Year : 2008 | Volume
: 19 | Issue : 5 | Page : 854--860
Calciphylaxis after Parathyroidectomy in Chronic Renal Failure
Muhammad A Wahab, Fahad Al Kanhal
Department of Nephrology, King Saud Medical Complex, Riyadh, Saudi Arabia
Muhammad A Wahab
Department of Nephrology, King Saud Medical Complex, Riyadh
A 33-year-old man, who was maintained on hemodialysis for more than 9 years, was diagnosed to have secondary hyperparathyroidism with a nodule in a parathyroid gland revealed with ultrasound and CT scan. He underwent parathyroidectomy and presented with bilateral lower limb painful ulcers two months later. Skin biopsy from these ulcers was consistent with calciphylaxis.
|How to cite this article:|
Wahab MA, Al Kanhal F. Calciphylaxis after Parathyroidectomy in Chronic Renal Failure.Saudi J Kidney Dis Transpl 2008;19:854-860
|How to cite this URL:|
Wahab MA, Al Kanhal F. Calciphylaxis after Parathyroidectomy in Chronic Renal Failure. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2021 Mar 4 ];19:854-860
Available from: https://www.sjkdt.org/text.asp?2008/19/5/854/42479
Calciphylaxis is a rare, but serious disorder characterized by systemic medial calcification of the arteries those results in ischemic necrosis of skin and soft tissues. The incidence of calciphylaxis among hemodialysis (HD) population is 1–4%,  but mortality is more than 60%.  In the past, parathyroidectomy was the only treatment option available for HD patients with secondary hyperparathyroidism, but currently there are several other treatment modalities available such as calcimimetics and sodium thiosulfate.
The occurrence of calciphylaxis is very rare after parathyroidectomy. We report a patient who developed calciphylaxis after parathyroidectomy and treated successfully with conservative management.
A 33–year-old man, who has been receiving chronic hemodialysis for more than 9 years, was diagnosed four years after starting dialysis to have secondary hyperparathyroidism, and his laboratory investigations revealed hemoglobin 9.5 gm/dL, white cell count 6500/mm 3 , blood urea nitrogen 33.2 mmol/L, creatinine 930 µmol/L, serum calcium 2.64 mmol/L, serum phosphorus 2.33 mmol/L, calcium phosphate product 6.15 mmol 2 /L 2 , alkaline phosphatase 750 U/L, and parathyroid hormone 370 pmol/ L. He was treated initially with non-calcium containing phosphate binders (sevelamer) 800 mg orally three times a day, as well as hemodialysis with low calcium containing dialysate. His dialysis frequency was also increased to 4 times a week. Despite all these measures, the patient's hyperparathyroidism was not controlled, and he underwent parathyroidectomy on 11/02/2006. Three and a half of his parathyroid glands were removed, and the remainning half was implanted in the left sternocledomastoid muscle.
Seven weeks after surgery the patient presented with bilateral below knee leg ulcers. Local examination revealed extensive skin necrosis including multiple circumferential dry and dark ulcers with necrotic base [Figure 1]. Laboratory investigations revealed absent antinuclear antibodies, anti-neutrophilic cytoplasmic antibodies, rheumatoid factor, and cryoglobulins, besides within normal limits C3 and C4. Serum calcium level was 1.8 mmol/L, serum phosphorus 0.98 mmol/L, and parathyroid hormone levels 5.05 pmol/L. Skin biopsy obtained from necrotic ulcers demonstrated the presence of focal calcification and narrowing of the vessel wall with focal panniculitis [Figure 2] and [Figure 3].
The patient was managed with daily dressing of the ulcers along with appropriate antibiotics. Once these ulcers were free of infection, successful skin grafting was performed [Figure 4].
Calciphylaxis may occur in patients with endstage renal disease (ESRD), whether they received dialysis or recent renal transplant. On rare occasions, it has also been observed in patients with chronic kidney disease (CKD) prior to the initiation of renal replacement therapy. Rarely, calciphylaxis has been reported in patients with breast carcinoma, alcoholic liver cirrhosis, cholangiocarcinoma,  crohn's disease,  rheumatoid arthritis,  and systemic lupus erythmatosis  with or without CKD.
The term "calciphylaxis" itself is a misnomer, since it implicates an immune type of reaction. A more accurate name is calcific uremic arteriolopathy. The pathogenesis remains obscure, and it is probably the result of a multiplicity of comorbid factors. Disorders implicated in the pathogenesis of calciphylaxis include hypercalcemia, hyperphosphatemia, an elevated calcium phosphate product, and secondary hyperparathyroidism. Although these abnormalities are extremely common in patients with ESRD, calciphylaxis is relatively uncommon in early stages of CKD.
Clinical improvement of calciphylaxis following parathyroidectomy suggests the role of parathyroid hormone in the pathogenesis of calciphylaxis. However, most patients with severe hyperparathyroidism do not have lesions of calciphylaxis and few patients of calciphylaxis do not have hyperparathyroidism, indicating the role of additional factors in pathogenesis of calciphylaxis. Administration of high dose vitamin D analogues in ESRD patients is also suspected as a contributing factor to calciphylaxis. Other described risk factors include white race, female sex, morbid obesity, type 1 diabetes mellitus, recent severe weight loss, low serum albumin, and impaired activity of protein C and S.
Low levels of inhibitors of vascular calcification such as fetuin A and matrix glycoprotein A maybe involved in the pathogenesis of calciphylaxis in ESRD patients. Fetuin-A is a serum glycol-protein that binds calcium and phosphorus in the circulation and forms "calciprotein parti-cles" in order to clear the circulation of excess calcium and phosphorus,  and matrix glycoprotein A, synthesized by vascular smooth muscle and chondrocytes, has been character-rized in an animal model to actively inhibit calcification of arteries and cartilage.  Fetuin A and matrix glycoprotein A levels are low in HD patients, and result in impaired capacity to inhibit calcium and phosphorus precipitation.
Pathological lesions reveal calcium deposits in the walls of the medium and small blood vessels along with necrosis of subcutaneous fat without evidence of vasculitis. The most prominent pathological lesion in calciphylaxis is acute and chronic calcifying septal panniculitis. Sludging of red blood cells and thrombosis in capillaries are also observed.
Patients usually present with painful violacious skin ulcers with indurated base. Calciphylaxis can be classified as proximal and distal types. Distal calciphylaxis occurs on lower extremities in patients on long-term HD with markedly elevated parathyroid hormone levels; such patients frequently respond to parathyroidectomy. Our patient presented with features of distal calciphylaxis. In contrast, proximal calciphylaxis presents with painful lesions over thigh, abdomen, and buttocks; such patients are either not yet on HD or on dialysis for a short duration. Serum parathyroid hormone levels are frequently normal in these patients. White race, female gender, recent loss of weight, severe obesity and poor nutrition are more frequently observed in proximal calciphylaxis.
Lesions of calciphylaxis should be differentiated from warfarin induced skin necrosis, sclerosing pannicullitis, vasculitis, pheripheral ischemia and gadolinium induced nehrogenic fibrosing dermopathy.
Diagnosis of calciphylaxis should be considered in patients with ESRD, whenever they present with painful subcutaneous nodules or non healing painful skin ulcerations. Diagnosis should be confirmed with skin biopsy, since there are other conditions that may mimic calciphylaxis. Though histology is of great help in confirming the diagnosis, the specificity and sensitivity of skin biopsy in the diagnosis of calciphylaxis have not been determined, and definitive criteria for diagnosis have been established. A skin biopsy should be avoided in cases when patients have active infection since it may exacerbate the skin lesion. Additional possible risks with the procedure include ulceration in the region of the incision and poor healing. Bone scan can be advantageous, since a positive three phase technetium 99m methylene diphosphate bone scintigraphy may reveal calcifications in subcutaneous nodules or non-ulcerating lesions in viable tissue. Fine and Zacharias reported positive bone scan in 32 out of 36 patients.  Furthermore, radioimaging using mammography technique may also be used to confirm the diagnosis of calciphylaxis. It was found superior to CT scan in revealing diffuse arteriolar calcification in a meshlike pattern of an involved calciphylaxis lesion.  In patients with inconclusive radioimaging and histology diagnosis, a provisional clinical diagnosis of calciphylaxis can be entertained and treated accordingly.
Incidence of calciphylaxis is very rare after parathyroidectomy. Interestingly, our patient developed lesions of calciphylaxis about two month after parathyroidectomy. Similarly, Matsuoka et al  from Japan reported six patients who developed calciphylaxis after parathyroidectomy in a series of 1499 patients, who underwent parathyroidectomy from 1972 to 2003. In five of these six patients, calciphylaxis was classified as distal type. Our patient also had features of distal type of calciphylaxis.
Disorders of bone and mineral metabolism associated with secondary hyperparathyroidism in patients with ESRD usually improve after renal transplantation. Rarely features of secondary hyperparathyroidism might persist or may progress after successful renal transplantation. Occasionally, calciphylaxis was reported in kidney transplant patient. Hilde  reported a unique patient with normal transplant function who developed fatal calciphylaxis more than 20 years after kidney transplant.
Treatment of calciphylaxis is always challenging. Medical care of ulcerative calciphylactic lesions is mainly supportive. Serum calcium and phosphorus concentrations must be controlled to low-normal levels as quickly as possible. This can be achieved with dietary alteration, use of non-calcium, non-aluminum phosphate binders and low-calcium dialysis bath. Some benefit may be achieved with increasing the frequency or duration of dialysis sessions.
If conservative management fails, parathyroidectomy should be performed, however, only in case hyperparathyroidism was present. The role of urgent parathyroidectomy is uncertain even in calciphylaxis associated with frank hyperparathyroidism. Total or subtotal parathyroidectomy with auto transplantation has been shown to be of therapeutic benefit to many, but not all patients. Only a few studies have been able to demonstrate a decrease in the mortality rate in patients of calciphylaxis who undergo parathyroidectomy. 
In addition to conservative measures and parathyroidectomy mentioned above, there have been recently new treatment options available in the form of drugs such as calcimimetics and sodium thiosulfate.
The calcium-sensing receptor regulates the secretion of parathyroid hormone. Calcimimetic agents increase the sensitivity of the calciumsensing receptors to extra cellular calcium. These agents inhibit the release of parathyroid hormone, and lower plasma parathyroid hormone levels within a few hours after administration. This mechanism of action differs fundamentally from that of vitamin D sterols, which diminish the transcription of the parathyroid hormone gene and hormone synthesis over a period of several days. Results of previous small clinical trials indicate that the calcimimetic agent, cinacalcet hydrochloride, not only reduces parathyroid hormone levels, but also lowers serum calcium and phosphorus levels in patients with secondary hyperparathyroidism. Robinson et al  reported a case of calciphylaxis with secondary hyperparathyroidism treated successfully with cinacalcet. A similar case report by Velasco et al  demonstrated a significant improvement with cinacalcet in an ESRD patient who presented with calciphylaxis and secondary hyperparathyroidism.
Calcimimetics not only control serum calcium, phosphorus and parathyroid hormone in patients with calciphylaxis secondary to hyperparathyroidism, but also help in regression of soft tissue calcification. Ismail et al  reported an obese old woman, who had ESRD and multiple painful lumps with ulceration over her lower abdomen and thigh, was diagnosed to have calciphylaxis managed successfully with cinacalcet administered for 4 months, and achieved complete healing of her ulcers.
Sodium thiosulfate is an antioxidant agent and a calcium ion chelator that is used as an antidote in cyanide and cisplatin toxicity. The antioxidant properties may help restore endothelial cell function and promote vasodilation. Enhanced aqueous solubility of calcium thiosulfate allows for successful mobilization and clearance of the vascular and soft tissue calcium deposits. There has been growing interest in the use of intravenous sodium thiosulfate as an adjunctive treatment in patients with calciphylaxis skin lesions. Meissner et al  reported a case of calciphylaxis treated with intravenous sodium thiosulphate. Two weeks after treatment, no new lesions were detectable and there was a dramatic pain relief. In the following 4 weeks, a successive decline of the ulcers and the healing of individual tissue defects were observed. A similar case of calciphylaxis was also described by Subramanaim et al  which failed to respond to conventional treatment, and the patient was initiated on IV infusion of 25 g of sodium thiosulphate three times per week. Two weeks later, his pain resolved completely. By 12 weeks, the lesions healed completely and the infusions were discontinued. Two months later, lesions of calciphylaxis recurred, however, they resolved again within 3 months of retreatment with sodium thiosulfate, which was continued for 8 more months. The treatment was well tolerated, and there was no recurrence of the lesions during 18 months of follow-up.
Similarly, Carlos E Araya et al  reported a case study of 3 patients with calciphylaxis treated intravenously with sodium thiosulfate 25 gm/1.73 m 2 body surface area per dose. For optimization of removal of calcium deposits, all the patients received a combination of sodium thiosulfate and continuous venovenous hemofiltration for the first 10 days, demonstrated rapid pain relief, and skin indurations and joint mobility of the extremities improved within weeks. Radiographic evidence of reduction in the calcium deposits manifested within 3 months of initiation of sodium thiosulfate. The only complication observed was prolonged QT interval in one patient as a result of hypocalcemia, which resolved by use of a higher dialysate calcium concentration.
Although there was variability in dosages and duration of sodium thiosulfate treatment, all reported patients have so far tolerated the therapy well. Increased anion gap metabolic acidosis, due to sulfate retention has been reported in few patients treated with sodium thiosulfate. Although sodium thiosulfate is being increasingly used, prospective studies are required to assess its safety and efficacy in large numbers of patients before this treatment can be used as a standard care in calciphylaxis.
Dr. Akram Askar (Chairman of RNTC): Now we open the floor for questions and comments.
Audience: Skin biopsy is an essential tool for diagnosis of calciphylaxis, however, I find unclear role for the bone scan. Would you elaborate on that?
Dr. Abdul Wahab: We do not have a gold standard tool for diagnosis of calciphylaxis. However, we attempt to collect evidence from the available tools. Skin biopsy and bone scan can be looked at as complementary investigations, and in our hospital we do not perform bone scans routinely for evaluation of CKD patients with vascular calcifications.
Dr. Souqiyyeh (SCOT): It seems that we do not know the exact pathogenesis of calciphylaxis whether it happens before or after parathyroidectomy. Did anybody work this out?
Dr. Abdul Wahab: This is the main problem with this condition that we do not know its pathogenesis mostly, I believe, because its rarity. Unless we have an animal model or large studies, the issue will remain a matter of speculation.
Prof. Jamal Al-Wakeel (King Khaled University Hospital): Is there any role for plain MRI in diagnosing the calciphylaxis.
Dr. Abdul Wahab: I have not come across any data concerning the role of MRI.
Audience: Is there any role for sodium thiosulfate in decreasing the calcifications in the patients with malignancy?
Dr. Abdul Wahab: Though the effect of this drug on calcifications is promising, but its effect on patients with malignancy is not known.
Audience: Do you know any effect of thiosulfate on the incidence of vascular calcifications in CKD patients.
Dr. Abdul Wahab: there are no available studies as far as I know that address this issue.
Audience: I have a comment. I have observed some cases of calciphylaxis, which were challenging in terms of diagnosis and management. It is usually a painful condition to both the physician and the patient.
Dr. Kumar (Riyadh Medical Complex): (commenting): I concur that calcimimetics have improved the armamentarium for the treatment of the CKD related bone disease and mineral metabolism disturbances, and there is even a trend for its use in the primary hyperparathyroidism.
Dr. Askar: Thank you everybody for your attendance.
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