Calciphylaxis: Diagnosis, Pathogenesis, and Treatment

Calciphylaxis is a cutaneous ischemic infarct caused by occlusion of blood vessels in the subcutaneous fat and dermis. Severe pain and propensity for infections make calciphylaxis highly debilitating with an annual mortality of 40% to 80%.¹

“Calciphylaxis” is derived from “calci” meaning calcification and “phylaxis,” meaning protection, and literally means protection by calcification. The term was coined by Dr Seyle in 1961 to describe the formation of a calcium shell on rat skin.² In a high calcium and phosphate milieu generated by ingestion of parathyroid hormone (PTH) or vitamin D, a minor skin trauma by iron dextran injection or hair removal precipitated a massive calcium deposition. Over the next 3 weeks, the calcified skin detached itself from the underlying skin. By the fourth week, the rat crept out of its hard calcium “shell” with completely new and normal skin. Dr Seyle postulated that the rat skin developed a calcium shell to protect it from further injuries, hence the term “calciphylaxis.”²

Later, calcifying skin lesions that developed in humans with renal failure were named calciphylaxis because of their similarities to the calcified rat skin.^3,4 Besides sharing the histologic hallmark of calcification, both human and rat calciphylaxis developed under the seemingly same metabolic conditions of high PTH and phosphate levels.

As more cases of calciphylaxis in humans were described, important differences between rat and human calciphylaxis were noted.⁵ While calcification develops outside the vessels in both rats and humans, only in humans does it also develop within the vessel walls. In rats, the calcified skin is replaced with a new skin, but no such replacement occurs in humans; accordingly, it is life-threatening to humans.

The last two decades have seen significant advances in clinical understanding of how calciphylaxis develops: in humans, it appears to be the skin equivalent of a myocardial infarction, not a protective response. As a result, patients now have a new paradigm for its treatment with promising potential therapeutic targets. This article is a narrative review summarizing the clinical features, diagnosis, pathogenesis, and treatment of calciphylaxis.

METHODS

Information for this review was collected from textbooks, a review of references, and PubMed searches. The MeSH term “calciphylaxis” was used to identify 835 articles in English published between 1960 and 2018. Of these, 548 articles were categorized under the subheading “etiology,” 262 articles under “diagnosis” or “pathology,” and 333 articles under “therapy.” There were 131 review articles and 3 clinical trials. All articles were selected based on their relevance for diagnosis, pathogenesis, and treatment of calciphylaxis. This review contains 50 key references.

KEY CLINICAL FEATURES

Calciphylaxis is primarily a disease of renal failure; a majority of patients are nearing or on dialysis. Calciphylaxis that develops in end-stage renal disease (ESRD) patients is classified as uremic calciphylaxis. Estimates for the annual incidence of uremic calciphylaxis vary from as high as 4% in early and single-center studies^1,6 and as low as 0.04% in Germany and 0.35% in the US in more recent and national studies.^7,8 The actual incidence is probably higher than the most recent estimates; some cases were likely missed from misdiagnosis and underreporting. Despite the relatively low incidence, calciphylaxis will continue to be encountered in clinical practice for the foreseeable future, because of the rising number of ESRD patients in the last 25 years: in 2015, nearly half a million patients were on hemodialysis and peritoneal dialysis in the US.⁹

Calciphylaxis in patients with preserved renal function is known as nonuremic calciphylaxis. Its incidence is unknown but is likely much lower than that of uremic calciphylaxis. As of 2016, only 116 cases were reported in the literature.¹⁰

The risk factors for calciphylaxis fall into four major categories (Table 1). The strongest risk factor is renal failure, with a majority of cases of calciphylaxis developing in dialysis or renal transplant patients. Second, derangements in calcium and phosphate homeostasis, including hyperphosphatemia, hypercalcemia, and hyper- and hypoparathyroidism, predispose to the development of calciphylaxis.⁸ Third, vitamin K deficiency greatly increases risk because vitamin K activates a potent inhibitor of calcification, as described below.¹¹ At the time of presentation, 40% to 50% of calciphylaxis patients are taking a vitamin K antagonist such as warfarin.⁷ Finally, obesity, diabetes mellitus, and female sex are risk factors.^1,12

Severe pain is a prominent and nearly universal feature of calciphylaxis.¹² Pain, which is believed to be both ischemic and neuropathic in origin, is often out of proportion to the clinically evident skin injuries and can even precede the appearance of skin lesions.^13,14 A high dose of analgesics is required, but pain may be refractory. A majority of patients end up confined to a wheelchair or to bed because of calciphylaxis.¹²

Calciphylaxis lesions include livedo reticularis, plaques, nodules, and ulcers (Figure 1).¹⁴ Livedo reticularis, a lesion that presents early in the disease process, is a net-like (or reticulated) violaceous or livid skin discoloration. The unique pattern of discoloration results from the altered vascular supply to the skin. Each cutaneous arteriole, which originates deep in the dermis, supplies a cone of skin with a 1- to 3-cm circular base on the surface and its apex in the deep dermis.^15,16 At the boundaries of each cone are watershed areas with relatively diminished blood flow, which are vulnerable to ischemia. When subcutaneous and dermal arteries become occluded, ischemia develops preferentially in the watershed areas, while the central areas are spared, giving rise to a pattern of discoloration.

Plaques or nodules are the most common presenting lesions; a plaque was the presenting lesion in 80% of patients in one study.¹

Plaques may be confused with cellulitis because they are both red, warm, and tender. The induration unique to calciphylaxis can help differentiate it from cellulitis. One-third of plaques progress to ulcers. Leg ulcers in calciphylaxis are almost always bilateral; there may be one large confluent ulcer or a crop of multiple small ulcers. They often become superinfected.

Calciphylaxis preferentially involves the adipose tissues; the most frequently affected sites are the thighs and abdomen.⁸ Calciphylaxis also tends to appear on sites of repeated skin trauma, for example, the risk of calciphylaxis on the abdomen and/or thighs progressively rises with the increasing number of daily insulin injections.⁸

Calciphylaxis lesions typically appear after patients have been on dialysis for a few years. In the largest retrospective review of more than 1,000 dialysis patients with calciphylaxis, the median time between dialysis initiation and development of calciphylaxis was 2.5 years.⁸

PATHOPHYSIOLOGY

Calciphylaxis is an occlusive disease of cutaneous blood vessels (Figure 2A).⁵ Their lumens undergo progressive narrowing first by calcification within the media layer of vessel walls (also known as medial calcification) and proliferation of endothelial cells and fibrosis underneath the intima (also known as subintimal fibroplasia). When thrombosis later develops in the vessel lumen, ischemic injuries develop.

On this march toward complete occlusion, vascular calcification is the inciting and central event. (In the rest of this review, vascular calcification will be used to refer to medial calcification to avoid confusion with the more common use of medial as referring to the center of the body.) Vascular calcification is actually an ectopic bone formation in the vessel walls by vascular smooth muscle cells. In response to hyperphosphatemia, hypercalcemia, and hyperglycemia, vascular smooth muscle cells transform into osteoblast-like cells able to produce and deposit hydroxyapatite crystals, building blocks of bone.^17,18 In addition, adipocytes exposed to high phosphate can transform vascular smooth muscle cells to calcify in vitro, providing a possible explanation for the propensity of calciphylaxis in adipose tissues.¹⁹ Vascular endothelial growth factor A and leptin released from adipocytes appear to be mediators. Notably, the conditions that transform vascular smooth cells are the very risk factors for calciphylaxis. Accordingly, calciphylaxis risk factors confer their risk by promoting transformation of vascular smooth muscle cells into osteoblast-like cells.

The most common clinical scenario that gives rise to calciphylaxis is a lack of molecular calcification inhibitors in the vessel wall.^20,21 This deficiency is most commonly attributable to a lack of vitamin K (Figure 2B). Vitamin K activates a potent inhibitor of calcification called matrix Gla protein (MGP), secreted by vascular smooth muscle cells and endothelial cells.^17,21

There are two common reasons for vitamin K deficiency in ESRD patients. First, intake of leafy green vegetables and dairy products, both rich in vitamin K, is restricted in ESRD patients to limit potassium and sodium intake.²² Second, a vitamin K antagonist like warfarin inhibits the recycling of vitamin K. Nearly 40% to 50% of ESRD patients with calciphylaxis are taking warfarin at the time of diagnosis.⁷

Thrombosis is the final event that leads to complete vessel occlusion. The propensity for thrombosis in calciphylaxis is explained by the high prevalence of congenital and acquired hypercoagulable conditions in calciphylaxis patients. In 55 patients with calciphylaxis, 36 patients (65%) had at least one hypercoagulable condition, with 11 (20%) having two conditions.²³ Among the most common conditions were antithrombin deficiency, lupus anticoagulants, and protein C and S deficiency. In a case-control study of 38 calciphylaxis patients, lupus anticoagulants, protein C deficiency, and the presence of two hypercoagulable conditions were associated with the increased risk of calciphylaxis.²⁴

In summary, calciphylaxis develops because the peculiar biochemical environment in ESRD of abnormal phosphate, calcium, and PTH and vitamin K deficiency causes the skin vessels to calcify. Because a majority of calciphylaxis patients have preexisting hypercoagulable conditions, thrombosis readily occurs in the calcified vessels (Figure 3).

DIAGNOSIS

Diagnosis can be made on clinical grounds alone when a patient with ESRD presents with indurated tender plaques or ulcers on the abdomen and/or legs.¹⁴ However, skin biopsy may be necessary to differentiate calciphylaxis from its mimics (eg, pyoderma gangrenosum, Martorell hypertensive ischemic leg ulcer, cholesterol emboli, etc; Table 2), especially when calciphylaxis presents in early stages with clinically nondescript lesions such as a small papule and erosion.^25,26 Skin biopsy is also recommended to help diagnose nonuremic calciphylaxis.¹⁴

In contrast, skin biopsy is not always indicated in uremic calciphylaxis because the likelihood of calciphylaxis is much higher when an ESRD patient presents with characteristic skin lesions, as compared with patients with preserved renal function. No consensus exists on the role of a skin biopsy in diagnosing uremic calciphylaxis. When 12 European experts on calciphylaxis were asked, five (42%) reported that a skin biopsy is a prerequisite for diagnosis, while four (33%) did not, and three (25%) were undecided.²⁷ The results of this survey reflect the current practice pattern in the US. In a study of more than 1,000 patients with calciphylaxis, 55% were diagnosed with a skin biopsy, and the remaining 45% were diagnosed clinically.⁸ The possibility of nondiagnostic biopsies (resulting in a need for repeat biopsies) and the risk of complications are the reasons why biopsies are not universally pursued.

A punch biopsy with a double trephine technique is the preferred biopsy method.^14,28 An 8-mm circular core of superficial tissue is first obtained using an 8-mm punch tool. Then, a 4- to 6-mm punch tool is inserted within the center of the 8-mm defect to obtain the deep subcutaneous fat. A single punch biopsy should be avoided because the deep subcutaneous fat where pathologic features of calciphylaxis are most frequently found may not be sampled. An excisional biopsy should also be avoided because of the potential for ulceration, necrosis, and bleeding.^1,29 The biopsy should be taken from the margin of the lesion, avoiding the center of the lesion or the necrotic area where nonspecific necrotic tissue is more likely to be found.^1,29

Bone scan may prove to be a reliable, noninvasive diagnostic test for calciphylaxis, especially when biopsy findings are nondiagnostic or when a biopsy cannot be performed. The bone scan is positive when the tracer technetium 99m-labeled medronic acid binds to hydroxyapatite crystals at the calcified areas in the dermis and subcutaneous fat. In one study, bone scan yielded a sensitivity of 87% and a specificity of 97%.³⁰ False-negatives resulted only from ulcers, which had no tracer uptake either because the occluded vessels prevented tracer delivery or because the calcified tissue was sloughed off. Mammogram and X-rays may also show calcification but have a lower sensitivity.^1,31 Their specificities are unknown.

Laboratory evaluation is diagnostically unhelpful. While hyperphosphatemia, hypercalcemia, and hypo/hyperparathyroidism are risk factors for calciphylaxis, many patients do not present with abnormal values. As a corollary, normal and even low calcium and phosphate levels do not rule out calciphylaxis (Figure 4).

PREVENTION AND TREATMENT

Treatment of calciphylaxis requires a multidisciplinary approach involving nephrologists, dermatologists, plastic surgeons, dietitians, and wound care specialists.⁸ Because vascular calcification is the critical event that ultimately leads to vascular occlusion, a logical treatment objective is to stop the vascular calcification. In fact, many of the conventional treatment options are agents to stop vascular calcification. Decalcification of the calcified vessels to restore blood flow is a second treatment objective. The final objective is wound care and pain management.

It should be noted that the treatment recommendations discussed in this section lack robust data: the data come from observational retrospective studies with small sample sizes, surveys of clinicians, case series, and expert opinions.³² Clearly, more rigorous investigations are needed, and in fact some are underway (as will be discussed). Considering the debilitating and lethal nature of calciphylaxis, however, the lack of robust data should not dissuade the adoption of treatment options after a frank discussion with the patient about the risks, benefits, and limitations of each treatment option.

Strategies to Stop Vascular Calcification

Countermeasures to stop vascular calcification aim to either ameliorate or eliminate each of the risk factors for calciphylaxis (Table 3).

Hyperphosphatemia is treated by increasing phosphate removal and decreasing phosphate intake. Hemodialysis, which is the only route of phosphate elimination for patients on hemodialysis, may need to be increased to four to five times a week to achieve adequate phosphate removal.³³ Avoiding foods rich in phosphate, such as colas and processed foods, and consistent use of oral phosphate binders to reduce absorption of dietary phosphate are crucial. Target blood phosphate level is around 3 mg/dL.

Hypercalcemia is treated by increasing calcium removal by dialysis and reducing calcium intake.³³ Calcium-based phosphate binders such as calcium acetate should be avoided because the absorption of calcium can cause hypercalcemia.³³ The goal blood calcium level is around 8 mg/dL.

The ideal PTH level in calciphylaxis is not known, but both extremely high and low values should be avoided.⁸ Levels of PTH in blood can be lowered by suppressing its secretion by cinacalcet, and in refractory cases by parathyroidectomy. Vitamin D supplements should be stopped.⁸

Warfarin should be discontinued in patients with calciphylaxis, and the need for continuing anticoagulation with an alternative anticoagulant should be carefully assessed.^8,29 Stroke prevention in atrial fibrillation is the most common indication for warfarin in dialysis patients. However, no data exist to support anticoagulant use for this indication, and therefore anticoagulation can be stopped altogether.³⁴ Less commonly, clinical scenarios do arise, such as treatment of pulmonary embolism and prevention of clots on mechanical heart valves, when anticoagulation cannot be stopped. In these situations, apixaban, a direct factor Xa inhibitor, has been used.^35,36 A note of caution for bleeding complications needs to be issued, because there are only limited safety profile data for apixaban in patients with advanced chronic kidney disease.

The transition to hemodialysis should be considered for peritoneal dialysis patients who develop calciphylaxis; the benefit is attributed to better phosphate and calcium control.⁸ In addition, hemodialysis allows the concurrent administration of IV sodium thiosulfate during hemodialysis sessions (see below).

Strategies to Decalcify Calcified Vessels

Two agents have been shown to promote blood vessel decalcification.

Sodium thiosulfate. Since its first report of successful use in 2004, sodium thiosulfate is now considered by most to be a standard therapy for calciphylaxis.^8,37 Multiple mechanisms have been proposed to account for its therapeutic benefits.^38,39 As a calcium chelator, sodium thiosulfate has been shown to decalcify the calcified vessel walls.⁴⁰ Thiosulfate binds the calcium ions, and the resulting complexes of thiosulfate and calcium, which are highly water-soluble, are eliminated in urine or by dialysis. As an antioxidant, sodium thiosulfate may neutralize reactive oxygen species that promote inflammation, thrombosis, and vasoconstriction.

Intravenous delivery during the last hour of a hemodialysis session is standard. The dose is weight based: 25 g for weight greater than 60 kg and 12.5 g for weight less than 60 kg. A minimum duration of treatment is 3 months. Typically, the total duration of treatment is about 6 months or until the lesions completely heal.⁸

Sodium thiosulfate has been successfully used by directly injecting it around the border of and into the center of the lesion.⁴¹ The injection is useful for patients with limited intravenous access. The dose is 0.25 to 0.75 g (or 1–;3 mL of the 250 mg/mL sodium thiosulfate solution). This therapy is well tolerated. While common, nausea and vomiting are self-limited in most patients and only rarely necessitate discontinuation. Metabolic acidosis is common but is clinically insignificant.⁴²

Sodium thiosulfate appears to be beneficial in a majority of patients with calciphylaxis. The best available data on its efficacy come from surveys of clinicians at US hemodialysis centers.⁴² Of the 53 patients whose clinicians returned the surveys, nearly three-quarters had either a complete (26%) or a partial (47%) response. Only three patients (6%) showed no response. The response was unknown in 11 (21%) because of incomplete surveys. To more definitively answer the question of its efficacy, randomized clinical trials are underway, comparing sodium thiosulfate to placebo (Current Controlled Trials no. ISRCTN73380053 and ClinicalTrials.gov no. NCT03150420).

Sodium thiosulfate also appears to confer a mortality benefit. One-year mortality for calciphylaxis before the advent of sodium thiosulfate was estimated at around 55%.⁴³ In the study that assessed clinical response to sodium thiosulfate by surveys, 1-year mortality was lower, at 35%.⁴²

Vitamin K. The discovery that vitamin K deficiency prevents MGP activation and consequently promotes vascular calcification has spurred investigations of vitamin K as a decalcifying agent. Vitamin K retarded the progression of calcification in the coronary arteries and aortic valves in selected studies.^44–46 Vitamin K has also successfully treated calciphylaxis in a single patient.⁴⁷

A proof-of-concept study for vitamin K as therapy for calciphylaxis is ongoing (ClinicalTrials.gov no. 02278692). This trial will randomize 20 patients with calciphylaxis to vitamin K 10 mg orally three times a week for 12 weeks versus placebo. Notably, the treatment dose is approximately 30 times higher the normal dietary intake (0.10–0.15 mg/d). The primary outcome is a change in the carboxylation status of MGP. The secondary outcomes are change in pain levels and the size of lesions.

Wound Care and Pain Management

Optimization of wound healing entails a three-pronged approach with nutrition support, meticulous wound bed management, and possibly oxygenation augmentation.

Wound bed management focuses on moisture control with appropriate dressings, removal of devitalized tissue, and prevention and treatment of infection. Surgical debridement should be strongly considered for infected wounds (to prevent systemic infection) and for large wounds with exudate.⁸ Surgical debridement has been associated with survival benefit in a few small retrospective studies.^12,48 However, because the patient selection was not controlled, improved survival might have resulted from a selection of patients with more limited disease or fewer comorbid conditions. It should be remembered that severe pain in the wound bed makes any debridement, let alone surgical debridement, a challenge to perform. Severe hypoxia in the wound bed means that any surgical debridement runs the risk of poor wound healing and even wound expansion. For dry, uninfected wounds, the literature advocates for nonsurgical debridement (eg, enzymatic and autolytic).⁴⁹

Hyperbaric oxygen therapy may be considered for recalcitrant wounds. It entails delivery of 100% oxygen at 2 to 2.5 times the atmospheric pressure in a sealed chamber for approximately 2 hours and aims to correct the ischemia pervasive in calciphylaxis wounds. In a retrospective study of 34 patients, 20 patients (58%) showed improvement in their wounds, with more than half achieving complete healing.⁵⁰ However, 12 patients (35%) experienced deterioration and 2 patients (6%) had no change, and most of them died within a year.

Pain management is crucial but is often challenging as pain may not be responsive to even high-dose analgesics.¹³ Morphine should be avoided in patients with calciphylaxis because it has active metabolites that accumulate in renal failure and cause respiratory depression.⁵¹ Fentanyl and methadone are preferred opioids because they have no active metabolites that accumulate in renal failure. Again, sodium thiosulfate can provide significant pain relief even before improvement in skin lesions.

CONCLUSIONS

Calciphylaxis is a cutaneous ischemic infarct caused by total occlusion of blood vessels in the subcutaneous fat and dermis. The occlusion is initiated by vascular wall calcification and is completed by thrombosis, resulting in painful plaques and ulcers. Until recently, treatments have been limited to controlling its risk factors and optimizing wound care. However, recent advances in our understanding of the mechanism of vascular calcification in calciphylaxis have identified promising potential therapeutic targets.

As providers gain more insight into how calciphylaxis develops and identify additional novel therapeutic targets, it may soon be possible to effectively treat what has been a highly debilitating illness since its first description half a century ago.

 

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