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Hong Kong J Nephrol 2001;3(2):103-106. YH CHAN, et al

Atypical presentation of calciphylaxis in a patient with renalfailure: successful treatment with unfractionated heparinYiu-Han CHAN1, Kim-Ming WONG1, Philip Chong-Hei KWOK2, Chi-Yuen CHEUNG1,Wai-Leung CHAK1, Koon-Shing CHOI1, Ka-Foon CHAU1, Chun-Sang LI1

1Renal Unit, Departments of Medicine and 2Radiology and Imaging, Queen Elizabeth Hospital, Hong Kong.

AbstractCalciphylaxis is a rare but serious complication in patients with end-stage renal failure. The conditionis associated with high morbidity and mortality. The exact pathogenesis of calciphylaxis and theoptimal treatment are still not known. A disturbance of coagulation seems to be relevant in thepathogenesis, and anticoagulation therapy seems to be a rational therapy. Reported herein is acase of calciphylaxis developed in a renal failure patient receiving peritoneal dialysis who wassuccessfully treated with intravenous unfractionated heparin.

Key words: Calciphylaxis, Heparin, Parathyroidectomy, Renal failure, Skin ulcer

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C A S E

R E P O R T

Correspondence: Dr. Yiu-Han CHAN, Renal Unit, Department of Medicine, Queen Elizabeth Hospital, Gascoigne Road, Kowloon,Hong Kong. Fax: (852) 2388 5389, E-mail: cyh201@hotmail.com

Hong Kong Journal of Nephrology2001;3(2):103-106.

Hong Kong Journal of Nephrology, October 2001©2001 Hong Kong Society of Nephrology

INTRODUCTIONAlthough uncommon, calciphylaxis is a seriouscomplication in patients with end-stage renal failure(ESRF) (1,2). It is characterized by progressive ischemicskin necrosis associated with calcification of arteriolesand small dermo-hypodermic arteries (3). The exactpathogenesis of calciphylaxis is still not well understood,and most cases are associated with chronic renal failure,usually with secondary or tertiary hyperparathyroidism(4). Controversies exist in the optimal treatment of thecondition, and the role of parathyroidectomy in treat-ing established calciphylaxis (5-10). Anecdotallylow-molecular-weight heparin (LMWH) has beendemonstrated to be useful (2,11). Herein, we report acase of calciphylaxis developed in a patient with renalfailure who had received peritoneal dialysis for 1 month,and was treated successfully with intravenous un-fractionated heparin.

CASE REPORTA 67-year-old Chinese man (body mass index, 25.1 kg/m2)

presented with ESRF secondary to diabetic nephro-pathy. He was diagnosed with diabetes mellitus andhypertension during a routine checkup in 1992.Significant proteinuria and renal impairment werenoticed in 1997 by his family physician, and he was thenreferred to the Renal Unit of the Queen Elizabeth Hospitalfor further management. At that time, his 24-hour urineprotein was approximately 3 g/d with a creatinine clearanceof 45 mL/min and serum creatinine concentration of180 µM. He was also found to have proliferative diabeticretinopathy requiring laser therapy. He had coronaryartery bypass surgery and mechanical mitral valvularreplacement in 1998 for ischemic heart disease andfunctional mitral regurgitation secondary to ischemiccardiomyopathy, and had been receiving warfarin therapysince then. His renal function continued to deteriorateprogressively. At the same time, he suffered fromrepeated attacks of congestive heart failure. His serumcreatinine concentration rose to 499 µM and creatinineclearance decreased to 6 mL/min in December 1999.Peritoneal dialysis therapy was commenced in January

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2000. During the perioperative period for Tenckhoffcatheter insertion, warfarin was temporarily withheld andLMWH was given. Warfarin therapy was recommencedafter the surgery, and the result of his blood internationalnormalized ratio (INR) was adjusted back to acceptablerange (INR, 2-3) on discharge.

Two weeks after the Tenckhoff catheter insertion, thepatient had an episode of warfarin overdose withprolonged INR. Mini-dose vitamin K1 was given tocontrol the excessive oozing from the previous surgicalwound (12). Warfarin was restarted 3 days later whenthe INR result returned to acceptable level. Two weekslater, he developed a red painful tender spot over hisglans penis. The red spot expanded gradually and formeda well-demarcated ulcer over the glans penis. It had asmooth and nonundulating irregular edge with yellow-ish fibrous material adhered to the base. Physical ex-amination did not reveal any other ulcers over the body.His blood pressure was continually stable, and all theperipheral pulses were palpable. He denied having sexualcontact in the past 2 years, and had not received anycalcium-containing compound or vitamin D preparations.Laboratory values revealed a white blood cell count of11.3 x 109/L, hemoglobin 10 g/dL, platelet count 553 x109/L, urea 15.8 mM, creatinine 370 µM, alkalinephosphatase 273 IU/L, albumin 27 g/L, calcium 2.1 mM,phosphate 1.28 mM, and parathyroid hormone 39 pM(normal range, 1.1-5.7 pM). His diabetes was undersatisfactory control with a hemoglobin A1c level of 7%.Other pertinent investigations, including venereal diseaseresearch laboratory, fluorescent treponemal antibody, andtreponemal pallidum passive particle agglutination test,were all nonreactive. The antinuclear factor was weaklypositive (1:160), antidouble-stranded DNA was negative,antineutrophil cytoplasmic antibody C and P werenegative, and anticardiolipin antibodies immunoglobulinG level was 6.6 GPL U/mL (<10 GPL U/mL). X-raysshowed calcification of radial and ulcer artery of bothhands, and calcification in the internal pudendal artery,the penile artery, the dorsal penile artery, and arteries tothe bulb of corpus spongiosum (Fig. 1). A biopsy of theulcer was offered but declined by the patient. Clinicallyhe was diagnosed with calciphylaxis.

The penile ulcer was treated with aggressive local wounddressing and appropriate antibiotic. Low calciumconcentration peritoneal dialysis solution was used(Baxter Dianeal, Baxter Healthcare Corporation, Illiniois,US), and aluminum-containing phosphate binder wasadded to achieve better serum phosphate control.However, there was no improvement in the penile ulcerfor the initial 3 weeks, and the ulcer increased in sizeprogressively. As a rescue therapy, warfarin was

discontinued, and the patient was maintained onintravenous unfractionated heparin. The dosage ofheparin was adjusted to achieve an activated partialthromboplastin time 1.5 to 2 times that of baseline. Thepenile ulcer improved gradually after the patient wasplaced on intravenous unfractionated heparin, and ithealed completely after 8 weeks of therapy. Warfarinwas reintroduced carefully, and no recurrence of skinulcer was noticed after 6 months of follow-up. An assayon protein C and protein S functional activity wasperformed, which showed no evidence of functionaldeficiency.

DISCUSSIONHerein we report a case of calciphylaxis in a renal failurepatient who presented with penile ulceration that healedafter receiving intravenous unfractionated heparintherapy. Calciphylaxis is a rare but serious complicationin patients with ESRF (1). It is characterized by pro-gressive ischemic skin necrosis with a stereotypic anddiagnostic clinical picture associated with calcificationof arterioles and small dermo-hypodermic arteries (3,4).Typically, the skin lesions presented as areas of painfulmolting resembling livido reticularis with superficialviolaceous nodules involving the tip of the toes or fingers,or areas above the ankles, thighs, or buttocks (1,4).Persistent palpable pulse distal to the necrosis is one ofthe characteristic features (4,16). Ninety percent ofpatients have lower extremity involvement (1), and casesof penile involvement have been reported in the literature(13-15). Prognosis of the condition is often poor, withan overall mortality of 60%; patients usually die of sepsis(4). Prognosis is better for distal-limited lesion comparedwith the proximal lesion (1).

Figure 1. Pelvic radiograph showing calcification in the internalpudendal artery, the penile artery, the dorsal penile artery, andarteries to the bulb of corpus spongiosum.

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The landmark series of calciphylaxis syndrome in hu-mans was described by Gipstein et al (5) in 1976. Theyreported a syndrome of tissue necrosis and vascularcalcification in 11 patients with chronic renal failure andpresumed secondary hyperparathyroidism. All thepatients had severe hyperphosphatemia, and the tissuenecrosis healed after parathyroidectomy in seven of 10patients (5). At that time, dysregulation of calcium andphosphorous control mechanisms and hyperpara-thyroidism were believed to be the necessary conditionsfor the development of calciphylaxis (17,18). However,cases without significant abnormalities in serum calcium,phosphate, and parathyroid hormones, and cases thatdeveloped after successful parathyroidectomy weredescribed afterward (1,4,17,18). Other risk factors suchas significant weight loss, low serum albumin, andobesity in white women have also recently surfaced asimportant factors predictive of the development ofcalciphylaxis (11,17).

Because thrombi can be found in calcified arterioleadjacent to areas of skin necrosis, pre-existing dis-turbance of coagulation seems to be relevant in thepathogenesis of the condition (20). Impaired protein Cactivity (6,19) and functional protein S deficiency havebeen demonstrated in patients with calciphylaxis (3,6,19). As in the patient reported here, a high prevalence ofpatients with calciphylaxis on warfarin therapy has alsobeen noted (4,11). This may be attributed to the fluc-tuation of plasma protein C and protein S levels after thecommencement of warfarin therapy (4). However, a clearcausation between coagulation proteins and calciphylaxishas not been established yet. Although we were not ableto demonstrate functional protein C and S deficiency inthis patient, fluctuation in his blood INR level wasnoticed during the perioperative period of Tenckhoffinsertion, and this may trigger the development ofcalciphylaxis.

This case of calciphylaxis occurred around 4 weeks afterinitiation of peritoneal dialysis. Generally it is believedthat a longer exposure to renal replacement therapy inpatients with end-stage renal disease may increase thelikelihood of developing calciphylaxis by increasing theexposure time to factors that predispose to calciphylaxis(24). However, the time period for the onset of symptomsof calciphylaxis can range from less than 1 month to aslong as 12 years after the onset of end-stage renal diseasewith a median of 2.75 years (1,17). A few cases evenpresented with symptoms before the onset of ESRF (1).Long-standing diabetes in this patient causing diabeticarteriosclerosis may have contributed to the calcificationof the pudendal artery. This may have shortened theperiod between the onset of symptoms of calciphylaxis

and the onset of end-stage renal disease.

Initial management of calciphylaxis includes aggress-ive wound care with debridement of necrotic tissueand appropriate systemic antibiotic. Control ofhyperphosphatemia and normalization of calcium-phosphate products by restricting phosphate in the dietand using phosphate-binding agents are also essential(9,16). However, calcium-containing phosphate bindershould be avoided and vitamin D supplements shouldbe used cautiously (20). Emphasis should also be placedon using peritoneal dialysate solution of low-calciumconcentration. In the past, parathyroidectomy wasconsidered by many as a crucial therapy for the controlof hyperparathyroidism, and previous reports showedbetter patient survival after parathyroidectomy (5,7,9,21). However, recent reports have shown that theimprovement in calciphylaxis after parathyroidectomyis not as dramatic and encouraging as it was initiallythought (6,8,10). The benefit of parathyroidectomyremains to be controversial, especially for those patientswith mildly elevated or normal serum parathyroidhormone level (20).

Because thrombosis of the arteriole is a distinctive risk,the use of anticoagulants seems to be a rationale approach(11,20). Fluctuation in plasma protein C and protein Slevels need to be avoided. Substitution of LMWH(enoxaparin 1 mg/kg; Rhone-Poulenc, France) forwarfarin has resulted in healing of lesions in one patient,and arresting the progressive lesions in another patient(11). A remarkable response to treatment with LMWH(Fraxiparine 15 000 Axa/day; Sanofi, France) has alsobeen reported in a patient with demonstrable functionalprotein S deficiency (2). Hence, LMWH may be a usefulform of treatment, especially for patients with relativelynormal parathyroid hormone or phosphate level (2).However, the use of LMWH for prosthetic heart valvehas not been well documented. Treatment failuresresulting in thrombosed heart valves with stormy clinicalpresentations have been reported in patients on LMWH(22). The penile ulcer of our patient deteriorated despiteaggressive wound treatment, use of low-calcium con-centration dialysate solution, and aggressive phosphatecontrol. As a life-saving measure, withholding warfarinand commencing unfractionated heparin therapy was theonly therapeutic option remaining. Remarkably, thisresulted in dramatic improvement and later completehealing of the penile ulceration. According to ourknowledge, this is the first case report demonstrating thesuccessful use of conventional unfractionated heparinin the treatment of calciphylaxis.

Although heparin therapy may be helpful in the treatment

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of calciphylaxis, recently there was a report of a dialysispatient presenting with skin ulceration resemblingcalciphylaxis induced by heparin and protein S deficiency(23). The combined presence of heparin-dependentplatelet activating antibodies and functional S deficiencywas identified in the patient. The authors suggest that itis important to perform skin biopsy and testing for ahypercoagulable state in patients with end-stage renaldisease and skin ulceration to differentiate betweencalciphylaxis and heparin-induced necrosis, which isimportant because heparin will be contraindicated in thiscondition and distinct treatment options exist for bothconditions.

CONCLUSIONIn summary, calciphylaxis is still a condition associatedwith high morbidity and mortality, of which the patho-genic mechanism is still not well understood. Control ofserum calcium, phosphate, and parathyroid hormonelevels is essential for its management, and anti-coagulation is a rational approach. Both conventionalunfractionated heparin and LMWH might have thebenefit of avoiding fluctuation in plasma protein C andprotein S levels, and this may result in the improvementof skin ulceration and better patient survival. It is stillimportant to look for other causes of skin ulceration inpatients with end-stage renal disease that require adistinct form of treatment in which heparin therapy maybe contraindicated.

REFERENCES1. Budisavljevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal

failure. J Am Soc Nephrol 1996;7:978-82.

2. Perez-Mijares R, Guzman-Zamudio JL, Payan-Lopez J, Rodriguez-

Fernandez A, Gomez-Fernandez P, Almaraz-Jimenez M.

Calciphylaxis in a haemodialysis patient: functional protein S

deficiency? Nephrol Dial Transplant 1996;11:1856-9.

3. Selye H, Gobbiani G, Strebel R. Sensitization of calciphylaxis by

endogenous parathyroid hormone. Endocrinology 1962;71:554-8.

4. Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: study of three

cases with literature review. Hum Pathol 1995;26:1055-64.

5. Gipstein RM, Coburn JW, Adams DA, Lee DB, Parsa KP, Sellers

A, Suki WN, Massry SG. Calciphylaxis in man. A syndrome of tissue

necrosis and vascular calcification in 11 patients with chronic renal

failure. Arch Intern Med 1976;136:1273-80.

6. Chan YL, Mahony JF, Turner JJ, Posen S. The vascular lesions

associated with skin necrosis in renal disease. Br J Dermatol 1983;

109:85-95.

7. Fox R, Banowsky LH, Cruz AB Jr. Post-renal transplant

calciphylaxis: successful treatment with parathyroidectomy. J Urol

1983;129:362-3.

8. Adrogue HJ, Frazier MR, Zeluff B, Suki WN. Systemic calciphylaxis

revisited. Am J Nephrol 1981;1:177-83.

9. Duh QY, Lim RC, Clark OH. Calciphylaxis in secondary

hyperparathyroidism. Diagnosis and parathyroidectomy. Arch Surg

1991;126:1213-8.

10.Poch E, Almirall J, Alsina M, del Rio R, Cases A, Revert L.

Calciphylaxis in a hemodialysis patient: appearance after

parathyroidectomy during a psoriatic flare. Am J Kidney Dis 1992;

19:285-8.

11. Coates T, Kirkland GS, Dymock RB, Murphy BF, Brealey JK,

Mathew TH, Disney AP. Cutaneous necrosis from calcific uremic

arteriolopathy. Am J Kidney Dis 1998;32:384-91.

12.Weibert RT, Le DT, Kayser SR, Rapaport SI. Correction of excessive

anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997;

126:959-62.

13.Boccaletti VP, Ricci R, Sebastio N, Cortellini P, Alinovi A. Penile

necrosis. Arch Dermatol 2000;136:261, 264.

14.Wood JC, Monga M, Hellstrom WJ. Penile calciphylaxis. Urology

1997;50:622-4.

15. Jhaveri FM, Woosley JT, Fried FA. Penile calciphylaxis: rare necrotic

lesions in chronic renal failure patients. J Urol 1998;160:764-7.

16.Llach F. Calcific uremic arteriolopathy (calciphylaxis): an evolving

entity? Am J Kidney Dis 1998;32:514-8.

17.Bleyer AJ, Choi M, Igwemezie B, de la Torre E, White WL. A case

control study of proximal calciphylaxis. Am J Kidney Dis 1998;32:

376-83.

18.Smiley CM, Hanlon SU, Michel DM. Calciphylaxis in moderate renal

insufficiency: changing disease concepts. Am J Nephrol 2000;20:

324-8.

19.Mehta RL, Scott G, Sloand JA, Francis CW. Skin necrosis

associated with acquired protein C deficiency in patients with renal

failure and calciphylaxis. Am J Med 1990;88:252-7.

20. Janigan DT, Hirsch DJ, Klassen GA, MacDonald AS. Calcified

subcutaneous arterioles with infarcts of the subcutis and skin

(calciphylaxis) in chronic renal failure. Am J Kidney Dis 2000;35:

588-97.

21.Hafner J, Keusch G, Wahl C, Sauter B, Hurlimann A, von Weizsacker

F, Krayenbuhl M, Biedermann K, Brunner U, Helfenstein U. Uremic

small artery disease with medial calcification and intimal hypertrophy

(so-called calciphylaxis): a complication of chronic renal failure and

benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954-

62.

22.Lev-Ran O, Kramer A, Gurevitch J, Shapira I, Mohr R. Low-

molecular-weight heparin for prosthetic heart valves: treatment

failure. Ann Thorac Surg 2000;69:264-5.

23.Denton MD, Mauiyyedi S, Bazari H. Heparin- induced skin necrosis

in a patient with end-stage renal failure and functional protein S

deficiency. Am J Nephrol 2001;21:289-93.

24. Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan MJ, Davis

CL, Stehman-Breen CO. Risk factors and mortality associated with

calciphylaxis in end-stage renal disease. Kidney Int 2001;60:324-32.