Nephrology Division, Newark Beth Israel Medical Center, Newark, NJ 07112, USA
Keywords: hyperparathyroidism; calcium load; hyper-phosphataemia; phosphorous; uraemia
Introduction
The syndrome of calciphylaxis has evolved over the last three decades. In 1962, Selye first described a syndrome in the experimental animal [1] and postulated that two steps are required to produce ectopic systemic calcification. First, a systemic sensitization induced by agents such as parathyroid hormone (PTH), vitamin D or a diet high in calcium (Ca) and phosphorus (P). Secondly after a time interval (the critical period) exposure to appropriate challenging agents by subcutaneous injection which results in macroscopically visible deposits of calcium salts (hydroxapatite) systemically and at the site of injection within 2 to 3 days. The challenging agents include local trauma, iron salt, egg albumin, polymycin and glucocorticoids. Selye named the syndrome calciphylaxis. A few years later a syndrome characterized by peripheral ischaemic tissular necrosis, vascular calcifications and cutaneous ulcerations was reported in uraemic patients, and because of its resemblance to Selye's animal model, it was also named calciphylaxis [23]. However, the syndrome described in the uraemic patients only resembles Selye's model. Though a useful concept, the analogy with Selye's model may not be warranted, since the term calciphylaxis has pathogenic implications that have not been confirmed in humans. Thus, significant differences exist between Selye's model and calciphylaxis in uraemia. The former is characterized by metastatic systemic calcifications developing after significant invasive manipulations of the animal model, but vascular calcifications are not present. The latter occurs primarily in the presence of uraemia with abnormalities in divalent ions, i.e. high plasma PTH, hypercalcaemia and hyperphosphataemia and, most importantly, small vessel calcifications are noted at the site of lesions.
Retrospectively, it appears now that the syndrome that is most analogous to Selye's is that of uraemic soft tissue calcifications. Seyle's model did not exhibit the histology consistently described with uraemic calciphylaxis, i.e. small vessel calcifications and intimal hypertrophy in association with panniculitis and small vessel thrombosis [2].
As more cases with uraemic calciphylaxis have been described over the last two decades, it is becoming inappropriate to use the term calciphylaxis. It is misleading, since in many instances abnormalities in plasma Ca, P or PTH are absent. A more appropriate term, as suggested by Coates et al. [4], is calcific uraemic arteriolopathy (CUA).
The first description of CUA were made in the late 1960's and early 1970's, as a syndrome characterized by cutaneous eruptions usually occurring in patients on dialysis or after renal transplantation [56]. The skin lesions often presented as areas of painful mottling, resembling livedo reticularis with superficial violaceous nodules involving the tip of the toes or fingers, or occurring at the ankles, thighs or buttocks. As the lesions progress, they become haemorrhagic with ischaemic dry necrosis. The bilateral symmetry, superficial nature of these lesions and persistence of palpable pulses distal to the necrosis are characteristic findings (Figure 1). As the lesions progress cutaneous necrosis ensues as well as the development of ischaemic digital pain and in many cases gangrene of the digits. At that time, biopsy of the skin nodules show calcium deposits within small arteris (30600 µm, average 100 µm) in the vessel walls. This is associated with lobular fat necrosis, calcifications and an infiltrate of neutrophils, lymphocytes and macrophages. In the early reports, the lesions were located distally in the extremities and there was clinically significant hyperparathyroid bone disease [6]. A link between CUA and hyperparathyroidism (HPT) was further supported by the early observations that parathyroidectomy (PTx) dramatically improved the syndrome [67]. Thus, ulcerations that had persisted for months healed dramatically within weeks after PTx [6]. Later, PTx performed in other patients did not result in improvement of the patient and aggravated the condition further, leading to a high mobility and mortality [8].
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It is apparent that this syndrome has evolved and changed over the last few years. The presence of obesity, especially in Caucasian females, has been noted to be an important predisposing factor to develop CUA [4,12]. Supposedly, the areas rich in adipose tissue may be more prone to damage of the small vessels, thus promoting calcifications before the cutaneous lesions and necrosis of the skin become clinically apparent. Obese patients usually develop CUA proximally in the abdomen, buttocks and thighs, presenting as deeply seated painful nodules, in contrast the more distal superficial lesions noted earlier in patients with high PTH levels (acral CUA). Furthermore, a low serum albumin together with a relatively low PTH in the obese dialysis patient is predictive of CUA [12]. Others have noted an association with insulin-dependent diabetes mellitus and CUA [13]. Of special interest is the observation that in four patients the lesions developed in areas that had previously been the site of insulin injections [13]. Local trauma such as subcutaneous injections of heparin or iron dextran may also be precipitating factors in the local development of CUA [1314].
Finally, protracted hyperphosphataemia still remains an important predisposing factor. It has become more so in the patient with adynamic bone lesion, and in the parathyroidectomized patient. In these patients successful strict control of the hyperphosphataemia has been shown to reverse CUA [6,15,16]. Obese patients with proximal CUA have a poorer prognosis than those with acral CUA [1719].
Therapeutic considerations
The prognosis of patients with CUA is poor. Most of them die of sepsis and ischaemic events. Since we do not have a clear understanding of the pathogenesis, treatment of this syndrome is extremely difficult. The first step is normalization of the CaxP product. Hyperphosphataemia, as mentioned above, should be strictly controlled. Thus dietary compliance, use of appropriate phosphate binders and adequate dialytic treatment are mandatory. The use of Ca-containing phosphate binders should be avoided, since ingestion of large amounts of Ca can trigger CUA [11]. In our experience, emphasis should be placed on using a low dialysate Ca. We have evaluated 17 patients with CUA over the last 5 years [20]. In eight patients we used a zero Ca dialysate for at least 812 weeks; in addition, patients were dialyzed 56 days a week. The rationale behind this approach was to induce hypocalcaemia and establish a Ca gradient favouring a shift of Ca from soft tissue to intravascular space. Figure 2 displays a decrease in serum Ca during a 4-h dialysis with a zero Ca dialysate and a dramatic increase in serum Ca 3 h post-dialysis in a patient with CUA. It can be noted that serum Ca decreased from 9.7 mg/dl (pre-dialysis) to 6.7 mg/dl (post-dialysis), and 3 h later it increased again to 9.9 mg/dl. These changes suggest a shift of Ca from the intracellular space, most likely skin and soft tissue, to the intravascular space. These changes were noted with each dialysis over the ensuing 8- to 12-week period. Symptoms related to dialysis-induced hypocalcaemia did not develop, most likely reflecting the continuous shift of Ca from tissue ameliorating the hypocalcaemia. In addition to the zero Ca dialysis, Ca-containing phosphate binders were discontinued and hyperphosphataemia was managed with Renagel. Six of the eight patients had a dramatic improvement of skin lesions, and in four there was total healing of the lesions. A second important therapeutic step is aggressive wound care with debridement of necrotic tissue and systemic antibiotic therapy, since sepsis is the major cause of mortality. Thirdly, PTx should be performed only in those cases with significantly elevated plasma PTH levels. Early reports recommending PTx described mostly patients with severe HPT [6]. Later, PTx was not successful in many patients [8,18]. Thus, Chan et al. reviewed 47 cases with CUA and noted that the survival rate of patients who underwent PTx was similar to those who did not [19]. Not only did patients with low PTH levels develop CUA which failed to respond to PTx, but CUA has also been described with increasing frequency in patients after PTx. Thus, the available data strongly suggest that PTx should not be performed in patients with low PTH. Budisavijevic et al. reviewed 47 patients with CUA, of whom 31 patients had PTx performed after the development of CUA [17]. Fifty percent of these patients died within a median period of 9 weeks after PTx [17].
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In summary, CUA is a relatively rare, but life-threatening complication in uraemic patients. Its frequency seems to have increased over the last 15 years. The overall clinical picture of this syndrome has gradually evolved as our therapeutic approach has changed. In this regard certain points should be made: first, the term calciphylaxis does not describe this syndrome adequately, since it resembles only remotely Seyle's syndrome of calciphylaxis. It may be advisable to use another term such as Calcific Uraemic Arteriolopathy. Secondly, at present the classic divalent ion abnormalities such as overt hypercalcaemia or hyperphosphataemia as well as high PTH are not common; thus, parathyroidectomy is rarely indicated unless PTH levels are significantly elevated. Thirdly, other causes predisposing to CUA should be considered. They include obesity, mild hyperphosphataemia and an increased calcium load. Fourthly, in the future prevention is indicated to minimize predisposing systemic and local factors, especially in the obese patient.
Notes
Correspondence and offprint requests to: Francisco Llach, MD, Newark Beth Israel Medical Center, 201 Lyons Avenue, Newark, NJ 07112, USA.
References