|Year : 2015 | Volume
| Issue : 3 | Page : 150-154
Pauci-immune crescentic glomerulonephritis: A series of 21 cases
Thingujam Bipin Singh, Thangjam Babina, Leena Konjengbam, David Howdijam
Department of Pathology, BABINA Diagnostics, Imphal, Manipur, India
|Date of Web Publication||1-Dec-2015|
Thingujam Bipin Singh
Department of Pathology, BABINA Diagnostics, Soibam Leikai, Porompat, Imphal, Manipur
Source of Support: None, Conflict of Interest: None
Background: Pauci-immune crescentic glomerulonephritis is the most common cause of crescentic glomerulonephritis (CrGN). Patients usually present with rapidly progressive glomerulonephritis (RPGN) with hematuria, proteinuria, and elevated serum creatinine levels. The characteristic feature of pauci-immune CrGN is focal necrotizing CrGN associated with little or no glomerular staining for immunoglobulin (Ig) by immunofluorescence microscopic examination. Most patients (80-85%) with pauci-immune CrGN, including the patients with and without systemic vasculitis, have antineutrophil cytoplasmic autoantibodies (ANCAs). Aims and Objectives: To study and compare the histological and laboratory features of ANCA-positive and ANCA-negative pauci-immune CrGN. Materials and Methods: Patients who were diagnosed with pauci-immune CrGN from January 2012 to May 2015, at BABINA Diagnostics, were included in this retrospective study. The terms "pauci-immune" and "crescentic glomerulonephritis" were defined according to standard guidelines. The demographic and laboratory data were extracted from the Laboratory Information System (LIS) for analysis. ANCA tests were performed by both indirect immunofluorescence (IIF) assay (EUROIMMUN, Lubeck, Germany) and antigen-specific enzyme-linked immunosorbent assay (ELISA) (ORGENTEC Diagnostika GmbH, Germany). Renal specimens were evaluated using direct immunofluorescence (for Ig and complement components) and light microscopy using routine and special stains. Results: Four (19%) out of the 21 cases of pauci-immune CrGN were ANCA negative. Acute features on histology were seen more than chronic features than ANCA-negative cases. Conclusion: Among the patients with pauci-immune CrGN, ANCA-negative patients were not rare. Compared with ANCA-positive patients, ANCA-negative patients had a lower percentage of normal glomeruli, more of chronic features, and a higher level of proteinuria.
Keywords: Anti-neutrophil cytoplasmic autoantibody (ANCA), crescentic, glomerulonephritis, immune, pauci
|How to cite this article:|
Singh TB, Babina T, Konjengbam L, Howdijam D. Pauci-immune crescentic glomerulonephritis: A series of 21 cases. J Med Soc 2015;29:150-4
| Introduction|| |
Renal biopsies in patients with the clinical findings of rapidly progressive glomerulonephritis (RPGN) usually demonstrate crescentic glomerulonephritis (CrGN). 
CrGN is a severe form of glomerular injury that is characterized by disruption of the glomerular basement membrane (GBM); this disruption leads to cellular proliferation within the Bowman space and is often accompanied by fibrinoid necrosis. The disruption of glomerular capillaries allows inflammatory mediators and leucocytes to enter the Bowman space where they induce epithelial cell proliferation and macrophage maturation, which leads to the formation of cellular crescents. 
Patients with CrGN often experience rapid loss of renal function, accompanied by oliguria and anuria; typical features of glomerulonephritis include proteinuria and dysmorphic hematuria. CrGN must be diagnosed promptly and precisely to facilitate timely treatment. Delay in diagnosis and treatment can have a major, negative influence on the prognosis. 
The diagnosis of CrGN is based on the presence of crescents within the glomeruli on kidney biopsy. The type of crescentic GN is determined by the immunofluorescent staining pattern of glomeruli. The major categories of CrGN are anti-GBM antibody CrGN, immune-complex CrGN, and pauci-immune CrGN. 
Pauci-immune CrGN is one of the most common causes of RPGN accounting for 80% of all cases and is often, but not always, associated with and possibly mediated by antineutrophil cytoplasmic autoantibodies (ANCAs).  While serological investigations are indicative, the morphologic changes in the renal biopsy are still the gold standard for establishing a diagnosis.
The characteristic feature of pauci-immune CrGN is focal necrotizing and CrGN with little or no glomerular staining for immunoglobulin (Ig) by immunofluorescence microscopy examination. The typical description of immunofluorescence findings in ANCA-associated glomerulonephritis is that of a so-called pauci-immune pattern, first described by Jennette et al. and defined as <2+ glomerular immunostaining for Igs.
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. 
Most patients with pauci-immune CrGN, including the patients with and without systemic vasculitis have ANCAs. Out of all the patients, 80-85% with active untreated pauci-immune CrGN have been reported to be ANCA-positive.  Cases of CrGN not associated with ANCA and which do not show evidence for immune complexes or anti-GBM mediation are rare and may account for approximately 10-20% of patients with RPGN. 
This study was undertaken to study the histological and laboratory features of pauci-immune CrGN and make a comparison between ANCA-positive and ANCA-negative cases.
| Materials and Methods|| |
A retrospective study was undertaken including all patients who were diagnosed with pauci-immune CrGN from January 2012 to May 2015, at BABINA Diagnostics.
Renal biopsy was received referred by nephrologists with detailed history in prescribed format for diagnosis. The term "crescentic glomerulonephritis" was defined as "over 50% of glomeruli having crescent formation in the renal specimen" and "pauci-immune" as "intensity of glomerular immunoglobulin staining by direct immunofluorescence assay in renal sections being 0 to 1+ on a scale of 0 to 4+," respectively.  Patients with secondary vasculitis or with anti-GBM antibodies were excluded.
The demographic and laboratory data were extracted from the Laboratory Information System (LIS) for analysis.
ANCA tests were performed by both indirect immunofluorescence (IIF) assay (EUROIMMUN, Lubeck, Germany) and antigen-specific enzyme-linked immunosorbent assay (ELISA), ORGENTEC Diagnostika GmbH, Germany.
Renal specimens were evaluated using direct immunofluorescence [for Ig and complement components] and light microscopy. Paraffin sections were stained with Grocott's methenamine silver, Periodic Acid-Schiff, hematoxylin and eosin, and Masson's trichrome stain.
Each glomerulus was studied according to histopathologic classification of ANCA-associated glomerulonephritis, proposed by Berden et al.
| Results|| |
Of all the 21 patients diagnosed with pauci-immune CrGN, majority were females (13/61.9%). A wide age range was seen (17-59), 37 years being the median age. Seventeen (81%) of the ANCA-positive patients, of which cytoplasmic (c)-ANCA 6 (35%) were more in number than perinuclear (p)-ANCA 11 (65%) [Figure 1] and [Figure 2]. The remaining four (19%) patients were ANCA negative [Table 1].
Of all the 21 patients with pauci-immune CrGN, 11 (52.3%) had hematuria. Eight patients (38.1%) had nephrotic range proteinuria. The level of initial serum creatinine was 5.2 ± 2.8 mg/dL (range 0.7-1.3 mg/dL). All the patients (100%) had elevated level of initial serum creatinine, and 12 patients (57%) were dialysis dependent at the time of biopsy [Table 2].
|Table 2: Comparison of clinical and laboratory features of patients with pauci-immune CrGN with and without ANCA|
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Compared with the 17 (81%) patients with ANCA-positive pauci-immune CrGN, 4 (19%) patients with negative ANCA belonging to a younger age group (25.7 ± 7.6 years) had higher prevalence of nephrotic syndrome (2/50%) but lower levels of serum creatinine (5.2 ± 2.9 mg/dL vs 2.8 ± 2.1 mg/dL).
Clinical manifestations were more in ANCA-positive patients while laboratory findings were seen to be comparable [Table 2].
In each renal biopsy specimen, an average of 10 ± 2.7 glomeruli could be seen, with average percentage of normal glomeruli being 16.2 ± 11.6%.
Compared with the 17(81%) patients with ANCA-positive pauci-immune CrGN, 4(19%) patients with negative ANCA had a significantly lower percentage of normal glomeruli (6.9 ± 8.3% vs 18.38 ± 11.37%) [Figure 3], [Figure 4] and [Figure 5]. Among glomeruli with crescent formation, the percentage of cellular crescent tended to be lower in patients with negative ANCA than those with positive ANCA (54.92 ± 3.86% vs 68.94 ± 10.04%) [Figure 6]. Global sclerosis, interstitial infiltration, and tubular atrophy tended to be more in ANCA-negative patients [Table 3] and [Table 4].
|Figure 4: Cellular crescent with segmental necrosis and rupture of basement membrane, HE ×400|
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|Figure 5: Circumferential cellular crescent with endocapillary proliferation, HE ×400|
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|Figure 6: Vasculitis, note numerous neutrophils, and scattered eosinophils, HE ×400|
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| Discussion|| |
In our study of 21 patients with CrGN, 4 (19%) were ANCA negative. Majority of the patients under this study were females (61.9%), which may be attributed to the particular ethnic profile of the population studied. Chen et al.,  Hedger et al.,  Eisenberger et al.,  Hung et al.,  and Jain et al.,  have, however, reported no particular sexual predilection.
More number of ANCA-negative patients belonged younger age groups compared to ANCA-positive patients as has been reported by Chen et al.,  Eisenberger et al.,  Hung et al.,  and Jain et al. Hedger et al. , however, observed a comparable age.
A higher prevalence of chronic glomerular lesions, clinical manifestations, proteinuria, and hematuria was also seen in the ANCA-negative cases. Acute glomerular lesions were, however, seen to be comparable. Similar observations compare well with the study of Chen et al.
| Conclusion|| |
In our study, clinical and histologic features of pauci-immune CrGN were analyzed. A comparison was made of the features studied between ANCA-positive and ANCA-negative cases. While the study is limited by the small sample size, because of the rarity of the disease, it was observed that, among the patients of pauci-immune CrGN, ANCA-negative cases are not rare, and might represent an independent disease entity from ANCA-positive vasculitis.
We observed significant differences between ANCA-negative group and ANCA-positive group. Compared with ANCA-positive patients, ANCA-negative patients had comparable initial serum creatinine levels, but 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). ANCA-positive and ANCA-negative patients showed quite similar active lesions, whereas chronic lesions, including interstitial fibrosis and glomerulosclerosis, were more prominent in ANCA-negative patients.
Although the pathogenesis of ANCA-negative pauci-immune CrGN is unclear, the observation of a higher prevalence of chronic glomerular features as compared with ANCA-positive cases may well explain reported poorer outcomes.
This study highlights the implications for the understanding of CrGN and the importance of taking into account the importance of the assessment of ANCA status when diagnosing and treating individuals with pauci-immune CrGN.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Harris AA, Falk RJ, Jennette JC. Crescentic glomerulonephritis with a paucity of glomerular immunoglobulin localization. Am J Kidney Dis 1998;32:179-84
Chen M, Kallenberg CG, Zhao MH. ANCA-negative pauci-immune crescentic glomerulonephritis Nat Rev Nephrol 2009;5:313-8.
Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003;63:1164-77.
Ellis CL, Manno RL, Havill JP, Racusen LC, Geetha D. Validation of the new classification of pauci-immune glomerulonephritis in a United States cohort and its correlation with renal outcome. BMC Nephrol 2013;14:210.
Jennette JC, Wilkman AS, Falk RJ Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989;135:921-30.
Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, et al
. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 2010;21:1628-36.
Hedger N, Stevens J, Drey N, Walker S, Roderick P. Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: A 10-year retrospective study. Nephrol Dial Transplant 2000;15:1593-9.
Eisenberger U, Fakhouri F, Vanhille P, Beaufils H, Mahr A, Guillevin L, et al
. ANCA-negative pauci-immune renal vasculitis: Histology and outcome. Nephrol Dial Transplant 2005;20:1392-9.
Hung PH, Chiu YL, Lin WC, Chiang WC, Chen YM, Lin SL, et al
. Poor renal outcome of antineutrophil cytoplasmic antibody negative Pauci-immune glomerulonephritis in Taiwanese. J Formos Med Assoc 2006;105:804-12.
Jain M, Prasad N, Sharma RK. ANCA negative pauci-immune crescentic glomerulonephritis: Histological features and outcomes. Histopathology paper presentations. Histopathology 2012;61(Suppl 1): 1-233.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]