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Calciphylaxis

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare and devastating syndrome characterized by calcification of small blood vessels (arterioles) in the dermis and subcutaneous fat, leading to ischemia, thrombosis, and subsequent painful skin necrosis.^[1] It most commonly affects patients with end-stage renal disease (ESRD), particularly those undergoing long-term dialysis, though non-uremic forms occur in individuals without kidney failure.^[2] The condition is marked by a high mortality rate, exceeding 50% within one year, often due to sepsis from infected ulcers or cardiovascular complications.^[1] The pathophysiology involves medial calcification of arterioles, endothelial injury, and microthrombi formation, which impair blood flow and cause tissue death.^[1] While the exact etiology remains incompletely understood, it is strongly associated with disorders of mineral metabolism, such as hyperparathyroidism, elevated calcium-phosphate product, and imbalances in vitamin D or parathyroid hormone levels, frequently seen in chronic kidney disease.^[2] Additional contributing factors include hypercoagulable states, inflammation, and vascular injury, exacerbated by dialysis-related factors like heparin use or bioincompatible membranes.^[1] Clinically, calciphylaxis presents with early signs such as livedo reticularis—a mottled, net-like purple skin pattern—and tender subcutaneous nodules, which progress to exquisitely painful ulcers with black eschar, commonly on the lower extremities, abdomen, thighs, or buttocks.^[2] Diagnosis is primarily clinical in high-risk patients but often confirmed by skin biopsy revealing arteriolar calcification and thrombosis, though biopsy carries risks of worsening necrosis.^[1] Risk factors include female sex, obesity, diabetes mellitus, Caucasian ethnicity, liver disease, and exposure to certain medications like warfarin or corticosteroids.^[1] The incidence in dialysis populations ranges from 0.04% to 4%, with a noted increase over recent decades possibly due to improved ESRD survival.^[1] Management is multidisciplinary and supportive, focusing on wound care, pain control, infection prevention, and addressing underlying metabolic derangements through phosphate binders, cinacalcet for hyperparathyroidism, or sodium thiosulfate infusions to inhibit calcification.^[1] In severe cases, parathyroidectomy or intensified dialysis may be considered, but no standardized therapy exists, and outcomes remain poor without early intervention.^[2] Ongoing research emphasizes multimodal approaches to improve survival in this challenging condition. Recent advances as of 2025 include promising results from Vitamin K therapy and phase III trials of SNF472 for inhibiting calcification.^[1]^[3]^[4]

Definition and Background

Definition

Calciphylaxis is a rare, progressive vasculopathy characterized by calcification of the medial layer of small dermal and subcutaneous arterioles, which leads to endothelial injury, thrombosis, ischemia, and subsequent skin necrosis.^[1] This condition primarily affects patients with end-stage renal disease (ESRD), though it can occur in non-uremic forms associated with underlying conditions such as malignancy, connective tissue diseases, or primary hyperparathyroidism.^[1]^[5] The disorder is also known as calcific uremic arteriolopathy (CUA), a term that highlights its frequent link to uremia, but it is distinct from other calcifying disorders like metastatic calcification, where calcium deposits occur in normal tissues due to systemic hypercalcemia without the ischemic vascular occlusion seen in calciphylaxis.^[1]^[6] The term "calciphylaxis" was coined in 1962 by Hans Selye to describe a hypersensitivity reaction to calcium, derived from "calci-" meaning calcium and "-phylaxis" implying protection.^[7]

Historical Development

Calciphylaxis was first described in 1898 by Bryant and White as a form of provisional calcification of the skin occurring in patients with renal failure and uremia.^[8] This early observation highlighted the association between chronic kidney disease and cutaneous vascular calcification leading to tissue necrosis, though the full syndrome was not yet delineated.^[7] The term "calciphylaxis" was coined in 1962 by Hans Selye and colleagues, including G. Gabbiani, based on experimental models in rats that demonstrated systemic hypersensitivity to calcium, induced by a sensitizing agent followed by a challenger such as parathyroid hormone.^[9] These studies portrayed calciphylaxis as a condition of induced calcification in response to specific physiological stressors, shifting focus from mere descriptive pathology to underlying hypersensitivity mechanisms.^[7] In the 1970s and 1980s, as long-term hemodialysis became more common, the condition gained wider recognition as calcific uremic arteriolopathy, a severe complication in dialysis patients characterized by arteriolar calcification, thrombosis, and ischemic necrosis.^[10] A seminal 1976 report by Gipstein et al. detailed 11 cases in patients with chronic renal failure, emphasizing its link to end-stage kidney disease and high mortality, which spurred clinical awareness during the expansion of dialysis programs.^[11] During the 1990s, research solidified key risk associations, including secondary hyperparathyroidism, with studies showing elevated parathyroid hormone levels in affected patients and exploring parathyroidectomy as an intervention to halt progression.^[12] Concurrently, investigations linked warfarin use to the development of calciphylaxis, with case series and analyses from the mid-1990s identifying it as a precipitating factor through inhibition of vitamin K-dependent proteins that regulate vascular calcification.^[13] In the late 2000s and 2010s, medical understanding evolved to emphasize non-uremic forms of calciphylaxis, occurring in patients without end-stage renal disease, alongside the promotion of multidisciplinary approaches involving nephrology, dermatology, and wound care for improved outcomes.^[5] A significant milestone in this era is the 2024 CALCIPHYX trial, which evaluated hexasodium fytate as a potential inhibitor of vascular calcification in calciphylaxis patients.^[14] In 2025, studies identified the IL-6–tissue factor signaling pathway as a key contributor to the pathogenesis of uremic calciphylaxis.^[15]

Epidemiology

Incidence and Prevalence

Calciphylaxis is a rare condition with an estimated prevalence of less than 1% in the general population, though it primarily affects individuals with end-stage renal disease (ESRD). Among patients with ESRD on dialysis, the prevalence ranges from 1% to 4%, with a reported incidence rate of 3.5 new cases per 1,000 patient-years in large U.S. cohorts from 2010–2014.^[16] In the United States, administrative data indicate an annual incidence of approximately 35 cases per 10,000 dialysis patients, based on analyses from major dialysis networks.^[17] Global variations in incidence reflect differences in dialysis practices, genetic factors, and diagnostic awareness. In Europe, rates are estimated at 4 cases per 10,000 dialysis patients annually, as observed in German registries. In contrast, Asian cohorts report lower figures, such as a 1.24% prevalence among Chinese hemodialysis patients in a multicenter survey from 2022, potentially due to underdiagnosis in resource-limited settings where access to biopsy confirmation is restricted.^[17]^[18] The incidence rate among dialysis patients has shown a slight increase since 2010, from around 3.5 per 1,000 patient-years to 4.5 per 1,000 patient-years as of 2019–2022 in Australia and New Zealand, with recent U.S. data from 2020–2024 indicating steadily rising prevalence. Increased recognition has highlighted non-uremic cases, which occur rarely outside ESRD and are associated with conditions like malignancies. Longer duration of dialysis is associated with higher risk, contributing to these patterns.^[19]^[5]^[20]^[21]

Demographic Patterns

Calciphylaxis predominantly affects adults aged 40 to 70 years, with the peak incidence occurring in the 50s to 60s; mean ages reported in large cohorts range from 49 to 59 years.^[22] The condition exhibits a marked female predominance, accounting for 70% to 80% of cases, which may be linked to factors such as hormonal influences or higher rates of obesity among affected women.^[22]^[8] Approximately 90% of calciphylaxis cases occur in patients with end-stage renal disease (ESRD), particularly those on long-term dialysis, while the remaining 10% are non-uremic and associated with conditions like liver disease, primary hyperparathyroidism, malignancy, or autoimmune disorders.^[5]^[23] Demographic patterns show an overrepresentation among Caucasians, with studies reporting 64% to 90% of cases in white populations, potentially influenced by disparities in dialysis access and vascular risk profiles; however, analyses from 2022 to 2024 highlight underreporting and higher prevalence among racial minorities, including Black populations, suggesting sociocultural health disparities rather than inherent racial risks.^[22]^[24]^[21] Comorbidity clusters frequently involve obese females with diabetes mellitus and extended dialysis duration exceeding 5 years, often compounded by hyperparathyroidism and warfarin use in ESRD settings.^[22]^[25]

Pathophysiology

Mechanisms of Calcification

Calciphylaxis is characterized by medial calcification of small arteries and arterioles in the dermis and subcutis, leading to luminal narrowing, ischemia, and subsequent thrombosis that impairs blood flow and causes tissue necrosis.^[1] This calcification primarily affects the tunica media, distinguishing it from intimal calcification seen in atherosclerosis, and results in a progressive occlusion of vessels.^[22] The process is driven by an imbalance in calcium-phosphate metabolism, where elevated serum phosphate levels promote the transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells capable of producing bone matrix proteins and facilitating ectopic mineralization.^[7] High phosphate concentrations induce this phenotypic switch through signaling pathways involving sodium-dependent phosphate transporters, leading to the expression of osteogenic genes such as core-binding factor alpha-1 (Cbfa1) and alkaline phosphatase.^[26] Deficiencies in natural calcification inhibitors exacerbate this uncontrolled deposition of calcium-phosphate crystals. Fetuin-A, a circulating protein, forms complexes with calcium and phosphate to create soluble calciprotein particles that prevent crystal nucleation and growth in soft tissues, and its downregulation in chronic kidney disease (CKD) patients correlates with increased vascular calcification.^[27] Similarly, matrix Gla protein (MGP), a vitamin K-dependent inhibitor, blocks the crystallization of hydroxyapatite by binding to it after carboxylation; uncarboxylated MGP, often elevated in CKD due to vitamin K deficiency or warfarin use, fails to inhibit calcification effectively.^[28] Pyrophosphate serves as another potent local inhibitor by directly adsorbing to nascent hydroxyapatite crystals and halting their propagation, with reduced levels contributing to medial vascular mineralization.^[29] An associated inflammatory cascade amplifies the damage through endothelial dysfunction, which exposes subendothelial collagen and triggers platelet adhesion and microthrombi formation.^[22] Complement activation further promotes local inflammation and VSMC proliferation, creating a prothrombotic environment that sustains ischemia. Recent research has identified the interleukin-6 (IL-6) signaling pathway as central to the initiation and progression of skin lesions, involving interactions between subcutaneous fat, sweat glands, and small blood vessels.^[30] In uremic calciphylaxis, prevalent in end-stage renal disease (ESRD), hyperphosphatemia from impaired phosphate excretion is the primary driver, compounded by secondary hyperparathyroidism and CKD-mineral bone disorder.^[7] Non-uremic forms, occurring in patients with preserved renal function, are instead propelled by local inflammatory triggers such as trauma or malignancy-associated factors that disrupt inhibitor balance and initiate calcification independently of systemic phosphate overload.^[1]

Risk Factors

Calciphylaxis is strongly associated with end-stage renal disease (ESRD), where renal factors play a central role in disease susceptibility. Patients with ESRD on hemodialysis face a higher risk compared to those on peritoneal dialysis, with hemodialysis being the predominant modality among affected individuals.^[19] Longer duration of dialysis, particularly exceeding one year, correlates with increased incidence, as does inadequate dialysis adequacy, which exacerbates uremic toxins and mineral imbalances.^[22] Metabolic derangements further heighten vulnerability, particularly in the context of chronic kidney disease. Hyperparathyroidism, often secondary to renal failure, promotes vascular calcification through elevated parathyroid hormone levels. Hyperphosphatemia, defined as serum phosphate levels greater than 5.5 mg/dL, is a key risk factor, while an elevated calcium-phosphate product exceeding 55 mg²/dL² amplifies the propensity for medial arteriolar calcification.^[19] Certain medications significantly elevate the risk of calciphylaxis by interfering with calcification inhibitors or promoting thrombotic tendencies. Warfarin use is particularly implicated, increasing the odds by up to 10-fold through inhibition of vitamin K-dependent proteins such as matrix Gla protein (MGP), which normally prevents vascular calcification; this effect is independent of its anticoagulant properties on protein C. Corticosteroids contribute via induction of hypercoagulability and metabolic disturbances, while overuse of vitamin D analogs can worsen hypercalcemia and phosphate retention.^[31]^[22] Additional patient-specific factors include obesity (BMI >30), which is linked to proximal skin involvement and adipose tissue inflammation; diabetes mellitus, a common comorbidity that impairs wound healing and vascular integrity; and female sex, with affected patients showing a 2:1 female predominance. Recent parathyroidectomy heightens risk due to postoperative metabolic rebound, including transient hypocalcemia followed by hypercalcemia.^[19]^[22] Non-uremic calciphylaxis occurs in patients without advanced kidney disease and is associated with autoimmune conditions such as systemic lupus erythematosus (SLE), malignancies including breast cancer, and liver disease, which may involve inflammatory or thrombophilic mechanisms.^[22]

Clinical Presentation

Signs and Symptoms

Calciphylaxis often presents early with painful, indurated subcutaneous nodules or plaques, primarily affecting areas rich in adipose tissue such as the lower extremities, abdomen, or thighs.^[1] These lesions may initially appear as violaceous or erythematous subcutaneous changes without overt skin breakdown.^[1] Pain frequently precedes visible skin alterations, manifesting as a hallmark feature that significantly contributes to patient morbidity.^[32] As the condition progresses, the skin develops livedo racemosa, a reticulated pattern of purple mottling due to underlying ischemia, which can evolve into deep ulceration covered by black eschar and surrounded by erythema.^[33] Ulcerations typically enlarge in a star-like fashion, becoming foul-smelling and prone to secondary infection, with the affected tissue hardening into a leathery consistency.^[32] The associated pain is severe, burning, and often disproportionate to the apparent extent of the lesions, frequently proving refractory to high-dose opioids and requiring multimodal analgesia.^[19] Systemic symptoms accompany the cutaneous findings in many cases, including fever, malaise, and myalgias, reflecting the vasculopathy's broader impact.^[1] Rare manifestations involve proximal muscle calcification, contributing to myalgias, while severe systemic involvement can lead to myocardial calcification termed "heart of stone," resulting in diastolic heart failure.^[34] Site-specific presentations rarely affect areas such as the breast or penis; digits may be involved in distal cases, where lesions may rapidly progress to gangrene and necessitate amputation.^[32]

Disease Variants

Calciphylaxis is broadly classified into uremic and non-uremic variants, with the former accounting for approximately 80-90% of cases and strongly linked to end-stage renal disease, particularly in patients on long-term dialysis.^[19] Uremic calciphylaxis, also termed calcific uremic arteriolopathy, arises from dysregulation of calcium-phosphate metabolism in chronic kidney disease, leading to vascular calcification and thrombosis predominantly in the skin and subcutaneous tissues. In contrast, non-uremic calciphylaxis comprises about 10-20% of cases and occurs in patients with normal or near-normal renal function, often associated with conditions such as connective tissue diseases, malignancies, alcoholic liver disease, or post-renal transplantation.^[5] This variant tends to have a somewhat lower mortality rate compared to its uremic counterpart, though overall prognosis remains poor due to similar ischemic complications.^[19] Within these categories, calciphylaxis manifests in proximal and distal subtypes based on lesion location, influencing disease aggressiveness and outcomes. The proximal subtype affects areas rich in adipose tissue, such as the thighs, abdomen, buttocks, and breasts, and is characterized by more severe, deep-seated lesions that progress rapidly to necrosis. It carries a higher mortality rate of 60-80%, primarily from sepsis secondary to extensive ulceration.^[35] Conversely, the distal subtype often involves acral sites like the calves, ankles, and toes, presenting with more superficial livedo reticularis or smaller ulcers. This form is associated with a relatively better prognosis, with improved survival linked to less aggressive tissue involvement and fewer systemic complications.^[36] Rare special-site involvements highlight the disease's potential for atypical and life-threatening presentations. Penile calciphylaxis, occurring in 1-5% of cases, predominantly affects male patients with end-stage renal disease and carries a high risk of penile amputation due to rapid progression to gangrene and infection; recent case reports as of 2024 emphasize the need for prompt surgical debridement to mitigate outcomes.^[37] Visceral calciphylaxis, though exceedingly uncommon, can involve internal organs such as the heart—termed "heart of stone" due to extensive myocardial calcification—leading to arrhythmias, heart failure, or sudden death, often without preceding cutaneous signs.^[38] Other visceral sites, including the intestines, lungs, and brain, may present with ischemia or infarction, underscoring the systemic nature of severe disease.^[19]

Diagnosis

Clinical Evaluation

Clinical evaluation of suspected calciphylaxis begins with a thorough patient history to identify key risk factors and contextual clues. Clinicians should inquire about the presence of end-stage renal disease (ESRD), including the duration of dialysis (dialysis vintage), as longer exposure increases susceptibility. History of warfarin use, recent trauma, or surgical interventions is critical, given their association with lesion onset. Pain assessment is paramount, often quantified using the Visual Analog Scale (VAS), where scores greater than 7/10 reflect the severe, ischemic nature of the discomfort prompting evaluation.^[33]^[1] Physical examination focuses on cutaneous and systemic findings to support suspicion. Inspection reveals characteristic skin changes, including livedo reticularis, violaceous mottling, subcutaneous nodules, and indurated plaques, predominantly on the lower extremities, abdomen, or thighs. Palpation confirms firmness and exquisite tenderness of lesions, while evaluation for peripheral edema, fever, or signs of systemic inflammation helps gauge overall disease impact. Early lesions may appear as erythematous papules progressing to necrotic ulcers, with rapid evolution distinguishing the condition.^[33]^[1] Differential diagnosis requires careful distinction from mimicking vasculopathies and ischemic conditions. Calciphylaxis must be differentiated from ANCA-associated vasculitis, which often involves systemic organ involvement beyond skin; warfarin-induced skin necrosis, typically occurring early in therapy without renal linkage; pyoderma gangrenosum, featuring undermined borders and pathergy; and atherosclerotic peripheral artery disease (PAD), where pulses are absent unlike in calciphylaxis. The rapid progression of lesions and strong ESRD association favor calciphylaxis over these alternatives.^[39]^[40] A multidisciplinary approach is integral, involving early consultation with dermatology, nephrology, and vascular surgery specialists to integrate expertise and avoid misdiagnosis as cellulitis or infection. Current guidelines underscore holistic assessment, incorporating patient comorbidities for timely intervention. Clinical risk stratification, though lacking a formal scoring tool, relies on factors like obesity (e.g., BMI >30 kg/m²), hypoalbuminemia (<3 g/dL), and elevated phosphate (>5.5 mg/dL) to gauge probability in at-risk ESRD patients.^[41]^[22]

Diagnostic Tests

Laboratory tests play a crucial role in evaluating metabolic derangements associated with calciphylaxis, particularly in patients with end-stage renal disease. Key assessments include serum calcium, phosphorus, and the calcium-phosphate product, where a product exceeding 70 mg²/dL² is suggestive of increased risk for vascular calcification. Parathyroid hormone (PTH) levels are often markedly elevated, with values above 300 pg/mL supporting clinical suspicion, alongside measurements of alkaline phosphatase to gauge bone turnover. To exclude superimposed infection, inflammatory markers such as C-reactive protein (CRP) and wound cultures are recommended.^[1]^[7]^[42] Imaging modalities provide non-invasive insights into vascular and soft tissue involvement. Plain X-rays can reveal characteristic netlike vascular calcifications in the dermis and subcutaneous tissues, aiding in diagnosis when biopsy is contraindicated. Doppler ultrasound assesses for peripheral ischemia by evaluating blood flow in affected limbs, while MRI delineates the extent of soft tissue edema and necrosis. Bone scintigraphy, using technetium-99m-labeled tracers, detects systemic calcification and may monitor disease progression, though it is not routinely used. Routine angiography is generally avoided due to the risks of contrast-induced nephropathy in renal patients.^[43]^[42]^[1] Skin biopsy remains the gold standard for confirming calciphylaxis, typically performed as a deep incisional or punch biopsy to include subcutaneous tissue. Histopathologic findings include medial calcification of dermal and subcutaneous arterioles, intimal hyperplasia, endovascular fibrosis, and microthrombi, without evidence of vasculitis. Extravascular calcification, fat necrosis, and panniculitis may also be present. However, biopsy carries significant risks, including ulceration, infection, bleeding, and poor wound healing, particularly in nonulcerated lesions; thus, it is reserved for cases with diagnostic uncertainty.^[1]^[42]^[43] Advanced diagnostic approaches, such as dermoscopy, can identify early reticulated livedo patterns suggestive of microvascular occlusion. Emerging non-invasive techniques, including point-of-care ultrasound (POCUS), highlight hyperechoic calcium deposits in the skin and vessels, offering a safer alternative for initial evaluation. Recent 2024 reviews emphasize prioritizing these non-invasive methods to reduce biopsy-related complications and improve diagnostic accuracy in high-risk patients.^[44]^[1]

Treatment

Wound Care and Supportive Measures

Wound management in calciphylaxis focuses on promoting healing of painful, necrotic skin lesions while minimizing trauma to fragile tissues. Gentle debridement using autolytic or enzymatic methods is preferred to remove necrotic tissue, as sharp debridement may exacerbate vascular compromise and is generally avoided unless infection is severe.^[19] Dressings such as hydrocolloids or silver-impregnated materials are recommended to maintain a moist environment, absorb exudate, and prevent infection without adhering to the wound bed.^[45] Routine cleansing with saline and vigilant monitoring for secondary infection are essential components of daily care.^[1] Pain control is a cornerstone of supportive care, given the intense, burning pain associated with calciphylaxis lesions. Multimodal analgesia incorporating opioids such as fentanyl patches provides effective relief, while nonsteroidal anti-inflammatory drugs (NSAIDs) should be used cautiously due to renal impairment risks.^[45] Non-pharmacological strategies, including cool compresses and limb elevation, help reduce inflammation and discomfort without additional systemic burden.^[19] Nutritional support addresses hypoalbuminemia, a common risk factor that impairs calcification inhibition and wound healing. Hyperalimentation is indicated for serum albumin levels below 3 g/dL to replenish protein stores and support tissue repair.^[41] In patients with end-stage renal disease, a protein intake of 1.2-1.5 g/kg/day is recommended to counteract malnutrition and promote recovery, often requiring enteral or parenteral supplementation.^[19] Additional supportive measures include dialysis optimization and adjunctive therapies for non-healing ulcers. Intensifying dialysis to daily sessions enhances clearance of uremic toxins and may facilitate ulcer resolution in end-stage renal disease patients.^[19] Hyperbaric oxygen therapy improves tissue oxygenation in ischemic wounds, with studies showing wound improvement in approximately 58% of cases and complete healing in over half of responders after multiple sessions.^[46] Multidisciplinary involvement from wound care clinics is crucial as of 2025, emphasizing trauma avoidance at lesion sites to prevent progression.^[41]

Pharmacological Interventions

Pharmacological interventions for calciphylaxis primarily target the underlying metabolic disturbances, such as hyperphosphatemia and secondary hyperparathyroidism, which contribute to vascular calcification. Non-calcium-based phosphate binders like sevelamer are preferred over calcium-containing agents to avoid exacerbating hypercalcemia, with typical dosing of 800-1600 mg three times daily with meals to bind dietary phosphate and maintain serum levels below 5 mg/dL. Intensification of hemodialysis, often to daily sessions, further aids in achieving this phosphate target by enhancing clearance, particularly in end-stage renal disease patients where hyperphosphatemia is a key risk factor. These measures have been associated with stabilization or improvement in lesion progression in observational studies. Management of parathyroid hormone (PTH) elevation involves calcimimetics such as cinacalcet, which sensitizes calcium-sensing receptors on parathyroid glands to suppress PTH secretion. Standard dosing starts at 30 mg daily, titrated up to 60 mg daily as needed to normalize PTH levels (typically targeting 150-300 pg/mL in dialysis patients), while monitoring for hypocalcemia. Excessive use of vitamin D analogs should be avoided, as they can worsen hypercalcemia and calcification without providing additional PTH control benefits in this context. Cinacalcet has demonstrated efficacy in reducing PTH by up to 60-80% and promoting ulcer healing in case series of calciphylaxis patients. Sodium thiosulfate (STS) serves as a key anticalcification agent, administered intravenously at 25 g post-dialysis three times weekly over 30-60 minutes, with treatment duration often extending 3-6 months or until response. Its mechanisms include calcium chelation to form soluble complexes for renal or dialytic clearance, antioxidant effects to mitigate oxidative stress in vessel walls, and potential vasodilatory properties to improve tissue perfusion. In a retrospective review of 172 patients, STS yielded positive responses (complete resolution, marked improvement, or partial improvement) in approximately 74%, though randomized data are limited. Adverse effects are generally mild, including nausea and metabolic acidosis, which resolve with dose adjustment. Emerging therapies focus on direct inhibition of vascular calcification. SNF472 (hexasodium fytate), an inhibitor of hydroxyapatite crystal formation in the arterial media, was evaluated in the 2024 phase 3 CALCIPHYX trial, a randomized, double-blind, placebo-controlled study of 71 patients on hemodialysis with ulcerated calciphylaxis. Administered at 7 mg/kg intravenously during dialysis sessions three times weekly for 12 weeks (with open-label extension), it did not meet the primary endpoints of improvement in wound assessment score or pain reduction but showed secondary benefits, including lower mortality (5% vs. 21% placebo) and reduced calciphylaxis-related infections (3% vs. 21%).^[4] In non-uremic calciphylaxis or cases linked to specific etiologies, other agents may be considered. Bisphosphonates, such as ibandronate (administered as 3 mg IV monthly), inhibit vascular calcification by suppressing hydroxyapatite deposition and have shown promise in case reports of non-uremic variants, with ulcer resolution in 4-6 months when combined with wound care. For warfarin-associated calciphylaxis, prompt reversal involves discontinuing warfarin and switching to alternative anticoagulants like unfractionated heparin or direct oral agents (e.g., apixaban at 5 mg twice daily, adjusted for renal function), which has halted progression and improved outcomes in retrospective analyses without increasing thrombotic risk.

Surgical and Procedural Options

Surgical debridement serves as a primary invasive option for stable patients with advanced calciphylaxis, focusing on the excision of necrotic tissue to halt progression and mitigate infection risks. This procedure is particularly indicated for wounds showing significant necrosis or infection without granulation tissue formation, ideally performed by specialized wound or plastic surgeons to optimize outcomes. Timely execution is essential, as delays can precipitate sepsis, a major contributor to the high mortality observed in untreated cases. Evidence from systematic reviews indicates that judicious surgical debridement correlates with statistically significant improvements in survival compared to conservative management alone.^[41]^[47]^[19] Parathyroidectomy is reserved for refractory cases driven by severe secondary hyperparathyroidism, typically when parathyroid hormone (PTH) levels surpass 1000 pg/mL despite medical optimization. This intervention applies to approximately 20-30% of uremic calciphylaxis instances where hyperparathyroidism exacerbates vascular calcification. While it can facilitate wound healing, pain relief, and extended survival in responsive patients, drawbacks include risks of postoperative hypocalcemia and hungry bone syndrome, attributed to abrupt metabolic shifts post-resection.^[48]^[49]^[50] Vascular access procedures, such as arteriovenous fistula creation or revision, are employed to enhance dialysis adequacy and reduce ischemic stressors in end-stage renal disease patients with calciphylaxis. For irreversible gangrene, amputation becomes necessary in 5-20% of affected cases, with higher incidence in distal limb or penile involvement due to progressive tissue necrosis. Tunneled catheters provide an alternative for immediate dialysis optimization when fistula maturation is delayed.^[1]^[51]^[41] Following debridement, reconstructive techniques like split-thickness skin grafting may be applied to promote epithelialization and wound closure in select stable patients. Endovascular interventions, such as angioplasty for proximal arterial stenoses, have been reported as adjunctive options in cases with identifiable vascular occlusions, though long-term efficacy data remain preliminary.^[41]^[52] Surgical and procedural interventions are contraindicated in hemodynamically unstable patients, where perioperative mortality can approach 50% owing to compounded sepsis and cardiovascular risks. Multidisciplinary assessment is imperative to weigh benefits against these elevated hazards in advanced disease.^[53]^[54]

Prognosis

Survival and Outcomes

Calciphylaxis is associated with high mortality, with rates ranging from 45% to 80% within one year of diagnosis.^[1] The primary causes of death are sepsis, accounting for the majority of fatalities due to secondary infections in necrotic wounds, followed by cardiovascular events in the context of underlying end-stage renal disease.^[1]^[19] One-year survival rates typically range from 40% to 60%, with early intervention improving outcomes to around 45-55% in managed cases.^[55] Survival is notably better for distal or non-uremic forms, approaching 70%, compared to proximal lesions, where rates drop to 20-30% due to more extensive vascular involvement.^[8]^[56] Key prognostic factors include low serum albumin levels below 2.5 g/dL, which strongly predict poorer outcomes by exacerbating vascular calcification; multi-site involvement; and delayed diagnosis, all of which increase mortality risk.^[57] A 2025 multicenter study reported one-year all-cause mortality of 48.5% and disease-specific mortality of 28.9%, indicating improved outcomes compared to historical rates.^[58] Among survivors, recurrence rates are approximately 5% at one year and 18% at five years, often triggered by persistent risk factors like ongoing dialysis.^[59] Renal transplantation may promote resolution of calciphylaxis in many cases and is associated with low recurrence risk.^[60]

Complications

Calciphylaxis lesions frequently become sites for secondary bacterial infections due to compromised skin integrity and impaired immune response in affected patients. Wound superinfections, often involving gram-negative organisms, can progress to systemic sepsis, with cutaneous ulceration present in a majority of severe cases. Proximal lesions may extend to deeper tissues, leading to osteomyelitis in some instances.^[1]^[7]^[61] Beyond cutaneous involvement, calciphylaxis can cause visceral calcification, where calcium deposits affect internal organs such as the heart, lungs, and intestines. In the cardiovascular system, this may manifest as myocardial calcification, sometimes referred to as a "heart of stone," potentially contributing to arrhythmias or heart failure through vascular occlusion and ischemia. Such systemic calcifications occur in a subset of patients, exacerbating underlying comorbidities like chronic kidney disease.^[1]^[19]^[8] Renal complications arise from the interplay of calciphylaxis with end-stage renal disease (ESRD), including worsening kidney function due to dehydration from painful lesions or exposure to nephrotoxic agents like iodinated contrast during diagnostic imaging. Following parathyroidectomy—a common intervention—patients may develop severe hypocalcemia, known as hungry bone syndrome, due to rapid shifts in calcium metabolism and reduced parathyroid hormone levels. This iatrogenic hypocalcemia requires vigilant monitoring and supplementation to prevent further morbidity.^[19]^[62]^[50] The disease imposes substantial non-infectious burdens, including chronic pain syndrome from ischemic necrosis, which is often intractable and requires multimodal analgesia. Leg and proximal ulcers lead to significant mobility loss, confining patients to bed or wheelchairs and increasing dependency. Psychological effects are profound, with many experiencing depression and distress from disfigurement, isolation, and unrelenting symptoms. Iatrogenic issues from management include gastrointestinal side effects like nausea from sodium thiosulfate therapy and wound dehiscence following surgical debridement.^[1]^[63]^[41] Penile involvement in calciphylaxis, though uncommon, presents unique challenges with painful necrotic lesions that poorly respond to conservative care. Untreated cases frequently necessitate partial or total penectomy to control infection and necrosis, with literature reviews indicating high rates of surgical intervention in advanced presentations. Recent 2025 case analyses highlight rising recognition of this manifestation in dialysis patients, emphasizing multidisciplinary approaches to mitigate progression to amputation.^[64]^[65]^[66]

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Rapid regression of calciphylaxis in a hemodialysis patient after ...
May 10, 2019 · Its estimated annual incidence is 35 cases per 10,000 patients undergoing hemodialysis (HD) in the USA [5], 4 per 10,000 in Germany [2], and ...
[15]
Prevalence and Clinical Characteristics of Calciphylaxis in Chinese ...
The prevalence of calciphylaxis in Chinese hemodialysis patients was 1.24% according to regional epidemiological survey.Missing: Asia | Show results with:Asia
[16]
https://pmc.ncbi.nlm.nih.gov/articles/PMC5907931/
[17]
Calciphylaxis: Risk Factors, Diagnosis, and Treatment - PMC - NIH
Calciphylaxis is a rare and highly morbid condition that has continued to challenge the medical community since its early descriptions.
[18]
Demographics, Comorbid Conditions, and Outcomes of Patients ...
Jan 2, 2019 · This study analyzes medical records of patients with nonuremic calciphylaxis from the University of Washington Hospital System to evaluate ...
[19]
Calciphylaxis: An Analysis of Concomitant Factors, Treatment ...
Apr 5, 2020 · Calciphylaxis is a rare but severe complication mostly affecting patients with end-stage renal disease (ESRD) and is associated with high morbidity and ...
[20]
https://www.kireports.org/article/S2468-0249(24)00036-6/fulltext
[21]
Fetuin-A Protects against Atherosclerotic Calcification in CKD - NIH
In conclusion, fetuin-A inhibits pathologic calcification in both the soft tissue and vasculature, even in the setting of atherosclerosis. Hemodialysis (HD) ...
[22]
Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences ...
Jan 3, 2017 · Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity ...
[23]
Vascular Calcification: an Update on Mechanisms and Challenges ...
Pyrophosphate and bisphosphonates have been found to inhibit both vascular calcification and calciphylaxis in a several animal studies [27].
[24]
Warfarin-Associated Nonuremic Calciphylaxis - PubMed Central - NIH
Warfarin-associated calciphylaxis is distinct from classic calciphylaxis in pathogenesis, course, and, particularly, outcome.<|separator|>
[25]
Risk Factors Associated With the Development of Calciphylaxis in ...
Dec 8, 2024 · Table 1: The table represents the characteristic findings from each of the articles reviewed. ESRD: end-stage renal disease; PTH: parathyroid ...Missing: sex | Show results with:sex
[26]
Calciphylaxis: Symptoms & Causes - Cleveland Clinic
The risk of death within a year in non-uremic calciphylaxis cases is between 25% and 45%. With uremic calciphylaxis, the risk of death is between 45% and 80%.
[27]
Calciphylaxis Clinical Presentation - Medscape Reference
Oct 10, 2024 · Calciphylaxis may manifest as rapidly progressive, diffuse and extensive, cutaneous necrosis, as is seen in this patient with chronic renal ...
[28]
Proximal calciphylaxis treated with calcimimetic 'cinacalcet'
Oct 2, 2007 · Calciphylaxis is a potentially lethal disease, with a high mortality rate (60–80%) principally due to ischaemic events and sepsis ...
[29]
Calciphylaxis Prevention and Treatment Strategies - Clinical Advisor
Jun 10, 2021 · Calciphylaxis can be life-threatening, with mortality rates ranging from 50% to 80% at 2 years.1,3 The mortality rate is dependent on location.
[30]
Penile calciphylaxis: A severe case managed with partial penectomy
Oct 16, 2020 · In this report, we present a case of penile calciphylaxis in a hemodialysis-dependent patient with end stage renal disease (ESRD).
[31]
Calciphylaxis: A Review - PMC - NIH
Calciphylaxis reflects a form of severe tissue compromise attributable to a unique microangiopathy that combines features of vascular thrombotic occlusion with ...Missing: definition | Show results with:definition
[32]
Calciphylaxis and its diagnosis: A review - PMC - PubMed Central
Sep 30, 2019 · Calciphylaxis is characterized by intense deposition of calcium in small blood vessels, skin, and other organs that develops as a result of secondary ...
[33]
Calciphylaxis Diagnosis and Management in Primary Care
Jun 2, 2022 · Making the Diagnosis. Taking a detailed patient history and conducting a physical examination can assist in the differential diagnosis. Other ...
[34]
Ten tips on how to deal with calciphylaxis patients - Oxford Academic
A recent randomized, double-blind, phase 3, placebo-controlled trial of hexasodium phytate for the treatment of calciphylaxis (CALCIPHYX) conducted among 71 ...
[35]
Calciphylaxis Workup: Laboratory Studies, Imaging Studies ...
Oct 10, 2024 · In the workup for calciphylaxis (also referred to as calcific uremic arteriolopathy), the following laboratory measurements may be considered.Missing: guidelines | Show results with:guidelines
[36]
Calciphylaxis - Diagnosis and treatment - Mayo Clinic
Jul 9, 2024 · Imaging tests. X-rays may show calcium buildups in the blood vessels. These buildups are common in calciphylaxis and in other advanced kidney ...
[37]
Outcomes in an educational skin‐model session on point‐of‐care ...
Oct 28, 2024 · Due to its non-invasive nature, POCUS may be an optimal tool to detect calciphylaxis, especially given the classic signs of hyperechoic calcium ...
[38]
Management of Cutaneous Calciphylaxis - PMC - NIH
Sep 30, 2020 · Local wound treatment regimens should involve removal of wound debris, application of non-adhesive wound dressings, and utilization of ...
[39]
Hyperbaric oxygen in the treatment of calciphylaxis: A case series ...
The aim of this study was to determine whether hyperbaric oxygen therapy (HBOT) is effective in healing calciphylaxis lesions.
[40]
Perioperative Management of Calciphylaxis: Literature Review and ...
Aug 24, 2022 · Low-dose ketamine infusions have been used in opioid-tolerant patients for acute pain control without adverse effects or need for dose ...
[41]
Calciphylaxis due to hyperparathyroidism - PubMed
When medical therapy has failed in the setting of secondary/tertiary hyperparathyroidism with calciphylaxis, parathyroidectomy is the preferred treatment.
[42]
Parathyroidectomy promotes wound healing and prolongs survival ...
Parathyroidectomy can be performed with minimal morbidity and is associated with resolution of pain, wound healing, and a significantly longer median survival.
[43]
Calciphylaxis Following Parathyroidectomy in Chronic Kidney ...
Calcific uremic arteriolopathy, also known as calciphylaxis, is a rare and often fatal condition most commonly occurring in patients with end-stage renal ...
[44]
Calciphylaxis: a poor prognostic indicator for limb salvage - PubMed
Two of these patients were revascularized. One underwent primary amputation, and the final patient died before revascularization. The mortality rate for this ...
[45]
Calciphylaxis: ongoing challenges and treatment opportunities ... - NIH
Calciphylaxis is a rare, progressive disorder characterized by subcutaneous adipose and dermal microvascular calcifications, microthrombi, and endothelial ...
[46]
Elevated Perioperative Morbidity After Parathyroidectomy for ...
Although sodium thiosulfate, cinacalcet, and phosphate binders are viable options, results are preliminary, with treatment primarily focused on supportive care.
[47]
Perioperative Management of Calciphylaxis: Literature Review and ...
Aug 25, 2022 · A retrospective analysis of 5 patients with calciphylaxis undergoing parathyroidectomy showed no additional surgical risks.
[48]
Calciphylaxis epidemiology, risk factors, treatment and survival ...
Feb 26, 2020 · Calcific uremic arteriolopathy (CUA), also called calciphylaxis, is a rare but devastating disease involving patients with end stage renal disease (ESRD).
[49]
Calciphylaxis in patients with chronic kidney disease - Nefrología
It is a rare pathology, whose real incidence is unknown, although it seems to be increasing, but this could simply reflect a better knowledge of the disease.
[50]
Intravenous Sodium Thiosulphate for Calciphylaxis of Chronic ...
Apr 26, 2023 · These results suggest that studies of intravenous STS on patients with CKD experiencing calciphylaxis have not found an improvement in skin lesion outcomes or ...
[51]
Resolution of Calciphylaxis After Urgent Kidney Transplantation in 3 ...
Oct 25, 2016 · These cases indicate that urgent KTX may contribute to an efficient treatment for end-stage renal disease patients with CUA.
[52]
Calciphylaxis: Beating the Odds | Cureus
Jan 6, 2025 · These interventions are essential in controlling the calcium-phosphate balance and preventing vascular calcification and subsequent tissue ...Missing: endovascular | Show results with:endovascular
[53]
Surgical treatment of nonuremic calciphylaxis: a case report ... - NIH
Dec 15, 2022 · Aggressive surgical wound debridement is often controversial in the treatment of calciphylaxis [8]. Some surgical procedures for investigation ...
[54]
Parathyroidectomy as a Cure for Calciphylaxis in a Non-Dialysis ...
One of the proposed mechanisms for the development of calciphylaxis after parathyroidectomy is that low level of parathyroid hormone and decrease bone turnover ...
[55]
Calciphylaxis and Intractable Pain in a Veteran with Psychological ...
Apr 17, 2024 · A 60-year-old male veteran receiving hemodialysis presented with calciphylaxis of the left lower extremity and intractable pain.Missing: mobility impact
[56]
A Fatal Case of Penile Calciphylaxis - PMC - NIH
Presented here is a severe case of systemic calciphylaxis initially presented as penile necrosis treated with sodium thiosulfate and amputation.
[57]
Penile Calciphylaxis: Two Clinical Cases and a Literature Review
Jul 4, 2025 · It is most commonly associated with end-stage chronic kidney disease [3,4] and may lead to amputation of affected tissues or limbs [5]. The ...
[58]
Penile Calciphylaxis: Analysis of Rish Factors and Mortality
Systemic calciphylaxis affects 1% of patients with end stage renal disease. Penile involvement has rarely been reported and different terminologies have ...Missing: percentage | Show results with:percentage