- Email: [email protected]
Rapidly Progressive Glomerulonephritis with d -Penicillamine
Rapidly Progressive Glomerulonephritis with D-Penicillamine YUKI NANKE, MD; HIDETO AKAMA, MD; CHIHIRO TERAI, MD; NAOYUKI KAMATANI, MD
ABSTRACT: We present 3 cases of anti-myeloperoxidase, anti-neutrophil cytoplasmic antibody (MPOANCA)-positive rapidly progressive glomerulonephritis developed during the treatment with D-penicillamine (D-PC) for rheumatoid arthritis. Rheumatoid arthritis was diagnosed in these patients, and D-PC was administered to them at doses of 100, 200, and 300 mg per day for 32, 42, and 39 months, respectively. They developed proteinuria, hematuria, renal insufficiency, and anemia, and D-PC was stopped. On admission, MPO-ANCA was strongly positive in their sera. Renal biopsy showed glomerulonephritis with cellular crescents. Immunoflu-
orescence examination revealed deposits of granular IgG, IgM, IgA, C1q, and C3 in the mesangium. The 3 patients were treated with steroid pulse therapy along with administration of anticoagulants, and cyclophosphamide was also used in 2 patients. Their renal function improved gradually and MPO-ANCA disappeared after immunosuppressive treatment. KEY INDEXING TERMS: D-penicillamine; Anti-neutrophil cytoplasmic antibody; Rapidly progressive glomerulonephritis; Immune-complex type; Cytokine theory. [Am J Med Sci 2000;320(6):398–402.]
T
genesis of D-PC-induced RPGN and MPO-ANCA– related glomerulonephritis.
here are many causes for renal involvement in patients with rheumatoid arthritis (RA): amyloidosis, vasculitis, overlap of other collagen diseases, and such drugs as nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs.1,2 Recently, anti-neutrophil cytoplasmic antibodies (ANCAs) have been found in sera of patients with systemic vasculitis and crescentic glomerulonephritis.3,4 We experienced 3 cases of anti-myeloperoxidase (MPO)-ANCA-positive rapidly progressive glomerulonephritis (RPGN) developed during the administration of D-penicillamine (D-PC) for RA. These 3 patients showed proteinuria, hematuria, and renal insufficiency accompanied by anemia. Renal biopsy specimens revealed crescentic glomerulonephritis with immune-complex deposition. The cessation of D-PC and initiation of immunosuppressive therapies, including steroid pulse therapy, were effective for the renal disorder. The clinical courses of the present cases and a review of similar cases may give some important insights for discussion of the patho-
From the Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan. Submitted March 21, 2000; accepted July 18, 2000. This article is partly based on a study first reported in Nihon Rinsho Meneki Gakkai Kaishi 1999;225:354-9. Correspondence Yuki Nanke, M.D., Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan (E-mail: [email protected]).
398
Case Reports Case 1. In June 1994, a 27-year-old woman visited the outpatient clinic of the Institute of Rheumatology, Tokyo Women’s Medical University, because of polyarthralgia and morning stiffness. RA (stage I, class I) was diagnosed in this patient according to the American Rheumatism Association revised criteria for RA published in 1987.5 D-PC was administered at a dose of 100 mg/day in January 1995. In March 1997, D-PC was increased to 200 mg/day. At the end of April, she caught a common cold. In August 1997, regular laboratory examination revealed proteinuria, hematuria, and renal insufficiency. D-PC was stopped and prednisolone was started at 5 mg/day. She was admitted to our hospital in September. On admission, she had neither edema nor active synovitis. Blood pressure was normal (126/72 mm Hg). The erythrocyte sedimentation rate (ESR) was 76 mm in the first hour. Dipstick test showed 3⫹ for protein, examination of the urine sediment showed numerous red blood cells (2.51 ⫻ 106/L), and hemoglobin (Hb) was 7.3 g/dL. Total white blood cell (WBC) count was 5400/L (28% lymphocytes). Serum creatinine level (Cr) was 1.7 mg/dL, serum urea nitrogen was 23 mg/dL, 24-hour creatinine clearance was 49 mL/min, and 24-hour urine protein excretion was 0.97 g. Immunological tests revealed: RAPA (rheumatoid arthritis factor, particle agglutination) titer of 1:40, antinuclear antibody (ANA) titer of 1:5120 (homogeneous and speckled pattern), anti-DNA antibody of 175 IU/mL (reference range, ⬍7 IU/mL), IgG antibodies to double-stranded DNA of 51 IU/mL (reference range, ⬍11 IU/mL), C3 of 38 mg/dL, C4 of 21 mg/dL, positive circulating immune complexes, C1q method, 7.6 g/mL; C3d method, 17.4 g/mL. Tests for cytoplasmic ANCA, antiglomerular basement membrane antibody, cryoglobulins, and antibodies for hepatitis B and C were negative. MPO-ANCA titer was 275 EU (ELISA unit) (reference range, ⬍10 EU). A radiograph of her hands revealed erosive changes in the left wrist. December 2000 Volume 320 Number 6
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Figure 1. Patient 1. (A) Light microscopy showed extracapillary proliferative glomerulonephritis with cellular crescents and tubular atrophy and infiltration of inflammatory cells in the interstitium. Periodic acid-Schiff staining (magnification, 130⫻). (B) Immunofluorescence examination showing the deposits of granular IgG (magnification, 130⫻). Reproduced with permission Nanke, Akama, Terai, et al.
Abdominal echography showed slightly enlarged kidneys.A percutaneous renal biopsy was performed. Light microscopy (Figure 1A) showed extracapillary proliferative glomerulonephritis with cellular crescents in 6 of the 10 glomeruli. Tubular atrophy and infiltration of inflammatory cells in the interstitium were also seen. Immunofluorescence (IF) microscopy disclosed diffuse granular deposition of IgG, IgA, C1q, and C3 in the mesangium (Figure 1B). The patient was treated with methylprednisolone pulse therapy followed by prednisolone (40 mg) along with administration of 2 mg of warfarin per day. In 6 weeks, Cr improved to 0.8 mg/dL and Hb increased to 10.2 g/dL. MPO-ANCA decreased to less than 10 EU in 6 months. Case 2. A 61-year-old man had experienced RA (according to the 1987 American Rheumatism Association criteria) for 10 years. From May 1991, the patient was treated with D-PC at a dose of 100 mg/day. In August 1994, he noticed malaise and sore throat and a common cold was diagnosed. He was first found to have microscopic hematuria, proteinuria, and anemia in October when D-PC was stopped. In December, his renal function decreased and he was admitted to our hospital for further evaluation. On admission, the patient had no symptoms. Laboratory studies revealed: dipstick test 1⫹ for protein and 3⫹ for occult blood; ESR, 96 mm in the first hour; Hb, 9.5 g/dL; WBC, 8800/L; THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 2. Patient 2. (A) Light microscopy revealed cellular crescents. Periodic acid-Schiff stain (magnification, 130⫻). (B) Immunofluorescence examination showing diffuse granular deposition of C3 (magnification, 130⫻). serum urea nitrogen, 60 mg/dL; Cr, 4.0 mg/dL; 24-hour creatinine clearance, 17 mL/min; and urine protein excretion, 0.40 g/day. Immunological tests revealed RAPA positive at a titer of 1:640, and an ANA titer of 1:20. Tests for anti-DNA antibodies, cytoplasmic ANCA, and anti-glomerular basement membrane antibodies were negative. MPO-ANCA level was 345 EU. Microscopic examination of a renal biopsy specimen revealed cellular crescents in two thirds of the glomeruli (Figure 2A), and diffuse granular deposits of IgG, IgM, and C3 were demonstrated in IF studies (Figure 2B). The patient was treated with methylprednisolone pulse therapy, warfarin (3 mg per day), and cyclophosphamide (50 mg per day). Cr improved from 4.0 mg/dL to 1.2 mg/dL, and MPO-ANCA decreased to 18 EU in 4 months. Case 3. A 43-year-old woman was diagnosed with RA (stage II, class II) in 1992, and 6 mg of prednisolone and 300 mg of D-PC were administered. Urinalysis and complete blood counts were normal until February 1993, when microscopic hematuria was first noted. On first admission in August 1993, her urine showed 1⫹ blood and no protein, and Cr was 0.7 mg/dL. Her arthritis subsided gradually, and she was treated with 1 mg of prednisolone and 200 mg of D-PC per day. In April 1994, proteinuria was detected, and progressive renal failure became evident, so D-PC was stopped. On admission, the patient was pale but normotensive. Her fingers and knees were swollen. Laboratory studies revealed the following: dipstick test 2⫹ for protein and 4⫹ for occult blood; ESR, 94 mm in first hour; Hb, 6.8 g/dL; WBC, 7500/L; Cr, 4.9 mg/dL; and urine protein, 0.39 g/day. Immunological tests demonstrated a negative rheumatoid factor, an ANA
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therapy, warfarin (3 mg per day), and cyclophosphamide (50 mg per day). The Cr improved to 2.4 mg/dL in 1 month, 2.0 mg/dL 1 year later, and 1.7 mg/dL in July 2000. The titer of MPO-ANCA decreased to 56 EU the next month, and to 10 EU 1 year later.
Discussion
Figure 3. Patient 3. (A) Light microscopy revealed cellular or fibrous crescents. Periodic acid-Schiff stain (magnification, 130⫻). (B) Immunofluorescence examination showing diffuse granular deposition of C3 (magnification, 130⫻).
titer of 1:40, and MPO-ANCA of 205 EU. The renal biopsy specimen contained 22 glomeruli, 18 of which showed cellular or fibrous crescents with 14 organized glomeruli (Figure 3A). IF revealed mild IgG and C3 depositions in the mesangium (Figure 3B). The patient was treated with methylprednisolone pulse
These 3 patients had been treated with D-PC at doses of 100, 200, and 300 mg/day for 32, 42, and 39 months, respectively, when renal dysfunction developed. Several weeks after an upper respiratory tract infection, they abruptly developed proteinuria and hematuria concomitant with severe anemia. Percutaneous renal biopsies revealed crescentic glomerulonephritis with granular deposits of immunoglobulins and complements. The use of D-PC is frequently complicated by the appearance of proteinuria and/or hematuria. The renal biopsies of these cases usually showed membranous glomerulonephritis or focal glomerulonephritis. The prognosis of patients with these types of renal involvement is usually good. However, several cases of fatal RPGN induced by D-PC have been reported. The clinical data and the outcome of the reported cases with D-PC-induced RPGN in RA patients are summarized in Table 1.6 –17 The doses and durations of D-PC in these cases differed widely. The dosage of D-PC employed in our patients may seem to be low (100, 200, and 300 mg daily, respectively). In Japan, a low-dose regimen of 100 to 600 mg per day has been introduced to virtually all patients.18,19 There is no significant difference in efficacy between groups receiving large doses and groups receiving small doses of D-PC, and fewer serious side-effects have been noted in groups receiving small doses.18 The pathogenetic mechanism leading to RPGN associated with D-PC has not been elucidated. The existence of an accumulative effect related to the dosage is suggested, because in most patients there is a delayed appearance of symptoms. However, a case has been reported in which this time interval
Table 1. D-PC induced RPGN in RA
Reference
Year
Case
Daily Dose (mg/day)
Duration (months)
1 Gibson6 2 McCormick7 3 Gavaghan8 4 Swainson9 5 Banfi10 6 Sadjadi11 7 Jones12 8 Macarron13 9 Almirall14 10 Mathieson15 11 Case 116 12 Case 2 13 Case 317
1976 1977 1981 1982 1983 1985 1992 1992 1993 1996 1998 1998 1996
51M 39F 53M 20F 61F 54M 73F 39M 67F 55M 27F 61M 43F
1200 1000 750 750 1000 1750 650 250 250 750 200 100 300
32 10 84 7 3 24 24 63 5 60 32 42 39
ANCA (EU)
IF
GBM P-I IC IC IC IC P-I P-I IC IC IC
320
273 345 205
Outcome HD Died Improved Improved Died Died Died Improved Improved Improved Improved Improved Improved
IF, immunofluorescence study; HD, hemodialysis; P-I, pauci-immune; IC, immune complex.
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was only 3 months.10 Therefore, it might develop as an allergic reaction. In 1982, Davies et al found ANCA in the serum of a patient with idiopathic necrotizing and crescentic glomerulonephritis.2 In crescentic glomerulonephritis, central to the issue is damage to the glomerular capillary wall, which is mediated by neutrophils, macrophages, and complement components. ANCA could be a pathogenetic factor responsible for vascular injury in vasculitis. By IF of ethanol-fixed neutrophils, cytoplasmic and perinuclear patterns of ANCAs have been recognized,3 and MPO is the major antigen of perinuclear ANCA. Cases of MPO-ANCA–related glomerulonephritis induced by such drugs as propylthiouracil, hydralazine, and D-PC have been reported.12,16,17,20 –22 Approximately 80% of cases of crescentic glomerulonephritis are reported to be of the pauci-immune type.20 Cases of D-PC-induced RPGN in RA seemed mainly to be of the immune-complex type, although the number of reported cases is too small to allow generalizations about the observed patterns of immunofluorescence. This difference might be derived from the drugs used or the diseases themselves. D-PC has been reported to cause several autoimmune phenomena, including systemic lupus erythematosus, polymyositis, and Graves disease. In addition, double-stranded DNA antibody is occasionally detected in patients treated with D-PC.23 In fact, one of the patients (patient 1) fulfilled the criteria24 for systemic lupus erythematosus at the admission. Review of the literature showed the occurrence of RPGN in patients with RA,10,11,14,25 systemic sclerosis,26,27 and Wilson disease,28 most of whom were treated with D-PC. These results suggest that this complication is related to D-PC rather than to the disease itself. In 1994, Jennette et al reported an ANCA-cytokine sequence theory.29 They suggested that ANCAinduced degranulation of neutrophils was enhanced by tumor necrosis factor (TNF) priming. In fact, the majority of patients, including our 2 patients, with ANCA-associated disease experienced a “flu-like” prodrome before the onset of vasculitis or nephritic symptoms. Through priming of neutrophils by TNF, which is secreted during infection, MPO is expressed on the cell surface and becomes accessible to MPOANCA. In concert with leukocyte-priming factors, ANCA may induce neutrophils to release toxic oxygen radicals and noxious granule constituents that cause vascular injury. In fact, Falk et al noted that the surface expression of MPO with TNF pretreatment correlates well with the release of reactive oxygen species caused by ANCA stimulation in vitro.30 In summary, we described 3 patients with MPOANCA–positive, D-PC-induced RPGN. Because RPGN can be a fatal disease if renal insufficiency develops with positive MPO-ANCA during treatTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ment with D-PC, prompt and correct diagnosis of the renal disorder could lead to a better prognosis, as in these cases. References 1. Hough AJ Jr. Pathology of rheumatoid arthritis and allied conditions. In: McCarty DJ, Koopman WJ, editors. Arthritis and allied conditions, 12th ed. Philadelphia: Lea and Febiger; 1993. p. 737– 61. 2. Davies DJ, Moran JE, Niall JF, et al. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 1982;285:606. 3. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988;318:1651–7. 4. Cohen Tervaert JW, Goldschmeding R, Elema JD, et al. Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int 1990;37:799 – 806. 5. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: 315–24. 6. Gibson T, Burry HC, Ogg C. Goodpasture syndrome and D-penicillamine [letter]. Ann Intern Med 1976;84:100. 7. McCormick JN, Wood P, Bell D. Penicillamine-induced Goodpasture’s syndrome. In: Penicillamine research in rheumatoid disease. Oslo, Norway: Fabritius; 1977. p. 268 –78. 8. Gavaghan TE, McNaught PJ, Ralston M, et al. Penicillamine-induced. “Goodpasture’s syndrome”: successful treatment of a fulminant case. Aust N Z J Med 1981;11:261–5. 9. Swainson CP, Thomson D, Short AI, et al. Plasma exchange in the successful treatment of drug-induced renal disease. Nephron 1982;30:244 –9. 10. Banfi G, Imbasciati E, Guerra L, et al. Extracapillary glomerulonephritis with necrotizing vasculitis in D-penicillamine-treated rheumatoid arthritis. Nephron 1983;33:56 – 60. 11. Sadjadi SA, Seelig MS, Berger AR, et al. Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high-dosage D-penicillamine. Am J Nephrol 1985;5:212– 6. 12. Jones BF, Major GA. Crescentic glomerulonephritis in a patient taking penicillamine associated with antineutrophil cytoplasmic antibody. Clin Nephrol 1992;38:293. 13. Macarron P, Garcia Diaz JE, Azofra JA, et al. D-penicillamine therapy associated with rapidly progressive glomerulonephritis. Nephrol Dial Transplant 1992;7:161– 4. 14. Almirall J, Alcorta I, Botey A, et al. Penicillamine-induced rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis. Am J Nephrol 1993;13:286 – 8. 15. Mathieson PW, Peat DS, Short A, et al. Coexistent membranous nephropathy and ANCA-positive crescentic glomerulonephritis in association with penicillamine. Nephrol Dial Transplant 1996;11:863– 6. 16. Nanke Y, Akama H, Terai C, et al. MPO-ANCA-positive rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with D-penicillamine. Nihon Rinsho Meneki Gakkai Kaishi 1999;22:354 –9. 17. Totogawa S, Terai C, Tateishi M, et al. A case of Dpenicillamine induced MPO-ANCA positive rapidly progressive glomerulonephritis. Ryumachi 1996;36:442. 18. Uchida S, Watanabe F, Nishimura K, et al. Ten-year clinical results of D-penicillamine in the treatment of rheumatoid arthritis. Int J Immunother 1994;10:119 –30.
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19. Hakoda M, Taniguchi A, Kamatani N, et al. Intermittent treatment with D-penicillamine is effective in lower doses and with fewer adverse effects in patients with rheumatoid arthritis. J Rheumatol 1994;21:1637– 41. 20. Vogt BA, Kim Y, Jennette JC, et al. Antineutrophil cytoplasmic autoantibody-positive crescentic glomerulonephritis as a complication of treatment with propylthiouracil in children. J Pediatr 1994;124:986 – 8. 21. Tanemoto M, Miyakawa H, Hanai J, et al. Myeloperoxidaseantineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis complicating the course of Graves’ disease: report of three adult cases. Am J Kidney Dis 1995;26:774 – 80. 22. Almroth G, ⌭neström S, Hed J, et al. Autoantibodies to leucocyte antigens in hydralazine-associated nephritis. J Intern Med 1992;231:37– 42. 23. Enzenauer RJ, West SG, Rubin RL. D-penicillamine-induced lupus erythematosus. Arthritis Rheum 1990;33:1582–5. 24. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7. 25. Yoshihara R, Tanaka Y, Shiozawa K, et al. Rapidly progressive glomerulonephritis associated with myeloperoxidase
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26.
27.
28.
29.
30.
specific-antineutrophil cytoplasmic antibody in patients with rheumatoid arthritis: report of three cases. Ryumachi 1996; 36:762– 8. Devogelaer J-P, Pirson Y, Vandenbroucke J-M, et al. D-penicillamine induced crescentic glomerulonephritis: report and review of the literature. J Rheumatol 1987;14:1036 – 41. Hillis GS, Khan IH, Simpson JG, et al. Scleroderma, D-penicillamine treatment, and progressive renal failure associated with positive antimyeloperoxidase antineutrophil cytoplasmic antibodies. Am J Kidney Dis 1997;30:279 – 81. Sternlieb I, Bennett B, Scheinberg IH. D-penicillamine induced Goodpasture’s syndrome in Wilson’s disease. Ann Intern Med 1975;82:673– 6. Yang JJ, Jennette JC, Falk RJ. Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase. Clin Exp Immunol 1994;97:466 –73. Falk RJ, Terrell RS, Charles LA, et al. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990;87:4115–9.
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ABSTRACT: We present 3 cases of anti-myeloperoxidase, anti-neutrophil cytoplasmic antibody (MPOANCA)-positive rapidly progressive glomerulonephritis developed during the treatment with D-penicillamine (D-PC) for rheumatoid arthritis. Rheumatoid arthritis was diagnosed in these patients, and D-PC was administered to them at doses of 100, 200, and 300 mg per day for 32, 42, and 39 months, respectively. They developed proteinuria, hematuria, renal insufficiency, and anemia, and D-PC was stopped. On admission, MPO-ANCA was strongly positive in their sera. Renal biopsy showed glomerulonephritis with cellular crescents. Immunoflu-
orescence examination revealed deposits of granular IgG, IgM, IgA, C1q, and C3 in the mesangium. The 3 patients were treated with steroid pulse therapy along with administration of anticoagulants, and cyclophosphamide was also used in 2 patients. Their renal function improved gradually and MPO-ANCA disappeared after immunosuppressive treatment. KEY INDEXING TERMS: D-penicillamine; Anti-neutrophil cytoplasmic antibody; Rapidly progressive glomerulonephritis; Immune-complex type; Cytokine theory. [Am J Med Sci 2000;320(6):398–402.]
T
genesis of D-PC-induced RPGN and MPO-ANCA– related glomerulonephritis.
here are many causes for renal involvement in patients with rheumatoid arthritis (RA): amyloidosis, vasculitis, overlap of other collagen diseases, and such drugs as nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs.1,2 Recently, anti-neutrophil cytoplasmic antibodies (ANCAs) have been found in sera of patients with systemic vasculitis and crescentic glomerulonephritis.3,4 We experienced 3 cases of anti-myeloperoxidase (MPO)-ANCA-positive rapidly progressive glomerulonephritis (RPGN) developed during the administration of D-penicillamine (D-PC) for RA. These 3 patients showed proteinuria, hematuria, and renal insufficiency accompanied by anemia. Renal biopsy specimens revealed crescentic glomerulonephritis with immune-complex deposition. The cessation of D-PC and initiation of immunosuppressive therapies, including steroid pulse therapy, were effective for the renal disorder. The clinical courses of the present cases and a review of similar cases may give some important insights for discussion of the patho-
From the Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan. Submitted March 21, 2000; accepted July 18, 2000. This article is partly based on a study first reported in Nihon Rinsho Meneki Gakkai Kaishi 1999;225:354-9. Correspondence Yuki Nanke, M.D., Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan (E-mail: [email protected]).
398
Case Reports Case 1. In June 1994, a 27-year-old woman visited the outpatient clinic of the Institute of Rheumatology, Tokyo Women’s Medical University, because of polyarthralgia and morning stiffness. RA (stage I, class I) was diagnosed in this patient according to the American Rheumatism Association revised criteria for RA published in 1987.5 D-PC was administered at a dose of 100 mg/day in January 1995. In March 1997, D-PC was increased to 200 mg/day. At the end of April, she caught a common cold. In August 1997, regular laboratory examination revealed proteinuria, hematuria, and renal insufficiency. D-PC was stopped and prednisolone was started at 5 mg/day. She was admitted to our hospital in September. On admission, she had neither edema nor active synovitis. Blood pressure was normal (126/72 mm Hg). The erythrocyte sedimentation rate (ESR) was 76 mm in the first hour. Dipstick test showed 3⫹ for protein, examination of the urine sediment showed numerous red blood cells (2.51 ⫻ 106/L), and hemoglobin (Hb) was 7.3 g/dL. Total white blood cell (WBC) count was 5400/L (28% lymphocytes). Serum creatinine level (Cr) was 1.7 mg/dL, serum urea nitrogen was 23 mg/dL, 24-hour creatinine clearance was 49 mL/min, and 24-hour urine protein excretion was 0.97 g. Immunological tests revealed: RAPA (rheumatoid arthritis factor, particle agglutination) titer of 1:40, antinuclear antibody (ANA) titer of 1:5120 (homogeneous and speckled pattern), anti-DNA antibody of 175 IU/mL (reference range, ⬍7 IU/mL), IgG antibodies to double-stranded DNA of 51 IU/mL (reference range, ⬍11 IU/mL), C3 of 38 mg/dL, C4 of 21 mg/dL, positive circulating immune complexes, C1q method, 7.6 g/mL; C3d method, 17.4 g/mL. Tests for cytoplasmic ANCA, antiglomerular basement membrane antibody, cryoglobulins, and antibodies for hepatitis B and C were negative. MPO-ANCA titer was 275 EU (ELISA unit) (reference range, ⬍10 EU). A radiograph of her hands revealed erosive changes in the left wrist. December 2000 Volume 320 Number 6
Nanke et al
Figure 1. Patient 1. (A) Light microscopy showed extracapillary proliferative glomerulonephritis with cellular crescents and tubular atrophy and infiltration of inflammatory cells in the interstitium. Periodic acid-Schiff staining (magnification, 130⫻). (B) Immunofluorescence examination showing the deposits of granular IgG (magnification, 130⫻). Reproduced with permission Nanke, Akama, Terai, et al.
Abdominal echography showed slightly enlarged kidneys.A percutaneous renal biopsy was performed. Light microscopy (Figure 1A) showed extracapillary proliferative glomerulonephritis with cellular crescents in 6 of the 10 glomeruli. Tubular atrophy and infiltration of inflammatory cells in the interstitium were also seen. Immunofluorescence (IF) microscopy disclosed diffuse granular deposition of IgG, IgA, C1q, and C3 in the mesangium (Figure 1B). The patient was treated with methylprednisolone pulse therapy followed by prednisolone (40 mg) along with administration of 2 mg of warfarin per day. In 6 weeks, Cr improved to 0.8 mg/dL and Hb increased to 10.2 g/dL. MPO-ANCA decreased to less than 10 EU in 6 months. Case 2. A 61-year-old man had experienced RA (according to the 1987 American Rheumatism Association criteria) for 10 years. From May 1991, the patient was treated with D-PC at a dose of 100 mg/day. In August 1994, he noticed malaise and sore throat and a common cold was diagnosed. He was first found to have microscopic hematuria, proteinuria, and anemia in October when D-PC was stopped. In December, his renal function decreased and he was admitted to our hospital for further evaluation. On admission, the patient had no symptoms. Laboratory studies revealed: dipstick test 1⫹ for protein and 3⫹ for occult blood; ESR, 96 mm in the first hour; Hb, 9.5 g/dL; WBC, 8800/L; THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 2. Patient 2. (A) Light microscopy revealed cellular crescents. Periodic acid-Schiff stain (magnification, 130⫻). (B) Immunofluorescence examination showing diffuse granular deposition of C3 (magnification, 130⫻). serum urea nitrogen, 60 mg/dL; Cr, 4.0 mg/dL; 24-hour creatinine clearance, 17 mL/min; and urine protein excretion, 0.40 g/day. Immunological tests revealed RAPA positive at a titer of 1:640, and an ANA titer of 1:20. Tests for anti-DNA antibodies, cytoplasmic ANCA, and anti-glomerular basement membrane antibodies were negative. MPO-ANCA level was 345 EU. Microscopic examination of a renal biopsy specimen revealed cellular crescents in two thirds of the glomeruli (Figure 2A), and diffuse granular deposits of IgG, IgM, and C3 were demonstrated in IF studies (Figure 2B). The patient was treated with methylprednisolone pulse therapy, warfarin (3 mg per day), and cyclophosphamide (50 mg per day). Cr improved from 4.0 mg/dL to 1.2 mg/dL, and MPO-ANCA decreased to 18 EU in 4 months. Case 3. A 43-year-old woman was diagnosed with RA (stage II, class II) in 1992, and 6 mg of prednisolone and 300 mg of D-PC were administered. Urinalysis and complete blood counts were normal until February 1993, when microscopic hematuria was first noted. On first admission in August 1993, her urine showed 1⫹ blood and no protein, and Cr was 0.7 mg/dL. Her arthritis subsided gradually, and she was treated with 1 mg of prednisolone and 200 mg of D-PC per day. In April 1994, proteinuria was detected, and progressive renal failure became evident, so D-PC was stopped. On admission, the patient was pale but normotensive. Her fingers and knees were swollen. Laboratory studies revealed the following: dipstick test 2⫹ for protein and 4⫹ for occult blood; ESR, 94 mm in first hour; Hb, 6.8 g/dL; WBC, 7500/L; Cr, 4.9 mg/dL; and urine protein, 0.39 g/day. Immunological tests demonstrated a negative rheumatoid factor, an ANA
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therapy, warfarin (3 mg per day), and cyclophosphamide (50 mg per day). The Cr improved to 2.4 mg/dL in 1 month, 2.0 mg/dL 1 year later, and 1.7 mg/dL in July 2000. The titer of MPO-ANCA decreased to 56 EU the next month, and to 10 EU 1 year later.
Discussion
Figure 3. Patient 3. (A) Light microscopy revealed cellular or fibrous crescents. Periodic acid-Schiff stain (magnification, 130⫻). (B) Immunofluorescence examination showing diffuse granular deposition of C3 (magnification, 130⫻).
titer of 1:40, and MPO-ANCA of 205 EU. The renal biopsy specimen contained 22 glomeruli, 18 of which showed cellular or fibrous crescents with 14 organized glomeruli (Figure 3A). IF revealed mild IgG and C3 depositions in the mesangium (Figure 3B). The patient was treated with methylprednisolone pulse
These 3 patients had been treated with D-PC at doses of 100, 200, and 300 mg/day for 32, 42, and 39 months, respectively, when renal dysfunction developed. Several weeks after an upper respiratory tract infection, they abruptly developed proteinuria and hematuria concomitant with severe anemia. Percutaneous renal biopsies revealed crescentic glomerulonephritis with granular deposits of immunoglobulins and complements. The use of D-PC is frequently complicated by the appearance of proteinuria and/or hematuria. The renal biopsies of these cases usually showed membranous glomerulonephritis or focal glomerulonephritis. The prognosis of patients with these types of renal involvement is usually good. However, several cases of fatal RPGN induced by D-PC have been reported. The clinical data and the outcome of the reported cases with D-PC-induced RPGN in RA patients are summarized in Table 1.6 –17 The doses and durations of D-PC in these cases differed widely. The dosage of D-PC employed in our patients may seem to be low (100, 200, and 300 mg daily, respectively). In Japan, a low-dose regimen of 100 to 600 mg per day has been introduced to virtually all patients.18,19 There is no significant difference in efficacy between groups receiving large doses and groups receiving small doses of D-PC, and fewer serious side-effects have been noted in groups receiving small doses.18 The pathogenetic mechanism leading to RPGN associated with D-PC has not been elucidated. The existence of an accumulative effect related to the dosage is suggested, because in most patients there is a delayed appearance of symptoms. However, a case has been reported in which this time interval
Table 1. D-PC induced RPGN in RA
Reference
Year
Case
Daily Dose (mg/day)
Duration (months)
1 Gibson6 2 McCormick7 3 Gavaghan8 4 Swainson9 5 Banfi10 6 Sadjadi11 7 Jones12 8 Macarron13 9 Almirall14 10 Mathieson15 11 Case 116 12 Case 2 13 Case 317
1976 1977 1981 1982 1983 1985 1992 1992 1993 1996 1998 1998 1996
51M 39F 53M 20F 61F 54M 73F 39M 67F 55M 27F 61M 43F
1200 1000 750 750 1000 1750 650 250 250 750 200 100 300
32 10 84 7 3 24 24 63 5 60 32 42 39
ANCA (EU)
IF
GBM P-I IC IC IC IC P-I P-I IC IC IC
320
273 345 205
Outcome HD Died Improved Improved Died Died Died Improved Improved Improved Improved Improved Improved
IF, immunofluorescence study; HD, hemodialysis; P-I, pauci-immune; IC, immune complex.
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was only 3 months.10 Therefore, it might develop as an allergic reaction. In 1982, Davies et al found ANCA in the serum of a patient with idiopathic necrotizing and crescentic glomerulonephritis.2 In crescentic glomerulonephritis, central to the issue is damage to the glomerular capillary wall, which is mediated by neutrophils, macrophages, and complement components. ANCA could be a pathogenetic factor responsible for vascular injury in vasculitis. By IF of ethanol-fixed neutrophils, cytoplasmic and perinuclear patterns of ANCAs have been recognized,3 and MPO is the major antigen of perinuclear ANCA. Cases of MPO-ANCA–related glomerulonephritis induced by such drugs as propylthiouracil, hydralazine, and D-PC have been reported.12,16,17,20 –22 Approximately 80% of cases of crescentic glomerulonephritis are reported to be of the pauci-immune type.20 Cases of D-PC-induced RPGN in RA seemed mainly to be of the immune-complex type, although the number of reported cases is too small to allow generalizations about the observed patterns of immunofluorescence. This difference might be derived from the drugs used or the diseases themselves. D-PC has been reported to cause several autoimmune phenomena, including systemic lupus erythematosus, polymyositis, and Graves disease. In addition, double-stranded DNA antibody is occasionally detected in patients treated with D-PC.23 In fact, one of the patients (patient 1) fulfilled the criteria24 for systemic lupus erythematosus at the admission. Review of the literature showed the occurrence of RPGN in patients with RA,10,11,14,25 systemic sclerosis,26,27 and Wilson disease,28 most of whom were treated with D-PC. These results suggest that this complication is related to D-PC rather than to the disease itself. In 1994, Jennette et al reported an ANCA-cytokine sequence theory.29 They suggested that ANCAinduced degranulation of neutrophils was enhanced by tumor necrosis factor (TNF) priming. In fact, the majority of patients, including our 2 patients, with ANCA-associated disease experienced a “flu-like” prodrome before the onset of vasculitis or nephritic symptoms. Through priming of neutrophils by TNF, which is secreted during infection, MPO is expressed on the cell surface and becomes accessible to MPOANCA. In concert with leukocyte-priming factors, ANCA may induce neutrophils to release toxic oxygen radicals and noxious granule constituents that cause vascular injury. In fact, Falk et al noted that the surface expression of MPO with TNF pretreatment correlates well with the release of reactive oxygen species caused by ANCA stimulation in vitro.30 In summary, we described 3 patients with MPOANCA–positive, D-PC-induced RPGN. Because RPGN can be a fatal disease if renal insufficiency develops with positive MPO-ANCA during treatTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
ment with D-PC, prompt and correct diagnosis of the renal disorder could lead to a better prognosis, as in these cases. References 1. Hough AJ Jr. Pathology of rheumatoid arthritis and allied conditions. In: McCarty DJ, Koopman WJ, editors. Arthritis and allied conditions, 12th ed. Philadelphia: Lea and Febiger; 1993. p. 737– 61. 2. Davies DJ, Moran JE, Niall JF, et al. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 1982;285:606. 3. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988;318:1651–7. 4. Cohen Tervaert JW, Goldschmeding R, Elema JD, et al. Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int 1990;37:799 – 806. 5. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: 315–24. 6. Gibson T, Burry HC, Ogg C. Goodpasture syndrome and D-penicillamine [letter]. Ann Intern Med 1976;84:100. 7. McCormick JN, Wood P, Bell D. Penicillamine-induced Goodpasture’s syndrome. In: Penicillamine research in rheumatoid disease. Oslo, Norway: Fabritius; 1977. p. 268 –78. 8. Gavaghan TE, McNaught PJ, Ralston M, et al. Penicillamine-induced. “Goodpasture’s syndrome”: successful treatment of a fulminant case. Aust N Z J Med 1981;11:261–5. 9. Swainson CP, Thomson D, Short AI, et al. Plasma exchange in the successful treatment of drug-induced renal disease. Nephron 1982;30:244 –9. 10. Banfi G, Imbasciati E, Guerra L, et al. Extracapillary glomerulonephritis with necrotizing vasculitis in D-penicillamine-treated rheumatoid arthritis. Nephron 1983;33:56 – 60. 11. Sadjadi SA, Seelig MS, Berger AR, et al. Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high-dosage D-penicillamine. Am J Nephrol 1985;5:212– 6. 12. Jones BF, Major GA. Crescentic glomerulonephritis in a patient taking penicillamine associated with antineutrophil cytoplasmic antibody. Clin Nephrol 1992;38:293. 13. Macarron P, Garcia Diaz JE, Azofra JA, et al. D-penicillamine therapy associated with rapidly progressive glomerulonephritis. Nephrol Dial Transplant 1992;7:161– 4. 14. Almirall J, Alcorta I, Botey A, et al. Penicillamine-induced rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis. Am J Nephrol 1993;13:286 – 8. 15. Mathieson PW, Peat DS, Short A, et al. Coexistent membranous nephropathy and ANCA-positive crescentic glomerulonephritis in association with penicillamine. Nephrol Dial Transplant 1996;11:863– 6. 16. Nanke Y, Akama H, Terai C, et al. MPO-ANCA-positive rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with D-penicillamine. Nihon Rinsho Meneki Gakkai Kaishi 1999;22:354 –9. 17. Totogawa S, Terai C, Tateishi M, et al. A case of Dpenicillamine induced MPO-ANCA positive rapidly progressive glomerulonephritis. Ryumachi 1996;36:442. 18. Uchida S, Watanabe F, Nishimura K, et al. Ten-year clinical results of D-penicillamine in the treatment of rheumatoid arthritis. Int J Immunother 1994;10:119 –30.
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19. Hakoda M, Taniguchi A, Kamatani N, et al. Intermittent treatment with D-penicillamine is effective in lower doses and with fewer adverse effects in patients with rheumatoid arthritis. J Rheumatol 1994;21:1637– 41. 20. Vogt BA, Kim Y, Jennette JC, et al. Antineutrophil cytoplasmic autoantibody-positive crescentic glomerulonephritis as a complication of treatment with propylthiouracil in children. J Pediatr 1994;124:986 – 8. 21. Tanemoto M, Miyakawa H, Hanai J, et al. Myeloperoxidaseantineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis complicating the course of Graves’ disease: report of three adult cases. Am J Kidney Dis 1995;26:774 – 80. 22. Almroth G, ⌭neström S, Hed J, et al. Autoantibodies to leucocyte antigens in hydralazine-associated nephritis. J Intern Med 1992;231:37– 42. 23. Enzenauer RJ, West SG, Rubin RL. D-penicillamine-induced lupus erythematosus. Arthritis Rheum 1990;33:1582–5. 24. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7. 25. Yoshihara R, Tanaka Y, Shiozawa K, et al. Rapidly progressive glomerulonephritis associated with myeloperoxidase
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