d -Penicillamine–Induced ANCA-Associated Crescentic Glomerulonephritis in Wilson Disease

CASE REPORTS D-Penicillamine–Induced

ANCA-Associated Crescentic Glomerulonephritis in Wilson Disease

Frank Bienaimé, MD,1 Gaétan Clerbaux, MD,1 Emmanuelle Plaisier, MD, PhD,1 Béatrice Mougenot, MD,2 Pierre Ronco, MD, PhD,1 and Jean-Philippe Rougier, MD, PhD1 Several drugs, including hydralazine and propylthiouracil, can induce antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. D-Penicillamine was implicated in a few patients with rheumatoid arthritis or systemic sclerosis, but in patients with both diseases, ANCA-associated vasculitides were described in the absence of the drug. Therefore, the role of D-penicillamine treatment could not be established. We report the first case of antimyeloperoxidase antibody–associated vasculitis in a patient treated with D-penicillamine for Wilson disease. Because Wilson disease was never associated with ANCA-related nephritis, this case strongly supports that D-penicillamine can induce ANCA-vasculitis. The presentation and rapidly progressive and potentially severe outcome of this complication dramatically contrast with those of membranous and minimal change glomerulopathy, also induced by the sulfhydryl compound. Am J Kidney Dis 50:821-825. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Antineutrophil cytoplasmic antibody (ANCA)-induced glomerulonephritis; D-penicillamine; Wilson disease.

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rug-induced antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis with renal involvement is well documented for hydralazine and thionamide antithyroid drugs.1 D-Penicillamine is a sulfhydryl compound used for the treatment of patients with Wilson disease and other illnesses, including rheumatoid arthritis and systemic sclerosis. As many as 7% of patients receiving prolonged D-penicillamine therapy develop such renal side effects as membranous nephropathy and minimal change disease.2,3 D-Penicillamine withdrawal usually induces remission of the renal disease, although this may take years. ANCA-associated vasculitides occasionally were reported in patients with rheumatoid arthritis or systemic sclerosis treated with D-penicillamine. However, they also were reported in patients with these diseases in the absence of D-penicillamine therapy. Therefore, the relationship between ANCA-associated vasculitis and D-penicillamine treatment is questionable.4,5 Here, we report the first fully documented case of ANCA-associated small-vessel vasculitis with renal involvement in a patient with Wilson disease treated with D-penicillamine. CASE REPORT A 19-year-old woman was referred to our nephrology department for acute renal failure, nephrotic-range proteinuria, and hematuria. Two years earlier, Wilson disease was

diagnosed based on clinical neurological examination abnormalities, Kayser-Fleischer rings, cirrhosis, and excessive copper content in liver tissue. D-Penicillamine was administered as copper chelator at 900 mg/d and was well tolerated. It dramatically improved the patient’s neurological symptoms during a 2-year period. At that time, renal function was normal, with serum creatinine level of 0.8 mg/dL (67 ␮mol/L) and estimated glomerular filtration rate using the Modification of Diet in Renal Disease Study equation of 101 mL/min/ 1.73 m2 (1.68 mL/s/1.73 m2), without proteinuria (protein ⬍ 0.02 g/L) or hematuria. Between July and November 2003, the patient lost 20 kg and developed microcytic anemia and alopecia without photosensitivity. In December 2003, laboratory findings showed a moderate decrease in kidney function, nephrotic syndrome, and microscopic hematuria. When she was referred to our department, blood pressure was 150/85 mm Hg and temperature was 38.6oC. She was eupneic with 96% oxygen saturation measured by using pulse oximetry in ambient air. Physical examination showed bilateral pleural effusion. Neurological examination showed unmodified changes related to Wilson disease. There was no sinonasal

From the 1Department of Nephrology and Dialysis, APHP, and 2Department of Pathology, Tenon Hospital, APHP, Paris. Received January 3, 2007. Accepted in revised form May 18, 2007. Originally published online as doi: 10.1053/j.ajkd.2007.05.026 on August 1, 2007. Address correspondence to Jean-Philippe Rougier, MD, PhD, Department of Nephrology and Dialysis, Tenon Hospital, APHP, 4 rue de la Chine, 75020 Paris, France. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/5005-0016$32.00/0 doi:10.1053/j.ajkd.2007.05.026

American Journal of Kidney Diseases, Vol 50, No 5 (November), 2007: pp 821-825

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822 disease or hearing loss. There was no other abnormal clinical finding. Serum creatinine level was 1.9 mg/dL (146 ␮mol/L), with estimated glomerular filtration rate of 42 mL/min/1.73 m2 (0.70 mL/s/1.73 m2). The patient had hypoalbuminemia (albumin, 2.32 g/dL [23.2 g/L]), a urine protein-creatinine ratio of 906 mg/mmol, and microscopic hematuria (200 red blood cells/␮L), but no leukocyturia. Hemogram showed microcytic anemia with hemoglobin level of 8.5 g/dL (85 g/L) and increased white blood cell count (12 ⫻ 103/␮L [12 ⫻ 109/L]) with neutrophils at 9.4 ⫻ 103/␮L (9.4 ⫻ 109/L). Platelet count and hepatic test results were unremarkable. ANCA testing by means of immunofluorescence was positive (titer, 1/20; normal, ⬍1/10) for perinuclear ANCA that were antimyeloperoxidase (anti-MPO)–specific immunoglobulin G (IgG) by means of enzyme-linked immunosorbent assay (33 U/mL; positive, ⬎20 U/mL). Antinuclear factors also were positive (titer, 1/1000). Testing for other autoantibodies, including anti–glomerular basement membrane antibodies and cryoglobulinemia, was negative. Complement components were normal. There was no evidence for hemolysis. All bacteriological and virological tests on blood, urine, and bronchoalveolar fluid had negative results. Chest radiography showed bilateral pleural effusion, which was noninflammatory after analysis of drained fluid. Cardiac ultrasound showed a mild noncompressive pericardial effusion. Kidneys were normal by means of ultrasound. Bronchoscopy results were unremarkable. Computed tomography and alveolar cytological test results were consistent with intra-alveolar hemorrhage. Bronchoalveolar lavage fluid contained almost exclusively red blood cells, with a small contingent of alveolar macrophages that were all Perls positive siderophages.

Figure 1. Necrotizing and crescentic glomerular lesions. By means of light microscopy, percutaneous renal biopsy specimen shows typical features of pauci-immune necrotizing glomerulonephritis: focal fibrinoid necrosis of the floculus (arrow) and crescentic cell proliferation (arrowhead) were seen in 50% of glomeruli. Fibrin deposition was seen by means of immunofluorescence (inset). (Masson trichrome stain; original magnification ⫻400; insert: antifibrin antibody.)

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Figure 2. Large crescentic glomerular lesions. The figure shows a more severely injured glomerulus than in Fig 1, with a large crescentic cell proliferation. (Masson trichrome stain; original magnification ⫻400.)

Standard staining of the kidney biopsy specimen showed typical figures of extracapillary proliferation with segmental (Fig 1) or global crescents (Fig 2) and fibrinoid necrosis (Fig 1) in 50% of glomeruli. Cortical interstitium showed mild diffuse fibrosis with a mild mononucleated cell infiltrate and no significant vascular lesion. Endocapillary or mesangial proliferation was not reported. By means of immunofluorescence, antifibrin antibody showed segmental deposit in Bowman space (Fig 1 insert). There was weak mesangial IgA and C3 deposits, but no significant IgM, IgG, or C1q deposit (data not shown). The patient therefore was given a diagnosis of ANCAassociated vasculitis, crescentic glomerulonephritis, and intra-alveolar hemorrhage that we attributed to prolonged D-penicillamine treatment. Shortly after admission, the patient’s condition worsened, with acute respiratory distress, high fever reaching 40oC, and rapidly progressive renal failure (creatinine level to 2.4 mg/dL [210 ␮mol/L]). Oral zinc therapy was immediately substituted for D-penicillamine to control copper levels, and immunosuppression was started. The patient was administered 3 methylprednisolone daily pulses (500 mg/d), followed by 1 mg/kg/d of methylprednisolone orally, and a total of 7 monthly cyclophosphamide pulses (0.5 g/m2). Ramipril, co-trimoxazole, vitamin D, and bisphosphonate therapies were started at the same time. The patient’s condition rapidly improved, with apyrexia and normalization of respiratory condition within 48 hours of steroid treatment. Pleural and pericardial effusions resolved within 2 weeks. Weight progressively increased. Renal function normalized within 3 weeks (serum creatinine, 0.6 mg/dL [51 ␮mol/L]), hematuria disappeared within 4 months, and albuminuria decreased to albumin less than 1 g/d at 5 months and finally disappeared. Anemia corrected slowly with iron and folic acid supplementation after inflammation resolved. ANCAs remained positive for 3 months, and then definitively disappeared. Full remission was achieved after 6 months, and maintenance immunosuppressive therapy was started with mycophenolate mofetil. The steroid dosage was slowly de-

DP-induced ANCA Nephritis in Wilson Disease creased and stopped 18 months after the onset. After 24 months of immunosuppression, the patient maintained systemic and renal remission, and mycophenolate mofetil therefore was progressively stopped without clinical or biological signs of relapse 12 months later.

DISCUSSION

Wilson disease is an inherited autosomal recessive disorder caused by loss of function of a copper exchanger adenosinetriphosphatase encoded by ATP7B, which results in impaired biliary copper excretion and accumulation of copper in plasma and tissues.6 In the kidney, copper accumulation may affect tubular cells, but was never associated with glomerular lesions. In our patient, the disease was adequately controlled with D-penicillamine therapy, and she did not show signs of tubular dysfunction or copper accumulation in the renal biopsy specimen. D-Penicillamine has been used since 1956 as a copper chelator to treat patients with symptomatic or latent Wilson disease.7 In 1975, Sternlieb et al8 first reported 3 crescentic glomerulonephritides in 3 patients with Wilson disease treated with D-penicillamine. Those patients were described as Goodpasture syndrome based on their clinical presentation, but anti–glomerular basement membrane antibodies were not detected and ANCA was not investigated. Immunofluorescence was performed on the kidney biopsy specimen in 1 patient only, showing patchy IgG and C3 deposition within the capillary wall and mesangium. Since this initial description, 1 case of IgA crescentic nephritis was reported in a patient with Wilson disease and cirrhosis who was not on D-penicillamine treatment.9 Thirtythree cases of renal small-vessel vasculitis were published for patients with rheumatoid arthritis and systemic sclerosis treated with D-penicillamine, 13 of which were associated with anti-MPO antibodies, but none with anti– proteinase-3 antibodies. 4,8,10-38 However, pauci-immune crescentic glomerulonephritis also was reported in association with either disease in the absence of D-penicillamine treatment; thus, the causative link between Dpenicillamine treatment and the renal vasculitis remains questionable.4,17,39-41 Our patient’s clinical and biological presentation, as well as pathological findings, was consistent with ANCA-associated crescentic glo-

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merulonephritis. She had been administered for 2 years when she developed the ANCA-associated vasculitis, a complication never associated with Wilson disease. Thus, the case we report here strongly suggests that D-penicillamine alone can trigger severe ANCAassociated vasculitis, which results in severe acute renal failure and respiratory distress. The potential alternative diagnosis of rapidly progressive IgA nephropathy associated with ANCArelated vasculitis and pulmonary involvement was briefly considered. However, in our patient, IgA deposits were scarce, strictly limited to the mesangium, and absent from the capillary wall, therefore considered coincidental and related to the cirrhosis, a condition frequently associated with mesangial IgA deposition,42,43 but not with anti-MPO antibody–associated systemic vasculitis. In our patient, ANCA were specifically directed against MPO. MPO is localized to azurophilic granules of neutrophilic granulocytes and lysosomes of monocytes and catalyzes the production of hypochlorite from hydrogen peroxide. 44 D-Penicillamine interacts with neutrophil MPO, a property that D-penicillamine shares with propylthiouracil, also associated with vasculitis. Hydralazine, another drug that may induce MPOassociated vasculitis, is metabolized by MPO, and its metabolites interact with neutrophil membrane. Interaction with MPO seems to be a key feature in drug-induced anti-MPO–associated vasculitis. However, it is not very clear how D-penicillamine induces autoimmunity. D-Penicillamine may react with thiol groups on membrane proteins or intracytoplasmic or intranuclear components and affect protein trafficking and processing in different cell lineages, including immunocompetent cells.45 The interaction of D-penicillamine with MPO also could alter MPO antigenic properties and promote a breach into self-antigen tolerance. Although the exact pathogenic mechanisms involved remain to be elucidated, both cell-mediated and humoral immunity appear to have important roles.46 As previously reported, D-penicillamine–associated vasculitis is a severe and potentially lifethreatening disease.4,8,10-38 Our patient initially presented with a very serious condition, including weight loss, high fever, acute renal failure, and respiratory distress syndrome. Initial treatment included substitution of D-penicillamine D-penicillamine

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with oral zinc. An aggressive immunosuppressive therapy with high doses of cyclophosphamide and steroids dramatically improved every aspect of the disease within days or weeks. No relapse has occurred 48 months after D-penicillamine therapy was stopped. In contrast to previous reports of ANCAassociated vasculitis in which systemic sclerosis or rheumatoid arthritis questioned the responsibility of D-penicillamine as the causing agent, our case more clearly suggests that D-penicillamine alone may trigger a severe ANCA-associated vasculitis with acute renal failure and respiratory distress. The severity of the disease urgently requests immediate and aggressive immunosuppressive treatment, as well as definitive D-penicillamine treatment withdrawal, to ensure a favorable relapse-free outcome. Substitutes for D-penicillamine, such as oral zinc, should be started to prevent copper accumulation.6 ACKNOWLEDGEMENTS Support: This work was supported in part by the Association pour l’Utilisation du Rein Artificiel (AURA) and the Institut National de la Santé Et de la Recherche Médicale (INSERM), Paris, France. Financial Disclosure: None.

REFERENCES 1. Merkel PA: Drug-induced vasculitis. Rheum Dis Clin North Am 27:849-862, 2001 2. Meyboom RHB, Brodie-Meijer CCE: Metal antagonists, in Dukes MNG (ed): Meyler’s Side Effects of Drugs. Oslo, Norway, Elsevier Science, 2000, pp 723-753 3. Hall CL, Jawad S, Harrison PR, et al: Natural course of penicillamine nephropathy: A long term study of 33 patients. Br Med J 296:1083-1086, 1988 4. Endo H, Hosono T, Kondo H: Antineutrophil cytoplasmic autoantibodies in 6 patients with renal failure and systemic sclerosis. J Rheumatol 21:864-870, 1994 5. Messiaen T, M’Bappe P, Boffa JJ, et al: MPO-ANCA necrotizing glomerulonephritis related to rheumatoid arthritis. Am J Kidney Dis 32:E6, 1998 6. Gitlin JD: Wilson disease. Gastroenterology 125:18681877, 2003 7. Walshe JM: Penicillamine, a new oral therapy for Wilson’s disease. Am J Med 21:487-495, 1956 8. Sternlieb I, Bennett B, Scheinberg IH: D-Penicillamine induced Goodpasture’s syndrome in Wilson’s disease. Ann Intern Med 82:673-676, 1975 9. Sarles J, Durand JM, Scheiner C, Picon G: [Wilson disease, IgA glomerulonephritis and vascular purpura: An incidental association?]. Arch Fr Pediatr 50:501-504, 1993 10. Garcia-Porrua C, Gonzalez-Gay MA, Bouza P: DPenicillamine-induced crescentic glomerulonephritis in a patient with scleroderma. Nephron 84:101-102, 2000

11. Marchand-Courville S, Dhib M, Fillastre JP, Godin M: [Extracapillary glomerulonephritis secondary to Dpenicillamine. Apropos of 1 case and review of the literature]. Nephrologie 19:25-32, 1998 12. Locke IC, Worrall JG, Leaker B, Black CM, Cambridge G: Autoantibodies to myeloperoxidase in systemic sclerosis. J Rheumatol 24:86-89, 1997 13. Chalmers A, Thompson D, Stein HE, Reid G, Patterson AC: Systemic lupus erythematosus during penicillamine therapy for rheumatoid arthritis. Ann Intern Med 97:659663, 1982 14. Gibson T, Burry HC, Ogg C: Goodpasture syndrome and D-penicillamine. Ann Intern Med 84:100, 1976 (letter) 15. Falck HM, Tornroth T, Kock B, Wegelius O: Fatal renal vasculitis and minimal change glomerulonephritis complicating treatment with penicillamine. Report on two cases. Acta Med Scand 205:133-138, 1979 16. Gavaghan TE, McNaught PJ, Ralston M, Hayes JM: Penicillamine-induced “Goodpasture’s syndrome”: Successful treatment of a fulminant case. Aust N Z J Med 11:261265, 1981 17. Omote A, Muramatsu M, Sugimoto Y, et al: Myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibodies– related scleroderma renal crisis treated with double-filtration plasmapheresis. Intern Med 36:508-513, 1997 18. Swainson CP, Thomson D, Short AI, Winney RJ: Plasma exchange in the successful treatment of druginduced renal disease. Nephron 30:244-249, 1982 19. Hasselmann M, Maurier F, Lutun P, Vetter JM, Tempe JD: [Goodpasture’s syndrome in rheumatoid arthritis treated with D-penicillamine]. Rev Med Interne 3:237-238, 1982 20. Banfi G, Imbasciati E, Guerra L, Mihatsch MJ, Ponticelli C: Extracapillary glomerulonephritis with necrotizing vasculitis in D-penicillamine-treated rheumatoid arthritis. Nephron 33:56-60, 1983 21. Sadjadi SA, Seelig MS, Berger AR, Milstoc M: Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high-dosage D-penicillamine. Am J Nephrol 5:212-216, 1985 22. Bonan G, Caubarrere I, Beaufils H, Lucsko M, Aubert P: [Diffuse alveolar hemorrhage and severe glomerulonephritis induced by D-penicillamine. Apropos of a case report with review of the literature]. Therapie 41:297-298, 1986 23. Ntoso KA, Tomaszewski JE, Jimenez SA, Neilson EG: Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive systemic sclerosis: Successful treatment of two patients and a review of the literature. Am J Kidney Dis 8:159-163, 1986 24. Williams AJ, Fordham JN, Barnes CG, Goodwin FJ: Progressive proliferative glomerulonephritis in a patient with rheumatoid arthritis treated with D-penicillamine. Ann Rheum Dis 45:82-84, 1986 25. Devogelaer JP, Pirson Y, Vandenbroucke JM, Cosyns JP, Brichard S, Nagant de Deuxchaisnes C: D-Penicillamine induced crescentic glomerulonephritis: Report and review of the literature. J Rheumatol 14:1036-1041, 1987 26. Peces R, Riera JR, Arboleya LR, Lopez-Larrea C, Alvarez J: Goodpasture’s syndrome in a patient receiving penicillamine and carbimazole. Nephron 45:316-320, 1987 27. Lauque D, Courtin JP, Fournie B, Oksman F, Pourrat J, Carles P: [Pneumorenal syndrome induced by D-penicilla-

DP-induced ANCA Nephritis in Wilson Disease mine: Goodpasture’s syndrome or microscopic polyarteritis?]. Rev Med Interne 11:168-171, 1990 28. Jones BF, Major GA: Crescentic glomerulonephritis in a patient taking penicillamine associated with antineutrophil cytoplasmic antibody. Clin Nephrol 38:293, 1992 29. Macarron P, Garcia Diaz JE, Azofra JA, et al: DPenicillamine therapy associated with rapidly progressive glomerulonephritis. Nephrol Dial Transplant 7:161-164, 1992 30. Almirall J, Alcorta I, Botey A, Revert L: Penicillamineinduced rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis. Am J Nephrol 13:286-288, 1993 31. Donnelly S, Levison DA, Doyle DV: Systemic lupus erythematosus-like syndrome with focal proliferative glomerulonephritis during D-penicillamine therapy. Br J Rheumatol 32:251-253, 1993 32. Gaskin G, Thompson EM, Pusey CD: Goodpasturelike syndrome associated with anti-myeloperoxidase antibodies following penicillamine treatment. Nephrol Dial Transplant 10:1925-1928, 1995 33. Mathieson PW, Peat DS, Short A, Watts RA: Coexistent membranous nephropathy and ANCA-positive crescentic glomerulonephritis in association with penicillamine. Nephrol Dial Transplant 11:863-866, 1996 34. Karpinski J, Jothy S, Radoux V, Levy M, Baran D: D-Penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma. Case report and review of the literature. Am J Nephrol 17:528-532, 1997 35. Marlier S, Gisserot O, Yao N, et al: [Extra-capillary glomerulonephritis induced by D-penicillamine therapy]. Presse Med 28:689-690, 1999 36. Kyndt X, Ducq P, Bridoux F, et al: [Extracapillary glomerulonephritis with anti-myeloperoxidase antibodies in 2 patients with systemic scleroderma treated with penicillamine D]. Presse Med 28:67-70, 1999

825 37. Nanke Y, Akama H, Terai C, Kamatani N: Rapidly progressive glomerulonephritis with D-penicillamine. Am J Med Sci 320:398-402, 2000 38. Derk CT, Jimenez SA: Goodpasture-like syndrome induced by D-penicillamine in a patient with systemic sclerosis: Report and review of the literature. J Rheumatol 30:16161620, 2003 39. Hsieh HS, Chang CF, Yang AH, Kuo HL, Yang WC, Lin CC: Antineutrophil cytoplasmic antibody-negative pauciimmune crescentic glomerulonephritis associated with rheumatoid arthritis: An unusual case report. Nephrology (Carlton) 8:243-247, 2003 40. Harper L, Cockwell P, Howie AJ, et al: Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis. QJM 90:125-132, 1997 41. Anders HJ, Wiebecke B, Haedecke C, Sanden S, Combe C, Schlondorff D: MPO-ANCA-positive crescentic glomerulonephritis: A distinct entity of scleroderma renal disease? Am J Kidney Dis 33:E3, 1999 42. Suganuma T: [Glomerular IgA deposits in an autopsy study]. Nippon Jinzo Gakkai Shi 36:813-822, 1994 43. Waldherr R, Rambausek M, Duncker WD, Ritz E: Frequency of mesangial IgA deposits in a non-selected autopsy series. Nephrol Dial Transplant 4:943-946, 1989 44. Cuperus RA, Muijsers AO, Wever R: Antiarthritic drugs containing thiol groups scavenge hypochlorite and inhibit its formation by myeloperoxidase from human leukocytes. A therapeutic mechanism of these drugs in rheumatoid arthritis? Arthritis Rheum 28:1228-1233, 1985 45. Goldman M, Druet P, Gleichmann E: TH2 cells in systemic autoimmunity: Insights from allogeneic diseases and chemically-induced autoimmunity. Immunol Today 12: 223-227, 1991 46. Doyle MK, Cuellar ML: Drug-induced vasculitis. Expert Opin Drug Saf 2:401-409, 2003