, Williams AW. Survival, Risk Factors, and Effect of Treatment in 101 Patients With Calciphylaxis. Mayo Clin Proc. 2016 Oct;91(10):1384-1394. doi: 10.1016/j.mayocp.2016.06.025. PMID: 27712637.
  6. McCulloch N, Wojcik SM, Heyboer M 3rd. Patient Outcomes and Factors Associated with Healing in Calciphylaxis Patients Undergoing Adjunctive Hyperbaric Oxygen Therapy. J Am Coll Clin Wound Spec. 2016 Aug 30;7(1-3):8-12. doi: 10.1016/j.jccw.2016.08.004. PMID: 28053862; PMCID: PMC5197060.
  7. Ong S, Coulson IH. Diagnosis and treatment of calciphylaxis. Skinmed. 2012 May-Jun;10(3):166-70. PMID: 22779099.
  8. Udomkarnjananun S, Kongnatthasate K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, Susantitaphong P. Treatment of Calciphylaxis in CKD: A Systematic Review and Meta-analysis. Kidney Int Rep. 2018 Oct 9;4(2):231-244. doi: 10.1016/j.ekir.2018.10.002. PMID: 30775620; PMCID: PMC6365410.
  9. Wollina U. (2013). Update on cutaneous calciphylaxis. Indian journal of dermatology58(2), 87–92. https://doi.org/10.4103/0019-5154.108026

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