Larva Terapia.com.ecDr. C.A. Vincent M.D.INTERNISTAManuel Galecio 1208 y Av. del Ejército (Centro Guayaquil)Bálsamos #629 e/ Ficus y Las Monjas (Urdesa)Telf.: 2280008 / 2320936 Cel.: 0981137366 / 097226405Guayas - Ecuador
Fatal Calcific Uraemic Arteriolopathy (Cua): A Case Report And ReviewOf The LiteratureN 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,West LothianCorrespondence to: email@example.comSMJ 2004 49(3): 108-1 11Abstract:Calciphylaxis, now better known as Calcific uraemic arteriolopathy (CUA), is anuncommon condition characterised by small vessel calcification and occlusion withresultant painful violaceous skin lesions that typically ulcerate to form non-healinggangrenous ulcers. The syndrome is usually found in patients with renal failure. In thisreport we describe a 61 year old lady who developed lower limb ulceration secondary tocalciphylaxis and discuss the current treatment options for this serious condition.Keywords: Calcific uraemic arteriolopathy, calciphylaxis, renal failure, ulceration.Case reportA 61 year old lady developed end stage renal failure of uncertain aetiology in 1993 andcommenced chronic ambulatory peritoneal dialysis (CAPD). She received a cadavericrenal transplant in 1994 but developed chronic allograft nephropathy and renaldysfunction (serum creatinine (Cr) 249µmol/l and creatinine clearance 18ml/min. inJuly 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 withcyclosporin A (75mg bd), mycophenolate mofetil ([MMF] 500mg tds), prednisolone(5mg od), ramipril, doxazosin, metoprolol, bumetanide, 1-alphacalcidol, ferrousgluconate, warfarin, omeprazole and pravastatin. In July 2002, an area of tender slightlyreddened skin was noted on her right calf compatible with ‘thrombophlebitis’. Inaddition, 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 andthe bumetanide dosage was therefore increased. In addition, the dose of 1-alfacalcidolwas increased to combat her secondary hyperparathyroidism (parathyroid hormone[PTH] concentration 272ng/l [normal < 65ng/l]). The calf pain remained unchangeddespite some evidence of fluid loss. She developed increasing calf discomfort and wasprescribed antibiotics from her GP for bilateral calf cellulitis.The underlying cause of her calf pain was still unclear and a diagnosis of painfuluraemic neuropathy was considered (Urea 35 mmol/l) and treatment with Gabapentinwas initiated. In mid February 2003, she was admitted to the Renal Unit of the RoyalInfirmary of Edinburgh. She had developed an increasingly painful, erythematous rightcalf and had received two courses of oral Co- Amoxiclav from her GP. However, anarea of skin ulceration developed with clinical examination confirming an 8x5cmulcerated lesion surrounded by tender, erythematous skin. The ulcer was felt to bemainly the result of pressure as she admitted to sitting in a chair with her calves restingon a stool for several hours each day. She was treated with intravenous antibiotics(penicillin V, flucloxacillin and metronidazole) and underwent lower limb angiographyin order to exclude significant large vessel disease. This revealed some calcified plaquebut no significant stenoses that required interventional treatment. The appearance of theulcer improved with antibiotic treatment and she was discharged and referred to theplastic 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 withnew ulceration of the left calf. She was febrile and therefore commenced on intravenousantibiotics. 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, correctedcalcium 2.23 mmol/l, phosphate 2.19 mmol/l and C reactive protein 166 IU/l (normalrange <101U/l). Swabs of the ulcers variably grew commensal organisms, anaerobesand MRSA and she was treated with intravenous teicoplanin and metronidazole. Thedose of MMF was reduced and the ramipril was discontinued in view of her worseningrenal function and hyperkalaemia. A renal ultrasound demonstrated no evidence ofobstruction and cyclosporin A levels were non-toxic. She was commenced onintermittent haemodialysis. She was reviewed by the plastic surgeons and an initialdiagnosis of pressure sores was made. She underwent surgical debridement of theulcers. However, pathological examination of specimens of debrided tissue revealednecrotic, ulcerated skin with small foci of calcification within the walls of blood vesselssuggestive of calcific uraemic arteriolopathy. (Fig 1*): Urgent parathyroidectomy wasconsidered but decided against as calcium and phosphate levels were relatively wellcontrolled with medical management. Plain X-rays of her thighs and calves confirmedsmall vessel calcification (Fig 3). Investigations for an underlying vasculitic illnesswere negative and Protein C and Protein S deficiencies were excluded.Further management involved maintaining excellent calcium and phosphate controlwith non-calcium containing phosphate binders and diet and regular ulcer dressings.She was unresponsive to erythropoietin (EPO) and therefore, in order to optimiseoxygen delivery to the tissues, receive intermittent blood transfusions to maintain herhaemoglobin above 100g/dl. Her warfarin treatment was discontinued. Two weeks latershe complained of increasing pain over the lateral and anterior surface of her thighs withthese areas developing livedo reticularis. The skin rapidly became gangrenous andsloughed to form further large areas of ulceration (Fig 2A + 2B). Pain remained asignificant problem despite specialist input from the pain control team. The ulcersbecame repeatedly infected and she ultimately opted to withdraw from dialysis andaggressive antibiotic treatment. She died from septicaemia and uraemia just over onemonth after the firm diagnosis of calcific uraemic arteriolopathy was made.DiscussionBackground and pathology
This condition was originally called calciphylaxis by Selye in 1962 but is now termedcalcific 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 proliferationand often thrombosis.Pathogenesis athogenesisCUA is considered to be rare although some reports suggest that the incidence isincreasing and that up to 4% of the dialysis population may be affected.1,2 Theincreased incidence may relate to the more widespread use of calcium containingphosphate binders and treatment with parenteral Vitamin D and iron dextran.3,4Although almost entirely confined to patients with end-stage renal failure it has beeninfrequently reported in other patient groups.5,6 CUA is a serious condition with agrave prognosis. It has a mortality rate of approximately 60-80% with most deathsattributable to septicaemia from secondary infection of skin lesions.2,4 . Thepathogenesis of calciphylaxis is incompletely understood but is related to abnormalcalcium-phosphate metabolism and hyperparathyroidism causing an elevated CaxPO4product.3,7 Other risk factors include female sex (male:female ratio of 1:3), obesity,Caucasian race, diabetes, malnutrition, warfarin, glucocorticoids and possiblyintravenous iron.4 It is noteworthy that, similar to the patient described in this report,many patients developing calciphylaxis exhibit multiple risk factors and commonlyhave a precipitating factor. This may be local trauma, hypotension, thrombosis or sepsisthereby 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 ofsitting with her calves resting on a stool for prolonged periods. It is likely that theresultant prolonged pressure may have precipitated the initial ulceration of the calf.However, recent research has greatly informed in this clinical area and indicates thathomeostatic mechanisms exist to combat vascular calcification. There are severalendogenous inhibitors of calcification that act within blood vessels such as osteopontin(OPN)8, matrix Gla protein (MGP)9 and alpha 2-Heremans-Schmidglycoprotein/fetuin A [ahsg/fetuin].10 Mice targeted for the deletion of these genesexhibit an increased propensity to vascular and genitourinary calcification.10,11 OPN
and MGP double knockout mice exhibit dramatically increased levels of vascularcalcification such that they die from calcific vessel rupture.12 It is therefore tempting tospeculate that these mechanisms may become dysfunctional in uraemic patients andthereby contribute to the development of CUA as well as the burden of cardiovasculardisease carried by the dialysis population as a whole.13 It is well documented that anelevated acute phase response as indicated by an elevated C reactive protein level is astrong predictor of mortality.14 It is therefore pertinent that ahsg/fetuin is a negativeacute phase reactant with levels falling in states of chronic inflammation.15 Thecirculating levels of ahsg/fetuin were found to be lower in dialysis populationscompared to controls and was an independent risk factor for patient death.16Clinical presentationClinically, calciphylaxis usually presents with violaceous mottling, livedo reticularis oras erythematous plaques, nodules or papules. When the condition is non-ulcerating theclinical findings may be confused, as in our patient, with cellulitis. These lesions aretypically intensely painful and firm to touch. Ninety percent of lesions are found on thelower extremities.2 Calciphylaxis may affect the distal limbs (calves and forearms) ormay 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 mayalso involve other organs including muscles (causing a painful myopathy), heart, joints,lungs, pancreas and the eye.4 The differential diagnosis includes peripheral vasculardisease, atheroembolic disease, cryoglobulinaemia and vasculitis.DiagnosisThe diagnostic gold standard is a tissue biopsy that demonstrates the typical histologicalfeatures of calciphylaxis. However, it must be recognised that this should be avoided ifpossible as there is a significant risk in performing biopsies of suspicious lesions asulceration commonly ensues. Other investigations should include measurement ofserum calcium, phosphate and PTH levels as well as assay of coagulation factors,cryoglobulins and a vasculitis screen including assay for ANCA. Arterial duplexdoppler scanning and even peripheral angiography should be undertaken if there isclinical suspicion of large vessel peripheral vascular disease. X-rays usually show
vascular calcification within the dermis and subcutaneous tissue but this may be seen inpatients with end-stage renal failure and is not specific to calciphylaxis.Treatment optionsTreatment options for calciphylaxis are limited.4,7 There are reports indicating benefitfrom urgent parathyroidectomy performed on patients with CUA in associationhyperparathyroidism17,18 with larger studie suggesting benefit only in cases withmarkedly elevated PTH levels.19 It is important to control the [calcium x phosphate]product with non-calcium containing phosphate binders such as Aluminium Hydroxideor Sevelamer.20 Consideration should also be made to the discontinuation of Warfarinin view of the similarities between calciphylaxis and Warfarin skin necrosis. Amultidisciplinary approach involving meticulous wound care,21 the judicious use ofantibiotics and close liaison with surgical colleagues is essential.22,23 Other therapiesare principally aimed at Fig3: Plain X-ray of the thighs indicate extensive small vesselcalcification. maximising tissue oxygen delivery since measurement of transcutaneousoxygen tension indicates abnormally low oxygen tensions in affected and non-affectedareas of skin in patients with CUA.24 Anaemia should be corrected; hypotension andexcessive peripheral oedema should be avoided. In a further attempt to improve tissueoxygenation hyperbaric oxygen therapy has proved to be effective in selectedpatients.25ConclusionIn summary, calciphic uraemic arteriolopathy is an uncommon condition with a verypoor prognosis. The diagnosis is often considerably delayed whilst other, more commondiagnoses, are considered. The treatment options are few and, as with our patient, thespeed of progression of the disease can preclude more specialist treatment optionsincluding hyperbaric oxygen therapy. However, the mechanisms whereby vascularcalcification is regulated are slowly being unravelled and this does raise the possibilityof novel therapeutic strategies in the future for patients at risk.Fig 1* Copies of this figure are available from the authorREFERENCES
1 Angelis, M, L.L. Wong, S.A. Myers, and L.M. Wong. Calciphylaxis in patients onhemodialysis: 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 liverdisease 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 renalfailure or elevated parathyroid hormone: possible aetiological role of chemotherapy. BrJ 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 withhyperphosphatemia and increased osteopontin expression by vascular smooth musclecells. Am J Kidney Dis. 2001; 37, no. 6:1267-76.9 Canfield, A.E., C. Farrington, M.D. Dziobon, et al. The involvement of matrixglycoproteins in vascular calcification and fibrosis: an immunohistochemical study. JPathol. 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 ofcalcium 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 geneenhances vascular calcification of matrix Gla protein-deficient mice: evidence forosteopontin 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-regulatoryproteins 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. Inflammationenhances 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 inflammatoryprocess: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant. J ClinInvest. 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 andalpha-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 failureand 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. Iscalciphylaxis 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 uremicarteriolopathy in a hemodialysis patient responds to lowering of Ca x P product andaggressive wound care. Clin Nephrol. 2002; 58, no. 3:238-43.21 Tittelbach, J., T. Graefe, and U. Wollina. Painful ulcers in calciphylaxis - combinedtreatment with maggot therapy and oral pentoxyfillin. J Dermatolog Treat. 2001; 12, no.4:211-4.22 Milas, M., R.L. Bush, P. Lin, K., et al. Calciphylaxis and nonhealing wounds: he roleof the vascular surgeon in a multidisciplinary treatment. J Vasc Surg. 2003; 37, no.3:501-7.23 Don, B.R., and A.I. Chin. A strategy for the treatment of calcific uremicarteriolopathy (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.