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Figure.
Patients With Calciphylaxis
Patients With Calciphylaxis

The arrowheads indicate uptake of radiotracer. A, Bone scintigraphy of a patient with biopsy-proven calciphylaxis showing patchy uptake of the radiotracer throughout the body, including bilateral arms, chest wall, pelvis, buttocks, and medial thighs. B, Bone scintigraphy of another patient with biopsy-proven calciphylaxis, before treatment with sodium thiosulfate. The radiotracer uptake can be seen in the pelvis, medial thigh, and medial and lateral calf. C, Six months after treatment, bone scintigraphy in the same patient reveals minimal uptake in the medial calf.

Table.  
Summary of Clinical Findings in 18 Patients With Calciphylaxis
Summary of Clinical Findings in 18 Patients With Calciphylaxis
1.
Hayashi  M.  Calciphylaxis: diagnosis and clinical features. Clin Exp Nephrol. 2013;17(4):498-503.
PubMedArticle
2.
Wilmer  WA, Magro  CM.  Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15(3):172-186.
PubMedArticle
3.
Mochel  MC, Arakaki  RY, Wang  G, Kroshinsky  D, Hoang  MP.  Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol. 2013;35(5):582-586.
PubMedArticle
4.
Han  MM, Pang  J, Shinkai  K, Franc  B, Hawkins  R, Aparici  CM.  Calciphylaxis and bone scintigraphy: case report with histological confirmation and review of the literature. Ann Nucl Med. 2007;21(4):235-238.
PubMedArticle
5.
Norris  B, Vaysman  V, Line  BR.  Bone scintigraphy of calciphylaxis: a syndrome of vascular calcification and skin necrosis. Clin Nucl Med. 2005;30(11):725-727.
PubMedArticle
6.
Fine  A, Zacharias  J.  Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61(6):2210-2217.
PubMedArticle
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Research Letter
December 16, 2015

The Role of Bone Scintigraphy in the Diagnosis of Calciphylaxis

Author Affiliations
  • 1Medical student at Harvard Medical School, Boston, Massachusetts, at the time of the study
  • 2now with Department of Medicine and Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, Florida
  • 3Department of Radiology, Massachusetts General Hospital, Boston
  • 4Department of Dermatology, Massachusetts General Hospital, Boston
  • 5Department of Nephrology, Massachusetts General Hospital, Boston
JAMA Dermatol. Published online December 16, 2015. doi:10.1001/jamadermatol.2015.4591

Calciphylaxis is a rare, life-threatening small vessel vasculopathy,1 predominantly seen in patients with end-stage renal disease (ESRD). Most physicians rely on clinical findings and risk factors to diagnose calciphylaxis. However, mimickers exist,2 and tissue biopsy can be helpful to differentiate these diseases. Unfortunately, histopathological confirmation sometimes requires multiple biopsies, resulting in delayed treatment and possibly propagating new lesion formation.3 A noninvasive early testing modality would be preferred.

Using bone scintigraphy to diagnose calciphylaxis has been reported.46 In the study by Fine and Zacharias,6 bone scintigraphy was positive in 97% of cases, but only 4 of 36 patients with calciphylaxis had biopsy-confirmed disease, and the specificity of bone scintigraphy was not addressed. Herein, we performed a retrospective analysis of the use of bone scintigraphy to diagnose calciphylaxis.

Methods

The Massachusetts General Hospital Institutional Review Board approved this study. We performed a retrospective case-control study involving 49 patients, including 18 patients with clinically diagnosed calciphylaxis between May 13, 2005, and November 25, 2013, who underwent bone scintigraphy at diagnosis and 31 control patients with ESRD without calciphylaxis who underwent bone scintigraphy for other reasons during the course of their illness between September 22, 2005, and July 17, 2014. Among the latter, 10 of 31 control patients had undergone renal transplantation. Bone scintigraphy was performed using technetium Tc 99m disphosphonates with radiologist (C.A.R.) interpretation. The dates of our study analysis were May 5, 2014, to September 30, 2014.

Results

Findings among calciphylaxis cases are summarized in the Table. Bone scintigraphy was reported as positive for calciphylaxis based on increased heterogeneous radiotracer uptake within soft tissues throughout the body, with a predilection for areas corresponding to clinical findings (Figure, A). This result was found in 16 of 18 calciphylaxis cases and in 1 of 31 control patients, yielding a sensitivity of 89% (95% CI, 65%-98%) and a specificity of 97% (95% CI, 83%-99%). The positive likelihood ratio was 27.6 (95% CI, 3.9-190.8), and the negative likelihood ratio was 0.1 (95% CI, 0.0-0.4). There was more intense uptake in areas corresponding to plaques and nodules rather than ulcerations. In 2 patients with calciphylaxis, bone scintigraphy demonstrated an interval decrease in uptake following sodium thiosulfate therapy, corresponding to a clinical response to treatment (Figure, B and C).

Discussion

Our study confirms that bone scintigraphy is highly sensitive and specific for the diagnosis of calciphylaxis. Bone scintigraphy could also be used to monitor treatment response to sodium thiosulfate, noted as diffusely decreased skin uptake, which could indicate treatment completion. Moreover, our study findings suggest that bone scintigraphy is most useful for early diagnosis, before ulcer development. Radiotracer uptake intensity corresponds to the clinical spectrum of calciphylaxis, with some uptake occurring before skin lesion appearance, increasing with erythema, and peaking with indurated plaques and nodules. There was no radiotracer uptake at sites of ulceration in most patients, which could be explained by vascular thrombosis that is associated with calciphylaxis, resulting in both decreased blood flow and radiotracer delivery to the dead tissue found within sites of ulceration.

Another characteristic bone scintigraphy finding was the widespread radiotracer uptake that was noted throughout the body of patients with calciphylaxis, in addition to the clinically obvious areas of involvement. This result is consistent with the systemic nature of calciphylaxis and is also important in that it differentiates calciphylaxis from other inflammatory conditions, such as cellulitis, in which radiotracer uptake is localized to a discrete area.

There are several limitations to our study. This investigation was a retrospective study, with a limited number of patients. All control patients had ESRD but were not matched for duration of renal failure, dialysis use, sex, or other risk factors for calciphylaxis. In total, 10 of 31 control patients had undergone renal transplantation, making it is less likely that they had ESRD at the time of bone scintigraphy. Future studies are also needed to address whether bone scintigraphy can differentiate calciphylaxis-like skin lesions from calciphylaxis.

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Article Information

Accepted for Publication: September 29, 2015.

Corresponding Author: Daniela Kroshinsky, MD, MPH, Department of Dermatology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114-2696 (dkroshinsky@mgh.harvard.edu).

Published Online: December 16, 2015. doi:10.1001/jamadermatol.2015.4591.

Author Contributions: Dr Kroshinsky had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Paul, Rabito, Nigwekar, Kroshinsky.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Paul, Vedak, Nigwekar, Kroshinsky.

Administrative, technical, or material support: Paul, Rabito, Vedak.

Study supervision: Nigwekar, Kroshinsky.

Conflict of Interest Disclosures: Dr Nigwekar reported being supported by the National Kidney Foundation’s Young Investigator Award and by the Fund for Medical Discovery Award from the Massachusetts General Hospital’s Executive Committee on Research. No other disclosures were reported.

References
1.
Hayashi  M.  Calciphylaxis: diagnosis and clinical features. Clin Exp Nephrol. 2013;17(4):498-503.
PubMedArticle
2.
Wilmer  WA, Magro  CM.  Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15(3):172-186.
PubMedArticle
3.
Mochel  MC, Arakaki  RY, Wang  G, Kroshinsky  D, Hoang  MP.  Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol. 2013;35(5):582-586.
PubMedArticle
4.
Han  MM, Pang  J, Shinkai  K, Franc  B, Hawkins  R, Aparici  CM.  Calciphylaxis and bone scintigraphy: case report with histological confirmation and review of the literature. Ann Nucl Med. 2007;21(4):235-238.
PubMedArticle
5.
Norris  B, Vaysman  V, Line  BR.  Bone scintigraphy of calciphylaxis: a syndrome of vascular calcification and skin necrosis. Clin Nucl Med. 2005;30(11):725-727.
PubMedArticle
6.
Fine  A, Zacharias  J.  Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61(6):2210-2217.
PubMedArticle
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