Renal biopsy lesions in primary glomerular diseases with deposits

Renal biopsy lesions in primary glomerular diseases with deposits The classic approach to renal pathology has been one of morphology, based on light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM), integrated with clinical findings. As our understanding of glomerular disease expands, we move toward pathogenesis as an approach to diagnosis. Immunoglobulin A (IgA) nephropathy is defined by dominant or codominant IgA staining by IF compared with other immunoglobulin staining. LM findings are variable, from minimal mesangial expansion to diffuse endocapillary hypercellularity, crescents and glomerulosclerosis. Mesangial deposits are present by EM. Subendothelial deposits may be present, particularly in more active disease. The pathogenesis of IgA nephropathy has been described as antibodies (IgG or IgA) targeting the galactose-deficient hinge region of IgA1 [1]. However, there are no markers of pathogenesis to distinguish it from other causes of dominant IgA deposition. The Oxford IgA nephropathy classification defined morphologic findings for prognosis based on LM lesions [2]. Bad prognostic markers include significant mesangial proliferation, endocapillary hypercelluarity, segmental sclerosis and significant tubulointerstitial fibrosis (MEST), and recently crescents also have been determined to influence prognosis and response to treatment [3]. Membranous nephropathy is defined by subepithelial immune complex deposits. During different stages of membranous nephropathy, deposits give the appearance of holes and spikes along the glomerular basement membrane on silver stain by LM. IF shows granular staining along capillary loops for polyclonal IgG. The differentiation between apparent primary and extrarenal etiologies for membranous nephropathy is important to direct treatment. M-type phospholipase A2 receptor (PLA2R) is the target antigen in 70% of patients with membranous nephropathy without apparent extrarenal cause, with additional rare cases having autoantibodies to thrombospondin type-1 domain-containing 7 A (THSD7A) [4, 5]. Multiple secondary etiologies have now been associated with positive PLA2R staining, such as e.g. sarcoidosis and non-steroidal anti-inflammataory drugs (NSAIDs). Thus, PLA2R staining in itself does not definitively define pathogenesis. Membranoproliferative glomerulonephritis (MPGN) is a lesion defined by subendothelial and mesangial deposits with endocapillary hypercellularity and double contours of glomerular basement membranes. The specific morphologic appearance and IF staining varies according to the specific pathogenesis. MPGN may occur due to polyclonal immune complex (e.g. lupus full-house pattern), monoclonal protein (proliferative glomerulonephritis with monoclonal deposits) or complement (C3 glomerulopathies, C3GP) deposition. C3GP is defined by strong C3 staining, at least two intensities greater than immunoglobulin and C1q [6]. C3GP is further defined by the morphology of deposits by EM with the presence (dense deposit disease, Figure 1) or absence (C3 glomerulonephritis) of dense transformation of the glomerular basement membrane lamina densa. Further pathogenesis is determined through laboratory and genetic studies to identify specific points of dysregulation in the complement alternative pathway that are causal in the C3 deposition. FIGURE 1 View largeDownload slide Dense deposit disease with membranoproliferative pattern of injury by LM (A, Jones’ silver stain, ×400, original magnification), and strong C3 globular mesangial and ribbon-like capillary loop staining by IF (B, IF microscopy, anti–C3, ×200, original magnification) with corresponding globular mesangial deposits and dense transformation of the glomerular basement membrane by EM (C, electron microscopy, ×3500, original magnification). FIGURE 1 View largeDownload slide Dense deposit disease with membranoproliferative pattern of injury by LM (A, Jones’ silver stain, ×400, original magnification), and strong C3 globular mesangial and ribbon-like capillary loop staining by IF (B, IF microscopy, anti–C3, ×200, original magnification) with corresponding globular mesangial deposits and dense transformation of the glomerular basement membrane by EM (C, electron microscopy, ×3500, original magnification). Other rare diseases previously recognized by organized deposits, and differentiated by the substructure in deposits, such as fibrillary glomerulonephritis and immunotactoid glomerulopathy, are now on the verge of molecular characterization. Fibrillary glomerulonephritis is defined by randomly oriented fibrils by EM that stain with polyclonal IgG by IF and are Congo red negative (Figure 2). DNAJB9 has recently been recognized as a characteristic component of deposits in fibrillary glomerulonephritis by immunohistochemistry staining [7]. The triggers for the autoantibody formation remain unknown. FIGURE 2 View largeDownload slide Fibrillary glomerulonephritis with mesangial proliferation by LM (A, Jones’ silver stain, ×400, original magnification), and polyclonal IgG smudgy mesangial and capillary loop staining by IF (B, IF microscopy, anti–IgG, ×200, original magnification) with corresponding mesangial and glomerular basement membrane deposition of randomly arranged fibrils with diameter of 18–28 nm by EM (C, electron microscopy, ×22 000, original magnification). FIGURE 2 View largeDownload slide Fibrillary glomerulonephritis with mesangial proliferation by LM (A, Jones’ silver stain, ×400, original magnification), and polyclonal IgG smudgy mesangial and capillary loop staining by IF (B, IF microscopy, anti–IgG, ×200, original magnification) with corresponding mesangial and glomerular basement membrane deposition of randomly arranged fibrils with diameter of 18–28 nm by EM (C, electron microscopy, ×22 000, original magnification). Taken together, molecular characterization of glomerular diseases can define specific etiologic agents, pathways of injury and specific disease mechanisms, which can lead to individualized patient therapies. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Berthoux F , Suzuki H , Thibaudin L et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy . J Am Soc Nephrol 2012 ; 23 : 1579 – 1587 Google Scholar CrossRef Search ADS PubMed 2 Roberts I , Cook HT , Troyanov S et al. The Oxford classification of IgA nephropathy: pathology definitions, correlations and reproducibility . Kidney Int 2009 ; 76 : 546 – 556 Google Scholar CrossRef Search ADS PubMed 3 Haas M , Verhave JC , Liu Z et al. A multicenter study of the predictive value of crescents in IgA nephropathy . J Am Soc Nephrol 2017 ; 28 : 691 – 701 Google Scholar CrossRef Search ADS PubMed 4 Beck LH , Bonegio RG , Lambeau G et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy . N Engl J Med 2009 ; 361 : 11 – 21 Google Scholar CrossRef Search ADS PubMed 5 Tomas NM , Beck LH , Meyer-Schwesinger C et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy . N Engl J Med 2014 ; 371 : 2277 – 2287 Google Scholar CrossRef Search ADS PubMed 6 Pickering MC , D'Agati VD , Nester CM et al. C3 glomerulopathy: consensus report . Kidney Int 2013 ; 84 : 1079 – 1089 Google Scholar CrossRef Search ADS PubMed 7 Nasr SH , Vrana JA , Dasari S et al. DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis . Kidney Int Rep 2018 ; 3 : 56 – 64 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Renal biopsy lesions in primary glomerular diseases with deposits

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Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
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1460-2385
D.O.I.
10.1093/ndt/gfy101
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Abstract

The classic approach to renal pathology has been one of morphology, based on light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM), integrated with clinical findings. As our understanding of glomerular disease expands, we move toward pathogenesis as an approach to diagnosis. Immunoglobulin A (IgA) nephropathy is defined by dominant or codominant IgA staining by IF compared with other immunoglobulin staining. LM findings are variable, from minimal mesangial expansion to diffuse endocapillary hypercellularity, crescents and glomerulosclerosis. Mesangial deposits are present by EM. Subendothelial deposits may be present, particularly in more active disease. The pathogenesis of IgA nephropathy has been described as antibodies (IgG or IgA) targeting the galactose-deficient hinge region of IgA1 [1]. However, there are no markers of pathogenesis to distinguish it from other causes of dominant IgA deposition. The Oxford IgA nephropathy classification defined morphologic findings for prognosis based on LM lesions [2]. Bad prognostic markers include significant mesangial proliferation, endocapillary hypercelluarity, segmental sclerosis and significant tubulointerstitial fibrosis (MEST), and recently crescents also have been determined to influence prognosis and response to treatment [3]. Membranous nephropathy is defined by subepithelial immune complex deposits. During different stages of membranous nephropathy, deposits give the appearance of holes and spikes along the glomerular basement membrane on silver stain by LM. IF shows granular staining along capillary loops for polyclonal IgG. The differentiation between apparent primary and extrarenal etiologies for membranous nephropathy is important to direct treatment. M-type phospholipase A2 receptor (PLA2R) is the target antigen in 70% of patients with membranous nephropathy without apparent extrarenal cause, with additional rare cases having autoantibodies to thrombospondin type-1 domain-containing 7 A (THSD7A) [4, 5]. Multiple secondary etiologies have now been associated with positive PLA2R staining, such as e.g. sarcoidosis and non-steroidal anti-inflammataory drugs (NSAIDs). Thus, PLA2R staining in itself does not definitively define pathogenesis. Membranoproliferative glomerulonephritis (MPGN) is a lesion defined by subendothelial and mesangial deposits with endocapillary hypercellularity and double contours of glomerular basement membranes. The specific morphologic appearance and IF staining varies according to the specific pathogenesis. MPGN may occur due to polyclonal immune complex (e.g. lupus full-house pattern), monoclonal protein (proliferative glomerulonephritis with monoclonal deposits) or complement (C3 glomerulopathies, C3GP) deposition. C3GP is defined by strong C3 staining, at least two intensities greater than immunoglobulin and C1q [6]. C3GP is further defined by the morphology of deposits by EM with the presence (dense deposit disease, Figure 1) or absence (C3 glomerulonephritis) of dense transformation of the glomerular basement membrane lamina densa. Further pathogenesis is determined through laboratory and genetic studies to identify specific points of dysregulation in the complement alternative pathway that are causal in the C3 deposition. FIGURE 1 View largeDownload slide Dense deposit disease with membranoproliferative pattern of injury by LM (A, Jones’ silver stain, ×400, original magnification), and strong C3 globular mesangial and ribbon-like capillary loop staining by IF (B, IF microscopy, anti–C3, ×200, original magnification) with corresponding globular mesangial deposits and dense transformation of the glomerular basement membrane by EM (C, electron microscopy, ×3500, original magnification). FIGURE 1 View largeDownload slide Dense deposit disease with membranoproliferative pattern of injury by LM (A, Jones’ silver stain, ×400, original magnification), and strong C3 globular mesangial and ribbon-like capillary loop staining by IF (B, IF microscopy, anti–C3, ×200, original magnification) with corresponding globular mesangial deposits and dense transformation of the glomerular basement membrane by EM (C, electron microscopy, ×3500, original magnification). Other rare diseases previously recognized by organized deposits, and differentiated by the substructure in deposits, such as fibrillary glomerulonephritis and immunotactoid glomerulopathy, are now on the verge of molecular characterization. Fibrillary glomerulonephritis is defined by randomly oriented fibrils by EM that stain with polyclonal IgG by IF and are Congo red negative (Figure 2). DNAJB9 has recently been recognized as a characteristic component of deposits in fibrillary glomerulonephritis by immunohistochemistry staining [7]. The triggers for the autoantibody formation remain unknown. FIGURE 2 View largeDownload slide Fibrillary glomerulonephritis with mesangial proliferation by LM (A, Jones’ silver stain, ×400, original magnification), and polyclonal IgG smudgy mesangial and capillary loop staining by IF (B, IF microscopy, anti–IgG, ×200, original magnification) with corresponding mesangial and glomerular basement membrane deposition of randomly arranged fibrils with diameter of 18–28 nm by EM (C, electron microscopy, ×22 000, original magnification). FIGURE 2 View largeDownload slide Fibrillary glomerulonephritis with mesangial proliferation by LM (A, Jones’ silver stain, ×400, original magnification), and polyclonal IgG smudgy mesangial and capillary loop staining by IF (B, IF microscopy, anti–IgG, ×200, original magnification) with corresponding mesangial and glomerular basement membrane deposition of randomly arranged fibrils with diameter of 18–28 nm by EM (C, electron microscopy, ×22 000, original magnification). Taken together, molecular characterization of glomerular diseases can define specific etiologic agents, pathways of injury and specific disease mechanisms, which can lead to individualized patient therapies. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Berthoux F , Suzuki H , Thibaudin L et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy . J Am Soc Nephrol 2012 ; 23 : 1579 – 1587 Google Scholar CrossRef Search ADS PubMed 2 Roberts I , Cook HT , Troyanov S et al. The Oxford classification of IgA nephropathy: pathology definitions, correlations and reproducibility . Kidney Int 2009 ; 76 : 546 – 556 Google Scholar CrossRef Search ADS PubMed 3 Haas M , Verhave JC , Liu Z et al. A multicenter study of the predictive value of crescents in IgA nephropathy . J Am Soc Nephrol 2017 ; 28 : 691 – 701 Google Scholar CrossRef Search ADS PubMed 4 Beck LH , Bonegio RG , Lambeau G et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy . N Engl J Med 2009 ; 361 : 11 – 21 Google Scholar CrossRef Search ADS PubMed 5 Tomas NM , Beck LH , Meyer-Schwesinger C et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy . N Engl J Med 2014 ; 371 : 2277 – 2287 Google Scholar CrossRef Search ADS PubMed 6 Pickering MC , D'Agati VD , Nester CM et al. C3 glomerulopathy: consensus report . Kidney Int 2013 ; 84 : 1079 – 1089 Google Scholar CrossRef Search ADS PubMed 7 Nasr SH , Vrana JA , Dasari S et al. DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis . Kidney Int Rep 2018 ; 3 : 56 – 64 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Apr 23, 2018

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