As a final diagnosis, primary hyperparathyroidism with secondary brown tumour and calciphylaxis were admitted. The lesions of calciphylaxis disappeared as haemodialysis, carbonate sevelamer and cinacalcet were initiated, with no further treatment required. The iPTH regressed to 1064 pg/ml and the patient is waiting for parathyroidectomy.

CASE 2

A 59-year-old Caucasian woman with past medical history relevant for uterine cancer treated with radiotherapy, complicated by radiation cystitis, radic colitis with colostomy. She developed severe nephrotic syndrome associated with amyloidosis in renal and skin biopsies, not able to be characterized by immunohistochemistry, was admitted due to acute on chronic renal failure [plasmatic urea (Pu) 115mg/dl, plasmatic creatinine (Pcr) 2.6 mg/dl] secondary to dehydration, Escherichia Coli urinary infection and bilateral hydronephrosis.

Renal function improved after initiation of antibiotics and ureter catheterization. At the 26th day, following a nosocomial infection, a further deterioration of the renal function was observed. Laboratory findings revealed Pu: 138 mg/dl; Pcr 4.1mg/dl; Pi 14.9mg/dl; serum calcium 6.6 mg/dl; iPTH 265 pg/dl; Albumin: 1.2 mg/dl. A livedo reticularis in the lower limbs (thighs and legs) changed rapidly to extensive necrosis plaques. A biopsy specimen of the skin confirmed the suspicion of calciphylaxis.

The patient started an intensive dialysis programme along with sevelamer and local wound care with surgical debridement, which improved her condition.

One month later, a general clinical worsening was observed associated to bleeding dyscrasia (INR: 14.4; apTT: 82.1 s), most likely associated to factor X deficit, resultant of its connection to amyloid fibrils. The patient continued to deteriorate and died on the 75th day.

HOW TO RECOGNIZE AND DIAGNOSE CALCIPHYLAXIS

Confirmation of calciphylaxis is a crucial issue as late intervention is associated with unjustified therapeutic measures and poorer prognosis.

Diagnosis requires a high degree of clinical suspicion and is made clinically based in a triad: a) Painful skin lesions, often refractory to standard analgesics⁴.

b) Cutaneous lesions with characteristic progressive appearance. Initial lesions appear as red sub-cutaneous nodules or violaceous plaques, often in a livedo reticularis pattern. Lesions may increase in size and form ecchymosis or single indurated plaque formation, finally ending in characteristic black skin, deeply ulcerated scars and necrosis⁷.

c) Medial calcification and intimal proliferation in small arteries are characteristic histological features⁴, along with thrombotic vaso -occlusion, without vasculitic pattern.

Tissue biopsy remains the gold standard for diagnosis, but should not be routinely performed because of the risk of sampling error, inoculating or spreading infection and tissue trauma leading to ulcer progression^7-9.

The progressive lesions may reflect two processes of disease: initially calcific arteriolopathy, and lately ischaemic necrosis, related to reduced perfusion or vascular thrombosis^10,11. This suggests that these skin lesions may be the equivalent of the lesions found in myocardial infarction¹². Lesions frequently occur over areas with high adipose tissue content as it has less blood supply than other tissues^8,9. These lesions can be classified as distal (extremities), often in slim and malnourished patients, or proximal (trunk, thighs and/or buttocks), often in obese patients.

Proximal pattern is more associated with deep ulcerations and fat tissue necrosis8. The distal pattern appears to have a better survival rate¹³.

Many dermatologic disorders resemble the superficial lesions of calciphylaxis, but a careful patient history and histopathology can distinguish them⁷.

Clotting disorders, such as protein C, protein S and antithrombin III deficiency and autoimmune diseases, may present with similar skin lesions and should be excluded⁴. A detailed list of differential diagnoses, as peripheral vascular disease, vasculitis, atheroembolism, warfarin therapy, has been published¹⁰.

Currently, imaging plays a limited role in diagnosing calciphylaxis. Mammography has been proposed but can be a painful procedure¹⁴, but bone scintigraphy with Tc99m methylene diphosphate has shown promise as a diagnostic tool for calciphylaxis in the detection of subcutaneous calcium deposits^9,15.

SEARCHING THE RECIPE FOR CALCIPHYLAXIS

The pathophysiology of calciphylaxis is complex and poorly understood. Many factors have been appointed as potential risk factors for the development of calciphylaxis but they faced significant limitations in the distinction between causality and pure association.

The most mentioned risk factor is CKD, particularly end-stage renal disease, metabolic abnormalities, and therapies associated as chronic kidney disease–mineral bone disorders^5,9,16,17, (CKD -MBD) definition according to the KDIGO nomenclature¹⁸.

Hyperphosphataemia, hypercalcaemia and hyperparathyroidism play a well documented pathologic role in vascular calcification but its effect on the genesis of calciphylaxis is not as well established^4,8,13,17.

The vast majority of dialysis patients with comparable degrees of CKD -MBD never develop calciphylaxis and often calciphylaxis patients do not show uncontrolled values of mineral metabolism at the time of diagnosis. The discrepancy found in biochemical parameters may be partly explained by methodological variations in assays and by different intervals between the exposition to calcification promoting factors and clinical manifestations of calciphylaxis¹⁹.

For the development of calcyphilaxis, the total calcium load and hyperphosphataemia period seems much more relevant than the isolated measurement of high calcium or high phosphate serum levels.

In recent reports, warfarin therapy⁸, low serum albumin level and high plasma glucose level were significantly associated with calciphylaxis^6,8.

Albumin level has already been related to the risk of thrombotic complications in nephrotic syndrome and as a marker for calcification. Even so, its role is confounded as it is regulated as negative acute-phase reactant, and can reflect malnutrition and increased dialysis -related mortality^13,14,20.

Other risk factors frequently mentioned include female gender^9,16, probably related to increased fat mass, diabetes^4,5,8,9,16, obesity^14,16 and hypercoagulable states, resulting from protein C and S deficiency^17,21,22, or antiphospholipid syndrome²³. The pathologic changes of calciphylaxis promote by themselves thrombus formation that can be exacerbating by hypercoagulable states¹⁶.

A systematic review of conditions associated with non-uraemic calciphylaxis has been published¹⁹. Most cases are due to primary hyperparathyroidism, malignancies^24,25, connective tissue diseases^26,27 and alcoholic liver disease^16,19,22. Hyperparathyroidism is the most commonly reported condition but still has not been consistently recognized as an independent risk factor for the development of calciphylaxis^4,19.

Research in cardiovascular and bone diseases has identified a link between bone and vascular calcification.

Factors such as receptor activator of nuclear factor-kB [RANK], RANK ligand and osteoprotegerin (OPG), which plays important roles in mineral deposition and bone resorption, also seems to regulate extra -skeletal mineralization. Derangement of this system has been tied to certain bone diseases and may underlie the pathogenesis of calciphylaxis^12,16,28.

Also, polymorphisms or deficiencies of OPG result in increased arterial calcification²⁹.

Some of the factors that can predispose to calciphylaxis (iPTH, corticosteroids, aluminum, liver disease, autoimmune states and various forms of inflammation) are known to increase the expression of RANK ligand, decreasing the expression of OPG, thus activating RANK and prompting calciphylaxis^16,19.

Furthermore, histological examinations suggest that calcification is associated with increased expression of osteopontin by smooth muscle cells²⁰.

In the first patient, we find that primary hyperparathyroidism, supported by the osteolitic lesions and Brown tumour, was the sensitizing factor (despite the normal calcium and phosphorus serum levels at presentation) and that renal failure was the trigger to calciphylaxis. For the development of calciphylaxis, the total calcium load and hyperphosphataemia period seems much more relevant than the isolated measurement of high calcium or high phosphate serum levels.

In the second patient we can assume that factor X deficit, associated to amyloidosis, CKD and severe hypoalbuminaemia (Alb: 1.2 g/dl) were the predisposing factors. While acute exacerbation of chronic kidney failure, associated with acute hyperphosphataemia (Pi: 14.9 mg/dl), was the main trigger to calciphylaxis. In both cases CKD, as well as CKD -MBD, were present.

ROLE OF CALCIFICATION INHIBITORS

Deficiencies in vascular calcification inhibitors, such as fetuin-A and matrix Gla protein (MGP), have been postulated to play a key role in calciphylaxis^12,28,30.

Fetuin-A levels are reduced in patients with renal failure and in patients with inflammation³¹.

Serum levels of both calcification inhibitors are especially low in patients with calciphylaxis, and the ability to inhibit basic calcium phosphate precipitation is much lower than in healthy controls^30,31.

Warfarin suppresses MGP function, which may explain the increased risk of calciphylaxis associated with this therapy^4-6,32.

The fact that only a small minority of patients develop calciphylaxis makes a multifactorial pathogenesis most likely. Selye’s induced calcification in a two -step model, suggesting a sequential course of pathophysiological events, which closely approximates the description of vascular calcification that might occur in human calciphylaxis¹. In a modern definition of Selye’s calciphylaxis we may admit that probably the disease is a result of multiple factors that can sensitize and predispose patients to calciphylaxis development. These factors directly or indirectly activate NFkB, resulting in bone pathology and vascular calcification¹².

HOW TO TREAT CALCIPHYLAXIS?

There is no evidence -based medicine treatment option available for patients with calciphylaxis and a standard protocol has not been formally developed, due to late diagnosis and dismal prognosis. The heterogeneity of treatment amplifies the difficulties in establishing a correct evaluation of the success of different therapeutic approaches. Moreover, with the advances in our understanding new treatment options have emerged.

Calciphylaxis involves a multidisciplinary approach. Dermatologists, surgeons and nephrologists need to work hand-in-hand.

The initial management of the disease consists of supportive management, such as diligent wound care. Patients undergoing wound debridement appear to have improved survival¹⁶. Aggressive infection therapy is needed, as sepsis is the chief cause of death. Pain control is of great importance and nutritional support of patients affected by malnutrition is vital.

Reduce or, if possible, discontinue medications that have been implied in calchiphylaxis⁸. Probably the role of the iatrogenic intervention has been fundamental in the final step of the disease leading sensitized patients to calciphylaxis³³. Indeed, calciphylaxis does not appear to be part of natural progressive CKD (as renal anaemia), since most patients do not develop it. Surprisingly, most patients with calciphylaxis benefited of medical surveillance and, therefore, the development of calciphylaxis might actually have iatrogenic components^8,33.

In fact, various pharmacologic or biological agents have been implicated in causing calciphylaxis, the most well-known being high -dose vitamin D and its analogues^9,16, calcium supplementation⁹, warfarin¹⁶, chemotherapy agents²¹, iron dextran^9,38 and erythropoietin¹³.

Steroids are controversial and have been implicated as a cause¹⁶, as well as a therapeutic option^9,16,17,19.

Control of metabolic disturbances (hyperparathyroidism, hypercalcaemia, hyperphosphataemia) makes good clinical sense, although better outcomes have not been demonstrated^16,34. Calcium loads can be decreased by reducing dialysate calcium to levels of ≤ 1.25 mmol/L and administering calcium-free phosphate binders. It has been showed that reducing the amount of calcium salts administered can drop the incidence of calciphylaxis³³. Intensifying dialysis sessions in affected patients to increase calcium and phosphate removal⁸ or changing from peritoneal to haemodialysis may help³³.

The most significant progress in treatment has been the use of sodium thiosulphate(STS)^35,36. STS sequesters calcium ions to form highly soluble calcium thiosulfate complexes and can prevent calcium phosphate precipitation^36-38. It is also an effective antioxidant and may, thus, limit tissue damage³⁹. The benefits of STS in calciphylaxis patients include rapid pain relief and successful wound healing within weeks to months of initiating therapy^37,39. Side-effects, as metabolic acidosis, are low. One interesting new development may be the topical use of a 25% STS ointment⁴⁰.

Hyperbaric oxygen therapy (HBO) has been shown to improve wound healing counteracting tissue hypoxia by supplying high concentrations of oxygen; however, positive effects were largely limited to patients with distal forms of calciphylaxis^4,36.

Parathyroidectomy can improve calciphylaxis, but it should be limited to cases of refractory hyperparathyroidism with calcium receptor antagonists^3,41.

Cinacalcet has the unique ability to lower parathyroid hormone, calcium, and phosphate levels^7,42. Application of bisphosphonates⁴² and vitamin K supplementation is controversial³².

All treatment alternatives available should be used for the treatment of calciphylaxis to promote synergistical actions that maximize the potential for wound healing and subsequent patient recovery⁷.

As the pathogenesis of calciphylaxis is being better understood, targeted molecular therapies may become the way for therapeutic prevention.

PROGNOSIS

Calciphylaxis is a severe and life-threatening condition, with a mortality rate ranging from 46% to 80%¹⁶. It has been noted that the highest mortality is associated with secondary infection of the cutaneous lesions, leading to sepsis⁷.

Factors associated with poorer overall prognosis include skin lesions involving the trunk, ulceration of skin lesions, female gender, increased weight, and the need for vascular surgical intervention^9,17,43.

CONCLUSION

Calciphylaxis is a rare, life-threatening complication of ESRD, although not exclusive to these patients.

There is a critical need to understand pathogenesis of calciphylaxis. Its comprehension is the only way to improve the survival of these patients and it may help to elucidate the pathophysiology of vascular calcification in general.

As seen in our case reports, it is fundamental to recognize the risk factors and keep great awareness to make the diagnosis as soon as possible in order to start the treatment and try to prevent the drastic consequences of the disease.

As we further expand our understanding of the complexity of vascular calcification, new therapeutic agents with the potential for preventing vascular calcification will arise. The effect of the introduction of non calcium-containing phosphate binders on the incidence and prevalence of calciphylaxis remains to be seen.

The participation in national and international registers of calchiphylaxis is an excellent tool to get an idea of the epidemiology of the disease⁵.

Educating physicians to prevention and detection of calciphylaxis is crucial. Only by increasing the knowledge of risk factors, pathophysiology, response to treatment and outcome, will we be able to improve prophylaxis as well as the therapy of patients, and to decrease the high mortality of this entity.

References