|Year : 2020 | Volume
| Issue : 2 | Page : 226-229
|Anti-glomerular basement membrane disease: A clinicomorphological study of 16 cases
Srinivasrao Vavilapalli1, Nishika Madireddy1, Megha S Uppin1, Karthik Kalidindi2, Swarnalatha Gudithi2, Gangadhar Taduri2, Sree Bhushan Raju2
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
Click here for correspondence address and email
|Date of Web Publication||18-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 30];63:226-9. Available from: http://www.ijpmonline.org/text.asp?2020/63/2/226/282713
| Introduction|| |
Anti-glomerular basement membrane (GBM) disease is a rare autoimmune disorder that most commonly presents as rapidly progressive renal failure.,, 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,, 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.,, 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|| |
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.
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.
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.
All the cases were treated with plasmapheresis, corticosteroids, and cyclophosphamide.
| Results|| |
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.
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|
Click here to view
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|
Click here to view
| Discussion|| |
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.,,,,, 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.,,
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., However a retrospective study conducted by in Lazor et al. 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). 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 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.,, 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.,,,,,,,, Several studies have identified a strong correlation between the percentage of glomerular crescents and renal outcome.,,,,, 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 glomerular tuft necrosis was identified in 88% of the cases and an Indian study conducted by Gupta et al. 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. In our study, we had two cases showing periglomerular granulomas. In a study conducted by Rutger et al. 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 also reported periglomerular granulomas in 10% of the cases in anti-GBM disease without any ANCA positivity.
Dalen et al. 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.,, 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.,, The results regarding the impact of dual positivity on the renal outcome are conflicting. While Rutgers et al. observed no significant difference in the 1-year survival of patients with dual positivity and those with anti-GBM antibodies alone, Bosch et al. 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.,,, 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. and Troxelland Houghton 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
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am SocNephrol 1999;10:2446-53.
McAdoo SP, Pusey CD. Anti-glomerular basement membrane disease. Clin J Am SocNephrol 2017;12:1162-72.
Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003;63:1164-77.
Tang W, McDonald SP, Hawley CM, Badve SV, Boudville NC, Brown FG, et al
. Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease. Kidney Int 2013:83:503-10.
Alchi B, Griffiths M, Sivalingam M, Jayne D, Farrington K. Predictors of renal and patient outcomes in anti-GBM disease: Clinicopathologic analysis of two-centre cohort. Nephrol Dial Transplant 2015;30:814-21.
Fischer EG, Lager DJ. Anti-glomerular basement membrane glomerulonephritis: A morphologic study of 80 cases. Am J Clin Pathol 2006;125:445-50.
van Daalen EE, Jennette JC, McAdoo SP, Pusey CD, Alba MA, Poulton CJ, et al
. Predicting the outcome in patients with anti-GBM glomerulonephritis. Clin J Am Soc Nephrol 2018;13:63-72.
Canney M, O'Hara PV, McEvoy CM, Medani S, Connaughton DM, Abdalla AA, et al
. Spatial and temporal clustering of anti-glomerular basement membrane disease. Clin J Am Soc Nephrol 2016;11:1392-9.
Savage CO, Pusey CD, Bowman C, Rees AJ, Lockwood CM. Antiglomerular basement membrane antibody mediated disease in the British Isles 1980-4. Br Med J (Clin Res Ed) 1986;292:301-4.
Wilson CB, Dixon FJ. Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney Int 1973;3:74-89.
Ahmad M, Sharma RK, Gupta A, Gulati S, Kumar A, Prasad N, et al
. Anti-glomerular basement disease – An Indian scenario. Indian J Nephrol 2004;14:182-6.
Gupta A, Agrawal V, Kaul A, Verma R, Pandey R. Anti-glomerular basement membrane crescentic glomerulonephritis: A report from India and review of literature. Indian J Nephrol 2016;26:335-9.
] [Full text]
Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033-42.
Lazor R, Bigay-Gamé L, Cottin V, Cadranel J, Decaux O, Fellrath JM, et al
. Alveolar hemorrhage in anti-basement membrane antibody disease. Medicine 2007;86:181-93.
Herody M, Bobrie G, Gouarin C, Grünfeld JP, Noel LH. Anti-GBM disease: Predictive value of clinical, histological and serological data. Clin Nephrol 1993;40:249-55.
Walker RJ, Scheinkestel C, Becker GJ, Owen JE, Dowling JP, Smith PK. Clinical and morphological aspects of the managment of crescentic anti-glomerular basement membrane antibody (Anti-GBM) nephritis/Goodpasture's syndrome. Q J Med 1985;54:75-89.
Lindic J, Vizjak A, Ferluga D, Kovac D, Ales A, Kveder R, et al.
Clinical outcome of patients with coexistent antineutrophil cytoplasmic antibodies and antibodies against glomerular basement membrane. Ther Apher Dial 2009;13:278-81.
Rutgers A, Slot M, van Paassen P, van Breda Vriesman P, Heeringa P, Tervaert JW. Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis. Am J Kidney Dis 2005;46:253-62.
Bosch X, Mirapeix E, Font J, Borrellas X, Rodríguez R, López-Soto A. Prognostic implication of anti-neutrophil cytoplasmic autoantibodieswith myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol 1991;36:107-13.
Cui Z, Zhao J, Jia XY, Zhu SN, Jin QZ, Cheng XY, et al
. Anti-glomerular basement membrane disease: Outcomes of different therapeutic regimens in a large single-center Chinese cohort study. Medicine (Baltimore) 2011;90:303-11.
Nasr SH, Collins AB, Alexander MP, Schraith DF, Herrera Hernandez L, Fidler ME, et al
. The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis. Kidney Int 2016;89:897-908.
Troxell ML, Houghton DC. Atypical anti-glomerular basement membrane disease. Clin Kidney J 2015;9:211-21.
Megha S Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta - 500 082, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
| Article Access Statistics|
| Viewed||266 |
| Printed||2 |
| Emailed||0 |
| PDF Downloaded||26 |
| Comments ||[Add] |