- Email: [email protected]
IgG antineutrophil cytoplasmic antibodies in IgA nephropathy: A clinical variant?
IgG Antineutrophil Cytoplasmic Antibodies in IgA Nephropathy: A Clinical Variant? Sylvia B. Ramirez, MD, Seymour Rosen, MD, John Niles, MD, and Michael J.G. Somers, MD ● Anti-neutrophil cytoplasmic antibodies (ANCAs) of the immunoglobulin (Ig) G isotype are associated with rapidly progressive glomerulonephritis. These have been detected rarely in patients with Henoch-Scho¨nlein purpura (HSP) and have only been previously reported once in a patient with IgA nephropathy (IgAN). In contrast, IgA-ANCAs have been detected in patients with HSP or IgAN, although further verification of this finding by various investigators has yielded conflicting results. We report a case of biopsy-proven IgAN in which the patient developed a rapidly progressive glomerulonephritis and was determined to have ANCAs of both IgA and IgG isotypes. This report suggests an association between fulminant IgAN and ANCA-associated disease and that ANCAs may be underdetected in children with previously diagnosed IgAN. Identification of these antibodies may guide further management of these patients. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Anti-neutrophil cytoplasmic antibodies (ANCA); IgA nephropathy; rapidly progressive glomerulonephritis.
T
HE PRESENCE of anti-neutrophil cytoplasmic antibodies (ANCAs) is virtually diagnostic of pauci-immune crescentic glomerulonephritis, approaching a sensitivity and specificity of 95% and 99%, respectively.1 Although ANCAs may be one of several immunoglobulin isotypes, pathological ANCAs are generally of the immunoglobulin (Ig) G isotype, especially p-ANCA directed against myeloperoxidase.2 In contrast, the pathological significance of ANCA of the IgA isotype remains unclear. IgA-ANCA has been described sporadically in certain patients with Henoch-Scho¨nlein purpura (HSP) and more rarely with IgA nephropathy (IgAN),3-5 but this finding has not been confirmed by others testing specifically for ANCA in patients with these same disease processes.6-8 IgG-ANCA, however, has only rarely been associated with either HSP or IgAN. We report a case of a child with biopsy-documented IgAN who subsequently developed a rapidly progressive crescenteric glomerulonephritis associated with both IgG-pANCA and IgA-ANCA. This finding raises the question of the pathological significance of IgGANCA in the setting of rapidly progressive renal failure in patients with IgAN. CASE REPORT In February 1996, a 10-year-old girl was referred to Children’s Hospital for persistent microscopic hematuria after an isolated episode of painless gross hematuria concomitant with a viral illness. She had an unremarkable medical profile, including no history of hypertension, purpuric rash, or joint or abdominal pain. There was no family history of renal disease. On presentation, blood pressure was normal, and physical
examination was unremarkable. Urinalysis showed 3⫹ proteinuria and 3⫹ hematuria, with 15 to 20 glomerular red blood cells (RBC)/high-power field (HPF) and three to five granular casts/HPF. A random urine protein-to-creatinine ratio was elevated, at 1.1 (mg/mg), correlating to an approximate 24-hour protein excretion of 450 mg. Other laboratory findings included a mild elevation of serum creatinine to 1.1 mg/dL (calculated glomerular filtration rate of 70 mL/min/1.73m2 ), negative antistreptolysin titers, normal complement values, normal immunoglobulin levels and a normal serum albumin. A renal ultrasound was unremarkable. Renal biopsy was recommended, but the family deferred for 6 months, at which point the child was noted to have increased proteinuria with quantitative urine collection showing a protein excretion of 1.1 g/24 hours. A renal biopsy then was performed, which showed glomeruli with mild mesangial expansion (Fig 1A), as well as some glomeruli with global and segmental sclerosis. There was mild interstitial fibrosis and tubular atrophy and no significant vascular lesions. Immunofluorescence was remarkable for mesangial IgA deposition. Electron microscopy showed an increase in mesangial matrix and occasional subepithelial and mesangial deposits. A diagnosis of IgAN was made, and potential treatment options, including oral prednisone, azathioprine, fish oil, and angiotensin-converting enzyme inhibitors, were discussed. Because of the patient’s perceived difficulty swallowing any
From the Division of Nephrology, Children’s Hospital; the Department of Pathology, Beth Israel Deaconess Medical Center; and the Renal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Received June 11, 1997; accepted as submitted July 25, 1997. Address reprint requests to Michael J.G. Somers, MD, Division of Nephrology, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3102-0022$3.00/0
American Journal of Kidney Diseases, Vol 31, No 2 (February), 1998: pp 341-344
341
342
RAMIREZ ET AL
Fig 1. (A) Representative glomerulus from initial renal biopsy. Glomerulus is generally unremarkable except for mild mesangial matrix expansion without endocapillary or extracapillary proliferation. (Periodic acid-Schiff stain; original magnification ⴛ2,800.) (B) Representative glomerulus from follow-up renal biopsy. There is marked extracapillary proliferation with a large fibrocellular crescent. Note collapse of glomerulus and rupture of Bowman’s capsule (arrow). There is severe interstitial fibrosis and tubular atrophy. (Periodic acid-Schiff stain, original magnification ⴛ2,800.)
medications, the parents chose to forgo therapy and did not schedule a follow-up nephrology visit. Four months later, the patient was urgently referred by her family practitioner with a 2-week history of respiratory symptoms, peripheral edema, and hypertension. She had a 1-month history of mild epistaxis, a 9-pound weight gain, and decreased urine output. Physical examination was notable for blood pressure of 159/91 mm Hg, pallor, bilateral rales, and bipedal edema. A chest radiograph showed increased pulmonary vascular markings. Urinalysis showed 3⫹ protein, 4⫹ hematuria, 10 to 20 white blood cells/HPF, 20 to 50 glomerular RBC/HPF, and many waxy casts, mixed cellular casts, and degenerated cellular casts. Further laboratory evaluation showed a hematocrit of 19%, a sedimentation rate of 94 mm/hr, a serum creatinine of 10.8 mg/dL, a blood urea nitrogen of 142 mg/dL, and a serum albumin of 2.0 g/dL. Complement levels were normal. Anti-glomerular basement membrane antibody was negative. ANCA levels were obtained. Indirect immunofluoresecence showed a p-ANCA pattern of reactivity. Enzyme-linked immunosorbent assay (ELISA) confirmed the presence of IgG against myeloperoxidase (p-ANCA) with an activity of 63 units (normal, ⬍2.8 units). IgA-ANCA was also present. The patient underwent emergent hemodialysis, and a second renal biopsy was performed. This biopsy differed significantly from the earlier one, with light microscopy (Fig 1B) showing a proliferative glomerulonephritis with large fibrocellular crescents in 50% of the glomeruli and global sclerosis in the remainder. In contrast to the profound extracapillary proliferation, there was limited endocapillary
proliferation. Many glomeruli exhibited destruction of Bowman’s capsule and a neutrophilic infiltrate. Immunofluorescence could not be performed because there were no glomeruli in the sample sent for immunofluorescence. Electron microscopy showed severe injury in the glomerular tufts, and extensive foot process fusion with microvilli formation. There were no electron-dense deposits visualized, and thus there was no overt evidence of immune complex disease. Altogether, the biopsy findings were compatible with microscopic polyangiitis. The degree of interstitial fibrosis and tubular atrophy had also progressed from the initial biopsy. The patient received a 3-day pulse of intravenous methylprednisolone (1 g/day) followed by oral prednisone at a dose of 2 mg/kg/day. One dose of intravenous cyclophosphamide (1 g/m2 ) was also given. A sural nerve biopsy performed to identify extrarenal manifestations of microscopic polyarteritis was normal.9 Despite therapy, the patient remained dialysis dependent and was subsequently discharged home on continuous cycling peritoneal dialysis (CCPD). One month postcyclophosphamide therapy, p-ANCA activity had fallen to near-normal levels, where they have subsequently remained.
DISCUSSION
ANCAs of the IgA isotype directed specifically against myeloperoxidase have been detected in HSP and IgAN.3-5 For instance, Ronda
IgG-ANCA AND IgA NEPHROPATHY
et al3 reported the presence of IgA-ANCA detected by ELISA in 79% of patients with HSP and in 3% of patients with IgAN.3 The significance of this finding is not known, although there appeared to be a correlation between IgA-ANCA titer and disease activity of HSP. In comparison, Robson et al6 were unable to detect any isotype of ANCA when assessing the sera from 19 patients with HSP in different stages of disease activity.6 Saulsbury et al7 suggested that the presence of IgA-rheumatoid factor in HSP or IgAN may result in false-positive IgA-ANCA titers, whereas Sinico et al8 concluded that increased IgA-ANCA may be secondary to increased IgA-fibronectin circulating complexes and are neither immunologically nor diagnostically specific. In contrast to IgA-ANCA, IgG-ANCA has only rarely been described in HSP or IgAN, most often in patients with an overlap syndrome between HSP and microscopic polyangiitis. Recently Martin et al10 reported the case of an adult renal allograft recipient with recurrent IgAN who subsequently lost the graft because of a fulminant ANCA-associated crescenteric process.10 Retrospective analysis of stored serum samples from this patient showed IgA-ANCA activity correlating with disease activity both before and after transplantation. IgG-ANCA was similarly detectable in significant quantities both before and after transplantation, leading to speculation that rare patients may present an overlap syndrome between IgG-ANCA–positive systemic disease and IgAN. The child in this report had no manifestations of a systemic vasculitis, and initial clinical history, laboratory evaluation, and renal biopsy were characteristic of IgAN. Her sudden decline in renal function was not accompanied by any outward manifestation of an IgAN acute nephrotic flare such as a protracted episode of gross hematuria. The histology in her second biopsy had evolved dramatically with a fulminant crescentic process and neutrophilic infiltration compatible with an entity such as an ANCA mediated rapidly progressive glomerulonephritis rather than the typical histology of IgAN. Although immunofluorescence could not be performed on the second biopsy, the patient’s family had refused any therapy for her IgAN; thus, it is unlikely that this process had remitted spontaneously. It is
343
unclear, however, whether this patient’s rapidly progressive glomerulonephritis represented dramatic progression of her IgAN or the superimposition of an acute process on her chronic disease. In any case, by the time of her rapidly progressive glomerulonephritis, her ANCA serologies were positive for both IgA and IgG isotypes. To our knowledge, this is the first report of positive IgG-ANCA serologies in a pediatric patient with IgAN. Taken together, this case and the report from Martin raise the possibility that, in rare patients, there may be an association between fulminant IgAN and ANCA-associated disease.10 Because ANCA serologies are rarely measured in the pediatric patient with clinical, laboratory, and histological evidence of IgAN, it remains unclear whether IgG-ANCA in the setting of IgAN may be underdetected and may be a potential marker for more aggressive IgAN. In these patients, such a relationship could have potential implications for therapy. Similar to regimens used in classic ANCA-mediated disease, aggressive treatment of such a variant with cyclophosphamide and pulse steroids may serve to prolong renal function as well as to decrease the potential for life-threatening extrarenal complications such as pulmonary hemorrhage.11 Recent retrospective studies of patients with end-stage renal disease from ANCA-associated vasculitis who subsequently underwent renal transplantation have also suggested that the incidence of future recurrence of ANCA-mediated disease may be reduced by treatment with cyclophosphamide to lower the circulating ANCA titer.12,13 Thus, it may be concluded that patients with IgAN may have associated IgA- and IgG-ANCA isotypes. Identification of these antibodies and a possible syndrome in which severe IgAN and microscopic polyarteritis coexist may help tailor management and follow-up of these patients. REFERENCES 1. Niles JL, Pan G, Collins AB, Shannon T, Skates S, Fienberg R, Ahaout MA, McCluskey RT: Value of antigenspecific radioimmunoassay for measuring anti-neutrophil cytoplasmic antibodies (ANCA) in the differential diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 2:27-36, 1991 2. Schultz DR, Tozman EC: Antineutrophil cytoplasmic antibodies: Major autoantigens, pathophysiology, and disease associations. Semin Arthritis Rheum 25:143-159, 1995 3. Ronda N, Esnault VLM, Layward L, Sepe V, Allen A,
344
Feehaly J, Lockwood CM: Antineutrophil cytoplasm antibodies (ANCA) of IgA isotype in adult Henoch-Schonlein purpura. Clin Exp Immunol 95:49-55, 1994 4. Esnault VLM, Ronda N, Jayne DRW, Lockwood CM: Association of ANCA isotype and affinity with disease expression. J Autoimmun 6:197-205, 1993 5. Wall Bake AWL, Lobatto S, Jonges L, Daha MR, Van Es LA: IgA antibodies directed against cytoplasmic antigens of polymorphonuclear leukocytes in patients with HenochSchonlein purpura. Adv Exp Med Biol 216:1593-1598, 1987 6. Robson WLM, Leung AKC, Woodman RC: The absence of anti-neutrophil cytoplasmic antibodies in patients with Henoch-Schonlein purpura. Pediatr Nephrol 8:295298, 1994 7. Saulsbury FT, Kirkpatrick PR, Bolton WK: IgA antineutrophil cytoplasmic antibody in Henoch-Schonlein purpura. Am J Nephrol 11:295-300, 1991 8. Sinico RA, Tadros M, Radice A, Pozzi C, Quarenghi M, Comotti C, Gregorini G, Castiglioni A, Arrigo G, D’Amico G: Lack of IgA antineutrophil cytoplasmic antibodies in Henoch-Schonlein purpura and IgA nephropathy. Clin Immunol Immunopathol 73:19-26, 1994 9. Cid MC, Grau JM, Casademont J, Campo E, Coll-
RAMIREZ ET AL
Vinent B, Lopez-Soto A, Ingelmo M, Urbano-Marquez A: Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa. Arthritis Rheum 7:1055-1061, 1994 10. Martin SJ, Audrain MAP, Baranger T, Moreau A, Dantal J, Testa A, Esnault VLM: Recurrence of immunoglobulin A nephropathy with immunoglobulin A antineutrophil cytoplasmic antibodies following renal transplantation. Am J Kidney Dis 29:125-131, 1997 11. Jennette JC, Falk RJ: Antineutrophil cytoplasmic autoantibodies and associated diseases: A review. Am J Kidney Dis 15:517-529, 1990 12. Rostaing L, Modesto A, Oksman F, Cisterne J, Le Mao G, Durand D: Outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis following cadaveric kidney transplantation. Am J Kidney Dis 29:96102, 1997 13. Grotz W, Wanner C, Rother E, Schollmeyer P: Clinical course of patients with antineutrophil cytoplasm antibody positive vasculitis after kidney transplantation. Nephron 69:234-236, 1995
T
HE PRESENCE of anti-neutrophil cytoplasmic antibodies (ANCAs) is virtually diagnostic of pauci-immune crescentic glomerulonephritis, approaching a sensitivity and specificity of 95% and 99%, respectively.1 Although ANCAs may be one of several immunoglobulin isotypes, pathological ANCAs are generally of the immunoglobulin (Ig) G isotype, especially p-ANCA directed against myeloperoxidase.2 In contrast, the pathological significance of ANCA of the IgA isotype remains unclear. IgA-ANCA has been described sporadically in certain patients with Henoch-Scho¨nlein purpura (HSP) and more rarely with IgA nephropathy (IgAN),3-5 but this finding has not been confirmed by others testing specifically for ANCA in patients with these same disease processes.6-8 IgG-ANCA, however, has only rarely been associated with either HSP or IgAN. We report a case of a child with biopsy-documented IgAN who subsequently developed a rapidly progressive crescenteric glomerulonephritis associated with both IgG-pANCA and IgA-ANCA. This finding raises the question of the pathological significance of IgGANCA in the setting of rapidly progressive renal failure in patients with IgAN. CASE REPORT In February 1996, a 10-year-old girl was referred to Children’s Hospital for persistent microscopic hematuria after an isolated episode of painless gross hematuria concomitant with a viral illness. She had an unremarkable medical profile, including no history of hypertension, purpuric rash, or joint or abdominal pain. There was no family history of renal disease. On presentation, blood pressure was normal, and physical
examination was unremarkable. Urinalysis showed 3⫹ proteinuria and 3⫹ hematuria, with 15 to 20 glomerular red blood cells (RBC)/high-power field (HPF) and three to five granular casts/HPF. A random urine protein-to-creatinine ratio was elevated, at 1.1 (mg/mg), correlating to an approximate 24-hour protein excretion of 450 mg. Other laboratory findings included a mild elevation of serum creatinine to 1.1 mg/dL (calculated glomerular filtration rate of 70 mL/min/1.73m2 ), negative antistreptolysin titers, normal complement values, normal immunoglobulin levels and a normal serum albumin. A renal ultrasound was unremarkable. Renal biopsy was recommended, but the family deferred for 6 months, at which point the child was noted to have increased proteinuria with quantitative urine collection showing a protein excretion of 1.1 g/24 hours. A renal biopsy then was performed, which showed glomeruli with mild mesangial expansion (Fig 1A), as well as some glomeruli with global and segmental sclerosis. There was mild interstitial fibrosis and tubular atrophy and no significant vascular lesions. Immunofluorescence was remarkable for mesangial IgA deposition. Electron microscopy showed an increase in mesangial matrix and occasional subepithelial and mesangial deposits. A diagnosis of IgAN was made, and potential treatment options, including oral prednisone, azathioprine, fish oil, and angiotensin-converting enzyme inhibitors, were discussed. Because of the patient’s perceived difficulty swallowing any
From the Division of Nephrology, Children’s Hospital; the Department of Pathology, Beth Israel Deaconess Medical Center; and the Renal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Received June 11, 1997; accepted as submitted July 25, 1997. Address reprint requests to Michael J.G. Somers, MD, Division of Nephrology, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3102-0022$3.00/0
American Journal of Kidney Diseases, Vol 31, No 2 (February), 1998: pp 341-344
341
342
RAMIREZ ET AL
Fig 1. (A) Representative glomerulus from initial renal biopsy. Glomerulus is generally unremarkable except for mild mesangial matrix expansion without endocapillary or extracapillary proliferation. (Periodic acid-Schiff stain; original magnification ⴛ2,800.) (B) Representative glomerulus from follow-up renal biopsy. There is marked extracapillary proliferation with a large fibrocellular crescent. Note collapse of glomerulus and rupture of Bowman’s capsule (arrow). There is severe interstitial fibrosis and tubular atrophy. (Periodic acid-Schiff stain, original magnification ⴛ2,800.)
medications, the parents chose to forgo therapy and did not schedule a follow-up nephrology visit. Four months later, the patient was urgently referred by her family practitioner with a 2-week history of respiratory symptoms, peripheral edema, and hypertension. She had a 1-month history of mild epistaxis, a 9-pound weight gain, and decreased urine output. Physical examination was notable for blood pressure of 159/91 mm Hg, pallor, bilateral rales, and bipedal edema. A chest radiograph showed increased pulmonary vascular markings. Urinalysis showed 3⫹ protein, 4⫹ hematuria, 10 to 20 white blood cells/HPF, 20 to 50 glomerular RBC/HPF, and many waxy casts, mixed cellular casts, and degenerated cellular casts. Further laboratory evaluation showed a hematocrit of 19%, a sedimentation rate of 94 mm/hr, a serum creatinine of 10.8 mg/dL, a blood urea nitrogen of 142 mg/dL, and a serum albumin of 2.0 g/dL. Complement levels were normal. Anti-glomerular basement membrane antibody was negative. ANCA levels were obtained. Indirect immunofluoresecence showed a p-ANCA pattern of reactivity. Enzyme-linked immunosorbent assay (ELISA) confirmed the presence of IgG against myeloperoxidase (p-ANCA) with an activity of 63 units (normal, ⬍2.8 units). IgA-ANCA was also present. The patient underwent emergent hemodialysis, and a second renal biopsy was performed. This biopsy differed significantly from the earlier one, with light microscopy (Fig 1B) showing a proliferative glomerulonephritis with large fibrocellular crescents in 50% of the glomeruli and global sclerosis in the remainder. In contrast to the profound extracapillary proliferation, there was limited endocapillary
proliferation. Many glomeruli exhibited destruction of Bowman’s capsule and a neutrophilic infiltrate. Immunofluorescence could not be performed because there were no glomeruli in the sample sent for immunofluorescence. Electron microscopy showed severe injury in the glomerular tufts, and extensive foot process fusion with microvilli formation. There were no electron-dense deposits visualized, and thus there was no overt evidence of immune complex disease. Altogether, the biopsy findings were compatible with microscopic polyangiitis. The degree of interstitial fibrosis and tubular atrophy had also progressed from the initial biopsy. The patient received a 3-day pulse of intravenous methylprednisolone (1 g/day) followed by oral prednisone at a dose of 2 mg/kg/day. One dose of intravenous cyclophosphamide (1 g/m2 ) was also given. A sural nerve biopsy performed to identify extrarenal manifestations of microscopic polyarteritis was normal.9 Despite therapy, the patient remained dialysis dependent and was subsequently discharged home on continuous cycling peritoneal dialysis (CCPD). One month postcyclophosphamide therapy, p-ANCA activity had fallen to near-normal levels, where they have subsequently remained.
DISCUSSION
ANCAs of the IgA isotype directed specifically against myeloperoxidase have been detected in HSP and IgAN.3-5 For instance, Ronda
IgG-ANCA AND IgA NEPHROPATHY
et al3 reported the presence of IgA-ANCA detected by ELISA in 79% of patients with HSP and in 3% of patients with IgAN.3 The significance of this finding is not known, although there appeared to be a correlation between IgA-ANCA titer and disease activity of HSP. In comparison, Robson et al6 were unable to detect any isotype of ANCA when assessing the sera from 19 patients with HSP in different stages of disease activity.6 Saulsbury et al7 suggested that the presence of IgA-rheumatoid factor in HSP or IgAN may result in false-positive IgA-ANCA titers, whereas Sinico et al8 concluded that increased IgA-ANCA may be secondary to increased IgA-fibronectin circulating complexes and are neither immunologically nor diagnostically specific. In contrast to IgA-ANCA, IgG-ANCA has only rarely been described in HSP or IgAN, most often in patients with an overlap syndrome between HSP and microscopic polyangiitis. Recently Martin et al10 reported the case of an adult renal allograft recipient with recurrent IgAN who subsequently lost the graft because of a fulminant ANCA-associated crescenteric process.10 Retrospective analysis of stored serum samples from this patient showed IgA-ANCA activity correlating with disease activity both before and after transplantation. IgG-ANCA was similarly detectable in significant quantities both before and after transplantation, leading to speculation that rare patients may present an overlap syndrome between IgG-ANCA–positive systemic disease and IgAN. The child in this report had no manifestations of a systemic vasculitis, and initial clinical history, laboratory evaluation, and renal biopsy were characteristic of IgAN. Her sudden decline in renal function was not accompanied by any outward manifestation of an IgAN acute nephrotic flare such as a protracted episode of gross hematuria. The histology in her second biopsy had evolved dramatically with a fulminant crescentic process and neutrophilic infiltration compatible with an entity such as an ANCA mediated rapidly progressive glomerulonephritis rather than the typical histology of IgAN. Although immunofluorescence could not be performed on the second biopsy, the patient’s family had refused any therapy for her IgAN; thus, it is unlikely that this process had remitted spontaneously. It is
343
unclear, however, whether this patient’s rapidly progressive glomerulonephritis represented dramatic progression of her IgAN or the superimposition of an acute process on her chronic disease. In any case, by the time of her rapidly progressive glomerulonephritis, her ANCA serologies were positive for both IgA and IgG isotypes. To our knowledge, this is the first report of positive IgG-ANCA serologies in a pediatric patient with IgAN. Taken together, this case and the report from Martin raise the possibility that, in rare patients, there may be an association between fulminant IgAN and ANCA-associated disease.10 Because ANCA serologies are rarely measured in the pediatric patient with clinical, laboratory, and histological evidence of IgAN, it remains unclear whether IgG-ANCA in the setting of IgAN may be underdetected and may be a potential marker for more aggressive IgAN. In these patients, such a relationship could have potential implications for therapy. Similar to regimens used in classic ANCA-mediated disease, aggressive treatment of such a variant with cyclophosphamide and pulse steroids may serve to prolong renal function as well as to decrease the potential for life-threatening extrarenal complications such as pulmonary hemorrhage.11 Recent retrospective studies of patients with end-stage renal disease from ANCA-associated vasculitis who subsequently underwent renal transplantation have also suggested that the incidence of future recurrence of ANCA-mediated disease may be reduced by treatment with cyclophosphamide to lower the circulating ANCA titer.12,13 Thus, it may be concluded that patients with IgAN may have associated IgA- and IgG-ANCA isotypes. Identification of these antibodies and a possible syndrome in which severe IgAN and microscopic polyarteritis coexist may help tailor management and follow-up of these patients. REFERENCES 1. Niles JL, Pan G, Collins AB, Shannon T, Skates S, Fienberg R, Ahaout MA, McCluskey RT: Value of antigenspecific radioimmunoassay for measuring anti-neutrophil cytoplasmic antibodies (ANCA) in the differential diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 2:27-36, 1991 2. Schultz DR, Tozman EC: Antineutrophil cytoplasmic antibodies: Major autoantigens, pathophysiology, and disease associations. Semin Arthritis Rheum 25:143-159, 1995 3. Ronda N, Esnault VLM, Layward L, Sepe V, Allen A,
344
Feehaly J, Lockwood CM: Antineutrophil cytoplasm antibodies (ANCA) of IgA isotype in adult Henoch-Schonlein purpura. Clin Exp Immunol 95:49-55, 1994 4. Esnault VLM, Ronda N, Jayne DRW, Lockwood CM: Association of ANCA isotype and affinity with disease expression. J Autoimmun 6:197-205, 1993 5. Wall Bake AWL, Lobatto S, Jonges L, Daha MR, Van Es LA: IgA antibodies directed against cytoplasmic antigens of polymorphonuclear leukocytes in patients with HenochSchonlein purpura. Adv Exp Med Biol 216:1593-1598, 1987 6. Robson WLM, Leung AKC, Woodman RC: The absence of anti-neutrophil cytoplasmic antibodies in patients with Henoch-Schonlein purpura. Pediatr Nephrol 8:295298, 1994 7. Saulsbury FT, Kirkpatrick PR, Bolton WK: IgA antineutrophil cytoplasmic antibody in Henoch-Schonlein purpura. Am J Nephrol 11:295-300, 1991 8. Sinico RA, Tadros M, Radice A, Pozzi C, Quarenghi M, Comotti C, Gregorini G, Castiglioni A, Arrigo G, D’Amico G: Lack of IgA antineutrophil cytoplasmic antibodies in Henoch-Schonlein purpura and IgA nephropathy. Clin Immunol Immunopathol 73:19-26, 1994 9. Cid MC, Grau JM, Casademont J, Campo E, Coll-
RAMIREZ ET AL
Vinent B, Lopez-Soto A, Ingelmo M, Urbano-Marquez A: Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa. Arthritis Rheum 7:1055-1061, 1994 10. Martin SJ, Audrain MAP, Baranger T, Moreau A, Dantal J, Testa A, Esnault VLM: Recurrence of immunoglobulin A nephropathy with immunoglobulin A antineutrophil cytoplasmic antibodies following renal transplantation. Am J Kidney Dis 29:125-131, 1997 11. Jennette JC, Falk RJ: Antineutrophil cytoplasmic autoantibodies and associated diseases: A review. Am J Kidney Dis 15:517-529, 1990 12. Rostaing L, Modesto A, Oksman F, Cisterne J, Le Mao G, Durand D: Outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis following cadaveric kidney transplantation. Am J Kidney Dis 29:96102, 1997 13. Grotz W, Wanner C, Rother E, Schollmeyer P: Clinical course of patients with antineutrophil cytoplasm antibody positive vasculitis after kidney transplantation. Nephron 69:234-236, 1995