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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 63  |  Issue : 2  |  Page : 226-229
Anti-glomerular basement membrane disease: A clinicomorphological study of 16 cases


1 Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
2 Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India

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Date of Web Publication18-Apr-2020
 

   Abstract 


Introduction: Antiglomerular basement membrane disease manifests as rapidly progressive glomerulonephritis and alveolar hemorrhage. It encompasses 10–15% of crescentic glomerulonephritis and is associated with poor outcome. In this study, we have elaborated on the clinical details, morphological features, and outcome of anti-GBM glomerulonephritis. Materials and Methods: All the consecutive biopsy-proven cases of anti-GBM glomerulonephritis over a period of 4½ years were analyzed, retrospectively. Results: Sixteen cases were diagnosed as anti-GBM glomerulonephritis during the study period. Twelve patients presented with rapidly progressive renal failure of which four patients required hemodialysis at the time of presentation. Goodpasture's syndrome was noted in two patients. Thirteen cases were positive for circulating anti-GBM antibodies and two patients showed double positivity for both anti-GBM antibodies and ANCA. Fifteen biopsies revealed crescentic glomerulonephritis with linear deposition of IgG along the glomerular basement membrane in all the 16 cases. Conclusion: Renal biopsy analysis is important in the diagnosis of Anti GBM nephritis. Morphology is an important predictor of disease progression.

Keywords: Anti GBM antibody disease, crescentic glomerulonephritis, rapidly progressive glomerulonephritis

How to cite this article:
Vavilapalli S, Madireddy N, Uppin MS, Kalidindi K, Gudithi S, Taduri G, Raju SB. Anti-glomerular basement membrane disease: A clinicomorphological study of 16 cases. Indian J Pathol Microbiol 2020;63:226-9

How to cite this URL:
Vavilapalli S, Madireddy N, Uppin MS, Kalidindi K, Gudithi S, Taduri G, Raju SB. Anti-glomerular basement membrane disease: A clinicomorphological study of 16 cases. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 May 27];63:226-9. Available from: http://www.ijpmonline.org/text.asp?2020/63/2/226/282713





   Introduction Top


Anti-glomerular basement membrane (GBM) disease is a rare autoimmune disorder that most commonly presents as rapidly progressive renal failure.[1],[2],[3] It can present either as isolated glomerulonephritis or as Goodpasture's syndrome wherein it is accompanied by pulmonary haemorrhage. Binding of the IgG autoantibodies to the non-collagenous domain of the α3 chain of type IV collagen has been established as the underlying pathogenesis of Anti-GBM disease[4],[5],[6] Anti-GBM glomerulonephritis is characterized by circulating anti-GBM antibodies, necrotizing glomerulonephritis, and linear deposits of IgG along the capillary walls. Totally, 95% of the cases have crescents at the time of diagnosis and often lead to end-stage renal disease. Despite aggressive treatment with immunosuppressive agents and plasmapheresis, most cases rapidly progress to end-stage renal disease (ESRD) and require renal replacement therapy.[4],[5],[6] However, studies conducted in the past decade have suggested that timely diagnosis is highly pivotal and can improve the overall survival of the patients. In this study, we have tried to study the clinical details, morphological features, and outcome of anti-GBM glomerulonephritis.


   Materials and Methods Top


This was a retrospective study including 16 consecutive biopsy-proven cases of anti-GBM glomerulonephritis over a period of 4½ years from January 2014 to June 2018.

Patient characteristics

The demographic and clinical data including age, gender, clinical presentation, presence or absence of pulmonary hemorrhage, serum creatinine levels, serum anti-GBM antibody levels, ANCA status, treatment, and follow up data were retrieved from the medical records.

Histopathological evaluation

The biopsies were evaluated by light microscopy with the help of hematoxylin and eosin, Periodic acid Schiff, Masson Trichrome and Jones Methenamine Silver. All the glomerular, tubular, interstitial, and vascular features were carefully examined. The percentage and character of glomerular crescents were recorded in all the cases. Crescents were characterized as cellular when more than 50% of the lesion is occupied by cells, fibrocellular when composed of less than 50% cells but less than 90% fibrous matrix and as fibrous when composed of more than 90% fibrous matrix. Immunofluorescence was performed in all cases with the help of FITC tagged antibodies to IgM, IgA, IgG, C3, C1q and kappa and lambda chains.

Treatment

All the cases were treated with plasmapheresis, corticosteroids, and cyclophosphamide.


   Results Top


Over the study period, 82 cases of crescentic glomerulonephritis were identified of which 16 cases were diagnosed as ant-GBM glomerulonephritis.

Demographic and clinical data of the patients

Of the 16 biopsies included in this study, there were 10 female and 6 male patients. The mean age at the time of biopsy was 38.69 ± 15.72 years and 9 of these were below 20 years of age. The mean serum creatinine level at the time of biopsy was 11.52 ± 6.67 mg/dl. The urine examination showed macroscopic haematuria in all. Twelve patients presented with rapidly progressive renal failure of which four patients required hemodialysis at the time of presentation. Goodpasture's syndrome i.e., concomitant pulmonary hemorrhage was observed in two patients. Thirteen cases were positive for circulating anti-GBM antibodies (Mean titre of 342.4) whereas the serum anti-GBM antibody titre was normal in two other patients. Two patients showed double positivity for both anti-GBM antibodies and ANCA. These two patients had perinuclear-ANCA on IF and were anti-myeloperoxidase [anti-MPO] positive by ELISA with titres > U.

Histomorphological features

Fifteen biopsies showed features of crescentic glomerulonephritis (i.e., ≥50% of glomeruli showed crescents). One biopsy did not have glomeruli in the tissue sent for light microscopy. Of the 15 biopsies, nine biopsies showed circumferential cellular crescents, four showed fibrocellular crescents and fibrous crescents were observed in two biopsies. Glomerular tuft necrosis was seen in two patients (12.5%) and two patients showed pANCA positivity. Four biopsies showed the presence of neutrophils within the crescents and two biopsies showed periglomerular giant cells and granuloma. Acute tubular necrosis, interstitial inflammation, and edema were seen in all the biopsies [Figure 1].
Figure 1: (a) Glomerulus showing a circumferential cellular crescent. (b) Glomerular tuft necrosis (c) Presence of giant cells within the crescent forming periglomerular granuloma (d) Linear staining for IgG along the basement membrane

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Although one biopsy had no glomeruli in the tissue submitted for light microscopy, immunofluorescence revealed linear deposition of IgG along the glomerular basement membrane in all the 16 cases.

Treatment and follow-up

Eleven patients expired. One patient responded to treatment and is doing well with a serum creatinine of 1.2 mg/dl. Three patients are dialysis dependent. A 16-year-old girl received a live related renal transplant with mother as a donor after 6 months of diagnosis and is doing well with a good baseline serum creatinine of 0.8 mg/dl. Of the two patients with ANCA positivity, one patient is dialysis dependent and the other patient has received immunosuppression and is doing well. The clinical data, biopsy features, and follow-up details of all the 16 patients have been depicted in [Table 1].
Table 1: The clinical and biopsy features and follow up of all patients of Anti-GBM disease

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   Discussion Top


Anti-GBM disease is an aggressive autoimmune disease which can affect both renal and pulmonary capillaries and manifest as rapidly progressive glomerulonephritis and alveolar hemorrhage, respectively.[7],[8],[9],[10],[11],[12] It accounts for 10–15% of crescentic glomerulonephritis and is associated with extremely poor prognosis with most patients requiring dialysis or renal replacement therapy despite aggressive treatment.[3],[12],[13]

In our study, we describe a series of 16 cases of biopsy-proven anti-GBM glomerulonephritis, of which 12 patients presented with rapidly progressive renal failure. Several studies have shown that isolated Anti-GBM glomerulonephritis is much more common than Goodpasture's syndrome.[3],[8] However a retrospective study conducted by in Lazor et al.[14] showed that 75% of cases of anti-GBM diseases presented with alveolar hemorrhage. In our study, only two cases presented with pulmonary hemorrhage and were thus categorized as Goodpasture's syndrome.

Retrospective studies have shown that the peak incidence of anti-GBM antibody disease seems to be in the fourth decade with a female predominance. A previous study from India has shown that the mean age of onset was 33.4 ± 13.2 years with male predominance (16:2).[11] In our study, the mean age of presentation was 38.69 ± 15.72 (9-65) years, and there was a slight female predominance (M: F = 2:3). This observation was in concordance with the retrospective study conducted by Fischer and Langer[6] which also showed slight female predominance (M:F =1:1.3).

Several studies have stated that serum creatinine levels higher than 5 mg/dl are associated with adverse outcomes.[12],[13],[15] In our study the mean serum creatinine level at the time of biopsy was 11.52 ± 6.67 mg/dl with high disease-related mortality. This further explains the aggressive nature of the disease.

Anti-GBM is the most aggressive form of glomerulonephritis with more than 85% cases showing crescentic glomerulonephritis i.e., >% glomerular crescents.[3],[5],[6],[7],[8],[9],[10],[11],[12] Several studies have identified a strong correlation between the percentage of glomerular crescents and renal outcome.[5],[7],[12],[15],[16],[17] In our study, we observed crescentic glomerulonephritis in 15/16 biopsies of which four cases showed crescents in all the glomeruli. Nine of these cases showed cellular crescents, four fibrocellular and two fibrous crescents.

In a morphological study conducted by Fisher and Lager[6] glomerular tuft necrosis was identified in 88% of the cases and an Indian study conducted by Gupta et al.[12] showed glomerular tuft necrosis in 57.4% of the cases. It was however identified in only 2 of our biopsies.

Periglomerular granulomas are most commonly observed in Wegener's granulomatosis and polyarteritis nodosa however, they can be encountered in any type of severe necrotizing glomerulonephritis including any kind of ANCA positive glomerulonephritis as well as anti-GBM glomerulonephritis.[3] In our study, we had two cases showing periglomerular granulomas. In a study conducted by Rutger et al.[18] it was concluded that periglomerular granulomas were seen only in cases with double positivity for MPO and ANCA, however, no such association was observed in our study. Likewise, Fischer and Lager[6] also reported periglomerular granulomas in 10% of the cases in anti-GBM disease without any ANCA positivity.

Dalen et al.[7] conducted a study on the outcome of anti-GBM glomerulonephritis and identified the extent of interstitial inflammation as one of the factors associated with progression to ESRD. Interstitial inflammation and edema were observed in all 16 cases included in our study.

Presence of these varied morphologic features emphasizes the importance of performing a renal biopsy in suspected patients of Anti-GBM nephritis. The morphology has a direct bearing on the prognosis of the patients and immediate immunofluorescence can yield an early and accurate diagnosis especially in cases where serum Anti-GBM titres are false positive. Immunofluorescence studies demonstrate continuous linear immunostaining of the glomerular capillaries for IgG which is often accompanied by focal linear staining for C3.[5],[7],[12] In our cohort all 16 cases showed linear deposition of IgG along the glomerular basement membrane.

Dual positivity for anti-GBM antibody and ANCA is seen 20–25% of the cases anti-GBM glomerulonephritis with a majority being anti-MPO positive and often associated with vasculitis.[17],[18],[19] The results regarding the impact of dual positivity on the renal outcome are conflicting. While Rutgers et al.[18] observed no significant difference in the 1-year survival of patients with dual positivity and those with anti-GBM antibodies alone, Bosch et al.[19] implied that the concomitant presence of ANCA along with anti-GBM antibodies is a good prognostic factor. However several other studies have reported that a dual positivity is associated with poor prognosis.[3],[13],[17],[20] In our study we had two patients showing dual positivity for ANCA and anti-GBM antibody in our study, while one patient responded to treatment and attained normal renal function the other patient is dialysis dependent.

Anti-GBM glomerulonephritis is characterized by the presence of circulating anti-GBM antibodies, however, Nasr et al.[21] and Troxelland Houghton[22] reported atypical forms of anti-GBM glomerulonephritis which had linear deposits IgG antibodies but no circulating anti-GBM antibodies. Extremely few cases have been reported in the literature and seem to have an indolent course. However further studies are required to understand the clinicopathological features of these cases.

Anti-GBM glomerulonephritis is a rare but fulminant form of glomerulonephritis associated with poor renal outcome. Most of the patients rapidly progress to renal failure and the response to current treatment strategies is not satisfactory. The presence of elevated serum creatinine levels and percentage of glomerular crescents are associated with poor prognosis. The current modalities of treatment of anti-GBM glomerulonephritis include corticosteroids, plasmapheresis, and cyclophosphamide. Moderate success rates have been achieved when all three modalities were used in combination. Thus an early diagnosis is highly pivotal to improve the renal outcome of these patients and further studies are required to identify new treatment modalities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Megha S Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta - 500 082, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_712_18

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