Calciphylaxis (calcific uremic arteriolopathy)

INTRODUCTION — Calciphylaxis is a rare and serious disorder that presents with skin ischemia and necrosis and is characterized histologically by calcification of arterioles and capillaries in the dermis and subcutaneous adipose tissue [1]. It is a lethal disease that carries a high morbidity and mortality, with an estimated six-month survival of approximately 50 percent [2]. There is no approved treatment for calciphylaxis.

Calciphylaxis most commonly occurs in patients who have end-stage kidney disease (ESKD) and are on dialysis [2-4] but may also occur in kidney transplant recipients [4] and in non-ESKD patients [5,6].

The term "calciphylaxis" is a misnomer since it implies a systemic anaphylactic or hypersensitivity reaction [7]. Calcific uremic arteriolopathy is a more descriptive term for this process in ESKD patients; however, calciphylaxis is more widely used to describe this disorder. We use the term calciphylaxis to refer to calcific uremic arteriolopathy in ESKD patients. We continue to use the term calciphylaxis to refer to the disorder in non-ESKD patients.

This topic reviews the pathogenesis, diagnosis, and treatment of calciphylaxis in ESKD (calcific uremic arteriolopathy) and non-ESKD patients.

Other issues related to vascular calcification in ESKD are presented separately. (See "Vascular calcification in chronic kidney disease".)

PATHOGENESIS — Calciphylaxis is a poorly understood disorder. The skin lesions of calciphylaxis result from reductions in the arteriolar blood flow [8,9]. Reduced blood flow is caused by calcification, fibrosis, and thrombus formation primarily involving the dermo-hypodermic arterioles. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Microvascular calcification occurs first [10], likely via an active process involving upregulation of factors involved in osteogenesis and bone remodeling, including bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (RUNX-2) [1,11-13], and osteopontin [14,15]. Adipocytes may also play an important role in the development of vascular calcification of calciphylaxis [16]. Ongoing vascular endothelial injury causes cutaneous arteriolar narrowing and thrombosis leading to tissue infarction [17].

Factors presumed to be involved in the widespread calcification are chronic kidney disease-mineral bone disorder (CKD-MBD) and its treatment (including hyperparathyroidism, abnormalities in calcium and phosphate, and vitamin D administration), deficiencies of the inhibitors of vascular calcifications, and chronic inflammation. These are discussed below.

Hyperparathyroidism and vitamin D — Hyperparathyroidism, active vitamin D administration, hyperphosphatemia, and an elevated plasma calcium x phosphate product (Ca x P) have historically been implicated in calciphylaxis. A role for hyperparathyroidism was suggested by animal models that show that the administration of large amounts of parathyroid hormone (PTH) induces ischemic skin necrosis [18]. In addition, parathyroidectomy has been associated with clinical improvement in some patients [2,19]. The benefit of parathyroidectomy may be related to the transient uptake of calcium and phosphate into bone that occurs following surgery and the resultant lowering of serum calcium and phosphate levels.

However, there has been no prospective evaluation of the effectiveness of parathyroidectomy to treat calciphylaxis. Moreover, most patients with severe hyperparathyroidism do not have skin necrosis, and many patients with calciphylaxis do not have hyperparathyroidism, indicating other causes are responsible for calciphylaxis [4,20]. In a report from the German Calciphylaxis Registry, only 6 percent of patients with calciphylaxis had PTH levels above the Kidney Disease: Improving Global Outcomes (KDIGO) recommended target range [4]. Studies that report comprehensive data on PTH levels months to years prior to calciphylaxis diagnosis are required to determine the pathogenic role of hyperparathyroidism in calciphylaxis.

The use of cinacalcet to treat hyperparathyroidism may reduce the risk of calciphylaxis. This was suggested by an analysis of adverse event reports collected during the Evaluation of Cinacalcet (EVOLVE) trial [21]. Among 3861 participants who received at least one dose of the study drug, 24 developed calciphylaxis during follow-up [21]. The risk of calciphylaxis was lower among those who received cinacalcet compared with placebo (6 versus 18, unadjusted relative hazard ratio [HR] 0.31, 95% CI 0.13-0.79).

However, our confidence in the results of this trial is limited due to the low event rate of calciphylaxis and insufficient data regarding other factors (eg, warfarin use during the trial period). Although cinacalcet reduced the PTH level, the mechanism remains unclear as calciphylaxis developed in patients with both high and low PTH. In addition, in this trial, there was a high dropout rate in the cinacalcet group and a high rate of crossover in the placebo group [22]. In a large case-control study, cinacalcet use at dialysis initiation was associated with increased risk of subsequent calciphylaxis [23]. Further study is needed to determine the role of cinacalcet in the prevention and treatment of calciphylaxis [24].

The role of cinacalcet in treatment of calciphylaxis is discussed below. (See 'Treatment of calcium, phosphorus, and parathyroid hormone abnormalities' below.)

At high doses, vitamin D administration can induce calciphylaxis and exacerbate soft-tissue calcifications in experimental models [25,26]. This observation may be relevant because calcitriol and other vitamin D analogs are routinely administered to treat secondary hyperparathyroidism in end-stage kidney disease (ESKD) patients. Active vitamin D analogs may contribute to calciphylaxis either indirectly, through their actions to increase serum calcium and phosphate, or directly, through their effect on the vasculature. In one case-control study of patients on hemodialysis (62 calciphylaxis cases and 124 controls), calcitriol use was associated with increased odds of calciphylaxis (odds ratio [OR] 5.69, 95% CI 1.02-31.77) [20]. In another larger case-control study of patients on hemodialysis, nutritional vitamin D treatment was associated with increased odds of developing calciphylaxis (OR 2.11, 95% CI 1.41-2.95), and active vitamin D treatment was associated with increased odds of development of calciphylaxis involving peripheral body areas such as lower extremity distal to knees (OR 1.98, 95% CI 1.09-3.65) [23].

Early data suggest that polymorphisms in genes encoding vitamin D receptor (rs17882106 and rs10783223) and fibroblast growth factor 23 (rs7310492, rs11063118, and rs13312747) may be important in the development of calciphylaxis [27]; however, further evaluation of these preliminary findings is needed.

Inhibitors of vascular calcification — Deficiencies in inhibitors of vascular calcifications may play a role in calciphylaxis pathogenesis. Such inhibitors include fetuin-A (2-Heremens-Schmid glycoprotein) and matrix Gla protein (MGP):

●Fetuin-A (eg, 2-Heremens-Schmid glycoprotein) is an abundant serum glycoprotein that binds calcium and phosphate in the circulation, thereby forming "calciprotein particles" that help clear the circulation of excess Ca x P [28]. In animal models, fetuin-A limits organ and soft-tissue calcification and vascular calcium deposition [29]. Vitamin D-mediated tissue calciphylaxis is associated with fetuin-A downregulation [25].

Clinical observations also support a role for fetuin-A. Low fetuin-A levels correlate with a chronic inflammatory state and cardiovascular calcification in patients on hemodialysis [30]. Compared with serum fetuin-A levels in healthy individuals, fetuin-A levels in patients on hemodialysis are lower and have diminished capacity to inhibit ex-vivo Ca x P precipitation [31]. Fetuin-A is downregulated in inflammatory states [32] and has been reported to be decreased in calciphylaxis patients [4].

●MGP is a mineral-binding extracellular matrix protein that is synthesized by vascular smooth muscle, endothelium, and chondrocytes [33]. MGP inhibits calcification of arteries and cartilage in an animal model [34]. MGP activity depends upon vitamin K-dependent carboxylation [33]. In a case-control study of 20 hemodialysis-dependent patients with calciphylaxis (cases) and 20 hemodialysis-dependent patients without calciphylaxis (controls), cases had higher plasma levels of uncarboxylated MGP and carboxylated MGP than controls. However, the fraction of total MGP that was carboxylated was lower in cases than in controls [11]. This is relevant because warfarin (vitamin K antagonist) is a risk factor for calciphylaxis, and warfarin is known to inhibit vitamin K-dependent mechanisms. The warfarin-induced inhibition of vitamin K-dependent carboxylation of MGP may be a mechanism by which warfarin increases the risk of calciphylaxis [20,33-36]. (See 'Epidemiology and risk factors' below.)

●The calcification inhibitor pyrophosphate is degraded by tissue-neutral alkaline phosphatase, and adenosine inhibits tissue-neutral alkaline phosphatase [37]. Preliminary data suggest that polymorphisms in genes encoding cluster of differentiation 73 (CD73), responsible for local production of adenosine (rs9444348 and rs4431401), may be important in the development of calciphylaxis [27].

Chronic inflammation — Chronic inflammatory states may be involved in the development of calciphylaxis. Connective tissue diseases, Crohn disease, and autoimmune conditions have been reported in patients with uremic and nonuremic calciphylaxis [5,6,30,38-41]. (See 'Epidemiology and risk factors' below.)

Studies on the molecular regulators and inhibitors of skeletal and extraskeletal mineralization are needed to further our knowledge on the pathogenesis of calciphylaxis. (See "Vascular calcification in chronic kidney disease", section on 'Pathogenesis'.)

EPIDEMIOLOGY AND RISK FACTORS — Although previously considered rare, the incidence of calciphylaxis appears to be increasing, as suggested by an analysis of the United States Renal Data System [42]. The reasons for this apparent increase are unknown and may represent improved awareness of calciphylaxis and better recognition of clinical signs and associated risk factors. An early cross-sectional study of 242 outpatients on hemodialysis suggested a prevalence of 4 percent [43]. However, additional epidemiologic studies are required to reveal the true prevalence. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult dialysis patients".)

Studies have suggested the following risk factors for the development of calciphylaxis in end-stage kidney disease (ESKD) patients:

●Hyperphosphatemia [23,44]

●Medications including warfarin [20,23,35,44,45], calcium-based binders and vitamin D analogs [3], nutritional vitamin D [23], and systemic glucocorticoids [5,38]

●Female sex [21,36,44,46]

●Obesity (body mass index [BMI] >30) [21,23,47,48]

●Hypercoagulable states, such as protein C and S deficiency and antiphospholipid syndrome [49,50]

●Hypoalbuminemia [35]

●Diabetes [3,21,23]

●Longer dialysis vintage [43]

●Inflammatory and autoimmune conditions [5,6,30,38-41]

●Recurrent skin trauma [23]

Many studies and case reports have implicated warfarin as an important risk factor for the development of calciphylaxis. One retrospective cohort study including 2234 patients on hemodialysis identified four cases of calciphylaxis [45]. Of these 2234 patients, 142 were on warfarin. All cases of calciphylaxis occurred in the warfarin group (4 of 142 patients). In a large case-control study, 1030 calciphylaxis patients were compared with 2060 control patients without calciphylaxis [23]. In this study, warfarin use at dialysis initiation was associated with a subsequent development of calciphylaxis (odds ratio [OR] 3.22, 95% CI 2.11-4.65). In the German Calciphylaxis Registry, 52 percent of calciphylaxis patients received warfarin prior to calciphylaxis diagnosis [4]. The risk of calciphylaxis from vitamin K deficiency due to causes other than vitamin K antagonism needs further evaluation.

Observed associations between systemic glucocorticoid use and calciphylaxis may be due, at least in part, to the underlying autoimmune or inflammatory conditions that prompted treatment with glucocorticoids. Autoimmune disorders, including systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, temporal arteritis, and rheumatoid arthritis, may be risk factors for the development of calciphylaxis [39-41].

Iron administration has been proposed as a risk factor for calciphylaxis. Iron deposits have been demonstrated in biopsied tissue from patients with calciphylaxis [51,52].

One single-center study suggested that patients on peritoneal dialysis are at higher risk for calciphylaxis compared with patients on hemodialysis [3]. However, these data need further substantiation since high calciphylaxis incidence was subsequently linked to increased intake of calcium salts among patients on peritoneal dialysis [53]. The exact mechanism of a possible increase in calciphylaxis risk among patients on peritoneal dialysis is unclear. A single-center study of seven patients on peritoneal dialysis who developed calciphylaxis noted that five of these patients were previously on hemodialysis and were transitioned to peritoneal dialysis for access failure or inability to tolerate hemodialysis [54].

CALCIPHYLAXIS IN PATIENTS WITHOUT END-STAGE KIDNEY DISEASE — Calciphylaxis may occur among patients who do not have end-stage kidney disease (ESKD), including those with normal kidney function [5,6,38,55]. A systematic review revealed 36 reported cases of nonuremic calciphylaxis [5]. Most patients had a serum creatinine ≤1.2 mg/dL, and only three patients had a serum creatinine >2.5 mg/dL. The most commonly associated underlying conditions included primary hyperparathyroidism (28 percent), malignancy (22 percent), alcoholic liver disease (17 percent), and connective tissue diseases (4 percent). Sixty percent of patients had been previously treated with glucocorticoids, and 25 percent had been previously treated with warfarin.

In another retrospective series that included 15 non-ESKD patients with calciphylaxis, 80 percent were receiving glucocorticoids prior to the development of calciphylaxis, and 60 percent were receiving warfarin [38]. Sixty percent of patients had an autoimmune disorder (including systemic lupus erythematosus [SLE], polymyositis, Sjögren's disease, rheumatoid arthritis, sarcoidosis, and Crohn disease). Most patients in this series had impaired kidney function (though not ESKD); the estimated glomerular filtration rate (eGFR) was 20 mL/min/1.73 m² in three patients, 21 to 40 mL/min/1.73 m² in eight, 41 to 60 mL/min/1.73 m² in three, and >60 mL/min/1.73 m² in one.

As in studies of patients with ESKD, observed associations between systemic glucocorticoid use and calciphylaxis may be due, at least in part, to the underlying autoimmune or inflammatory conditions that prompted treatment with glucocorticoids.

CLINICAL MANIFESTATIONS

Signs and symptoms — Calciphylaxis is characterized by areas of excruciatingly painful ischemic necrosis [9,47]. In our experience, in some patients, pain may precede the development of skin lesions. The exact mechanism of pain in calciphylaxis is unclear and is thought to be ischemic in origin, but there may be a neuropathic component [39].

Lesions develop in areas with greatest adiposity [1,23]. Sites most commonly involved with skin lesions include distal lower extremities (55 percent), proximal lower extremities (39 percent), trunk (31 percent), distal upper extremities (7 percent), and proximal upper extremities (3 percent) [56]. Penile involvement may rarely occur (approximately 6 percent of patients) but is associated with high mortality [57].

The appearance of the lesions depends on the time of presentation. The most characteristic early lesions are violaceous, painful, plaque-like subcutaneous nodules, indurations, or livedo reticularis (picture 1) that progress to ischemic/necrotic ulcers with eschars once vascular thrombosis is advanced (picture 2) [17,58]. In our experience, lesions involving central body areas with thick adiposity (eg, abdomen, thighs, buttocks) are more likely to have a classic appearance with eschars compared with lesions involving acral areas (eg, fingers, toes). Eschars often become superinfected [47]. Atypical manifestations include papules, erythema resembling cellulitis, and erosions with hemorrhagic crust.

Ischemic myopathy, presenting as painful proximal muscle weakness, is an infrequent manifestation that can occur without skin necrosis [59].

Laboratory manifestations — There are no specific laboratory findings in patients with calciphylaxis. In some patients, increases in parathyroid hormone (PTH), phosphorus, and calcium may be observed, although these abnormalities are not always present [3].

Biopsy findings — Histologic examination of skin lesions reveals dermo-hypodermal and pannicular arteriolar calcification, subintimal fibrosis, and thrombotic occlusion (picture 3) [8,39,60]. There are no vasculitic changes. Calcification most commonly involves the medial layer of arteries, and arterioles as well as capillaries; however, involvement of the intimal layer and the interstitium of subcutaneous adipose tissue has also been reported [61]. Detection of microcalcification often requires special stains such as von Kossa or Alizarin red [62].

DIAGNOSIS

When to suspect calciphylaxis — Calciphylaxis should be suspected in patients with end-stage kidney disease (ESKD) or advanced chronic kidney disease who present with painful subcutaneous nodules or plaques; nonhealing ulcers; and/or cutaneous necrosis, particularly when present on the thigh and other areas of increased adiposity. Additional clinical features to suspect the diagnosis of calciphylaxis include warfarin use, obesity, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels over the preceding several months.

Calciphylaxis may be misdiagnosed, particularly in the early stages when typical clinical features are absent [63]. In one single-center study of 119 patients with calciphylaxis, 73 percent were initially misdiagnosed; the most common misdiagnoses were cellulitis (31 percent), skin infection (8 percent), and peripheral vascular disease (7 percent) [64]. (See 'Differential diagnosis' below.)

Confirming the diagnosis — In many patients with a suspected diagnosis of calciphylaxis (see 'When to suspect calciphylaxis' above), the diagnosis is made based upon the physical examination finding of classic painful ulcerated lesions that are covered by a black eschar (picture 1 and picture 2). A skin biopsy to confirm the diagnosis may not be necessary among ESKD patients presenting with such classic lesions. However, a skin biopsy is indicated if the diagnosis is uncertain, if the patient presents with atypical (eg, papules, erythema resembling cellulitis) or early lesions, or in patients presenting with characteristic calciphylaxis lesions who do not have advanced chronic kidney disease [65]. A dermatologist plays an important role during the initial evaluation to help eliminate conditions that mimic calciphylaxis and to perform a skin biopsy. We do not routinely obtain imaging studies for the diagnosis of calciphylaxis, although imaging studies may be required to diagnose complications such as a deep-seated infection.

If a skin biopsy is indicated, we request a 4 to 5 mm sample to be collected using a punch or telescoping biopsy technique. The biopsy should be performed by an experienced dermatologist or a surgeon. The sample should be collected from the periphery of the lesion, avoiding the frankly necrotic areas. We avoid performing an excisional biopsy due to the higher risk of complications associated with this technique. A skin biopsy is contraindicated if there is suspicion of a superimposed infection.

A skin biopsy in patients with calciphylaxis is not without risk. Among such patients, the procedural risks include intensification of pain, ulceration, superimposed infection, propagation of new lesions, bleeding, and induction of necrosis [3,39]. Preliminary data suggest that image-guided core needle biopsy may be safer than conventional biopsy and provide sufficient tissue to evaluate for calciphylaxis [66].

Definitive histologic criteria for the diagnosis of calciphylaxis have not been established. Histologic features that are typically ascribed to calciphylaxis are not specific and can be seen in other vascular and cutaneous diseases. As an example, one study compared the histologic findings of 38 skin biopsy samples from patients suspected to have calciphylaxis with 37 skin samples obtained from healthy margins of amputations in patients with ESKD with peripheral arterial disease without clinical evidence of calciphylaxis [67]. Histologic features were shared among patients with ESKD with and without calciphylaxis, and no finding in isolation was diagnostic of calciphylaxis. However, patients with calciphylaxis did have a sixfold higher prevalence of simultaneous medial calcification and thrombosis compared with the amputation samples. Thus, the presence of histologic changes suggestive of calciphylaxis in the absence of cutaneous lesions of calciphylaxis does not confer the diagnosis of calciphylaxis.

Although modalities such as radiography and computed tomography (CT) have been shown to detect tissue calcifications in patients with calciphylaxis [68-70], their diagnostic accuracy has not been evaluated in large studies. A three-phase technetium 99m methylene diphosphate bone scan may be a helpful adjunct to support diagnosis of calciphylaxis, especially to identify cutaneous calcifications (image 1) [71,72].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of calciphylaxis includes atherosclerosis, cholesterol embolization, warfarin necrosis, endarteritis obliterans, vasculitis, cellulitis, purpura fulminans, oxalate vasculopathy, antiphospholipid antibody syndrome, cardiac myxoma, radiation arteritis, Martorell hypertensive ischemic ulcer, and in early stages, nephrogenic systemic fibrosis (NSF) [39,73].

History, physical findings, laboratory and imaging tests, and skin histology evaluation help exclude other diagnoses.

In particular, patients with calciphylaxis typically lack other signs of vasculitis and, by contrast to patients with atherosclerosis, have intact peripheral pulses, bilateral necrosis, and more frequent involvement of the upper extremity [74]. (See "Overview of and approach to the vasculitides in adults", section on 'Clinical features suggestive of systemic vasculitis' and "Overview of lower extremity peripheral artery disease".)

By contrast to calciphylaxis, endarteritis obliterans typically affects distal extremities first, and patients describe symptoms of claudication and pain at rest (see "Thromboangiitis obliterans (Buerger disease)", section on 'Clinical features'). As noted, however, calciphylaxis can occasionally involve digits. (See 'Signs and symptoms' above.)

NSF is characterized by erythematous papules that coalesce into erythematous to brawny plaques, and the skin involved becomes thickened and woody in texture [75]. A history of gadolinium exposure as an inciting event supports an NSF diagnosis. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

As noted above, calciphylaxis is best distinguished from most other disorders by history and physical examination, with histologic examination of skin biopsy tissue if necessary.

TREATMENT

Initial treatment for all patients — There are no high-quality studies to guide the optimal treatment approach for patients with calciphylaxis. Our approach, which is based upon data from observational studies and our clinical experience, involves multidisciplinary management for all patients with calciphylaxis regardless of the severity of the disease [76-79]. The main components of this approach include analgesia, wound care, and mitigation of risk factors. These components are delivered in a collaborative manner in consultation with a dermatologist, a wound care specialist, a nephrologist, and a pain and palliative care specialist. Medications such as sodium thiosulfate (STS), bisphosphonates, and calcimimetics are frequently used; however, their efficacy remains uncertain.

Wound care and pain management — Wound care and pain control are critical aspects of the management of calciphylaxis. A wound care team should be involved in the selection of dressings and chemical debridement agents and in the administration of negative pressure wound therapy. In all patients, repetitive local trauma to skin (eg, subcutaneous injections) should be avoided altogether or at least minimized (eg, by rotating injection sites for therapies such as insulin). (See "Basic principles of wound management" and "Overview of treatment of chronic wounds".)

Opioid analgesics are often required to control pain associated with calciphylaxis. Patients typically need more analgesics and aggressive wound care after debridement. Because of the severity and complexity of pain in this population, consultation of a pain management service is often needed. (See "Use of opioids in the management of chronic non-cancer pain" and "Approach to the management of chronic non-cancer pain in adults".)

Treatment of infected wounds — Wound infection is a common complication of calciphylaxis that may present as increased pain, swelling, and/or purulent discharge at the site of the wound. Clinicians should maintain a high index of clinical suspicion for infection during the entire disease course. The treatment of suspected wound infections includes antimicrobial therapy and surgical debridement. Wounds with heavy necrotic burden that are at a high risk for infection should also be debrided.

In patients with calciphylaxis, it is typically not possible to identify a specific culprit organism. Superficial swabs of the wound are not reliable for the diagnosis of an infection or for isolation of the infecting organism. Thus, empiric antibiotic therapy for suspected wound infections should include drugs with activity against streptococci, methicillin-resistant Staphylococcus aureus, aerobic Gram-negative bacilli, and anaerobes. Details regarding antibiotic selection are discussed elsewhere. (See "Acute cellulitis and erysipelas in adults: Treatment" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)

Surgical debridement by an experienced wound surgeon is indicated for infected wounds or for wounds with heavy necrotic burden that are at a high risk for infection. Serial wound debridement should be combined with negative pressure therapy and followed by a split-thickness skin graft. Surgical debridement may confer mortality reduction [2,38]; however, careful patient selection is crucial. We avoid surgical debridement in the absence of an active infection or if the extent of necrosis is minimal.

Treatment of calcium, phosphorus, and parathyroid hormone abnormalities — In patients with calciphylaxis, we treat hyperphosphatemia (serum phosphate >4.5 mg/dL [1.45 mmol/L]) to target a serum phosphate between 3.5 and 4.5 mg/dL (1.13 to 1.45 mmol/L). We use non-calcium-containing phosphate binders, such as sevelamer carbonate or lanthanum carbonate, rather than calcium-based phosphate binders. There are no prospective studies to support this approach. Case reports suggest a benefit associated with lowering elevated serum phosphate and/or calcium x phosphate product (Ca x P), although the absolute threshold at which a benefit is conferred is uncertain [80-82]. We avoid the use of calcium-based binders as it may increase the rate of vascular calcifications [80-82]. (See "Management of hyperphosphatemia in adults with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

In patients with calciphylaxis who have a serum parathyroid hormone (PTH) level >300 pg/mL, we initiate treatment with cinacalcet and titrate the dose (generally 30 to 180 mg daily) to maintain a PTH level between 150 and 300 pg/mL. For patients who are already on cinacalcet, we uptitrate the dose if the PTH level is >300 pg/mL. This threshold for treatment, PTH goal, and choice of agent differ from those recommended by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines for patients on dialysis with hyperparathyroidism [83]. In the absence of robust comparative data, our practice of stricter control of hyperparathyroidism is based upon the potential important role of PTH in the pathogenesis of calciphylaxis. (See 'Hyperparathyroidism and vitamin D' above.)

We avoid vitamin D analogs, since they have a tendency to raise the serum calcium and phosphorus concentrations, whereas cinacalcet lowers serum calcium while suppressing PTH. We prefer cinacalcet over surgical parathyroidectomy, given the potential risks of hungry bone syndrome, surgical wound infection, and adynamic bone disease associated with surgical parathyroidectomy. However, for patients with calciphylaxis who have a PTH >600 pg/mL despite high-dose cinacalcet therapy for over one month, we suggest a parathyroidectomy. Some clinicians prefer to proceed directly to a parathyroidectomy (without use of cinacalcet) among patients with severe hyperparathyroidism (ie, PTH >800 pg/mL). (See "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics' and "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Refractory hyperparathyroidism'.)

Excessive suppression of PTH to <100 pg/mL should be avoided to prevent the development of adynamic bone disease, which may also predispose patients to vascular calcification. (See "Adynamic bone disease associated with chronic kidney disease", section on 'Vascular calcification'.)

There is no high-quality evidence to support the use of cinacalcet or parathyroidectomy in patients with calciphylaxis, and our approach is based upon our clinical experience, recognition of the role of hyperparathyroidism in the pathogenesis of calciphylaxis, and cautious interpretation of limited available data. Several case reports have suggested a benefit to cinacalcet [84-86]. However, in a meta-analysis of observational studies that compared outcomes among calciphylaxis patients treated with different treatment modalities, cinacalcet use was not associated with a lower risk of mortality, wound progression, or amputation [56]. Similarly, surgical parathyroidectomy was not associated with a lower risk of mortality or amputation but was associated with a slightly lower risk of wound progression. We do not change our practice based on the findings of this meta-analysis given the absence of any data from prospective clinical trials, the heterogeneity of the patients and study designs included in this analysis, as well as the selection and publication bias associated with such analysis.

Dialysis optimization — In patients with calciphylaxis who are on dialysis, we optimize the dialysis prescription to achieve the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) goals of dialysis adequacy [87,88]. We do not routinely intensify dialysis beyond the goals of dialysis adequacy, given insufficient evidence of benefit for this approach. However, we increase the duration and/or frequency of hemodialysis among patients who have refractory hyperphosphatemia despite dietary restrictions and medications. In addition, we do not routinely convert patients who are on peritoneal dialysis to hemodialysis unless they are failing peritoneal dialysis. (See "Prescribing and assessing adequate hemodialysis", section on 'Target Kt/V'.)

There are no confirmatory data that routine intensification of dialysis in patients with optimal adequacy parameters improves outcomes. In a retrospective analysis of 24 patients with calciphylaxis who were treated with a multi-intervention management program consisting of intensive hemodialysis (>20 hours per week), STS, wound care, analgesics, and discontinuation of trigger medications, complete or partial resolution of skin lesions occurred in 17 (71 percent) [79]. However, the direct benefit of intensive hemodialysis in this study is unclear given the concomitant use of other treatment modalities. By contrast, in another cohort of 117 patients with calciphylaxis, aggressive hemodialysis was associated with an increased risk of death (hazard ratio [HR] 3.21, 95% CI 1.32-7.82) [89].

Medication adjustment — We discontinue, if possible, all medications that may contribute to calciphylaxis, including vitamin D, calcium supplements, warfarin, and iron. Kidney transplant patients who have progressive or persistent calciphylaxis lesions may require adjustment of their immunosuppressive therapy with specific attention to avoiding agents that delay wound healing. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

In patients who are being treated with warfarin, the risk and benefits of continuing this medication need to be weighed against the risk of progressive, nonhealing necrotic ulcers. If possible, we prefer to discontinue warfarin and use alternative anticoagulants in patients with calciphylaxis. As an example, those who are receiving warfarin for nonvalvular atrial fibrillation or deep venous thrombosis can be switched to a direct oral anticoagulant (such as apixaban), which appears to be safe and effective in patients with calciphylaxis [78]. In patients who are receiving warfarin for a hypercoagulable disorder (eg, antiphospholipid antibody syndrome) or for a mechanical prosthetic heart valve, we switch to low molecular weight heparin. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Antithrombotic therapy for mechanical heart valves".)

We do not routinely administer vitamin K supplementation to treat calciphylaxis. Although a theoretical benefit of vitamin K supplementation has been postulated, data on the efficacy and safety of vitamin K supplementation are unclear in this setting.

We believe all iron products should be stopped since iron is a possible risk factor for calciphylaxis. However, a contributive role of iron to calciphylaxis has not been proven. (See 'Epidemiology and risk factors' above.)

Trial of sodium thiosulfate — We suggest a trial of STS in all patients with calciphylaxis for at least three to four weeks. Despite uncertain efficacy and limited data regarding its safety, STS is frequently considered as an off-label treatment for calciphylaxis. Dosing, duration of treatment, and monitoring and management of side effects are described below.

STS is an inorganic salt that is postulated to have vasodilatory and antioxidant properties [90] and, in an in vitro study, has been found to block the ability of adipocytes to induce calcification of vascular smooth muscle cells [16].

Evidence in support of the use of STS primarily comes from retrospective studies and case series [46,76,91,92]. However, meta-analyses of data from retrospective studies found no differences in the risk of mortality, wound progression, or amputation among calciphylaxis patients treated with and without STS [56,93]. We do not change our practice based upon the findings of these meta-analyses given the absence of any data from prospective clinical trials, the heterogeneity of the patients and study designs included in these analyses, as well as the selection and publication bias associated with such analyses. In addition, we have had success in treating patients with STS if there is clinical response within two to three weeks of STS initiation.

Dosing — We initiate intravenous (IV) STS at a dose of 25 g. We reduce the dose of STS to 12.5 g for patients weighing <60 kg and those weighing ≥60 kg who cannot tolerate the higher dose. Dosing frequency depends upon the patient's kidney function and dialysis modality:

●In patients on hemodialysis, we administer STS over 30 to 60 minutes during the last hour of each hemodialysis session.

●In patients on peritoneal dialysis, we administer STS over 60 minutes, three times weekly. In patients with significant residual kidney function, the frequency may be increased to four times per week as tolerated. This can be coordinated at a dialysis unit, an infusion center, or at home with visiting nurse services.

●In patients not on dialysis with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m², we initially administer STS twice weekly. We monitor the serum bicarbonate concentration on a weekly basis for two weeks for the development of metabolic acidosis. In the absence of overt metabolic acidosis (serum bicarbonate concentration below 18 mEq/L) or hypotension, we increase the STS frequency gradually to four times weekly as tolerated.

●In patients not on dialysis with an eGFR ≥60 mL/min/1.73 m², we initially administer STS twice weekly. We monitor the serum bicarbonate concentration on a weekly basis for two weeks for the development of metabolic acidosis. In the absence of overt metabolic acidosis (serum bicarbonate concentration below 18 mEq/L) or hypotension, we increase the STS frequency gradually up to five times weekly as tolerated.

In patients who experience gastrointestinal side effects from STS treatment, the duration of infusion can be increased by an additional 30 to 60 minutes.

In patients who cannot tolerate IV STS or who are unable to have IV access, intralesional STS can be administered with the help of a dermatologist. Limited data suggest that 1 to 3 mL of 250 mg/mL intralesional STS injected weekly in the areas of clinically active calciphylaxis may be helpful [94].

We do not use oral STS due to its low bioavailability or intraperitoneal STS due to the risk of chemical peritonitis [95,96].

Duration of treatment — The optimal duration of treatment with STS is not known. In most patients, we treat with STS for three months. However, we modify the duration of therapy depending upon the patient's response. In our experience, a clinical response within two to three weeks of STS initiation may be a predictor of favorable response. Among patients who experience significant improvement in the intensity of pain and the appearance of wounds, we frequently extend the duration of STS therapy until wound resolution. In patients who fail to respond to STS within the first two to four weeks, early cessation of therapy may be reasonable.

A dramatic reduction in pain has been reported within two weeks of starting STS, and almost complete resolution of calciphylaxis lesions has been reported within six months [97,98]. The median duration of STS treatment in the published reports has been 12 weeks (interquartile range 8 to 24 weeks) [56]. Duration of treatment should be balanced with an increased propensity for skeletal fractures and other major side effects seen among patients treated with long-term STS [99].

Side effects — The most commonly reported side effects include high anion gap metabolic acidosis in one-third of patients and nausea and vomiting in one-quarter of patients. Other less common side effects include volume overload, hypocalcemia, and corrected QT interval prolongation [39,56,100]. An increased propensity for skeletal fractures has been reported with long-term treatment with IV STS [99].

In our experience, the metabolic acidosis associated with STS can be severe. The mechanism by which STS causes acidosis is not known. STS itself is not an acid, as it does not donate protons. Thiosulfate is oxidized to sulfate either by the liver or by intestinal bacteria, which may contribute to its propensity to cause metabolic acidosis [101]. In patients with intact kidney function, STS is rapidly excreted and only partially metabolized. However, the excretion of nonmetabolized STS is diminished among patients on hemodialysis, resulting in a higher degree of metabolism to sulfate [95]. Among patients on hemodialysis, the use of high-bicarbonate dialysate may help limit the STS-induced metabolic acidosis [98].

Some of the side effects associated with STS may respond to dose reduction or increasing the duration of infusion. However, STS should be discontinued in patients who continue to experience the following:

●Presence of volume overload despite attempts at effective ultrafiltration and/or diuretic therapy

●Persistent severe metabolic acidosis despite dialysate bicarbonate adjustment or oral bicarbonate supplementation in predialysis chronic kidney disease patients

●Intractable nausea and vomiting

●Persistent severe hypocalcemia despite treatment

Monitoring the response to therapy — Response to the therapy is evaluated by assessing for changes in pain intensity and the size, number, and morphology of the lesions. Improvement is suggested by resolution of reticulate purpura or induration, decline in the intensity of pain, or formation of new granulation tissue. Conversely, an increase or new appearance of ulceration, erythema, discharge, or pain suggests disease progression.

We monitor serum calcium, phosphate, bicarbonate, anion gap, and white cell count on a weekly basis to guide modification of therapy as needed. (See 'Treatment of infected wounds' above and 'Treatment of calcium, phosphorus, and parathyroid hormone abnormalities' above and 'Dialysis optimization' above and 'Trial of sodium thiosulfate' above.)

Treatment of resistant disease — Calciphylaxis is considered treatment resistant when patients continue to have severe pain, progression, or complete lack of recovery of the skin lesions despite three months of the multimodal treatment described above. (See 'Initial treatment for all patients' above.)

Patients with treatment-resistant disease may have the following treatment modalities added in addition to the initial treatment for all patients described above. (See 'Initial treatment for all patients' above.)

Hyperbaric oxygen therapy — We treat with hyperbaric oxygen as a second-line therapy for recalcitrant calciphylaxis wounds unresponsive to optimal medical management as described above (see 'Initial treatment for all patients' above). We use it particularly in patients with lesions involving distal parts of extremities and in those with diabetes mellitus, when feasible. We administer hyperbaric oxygen (2.5 atm) or high-flow oxygen therapy (10 to 15 L/minute) 90 minutes per day for 25 sessions.

The use of hyperbaric oxygen for wound healing in calciphylaxis patients is supported by multiple case series and our personal clinical experience [76,102-104]. However, a meta-analysis of observational cohort studies that compared outcomes among calciphylaxis patients treated with or without hyperbaric oxygen found that hyperbaric oxygen did not reduce the risk of wound progression, rate of amputation, or mortality [56]. Disadvantages of hyperbaric oxygen therapy include its high cost, claustrophobia during treatment, and need for transportation to the chamber.

Bisphosphonates — We administer bisphosphonates to patients with treatment-resistant calciphylaxis who have hypercalcemia. We use an initial dose of 90 mg of IV pamidronate followed by three to four weekly doses of either 30 mg of IV pamidronate or 35 mg of oral alendronate.

The use of bisphosphonates has not been well studied among patients with advanced kidney disease or among those with calciphylaxis. In a meta-analysis of observational studies that compared clinical outcomes among patients with calciphylaxis treated with or without bisphosphonates, bisphosphonate treatment was not associated with a reduced risk of mortality or wound progression [56]. However, there was a trend toward a reduced risk of amputation.

The use of bisphosphonate therapy in patients with advanced kidney disease is discussed at length elsewhere. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Estimated glomerular filtration rate <30 mL/min'.)

Experimental therapies — A number of novel and experimental therapies have been evaluated in calciphylaxis and may be used in patients who have treatment-resistant lesions. In all cases, the limited data and experimental nature of the therapy should be disclosed to the patient, taking into account the cost, availability, and patient-related factors.

●Daily, low-dose infusion of tissue plasminogen activator was used successfully as adjuvant treatment in a small number of patients, but many such treatments were complicated by bleeding [105]. Low-dose infusion of tissue plasminogen activator may be used for treatment-resistant calciphylaxis patients with hypercoagulable states (such as protein C and S deficiency and antiphospholipid syndrome).

●Sterile maggot therapy with larvae of the greenbottle fly, Lucilia sericata, has been described as a second-line therapy in case reports [106,107].

●A single-center study reported the successful use of prednisone in end-stage kidney disease (ESKD) patients with nonulcerating plaques [3]. Among 14 patients without ulcers and an increased risk of infection, prednisone resulted in stabilization or improvement in 11. However, a retrospective, case-control study reported that systemic corticosteroids are a risk factor for calciphylaxis in non-ESKD patients with an autoimmune disorder [38]. Given the lack of an adequate control group and the marked risks associated with corticosteroids (particularly infection), further study is clearly needed to understand the role, if any, of corticosteroids in this setting.

●Leg revascularization was attempted in two patients with calciphylaxis, but the results were poor [108], and we do not use revascularization procedures for calciphylaxis treatment.

●Vitamin K supplementation was reported as part of a multimodal treatment regimen in 18 percent of patients from the German Calciphylaxis Registry [4]; however, data on its efficacy and safety are limited and are the focus of an ongoing randomized, controlled trial [109].

●Low-density lipoprotein apheresis and double-filtration rheopheresis have been reported to successfully treat calciphylaxis [110,111]. More data are necessary before we can recommend this therapy for calciphylaxis treatment.

●Kidney transplantation has been reported to heal calciphylaxis skin lesions approximately within two to four months after transplantation [112].

PROGNOSIS — Calciphylaxis is a lethal disease that carries a high morbidity and an estimated mortality of approximately 40 percent at six months and 44 percent at one year [2,113]. Because of the sporadic nature of the disease, prospective studies assessing outcomes are lacking. Infection is the primary cause of the high mortality associated with this condition (up to 58 percent in one report) [114]. Ulceration carries a mortality of >80 percent [3]. Mortality rates in patients on long-term hemodialysis with calciphylaxis were almost three times higher than those for patients on long-term hemodialysis without calciphylaxis in the United States Renal Data System [42]. Patients not on dialysis with calciphylaxis also have a high mortality rate, albeit better than that for patients on dialysis with calciphylaxis [2,5].

The response to any therapeutic regimen appears to be poor. Features that worsen prognosis include more advanced disease at the time of therapy, proximal ischemic and necrotic lesions in the skin and soft tissues, presence of cardiovascular disease, and use of warfarin [89,115]. Digital ischemia has a somewhat better prognosis than proximal skin necrosis, but these patients are still at significant morbidity and mortality risk [116,117].

CALCIPHYLAXIS REGISTRIES

●Partners Calciphylaxis Biobank – This is a national-level prospective registry of calciphylaxis patients designed to collect clinical data and biospecimens [118].

●European Calciphylaxis Registry – This is a prospective registry developed as a collaborative effort among seven European countries (Belgium, France, Germany, Italy, Spain, the Netherlands, and Portugal). The German Calciphylaxis Registry is incorporated under the European Calciphylaxis Registry [119].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Calciphylaxis is a serious disorder that presents with skin ischemia and necrosis and occurs most commonly, though not exclusively, in patients with end-stage kidney disease (ESKD). The pathogenesis of calciphylaxis is poorly understood. Skin lesions result from reductions in arteriolar blood flow caused by calcification, fibrosis, and thrombus formation primarily involving the dermo-hypodermic arterioles. Hyperparathyroidism, deficiencies in inhibitors of vascular calcification, and chronic inflammation have also been implicated. (See 'Pathogenesis' above.)

●Clinical manifestations – Calciphylaxis is characterized by areas of excruciatingly painful ischemic necrosis (picture 1 and picture 2). In some patients, pain may precede the development of skin lesions. Lesions develop in areas with greatest adiposity. Sites most commonly involved include distal lower extremities, proximal lower extremities, trunk, distal upper extremities, and proximal upper extremities. (See 'Clinical manifestations' above.)

●Diagnosis – Calciphylaxis should be suspected in patients with ESKD or advanced chronic kidney disease who present with painful subcutaneous nodules or plaques; nonhealing ulcers; and/or cutaneous necrosis, particularly when present on the thigh and other areas of increased adiposity. The diagnosis is made by the physical examination finding of classic painful ulcerated lesions that are covered by a black eschar. A skin biopsy is indicated if the diagnosis is uncertain, if the patient presents with atypical or early lesions, or in patients presenting with lesions with classic calciphylaxis morphology who do not have advanced chronic kidney disease. (See 'Diagnosis' above.)

●Treatment – Our approach to treatment of calciphylaxis, which is based upon data from observational studies and our clinical experience, involves multidisciplinary management for all patients with calciphylaxis regardless of the severity of the disease, as follows (see 'Initial treatment for all patients' above):

•Wound care and pain management – A dedicated wound care team should be involved in the selection of dressings and chemical debridement agents and in the administration of negative pressure wound therapy. Repetitive local trauma to skin should be avoided or minimized. Consultation of a pain management service is frequently needed. (See 'Wound care and pain management' above.)

•Infected wounds – The treatment of suspected wound infections includes antimicrobial therapy and surgical debridement. Wounds with heavy necrotic burden that are at a high risk for infection should also be debrided. Empiric antibiotic therapy for suspected wound infections should include drugs with activity against streptococci, methicillin-resistant Staphylococcus aureus, aerobic Gram-negative bacilli, and anaerobes (Grade 2C). In patients with calciphylaxis, it is typically not possible to identify a specific culprit organism. (See 'Treatment of infected wounds' above.)

•Calcium, phosphorus, and parathyroid hormone abnormalities – For patients with calciphylaxis and hyperphosphatemia (serum phosphate >4.5 mg/dL [1.45 mmol/L]), we suggest treating with non-calcium-containing phosphate binders, such as sevelamer carbonate or lanthanum carbonate, rather than calcium-based phosphate binders (Grade 2C). We target a serum phosphate between 3.5 and 4.5 mg/dL (1.13 to 1.45 mmol/L). (See 'Treatment of calcium, phosphorus, and parathyroid hormone abnormalities' above.)

In patients who have secondary hyperparathyroidism, we initiate treatment when the PTH level is >300 pg/mL and target a level between 150 and 300 pg/mL. We suggest treatment with cinacalcet rather than vitamin D analogs or surgical parathyroidectomy (Grade 2C). For patients with resistant hyperparathyroidism (PTH level >600 pg/mL) in spite of cinacalcet, we suggest surgical parathyroidectomy (Grade 2C). (See 'Treatment of calcium, phosphorus, and parathyroid hormone abnormalities' above.)

•Dialysis optimization – We optimize the dialysis prescription to achieve the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) goals of dialysis adequacy. We do not intensify dialysis beyond the goals of dialysis adequacy, except in cases of refractory hyperphosphatemia. (See 'Dialysis optimization' above.)

•Medication adjustment – We discontinue, if possible, all medications that may contribute to calciphylaxis, including vitamin D, calcium supplements, warfarin, and iron. Kidney transplant patients who have progressive or persistent calciphylaxis lesions may require adjustment of their immunosuppressive therapy with specific attention to avoiding agents that delay wound healing. (See 'Medication adjustment' above.)

•Sodium thiosulfate – For patients with calciphylaxis, we suggest a trial of intravenous sodium thiosulfate (STS) (Grade 2C). Among patients who respond, we extend the duration of STS therapy until wound resolution. We stop STS in patients who fail to respond to STS within the first two to four weeks. (See 'Trial of sodium thiosulfate' above and 'Dosing' above and 'Duration of treatment' above.)

●Monitoring – The response to therapy is evaluated by assessing for changes in pain intensity and the size, number, and morphology of the lesions. Improvement is suggested by resolution of reticulate purpura or induration, decline in the intensity of pain, or formation of new granulation tissue. Conversely, an increase or new appearance of ulceration, erythema, discharge, or pain suggests disease progression. (See 'Monitoring the response to therapy' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge J Edward Hartle, II, MD, and Peter W Santos, DO, who contributed to earlier versions of this topic review.