NDT Advance Access published April 2, 2015 Nephrol Dial Transplant (2015) 0: 1–4 doi: 10.1093/ndt/gfv080
The Bench-to-Bedside Transition Phospholipase A2 receptor and sarcoidosis-associated membranous nephropathy Thomas Stehlé1, Vincent Audard2,3, Pierre Ronco4 and Hanna Debiec4 Service de Néphrologie et Dialyse, Necker hospital, Assistance Publique–Hôpitaux de Paris (AP–HP), Paris, France, 2Service de Néphrologie
et Transplantation, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Hôpital Henri-Mondor, Assistance Publique– Hôpitaux de Paris (AP–HP), Université Paris-Est Créteil (UPEC), Créteil, France, 3INSERM U955, Equipe 21, Centre de Référence Syndrome Néphrotique Idiopathique, UPEC, Créteil, France and 4INSERM unit UMR_S1155, UPMC, APHP, Tenon hospital, Paris, France
Correspondence and offprint requests to: Hanna Debiec; E-mail: [email protected]
A B S T R AC T Of the glomerulonephritis associated with sarcoidosis, membranous nephropathy (MN) is the most prevalent. Coincidence or a causal relationship between these two diseases is unclear. Here, we present for the first time a high prevalence of PLA2R-related MN among patients with MN associated with active sarcoidosis. Our results suggest some causal link between sarcoidosis and PLA2R-related MN. Detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. This important observation can affect treatment decision in these patients. Keywords: membranous nephropathy, phospholipase A2 receptor, sarcoidosis
B AC K G R O U N D About 70–80% of cases of membranous nephropathy (MN) are idiopathic (iMN) whereas secondary causes such as infection (hepatitis B), autoimmune diseases, malignancies and drugs account for the remainder. MN is the most frequent glomerular disease associated with sarcoidosis although its occurrence is rare [1]. The molecular link between these two conditions remains unclear for at least two reasons: firstly, no target antigen or specific antibodies have yet been identified; secondly, sarcoidosis results from an uncontrolled cellmediated immune reaction involving macrophages and CD4 type-1 helper T (Th1) cells [2], after exposure to unidentified © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
antigens, whereas MN is a prototype of autoimmune diseases involving a Th2 response [3, 4]. Identification in 2009 of PLA2R as the major antigen associated with iMN provided the first diagnostic biomarker in this disease [5]. Since then, two reliable assays for the detection of circulating anti-PLA2R antibodies have been made available [6, 7]. Based on these assays, several studies have shown that anti-PLA2R antibodies are a specific biomarker of MN, being detected in 70–80% patients with iMN world-wide in early serum samples, while they are not found in healthy individuals and in patients with other nephropathies or autoimmune diseases [3]. Their prevalence in secondary MN is much lower than in iMN [3] although in this setting, it is often difficult to exclude coincidental occurrence of iMN with the underlying disorder. Only isolated cases of sarcoidosis-associated MN have been reported so far [8–10]. We aimed to test the prevalence of PLA2R-related MN in patients with sarcoidosis and to establish a possible relationship with sarcoidosis activity. To this end, we searched for PLA2R antigen in sub-epithelial immune deposits, a diagnostic test which is more sensitive than serology and enables the retrospective diagnosis of PLA2R-related MN [9, 11].
CASES REPORT Twenty-six patients with sarcoidosis and glomerular disease were retrospectively identified and followed between 1977 and 2014 in the nephrology departments of seven French hospitals [1]. We conducted this retrospective study by sending a questionnaire to all nephrology departments involved in the 1
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
1
Patient
Gender/ethnicity
Date of biopsy, Age at biopsy
Time interval from diagnosis of sarcoidosis to MN (years)
Activity of sarcoidosis at kidney biopsy
PLA2R in biopsy
Anti-PLA2R antibodies
1
M/African
−18.8
No
No
NA
2
M/African
January 2005 57 September 2006 27 February 2013
−7.7
Yes No
Yes Yes
3
M/Maghrebian
−0.2
Yes
Yes
4
M/Maghrebian
0
Yes
Yes
5
F/Maghrebian
0
Yes
Yes
6
M/Caucasian
0.5
Yes Yes
Yes Yes
7
M/Caucasian
1.1
No
No
2008, serum positive 2010, serum negative 2014, serum positive NA
8
M/Caucasian
5.8
No
No
NA
9
F/Caucasian
December 2001 52 March 2012 44 October 2010 50 January 2008 29 August 2014 May 1990 41 September 1983 27 December 2000 45
2006, serum positive 2007, serum positive 2012, serum negative 2013, serum negative NA
8.0
No
No
NA
management of glomerular diseases to determine whether some patients exhibited glomerular involvement in the context of sarcoidosis occurrence whatever the delay between the diagnosis of sarcoidosis and that of glomerular diseases. Eleven of 26 of patients with biopsy-proven glomerular lesions had MN without evidence of a secondary cause except for sarcoidosis. Two of them were not included in the present study because the remaining fragment of the biopsy contained no analysable glomerulus. Demographic, clinical and laboratory data were assessed for each patient at the time of kidney biopsy. Follow-up data were obtained for all patients (Supplementary data, Table S1). Detection of PLA2R antigen in kidney biopsy was performed as previously described [9, 11]. Anti-PLA2R antibodies were assessed by an ELISA test on archival sera when available [7]. There were 7 males and 2 females (Supplementary data, Table S1). Mean ages at the apparent onset of sarcoidosis and at the diagnosis of MN on kidney biopsy were 40 years (range of 19–53 years) and 41.5 years (range of 26–56 years), respectively. In six patients, the diagnosis of sarcoidosis was confirmed by organ or tissue biopsy. In three patients, the diagnosis of sarcoidosis was based only on compatible clinical, biological and radiographic presentations. Activity of sarcoidosis was determined clinically, by broncho-alveolar lavage and on biological parameters (serum calcium and angiotensinconverting enzyme level). Sarcoidosis antedated the diagnosis of MN in two patients; both diagnoses occurred within 5 months in four patients and that of sarcoidosis followed biopsy-proven MN in three patients (Table 1). In the patients with inactive sarcoidosis, a kidney biopsy was performed because of nephrotic range proteinuria or acute renal failure. All five patients with active sarcoidosis at the time of the kidney biopsy had PLA2R antigen in immune deposits while none of those with inactive sarcoidosis had detectable PLA2R. In the two patients (Patients 2 and 6) with available follow-up
2
2012, serum positive 2014, serum negative NA
sera (Figure 1A and B), anti-PLA2R antibody levels followed sarcoidosis activity. Circulating antibodies and deposited subclass were predominantly IgG4 in the three and two patients studied, respectively (Supplementary data, Figures S1 and S2).
DISCUSSION Five patients had MN and active sarcoidosis almost simultaneously diagnosed at a less than 6-month interval. These patients all had PLA2R antigen in deposits. Although the dominance of IgG4 and the presence of PLA2R in immune deposits are characteristics of the primary MN our findings suggest some causal link between the two diseases. Firstly, the prevalence of PLA2R-related MN (5/9, 55%) was unusually high in the setting of possible secondary MN. These data are at variance with a previous report by Hoxha et al. [12] showing that secondary MN is characterized by absence of PLA2R in immune deposits. Secondly, the causality hypothesis is strengthened by parallel evolution of anti-PLA2R antibodies and sarcoidosis activity in two patients. There is only one patient (#1) with a long time interval between the onset of sarcoidosis and MN, which suggests the absence of interaction between the two diseases in this patient. A weakness of our study is the small number of patients which is, however, explained by MN being a rare complication of sarcoidosis. In conclusion, our data show a high prevalence of PLA2Rrelated MN among patients with MN associated with active sarcoidosis. Therefore, detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. Because PLA2R antibodies are rarely detected in secondary MN, their occurrence in patients with active sarcoidosis suggests that the immunological setting of sarcoidosis might
T. Stehlé et al.
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
THE BENCH-TO-BEDSIDE TRANSITION
Table 1. Summarized characteristics of patients who had membranous nephropathy and sarcoidosis
trigger or enhance immunization against PLA2R; although further studies are needed to understand the pathogenetic mechanisms. Our findings potentially have important implications for the design of more personalized therapeutic approach and monitoring in these patients.
C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.
REFERENCES S U P P L E M E N TA R Y D ATA Supplementary data are available online at http://ndt. oxfordjournals.org.
AC K N O W L E D G E M E N T S Research is supported by Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE10002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases).
Phospholipase A2 receptor and sarcoidosis
1. Stehlé T, Joly D, Vanhille P et al. Clinicopathological study of glomerular diseases associated with sarcoidosis: a multicenter study. Orphanet J Rare Dis 2013; 8: 65 2. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357: 2153–2165 3. Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: an update. Semin Immunopathol 2014; 36: 381–397 4. Kuroki A, Iyoda M, Shibata T et al. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int 2005; 68: 302–310 5. Beck LH, Jr, 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 6. Hoxha E, Harendza S, Zahner G et al. An immunofluorescence test for phospholipase-A₂-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrol Dial Transplant 2011; 26: 2526–2532
3
THE BENCH-TO-BEDSIDE TRANSITION
main indication for the second renal biopsy was relapse of the nephrotic syndrome (Patient 6), and progressive deterioration of renal function with persistent, nephrotic range proteinuria (Patient 2), respectively. (B) Time course of sarcoidosis, circulating anti-PLA2R antibody levels (total IgG) and proteinuria. In Patient 6, organ involvement at the time of sarcoidosis diagnosis included lung parenchyma injury, peri-renal and peri-ureteral infiltration, optic neuritis and biopsy-proven mediastinal granulomatous lymphadenopathy. Moreover, angiotensin-converting enzyme (ACE) was elevated. During sarcoidosis relapse, this patient displayed small renal infarctions secondary to medium-sized vessel vasculitis, increased peri-renal infiltration, and high mediastinal lymph node metabolism assessed by F-fluorodeoxyglucose–positron-emission tomography/computed tomography. In Patient 2, sarcoidosis activity assessment was based on recurrent granulomatous uveitis, associated with high calcitriol level and persistent increase of ACE level. Symbols: red bar, positive sarcoidosis activity; green bar, negative sarcoidosis activity; blue bar, anti-PLA2R antibody levels; green–grey bar, steroid treatment; red flash, rituximab pulse.
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
F I G U R E 1 : (A) Glomeruli with granular capillary loop staining for PLA2R in biopsy from patients 6 and 2 (original magnification, ×400). The
7. Dähnrich C, Komorowski L, Probst C et al. Development of a standardized ELISA for the determination of autoantibodies against human M-type phospholipase A2 receptor in primary membranous nephropathy. Clin Chim Acta 2013; 421: 213–218 8. Knehtl M, Debiec H, Kamgang P et al. A case of phospholipase A₂ receptor-positive membranous nephropathy preceding sarcoid-associated granulomatous tubulointerstitial nephritis. Am J Kidney Dis 2011; 57: 140–143 9. Svobodova B, Honsova E, Ronco P et al. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy. Nephrol Dial Transplant 2013; 28: 1839–1844
10. Larsen CP, Messias NC, Silva FG et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol 2013; 26: 709–715 11. Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med 2011; 364: 689–690 12. Hoxha E, Kneißler U, Stege G et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int 2012; 82: 797–804
Received for publication: 6.11.2014; Accepted in revised form: 24.2.2015
THE BENCH-TO-BEDSIDE TRANSITION
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
4
T. Stehlé et al.
The Bench-to-Bedside Transition Phospholipase A2 receptor and sarcoidosis-associated membranous nephropathy Thomas Stehlé1, Vincent Audard2,3, Pierre Ronco4 and Hanna Debiec4 Service de Néphrologie et Dialyse, Necker hospital, Assistance Publique–Hôpitaux de Paris (AP–HP), Paris, France, 2Service de Néphrologie
et Transplantation, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Hôpital Henri-Mondor, Assistance Publique– Hôpitaux de Paris (AP–HP), Université Paris-Est Créteil (UPEC), Créteil, France, 3INSERM U955, Equipe 21, Centre de Référence Syndrome Néphrotique Idiopathique, UPEC, Créteil, France and 4INSERM unit UMR_S1155, UPMC, APHP, Tenon hospital, Paris, France
Correspondence and offprint requests to: Hanna Debiec; E-mail: [email protected]
A B S T R AC T Of the glomerulonephritis associated with sarcoidosis, membranous nephropathy (MN) is the most prevalent. Coincidence or a causal relationship between these two diseases is unclear. Here, we present for the first time a high prevalence of PLA2R-related MN among patients with MN associated with active sarcoidosis. Our results suggest some causal link between sarcoidosis and PLA2R-related MN. Detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. This important observation can affect treatment decision in these patients. Keywords: membranous nephropathy, phospholipase A2 receptor, sarcoidosis
B AC K G R O U N D About 70–80% of cases of membranous nephropathy (MN) are idiopathic (iMN) whereas secondary causes such as infection (hepatitis B), autoimmune diseases, malignancies and drugs account for the remainder. MN is the most frequent glomerular disease associated with sarcoidosis although its occurrence is rare [1]. The molecular link between these two conditions remains unclear for at least two reasons: firstly, no target antigen or specific antibodies have yet been identified; secondly, sarcoidosis results from an uncontrolled cellmediated immune reaction involving macrophages and CD4 type-1 helper T (Th1) cells [2], after exposure to unidentified © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
antigens, whereas MN is a prototype of autoimmune diseases involving a Th2 response [3, 4]. Identification in 2009 of PLA2R as the major antigen associated with iMN provided the first diagnostic biomarker in this disease [5]. Since then, two reliable assays for the detection of circulating anti-PLA2R antibodies have been made available [6, 7]. Based on these assays, several studies have shown that anti-PLA2R antibodies are a specific biomarker of MN, being detected in 70–80% patients with iMN world-wide in early serum samples, while they are not found in healthy individuals and in patients with other nephropathies or autoimmune diseases [3]. Their prevalence in secondary MN is much lower than in iMN [3] although in this setting, it is often difficult to exclude coincidental occurrence of iMN with the underlying disorder. Only isolated cases of sarcoidosis-associated MN have been reported so far [8–10]. We aimed to test the prevalence of PLA2R-related MN in patients with sarcoidosis and to establish a possible relationship with sarcoidosis activity. To this end, we searched for PLA2R antigen in sub-epithelial immune deposits, a diagnostic test which is more sensitive than serology and enables the retrospective diagnosis of PLA2R-related MN [9, 11].
CASES REPORT Twenty-six patients with sarcoidosis and glomerular disease were retrospectively identified and followed between 1977 and 2014 in the nephrology departments of seven French hospitals [1]. We conducted this retrospective study by sending a questionnaire to all nephrology departments involved in the 1
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
1
Patient
Gender/ethnicity
Date of biopsy, Age at biopsy
Time interval from diagnosis of sarcoidosis to MN (years)
Activity of sarcoidosis at kidney biopsy
PLA2R in biopsy
Anti-PLA2R antibodies
1
M/African
−18.8
No
No
NA
2
M/African
January 2005 57 September 2006 27 February 2013
−7.7
Yes No
Yes Yes
3
M/Maghrebian
−0.2
Yes
Yes
4
M/Maghrebian
0
Yes
Yes
5
F/Maghrebian
0
Yes
Yes
6
M/Caucasian
0.5
Yes Yes
Yes Yes
7
M/Caucasian
1.1
No
No
2008, serum positive 2010, serum negative 2014, serum positive NA
8
M/Caucasian
5.8
No
No
NA
9
F/Caucasian
December 2001 52 March 2012 44 October 2010 50 January 2008 29 August 2014 May 1990 41 September 1983 27 December 2000 45
2006, serum positive 2007, serum positive 2012, serum negative 2013, serum negative NA
8.0
No
No
NA
management of glomerular diseases to determine whether some patients exhibited glomerular involvement in the context of sarcoidosis occurrence whatever the delay between the diagnosis of sarcoidosis and that of glomerular diseases. Eleven of 26 of patients with biopsy-proven glomerular lesions had MN without evidence of a secondary cause except for sarcoidosis. Two of them were not included in the present study because the remaining fragment of the biopsy contained no analysable glomerulus. Demographic, clinical and laboratory data were assessed for each patient at the time of kidney biopsy. Follow-up data were obtained for all patients (Supplementary data, Table S1). Detection of PLA2R antigen in kidney biopsy was performed as previously described [9, 11]. Anti-PLA2R antibodies were assessed by an ELISA test on archival sera when available [7]. There were 7 males and 2 females (Supplementary data, Table S1). Mean ages at the apparent onset of sarcoidosis and at the diagnosis of MN on kidney biopsy were 40 years (range of 19–53 years) and 41.5 years (range of 26–56 years), respectively. In six patients, the diagnosis of sarcoidosis was confirmed by organ or tissue biopsy. In three patients, the diagnosis of sarcoidosis was based only on compatible clinical, biological and radiographic presentations. Activity of sarcoidosis was determined clinically, by broncho-alveolar lavage and on biological parameters (serum calcium and angiotensinconverting enzyme level). Sarcoidosis antedated the diagnosis of MN in two patients; both diagnoses occurred within 5 months in four patients and that of sarcoidosis followed biopsy-proven MN in three patients (Table 1). In the patients with inactive sarcoidosis, a kidney biopsy was performed because of nephrotic range proteinuria or acute renal failure. All five patients with active sarcoidosis at the time of the kidney biopsy had PLA2R antigen in immune deposits while none of those with inactive sarcoidosis had detectable PLA2R. In the two patients (Patients 2 and 6) with available follow-up
2
2012, serum positive 2014, serum negative NA
sera (Figure 1A and B), anti-PLA2R antibody levels followed sarcoidosis activity. Circulating antibodies and deposited subclass were predominantly IgG4 in the three and two patients studied, respectively (Supplementary data, Figures S1 and S2).
DISCUSSION Five patients had MN and active sarcoidosis almost simultaneously diagnosed at a less than 6-month interval. These patients all had PLA2R antigen in deposits. Although the dominance of IgG4 and the presence of PLA2R in immune deposits are characteristics of the primary MN our findings suggest some causal link between the two diseases. Firstly, the prevalence of PLA2R-related MN (5/9, 55%) was unusually high in the setting of possible secondary MN. These data are at variance with a previous report by Hoxha et al. [12] showing that secondary MN is characterized by absence of PLA2R in immune deposits. Secondly, the causality hypothesis is strengthened by parallel evolution of anti-PLA2R antibodies and sarcoidosis activity in two patients. There is only one patient (#1) with a long time interval between the onset of sarcoidosis and MN, which suggests the absence of interaction between the two diseases in this patient. A weakness of our study is the small number of patients which is, however, explained by MN being a rare complication of sarcoidosis. In conclusion, our data show a high prevalence of PLA2Rrelated MN among patients with MN associated with active sarcoidosis. Therefore, detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. Because PLA2R antibodies are rarely detected in secondary MN, their occurrence in patients with active sarcoidosis suggests that the immunological setting of sarcoidosis might
T. Stehlé et al.
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
THE BENCH-TO-BEDSIDE TRANSITION
Table 1. Summarized characteristics of patients who had membranous nephropathy and sarcoidosis
trigger or enhance immunization against PLA2R; although further studies are needed to understand the pathogenetic mechanisms. Our findings potentially have important implications for the design of more personalized therapeutic approach and monitoring in these patients.
C O N F L I C T O F I N T E R E S T S TAT E M E N T None declared.
REFERENCES S U P P L E M E N TA R Y D ATA Supplementary data are available online at http://ndt. oxfordjournals.org.
AC K N O W L E D G E M E N T S Research is supported by Agence Nationale pour la Recherche Programme Blanc SVSE1 (2012) Decision ANR-12-BSE10002-01, Fondation pour la Recherche Médicale Equipe FRM 2012 grant, and 7th Framework Programme of the European Community Contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases).
Phospholipase A2 receptor and sarcoidosis
1. Stehlé T, Joly D, Vanhille P et al. Clinicopathological study of glomerular diseases associated with sarcoidosis: a multicenter study. Orphanet J Rare Dis 2013; 8: 65 2. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357: 2153–2165 3. Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: an update. Semin Immunopathol 2014; 36: 381–397 4. Kuroki A, Iyoda M, Shibata T et al. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int 2005; 68: 302–310 5. Beck LH, Jr, 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 6. Hoxha E, Harendza S, Zahner G et al. An immunofluorescence test for phospholipase-A₂-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrol Dial Transplant 2011; 26: 2526–2532
3
THE BENCH-TO-BEDSIDE TRANSITION
main indication for the second renal biopsy was relapse of the nephrotic syndrome (Patient 6), and progressive deterioration of renal function with persistent, nephrotic range proteinuria (Patient 2), respectively. (B) Time course of sarcoidosis, circulating anti-PLA2R antibody levels (total IgG) and proteinuria. In Patient 6, organ involvement at the time of sarcoidosis diagnosis included lung parenchyma injury, peri-renal and peri-ureteral infiltration, optic neuritis and biopsy-proven mediastinal granulomatous lymphadenopathy. Moreover, angiotensin-converting enzyme (ACE) was elevated. During sarcoidosis relapse, this patient displayed small renal infarctions secondary to medium-sized vessel vasculitis, increased peri-renal infiltration, and high mediastinal lymph node metabolism assessed by F-fluorodeoxyglucose–positron-emission tomography/computed tomography. In Patient 2, sarcoidosis activity assessment was based on recurrent granulomatous uveitis, associated with high calcitriol level and persistent increase of ACE level. Symbols: red bar, positive sarcoidosis activity; green bar, negative sarcoidosis activity; blue bar, anti-PLA2R antibody levels; green–grey bar, steroid treatment; red flash, rituximab pulse.
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
F I G U R E 1 : (A) Glomeruli with granular capillary loop staining for PLA2R in biopsy from patients 6 and 2 (original magnification, ×400). The
7. Dähnrich C, Komorowski L, Probst C et al. Development of a standardized ELISA for the determination of autoantibodies against human M-type phospholipase A2 receptor in primary membranous nephropathy. Clin Chim Acta 2013; 421: 213–218 8. Knehtl M, Debiec H, Kamgang P et al. A case of phospholipase A₂ receptor-positive membranous nephropathy preceding sarcoid-associated granulomatous tubulointerstitial nephritis. Am J Kidney Dis 2011; 57: 140–143 9. Svobodova B, Honsova E, Ronco P et al. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy. Nephrol Dial Transplant 2013; 28: 1839–1844
10. Larsen CP, Messias NC, Silva FG et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol 2013; 26: 709–715 11. Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med 2011; 364: 689–690 12. Hoxha E, Kneißler U, Stege G et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int 2012; 82: 797–804
Received for publication: 6.11.2014; Accepted in revised form: 24.2.2015
THE BENCH-TO-BEDSIDE TRANSITION
Downloaded from http://ndt.oxfordjournals.org/ at New York University on May 20, 2015
4
T. Stehlé et al.
