Non-uraemic calciphylaxis (NUC) postliver transplantation

Abstract

Calciphylaxis is a rare and life-threatening disease characterized by cutaneous arteriolar stenosis and vascular thrombosis leading to skin ischaemia and necrosis. While calciphylaxis occurs mostly in patients with end-stage renal disease, the disorder has been described in patients with normal renal function, namely non-uraemic calciphylaxis (NUC). A 41-year-old African-American woman presented with a painful ulcerative rash on her thighs and right buttock 2 months after undergoing an orthotopic liver transplantation. She underwent debridement of the lesions and an excisional biopsy of one of the lesions, which revealed calciphylaxis. She was treated with sodium thiosulfate, cinacalcet and hyperbaric oxygen with complete resolution of the lesions 4–5 months after presentation. While she was treated with a course of high-dose glucocorticoids after the transplant, she did not have other risk factors for calciphylaxis. NUC should be considered in the differential diagnosis of necrotic skin lesions in postliver transplant patients.

Background

Calciphylaxis is characterized by calcium deposition in small-sized and medium-sized vessels resulting in painful ischaemic cutaneous lesions and is associated with high morbidity and mortality. Despite the initial description of calciphylaxis over 50 years ago, its aetiology is only beginning to be understood, which makes treatment difficult. Well described in patients with end-stage renal disease (ESRD) on dialysis, a rare subset of patients develop calciphylaxis in the setting of normal renal function, also known as non-uraemic calciphylaxis (NUC).^1–3 Known risk factors for NUC include primary hyperparathyroidism, connective tissue disease, malignancy and alcoholic liver disease.² Here we present a patient without these known risk factors who developed NUC within 2 months after liver transplant suggesting that liver transplantation should be added to the list of risk factors for NUC.

Case presentation

Forty-one-year-old African-American woman presented to a tertiary medical center for evaluation of painful necrotic lesions and ulcerations on her thighs and buttocks that developed 2 months postorthotopic liver transplantation (OLT) done for alcohol-related cirrhosis. Her post OLT course is notable for normalisation of liver function though the course was complicated by acute kidney injury requiring renal replacement therapy, which subsequently returned to baseline and Clostridium difficile infection. She had no other antecedent kidney disease. She initially noticed subcutaneous lesions 3 weeks prior to presentation. The skin started getting darker, purple, indurated with vesicles that subsequently ulcerated. These lesions were painful and progressively increased in size and other lesions developed on the contralateral leg and buttocks. Biochemical evaluation at presentation was significant for 25 hydroxy vitamin D 10 ng/mL (20–80 ng/mL), intact parathyroid hormone (iPTH) 56 pg/mL (8–54 pg/mL), calcium 8.8 mg/dL (8.6–10.2 mg/dL), albumin 3.0 g/dL (3.5–5.5 g/dL) and phosphorus 5.2 mg/dL (2.5–4.5 mg/dL). Renal function was normal with glomerular filtration rate(GFR) >60 mL/min and creatinine 0.72 mg/dL (0.52–1.04 mg/dL). The elevated iPTH was due to secondary hyperparathyroidism from vitamin D deficiency and was treated with high-dose ergocalciferol. In addition to the OLT, her medical history was significant for hypertension, diet-controlled type 2 diabetes mellitus, Roux-en-Y gastric bypass and obstructive sleep apnoea. She was on maintenance immunosuppression for the transplant with tacrolimus and mycophenolate though during the immediate postoperative period, she had a course of high-dose glucocorticoids. Other long-term medications included metoprolol, dapsone, valganciclovir, tramadol, pantoprazole, furosemide and magnesium. There was no history of calcium supplementation or warfarin use. She was not a current smoker. She quit drinking alcohol at the time of her diagnosis with liver disease.

Investigations

On examination, she was afebrile, blood pressure was 130/74 mm Hg, heart rate was 77 bpm and respiratory rate was 20 breaths/min with a pulse oximetry of 91% on room air. She appeared in mild distress due to pain. Physical examination was remarkable for bilateral pitting leg oedema up to her thighs with multiple tender subcutaneous lesions. On the left anterolateral thigh, there was an eschar measuring 8×16 cm with central 3×5 cm ulceration (figure 1A) and on the center of the right thigh, there was a 4×8 cm darkened ecchymotic area with a group of painful vesicles. Additional smaller scattered lesions were found on both buttocks. The remainder of her examination was unremarkable. Ultrasound (US) of the neck showed no evidence of a parathyroid adenoma. Other laboratory studies including immune serologies, free light chains, protein C and protein S were unremarkable. Excisional biopsy was performed, which showed calcification in the media of small-sized and medium-sized arterial wall with endothelial proliferation and luminal obliteration. Surrounding tissue was marked by haemorrhage, fibrin deposition and fat necrosis (H&E stain, high magnification) (figure 2) findings consistent with NUC.

Figure 1.

(A) Left anterolateral thigh, black eschar with central necrotic ulceration, (B) Left anterolateral thigh after excisional debridement and (C) NUC lesions completely resolved with residual scarring on the left anterolateral thigh.

Figure 2.

Histopathology of the skin biopsy stained with H&E stain (high magnification) shows calcification in the media of small-sized (A and C) and medium-sized (B) sized arterial wall with endothelial proliferation and luminal obliteration. Surrounding tissue was marked by haemorrhage, fibrin deposition and fat necrosis (A).

Treatment

She was admitted to the hospital and underwent excisional debridement (figure 1B) and elective skin grafting. Additional treatment included sodium thiosulfate 25 mg three times a week, broad-spectrum antibiotics to prevent secondary infection, ergocalciferol 100 000 IU weekly for 6 weeks for severe vitamin D deficiency, sevelamer 2400 mg three times a day for hyperphosphataemia, cinacalcet 30 mg three times a week and daily hyperbaric oxygen.

Outcome and follow-up

After 2 months of hospitalization, she was discharged to a rehabilitation center. NUC lesions completely resolved 4–5 months from the initial presentation but with residual scarring (figure 1C).

Discussion

Calciphylaxis is a devastating vascular disease that was initially described in animal models by Hans Selye in the 1960s.⁴ Diagnosis of calciphylaxis is based on both clinical and histopathological criteria. As with our patient, patients typically present with painful skin nodules or plaques that may resemble livedo reticularis. Lesions progress to necrotic eschars and non-healing ulcers. Calciphylaxis predominantly affects areas of fat deposition such as the inner thigh, buttocks and abdomen. In 90% of patients, lesions are only on lower extremities, although lesions on breast and genitalia have also been reported.^{5 6}

Skin biopsy of one of the lesions is the standard method to definitively diagnosis calciphylaxis.⁷ While some argue that a biopsy is not needed for ESRD patients with the classic presentation of a painful necrotic ulcer with black eschar, a biopsy should be considered if lesions are atypical or in a patient without ESRD.^{7 8} On histopathology, calciphylaxis lesions reveal a combination of vascular calcification of small-sized to medium-sized vessels along with signs of infarction accompanied by intimal proliferation and endovascular fibrosis. Additional histological findings include extravascular calcium deposition, proximal vascular thrombosis and tissue necrosis. Despite these finding, very few if any inflammatory cells are found in or around blood vessels unless the skin is secondarily infected.^{9 10}

Early investigators attributed the development of calciphylaxis to hyperparathyroidism and calcium–phosphorus imbalance. Today, calciphylaxis is believed to be mediated by deficiencies in vascular calcification inhibitory proteins such as matrix Gla protein and systemic globulin fetuin-A. Imbalances of receptor activator NFkB (RANK), RANK ligand and osteoprotegerin, which regulate extraskeletal mineralization, may also be involved with the vascular calcification seen with the disorder.^{11 12}

Classic calciphylaxis or calcific uraemic arteriopathy (CUA) is an uncommon, under recognized disorder, which is seen in patients with ESRD with abnormal calcium phosphorus metabolism and parathyroid hormone dysregulation.^{1 5 13} According to a recent review by Nigwekar and colleagues,¹² calciphylaxis is estimated to affect 35 cases per 10 000 patients undergoing haemodialysis (HD) in the USA,¹⁴ with lower rates in Germany (4 per 10 000)¹ and Japan (<1 per 10 000).¹⁵ Patients on peritoneal dialysis have a higher incidence of calciphylaxis than those treated with HD.¹⁵ The incidence in kidney transplant recipients and in patients with earlier stages of chronic kidney disease is unknown. Mean age of diagnosis is 50–70 years with 60%–70% of those affected being women.¹²

Calciphylaxis is not limited to ESRD and it has been reported in patients with normal or earlier stages of chronic renal disease, which is the so-called NUC. NUC is seen more commonly with Caucasian ethnicity, diabetes, obesity, female gender, immunosuppressive medications and warfarin therapy. Diseases reported to predispose to calciphylaxis include malignancies such as multiple myeloma and Hodgkin’s lymphoma, hyperthyroidism, alcohol-related liver disease and connective tissue disease.^{2 4 12}

To date, an association between NUC after liver transplant has been described in only two other case reports, though NUC has been reported in four patients with both kidney and liver transplants.¹⁶ Prabhakar and Tuffaha described a case of NUC after liver transplantation in a 65-year-old woman with hepatocellular carcinoma. She was treated successfully with sodium thiosulfate (STS) and hyperbaric oxygen.¹⁷ In the second case, Kless and colleagues described a 53-year-old man postliver transplantation for alcoholic cirrhosis treated with STS, cinacalcet, hyperbaric oxygen therapy and parathyroidectomy.¹⁸ Similar to these cases, our patient developed NUC postliver transplant and glucocorticoid therapy. Table 1 compares our present case with the two other cases.

Table 1.

Clinical characteristics of NUC in three liver transplant patients

Trait	Present case	Case 1	Case 2
Gender	Female	Female	Male
Race	African-American	Caucasian	Not reported
Age (years)	41	65	53
Cause of liver failure	Alcoholic cirrhosis	Hepatocellular carcinoma	Alcoholic cirrhosis
Calcium (mg/dL)	8.8	8.4	9.3
PO4 (mg/dL)	5.2	4.7	4.5
Ca/phos product	4 6	39.5	42
PTH (pg/mL)	56	11	96
Creatinine (mg/dL)	0.72	0.96	2.2
25 OH vitamin D (ng/mL)	10	84.2	20
Parathyroid US	Normal	Not available	Normal
Treatment	Sodium thiosulfate. Cinacalcet. Hyperbaric oxygen therapy.	Sodium thiosulfate. Hyperbaric oxygen therapy.	Sodium thiosulfate. Cinacalcet. Hyperbaric oxygen therapy. Subtotal parathyroidectomy.

NUC, non-uraemic calciphylaxis.

Calciphylaxis is associated with very high morbidity and mortality rates mostly from sepsis. One-year mortality can be as high as 35%–55%.¹⁹ Therefore, early recognition and management is crucial. Because of the low incidence of calciphylaxis, randomized control trials have not been performed to establish best treatment practices though the ‘Intravenous Sodium Thiosulfate for Acute Calciphylaxis Treatment’, a phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial looking at safety and efficacy of STS is currently underway. A multidisciplinary approach to treatment is essential for successful treatment. Analgesia to address the severe pain that accompanies calciphylaxis should be focused on first. Pain management is challenging because pain may be unresponsive to high-dose opioids. In refractory cases, concomitant treatment with gabapentin, ketamine or spinal anaesthetic agents is helpful.²⁰

The most commonly used pharmacological agent to treat calciphylaxis lesions is STS. Conclusive evidence on its effectiveness for calciphylaxis is limited as reports generally lack a control group and are retrospective.^21–25 Despite the absence of randomised control trials, case reports suggest that STS is effective as first-line treatment for calciphylaxis and is associated with improvements in both morbidity and mortality. Use of STS in NUC is based on its successful treatment of CUA. For example, Nigwekar et al reported on 53 haemodialysis patients with calciphylaxis treated with STS that resulted in complete resolution of calciphylaxis lesions in 26.4% of patients and marked improvement in skin lesions in another 18.9%.²² In a similar study by Zitt et al²³ involving 27 patients, 52% had complete remission and 19% had partial remission after treatment with intravenous STS.

The mechanism of action of STS is proposed to be through its antioxidant and chelating properties. Its antioxidant properties help reverse endothelial cell dysfunction and promote vasodilation.¹¹ The chelating effects facilitate mobilization of calcium deposits from affected vascular and soft tissue areas by enhancing the solubility of calcium deposits in aqueous solution. Over time, the size of subcutaneous plaques and vascular calcifications is reduced leading to improvement in healing, but this process requires several weeks to months.^{25 26} STS is usually well tolerated and easy to use in the inpatient setting. The standard dose of 25 g of STS is given intravenously over 30–60 min three times a week. Abdominal cramping, nausea, vomiting and/or diarrhoea may occur if STS is infused too rapidly. More serious reported side effects include volume overload, hypocalcaemia, QT-interval prolongation, hypotension and metabolic acidosis.¹² Duration of therapy is individualized with most recommending that STS treatment be continued for at least 2 months beyond complete healing of skin ulcerations.

Along with pain control and STS treatment, wound care with surgical debridement to remove exudate and necrotic tissue to prevent infection is essential. The addition of hyperbaric oxygen is also reported to improve calciphylaxis wound healing through decreased tissue hypoxia that leads to increased fibroblast proliferation, collagen production and angiogenesis.²⁷ Higher levels of tissue oxygenation via hyperbaric oxygen treatment has the additional benefit of improved neutrophil function and direct toxic effects on anaerobic bacteria.²⁸

Elimination of other risk factors for calciphylaxis is another important step in treating calciphylaxis. Hypercalcaemia and hyperphosphataemia should be corrected when possible and vitamin D and calcium supplements, including calcium-based phosphate binders, should be avoided. Optimal PTH levels for patients with calciphylaxis are unknown. To determine the effects of lower PTH levels on development of CUA, the EVOLVE trial randomized 3883 dialysis patients with moderate-to-severe secondary hyperparathyroidism to receive either cinacalcet or placebo. In the cinacalcet group, median PTH levels decreased by more than 50% from 690 pg/mL to 300 pg/mL. Associated with the lower PTH levels, there were fewer cases of calciphylaxis (cinacalcet treated: six cases (0.3%) vs placebo treated: 18 cases (0.9%)) (relative HR 0.25 (95% CI 0.10 to 0.67)). While this trial did not address the role of cinacalcet when calciphylaxis is present, the results of the trial are often cited as the reason for using cinacalcet when hyperparathyroidism and calciphylaxis coexist.²⁹ Parathyroidectomy is reserved for refractory cases of hyperparathyroidism when a calcimimetic agent does not adequately control PTH levels.³⁰

NUC is rare and less well understood than uraemic calciphylaxis. Based on this case and the previously reported cases of NUC in post-transplant liver patients, calciphylaxis may be an under-reported phenomenon in this population and should be considered a risk factor for NUC. NUC should be added to the differential diagnosis of necrotic skin lesions presenting in postliver transplant patients.

Learning points.

• Calciphylaxis classically presents with painful ischaemic cutaneous lesions and is associated with high morbidity and mortality.

• Non-uraemic calciphylaxis (NUC) is rare but should be considered in patients presenting with these lesions.

• Most common risk factors for NUC include primary hyperparathyroidism, connective tissue disease, malignancy and alcoholic liver disease.

• Based on our case, liver transplantation should be added to the list of risk factors for NUC.

• Early treatment of calciphylaxis with sodium thiosulfate, appropriate wound care and hyperbaric oxygen may result in better clinical outcomes for patients.