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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2019  |  Volume : 30  |  Issue : 1  |  Page : 215-220
Calciphylaxis in a renal transplant recipient with normal graft function: A case report and review of literature

1 Department of Nephrology, Aditya Birla Memorial Hospital, Pune, Maharashtra, India
2 Department of Pathology, Aditya Birla Memorial Hospital, Pune, Maharashtra, India
3 Department of Nephrology, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
4 Department of Medicine, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
5 Department of Nephrology, Apollo Hospitals, Hyderabad, Telangana, India
6 Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, USA

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Date of Submission14-Jan-2018
Date of Decision02-Mar-2018
Date of Acceptance05-Mar-2018
Date of Web Publication26-Feb-2019


Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare, life-threatening complication of end-stage renal disease. However, it may also occur in patients without renal failure, the nonuremic calciphylaxis. Most patients present with painful skin ulcers. Delayed diagnosis can lead to sepsis-related morbidity and mortality. Aberrations in calcium, phosphate, and parathyroid hormone physiology are common and biopsy is diagnostic. Early diagnosis and correction of vascular and metabolic aberrations may assist in healing as may the use of sodium thiosulfate and hyperbaric oxygen therapy. We report on successful treatment of a case of calciphylaxis in a renal transplant recipient with normal allograft function.

How to cite this article:
Kale G, Jeloka T, Shrividya S, Mulay A, Deshmukh M, Krishnan S, Nigwekar S. Calciphylaxis in a renal transplant recipient with normal graft function: A case report and review of literature. Saudi J Kidney Dis Transpl 2019;30:215-20

How to cite this URL:
Kale G, Jeloka T, Shrividya S, Mulay A, Deshmukh M, Krishnan S, Nigwekar S. Calciphylaxis in a renal transplant recipient with normal graft function: A case report and review of literature. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2021 Oct 18];30:215-20. Available from: https://www.sjkdt.org/text.asp?2019/30/1/215/252913

   Introduction Top

Calciphylaxis, also known as calcific uremic arteriolopathy, is characterized by thrombosis of calcified small- and medium-sized arteries and arterioles, along with fibrosis of the dermis and subcutaneous fat. It is a rare but potentially life-threatening complication of end-stage renal disease (ESRD). However, calciphylaxis can also occur in patients without ESRD and in renal transplant recipients, so-called nonuremic calciphylaxis.[1]

There are only a few reported cases of calciphylaxis occurring in patients after kidney transplantation.[2],[3],[4],[5],[6] Most of these reported cases have a history of abnormal calcium, phosphorus, or parathyroid hormone levels. We hereby describe an unusual case of calciphylaxis occurring 18 years after kidney transplantation with normal graft function and calcium-parathyroid physiology.

   Case Report Top

A 59-year-old male patient presented with painful ulcer over the right shin. The ulcer was progressive, painful and nonhealing for the past two months. He was managed by local physician with topical ointments and oral analgesics and antibiotics with no improvement. There were no systemic symptoms including fever. The ulcer had increased in size with a necrotic base, when he reported to us. His important past medical history included renal transplant in 1998 for the end-stage renal failure of unknown cause, from an unrelated donor. He had no complications related to the allograft with a stable baseline serum creatinine of 1 mg/dL [estimated glomerular filtration rate (eGFR) 77.7 mL/min]. He was well for 16 years, when he was diagnosed to have alcohol-related chronic liver disease and later during the same year, was diagnosed with mesenteric ischemia secondary to the venous occlusion that was treated with oral warfarin for three months. His medications included prednisolone (7.5 mg once daily), mycophenolate (500 mg thrice daily), and multivitamin supplements.

General physical examination was normal. There was no edema or lymphadenopathy and all peripheral pulses were present. His systemic examination was unremarkable except for free fluid in the abdomen. Local examination revealed a tender ulcer measuring 13 cm × 7 cm over his right shin, which had necrotic base [Figure 1].
Figure 1: Top panel shows the progression of the lesion and healed lesion; the bottom panel is histopathological examination showing calcification of the small and medium-sized arteries.

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The relevant laboratory investigations revealed hemoglobin – 8.6 g/dL; leukocyte count – 3600/mm3; platelet count – 59,000/mm3; blood urea nitrogen – 14.9 mg/dL; serum creatinine – 1.4 mg/dL (eGFR 55.5 mL/min); serum sodium – 121 mEq/L; serum potassium – 4.1 mEq/L; random blood sugar level – 129 mg/dL; serum calcium – 8.1 mg/dL; serum phosphorous – 3.6 mg/dL; serum uric acid – 5.9 mg/dL; serum albumin 2.7 gm/dL; serum intact parathyroid hormone – 41.2 ng/mL; and INR – 1.3. Autoimmune and prothrombotic work-up was not done. A swab from the ulcer grew Pseudomonas aeruginosa sensitive to ciprofloxacin. Patient received oral ciprofloxacin. Mycophenolate mofetil was reduced to 500 mg twice daily and oral prednisolone increased to 10 mg once daily.

A wedge biopsy from the ulcer margin showed medial calcification and myointimal hyperplasia of arteries along with acute inflammation, confirming the diagnosis of calciphylaxis [Figure 1]. The ulcer was surgically debrided and oral ciprofloxacin continued.

Oral Vitamin K supplements were also given. Soon, a similar small painful lesion appeared on the left shin. The initial ulcer worsened with increasing size and excruciating pain. As there was no improvement despite surgical debridement, sodium thiosulfate (STS) was started as slow infusions. A total dose of 275 g STS was administered over seven infusions. Concurrently, he was also taken for hyperbaric oxygen therapy (HBOT). A total of 26 daily sessions, each lasting for 90 min, and at a chamber pressure of 1.5 atmospheric pressure, were given.

The left leg lesion healed within two weeks of the start of STS and HBOT and the other larger ulcer also started healing in the next two weeks. His pain subsided and complete healing occurred in two months. He is doing well with no lesions at six months of follow-up.

   Discussion Top

In patients with ESRD, calciphylaxis has an incidence of 1% and prevalence of 1%–4%.[1] Patients generally present in their 50s with female predominance (M:F – 1:2). It has a high-mortality rate of 60%–80%. Death usually occurs secondary to sepsis and organ failure.[7]

Calciphylaxis usually presents with severe painful skin lesions (livedo reticularis, reticulate purpura, violaceous plaques, or indurated nodules) most often occurring in lower extremities, abdomen, and buttocks, which demonstrate poor healing and are frequently complicated by blistering and ulcerations with superimposed infections. Although skin manifestations dominate the clinical presentation, patients have been reported to have vascular calcifications in skeletal muscle, brain, lungs, kidneys, intestines, eyes, and mesentery.[8]

Histologically, calciphylaxis is characterized by medial calcification, microthrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.[8] Some of these histological findings are non specific and often seen in patients with renal failure, but a characteristic painful lesion with the above-mentioned pathology clinches the diagnosis while soft tissue radiography with small vessel calcification may be supportive.[1] Although lesional biopsy with dermatopathological examination remains the diagnostic gold standard, biopsy of lesions with overlying intact skin may run the risk of a nonhealing ulcer.

We describe a case of calciphylaxis occurring 18 years after kidney transplantation with normal allograft function. There are only few reported cases of calciphylaxis after kidney transplantation [Table 1]. These case reports show heterogeneity in the presentation. Calciphylaxis may present very early posttrans-plant[3],[5] or after few decades.[4] The case reported by Vanbelleghem et al was 20 years post transplant with functioning graft and history of parathyroidectomy three months posttransplant.[4] The initial lesion reported in his case was like that of infected hematoma, which later resulted in bilateral extensive ulcer on both lower extremities. Despite local care and intravenous antibiotics, he developed multi-organ failure and died in three weeks. Hanvesakul et al reported a case of calciphylaxis early posttransplant.[3] His case also had history of parathyroidectomy and was on calcium and alfacalcidiol supplements and developed calciphylactic lesions four months posttransplant on both the thighs. The lesions were infected with Pseudomonas and was managed with intravenous antibiotics and stopping of calcium supplements. He reported complete recovery with this conservative treatment. Fox et al also reported complete recovery in a case of calciphylaxis five months posttransplant after parathyroidectomy.[5]
Table 1: Summary and comparison of case reports available in literature.

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Posttransplant calciphylaxis has been noted with normal graft function[4],[5] as well as with graft dysfunction.[2] Brewster and Perazella reported an unusual case of calciphylaxis in the grafted kidney itself.[2] His patient had failed graft and was dialysis dependent. Most reported cases are in males as compared to female predominance in nontransplant population. The calciphylaxis lesions described in transplant patients are also painful but are reported in lower limbs only. These lesions may also get infected[3],[4],[6] and may lead to multi-organ failure and death.[4] Welte et al described a case of calicphylaxis 14 months posttransplant with history of secondary hyperparathyroidism, use of Vitamin K antagonist and mTOR inhibitor everolimus.[6] His case also was infected and was managed with multimodal therapy including antibiotics and STS with complete recovery.

There are several risk factors and trigger factors identified which precipitate calciphylaxis [Table 2]. Metabolic factors, systemic inflammation, oxidative stress, endothelial injury, along with certain triggers have all been implicated.[1] Risk factors identified in transplant cases include immunosuppressive drugs such as steroid, abnormal calcium, phosphorus, and parathyroid levels[2],[5],[6] and history of parathyroidectomy.[3],[4] In our patient, there were several risk factors, including a long history of steroid ingestion, history of warfarin therapy, hypoalbuminemia, and liver disease. Hepatopathy and chronic alcohol consumption predispose to low Vitamin K levels which also predispose to calciphylaxis. However, serum calcium, phosphorus, and parathyroid levels were normal.
Table 2: Risk factors and triggering factors in calcific uremic arteriolopathy.

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Recovery of calicphylactic lesions have been reported with conservative treatment like withdrawal of calcium supplements,[3] with parathyroidectomy,[5] and with the use of STS.[6] However, the appearance of calciphylaxis has also been reported in patients with a history of parathyroidectomy.[3],[4] There are no specific guidelines for the management of calciphylaxis and hence should be individualized. Overall, the management of calciphylaxis is suggested to be multimodal [Table 3]. It mainly focuses on wound and pain management, including the management of peripheral artery occlusive disease if present, analgesia, correction of metabolic abnormalities of calcium, phosphorus and parathyroid hormone, wound debridement, and treatment of infection. Early lesions may heal with this conservative treatment.[3] Off-label use of STS has been shown to improve the outcome in calciphylaxis.[6]
Table 3: Therapeutic modalities for calcific uremic arteriolopathy.

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In patients with failure of multimodal therapy, HBOT could be a secondary therapy with only rare serious side effects.[9] Hyperbaric oxygen is delivered in chambers which can be monoplace (for single person) or multiplace, pressurized with 100% oxygen. This delivers increased oxygenation to the affected tissue and improves healing. Generally, patients are recommended 40 to 60 treatments of 90 min each, under 2 to 2.5 atmospheres. However, HBOT has limited availability and has high cost.[9] Our case did not improve with initial conservative treatment and required STS and HBOT. Similar success was seen in patient who developed severe calciphylaxis 14 months after transplant.[6]

Calciphylaxis has poor prognosis. The average life expectancy of patients with calciphylaxis is 2.6–10.8 months after initial diagnosis[10] and better survival of 61.1% is reported in those who underwent wound debridement as compared to 27.4% in those who did not, at the end of one year.[8]

   Conclusion Top

Our case highlights the need for awareness of “nonuremic calciphylaxis” in transplant patients, the importance of both early diagnoses with leisonal biopsy and aggressive management using multimodal therapy. Should there be no response to conservative multimodal measures, a combination of sodium thiosulfate and HBOT may help in healing.

Conflict of interest:

None declared.

   References Top

Galperin TA, Cronin AJ, Leslie KS. Cutaneous manifestations of end stage renal disease. Clin J Am Soc Nephrol 2014; 9 (1): 201-18.  Back to cited text no. 1
Brewster UC, Perazella MA. Calcific uremic arteriolopathy in a transplanted kidney. Am J Med Sci 2005;329:102-3.  Back to cited text no. 2
Hanvesakul R, Silva MA, Hejmadi R, et al. Calciphylaxis following kidney transplantation: A case report. J Med Case Rep 2009; 3:9297.  Back to cited text no. 3
Vanbelleghem H, Terryn W, Van Leuven L, Van Caesbroeck D, Demetter P, Lameire N. A dramatic case of calciphylaxis 20 years after kidney transplantation. Nephrol Dial Transplant 2004;19:3183-5.  Back to cited text no. 4
Fox R, Banowsky LH, Cruz AB Jr. Post-renal transplant calciphylaxis: Successful treatment with parathyroidectomy. J Urol 1983;129:362-3.  Back to cited text no. 5
Welte T, Arnold F, Technau-Hafsi K. Successful management of calciphylaxis in a kidney transplant patient: Case report. Transplant Direct 2016;2:70.  Back to cited text no. 6
Reiter N, El-Shabrawi L, Leinweber B. Calcinosis cutis: Part I. Diagnostic pathway. J Am Acad Dermatol 2011;65:1-12.  Back to cited text no. 7
Nigwekar SU, Kroshinsky D, Nazarian RM, et al. Calciphylaxis: Risk factors, diagnosis, and treatment. Am J Kidney Dis 2015;66:133-46.  Back to cited text no. 8
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; 20:444-50.  Back to cited text no. 9
Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: Natural history, risk factor analysis, and outcome. J Am Acad Dermatol 2007;56:569-79.  Back to cited text no. 10

Correspondence Address:
Tarun Jeloka
Department of Nephrology, Aditya Birla Memorial Hospital, Pune - 411 033, Maharashtra
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DOI: 10.4103/1319-2442.252913

PMID: 30804284

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  [Table 1], [Table 2], [Table 3]


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