Nephrol Dial Transplant (1992) 7: 161-164 c 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology Dialysis Transplantation
Case Report D-penicillamine therapy associated with rapidly progressive glomerulonephritis P. Macarron1, J. E. Garcia Diaz2, J. A. Azofra3, J. Martin de Francisco4, E. Gonzalez2, G. Fernandez2 and J. Sampedro1 'Rheumatology Unit, 2 Renal Unit and 4Department of Pathology, Hospital 'Virgen de la Salud', Toledo; and 'Department of Internal Medicine, Fundacion Jimenez Diaz, Clinica de la Concepcion, Universidad Autonoma, Madrid, Spain
Abstract. A 55-year-old woman with advanced rheumatoid arthritis developed rapidly progressive glomerulonephritis with epithelial crescents and pulmonary hemorrhage following treatment with D-penicillamine. D-penicillamine was then withdrawn and a pulse therapy with methylprednisolone halted the progression of kidney and lung damage. We review the other cases previously reported and discuss pathogenesis and treatment of this rare condition. Key words: rheumatoid arthritis; D-penicillamine; rapidly progressive glomerulonephritis; haemoptysis
Introduction D-penicillamine is commonly used in the treatment of selected cases of rheumatoid arthritis, Wilson's disease, lead poisoning, cystinuria and systemic sclerosis. Unfortunately treatment with this drug has been associated with a variety of untoward side-effects, including renal damage [1]. The most frequent clinical feature of this complication is proteinuria [2]. Histological examination usually discloses either minimal-change, mesangioproliferative, or membranous nephropathy [1]. SporCorrespondeme and offprint requests to: Dr Josi' Eugenio Garcia Diaz, Ronda de Buenavista 26, portal 7J. 6" A. 45005. Toledo. Spain.
adic cases of extracapillary glomerulonephritis have also been reported [3,4-13]. We report a case of rapidly progressive glomerulonephritis associated with hemoptysis in a patient with rheumatoid arthritis receiving D-penicillamine.
Case report A 55-year-old woman with 10-year history of destructive seropositive rheumatoid arthritis developed haemoptysis, fever and renal failure. Treatment with D-penicillamine had been started 5 years earlier. A maintenance dosage of 750 mg/day was being given. Other medications she received were indomethacin (75 mg/24 h) and low doses of prednisone (5 mg/48 h). Since then a follow-up of monthly biochemical tests had always proved normal and no signs of acute arthritis were evident before admission. The patient was classified as class III in terms of functional capacity [14], renal function was preserved (serum creatinine 82.35 umol 1), and a thorax X-ray was normal. Serum latex fixation test for rheumatoid factor was positive in a titre of 1 :64. One month before admission she began to notice some blood in the sputum. A progressive invaliding dyspnoea ensued in the next few days and she was admitted to hospital. On admission she was pale, tachypnoeic and cyanotic. Rales were heard in both lungs. Blood pressure was 180,110 mmHg, temperature 38 C, pulse rate
162
P Macarron ei al
108 min. Chest roentgenogram showed diffuse bilateral alveolar opacities. Laboratory tests revealed haemoglobin 50 g/1 (5 g/dl), and leukocytes 10 000/mm 3 . The coagulation profile was normal, and urea and creatinine were 24.7 mmol/1 (148 mg/dl) and 366 umol/1 (4 mg/dl) respectively. Urinalysis showed 3 + protein and 3 + blood. Many granular casts were seen. A 24 h urine collection contained 9.4 g protein. Pulmonary function testing was not performed because intubation and mechanical ventilation were urgently needed. Pulmonary angiography was normal. The smear of sputum was full of siderophages. Treatment with pulse methylprednisolone (1 g/day for 3 days) was started; subsequently prednisone 1 mg/kg per day was administered. Seventeen days later lung function improved and the patient was extubated. Hypertension also subsided (Figure 1). The following laboratory investigations were either negative or normal: antinuclear antibody (ANA, by indirect immunofluorescence assays (IIF)), antiglomerular basement membrane antibody (antiGBM.RIA), circulating immune complexes (nephelometry), serum complement, and cryoglobulins. Antineutrophil cytoplasmic autoantibodies (ANCA, IIF) testing was not performed in the acute phase of the disease, but on subsequent occasions was always negative. Renal biopsy performed 3 days after admission showed extracapillary proliferative glomerulonephritis, with cellular crescents involving 75% of glomeruli and focal and segmental endocapillary pro-
Cr/i Ug//
liferation was observed (Figures 2, 3). Immunofluorescence (IF) studies disclosed diffuse granular deposits of fibrinogen in crescents, and there were no granular or linear deposits of immunoglobin and complement along capillar walls or mesangium. Electron-microscopy examination and direct immunofluorescence were not performed. After discharge on the 39th day after admission the patient did well; X-ray films of the chest became normal and renal function and proteinuria improved. Serum creatinine was 256 umol/1 (2.8 mg/dl), urine protein excretion was 1.2 g/24 h, C cr was 35.6 ml/min, haematocrit was 28% and haemoglobin 96 g/1. Twelve months later the patient remains well. Serum creatinine was 109 umol/1 (1.2 mg/dl), urine protein excretion was 90 mg/24 h, and the urine sediment showed only occasional red blood cells.
Discussion D-penicillamine is effective therapy for active rheumatoid arthritis [15], but the exact mechanism of action is not yet clear. Proteinuria in the nephrotic or subnephrotic range has been found in 15-30% of patients treated with this drug [2]. Proteinuria may be isolated, but is sometimes associated with eosinophilia, rash, and leukopenia [16]. This abnormality subsides once penicillamine is withdrawn [17]. Rare cases of rapidly progressive glomerulonephritis (RPGN), which is the most dreaded nephrotoxic
400 300-\ 20050 •6 M
ID 2D 3D 4D Admission PEN IND P
HP lg/IV/daj
I 17D 39D 6M Dismissal -I-
12M
AlUrnatt-dojr
Fig. 1. Course of the illness: MP. Methylprednisolone; P, prednisone; M, month; D, day; PEN, D-penicillamine; IND, indomethacin, Hto. haematocrit: Cr s. serum creatinine; Pr 24 h, unne protein excretion day; UE, unne excretion
D-peniciUamine and rapidly progressive glomerulonephritis
Fig. 2. Renal biopsy (H & E). Low power, showing diffuse crescentic disease.
reaction to D-penicillamine have been reported on occasions [3,4-13]. In cases previously reported, dosage and duration of therapy prior to the onset of glomerulonephritis have been diverse. In most instances D-penicillamine had been administered for more than 3 months in doses from 0.3 to 3.5 g/24 h [18]. In some other cases proteinuria was found previously to the full-blown RPGN picture [8,9]. In our case, however, before admission the sediment of the urine, as well as renal function were within normal limits. The mechanism whereby D-penicillamine induces RPGN is still unknown. Some authors suggest the existence of an accumulative effect related to the dosage, because in most cases there is delayed appearance of the symptoms [7]. However, a case has been reported in which this time interval was only 3 months [10]. Although has been postulated that RPGN is mediated by immune complexes (IC) [12], we believe that the absence of IC (in our case) and the normal profile of complement (in this and other cases) [7] argue against an immune-complex disease. Devogelaer et al. [13] have suggested that D-pen:ci!!arr.ine might
163
Fig. 3. Renal biopsy. High power, with epithelial proliferation in early stage and segmental proliferation (H & E).
induce sensitization against epitopes of the basement membrane different from those involved in Goodpasture's syndrome and not present in the glomerular basement membrane extracts used as antigens in the available assays. This hypothesis could explain the concomitant occurrence of lung haemorrhage. Only one of the reported cases showed basement membrane antibodies [3]. The majority of renal biopsies revealed granular deposits of IgG and C 3 [8,4,12]. In any case of crescentic GN, the presence of ANCA in the serum must be excluded. The association of RPGN-ANCA was described by Davies et al. [19], and RPGN can be classified as (1) antiGBM-antibody mediated, (2) immune-complex-mediated, and (3) ANCA-associated [20]. ANCA-associated RPGN occurs most frequently, but in our patient it was impossible to demonstrate during the acute phase of the disease, and afterwards the test was always negative. RPGN is a very serious disease, prognosis depending on the early recognition of the syndrome and its prompt treatment [12,13]. It is generally accepted that glucocorticoids at a
164
regular dose (1-1.5 mg/kg per day) do not improve patients with RPGN. Only the patients treated with pulse corticosteroids or corticosteroids plus immunosuppressive drugs did well [3,5-7,9,11-13,21]. Our case supports the usefulness of high-dose prednisolone therapy in RPGN associated with D-penicillamine. In any case, if RPGN develops in a patient receiving D-penicillamine, the drug must be withdrawn immediately.
P. Macarron et al.
8. 9. 10. 11. 12.
Acknowledgements. We are indebted to Jorge Garcia de Ancos for his help in the preparation of this manuscript. We thank Ms Encarnacion Macarron and Ms Rafi Cerdeno for excellent secretarial work
13 14.
References 1. Ross JH, McGinty F, Brewer DG. Pemcillamine nephropathy. Nephron 1980; 26: 184-186 2. Stockman A, Richter D, Barraclough D el al Difficulties in the use of D-penicillamine in the treatment of rheumatoid arthritis. Aust NZ J Med 1979; 9: 495-503 3. Peces R, Riera JR, Arboleya LR el al. Goodpasture's syndrome in a patient receiving pemcillamine and carbimazole Nephron 1987; 45: 316-320 4 Sternlieb I, Bennett B, Scheinberg 1H. D-penicillamine induced Goodpasture's syndrome in Wilson's disease. Ann Intern Med 1975; 82: 673-676 5 Gibson T, Burry HC, Chisholm O. Goodpasture's syndrome and D-penicillamine Ann Intern Med 1976; 84- 100 6. McCormick JN, Wood P, Bell D. Pemcillamine induced Goodpasture's syndrome. In: Munthe E. ed. Pemcillamine Research in Rheumatoid Disease. Oslo, Fabritius, 1977: 268-278 7. Malloff DS, Kaplan MM. D-penicillamine induced Goodpaslure's like syndrome in primary biliary cirrhosis. Successful
15. 16.
17. 18. 19. 20. 21.
treatment with plasmapheresis and immunosuppressives. Gastroemerohgy 1980, 78 1.046-1.049 Gavaghan TE, McNaught PJ, Ralston M et al Penicillamine induced 'Goodpasture's syndrome'. Successful treatment of a fulminant case. Aust NZ J Med 1981; 11- 261-265 Swainson CP, Thomson D, Short A1K et al Plasma exchange in the successful treatment of drug-induced renal disease. Nephron 1982; 30- 244-249 Banfi G, Imbasciati E, Guerra L et al. Extracapillary glomerulonephritis with necrotizing vasculitis in D-penicillamine treated rheumatoid arthritis. Nephron 1983; 33: 56-60 Hasselmann M, Maurier F, Lutun Ph et al Goodpasture's syndrome an cours d'une polyarthrite rheumatoide traite par la D-penicillamine. Revue Med Int 1982; 3: 237-238 Sadjadi SA, Seeling MS, Berger AR el al. Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high dosage D-penicillamine. Am J Nephrol 1985, 5. 212-216 Devogelaer JP, Pirson Y, Vanderbroucke JP et at D-penicillamine induced crescentic glomerulonephritis. Report and review of the literature. J Rheumawl 1987; 5: 1.036-1.041 Steinbroclter O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis JAMA 1949; 140: 659-662 Multiple Trial Group. Controlled trial of D-penicillamine in severe rheumatoid arthritis. Lancet 1973; 1' 275-280 Wooley PH, Griffin J, Panay GS el al. HLA-DR antigens and toxic reactions to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis. A' Engl J Med 1980; 303' 300-302 Hall CL, Jaead S, Harrison PR et al Natural course os penicillamine nephropathy A long term study of 33 patients. Br Med J 1988; 296: 1.083-1.086 Huskisson EC. Penicillamine and the rheumatologist: A review. Pharmatherapeulica 1976; 1-24 Davies DJ, Moran JE, Niall JF el al Segmental necrotizing glomerulonephritis with antineutrophil antibody: Possible arbovirus aetiology11 Br Med J 1982; 285- 606 Jennette JC, Wilkman AS, Falk BJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephntis and vasculitis Am J Palhol 1989: 135: 921-930 Cathcart E, Idelson B, Scheinburg M el al. Beneficial effects of methylprednisolone 'pulse' therapy in diffuse proliferative lupus nephritis. Lancet 1976, I: 163-166
Received for publication 19.3.91 Accepted in revised form 28 7 91
Nephrology Dialysis Transplantation
Case Report D-penicillamine therapy associated with rapidly progressive glomerulonephritis P. Macarron1, J. E. Garcia Diaz2, J. A. Azofra3, J. Martin de Francisco4, E. Gonzalez2, G. Fernandez2 and J. Sampedro1 'Rheumatology Unit, 2 Renal Unit and 4Department of Pathology, Hospital 'Virgen de la Salud', Toledo; and 'Department of Internal Medicine, Fundacion Jimenez Diaz, Clinica de la Concepcion, Universidad Autonoma, Madrid, Spain
Abstract. A 55-year-old woman with advanced rheumatoid arthritis developed rapidly progressive glomerulonephritis with epithelial crescents and pulmonary hemorrhage following treatment with D-penicillamine. D-penicillamine was then withdrawn and a pulse therapy with methylprednisolone halted the progression of kidney and lung damage. We review the other cases previously reported and discuss pathogenesis and treatment of this rare condition. Key words: rheumatoid arthritis; D-penicillamine; rapidly progressive glomerulonephritis; haemoptysis
Introduction D-penicillamine is commonly used in the treatment of selected cases of rheumatoid arthritis, Wilson's disease, lead poisoning, cystinuria and systemic sclerosis. Unfortunately treatment with this drug has been associated with a variety of untoward side-effects, including renal damage [1]. The most frequent clinical feature of this complication is proteinuria [2]. Histological examination usually discloses either minimal-change, mesangioproliferative, or membranous nephropathy [1]. SporCorrespondeme and offprint requests to: Dr Josi' Eugenio Garcia Diaz, Ronda de Buenavista 26, portal 7J. 6" A. 45005. Toledo. Spain.
adic cases of extracapillary glomerulonephritis have also been reported [3,4-13]. We report a case of rapidly progressive glomerulonephritis associated with hemoptysis in a patient with rheumatoid arthritis receiving D-penicillamine.
Case report A 55-year-old woman with 10-year history of destructive seropositive rheumatoid arthritis developed haemoptysis, fever and renal failure. Treatment with D-penicillamine had been started 5 years earlier. A maintenance dosage of 750 mg/day was being given. Other medications she received were indomethacin (75 mg/24 h) and low doses of prednisone (5 mg/48 h). Since then a follow-up of monthly biochemical tests had always proved normal and no signs of acute arthritis were evident before admission. The patient was classified as class III in terms of functional capacity [14], renal function was preserved (serum creatinine 82.35 umol 1), and a thorax X-ray was normal. Serum latex fixation test for rheumatoid factor was positive in a titre of 1 :64. One month before admission she began to notice some blood in the sputum. A progressive invaliding dyspnoea ensued in the next few days and she was admitted to hospital. On admission she was pale, tachypnoeic and cyanotic. Rales were heard in both lungs. Blood pressure was 180,110 mmHg, temperature 38 C, pulse rate
162
P Macarron ei al
108 min. Chest roentgenogram showed diffuse bilateral alveolar opacities. Laboratory tests revealed haemoglobin 50 g/1 (5 g/dl), and leukocytes 10 000/mm 3 . The coagulation profile was normal, and urea and creatinine were 24.7 mmol/1 (148 mg/dl) and 366 umol/1 (4 mg/dl) respectively. Urinalysis showed 3 + protein and 3 + blood. Many granular casts were seen. A 24 h urine collection contained 9.4 g protein. Pulmonary function testing was not performed because intubation and mechanical ventilation were urgently needed. Pulmonary angiography was normal. The smear of sputum was full of siderophages. Treatment with pulse methylprednisolone (1 g/day for 3 days) was started; subsequently prednisone 1 mg/kg per day was administered. Seventeen days later lung function improved and the patient was extubated. Hypertension also subsided (Figure 1). The following laboratory investigations were either negative or normal: antinuclear antibody (ANA, by indirect immunofluorescence assays (IIF)), antiglomerular basement membrane antibody (antiGBM.RIA), circulating immune complexes (nephelometry), serum complement, and cryoglobulins. Antineutrophil cytoplasmic autoantibodies (ANCA, IIF) testing was not performed in the acute phase of the disease, but on subsequent occasions was always negative. Renal biopsy performed 3 days after admission showed extracapillary proliferative glomerulonephritis, with cellular crescents involving 75% of glomeruli and focal and segmental endocapillary pro-
Cr/i Ug//
liferation was observed (Figures 2, 3). Immunofluorescence (IF) studies disclosed diffuse granular deposits of fibrinogen in crescents, and there were no granular or linear deposits of immunoglobin and complement along capillar walls or mesangium. Electron-microscopy examination and direct immunofluorescence were not performed. After discharge on the 39th day after admission the patient did well; X-ray films of the chest became normal and renal function and proteinuria improved. Serum creatinine was 256 umol/1 (2.8 mg/dl), urine protein excretion was 1.2 g/24 h, C cr was 35.6 ml/min, haematocrit was 28% and haemoglobin 96 g/1. Twelve months later the patient remains well. Serum creatinine was 109 umol/1 (1.2 mg/dl), urine protein excretion was 90 mg/24 h, and the urine sediment showed only occasional red blood cells.
Discussion D-penicillamine is effective therapy for active rheumatoid arthritis [15], but the exact mechanism of action is not yet clear. Proteinuria in the nephrotic or subnephrotic range has been found in 15-30% of patients treated with this drug [2]. Proteinuria may be isolated, but is sometimes associated with eosinophilia, rash, and leukopenia [16]. This abnormality subsides once penicillamine is withdrawn [17]. Rare cases of rapidly progressive glomerulonephritis (RPGN), which is the most dreaded nephrotoxic
400 300-\ 20050 •6 M
ID 2D 3D 4D Admission PEN IND P
HP lg/IV/daj
I 17D 39D 6M Dismissal -I-
12M
AlUrnatt-dojr
Fig. 1. Course of the illness: MP. Methylprednisolone; P, prednisone; M, month; D, day; PEN, D-penicillamine; IND, indomethacin, Hto. haematocrit: Cr s. serum creatinine; Pr 24 h, unne protein excretion day; UE, unne excretion
D-peniciUamine and rapidly progressive glomerulonephritis
Fig. 2. Renal biopsy (H & E). Low power, showing diffuse crescentic disease.
reaction to D-penicillamine have been reported on occasions [3,4-13]. In cases previously reported, dosage and duration of therapy prior to the onset of glomerulonephritis have been diverse. In most instances D-penicillamine had been administered for more than 3 months in doses from 0.3 to 3.5 g/24 h [18]. In some other cases proteinuria was found previously to the full-blown RPGN picture [8,9]. In our case, however, before admission the sediment of the urine, as well as renal function were within normal limits. The mechanism whereby D-penicillamine induces RPGN is still unknown. Some authors suggest the existence of an accumulative effect related to the dosage, because in most cases there is delayed appearance of the symptoms [7]. However, a case has been reported in which this time interval was only 3 months [10]. Although has been postulated that RPGN is mediated by immune complexes (IC) [12], we believe that the absence of IC (in our case) and the normal profile of complement (in this and other cases) [7] argue against an immune-complex disease. Devogelaer et al. [13] have suggested that D-pen:ci!!arr.ine might
163
Fig. 3. Renal biopsy. High power, with epithelial proliferation in early stage and segmental proliferation (H & E).
induce sensitization against epitopes of the basement membrane different from those involved in Goodpasture's syndrome and not present in the glomerular basement membrane extracts used as antigens in the available assays. This hypothesis could explain the concomitant occurrence of lung haemorrhage. Only one of the reported cases showed basement membrane antibodies [3]. The majority of renal biopsies revealed granular deposits of IgG and C 3 [8,4,12]. In any case of crescentic GN, the presence of ANCA in the serum must be excluded. The association of RPGN-ANCA was described by Davies et al. [19], and RPGN can be classified as (1) antiGBM-antibody mediated, (2) immune-complex-mediated, and (3) ANCA-associated [20]. ANCA-associated RPGN occurs most frequently, but in our patient it was impossible to demonstrate during the acute phase of the disease, and afterwards the test was always negative. RPGN is a very serious disease, prognosis depending on the early recognition of the syndrome and its prompt treatment [12,13]. It is generally accepted that glucocorticoids at a
164
regular dose (1-1.5 mg/kg per day) do not improve patients with RPGN. Only the patients treated with pulse corticosteroids or corticosteroids plus immunosuppressive drugs did well [3,5-7,9,11-13,21]. Our case supports the usefulness of high-dose prednisolone therapy in RPGN associated with D-penicillamine. In any case, if RPGN develops in a patient receiving D-penicillamine, the drug must be withdrawn immediately.
P. Macarron et al.
8. 9. 10. 11. 12.
Acknowledgements. We are indebted to Jorge Garcia de Ancos for his help in the preparation of this manuscript. We thank Ms Encarnacion Macarron and Ms Rafi Cerdeno for excellent secretarial work
13 14.
References 1. Ross JH, McGinty F, Brewer DG. Pemcillamine nephropathy. Nephron 1980; 26: 184-186 2. Stockman A, Richter D, Barraclough D el al Difficulties in the use of D-penicillamine in the treatment of rheumatoid arthritis. Aust NZ J Med 1979; 9: 495-503 3. Peces R, Riera JR, Arboleya LR el al. Goodpasture's syndrome in a patient receiving pemcillamine and carbimazole Nephron 1987; 45: 316-320 4 Sternlieb I, Bennett B, Scheinberg 1H. D-penicillamine induced Goodpasture's syndrome in Wilson's disease. Ann Intern Med 1975; 82: 673-676 5 Gibson T, Burry HC, Chisholm O. Goodpasture's syndrome and D-penicillamine Ann Intern Med 1976; 84- 100 6. McCormick JN, Wood P, Bell D. Pemcillamine induced Goodpasture's syndrome. In: Munthe E. ed. Pemcillamine Research in Rheumatoid Disease. Oslo, Fabritius, 1977: 268-278 7. Malloff DS, Kaplan MM. D-penicillamine induced Goodpaslure's like syndrome in primary biliary cirrhosis. Successful
15. 16.
17. 18. 19. 20. 21.
treatment with plasmapheresis and immunosuppressives. Gastroemerohgy 1980, 78 1.046-1.049 Gavaghan TE, McNaught PJ, Ralston M et al Penicillamine induced 'Goodpasture's syndrome'. Successful treatment of a fulminant case. Aust NZ J Med 1981; 11- 261-265 Swainson CP, Thomson D, Short A1K et al Plasma exchange in the successful treatment of drug-induced renal disease. Nephron 1982; 30- 244-249 Banfi G, Imbasciati E, Guerra L et al. Extracapillary glomerulonephritis with necrotizing vasculitis in D-penicillamine treated rheumatoid arthritis. Nephron 1983; 33: 56-60 Hasselmann M, Maurier F, Lutun Ph et al Goodpasture's syndrome an cours d'une polyarthrite rheumatoide traite par la D-penicillamine. Revue Med Int 1982; 3: 237-238 Sadjadi SA, Seeling MS, Berger AR el al. Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high dosage D-penicillamine. Am J Nephrol 1985, 5. 212-216 Devogelaer JP, Pirson Y, Vanderbroucke JP et at D-penicillamine induced crescentic glomerulonephritis. Report and review of the literature. J Rheumawl 1987; 5: 1.036-1.041 Steinbroclter O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis JAMA 1949; 140: 659-662 Multiple Trial Group. Controlled trial of D-penicillamine in severe rheumatoid arthritis. Lancet 1973; 1' 275-280 Wooley PH, Griffin J, Panay GS el al. HLA-DR antigens and toxic reactions to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis. A' Engl J Med 1980; 303' 300-302 Hall CL, Jaead S, Harrison PR et al Natural course os penicillamine nephropathy A long term study of 33 patients. Br Med J 1988; 296: 1.083-1.086 Huskisson EC. Penicillamine and the rheumatologist: A review. Pharmatherapeulica 1976; 1-24 Davies DJ, Moran JE, Niall JF el al Segmental necrotizing glomerulonephritis with antineutrophil antibody: Possible arbovirus aetiology11 Br Med J 1982; 285- 606 Jennette JC, Wilkman AS, Falk BJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephntis and vasculitis Am J Palhol 1989: 135: 921-930 Cathcart E, Idelson B, Scheinburg M el al. Beneficial effects of methylprednisolone 'pulse' therapy in diffuse proliferative lupus nephritis. Lancet 1976, I: 163-166
Received for publication 19.3.91 Accepted in revised form 28 7 91
