A Connor, MS Menon, JE Taylor
Department of Renal Medicine, Dorset County Hospital, Dorchester, Dorset DT1 2JY United Kingdom
Corresponding Author: Dr Andrew Connor: andrewconnor1974@hotmail.co.uk
Abstract
Calcific
uraemic arteriolopathy is a small vessel vasculopathy occurring almost
exclusively in patients with renal failure. Violaceous mottling of the lower
limbs, buttocks or lower abdomen precedes the development of painful, necrotic,
non-healing ulcers. We report two
atypical manifestations of calcific uraemic arteriolopathy and highlight a
condition which is seen increasingly frequently as the number of patients
undertaking dialysis continues to rise.
Case Report
A 62-year-old woman with a history of cigarette smoking presented with
claudication pain. Examination findings included the absence of lower limb
peripheral pulses and the presence of firm non-tender masses in the right flank
and suprapubic regions. The patient confirmed that these had been present for
four years. Initial investigations identified anaemia (haemoglobin 5.6 g/dL) and
renal failure (urea 63 mmol/L, creatinine 1478 mmol/L, calcium 2.32 mmol/L,
phosphate 0.61 mmol/L and parathyroid hormone
level 19 pmol/L). Computed tomography revealed extensive retroperitoneal
calcification with a shrunken left kidney and hydronephrotic right kidney.
Biopsy of the right kidney revealed marked interstitial fibrosis and
calcification. A diagnosis of end-stage renal disease (ESRD) secondary to
obstructive uropathy was made and treatment with haemodialysis was instituted.
Two years later the patient developed livedo reticularis over her lower limbs. This progressed rapidly to become multiple, painful, non-healing eschars which became infected (Figure 1). Serum parathyroid hormone levels had risen to 78.7 pmol/L. A thrombophilia screen revealed reduced functional protein C levels (62%, normal 70-120%) and positive anti-cardiolipin antibodies levels (16 ku/L, 0-10 ku/L). Systemic calcific uraemic arteriolopathy was diagnosed and repeated debridement undertaken. No signs of ischaemia were noted intra-operatively. However, the ulceration progressed - prompting parathyroidectomy to be performed. Despite serum parathyroid hormone levels normalizing, the ulcers deteriorated and the patient died from secondary sepsis.
Post-mortem examination identified extensive aortic calcification extending into virtually occluded iliac arteries. A large, calcific mass lay anterior to the bladder. Both kidneys were end-stage kidneys with hydronephrosis and hydroureter. The right kidney was completely encased by calcified tissue, which also partly surrounded the left kidney. There were multiple ischaemic leg ulcers, with calcification of the medial layer within the small vessels supplying the ulcerated leg tissue.
Our second patient was a 47 year-old man receiving haemodialysis for diabetic nephropathy and taking warfarin for atrial fibrillation. He developed a painful necrotic ulcer around his external urethral meatus (Figure 2). Localised calcific uraemic arteriolopathy was diagnosed. This progressed despite repeated debridement and became infected. The patient died from sepsis within one month.
Figure 2 Necrotic ulceration of the external urethral meatus.
Discussion
We report two cases of calcific uraemic arteriolopathy; one localized and one systemic. Initially known as calciphylaxis, calcific uraemic arteriolopathy is a small vessel vasculopathy occurring almost exclusively in patients with ESRD. Further risk factors include hyperparathyroidism, an elevated calcium-phosphate product (the result of multiplying the serum calcium and phosphate values together; normal range < 4.5), diabetes, obesity, coagulopathies and treatment with warfarin or iron dextran. Although previously considered uncommon, the incidence of calcific uraemic arteriolopathy is 4.1% amongst patients receiving dialysis.1 As the numbers of patients receiving this treatment continues to rise, the condition will be seen more frequently.
Calcific uraemic arteriolopathy typically presents with violaceous mottling of the lower limbs, buttocks or lower abdomen. Painful, necrotic, non-healing ulcers develop. These are highly susceptible to infection. The differential diagnosis of necrotic skin lesions in association with renal impairment includes peripheral vascular disease, cholesterol embolization, cryoglobulinaemia, leucocytoclastic vasculitis, systemic lupus erythematosus, Wegener’s granulomatosis, polyarteritis nodosa, endocarditis and coumarin necrosis. As these are distinguishable histologically, biopsy remains the gold standard investigation, demonstrating calcification within the medial portion of the small arteries in the absence of vasculitic change.2 However, the poor wound healing often discourages clinicians from this investigation.
The mainstay of treatment is wound care and the correction of abnormalities in serum calcium and phosphate levels. Parathyroidectomy is recommended when hyperparathyroidism co-exists.3 Cinacalcet (a calcimimetic medication which acts to reduce parathyroid hormone and, consequently, serum calcium levels) is a possible treatment in patients unsuitable for parathyroidectomy. Bisphosphonates, tissue plasminogen activator and hyperbaric oxygen are reportedly of benefit.2 There have been a number of descriptions of remission following therapy with intravenous sodium thiosulfate since it was first reported in 2004.4 Surgical treatment consists of debridement and amputation. However, no treatment is of proven benefit and mortality remains 80% at one year, usually from secondary infection.2
Our cases are unusual. In the first case, extensive calcification was evident prior to the development of calcific uraemic arteriolopathy and appears to have been the cause of the patient’s ESRD. The aetiology of the calcification remains obscure despite post-mortem examination. Calcific uraemic arteriolopathy in patients with protein C deficiency and ESRD has been previously described.5
Penile calcific uraemic arteriolopathy is also uncommon (37 previously reported cases).6 Diabetes is a particular risk factor (present in 76% of cases).7 As the penis receives an abundant blood supply from three arterial pathways, alternative aetiologies of penile necrosis are rare (but include infections, such as Fournier’s gangrene). Penectomy confers no advantage over local debridement.
As the pathogenesis and best treatment of calcific uraemic arteriolopathy remain unclear, a UK Calciphylaxis Registry has recently been established, to which all new cases should be reported.
In
summary, calcific uraemic arteriolopathy is an increasingly reported condition
which carries a high mortality. In the absence of effective treatments the early
identification of subjects at risk, and the subsequent modification of their
risk profiles, is essential.
References
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