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Antineutrophil Cytoplasmic Autoantibody–Negative Pauci-immune Crescentic Glomerulonephritis

Renal Division and Institute of Nephrology, Peking University First Hospital, Beijing, People’s Republic of China

Address correspondence to: Dr. Ming-Hui Zhao, Renal Division and Institute of Nephrology, Peking University First Hospital, Beijing 100034, P.R. China. Phone: +86-10-66551736; Fax: +86-10-66551055; E-mail: mhzhao{at}bjmu.edu.cn

Received for publication September 19, 2006. Accepted for publication November 24, 2006.

	Abstract

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Pauci-immune crescentic glomerulonephritis (CrGN) is one of the most common causes of rapidly progressive glomerulonephritis. The majority of patients with pauci-immune CrGN had circulating antineutrophil cytoplasmic autoantibody (ANCA). However, patients with ANCA-negative pauci-immune CrGN were not investigated fully. This study aimed to analyze the characteristics of this subgroup of patients. Patients whose pauci-immune CrGN was diagnosed from 1997 to 2006 in one center were studied retrospectively. The criteria of pauci-immune was defined as "the intensity of glomerular immunoglobulins staining by direct immunofluorescence assay in renal sections was negative to 1+ staining on a scale of 0 to 4+." Clinical and pathologic characteristics were compared between patients with and without ANCA. Among the 85 patients with pauci-immune CrGN, 28 (32.9%) were ANCA negative. Compared with the 57 ANCA-positive patients, the ANCA-negative patients were much younger (39.7 ± 17.0 versus 57.6 ± 14.0 yr; P < 0.001). The level of urinary protein and the prevalence of nephrotic syndrome were significantly higher in ANCA-negative patients than that in ANCA-positive patients (P < 0.01 and P < 0.001, respectively). However, the prevalence of extrarenal involvement was significantly lower in ANCA-negative patients than that in ANCA-positive patients. The renal survival was poorer in ANCA-negative patients than that in ANCA-positive ones (P < 0.05). ANCA-negative pauci-immune CrGN was not rare and might represent an independent disease entity from ANCA-positive vasculitis.

	Introduction

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Pauci-immune crescentic glomerulonephritis (CrGN) is one of the most common causes of rapidly progressive glomerulonephritis. The characteristic feature of pauci-immune CrGN is focal necrotizing and crescentic glomerulonephritis with little or no glomerular staining for Ig by immunofluorescence microscopy examination. The majority of patients with pauci-immune CrGN have glomerular diseases as a part of a systemic small vessel vasculitis, including Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, or as a part of renal-limited vasculitis (1–3).

Antineutrophil cytoplasmic autoantibody (ANCA) was a serologic marker for primary systemic small vessel vasculitis. Most patients with a cytoplasmic ANCA (cANCA) obtained by indirect immunofluorescence (IIF) assay have ANCA directed against proteinase-3 (PR3), as determined by antigen-specific ELISA. Patients with a perinuclear ANCA (pANCA) mostly have ANCA directed against one of a variety of antigens, such as myeloperoxidase (MPO). It was reported that approximately 80 to 90% of patients with pauci-immune CrGN had circulating ANCA (4,5), and ANCA might play a major role in the pathogenesis of pauci-immune CrGN (6).

It was noted in a number of patients with pauci-immune CrGN, however, that circulating ANCA was negative. Because patients with negative ANCA constituted a minority of patients with pauci-immune CrGN, this subgroup of patients had not been investigated fully except for a few studies (7,8). This study investigated the clinical and pathologic characteristics of patients with ANCA-negative pauci-immune CrGN, and a comparison was made in detail between patients with ANCA-negative and ANCA-positive pauci-immune CrGN.

	Materials and Methods

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Patients
Patients whose pauci-immune CrGN was diagnosed from 1997 to 2006 in the Renal Division and Institute of Nephrology, Peking University First Hospital, were enrolled in this retrospective study. Renal biopsy was performed at the time of diagnosis. "Pauci-immune" was defined as "the intensity of glomerular immunoglobulins staining by direct immunofluorescence assay in renal sections was negative to 1+ staining on a scale of 0 to 4+." "Crescentic glomerulonephritis" was defined as "over 50% of the glomeruli had crescents formation in the renal specimen." Patients with secondary vasculitis or with anti–glomerular basement membrane antibodies were excluded. The clinical and pathologic data were extracted for analysis. For extrarenal involvement, only manifestations that were both strongly suggestive of vasculitis and included in the Birmingham Vasculitis Activity Score (9) or the Vasculitis Damage Index (10) were counted when analyzed. The clinical manifestations were recorded at the time of presentation as well as during follow-up. Informed consent was obtained from each patient when renal biopsy was performed.

Detection of ANCA
ANCA tests were performed by both IIF assay and antigen-specific ELISA for all patients at the time of presentation before immunosuppressive treatment was instituted.

IIF Assay
Standard IIF assays were performed according to the manufacturer’s instructions (EUROIMMUN, Lübeck, Germany). Ethanol-fixed human polymorphonuclear leukocytes were used to detect ANCA, and monkey liver sections were used to exclude antinuclear antibodies. cANCA and pANCA were distinguished according to staining patterns by two experienced technicians.

Antigen-Specific ELISA
Two highly purified known ANCA antigens, PR3 and MPO, purified as previously reported (11), were used as solid-phase ligands in ELISA. Antigens were diluted to 1 to 2 µg/ml with 0.05 M bicarbonate buffer (pH 9.6) and were coated onto the wells of one half of a Costar microtiter plate; the wells in the other half were coated with coating buffer alone and acted as antigen-free wells. The volumes of this step and subsequent steps were 100 µl, all incubations were carried out at 37°C for 1 h, and plates were washed three times with PBS that contained 0.1% Tween-20 (PBST) between stages. Test serum samples were diluted 1:50 with PBST and coated in duplicate on both antigen-coated wells and antigen-free wells; every plate contained positive, negative, and blank (PBST) controls. The binding was detected with horseradish peroxidase–conjugated goat anti-human IgG Gibco (BRL, Grand Island, NY) 1:5000 in PBST. The horseradish peroxidase substrate o-phenylenediamine was used at 0.4 mg/ml in 0.1 mol/L citrate phosphate buffer (pH 5.0). The reaction was stopped by 2.0 mol/L H₂SO₄, and the results were recorded as the net A490 nm (average value of antigen wells minus average value of antigen-free wells) and expressed as percentage of the known positive controls. Samples were considered positive when they exceeded the mean + 3 SD from 100 normal blood donors.

Renal Histopathology
Renal specimens were evaluated using direct immunofluorescence (for Ig and complement components) and light and electron microscopy. For light microscopy, paraffin sections were stained with silver, periodic acid-Schiff, hematoxylin & eosin, and trichrome and were forwarded to two pathologists. Both pathologists scored the biopsies separately, blinded to patients’ data and the scores of the other observer, according to a previously standardized protocol for scoring renal biopsies of patients with ANCA-associated vasculitis (12–14). In short, each glomerulus was scored separately on the presence of fibrinoid necrosis, crescents (cellular/fibrous and segmental/circumferential), glomerulosclerosis (local/segmental/global), granulomatous reactions, and a number of other lesions. The presence of glomerular lesions was calculated as the percentage of the total number of glomeruli in a biopsy. Interstitial and tubular lesions were scored semiquantitatively on the basis of the percentage of the tubulointerstitial compartment that was affected: Interstitial infiltrates (–, 0%; +, 0 to 20%; ++, 20 to 50%; and +++, >50%), interstitial fibrosis (–, 0%; +, 0 to 50%; and ++, >50%), and tubular atrophy (–, 0%; +, 0 to 50%; and ++, >50%). Vascular lesions were scored as presence or absence. Differences in scoring between the two pathologists were resolved by re-reviewing the biopsies and coming to a consensus.

Statistical Analyses
Differences of quantitative parameters between groups were assessed using the t test (for data that were normally distributed) or nonparametric test (for data that were not normally distributed). Differences of semiquantitative results were tested using the Mann-Whitney U test. Differences of qualitative results were compared using ² test. Kaplan-Meier curves were used to analyze patient survival as well as renal survival. P < 0.05 was considered significant. Analysis was performed with SPSS statistical software package (version 13.0; Chicago, IL).

	Results

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Demographic Features and ANCA Specificity
Eighty-five patients received a diagnosis of pauci-immune CrGN. Twenty-eight (32.9%) of the 85 were ANCA negative both in IIF assay and ELISA. Nine (10.6%) of the 85 were cANCA positive, and all of the sera could recognize PR3. Forty-eight (56.5%) of the 85 were pANCA positive, and all of the sera could recognize MPO. Among the 28 patients with ANCA-negative pauci-immune CrGN, 16 were male and 12 were female. The average age at onset of the disease (defined as "patients had signs, symptoms, or laboratory findings closely related to the disease [including both renal and extrarenal]") was 39.7 yr (range 15 to 65 yr). The median interval between onset of the disease and renal biopsy was 1 mo (range 0.2 to 30 mo).

Compared with the 57 patients with ANCA-positive pauci-immune CrGN, patients with negative ANCA were significantly younger at onset of the disease (39.7 ± 17.0 versus 57.6 ± 14.0 yr; P < 0.001). The interval from onset of the disease to renal biopsy was significantly shorter in ANCA-negative group than that in ANCA-positive group (P < 0.01; Table 1).

Renal Manifestations
Of the 28 patients with ANCA-negative pauci-immune CrGN, all had hematuria and proteinuria. The level of urinary protein was 5.47 ± 3.32 g/24 h. Thirteen patients (46.4%) had nephrotic syndrome. The level of initial serum creatinine was 625.6 ± 374.5 µmol/L (range 99.3 to 1402 µmol/L). Twenty-four patients (85.7%) had elevated initial serum creatinine, and 15 patients (53.6%) were dialysis dependent on diagnosis. Compared with the 57 patients with ANCA-positive pauci-immune CrGN, patients with negative ANCA had higher level of urinary protein (5.47 ± 3.32 versus 2.23 ± 2.27 g/24 h; P < 0.01) and higher prevalence of nephrotic syndrome (46.4 versus 8.8%; ² = 16.0, P < 0.001; Table 1).

Renal Histology
In each renal biopsy specimen, an average of 23.7 ± 13.2 glomeruli could be seen. Of the 28 patients with ANCA-negative pauci-immune CrGN, 9.6 ± 12.2% (0 to 41.7%) of the glomeruli were normal, and 76.0 ± 17.1% (50.0 to 100%) of the glomeruli had crescents. The mean and median percentage of global sclerosis was 5.9 and 0.0% (0 to 50.0%), respectively. The mean and median percentage of fibrinoid necrosis of glomeruli tuft was 2.8 and 0.0% (0 to 25.0%), respectively. Compared with the 57 patients with ANCA-positive pauci-immune CrGN, patients with negative ANCA had a significantly lower percentage of normal glomeruli (9.6 ± 12.2 versus 16.3 ± 14.7%; P < 0.05). Among glomeruli with crescent formation, the percentage of cellular crescent tended to be higher in patients with negative ANCA than that in patients with positive ANCA (61.6 ± 35.3 versus 45.9 ± 34.1%; P = 0.05; Table 2).

View larger version (38K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Differences of tubulointerstitial lesion. (A) I versus II: P > 0.05; I versus III: P > 0.05. (B) I versus II: P > 0.05; I versus III: P > 0.05. (C) I versus II: P > 0.05; I versus III: P < 0.05.

Other Clinical Manifestations
Of the 28 patients with ANCA-negative pauci-immune CrGN, two (7.1%) had gastrointestinal involvement manifested as abdominal pain or bloody diarrhea. Only one (3.6%) patient had ophthalmic involvement manifested as conjunctivitis and uveitis. None had otic or nasal involvement. Compared with the 57 patients with ANCA-positive pauci-immune CrGN, the prevalences of ophthalmic, otic, and nasal involvement in patients with negative ANCA were significantly lower (3.6 versus 24.6% [² = 4.34, P < 0.05]; 0 versus 31.6% [² = 11.2, P < 0.001]; 0 versus 17.5% [² = 4.01, P < 0.05], respectively). When patients with pauci-immune CrGN were considered as part of systemic vasculitis, the level of Birmingham Vasculitis Activity Score (9) at diagnosis was significantly lower in patients with ANCA-negative pauci-immune CrGN than that in patients with ANCA-positive pauci-immune CrGN (13.9 ± 2.4 versus 20.1 ± 5.0; P < 0.001; Table 1).

Laboratory Findings
Of the 28 patients with ANCA-negative pauci-immune CrGN, 23 (82.1%) had anemia, four (14.3%) had leukocytosis, eight (28.6%) had thrombocytosis and 15 (53.6%) had elevated erythrocyte sedimentation rate.

Treatment and Outcomes
Treatment protocols were comparable between patients with ANCA-positive and ANCA-negative pauci-immune CrGN. The majority of patients (25 of 28) received corticosteroid combined with daily oral or monthly intravenous cyclophosphamide. Nineteen of the 28 patients received intravenous methylprednisolone pulse therapy. After the induction therapy, 18 (72.0%) of 25 patients achieved complete or partial remission. Seven (25.0%) of the 28 patients died, and 12 (42.9%) of 28 patients progressed to ESRD and received renal replacement therapy. The median time of survival and renal survival was 96.0 and 12.7 mo, respectively. Six (21.4%) and 11 (39.3%) of 28 patients died and progressed to ESRD within 1 yr after diagnosis, respectively.

Compared with the patients with positive ANCA, patients with negative ANCA had poorer renal outcome (P < 0.05; Figure 2). No significant difference was found between the survivals of these two subgroups of patients (Figure 3). The causes of death of the patients are listed in Table 3.

View larger version (34K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Renal survivals of patients with pauci-immune crescentic glomerulonephritis (CrGN) with and without antineutrophil cytoplasmic autoantibody (ANCA). The solid line represents ANCA-negative patients; the dashed line represents ANCA-positive patients.

View larger version (34K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Patient survivals of patients with pauci-immune CrGN with and without ANCA. The solid line represents ANCA-negative patients; the dashed line represents ANCA-positive patients.

	Discussion

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This study retrospectively analyzed 28 patients with ANCA-negative pauci-immune CrGN in our single center, which was one of the largest series to date focused on this subgroup of patients. It constituted nearly one third of patients with pauci-immune CrGN, and this proportion was higher than that in most other studies (7,13,18,19).

It was found in our study that among the patients with pauci-immune CrGN, there was significant difference between ANCA-negative group and ANCA-positive group. Compared with ANCA-positive patients, ANCA-negative patients had greater degree of proteinuria as well as higher prevalence of nephrotic syndrome; in renal histology, ANCA-negative patients tended to have more severe lesions on glomeruli (fewer normal glomeruli). It was speculated that these differences might be contributing factors to poorer renal outcome of ANCA-negative patients than ANCA-positive ones in our study. The level of initial serum creatinine was comparable between these two subgroups of patients. However, ANCA-negative patients had a shorter interval from onset of the disease to diagnosis. Therefore, the renal injury seemed to be a more "fulminant" process in ANCA-negative patients than in ANCA-positive ones.

The renal histology of the patients in our study was different from the study of Eisenberger et al. (7), which investigated 20 patients with ANCA-negative pauci-immune CrGN and found that active lesions were similar between ANCA-positive and ANCA-negative patients, whereas chronic lesions, including interstitial fibrosis and glomerulosclerosis, were more prominent in ANCA-negative patients. Because the numbers of patients in both studies were limited, sampling error could not be excluded. However, the proportion of fibrinoid necrosis in this study was much lower than others (20). This might be due to the limited number of sections of specimens in our study.

Regarding extrarenal involvement, Hedger et al. (8) investigated 35 patients with ANCA-negative rapidly progressive glomerulonephritis and found that they had fewer airway symptoms than ANCA-positive ones but failed to find any other difference between these two subgroups of patients. Similar results were confirmed by the study of Eisenberger et al. (7). However, the latter study did not compare the extrarenal involvement of ANCA-negative patients with ANCA-positive ones. In our study, it was found that ANCA-negative patients had many fewer constitutional symptoms and much less extrarenal involvement, including lung, eye, ear, nose, and throat, than ANCA-positive patients. ANCA-negative patients also were much younger at onset of disease than ANCA-positive ones. In another words, ANCA-negative patients seemed to have many fewer "vasculitic" manifestations than ANCA-positive ones.

The pathogenesis of ANCA-negative pauci-immune CrGN was not clear. It was found by Eisenberger et al. (7) that in patients with ANCA-negative pauci-immune CrGN, neutrophil infiltration could be found in glomerular lesions; therefore, neutrophils might play a pathogenic role even in the absence of ANCA. Substantial evidence suggested that ANCA, rather than a serologic marker, might play an important role in the pathogenesis of vasculitis and pauci-immune CrGN. For example, ANCA could stimulate leukocytes to undergo a respiratory burst and degranulate primary granular constituents, which supported a direct pathogenic role for ANCA (21). It also was found in mice that MPO-ANCA might possess the intrinsic ability to produce pauci-immune necrotizing and crescentic glomerulonephritis (22). Thus, it can be speculated that the absence of ANCA might be an important factor contributing to the discrepancies between patients with ANCA-negative and ANCA-positive pauci-immune CrGN. Besides ANCA, anti–endothelial cell antibody (AECA) was another potentially pathogenic factor in vasculitis and pauci-immune CrGN. It has been shown that AECA might be reactive against constitutively expressed endothelial cell antigen and might promote leukocyte recruitment across endothelium (23). Our further investigation suggested that the prevalence of AECA in patients with ANCA-negative pauci-immune CrGN was significantly lower than that in patients with ANCA-positive pauci-immune CrGN (53.6 versus 88.5%; P < 0.05; unpublished data). Therefore, the difference in the prevalence of AECA might be another potential factor contributing to the discrepancies of clinical manifestations between these two subgroups of patients. Whether there are some other mechanisms, such as lymphocytes or unidentified autoantibodies, involved in the pathogenesis of ANCA-negative pauci-immune CrGN needs further investigation. The substantial differences between these two subgroups of patients raised an interesting issue that pauci-immune CrGN might be composed of different diseases in origin.

	Conclusion

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Among the patients with pauci-immune CrGN, ANCA-negative patients were not rare. Compared with ANCA-positive patients, ANCA-negative patients had a higher level of proteinuria, poorer renal outcome, and less extrarenal involvement. It might represent an independent disease entity from ANCA-positive pauci-immune CrGN.

	Disclosures

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None.

	Acknowledgments

 
This study was supported by a grant from the Chinese 985 project (985-2-033-39).

We are very grateful to Dr. Jie E and Dr. Xin Zheng for assistance in collecting pathologic data of the patients.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: ASN.2006091021v1 18/2/599    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, M. Articles by Wang, H.-Y. Search for Related Content PubMed PubMed Citation Articles by Chen, M. Articles by Wang, H.-Y. Related Collections Related Article