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Membranous Nephropathy Associated With Immunological Disorder-Related Liver Disease: A Retrospective Study of 10 Cases.

Dauvergne M, Moktefi A, Rabant M, Vigneau C, Kofman T, Burtey S, Corpechot C, Stehlé T, Desvaux D, Rioux-Leclercq N, Rouvier P, Knebelmann B, Boffa JJ, Frouget T, Daugas E, Jablonski M, Dahan K, Brocheriou I, Remy P, Grimbert P, Lang P, Chazouilleres O, Sahali D, Audard V - Medicine (Baltimore) (2015)

Bottom Line: AIH whether isolated (n = 3) or associated with PBC (n = 2) or PSC (n = 2) was the most frequent autoimmune liver disease.Seven of the 9 patients with available renal tissue specimens displayed enhanced expression of PLA2R in glomeruli whereas PLA2R was not expressed in liver parenchyma from these patients or in normal liver tissue.The study of immunoglobulin (Ig) subclasses of deposits in glomeruli revealed that the most frequent pattern was the coexistence of IgG1 and IgG4 immune deposits with IgG4 predominating.Detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic MN.

View Article: PubMed Central - PubMed

Affiliation: From the Service de Néphrologie et Transplantation (MD, TK, TS, PR, PG, PL, DS, VA), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Centre de référence maladie rare Syndrome Néphrotique Idiopathique, Institut Francilien de recherche en Néphrologie et Transplantation (IFRNT), DHU VIC (Virus-Immunité-Cancer), AP-HP (Assistance Publique-Hôpitaux de Paris), Université Paris Est Créteil (UPEC), Créteil, France; Equipe 21 (MD, AM, TK, TS, DD, PG, PL, DS, VA), INSERM Unité 955, Université Paris Est Créteil, Créteil, France; Département de Pathologie (AM, DD), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, AP-HP, UPEC, Créteil, France; Service d'Anatomie pathologique (MR), Hôpital Necker - Enfants Malades, AP-HP, Université Paris Descartes, Paris, France; CHU Pontchaillou (CV, TF), Service de Néphrologie, Université de Rennes, Rennes, France; Service de Néphrologie et de Transplantation Rénale (SB), Hôpital de la Conception, AP-HM, Aix-Marseille Université, Marseille, France; Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie (CC, OC), Hôpital Saint-Antoine, Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie; Inserm, UMR-S 938, Centre de Recherche Saint-Antoine; AP-HP, Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Paris, France; CHU Pontchaillou (N R-L), Service d'Anatomie Pathologie, Université de Rennes, Rennes, France; Service d'Anatomie pathologique (PR), Hôpital de la Pitié-Salpétrière, AP-HP, UPMC, Paris, France; Service de Néphrologie et Dialyse (BK), Hôpital Necker-Enfants Malades, AP-HP, Université Paris Descartes, Paris, France; Service de Néphrologie et Dialyses (J-J B, KD), Hôpital Tenon, AP-HP, UMPC, Paris, France; Service de Néphrologie (ED, MJ), Groupe hospitalier Bichat/Claude-Bernard, AP-HP, Université Paris Diderot, Paris, France; Service d'Anatomie pathologique (IB), Hôpital Te

ABSTRACT
The association between membranous nephropathy (MN) and immunological disorder-related liver disease has not been extensively investigated, and the specific features of this uncommon association, if any, remain to be determined.We retrospectively identified 10 patients with this association. We aimed to describe the clinical, biological, and pathological characteristics of these patients and their therapeutic management. The possible involvement of the phospholipase A2 receptor (PLA2R) in these apparent secondary forms of MN was assessed by immunohistochemistry with renal and liver biopsy specimens.The mean delay between MN and liver disease diagnoses was 3.9 years and the interval between the diagnosis of the glomerular and liver diseases was <1.5 years in 5 patients. MN was associated with a broad spectrum of liver diseases including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). AIH whether isolated (n = 3) or associated with PBC (n = 2) or PSC (n = 2) was the most frequent autoimmune liver disease. Circulating PLA2R antibodies were detected in 4 out of 9 patients but the test was performed under specific immunosuppressive treatment in 3 out of 9 patients. Seven of the 9 patients with available renal tissue specimens displayed enhanced expression of PLA2R in glomeruli whereas PLA2R was not expressed in liver parenchyma from these patients or in normal liver tissue. The study of immunoglobulin (Ig) subclasses of deposits in glomeruli revealed that the most frequent pattern was the coexistence of IgG1 and IgG4 immune deposits with IgG4 predominating.Detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic MN.

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PLA2R immunostaining in normal liver and cases of autoimmune liver diseases (with or without MN). (A) Absence of PLA2R expression in hepatocytes and portal area in normal liver tissue specimen (original magnification ×20). (B) PLA2R immunostaining gave negative results in AIH (control) with portal infiltrate rich in plasmocytes (arrow) with interface hepatitis (original magnification ×40) and (C) in PBC (control) with portal inflammation and bile duct damage (arrow: intraepithelial lymphocyte in bile duct) (original magnification ×40). A similar pattern (no significant PLA2R signal) was observed in patients with autoimmune and/or immunological-related liver disease associated with MN (Table 3). (D) Nonspecific cytoplasmic staining in macrophages (arrow) and hepatocytes (lipofuschines: curved arrow) in patient 5 (original magnification ×40). The interlobular bile duct and portal vein are indicated with white and black stars, respectively. PLA2R = phospholipase A2 receptor.
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Figure 3: PLA2R immunostaining in normal liver and cases of autoimmune liver diseases (with or without MN). (A) Absence of PLA2R expression in hepatocytes and portal area in normal liver tissue specimen (original magnification ×20). (B) PLA2R immunostaining gave negative results in AIH (control) with portal infiltrate rich in plasmocytes (arrow) with interface hepatitis (original magnification ×40) and (C) in PBC (control) with portal inflammation and bile duct damage (arrow: intraepithelial lymphocyte in bile duct) (original magnification ×40). A similar pattern (no significant PLA2R signal) was observed in patients with autoimmune and/or immunological-related liver disease associated with MN (Table 3). (D) Nonspecific cytoplasmic staining in macrophages (arrow) and hepatocytes (lipofuschines: curved arrow) in patient 5 (original magnification ×40). The interlobular bile duct and portal vein are indicated with white and black stars, respectively. PLA2R = phospholipase A2 receptor.

Mentions: The nature of Ig and complement subepithelial deposits is shown in Table 2. C1q deposits were weakly positive for 2 patients (patients 2 and 4) with positive ANA but without diagnostic criteria for SLE. One patient displayed acute interstitial nephritis associated with MN diagnosis but immunohistochemistry for IgG4 antibody was negative, excluding the diagnosis of IgG4-related disease (data not shown). The most frequent IF pattern observed in 4 patients (patients 2, 6, 8, 9) was the coexistence of IgG1 and IgG4 immune deposits with predominance of IgG4 (Figure 1). In 2 patients, IgG4 was the predominant glomerular Ig subclass in association with IgG1 and IgG3 deposits in 1 case (patient 3) and exclusively associated with IgG3 deposits in the other (patient 7). In 1 patient (patient 4), IgG1 was the only Ig subclass found in glomerular deposits. Consistent with a previous study,35 we found a very weak basal expression of PLA2R in normal human kidney (Figure 2A). On the contrary, PLA2R expression, with a fine granular pattern, was clearly induced in glomeruli from patients with idiopathic MN (Figure 2B). A similar distribution was found in 7 of the 9 patients (77.8%) in whom renal biopsy was available (patients 1 and 3 were negative for PLA2R immunostaining and renal tissue specimen was not available for patient 2) (Figure 2C and D). We next analyzed PLA2R expression in liver parenchyma. In normal liver tissue, PLA2R was undetectable (Figure 3A). Then, hepatic biopsies from autoimmune liver diseases with (n = 7) and without MN (n = 7) were studied (Figure 3B and C). Regardless of the nature of liver diseases (including AIH, PBC, and PSC) and the presence or absence of MN, we did not detect significant PLA2R staining in liver biopsies (Table 2). PLA2R was not expressed in physiological or pathological conditions in intrahepatic bile duct, hepatocytes, portal areas, or central venules. The only positive signals observed were nonspecific staining in lipofuscin and pigmented macrophages (Figure 3D).


Membranous Nephropathy Associated With Immunological Disorder-Related Liver Disease: A Retrospective Study of 10 Cases.

Dauvergne M, Moktefi A, Rabant M, Vigneau C, Kofman T, Burtey S, Corpechot C, Stehlé T, Desvaux D, Rioux-Leclercq N, Rouvier P, Knebelmann B, Boffa JJ, Frouget T, Daugas E, Jablonski M, Dahan K, Brocheriou I, Remy P, Grimbert P, Lang P, Chazouilleres O, Sahali D, Audard V - Medicine (Baltimore) (2015)

PLA2R immunostaining in normal liver and cases of autoimmune liver diseases (with or without MN). (A) Absence of PLA2R expression in hepatocytes and portal area in normal liver tissue specimen (original magnification ×20). (B) PLA2R immunostaining gave negative results in AIH (control) with portal infiltrate rich in plasmocytes (arrow) with interface hepatitis (original magnification ×40) and (C) in PBC (control) with portal inflammation and bile duct damage (arrow: intraepithelial lymphocyte in bile duct) (original magnification ×40). A similar pattern (no significant PLA2R signal) was observed in patients with autoimmune and/or immunological-related liver disease associated with MN (Table 3). (D) Nonspecific cytoplasmic staining in macrophages (arrow) and hepatocytes (lipofuschines: curved arrow) in patient 5 (original magnification ×40). The interlobular bile duct and portal vein are indicated with white and black stars, respectively. PLA2R = phospholipase A2 receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 3: PLA2R immunostaining in normal liver and cases of autoimmune liver diseases (with or without MN). (A) Absence of PLA2R expression in hepatocytes and portal area in normal liver tissue specimen (original magnification ×20). (B) PLA2R immunostaining gave negative results in AIH (control) with portal infiltrate rich in plasmocytes (arrow) with interface hepatitis (original magnification ×40) and (C) in PBC (control) with portal inflammation and bile duct damage (arrow: intraepithelial lymphocyte in bile duct) (original magnification ×40). A similar pattern (no significant PLA2R signal) was observed in patients with autoimmune and/or immunological-related liver disease associated with MN (Table 3). (D) Nonspecific cytoplasmic staining in macrophages (arrow) and hepatocytes (lipofuschines: curved arrow) in patient 5 (original magnification ×40). The interlobular bile duct and portal vein are indicated with white and black stars, respectively. PLA2R = phospholipase A2 receptor.
Mentions: The nature of Ig and complement subepithelial deposits is shown in Table 2. C1q deposits were weakly positive for 2 patients (patients 2 and 4) with positive ANA but without diagnostic criteria for SLE. One patient displayed acute interstitial nephritis associated with MN diagnosis but immunohistochemistry for IgG4 antibody was negative, excluding the diagnosis of IgG4-related disease (data not shown). The most frequent IF pattern observed in 4 patients (patients 2, 6, 8, 9) was the coexistence of IgG1 and IgG4 immune deposits with predominance of IgG4 (Figure 1). In 2 patients, IgG4 was the predominant glomerular Ig subclass in association with IgG1 and IgG3 deposits in 1 case (patient 3) and exclusively associated with IgG3 deposits in the other (patient 7). In 1 patient (patient 4), IgG1 was the only Ig subclass found in glomerular deposits. Consistent with a previous study,35 we found a very weak basal expression of PLA2R in normal human kidney (Figure 2A). On the contrary, PLA2R expression, with a fine granular pattern, was clearly induced in glomeruli from patients with idiopathic MN (Figure 2B). A similar distribution was found in 7 of the 9 patients (77.8%) in whom renal biopsy was available (patients 1 and 3 were negative for PLA2R immunostaining and renal tissue specimen was not available for patient 2) (Figure 2C and D). We next analyzed PLA2R expression in liver parenchyma. In normal liver tissue, PLA2R was undetectable (Figure 3A). Then, hepatic biopsies from autoimmune liver diseases with (n = 7) and without MN (n = 7) were studied (Figure 3B and C). Regardless of the nature of liver diseases (including AIH, PBC, and PSC) and the presence or absence of MN, we did not detect significant PLA2R staining in liver biopsies (Table 2). PLA2R was not expressed in physiological or pathological conditions in intrahepatic bile duct, hepatocytes, portal areas, or central venules. The only positive signals observed were nonspecific staining in lipofuscin and pigmented macrophages (Figure 3D).

Bottom Line: AIH whether isolated (n = 3) or associated with PBC (n = 2) or PSC (n = 2) was the most frequent autoimmune liver disease.Seven of the 9 patients with available renal tissue specimens displayed enhanced expression of PLA2R in glomeruli whereas PLA2R was not expressed in liver parenchyma from these patients or in normal liver tissue.The study of immunoglobulin (Ig) subclasses of deposits in glomeruli revealed that the most frequent pattern was the coexistence of IgG1 and IgG4 immune deposits with IgG4 predominating.Detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic MN.

View Article: PubMed Central - PubMed

Affiliation: From the Service de Néphrologie et Transplantation (MD, TK, TS, PR, PG, PL, DS, VA), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Centre de référence maladie rare Syndrome Néphrotique Idiopathique, Institut Francilien de recherche en Néphrologie et Transplantation (IFRNT), DHU VIC (Virus-Immunité-Cancer), AP-HP (Assistance Publique-Hôpitaux de Paris), Université Paris Est Créteil (UPEC), Créteil, France; Equipe 21 (MD, AM, TK, TS, DD, PG, PL, DS, VA), INSERM Unité 955, Université Paris Est Créteil, Créteil, France; Département de Pathologie (AM, DD), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, AP-HP, UPEC, Créteil, France; Service d'Anatomie pathologique (MR), Hôpital Necker - Enfants Malades, AP-HP, Université Paris Descartes, Paris, France; CHU Pontchaillou (CV, TF), Service de Néphrologie, Université de Rennes, Rennes, France; Service de Néphrologie et de Transplantation Rénale (SB), Hôpital de la Conception, AP-HM, Aix-Marseille Université, Marseille, France; Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie (CC, OC), Hôpital Saint-Antoine, Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie; Inserm, UMR-S 938, Centre de Recherche Saint-Antoine; AP-HP, Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Paris, France; CHU Pontchaillou (N R-L), Service d'Anatomie Pathologie, Université de Rennes, Rennes, France; Service d'Anatomie pathologique (PR), Hôpital de la Pitié-Salpétrière, AP-HP, UPMC, Paris, France; Service de Néphrologie et Dialyse (BK), Hôpital Necker-Enfants Malades, AP-HP, Université Paris Descartes, Paris, France; Service de Néphrologie et Dialyses (J-J B, KD), Hôpital Tenon, AP-HP, UMPC, Paris, France; Service de Néphrologie (ED, MJ), Groupe hospitalier Bichat/Claude-Bernard, AP-HP, Université Paris Diderot, Paris, France; Service d'Anatomie pathologique (IB), Hôpital Te

ABSTRACT
The association between membranous nephropathy (MN) and immunological disorder-related liver disease has not been extensively investigated, and the specific features of this uncommon association, if any, remain to be determined.We retrospectively identified 10 patients with this association. We aimed to describe the clinical, biological, and pathological characteristics of these patients and their therapeutic management. The possible involvement of the phospholipase A2 receptor (PLA2R) in these apparent secondary forms of MN was assessed by immunohistochemistry with renal and liver biopsy specimens.The mean delay between MN and liver disease diagnoses was 3.9 years and the interval between the diagnosis of the glomerular and liver diseases was <1.5 years in 5 patients. MN was associated with a broad spectrum of liver diseases including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). AIH whether isolated (n = 3) or associated with PBC (n = 2) or PSC (n = 2) was the most frequent autoimmune liver disease. Circulating PLA2R antibodies were detected in 4 out of 9 patients but the test was performed under specific immunosuppressive treatment in 3 out of 9 patients. Seven of the 9 patients with available renal tissue specimens displayed enhanced expression of PLA2R in glomeruli whereas PLA2R was not expressed in liver parenchyma from these patients or in normal liver tissue. The study of immunoglobulin (Ig) subclasses of deposits in glomeruli revealed that the most frequent pattern was the coexistence of IgG1 and IgG4 immune deposits with IgG4 predominating.Detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic MN.

Show MeSH
Related in: MedlinePlus