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Calciphylaxis: A Rare But Fatal Delayed Complication of Roux-en-Y Gastric Bypass Surgery
Case Report Calciphylaxis: A Rare But Fatal Delayed Complication of Roux-en-Y Gastric Bypass Surgery Andrew S. Allegretti, MD,1 Rosalynn M. Nazarian, MD,2 Jeremy Goverman, MD,3 and Sagar U. Nigwekar, MD, MMSc1 Gastric bypass is a commonly used surgical procedure that has shown impressive health benefits for patients with morbid obesity. However, mineral bone abnormalities (hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism) and micronutrient (eg, iron) deficiencies are common complications after gastric bypass surgery due to alterations in the digestive anatomy. These abnormalities, their treatments, and a number of other factors associated with obesity can set up a perfect storm to induce calciphylaxis, a rare but highly fatal condition with severe comorbid conditions. We present a fatal case of nonuremic calciphylaxis coincident with symptomatic hypocalcemia in a morbidly obese man with a history of Roux-en-Y gastric bypass surgery. Am J Kidney Dis. -(-):---. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Calciphylaxis; gastric bypass; hypocalcemia; obesity; vitamin D.
G
astric bypass is a commonly used surgical procedure in morbidly obese patients, with impressive improvements in long-term survival and comorbid conditions such as diabetes mellitus.1-3 Compared to gastric banding, bypass is more effective at achieving weight loss and is performed more commonly by bariatric surgeons.4 Part of the success from this procedure is related to the bypass of the proximal small intestine that alters gastric hormonal secretion, creating functional malabsorption.4,5 Unfortunately, altered digestive anatomy is associated with mineral abnormalities, including hypocalcemia, hypovitaminosis D, secondary hyperparathyroidism, and deficiencies of micronutrients such as vitamin K and iron.6-9 Although often corrected with careful nutritional monitoring, counseling, and supplementation, therapies used to manage these abnormalities in combination with other factors associated with obesity can predispose patients to a rare but severe syndrome of calciphylaxis. We present a fatal case of nonuremic calciphylaxis coincident with symptomatic hypocalcemia in an obese man who underwent Roux-en-Y gastric bypass surgery years prior to the current presentation. How the interplay of various factors following gastric bypass surgery may predispose to calciphylaxis is reviewed.
CASE REPORT A 65-year-old man with morbid obesity status had Roux-en-Y gastric bypass surgery 20 years prior to the current presentation and had persistent obesity postsurgery (current body mass index . 40 kg/m2). His postsurgery course was complicated by hypocalcemia, hypovitaminosis D, and iron deficiency anemia, which required treatments with calcium carbonate, 500 mg, 3 times daily; ergocalciferol, 50,000 units, twice weekly; doxercalciferol, 0.25 mg, daily; and intravenous iron dextran, 100 mg, weekly. Other comorbid conditions included diabetes mellitus, heart failure, atrial fibrillation treated with warfarin, stage 3b Am J Kidney Dis. 2014;-(-):---
chronic kidney disease, and polymyalgia treated with prednisone (15 mg daily). The patient’s current presentation began with 6 months of worsening lower-extremity edema and cutaneous bullous lesions at pressure points to bed and chair. Outpatient laboratory findings in the weeks prior to admission were notable for the following values: serum urea nitrogen, 61 mg/dL; creatinine, 2.0 mg/dL; estimated glomerular filtration rate, 36 mL/min/1.73 m2 (by the IDMS-traceable 4-variable Modification of Diet in Renal Disease Study equation); calcium, 6.7 mg/dL; phosphorus, 3.8 mg/dL; magnesium, 1.7 mg/dL; albumin, 1.1 g/dL; 25-hydroxyvitamin D, 14 ng/mL; and parathyroid hormone, 773 (reference range, 12-65) pg/mL. His cutaneous lesions became intensely painful ulcers with violaceous borders and necrosis (Fig S1, available as online supplementary material), prompting presentation to the emergency department. He was found to be delirious and hypotensive with acute on chronic kidney injury (serum urea nitrogen, 86 mg/dL, and creatinine, 3.3 mg/dL), and international normalized ratio was elevated (10.6). He was intubated, started on treatment with vasopressors, and treated with intravenous ceftriaxone for Proteus species bacteremia (thought to be from a urinary source). Despite rapid hemodynamic correction, his skin lesions continued to worsen. He was taken for surgical debridement on hospital day 17. Pathology revealed concentric medial calcification of small and medium-sized vessels with fibrointimal hyperplasia, as well as fine granular calcium deposits in the subcutis with overlying ulceration, thrombosis, necrosis, and inflammation (Figs 1, 2, and 3). Clinicopathologic correlation was consistent with calciphylaxis. Upon extubation, he was noted to have diffuse spontaneous tetany, positive Chvostek sign, and a corrected QT interval of 513
From the 1Division of Nephrology, 2Dermatopathology Unit, Pathology Service, and 3Department of Surgery, Massachusetts General Hospital, Boston, MA. Received December 23, 2013. Accepted in revised form February 27, 2014. Address correspondence to Sagar U. Nigwekar, MD, MMSc, Bulfinch 127, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.02.029 1
Allegretti et al
Figure 1. (A) Concentric calcifications involving small to medium-sized arterioles in the panniculus (hematoxylin and eosin stain; original magnification, 3200) and (B) fibrointimal hyperplasia with narrowing of the lumen (hematoxylin and eosin stain; original magnification, 3400).
milliseconds that correlated with reduced serum calcium level of 6.0 mg/dL and ionized calcium level of 1.96 mEq/L. His management over a month-long hospital course included wound care, placement of a wound vacuum, pain control, 25 g of sodium thiosulfate intravenously 3 times weekly, hyperbaric oxygen therapy, and discontinuation of warfarin, doxercalciferol, ergocalciferol, and iron therapies. Calcium administration was limited to alleviate symptoms of hypocalcemia. Unfortunately, he developed a second insult of shock in the setting of Streptococcus species bacteremia and gastrointestinal hemorrhage. After discussions with the family, the patient died receiving comfort care measures.
Calciphylaxis is a calcification and thrombotic disorder of dermal arterioles typically seen in patients with end-stage renal disease (ESRD). Painful nodules and necrotic ulcers that frequently become superinfected characterize the disease.10,11 Calciphylaxis has heavy morbidity from nonhealing painful skin lesions and 1-year mortality of 45%-80%.12 It originally was described in 1961 as soft-tissue calcium deposition in a rat model exposed to vitamin D, parathyroid hormone extract, nephrotoxic insults, iron, glucocorticoids, and/or traumatic insults. However, no current consensus exists to define its mechanism.13,14
Despite original description of this condition more than 60 years ago, there is no effective treatment.15,16 Although the exact pathobiology of calciphylaxis remains obscure, risk factors such as uncontrolled hyperparathyroidism, hypoalbuminemia, and treatments with warfarin, calcitriol, iron, and calcium supplements have been reported.17-19 Calciphylaxis in the absence of ESRD (nonuremic calciphylaxis) is a case-reportable phenomenon. The largest review to date on this topic summarized 36 cases and identified primary hyperparathyroidism, solid tumors, and alcoholic liver disease as the most common associated conditions.20 Nonuremic calciphylaxis has similar morbidity and mortality as observed in uremic calciphylaxis and has no effective treatment. The patient discussed in this report did not have dialysis-dependent ESRD; however, creatinine clearance by 24-hour urine collection was not available and it is possible that estimated glomerular filtration rate may have been an overestimate considering the weight loss. Although the definitive pathophysiology for nonuremic calciphylaxis is unclear, it is possible that obesity and Roux-en-Y bypass had a major role in the
Figure 2. Fat necrosis and the presence of subtle, finely granular, basophilic stippled calcium deposits (black arrows) between adipocytes in the subcutis (hematoxylin and eosin stain; original magnification, 3400).
Figure 3. Epidermal ulceration and intravascular thrombosis, and marked necrosis and inflammation in the dermis (hematoxylin and eosin stain; original magnification, 340).
DISCUSSION
2
Am J Kidney Dis. 2014;-(-):---
Calciphylaxis After Roux-en-Y Gastric Bypass Surgery
development of calciphylaxis for this patient through several mechanisms, including mineral bone disorder, anemia, and use of a vitamin K antagonist. Given the current obesity epidemic facing the United States, bariatric surgery, specifically gastric bypass, is commonly performed.4 Although often successful, those unable to lose significant weight with the procedure, such as this patient, are left with obesity (which in itself has been implicated in calciphylaxis),21 as well as new risk factors for calciphylaxis. Patients commonly have nutritional deficiencies following gastric bypass; perhaps most relevant here are deficiencies of the fat-soluble vitamins D and K, due to poor absorption.6,7 Vitamin K deficiency may have a role in the pathogenesis of calciphylaxis because warfarin, a vitamin K antagonist, has been shown to promote vascular calcification in animal models by inhibition of carboxylation of endothelial matrix Gla protein.22,23 In this patient, the combination of poor vitamin K absorption resulting from the gastric bypass and concurrent warfarin use may have contributed to the intravascular calcification seen on his biopsy specimen. This mechanism has been implicated in a prior case series of patients with nonuremic calciphylaxis.24 Additionally, mineral bone abnormalities, such as hypocalcemia, hypovitaminosis D, and elevated parathyroid hormone levels, are highly prevalent in patients following gastric bypass due to poor absorption of fat-soluble vitamins and the need for higher repletion doses of calcium and vitamin D compared with patients with normal intestinal tracts.6-8 This patient was using 2 different vitamin D supplements, as well as oral calcium, yet still had low serum calcium levels. Symptomatic hypocalcemia in a patient with calciphylaxis has not been reported previously in the literature and poses a challenging clinical scenario because expert opinion favors discontinuation of all calcium products as part of the treatment for calciphylaxis.25 In a case report of a patient with ESRD, history of gastric bypass surgery, and recent subtotal parathyroidectomy resulting in life-threatening hypocalcemia, extremely high doses of multiple calcium and vitamin D products were required for several weeks to correct low serum calcium levels in the face of gastric bypass–driven malabsorption, hypoparathyroidism, and kidney disease.26 Similarly, our patient had several of these characteristics and was treated aggressively with calcium and vitamin D, which may have acted as a sensitizer for the development of calciphylaxis. Our case suggests that highdose supplementation with calcium and vitamin D likely have effects on vascular calcification that may not be predicted accurately by clinically available biochemistry tests, including serum calcium or serum 25-hydroxyvitamin D. It also is possible that elevated Am J Kidney Dis. 2014;-(-):---
parathyroid hormone level, as a common end point of hypocalcemia and hypovitaminosis D, is the driving factor in the pathogenesis of this disease because cinacalcet and parathyroidectomy have been suggested as potential treatments for calciphylaxis. The complexities of this case highlight the unique features of calciphylaxis and emphasize that we have much to learn about its pathogenesis and treatment. This patient, who underwent gastric bypass surgery, seemed to have a perfect storm of risk factors for the development of calciphylaxis because he was receiving intravenous iron, warfarin, high-dose exogenous calcium, and vitamin D and had a cadre of other comorbid conditions that served as potential contributors for the disease. Recognition of risk factors for calciphylaxis and careful risk-benefit assessment of therapies for other comorbid conditions are necessary in patients who are obese or have undergone bariatric surgery, in order to assess and prevent complications of this frequently fatal disease.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Nigwekar is supported by a Clinical Scientist in Nephrology Fellowship from the American Kidney Fund and a Sanofi Nephrology Fellowship award. The remaining authors declare that they have no relevant financial interests.
SUPPLEMENTARY MATERIAL Figure S1: Clinical photographs of the patient’s cutaneous lesions. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.02.029) is available at www.ajkd.org
REFERENCES 1. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8):753-761. 2. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577-1585. 3. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357(8):741-752. 4. Tice JA, Karliner L, Walsh J, Petersen AJ, Feldman MD. Gastric banding or bypass? A systematic review comparing the two most popular bariatric procedures. Am J Med. 2008;121(10): 885-893. 5. Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG, Aylwin SJ. Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety. Br J Surg. 2006;93(2):210-215. 6. Bloomberg RD, Fleishman A, Nalle JE, Herron DM, Kini S. Nutritional deficiencies following bariatric surgery: what have we learned? Obes Surg. 2005;15(2):145-154. 7. Alvarez-Leite JI. Nutrient deficiencies secondary to bariatric surgery. Curr Opin Clin Nutr Metab Care. 2004;7(5): 569-575. 8. Carlin AM, Rao DS, Yager KM, Genaw JA, Parikh NJ, Szymanski W. Effect of gastric bypass surgery on vitamin D nutritional status. Surg Obes Relat Dis. 2006;2(6):638-642. 3
Allegretti et al 9. Hage MP, El-Hajj Fuleihan G. Bone and mineral metabolism in patients undergoing Roux-en-Y gastric bypass. Osteoporos Int. 2013;25(2):423-439. 10. Bazari H, Jaff MR, Mannstadt M, Yan S. Case records of the Massachusetts General Hospital. Case 7-2007. A 59-year-old woman with diabetic renal disease and nonhealing skin ulcers. N Engl J Med. 2007;356(10):1049-1057. 11. Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxiscalcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol. 2005;4(1):4. 12. Hayden MR, Goldsmith D, Sowers JR, Khanna R. Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate. Int Urol Nephrol. 2008;40(2):443-451. 13. Selye H, Gentile G, Prioreschi P. Cutaneous molt induced by calciphylaxis in the rat. Science. 1961;134(3493):1876-1877. 14. Brandenburg VM, Kramann R, Specht P, Ketteler M. Calciphylaxis in CKD and beyond. Nephrol Dial Transplant. 2012;27(4):1314-1318. 15. O’Neill WC. Sodium thiosulfate: mythical treatment for a mysterious disease? Clin J Am Soc Nephrol. 2013;8(7):1068-1069. 16. Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8(7):1162-1170. 17. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61(6):2210-2217.
4
18. Hayashi M, Takamatsu I, Kanno Y, et al. A case-control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant. 2012;27(4):1580-1584. 19. Nigwekar SU, Bhan I, Turchin A, et al. Statin use and calcific uremic arteriolopathy: a matched case-control study. Am J Nephrol. 2013;37(4):325-332. 20. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3(4):1139-1143. 21. Janigan DT, Hirsch DJ. Does obesity play a role in the pathogenesis of calcific uraemic arteriolopathy? Nephrol Dial Transplant. 2006;21(4):865-868. 22. Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscleros Thromb Vasc Biol. 1998;18(9):1400-1407. 23. Danziger J. Vitamin K-dependent proteins, warfarin, and vascular calcification. Clin J Am Soc Nephrol. 2008;3(5):15041510. 24. Kalajian AH, Malhotra PS, Callen JP, Parker LP. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol. 2009;145(4):451-458. 25. Brandenburg VM, Cozzolino M, Ketteler M. Calciphylaxis: a still unmet challenge. J Nephrol. 2011;24(2):142-148. 26. Palal B, Sinsakul M, Reutrakul S. Life-threatening hypocalcemia following subtotal parathyroidectomy in a patient with renal failure and previous Roux-en-Y gastric bypass surgery. Case Rep Endocrinol. 2011;2011:370583.
Am J Kidney Dis. 2014;-(-):---
G
astric bypass is a commonly used surgical procedure in morbidly obese patients, with impressive improvements in long-term survival and comorbid conditions such as diabetes mellitus.1-3 Compared to gastric banding, bypass is more effective at achieving weight loss and is performed more commonly by bariatric surgeons.4 Part of the success from this procedure is related to the bypass of the proximal small intestine that alters gastric hormonal secretion, creating functional malabsorption.4,5 Unfortunately, altered digestive anatomy is associated with mineral abnormalities, including hypocalcemia, hypovitaminosis D, secondary hyperparathyroidism, and deficiencies of micronutrients such as vitamin K and iron.6-9 Although often corrected with careful nutritional monitoring, counseling, and supplementation, therapies used to manage these abnormalities in combination with other factors associated with obesity can predispose patients to a rare but severe syndrome of calciphylaxis. We present a fatal case of nonuremic calciphylaxis coincident with symptomatic hypocalcemia in an obese man who underwent Roux-en-Y gastric bypass surgery years prior to the current presentation. How the interplay of various factors following gastric bypass surgery may predispose to calciphylaxis is reviewed.
CASE REPORT A 65-year-old man with morbid obesity status had Roux-en-Y gastric bypass surgery 20 years prior to the current presentation and had persistent obesity postsurgery (current body mass index . 40 kg/m2). His postsurgery course was complicated by hypocalcemia, hypovitaminosis D, and iron deficiency anemia, which required treatments with calcium carbonate, 500 mg, 3 times daily; ergocalciferol, 50,000 units, twice weekly; doxercalciferol, 0.25 mg, daily; and intravenous iron dextran, 100 mg, weekly. Other comorbid conditions included diabetes mellitus, heart failure, atrial fibrillation treated with warfarin, stage 3b Am J Kidney Dis. 2014;-(-):---
chronic kidney disease, and polymyalgia treated with prednisone (15 mg daily). The patient’s current presentation began with 6 months of worsening lower-extremity edema and cutaneous bullous lesions at pressure points to bed and chair. Outpatient laboratory findings in the weeks prior to admission were notable for the following values: serum urea nitrogen, 61 mg/dL; creatinine, 2.0 mg/dL; estimated glomerular filtration rate, 36 mL/min/1.73 m2 (by the IDMS-traceable 4-variable Modification of Diet in Renal Disease Study equation); calcium, 6.7 mg/dL; phosphorus, 3.8 mg/dL; magnesium, 1.7 mg/dL; albumin, 1.1 g/dL; 25-hydroxyvitamin D, 14 ng/mL; and parathyroid hormone, 773 (reference range, 12-65) pg/mL. His cutaneous lesions became intensely painful ulcers with violaceous borders and necrosis (Fig S1, available as online supplementary material), prompting presentation to the emergency department. He was found to be delirious and hypotensive with acute on chronic kidney injury (serum urea nitrogen, 86 mg/dL, and creatinine, 3.3 mg/dL), and international normalized ratio was elevated (10.6). He was intubated, started on treatment with vasopressors, and treated with intravenous ceftriaxone for Proteus species bacteremia (thought to be from a urinary source). Despite rapid hemodynamic correction, his skin lesions continued to worsen. He was taken for surgical debridement on hospital day 17. Pathology revealed concentric medial calcification of small and medium-sized vessels with fibrointimal hyperplasia, as well as fine granular calcium deposits in the subcutis with overlying ulceration, thrombosis, necrosis, and inflammation (Figs 1, 2, and 3). Clinicopathologic correlation was consistent with calciphylaxis. Upon extubation, he was noted to have diffuse spontaneous tetany, positive Chvostek sign, and a corrected QT interval of 513
From the 1Division of Nephrology, 2Dermatopathology Unit, Pathology Service, and 3Department of Surgery, Massachusetts General Hospital, Boston, MA. Received December 23, 2013. Accepted in revised form February 27, 2014. Address correspondence to Sagar U. Nigwekar, MD, MMSc, Bulfinch 127, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.02.029 1
Allegretti et al
Figure 1. (A) Concentric calcifications involving small to medium-sized arterioles in the panniculus (hematoxylin and eosin stain; original magnification, 3200) and (B) fibrointimal hyperplasia with narrowing of the lumen (hematoxylin and eosin stain; original magnification, 3400).
milliseconds that correlated with reduced serum calcium level of 6.0 mg/dL and ionized calcium level of 1.96 mEq/L. His management over a month-long hospital course included wound care, placement of a wound vacuum, pain control, 25 g of sodium thiosulfate intravenously 3 times weekly, hyperbaric oxygen therapy, and discontinuation of warfarin, doxercalciferol, ergocalciferol, and iron therapies. Calcium administration was limited to alleviate symptoms of hypocalcemia. Unfortunately, he developed a second insult of shock in the setting of Streptococcus species bacteremia and gastrointestinal hemorrhage. After discussions with the family, the patient died receiving comfort care measures.
Calciphylaxis is a calcification and thrombotic disorder of dermal arterioles typically seen in patients with end-stage renal disease (ESRD). Painful nodules and necrotic ulcers that frequently become superinfected characterize the disease.10,11 Calciphylaxis has heavy morbidity from nonhealing painful skin lesions and 1-year mortality of 45%-80%.12 It originally was described in 1961 as soft-tissue calcium deposition in a rat model exposed to vitamin D, parathyroid hormone extract, nephrotoxic insults, iron, glucocorticoids, and/or traumatic insults. However, no current consensus exists to define its mechanism.13,14
Despite original description of this condition more than 60 years ago, there is no effective treatment.15,16 Although the exact pathobiology of calciphylaxis remains obscure, risk factors such as uncontrolled hyperparathyroidism, hypoalbuminemia, and treatments with warfarin, calcitriol, iron, and calcium supplements have been reported.17-19 Calciphylaxis in the absence of ESRD (nonuremic calciphylaxis) is a case-reportable phenomenon. The largest review to date on this topic summarized 36 cases and identified primary hyperparathyroidism, solid tumors, and alcoholic liver disease as the most common associated conditions.20 Nonuremic calciphylaxis has similar morbidity and mortality as observed in uremic calciphylaxis and has no effective treatment. The patient discussed in this report did not have dialysis-dependent ESRD; however, creatinine clearance by 24-hour urine collection was not available and it is possible that estimated glomerular filtration rate may have been an overestimate considering the weight loss. Although the definitive pathophysiology for nonuremic calciphylaxis is unclear, it is possible that obesity and Roux-en-Y bypass had a major role in the
Figure 2. Fat necrosis and the presence of subtle, finely granular, basophilic stippled calcium deposits (black arrows) between adipocytes in the subcutis (hematoxylin and eosin stain; original magnification, 3400).
Figure 3. Epidermal ulceration and intravascular thrombosis, and marked necrosis and inflammation in the dermis (hematoxylin and eosin stain; original magnification, 340).
DISCUSSION
2
Am J Kidney Dis. 2014;-(-):---
Calciphylaxis After Roux-en-Y Gastric Bypass Surgery
development of calciphylaxis for this patient through several mechanisms, including mineral bone disorder, anemia, and use of a vitamin K antagonist. Given the current obesity epidemic facing the United States, bariatric surgery, specifically gastric bypass, is commonly performed.4 Although often successful, those unable to lose significant weight with the procedure, such as this patient, are left with obesity (which in itself has been implicated in calciphylaxis),21 as well as new risk factors for calciphylaxis. Patients commonly have nutritional deficiencies following gastric bypass; perhaps most relevant here are deficiencies of the fat-soluble vitamins D and K, due to poor absorption.6,7 Vitamin K deficiency may have a role in the pathogenesis of calciphylaxis because warfarin, a vitamin K antagonist, has been shown to promote vascular calcification in animal models by inhibition of carboxylation of endothelial matrix Gla protein.22,23 In this patient, the combination of poor vitamin K absorption resulting from the gastric bypass and concurrent warfarin use may have contributed to the intravascular calcification seen on his biopsy specimen. This mechanism has been implicated in a prior case series of patients with nonuremic calciphylaxis.24 Additionally, mineral bone abnormalities, such as hypocalcemia, hypovitaminosis D, and elevated parathyroid hormone levels, are highly prevalent in patients following gastric bypass due to poor absorption of fat-soluble vitamins and the need for higher repletion doses of calcium and vitamin D compared with patients with normal intestinal tracts.6-8 This patient was using 2 different vitamin D supplements, as well as oral calcium, yet still had low serum calcium levels. Symptomatic hypocalcemia in a patient with calciphylaxis has not been reported previously in the literature and poses a challenging clinical scenario because expert opinion favors discontinuation of all calcium products as part of the treatment for calciphylaxis.25 In a case report of a patient with ESRD, history of gastric bypass surgery, and recent subtotal parathyroidectomy resulting in life-threatening hypocalcemia, extremely high doses of multiple calcium and vitamin D products were required for several weeks to correct low serum calcium levels in the face of gastric bypass–driven malabsorption, hypoparathyroidism, and kidney disease.26 Similarly, our patient had several of these characteristics and was treated aggressively with calcium and vitamin D, which may have acted as a sensitizer for the development of calciphylaxis. Our case suggests that highdose supplementation with calcium and vitamin D likely have effects on vascular calcification that may not be predicted accurately by clinically available biochemistry tests, including serum calcium or serum 25-hydroxyvitamin D. It also is possible that elevated Am J Kidney Dis. 2014;-(-):---
parathyroid hormone level, as a common end point of hypocalcemia and hypovitaminosis D, is the driving factor in the pathogenesis of this disease because cinacalcet and parathyroidectomy have been suggested as potential treatments for calciphylaxis. The complexities of this case highlight the unique features of calciphylaxis and emphasize that we have much to learn about its pathogenesis and treatment. This patient, who underwent gastric bypass surgery, seemed to have a perfect storm of risk factors for the development of calciphylaxis because he was receiving intravenous iron, warfarin, high-dose exogenous calcium, and vitamin D and had a cadre of other comorbid conditions that served as potential contributors for the disease. Recognition of risk factors for calciphylaxis and careful risk-benefit assessment of therapies for other comorbid conditions are necessary in patients who are obese or have undergone bariatric surgery, in order to assess and prevent complications of this frequently fatal disease.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Nigwekar is supported by a Clinical Scientist in Nephrology Fellowship from the American Kidney Fund and a Sanofi Nephrology Fellowship award. The remaining authors declare that they have no relevant financial interests.
SUPPLEMENTARY MATERIAL Figure S1: Clinical photographs of the patient’s cutaneous lesions. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.02.029) is available at www.ajkd.org
REFERENCES 1. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8):753-761. 2. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577-1585. 3. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357(8):741-752. 4. Tice JA, Karliner L, Walsh J, Petersen AJ, Feldman MD. Gastric banding or bypass? A systematic review comparing the two most popular bariatric procedures. Am J Med. 2008;121(10): 885-893. 5. Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG, Aylwin SJ. Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety. Br J Surg. 2006;93(2):210-215. 6. Bloomberg RD, Fleishman A, Nalle JE, Herron DM, Kini S. Nutritional deficiencies following bariatric surgery: what have we learned? Obes Surg. 2005;15(2):145-154. 7. Alvarez-Leite JI. Nutrient deficiencies secondary to bariatric surgery. Curr Opin Clin Nutr Metab Care. 2004;7(5): 569-575. 8. Carlin AM, Rao DS, Yager KM, Genaw JA, Parikh NJ, Szymanski W. Effect of gastric bypass surgery on vitamin D nutritional status. Surg Obes Relat Dis. 2006;2(6):638-642. 3
Allegretti et al 9. Hage MP, El-Hajj Fuleihan G. Bone and mineral metabolism in patients undergoing Roux-en-Y gastric bypass. Osteoporos Int. 2013;25(2):423-439. 10. Bazari H, Jaff MR, Mannstadt M, Yan S. Case records of the Massachusetts General Hospital. Case 7-2007. A 59-year-old woman with diabetic renal disease and nonhealing skin ulcers. N Engl J Med. 2007;356(10):1049-1057. 11. Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxiscalcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol. 2005;4(1):4. 12. Hayden MR, Goldsmith D, Sowers JR, Khanna R. Calciphylaxis: calcific uremic arteriolopathy and the emerging role of sodium thiosulfate. Int Urol Nephrol. 2008;40(2):443-451. 13. Selye H, Gentile G, Prioreschi P. Cutaneous molt induced by calciphylaxis in the rat. Science. 1961;134(3493):1876-1877. 14. Brandenburg VM, Kramann R, Specht P, Ketteler M. Calciphylaxis in CKD and beyond. Nephrol Dial Transplant. 2012;27(4):1314-1318. 15. O’Neill WC. Sodium thiosulfate: mythical treatment for a mysterious disease? Clin J Am Soc Nephrol. 2013;8(7):1068-1069. 16. Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8(7):1162-1170. 17. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61(6):2210-2217.
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