Calciphylaxis, also called calcific uraemic arteriolopathy (CUA), is an uncommon but serious condition with a high rate of mortality.1,2

CUA develops in the dermis and subcutaneous tissue, generally in areas of adiposity. It is characterised by pruritic or painful skin lesions, purplish nodules, ulcers and sores that develop into ischaemic necrosis of the skin.3 A histological examination may reveal medial calcification and intimal proliferation in the small arteries, with or without endovascular fibrosis, extravascular calcification and vascular thrombosis.4

It occurs more frequently in patients with advanced chronic kidney disease on dialysis or in renal transplant patients; however, cases of calciphylaxis have been reported in subjects with normal renal function, classified as “non-renal” CUA.5

The pathogenesis of this vascular disease is complex and not well understood, but there are several mechanisms thought to be involved in its development. Over the years, other risk factors have been added to the traditional factors of bone and mineral metabolism (hyperparathyroidism, hypercalcaemia and hyperphosphataemia) and its high prevalence in patients with low bone metabolism.6,7 These include: female gender, diabetes, obesity, local trauma, hypoalbuminaemia, hypercoagulable states and exposure to active vitamin D, calcium chelators, corticosteroids and vitamin K antagonists.8–11 This amalgam of factors has generated a new patient phenotype that shows lesions from calciphylaxis that are unlike the classic image of this condition.

Despite the poor prognosis of this condition, the use of multidisciplinary treatment in recent years (treatment of pain and of superinfections, intensification of haemodialysis, bisphosphonates, sodium thiosulfate, non-calcium chelators, cinacalcet, vitamin K and pentoxifylline) has seen survival increase in these patients.12–14

The objective of this study was to analyse the current epidemiology of calciphylaxis in the region of Hospital 12 de Octubre, the risk factors for its development and the patients’ clinical courses depending on the treatment received.

An observational and retrospective study was performed on a series of patients diagnosed with calciphylaxis between December 1999 and December 2015 at Hospital Universitario 12 de Octubre in Madrid.

The following data were recorded: gender, age, Charlson comorbidity index, status at diagnosis (patients on haemodialysis, with a normally functioning renal transplant or without kidney disease), aetiology of chronic kidney disease (CKD), time to renal replacement therapy (haemodialysis and renal transplantation), cardiovascular risk factors (hypertension, diabetes mellitus, obesity), chronic ischaemic syndrome, coronary artery disease, atrial fibrillation, presence of hepatitis C virus, bone metabolism parameters (PTH, calcium, phosphorus, alkaline phosphatase), serum albumin, type of involvement (distal or proximal), usual treatment of the patients prior to the development of calciphylaxis, diagnosis of calciphylaxis (by symptoms, biopsy or both), therapeutic strategies (conventional treatment – intensification of haemodialysis, support measures or amputation of the affected limb vs. multi-target treatment – conventional treatment with sodium thiosulfate, bisphosphonates, cinacalcet, non-calcium chelators or pentoxifylline), course of the lesions, follow-up, survival, calciphylaxis-related death (to establish this connection, the cutoff point was established in the first 6 months after the development of calciphylaxis) and other causes of death.

In the statistical analysis, the quantitative variables were expressed as the mean, standard deviation and range, while the qualitative variables were expressed as the absolute number and percentage. To compare the quantitative variables, the Student's t-test was used, and the chi-squared test was used for the qualitative variables. The clinical course from diagnosis to death was described using the Kaplan–Meier method. Values of p<0.05 were considered statistically significant. The statistical analysis was performed using SPSS (version 20 for Windows).

Calciphylaxis is a rare condition that is usually associated with CKD, with a prevalence between 1% and 4% in dialysis patients.1,15 In our series, 28 patients were diagnosed over a period of 16 years, which suggests that, despite the low incidence, calciphylaxis should be taken into account in any differential diagnosis.

Contrary to what might be expected, the patient profile has changed: calciphylaxis does not exclusively affect subjects with CKD on dialysis, but it also occurs in renal transplant patients with normal graft function and even in patients with no kidney disease16,17 (in our study, 21.4% had normal renal function).

In general, it is more prevalent in obese women,2 as our case-series shows. The majority of the patients showed cardiovascular risk factors (hypertension, diabetes mellitus, obesity), coronary disease and chronic ischaemia, which causes tissue hypoperfusion.8,10,18 These factors are replacing the classic protagonists of calciphylaxis, such as those attributed to bone and mineral metabolism.19,20 One example of this can be found in our series, where hyperparathyroidism, elevated blood phosphate levels and normal calcium were observed only in patients with CKD. However, other risk factors, such as steroids (in the group of renal transplant patients, 100% took these drugs) are increasingly prominent as the causes behind the onset of this condition. This finding is of great importance and clinical interest for reconsidering indicating these treatments for high-risk patients. With all these findings we can describe a new phenotype of patients with calciphylaxis to which we must pay more attention: a subject with renal failure (patient on dialysis or renal transplant patient), elevated comorbidity and a pronounced cardiovascular profile (hypertensive, diabetic and with peripheral vascular disease), treated with oral anticoagulants and with hypoalbuminaemia due to chronic inflammation or malnutrition.3,8

In all cases, the skin lesions showed a poor clinical course and were highly suggestive of calciphylaxis, which was confirmed with a biopsy in 78.6% of the cases; in some patients, X-rays were performed which showed the calcification of the vessels.

A fundamental and increasingly important aspect of calciphylaxis is the use of combined or multi-target treatment. There is strong evidence showing that skin lesions improve and survival increases when combined or multi-target treatment is used.13,21,22 Although there is no standardised therapy, it is recommended to discontinue calcium chelators, oral anticoagulants (using low molecular weight heparin instead) and vitamin D; the frequency of dialysis should also be increased (if necessary) to 5–6 weekly sessions with a low calcium bath.23 In addition, drugs such as non-calcium chelators24–26 (e.g. sevelamer, which inhibits ectopic calcifications and reduces cholesterol), cinacalcet27,28 (which reduces PTH, calcium and blood phosphates in patients on dialysis with secondary hyperparathyroidism), sodium thiosulfate29 (an antioxidant and anti-inflammatory that mobilises the calcium deposits in the vessels) and bisphosphonates30,31 (inhibitors of ectopic calcification formation, with an anti-inflammatory effect) should be used. Vitamin K administration should be considered in cases of deficiency.32 The use of hyperbaric oxygen therapy33 (it could be beneficial for distal lesions) and parathyroidectomy in cases of severe hyperparathyroidism is a subject of much debate, because they do not seem to improve the prognosis in these patients.2

The prognosis of this disease is very poor, as it shows a mortality rate of up to 60–80%, with calciphylaxis-related sepsis as the most common cause of death,2,4 as occurred in 64% of our patients. Specifically, proximal lesions have a higher mortality rate than distal lesions (p=0.04).9 In this series, the main risk factors for calciphylaxis-related death were the presence of CKD (p=0.03) and hypoalbuminaemia (p=0.02).

In addition, it is important to note that patients with normal renal function have an excellent prognosis with regard to calciphylaxis (none of them died due to this reason), compared with patients with CKD (especially renal transplant patients), who have a very high probability of dying within a few months (p=0.032).

This study has some important limitations: it is retrospective and single-centre, includes a small number of cases, and there was no comparative analysis with a control group of subjects without calciphylaxis. However, this study does reflect the current reality at the different nephrology centres.

In conclusion, although calciphylaxis is a rare condition, it has a high mortality rate. The patient profile has changed: it is not constrained to uraemic situations, but also occurs in patients with normal functioning renal transplants or in subjects with no kidney disease. Cardiovascular risk factors (diabetes, obesity, peripheral vascular disease, anticoagulation with vitamin K antagonists, steroids) are displacing the classic factors of bone and mineral metabolism. A “risk score” should be established for an early diagnosis, as well as standard treatment. Multicenter studies that enable the treatment of this condition to be standardised are needed.

The authors have no conflicts of interest to declare.