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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2016  |  Volume : 27  |  Issue : 6  |  Page : 1265-1269
Penile calcific uremic arteriolopathy occurring postparathyroidectomy in a hemodialysis patient


1 Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
2 Department of Nephrology, Aseer Central Hospital, Ministry of Health, Abha, Saudi Arabia
3 Department of Nephrology Department, College of Medicine, King Khalid University, Abha, Saudi Arabia

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Date of Web Publication28-Nov-2016
 

   Abstract 

Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare condition most frequently seen in patients with advanced chronic kidney disease. The clinical picture is characterized by painful skin lesions and ulcerations. The underlying pathology is medial calcification and intimal proliferation with microthrombi of small arteries. CUA is commonly associated with secondary hyperparathyroidism and high serum calcium and phosphate products. This article reports an atypical case where CUA developed after parathyroidectomy and in the course of treatment of hungry bone syndrome. The patient was on hemodialysis for 14 years. He had developed secondary hyperparathyroidism and severe osteodystrophy. Calcium, Vitamin-D supplements, and calcimimetics failed to control his condition. He underwent parathyroidectomy but developed hungry bone syndrome postoperatively. He was managed with large doses of calcium and active Vitamin-D analogs to maintain his serum calcium. Two weeks later, he developed a painful single lesion on the tip of the penis which was diagnosed as CUA on clinical and radiographic evidence. The patient refused surgical intervention and opted for traditional treatment with honey and herbs with an excellent outcome. The case highlights the risk of CUA complicating the aggressive management of post-parathyroidectomy hungry bone syndrome.

How to cite this article:
Bashir SO, Aamer MA, Omer HA, Morsy MD. Penile calcific uremic arteriolopathy occurring postparathyroidectomy in a hemodialysis patient. Saudi J Kidney Dis Transpl 2016;27:1265-9

How to cite this URL:
Bashir SO, Aamer MA, Omer HA, Morsy MD. Penile calcific uremic arteriolopathy occurring postparathyroidectomy in a hemodialysis patient. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Jan 22];27:1265-9. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1265/194685

   Introduction Top


Calcific uremic arteriolopathy (CUA), or calciphylaxis, is a potentially life-threatening vasculopathy involving the skin and subcutaneous tissues that is usually associated with chronic kidney disease (CKD). [1] The incidence of CUA is estimated to be approximately 1% in patients with CKD and 4% in patients on dialysis, [2] although recent reports suggest that it might be much less than that. [3] The uremic milieu of secondary hyperparathyroidism, high phosphorus and calcium are believed to be involved in the development of CUA. [4] Various reports have shown that CKD patients with sustained serum phosphorus concentrations >6.5 mg/dL and a calcium-phosphorus (Ca × P) product >55 mg 2 /dL 2 are at a high risk for developing CUA. [4],[5],[6] However, since the condition occurs in only small fraction of patients on dialysis with hyperparathyroidism, there is still uncertainty about the direct trigger factor or factors. Most victims are females, suggesting hormonal influences. Other risk factors/associated factors include diabetes, obesity, liver disease, calcium supplementation, Vitamin D treatment, use of corticosteroids, iron dextran, blood transfusions, warfarin, low-albumin serum levels, elevated alkaline phosphatase levels, and trauma. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10] As to which of the above factors are causative and which are just associated factors is yet to be established.

An alternative theory is that CUA is an active process mediated by vascular smooth muscle cells that develop a bone-forming phenotype from the uremic milieu. Electron microscopy and immune-staining have shown bone matrix vesicles and bone matrix protein expression in vascular specimens from patients with CUA. [7],[8] Due to vascular injury in association with a hypercoagulable state, a possible role of protein C and protein S deficiency has also been suggested. [5] CUA could also result from deficiency of inhibitors of calcification such as 2-Heremans-Schmid glycoprotein/fetuin A, osteopontin, and matrix Gla protein. [8],[9]

CUA usually involves areas of lower extremities with abundance of adipose tissue such as thighs and buttocks. [3] Less commonly, distal extremities such as the hands or lower legs are affected. Systemic involvement with ischemic infarction of the bowel, myocardium, brain, optic nerve, or muscles is rare. [3]

Diagnosis is based on clinical signs and symptoms and biopsy of the lesion, which shows calcification in the vascular media, intimal hyperplasia, inflammation, obliterative endovascular fibrosis and micro-thrombi in smalland medium-sized vessels of the skin, and subcutaneous tissue leading to necrosis of dermal, subdermal, and adipose tissues. [3] However, biopsies may cause problems because of poor healing and are therefore not considered essential for diagnosis. [6] The occurrence of calcification in the human penis is relatively rare. In the majority of cases, it is the result of local trauma or plastic indurations of the penis (Peyronie's disease). [11] In lieu of this, the current case may be worth of record.

Treatment of CUA includes correction of risk factors and surgical debridement. [1],[7] Some studies suggest that parathyroidectomy is helpful. Sodium thiosulfate, a potent antioxidant that also increases the solubility of calcium deposits, has been reported to lead to marked improvement of CUA. [12] The overall mortality associated with this disease was 64% with a mean time to death of 2.5 months. [7],[13],[14]


   Case Report Top


The patient in this case is a 46-year-old Saudi male with CKD on hemodialysis (HD). His original pathology was hypertensive nephrosclerosis. The patient had been on dialysis since 1998. A year after starting dialysis, he developed severe hyperparathyroidism with immuno parathormone (iPTH) levels of 2000 pg/mL. He was put on calcium carbonate, calcitriol, and non-calcium-containing phosphate binders (sevelamer hydrochloride 800 mg 2 × 3). His high iPTH levels persisted, and in 2006, cinacalcet (30 mg OD) was added to his therapy. However, his problem persisted and he developed pathological fractures of both femurs. The patient sought treatment in a private hospital where partial parathyroidectomy was performed in 2012. Three days after the operation, the patient presented to our center with severe hypocalcemia and hypophosphatemia (serum calcium: 4.5 mg% and phosphate: 3.7 mg%) and was diagnosed to have hungry bone syndrome. He was put on calcium infusion; 70 mg elemental calcium/hour, adjusted to maintain ionized calcium in the normal range. In addition, he received intravenous calcitriol 2 μg/day. He was also started on oral calcium carbonate (2 mg × 3 mg × 600 mg) and alfacalcidol 2 mg/day. The calcium infusion was gradually reduced when the level of ionized calcium attained the normal range. The patient became stable, and on discharge, his serum calcium was 7.2 mg%, phosphorus was 5.2 mg%, and iPTH was 891 pg/mL.

Two weeks after discharge, the patient presented with bluish discoloration of the tip of the penis associated with severe pain. The lesion measured 2 cm × 2.5 cm [Figure 1]. There were no other skin lesions. His serum calcium was 9.5 mg%, phosphorus was 7.4 mg%, calcium phosphate product was 70.3, and iPTH was 600 pg/mL.
Figure 1: Presenting lesion at the tip of the penis

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The presence of CUA was suspected. Biopsy was not considered because of fear of poor healing. Pelvic computerized tomogram (CT) was performed and extensive calcification of the pelvic vessels was seen, confirming the diagnosis [Figure 2]. The patient was dialyzed against low calcium dialysate and was put on a higher dose of sevelamer to control his serum calcium and phosphate levels. He was prescribed a local antibiotic (fucidin) to control secondary infection. The patient was investigated by an urologist who suggested partial amputation, but the patient declined. He sought traditional treatment in the form of honey and local herbs. He was reviewed regularly, and the lesion showed a good progress and after two months, there was a complete healing [Figure 3].
Figure 2: Computerized tomography scan of the pelvic vessels showing widespread calciphylaxis involving the penile vessels.

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Figure 3: The site of the lesion 3 months later showing complete healing.

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   Discussion Top


Our patient did not have the common features associated with CUA in HD patients. The patient was a male, non-diabetic, and not morbidly obese. He was not on corticosteroids or warfarin; there was no recent history of blood transfusion or iron dextran therapy or trauma. The most notable feature of this case is that the penile complication of CUA occurred almost immediately after parathyroidectomy for CUA. [4] Development of CUA after parathyroidectomy is relatively rare. However, a few studies have reported the occurrence of CUA in patients who underwent total or subtotal parathyroidectomy. Matsuoka et al reported six patients who developed CUA out of 1499 patients, who underwent parathyroidectomy; three had signs of CUA at the time of the surgery. [14] Wahab et al reported a case in a Saudi patient in 2008. [15] In one case, penile calcification occurred two years after parathyroidectomy associated with flare of psoriasis. [16],[17] In most of the other cases, no specific trigger was identified. It has been suggested that patients with low bone turnover associated with low PTH may be at a higher risk of soft tissue calcification, including CUA. [12],[13] The period between the surgery and development of CUA in previously reported cases ranged from 2-48 months. In our case, CUA developed within only two weeks of the surgery, which indicates an acute trigger mechanism.

The most likely triggering factor in our patient appears to be the large supplements of Vitamin-D and calcium he received to manage the hungry bone syndrome. Hungry bone syndrome is the most common complication of parathyroidectomy in renal patients with secondary hyperparathyroidism. [18],[19] The severe hypocalcemia seen in this condition is believed to be due to increased influx of calcium into bone and treatment is aimed at replenishing the severe calcium deficiency by using high doses of calcium, supplemented by high doses of active metabolites of Vitamin D. Initially, calcium is supplemented intravenously, with concomitant use of active metabolites of Vitamin D (calcitriol) or alfacalcidol (2-4 mg/day) orally. [20],[21] The large dose of calcium administered along with active Vitamin-D, over a short period, may have triggered the development of CUA in this patient. We are unaware of any similar case where CUA complicated the management of hungry bone syndrome. Gonzalez-Parra reported a case of CUA developing in a HD patient maintained on cinacalcet despite controlled levels of PTH and calcium × phosphate products. In their case, they suggested that high dialysate calcium and calcium-containing phosphate binders used to combat the cinacalcet induced hypocalcemia, which may have contributed to the development of CUA. [22]

The penis is a relatively rare site for CUA because of its rich blood supply from its dorsal and deep arteries and also from the urethral artery. The first literature review of cases of CUA involving the penis was performed in 1997 and involved ten cases. [23] A total of 38 cases were reported till 2007. [24] Only three cases have been reported in Saudi patients with ESRD. [25],[26],[27] A unique feature of our case is that the penile lesion healed completely without surgical intervention. The fact that it was a single lesion with no ulceration may have favored the healing process. We cannot ascertain the depth of the lesion since no biopsy was done. The degree of cutaneous and subcutaneous tissue involvement in CUA is said to be highly variable and may be limited to livedo reticularis or to single indurated plaque formation. [28],[29]

In conclusion, this report presents an unusual case of CUA occurring soon after parathyroidectomy in a non-diabetic patient presenting as a single penile lesion that healed with minimal intervention. An important cautionary note raised by this case concerns the management of post-parathyroidectomy hungry bone syndrome. Although it is essential to vigorously manage the hypocalcemia, the risk of CUA has to be considered during follow-up.

Conflict of interest: None declared.


   Acknowledgment Top


The authors sincerely acknowledge the cooperation of the patient, and the contribution of the urologist, dermatologist, and radiologist in the diagnosis and management of the case.

 
   References Top

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Guldbakke KK, Khachemoune A. Calciphylaxis. Int J Dermatol 2007;46:231-8.  Back to cited text no. 1
    
2.
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. 2
    
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Brandenburg VM, Cozzolino M, Ketteler M. Calciphylaxis: a still unmet challenge. J Nephrol 2011;24:142-8.  Back to cited text no. 3
    
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Block GA. Prevalence and clinical conesquences of elevated Ca x P product in hemodialysis patients. Clin Nephrol 2000;54:318-24.  Back to cited text no. 4
    
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Mathur AV, Azad S, Singh M, Anand N. Penile necrosis in association with chronic renal failure; calciphylaxis or calcific uremic arteriolopathy. J Diabetol 2013;2:5.  Back to cited text no. 5
    
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Cimmino CB, Costabile RA. Biopsy is contraindicated in the management of penile calciphylaxis. J Sex Med 2014;11:2611-7.  Back to cited text no. 6
    
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Ahmed S, O'Neill KD, Hood AF, Evan AP, Moe SM. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 2001;37:1267-76.  Back to cited text no. 8
    
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Matsuoka S, Tominaga Y, Uno N, et al. Calciphylaxis: a rare complication of patients who required parathyroidectomy for advanced renal hyperparathyroidism. World J Surg 2005; 29:632-5.  Back to cited text no. 14
    
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Oikawa S, Osajima A, Tamura M, et al. Development of proximal calciphylaxis with penile involvement after parathyroidectomy in a patient on hemodialysis. Intern Med 2004; 43:63-8.  Back to cited text no. 16
    
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Mawad HW, Sawaya BP, Sarin R, Malluche HH. Calcific uremic arteriolopathy in association with low turnover uremic bone disease. Clin Nephrol 1999;52:160-6.  Back to cited text no. 17
    
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Goldfarb M, Gondek SS, Lim SM, Farra JC, Nose V, Lew JI. Postoperative hungry bone syndrome in patients with secondary hyperparathyroidism of renal origin. World J Surg 2012;36:1314-9.  Back to cited text no. 18
    
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Witteveen JE, van Thiel S, Romijn JA, Hamdy NA. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Eur J Endocrinol 2013;168:R45-53.  Back to cited text no. 19
    
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Cozzolino M, Mazzaferro S, Brandenburg V. The treatment of hyperphosphataemia in CKD: calcium-based or calcium-free phosphate binders? Nephrol Dial Transplant 2011;26:402-7.  Back to cited text no. 20
    
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Cozzolino M, Gallieni M, Corsi C, Bastagli A, Brancaccio D. Management of calcium refilling post-parathyroidectomy in end-stage renal disease. J Nephrol 2004;17:3-8.  Back to cited text no. 21
    
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Gonzalez-Parra E, Martin-Cleary C, Martin J, Ortiz A. Calcific uremic arteriolopathy while on cinacalcet. J Postgrad Med 2011;57: 51-2.  Back to cited text no. 22
[PUBMED]  Medknow Journal  
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Atalay AC, Karaman MI. Distal penile gangrene in a patient with chronic renal failure. Int J Urol 1997;4:431-2.  Back to cited text no. 23
    
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Al-Ghamdi KM. Calciphylaxis in a 33-year-old man with end-stage renal disease. Ann Saudi Med 2005;25:415-8.  Back to cited text no. 25
[PUBMED]  Medknow Journal  
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Rizvi T, Al-Nakshabandi NA. Penile necrosis due to calciphylaxis in a patient of end stage renal disease. Saudi Med J 2009;30: 143-5.  Back to cited text no. 27
    
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Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int 2002;61:2210-7.  Back to cited text no. 28
    
29.
Galperin TA, Cronin AJ, Leslie KS. Cutaneous Manifestations of ERSD. Clinical Journal of the American Society of Nephrology. CJASN 2014:9(1):201-218.  Back to cited text no. 29
    

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Correspondence Address:
Salah Omar Bashir
Department of Physiology, College of Medicine, King Khalid University, Abha
Saudi Arabia
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DOI: 10.4103/1319-2442.194685

PMID: 27900978

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    Abstract
   Introduction
   Case Report
   Discussion
   Acknowledgment
    References
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