NDT Advance Access originally published online on March 1, 2008
Nephrology Dialysis Transplantation 2008 23(6):2084-2087; doi:10.1093/ndt/gfn092
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The patient with C-ANCA/PR3-ANCA-positive crescentic pauci-immune glomerulonephritis and recurrence of nephritic sediment
Department of Internal Medicine, University Hospital, Heidelberg, Germany
Correspondence and offprint requests to: Martin Andrassy, Medizinische Universitätsklinik Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail: Martin_Andrassy{at}med.uni-heidelberg.de
Keywords: anti-glomerular basement membrane (GBM) antibodies; anti-neutrophil cytoplasmatic antibodies (ANCA); glomerulonephritis (GN); Goodpasture's disease
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Introduction |
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Recently it has been shown that in a significant number of patients with Goodpasture's disease and anti-GBM (glomerular basement membrane) antibodies, ANCA (anti-neutrophil cytoplasmatic antibodies) may coexist [1]. In this setting, ANCA is usually specific for P-ANCA and restricted to myeloperoxidase (MPO). In general both antibodies can be detected at the time of clinical presentation. C-ANCA/PR3-ANCA is rarely found in Goodpasture's disease [2]. Sequential development of anti-GBM nephritis and ANCA-associated disease has been described occasionally, again more with P-ANCA/MPO-ANCA rather than with C-ANCA/PR3-ANCA [3]. We report on a patient who first had C-ANCA/PR3-ANCA-positive renal vasculitis and then subsequently, after a long-term therapy-free interval, developed anti-GBM disease followed by repeated (renal) relapses of C-ANCA/PR3-ANCA-positive renal vasculitis despite continued immunosuppression.
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Case report |
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A 60-year-old white woman (85 kg, 1.63 cm) presented to our clinic in April 1990 with a 6-month history of recurrent arthritis of both upper ankle joints and nephritic sediment. Her medical history included arterial hypertension as a part of a metabolic syndrome since 1985. Laboratory tests revealed an elevated C-reactive protein (CRP) (29 mg/dL) and elevated liver enzymes (
GT 37 U/L, NV < 18, alkaline phosphatase 187 U/L, NV < 170) next to normal renal function [serum creatinine (s-creatinine) 0.8 mg/dL, 70.7 µmol/L)]. Urine analysis showed nephritic sediment with erythrocyte casts (Table 1). Serological tests gave a positive C-ANCA/PR3-ANCA (Table 1) and a borderline-positive ANA (1:160) without anti-ds-DNA antibodies, and crithidia luciliae test was negative. Rheumatoid factor was negative, as were hepatitis B, C, HIV and cryoglobulins, during the whole observation period. Complement was normal (C3c: 148 mg/dL, C4: 77.6 mg/dL). HLA typing revealed A 25, A 29, B 44, B 18, Cw 1203, Cw 16, DRB1 07 and DRB1 1501. A renal biopsy disclosed a pauci-immune focal-segmental crescentic GN (Table 2 and Figure 1). The C-ANCA/PR3-ANCA-positive crescentic pauci-immune GN might have been a mild, renal-limited, form of Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) [4] because some systemic signs (arthritis, malaise) were present. Methylprednisolone (40 mg/day) was started and tapered down to 8 mg/day within 3 months because overt diabetes mellitus appeared (HbA1c 7.1%). C-ANCA decreased to 1:80 and haematuria to 9000 erythrocytes/mL. Five months later, methylprednisolone was reduced to 8 mg on an alternate day basis.
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In August 1991, the patient suffered from a severe respiratory infection with fever. A relapse of C-ANCA/PR3-ANCA-positive renal vasculitis was diagnosed because C-ANCA titre rose to 1:1280 with PR3-ANCA >140%, haematuria increased to 640 000 erythrocytes/mL, proteinuria increased to 0.99 g/day and s-creatinine to 1.31 mg/dL (115.8 µmol/L) (Table 1). Five cyclophosphamide boli (1 g each) were administered from August 1991 until March 1992. An additional immunosuppressive therapy with azathioprine was stopped because of side effects (cholestasis). The following disease course is shown in Table 1. Steroids were withdrawn in May 1992 and cyclophosphamide in July 1993 despite a highly positive C-ANCA (1:640–1:1280) and PR3-ANCA (>200%). Renal function was stable and, for the next seven years, the urine contained only traces of erythrocytes and protein.
The second relapse in December 2000 was again initiated by a severe respiratory infection. Serum creatinine rose to 1.92 mg/dL (169.7 µmol/L) and CRP to 17; C-ANCA/PR3-ANCA were high (Table 1). The other standard serological tests were all normal or negative. A renal biopsy disclosed an anti-GBM-positive (1:80) crescentic GN with linear deposits of immunoglobulins (IgG) and C3d along the GBM (Table 2 and Figure 2). Immunosuppression with cyclophosphamide boli (1 g every 3 weeks) and methylprednisolone 100 mg/day (reduced to 40 mg/day within 1 week) were initiated. Renal function improved slowly. Cyclophosphamide was switched to oral route (100 mg/day) and this was continued until December 2001. At that point, haematuria disappeared with remaining trace proteinuria and s-creatinine diminished to 1.37 mg/dL (111.1 µmol/L). C-ANCA was 1:80 and PR3-ANCA >200%; circulating anti-GBM antibodies and CRP became negative.
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In July 2003, the patient was admitted to our ward because of haematemesis, caused by a bleeding gastric ulcer. Serum creatinine had increased to 1.89 mg/dL (167.1 µmol/L); CRP persisted on 26 mg/L as well as C-ANCA (1:1280) and PR3-ANCA (>200%). Haematuria had increased to 190 000/mL and proteinuria to 1.02 g/day. A renal biopsy showed a crescentic and sclerosing GN. Immunohistology revealed a faint linear deposit of IgG without C3d. Circulating anti-GBM antibodies were negative. The patient received methylprednisolone 16 mg/day and oral cyclophosphamide 75 mg/day until October 2003. Cyclophosphamide was replaced by mycophenolate mofetil (MMF) (2–3 x 250 mg/day), and methylprednisolone was reduced from 8–4 mg/day and withdrawn in April 2004. Higher doses of MMF were not tolerated because of gastrointestinal complaints. In October 2004, the patient was again sent to our ward because of gastrointestinal bleeding. Upon gastroscopy, a pangastritis and a hiatus hernia was detected and high doses of a proton pump inhibitor were administered. Since s-creatinine (1.85 mg/dL (163.5 µmol/L)) and C-ANCA test (1:1280) were elevated and microhaematuria had increased to 76.000/mL, a kidney biopsy was performed to exclude a relapse. A pauci-immune sclerosing GN with a segmental fibrous crescent was found with distinct tubular interstitial changes but without evidence of active disease. Therefore, immunosuppressive therapy remained unchanged until July 2005 when a renal relapse was again identified. Two cyclophosphamide boli (750 mg each) controlled disease activity. In February 2006, C-ANCA was 1:640, PR3-ANCA >200%, s-creatinine 1.37 mg/dL (120.11 µmol/L), creatinine clearance 50.9 mL/min, CRP 10.6 g/L, proteinuria 0.47 g/day and haematuria 16 000/mL. The treatment remained unchanged. The total dose of cyclophosphamide from first referral up to now was 75 g. The immunosuppresssion was restricted to glucocorticoids, cyclophosphamide and (rather low doses of) MMF because of gastrointestinal side effects of the latter. Azathioprine was withdrawn because of side effects and the possible efficacy of anti-CD 20 antibodies in this situation was not known at this time.
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Discussion |
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TopIntroductionCase reportDiscussionReferences |
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In patients with Goodpasture's disease, a coexistence of antibodies against the GBM and against neutrophil cytoplasmatic constituents has been described. The specificity of ANCA is mainly P-ANCA with MPO as the target antigen [5]. The overall frequency of ANCA in Goodpasture's disease is
30% [1], whereas patients with P-ANCA/MPO-ANCA-positive vasculitis develop anti-glomerular basement antibodies in 5% of cases [6]. Usually both antibodies occur together at the time of clinical presentation. Whereas some authors describe an unfavourable outcome for those patients with double positivity [6,7], others disagree [8,9]. Our patient had an overlap of two diseases, C-ANCA/PR3-ANCA-positive renal vasculitis and Goodpasture's disease. She presented first with C-ANCA/PR3-ANCA-positive renal vasculitis and was treated with large doses of glucocorticoids and cyclophosphamide (total dose 42 g) before complete clinical remission was achieved. She was then off therapy for seven years before she developed Goodpasture's disease. Whether our patient had quiescent WG or MPA during this period remains uncertain because high-titre C-ANCA/PR3-ANCA persisted. It is unlikely that before the relapse in 2001, silent Goodpasture's disease existed because anti-GBM antibodies had never been detected. Since renal failure was mild, the anti-GBM antibody titre low and histologically the renal damage rather limited, we did not consider plasmapheresis necessary to overcome the renal disease which is in line with other observations [10].
The stimulus for (secondary) development of autoantibodies against the GBM is unknown although some injurious agents (organic solvents, hydrocarbon, chlorine, smoking) had been identified in the past in selected patients [11]. Furthermore, a secondary development of Goodpasture's disease had been described in patients with membranous GN [12]. Our patient had a genetic susceptibility for Goodpasture's disease with positive genotyping for HLA DR [11,13]. As outlined by Verburgh et al. [3], ANCA might have induced damage to the GBM leading to the release of cryptic epitopes and the induction of anti-GBM antibodies.
Sequential development of anti-GBM nephritis and ANCA-associated disease has been described occasionally with a dismal prognosis if C-ANCA/PR3-ANCA was associated with Goodpasture's disease [2,13,14]. There are some case reports describing the occurrence of ANCA-associated disease after the development of Goodpasture's disease [3,7,15,16]. In contrast, there is only one report describing the sequential development of anti-GBM GN after P-ANCA/MPO-ANCA-associated vasculitis [17]. To our knowledge, our patient is the first case reported with a secondary Goodpasture's disease following WG (or MPA) with C-ANCA/PR3-ANCA.
In summary, this is the first report of a sequential development of anti-GBM disease 10 years following the initial manifestation of C-ANCA/PR3-ANCA-positive crescentic pauci-immune GN and 7 years after clinical remission in a therapy-free interval. The persistently high ANCA titres might have played a role in the generation of anti-GBM nephritis in our patient. De novo onset of GN has to be considered in patients with ANCA-associated renal vasculitis, and anti-GBM nephritis is another form of secondary GN that might develop besides the more frequent IgA nephropathy [18, 19].
Conflict of interest statement. None declared.
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References |
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- Jayne DRW, Marshall PD, Jones SJ, et al. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int (1990) 37:965–970.[Web of Science][Medline]
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Accepted in revised form: 30. 1.08
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