Fatal Calcific Uraemic Arteriolopathy (Cua): A Case Report And Review
Of The Literature
N Lang, R Davie§, C Whitworth*, R Winney* J Hughes*
Department of Medicine, Queen Margaret Hospital, Whitefield Road, Dunfermline
*Department of Nephrology, Royal Infirmary of Edinburgh,
§Department of Pathology, St John’s Hospital at Howden, Howden Road, Livingston,
Correspondence to: email@example.com
SMJ 2004 49(3): 108-1 11
Calciphylaxis, now better known as Calcific uraemic arteriolopathy (CUA), is an
uncommon condition characterised by small vessel calcification and occlusion with
resultant painful violaceous skin lesions that typically ulcerate to form non-healing
gangrenous ulcers. The syndrome is usually found in patients with renal failure. In this
report we describe a 61 year old lady who developed lower limb ulceration secondary to
calciphylaxis and discuss the current treatment options for this serious condition.
Keywords: Calcific uraemic arteriolopathy, calciphylaxis, renal failure, ulceration.
A 61 year old lady developed end stage renal failure of uncertain aetiology in 1993 and
commenced chronic ambulatory peritoneal dialysis (CAPD). She received a cadaveric
renal transplant in 1994 but developed chronic allograft nephropathy and renal
dysfunction (serum creatinine (Cr) 249µmol/l and creatinine clearance 18ml/min. in
July 2002). She was referred to the nephrology clinic for a pre-dialysis assessment and
consideration for further transplantation. At this time she was receiving treatment with
cyclosporin A (75mg bd), mycophenolate mofetil ([MMF] 500mg tds), prednisolone
(5mg od), ramipril, doxazosin, metoprolol, bumetanide, 1-alphacalcidol, ferrous
gluconate, warfarin, omeprazole and pravastatin. In July 2002, an area of tender slightly
reddened skin was noted on her right calf compatible with ‘thrombophlebitis’. In
addition, reduced femoral and pedal pulses as well as a left femoral bruit were evident.
When reviewed in October 2002, she complained of exertional calf pain and tender legs,
especially over her lower calf. There was clinical evidence of lower limb oedema and
the bumetanide dosage was therefore increased. In addition, the dose of 1-alfacalcidol
was increased to combat her secondary hyperparathyroidism (parathyroid hormone
[PTH] concentration 272ng/l [normal < 65ng/l]). The calf pain remained unchanged
despite some evidence of fluid loss. She developed increasing calf discomfort and was
prescribed antibiotics from her GP for bilateral calf cellulitis.
The underlying cause of her calf pain was still unclear and a diagnosis of painful
uraemic neuropathy was considered (Urea 35 mmol/l) and treatment with Gabapentin
was initiated. In mid February 2003, she was admitted to the Renal Unit of the Royal
Infirmary of Edinburgh. She had developed an increasingly painful, erythematous right
calf and had received two courses of oral Co- Amoxiclav from her GP. However, an
area of skin ulceration developed with clinical examination confirming an 8x5cm
ulcerated lesion surrounded by tender, erythematous skin. The ulcer was felt to be
mainly the result of pressure as she admitted to sitting in a chair with her calves resting
on a stool for several hours each day. She was treated with intravenous antibiotics
(penicillin V, flucloxacillin and metronidazole) and underwent lower limb angiography
in order to exclude significant large vessel disease. This revealed some calcified plaque
but no significant stenoses that required interventional treatment. The appearance of the
ulcer improved with antibiotic treatment and she was discharged and referred to the
plastic surgeons for consideration of skin grafting.
However, she was readmitted two weeks later with a chest infection, reduced mobility,
increasing peripheral oedema and worsening ulceration of the right calf together with
new ulceration of the left calf. She was febrile and therefore commenced on intravenous
antibiotics. Blood tests on admission revealed: haemoglobin 96 g/dl, INR 1.3, urea 44
mmol/l, creatinine 358 µmol/l, potassium 6 mmol/l, bicarbonate 18 mmol/l, corrected
calcium 2.23 mmol/l, phosphate 2.19 mmol/l and C reactive protein 166 IU/l (normal
range <101U/l). Swabs of the ulcers variably grew commensal organisms, anaerobes
and MRSA and she was treated with intravenous teicoplanin and metronidazole. The
dose of MMF was reduced and the ramipril was discontinued in view of her worsening
renal function and hyperkalaemia. A renal ultrasound demonstrated no evidence of
obstruction and cyclosporin A levels were non-toxic. She was commenced on
intermittent haemodialysis. She was reviewed by the plastic surgeons and an initial
diagnosis of pressure sores was made. She underwent surgical debridement of the
ulcers. However, pathological examination of specimens of debrided tissue revealed
necrotic, ulcerated skin with small foci of calcification within the walls of blood vessels
suggestive of calcific uraemic arteriolopathy. (Fig 1*): Urgent parathyroidectomy was
considered but decided against as calcium and phosphate levels were relatively well
controlled with medical management. Plain X-rays of her thighs and calves confirmed
small vessel calcification (Fig 3). Investigations for an underlying vasculitic illness
were negative and Protein C and Protein S deficiencies were excluded.
Further management involved maintaining excellent calcium and phosphate control
with non-calcium containing phosphate binders and diet and regular ulcer dressings.
She was unresponsive to erythropoietin (EPO) and therefore, in order to optimise
oxygen delivery to the tissues, receive intermittent blood transfusions to maintain her
haemoglobin above 100g/dl. Her warfarin treatment was discontinued. Two weeks later
she complained of increasing pain over the lateral and anterior surface of her thighs with
these areas developing livedo reticularis. The skin rapidly became gangrenous and
sloughed to form further large areas of ulceration (Fig 2A + 2B). Pain remained a
significant problem despite specialist input from the pain control team. The ulcers
became repeatedly infected and she ultimately opted to withdraw from dialysis and
aggressive antibiotic treatment. She died from septicaemia and uraemia just over one
month after the firm diagnosis of calcific uraemic arteriolopathy was made.
Background and pathology
This condition was originally called calciphylaxis by Selye in 1962 but is now termed
calcific uraemic arteriolopathy (CUA). Although any systemic vessels may be affected,
CUA more commonly involves, cutaneous small and medium sized vessels.
Histologically, these vessels exhibit mural calcification, prominent intimal proliferation
and often thrombosis.
CUA is considered to be rare although some reports suggest that the incidence is
increasing and that up to 4% of the dialysis population may be affected.1,2 The
increased incidence may relate to the more widespread use of calcium containing
phosphate binders and treatment with parenteral Vitamin D and iron dextran.3,4
Although almost entirely confined to patients with end-stage renal failure it has been
infrequently reported in other patient groups.5,6 CUA is a serious condition with a
grave prognosis. It has a mortality rate of approximately 60-80% with most deaths
attributable to septicaemia from secondary infection of skin lesions.2,4 . The
pathogenesis of calciphylaxis is incompletely understood but is related to abnormal
calcium-phosphate metabolism and hyperparathyroidism causing an elevated CaxPO4
product.3,7 Other risk factors include female sex (male:female ratio of 1:3), obesity,
Caucasian race, diabetes, malnutrition, warfarin, glucocorticoids and possibly
intravenous iron.4 It is noteworthy that, similar to the patient described in this report,
many patients developing calciphylaxis exhibit multiple risk factors and commonly
have a precipitating factor. This may be local trauma, hypotension, thrombosis or sepsis
thereby suggesting a multiple hit theory of pathogenesis.
For example, our patient had multiple risk factors (female, warfarin,
hyperphosphataemia, elevated PTH level, steroid therapy) but also gave a history of
sitting with her calves resting on a stool for prolonged periods. It is likely that the
resultant prolonged pressure may have precipitated the initial ulceration of the calf.
However, recent research has greatly informed in this clinical area and indicates that
homeostatic mechanisms exist to combat vascular calcification. There are several
endogenous inhibitors of calcification that act within blood vessels such as osteopontin
(OPN)8, matrix Gla protein (MGP)9 and alpha 2-Heremans-Schmid
glycoprotein/fetuin A [ahsg/fetuin].10 Mice targeted for the deletion of these genes
exhibit an increased propensity to vascular and genitourinary calcification.10,11 OPN
and MGP double knockout mice exhibit dramatically increased levels of vascular
calcification such that they die from calcific vessel rupture.12 It is therefore tempting to
speculate that these mechanisms may become dysfunctional in uraemic patients and
thereby contribute to the development of CUA as well as the burden of cardiovascular
disease carried by the dialysis population as a whole.13 It is well documented that an
elevated acute phase response as indicated by an elevated C reactive protein level is a
strong predictor of mortality.14 It is therefore pertinent that ahsg/fetuin is a negative
acute phase reactant with levels falling in states of chronic inflammation.15 The
circulating levels of ahsg/fetuin were found to be lower in dialysis populations
compared to controls and was an independent risk factor for patient death.16
Clinically, calciphylaxis usually presents with violaceous mottling, livedo reticularis or
as erythematous plaques, nodules or papules. When the condition is non-ulcerating the
clinical findings may be confused, as in our patient, with cellulitis. These lesions are
typically intensely painful and firm to touch. Ninety percent of lesions are found on the
lower extremities.2 Calciphylaxis may affect the distal limbs (calves and forearms) or
may be more proximal and involve the thighs, buttocks or abdomen.4 Not uncommonly,
the genitals may be affected or it may be acral, affecting the fingers and toes. It may
also involve other organs including muscles (causing a painful myopathy), heart, joints,
lungs, pancreas and the eye.4 The differential diagnosis includes peripheral vascular
disease, atheroembolic disease, cryoglobulinaemia and vasculitis.
The diagnostic gold standard is a tissue biopsy that demonstrates the typical histological
features of calciphylaxis. However, it must be recognised that this should be avoided if
possible as there is a significant risk in performing biopsies of suspicious lesions as
ulceration commonly ensues. Other investigations should include measurement of
serum calcium, phosphate and PTH levels as well as assay of coagulation factors,
cryoglobulins and a vasculitis screen including assay for ANCA. Arterial duplex
doppler scanning and even peripheral angiography should be undertaken if there is
clinical suspicion of large vessel peripheral vascular disease. X-rays usually show
vascular calcification within the dermis and subcutaneous tissue but this may be seen in
patients with end-stage renal failure and is not specific to calciphylaxis.
Treatment options for calciphylaxis are limited.4,7 There are reports indicating benefit
from urgent parathyroidectomy performed on patients with CUA in association
hyperparathyroidism17,18 with larger studie suggesting benefit only in cases with
markedly elevated PTH levels.19 It is important to control the [calcium x phosphate]
product with non-calcium containing phosphate binders such as Aluminium Hydroxide
or Sevelamer.20 Consideration should also be made to the discontinuation of Warfarin
in view of the similarities between calciphylaxis and Warfarin skin necrosis. A
multidisciplinary approach involving meticulous wound care,21 the judicious use of
antibiotics and close liaison with surgical colleagues is essential.22,23 Other therapies
are principally aimed at Fig3: Plain X-ray of the thighs indicate extensive small vessel
calcification. maximising tissue oxygen delivery since measurement of transcutaneous
oxygen tension indicates abnormally low oxygen tensions in affected and non-affected
areas of skin in patients with CUA.24 Anaemia should be corrected; hypotension and
excessive peripheral oedema should be avoided. In a further attempt to improve tissue
oxygenation hyperbaric oxygen therapy has proved to be effective in selected
In summary, calciphic uraemic arteriolopathy is an uncommon condition with a very
poor prognosis. The diagnosis is often considerably delayed whilst other, more common
diagnoses, are considered. The treatment options are few and, as with our patient, the
speed of progression of the disease can preclude more specialist treatment options
including hyperbaric oxygen therapy. However, the mechanisms whereby vascular
calcification is regulated are slowly being unravelled and this does raise the possibility
of novel therapeutic strategies in the future for patients at risk.
Fig 1* Copies of this figure are available from the author
1 Angelis, M, L.L. Wong, S.A. Myers, and L.M. Wong. Calciphylaxis in patients on
hemodialysis: a prevalence study. Surgery. 1997; 122, no. 6:1083-9.
2 Fine, A., and J. Zacharias. Calciphylaxis is usually non-ulcerating: risk factors,
outcome and therapy. 2002; 61 6, no. 2210-7.
3 Zacharias, J.M., B. Fontaine, and A. Fine. Calcium use increases risk of calciphylaxis:
a case-control study. Perit Dial Int. 1999; 19, no. 3:248-52.
4 Mathur, R.V., J.R. Shortland, and A.M. el-Nahas. Calciphylaxis. Postgrad Med J.
2001; 77, no. 911:557-61.
5 Lim, S.P., K. Batta, and B.B. Tan. Calciphylaxis in a patient with alcoholic liver
disease in the absence of renal failure. Clin Exp Dermatol. 2003; 28, no. 1:34-6.
6 Goyal, S., K.M. Huhn, and T.T. Provost. Calciphylaxis in a patient without renal
failure or elevated parathyroid hormone: possible aetiological role of chemotherapy. Br
J Dermatol. 2000; 143, no. 5:1087-90.
7 Wilmer, W.A., and C.M. Magro. Calciphylaxis: emerging concepts in prevention,
diagnosis, and treatment. Semin Dial. 2002; 15, no. 3:172-86.
8 Ahmed, S., K.D. O’Neill, A.F. Hood, et al. Calciphylaxis is associated with
hyperphosphatemia and increased osteopontin expression by vascular smooth muscle
cells. Am J Kidney Dis. 2001; 37, no. 6:1267-76.
9 Canfield, A.E., C. Farrington, M.D. Dziobon, et al. The involvement of matrix
glycoproteins in vascular calcification and fibrosis: an immunohistochemical study. J
Pathol. 2002; 196, no. 2:228-34.
10 Schafer, C., A. Heiss, A. Schwarz, et al. The serum protein alpha 2-Heremans-
Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification.
J Clin Invest. 2003; 112, no. 3:357-66.
11 Wesson, J.A., R.J. Johnson, J. Hughes et al. Osteopontin is a critical inhibitor of
calcium oxalate crystal formation and retention in renal tubules. J Am Soc Nephrol.
2003; 14, no. 1:139-47.
12 Speer, M.Y., M.D. McKee, R.E. Guldberg, et al. Inactivation of the osteopontin gene
enhances vascular calcification of matrix Gla protein-deficient mice: evidence for
osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med. 2002;
196, no. 8:1047-55.
13 Ketteler, M., C. Wanner, T. Metzger,et al. Deficiencies of calcium-regulatory
proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia.
Kidney Int Suppl. 2003; 84:S84-7.
14 Zimmermann, J., S. Herrlinger, A. Pruy, T. Metzger, and C. Wanner. Inflammation
enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999;
55, no. 2:648-58.
15 Lebreton, J.P., F. Joisel, J.P. Raoult, B. Lannuzel, J.P. Rogez, and G. Humbert.
Serum concentration of human alpha 2 HS glycoprotein during the inflammatory
process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant. J Clin
Invest. 1979; 64, no. 4:1118-29.
16 Ketteler, M., C. Vermeer, C. Wanner, R. Westenfeld, W. Jahnen-Dechent, and J.
Floege. Novel insights into uremic vascular calcification: role of matrix Gla protein and
alpha-2-Heremans Schmid glycoprotein/fetuin. Blood Purif. 2002; 20, no. 5:473-6.
17 Bahar, G., D. Mimouni, M. Feinmesser, M. David, A. Popovzer, and R. einmesser.
Subtotal parathyroidectomy: a possible treatment for calciphylaxis. Ear Nose Throat J.
2003; 82, no. 5:390-3.
18 Younis, N., R.A. Sells, A. Desmond, et al. Painful cutaneous lesions, renal failure
and urgent parathyroidectomy. J Nephrol. 2002; 15, no. 3:324-9.
19 Kang, A.S., J.T. McCarthy, C. Rowland, D.R. Farley, and J.A. van Heerden. Is
calciphylaxis best treated surgically or medically? Surgery. 2000; 128, no. 6:967-71.
20 Russell, R., M.A. Brookshire, M. Zekonis, and S.M. Moe. Distal calcific uremic
arteriolopathy in a hemodialysis patient responds to lowering of Ca x P product and
aggressive wound care. Clin Nephrol. 2002; 58, no. 3:238-43.
21 Tittelbach, J., T. Graefe, and U. Wollina. Painful ulcers in calciphylaxis - combined
treatment with maggot therapy and oral pentoxyfillin. J Dermatolog Treat. 2001; 12, no.
22 Milas, M., R.L. Bush, P. Lin, K., et al. Calciphylaxis and nonhealing wounds: he role
of the vascular surgeon in a multidisciplinary treatment. J Vasc Surg. 2003; 37, no.
23 Don, B.R., and A.I. Chin. A strategy for the treatment of calcific uremic
arteriolopathy (calciphylaxis) employing a combination of therapies. lin Nephrol. 2003;
59, no. 6:463-70.
24 Wilmer, W.A., O. Voroshilova, I. Singh, D.F. Middendorf, and F.G. Cosio.
Transcutaneous oxygen tension in patients with calciphylaxis. Am J Kidney Dis. 2001;
37, no. 4:797-806.
25 Basile, C., A. Montanaro, M. Masi, G. Pati, P. De Maio, and A. Gismondi.
Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series. J Nephrol.
2002; 15., no. 6:676-80.