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Year : 2012  |  Volume : 55  |  Issue : 1  |  Page : 28-32
Renal histology in pauci-immune rapidly progressive glomerulonephritis: 8-year retrospective study

1 Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

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Date of Web Publication11-Apr-2012


Context: The need to perform reporting of renal biopsies of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides in a more uniform manner required relook at our eight-year data. Aims: To document detailed renal histopathology of pauci-immune rapidly progressive glomerulonephritis (RPGN) and also to seek any significant differences in renal histology of C-ANCA-positive, P-ANCA-positive, and ANCA-negative patients. Materials and Methods: A detailed analysis of the histopathologic features of renal biopsies of 48 patients in whom a diagnosis of pauci-immune glomerulonephritis was concluded on renal biopsy and who presented clinically as rapidly progressive renal failure was done. Statistical Analysis Used: One-way ANOVA and Pearson Chi square tests. Results: Compared with ANCA +ve patients, the ANCA -ve patients were much younger (46.85 ± 16.12 years vs 34.28±15.94 years). No significant differences were found between renal lesions of C-ANCA, P-ANCA, and ANCA-negative patients, except for diffuse tubular atrophy which was more severe and more frequently present with P-ANCA positivity (P value=0.013). Conclusions: Pauci-immune RPGN (irrespective of ANCA status) is a relatively rare disorder in patients who are undergoing the renal biopsy at our institute, constituting 2% of all renal biopsies submitted. It is mandatory to have ANCA serology status during reporting of a kidney biopsy showing pauci-immune crescentic or necrotizing glomerulonephritis. Also, if a uniform reporting strategy is followed throughout the country, the studies from this vast country will be comparable.

Keywords: Histology, pauci-immune, rapidly progressive glomerulonephritis

How to cite this article:
Minz RW, Chhabra S, Joshi K, Rani L, Sharma N, Sakhuja V, Duggal R, Pasricha N. Renal histology in pauci-immune rapidly progressive glomerulonephritis: 8-year retrospective study. Indian J Pathol Microbiol 2012;55:28-32

How to cite this URL:
Minz RW, Chhabra S, Joshi K, Rani L, Sharma N, Sakhuja V, Duggal R, Pasricha N. Renal histology in pauci-immune rapidly progressive glomerulonephritis: 8-year retrospective study. Indian J Pathol Microbiol [serial online] 2012 [cited 2022 Jun 28];55:28-32. Available from: https://www.ijpmonline.org/text.asp?2012/55/1/28/94850

   Introduction Top

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by rapid deterioration of renal function occurring within days or weeks together with signs of glomerulonephritis. [1] Pauci-immune glomerulonephritis is the commonest cause of RPGN and mortality as compared with immune complex or anti-glomerular basement disease. [2],[3] It is also the commonest condition showing crescents in more than 50% of glomeruli. This paper presents information on the prevalence of pauci-immune RPGN irrespective of ANCA (antineutrophil cytoplasmic antibodies) status in our institute over an eight-year period. In this retrospective study, we have described in detail the histopathology of renal biopsies of pauci-immune RPGN and compared histologic features of ANCA-negative vs. ANCA-positive RPGN. In addition, features of renal histological lesions between patients with ANCA-associated RPGN with various ANCA test results have also been analyzed to seek any particular histopathologic signature in renal biopsies which could be associated with ANCA serology.

   Materials and Methods Top

We retrospectively reviewed the records for all patients whose renal biopsies were referred to the department of immunopathology during 8-year study period (1999-2006). A total of 2 627 renal biopsies were received in the department during this time. Those biopsies that were dried up (i.e., not received in holding fluid)/formalin fixed (119 biopsies), or were inadequate/non-representative (358 biopsies) were excluded. From the remaining 2 150 biopsies, we searched for all the patients in whom pauci-immunity was concluded on direct immunofluorescence examination of renal biopsies and that presented with RPGN [Table 1]. The cases of lupus nephritis, Henoch-Schonlein purpura, and cases with non-glomerular pathology were therefore excluded.
Table 1: Histopathological diagnosis on the basis of renal biopsy findings in patients with pauci-immune rapidly progressive glomerulonephritis

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Renal Histopathology

Formalin-fixed paraffin-embedded sections were stained with silver, periodic acid-Schiff, and hematoxylin and eosin (H and E) stains. These biopsies were re-evaluated by an expert nephropathologist and various histopathological parameters were noted. In short, each glomerulus was examined separately for the presence of crescents (cellular, fibrocellular, fibrous), glomerulosclerosis (segmental/global), fibrinoid necrosis, intraglomerular fibrosis, periglomerular fibrosis, periglomerular infiltrates, granulomatous reactions, and a number of other lesions [Table 2]. The presence of glomerular lesions was calculated as the percentage of the total number of glomeruli in a biopsy. Most interstitial, tubular, and vascular lesions were scored as present or absent except for interstitial inflammation (mild/moderate/severe) and tubular atrophy (focal/diffuse) which were scored semiquantitatively [Table 3]. Together, 27 histological parameters were examined. The data were represented as mean ± SD. One-way ANNOVA and Pearson Chi square tests were used for statistical analysis. We have also tried to categorize the ANCA-associated glomerulonephritis according to classification schema proposed by Berden et al. [1]
Table 2: Detailed glomerular features in pauci-immune rapidly progressive glomerulonephritis (48 cases)

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Table 3: Other histological parameters in pauci-immune rapidly progressive glomerulonephritis (48 cases)

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Direct Immunofluorescence of Renal Biopsies

All the biopsies were obtained in holding fluid. Optimally diluted fluorescein isothiocyanate-labeled monospecific immunoglobulins (IgG, IgA, IgM), C3, and fibrin were layered onto the frozen sections embedded in OCT (optimal cutting temperature) medium and incubated at 37°C for 45 minutes to 1 hour. Then, the sections were washed in PBS (phospahate buffered saline pH 7.2, 0.1 M) thrice and mounted in buffered glycerin and finally viewed under a Nikon OPTOHOT-2, UV microscope. The pauci-immunity pattern, as first described by Jennette et al., [2] was concluded by the presence of <2+ glomerular immunostaining for immunoglobulins.

ANCA Assay

ANCA was tested using an IIF (indirect immunofluorescence) assay with "in house" ethanol-fixed neutrophil preparations in all the cases. The staining patterns were scored as cytoplasmic (C-ANCA), perinuclear (P-ANCA), or negative. More recently, as they have only now become routinely available, ANCA subsets, i.e., myeloperoxidase-ANCA (MPO-ANCA) and proteinase 3-ANCA (PR3-ANCA), were looked for in only 11 patients.

   Results Top


Sixty-eight potential cases of pauci-immune RPGN were identified that constituted 3% of the total renal biopsies referred to our department during 8-year study period. Of these 68 biopsies, 20 were referred from outside only for immunopathological analysis and so histopathology slides were not available for complete evaluation, thereby excluding them from the final analysis. The study group comprised of 48 cases [Figure 1] and of these, four belonged to the pediatric population (0-14 years of age). Mean age of P-ANCA-positive patients, C-ANCA-positive patients, and ANCA-negative patients was 47.9 ± 18.3 years, 45.6 ± 13.9 years, and 34.2 ± 15.9 years, respectively. The male to female ratio was 1.4:1.
Figure 1: Histopathological diagnoses on the basis of renal biopsy findings

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Histopathological Diagnosis

[Table 1] shows the histopathological diagnosis on the basis of renal biopsy findings. Of 48 cases of pauci-immune RPGN, crescentic glomerulonephritis [Figure 2] was reported in 26 biopsies (54%) and necrotizing crescentic GN [Figure 3] in 13 (27%). Three biopsies were interpreted as membranoproliferative GN, not otherwise specified (NOS) and three as diffuse global glomerulosclerosis; other biopsies included crescentic GN with interstitial vasculitis (2) and crescentic GN with tubulointerstitial nephritis (1).
Figure 2: Photomicrograph of crescentic glomerulonephritis showing glomeruli with global circumferential cellular crescent with glomerulitis. The underlying glomerular tuft is compressed (periodic acid Schiff, ×200)

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Figure 3: Photomicrograph of necrotizing crescentic glomerulonephritis showing glomerulus with segmental necrotizing lesion along with vasculitis of interstitial blood vessel (H and E, ×400)

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Histological Parameters in All Patients (48 cases)

The histological analysis showed that only 17% biopsies showed normal glomeruli with proportion of normal glomeruli varying from 5 to 33% per biopsy. Cellular and fibrous crescents were seen in 77% and 31% biopsies, respectively. Fibrinoid necrosis ofthe glomerular tuft was present in 33% of biopsies. In nine biopsies, fibrinoid necrosis was present in glomeruli without crescents, although crescents were found in other glomeruli in the same biopsy. Tubular casts and tubular necrosis were present in 66% and 8% of biopsies, respectively. Tubular atrophy was present in 46% of biopsies and in 19% cases, it was scored as diffuse (+++). Interstitial inflammatory infiltrates were present in 94% of biopsies; 36% of these were scored as mild (+) and 33% as severe (++). Mononuclear inflammatory cells were always present and usually formed the predominant part of infiltrates. Neutrophils were present in 21% of biopsies but predominant in only two cases. Eosinophils were seen in 12.5% of biopsies, but were never scored as predominant. Plasma cells were present in 10% of biopsies and formed the predominant cell population in two biopsies. Interstitial fibrosis was present in 40% of biopsies and in 4% was scored as diffuse. Interstitial vasculitis was present in only 6% of biopsies. Granuloma formation was seen in only three cases, in two cases in the interstitium and in one case in both glomeruli as well as the interstitium. Pauci-immunity was concluded in all the cases.

ANCA Serology in Patients of Pauci-immune RPGN

Among the 48 patients with pauci-immune RPGN, ANCA assay results by IIF were positive in 27 patients. Of these, 13 had the cytoplasmic staining ANCA (C-ANCA) and 14 perinuclear staining ANCA. Twenty-one patients (44%) had negative ANCA test results despite repeat testing. Of 11 patients where enzyme-linked immunosorbent assays (ELISAs) for MPO-ANCA and PR3-ANCA were performed [Table 2], [Table 3], [Table 4], PR3-ANCA was positive in five and MPO-ANCA in three patients. In these 11 patients, IIF and ELISA results were comparable.
Table 4: Comparative distribution of main glomerular lesions in P-ANCA positive, C-ANCA positive, and ANCA negative cases of pauci-immune rapidly progressive glomerulonephritis (48 cases)

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Differences Between P-ANCA-positive, C-ANCA-positive, and ANCA-negative renal biopsies

The occurrence of main glomerular lesions [Table 4] was similar in all the 3 groups (P value more than 0.05 in all). In patients with P-ANCA positivity, diffuse tubular atrophy was more frequently and more severely present than C-ANCA-positive and ANCA-negative patients (P value=0.013). Interstitial vasculitis was found in only three ANCA-positive GN and medullary angiitis in one case of C-ANCA-positive GN. Granulomas were noted in only three cases of P-ANCA-positive GN.

Categorization of ANCA-associated Glomerulonephritis (48 cases) According to Berden et al. Classification Schema [1]

As shown in [Table 5], maximum cases (27) fell into crescentic class while only four were in the sclerotic class. Focal class was not found in our study group as proportion of normal glomeruli (present in eight cases) per biopsy was in the range of 5 to 33% only (<50%).
Table 5: Classification of ANCA-associated glomerulonephritis

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   Discussion Top

This paper provides information that pauci-immune RPGN (irrespective of ANCA status) is apparently a rare disorder in patients who are attending the nephrology clinic at our tertiary care center and undergoing renal biopsy, constituting only 2% of all renal biopsies submitted.

The histopathological findings of ANCA-related vasculitis in the kidney are considered to show a variety of lesions, of which crescentic and/or focal necrotizing GN as well as small vessel arteritis are the most prominent. [4] In some cases, extensive glomerulosclerosis is found. [5] In our study, 42/48 (87%) showed features of crescentic GN on renal histology (In addition, 13 cases showed necrosis of the glomerular tuft and two cases showed interstitial vasculitis). The remaining six cases showed varied histopathologic picture as shown in [Table 1], which is consistent with previous studies. [6]

Forty-eight cases (2% of all renal biopsies submitted) included in the study were all ANCA associated. This figure of 2% underestimates the actual prevalence of ANCA-associated GN, largely because this analysis was done in the era when the more sensitive ELISAs for ANCA were not being performed in all cases at our center. Through this study, we would also emphasize that it is mandatory to have ANCA serology status during reporting of a kidney biopsy showing pauci-immune crescentic or necrotizing GN.

It is reported that approximately 80 to 90% of patients with pauci-immune glomerulonephritis had circulating ANCA and ANCA might play a major role in its pathogenesis. [7] However, in some patients with pauci-immune crescentic glomerulonephritis, serum ANCA was found to be negative. Chen et al. [8] have found that in their study cohort, 32.9% of patients of pauci-immune crescentic GN were ANCA negative. We have reported a slightly higher proportion of ANCA-negative pauci-immune GN cases (43.7%). This discrepancy might be due to the fact that ELISAs were done only in a limited number of patients as already discussed. ANCA-negative patients in their study were much younger (39.7 ± 17) than the ANCA-positive patients. Similar observation was also noted in our study. Compared with ANCA-positive patients, the ANCA-negative patients were much younger (46.85 ± 16.12 years vs. 34.28 ± 15.94 years). Chen et al. have also showed that ANCA-negative patients in their study tended to have more severe lesions on glomeruli (fewer normal glomeruli) that might be contributing to poorer renal outcome of ANCA-negative patients than ANCA-positive ones. Eisenberger et al. [9] have investigated 20 patients of ANCA-negative pauci-immune crescentic glomerulonephritis and found that chronic lesions, including interstitial fibrosis and glomerulosclerosis, were more prominent in ANCA-negative patients. We did not find any significant differences in renal pathology between ANCA-positive and ANCA-negative patients.

The extensive histologic analysis of P-ANCA-positive, C-ANCA-positive, and ANCA-negative kidney biopsies showed that there was no significant difference in the main glomerular lesions, tubular as well as interstitial histologic features between these three groups, but patients with P-ANCA positivity had significantly more tubular atrophy. Hauer et al. [6] have also reported that patients with MPO-ANCA had significantly more glomerulosclerosis, interstitial fibrosis, tubular atrophy, and tubular necrosis. Franssen et al. [10] have found that patients with PR3-ANCA positivity had more fibrinoid necrosis and a higher activity index, whereas the patients with MPO-ANCA positivity had more glomerulosclerosis and a higher chronicity index. By contrast, other studies have reported contradictory results or no differences between the groups. [6],[11],[12]

The biggest drawback of the study is that it falls short of completing the comparisons with other studies in extra-renal manifestations, treatment response, and final outcome of the cases which can form the basis of future studies.

Berden et al. [1] have proposed a histologic classification of ANCA-associated glomerulonephritis as it facilitates recognition of cases that will respond to aggressive therapy vs. those who will not and will have to resort to renal transplantation earlier. [1] This classification also conveys the importance of including vascular and tubulointerstitial involvement of the renal biopsy in ANCA-associated vasculitides. From our study, it emerges that predominantly our ANCA-associated cases fell into the crescentic and mixed classes, described by Berden et al. Focal category of ANCA-associated GN was not found in our ANCA-positive cases.

We propose that renal histology reporting of ANCA-associated GN should be done according to the proposal of Berden et al. and this will facilitate uniform reporting between centers.

   References Top

1.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.  Back to cited text no. 1
2.Jennette JC, Wilkman AS, Falk RJ. Antineutrophil cytoplasmic auto-antibody associated glomerulonephritis and vasculitis. Am J Pathol 1989;135:921-30.  Back to cited text no. 2
3.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.  Back to cited text no. 3
4.Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: Proposal of an international consensus committee. Arthritis Rheum 1994;37:187-92.  Back to cited text no. 4
5.Bajema IM, Hagen EC, van der Woude FJ, Bruijn JA. Wegener's granulomatosis: A meta-analysis of 349 literary case reports. J Lab Clin Invest 1997;129:17-22.  Back to cited text no. 5
6.Hauer HA, Bajema IM, van Houwelingen HC, Ferrario F, Noel LH, Waldherr R, et al. Renal histology in ANCA-associated vasculitis: Differences between diagnostic and serologic subgroups. Kidney Int 2002;61:80-9.  Back to cited text no. 6
7.Jennette JC, Falk RJ. The pathology of vasculitis involving the kidney. Am J Kidney Dis 1994;24:130-41.  Back to cited text no. 7
8.Chen M, Yu F, Su-Xia Wang, Wan-Zhong Zou, Ming-Hui Zhao, Hai-Yan Wang. Antineutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis. J Am Soc Nephrol 2007;18:599-605.  Back to cited text no. 8
9.Eisenberger U, Fakhouri F, Vanhille P, Beaufils H, Mahr A, Guillevin L, et al. ANCA-negative pauciimmune renal vasculitis: Histology and outcome. Nephrol Dial Transplant 2005;20:1392-9.  Back to cited text no. 9
10.Franssen CF, Stegeman CA, Kallenberg CG, Gans RO, de Jong PE, Hoorntje SJ, et al. Antiproteinase 3 and antimyeloperoxidase associated- vasculitis. Kidney Int 2000;57:2195-206.  Back to cited text no. 10
11.Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989;135:921-30.  Back to cited text no. 11
12.Fienberg R, Mark EJ, Goodman M, McCluskey RT, Niles JL. Correlation of antineutrophil cytoplasmic antibodies with the extrarenal histopathology of Wegener's (pathergic) granulomatosis and related form of vasculitis. Hum Pathol 1993;24:160-8.  Back to cited text no. 12

Correspondence Address:
Seema Chhabra
Department of Immunopathology, PGIMER, Chandigarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.94850

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  [Table 3], [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 4], [Table 5]

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