Anti-Phospholipase A2 Receptor Antibody - Clinical Application for Membranous Nephropathy - Dr. Gawad
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Anti-Phospholipase A2 Receptor Antibody - Clinical Application for Membranous Nephropathy - Dr. Gawad
- 1. Anti-Phospholipase A2 Receptor Antibody Clinical Application for Membranous Nephropathy Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria – EGY drgawad@gmail.com Mansoura MD Program – 12 / Jan / 2017
- 2. Steps of Management of MN Evaluation of secondary causes Therapy: Secondary: Treat the cause Idiopathic: Specific Treatment Kidney Int Suppl. 2012;2:139-274
- 3. Subepithelial deposits MN Possible Mechanisms Glassock RJ. N Engl J Med 2009;361:81-83. Possible Mechanisms of the Formation of Subepithelial Deposits in Experimental Models of, and Patients with, Membranous Nephropathy. 1ry MN2ry MN 2ry MN
- 4. Podocyte Antigens • Phospholipase A2 Receptor • Thrombospondin type - 1 domain -containing 7A (THSD7A)
- 5. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 6. Human Podocyte Antigens Phospholipase A2 Receptor
- 7. N terminal cysteine rich domain Fibronectin type II domain Transmembrane domain Short intracellular C terminal tail C type lectin like domains J Am Soc Nephrol. 2015 Feb;26(2) N Engl J Med. 2009 Jul 2;361(1) A major epitope that is recognized by 90% of human anti-PLA2R autoantibodies
- 8. Anti-PLA2R Auto-antibodies J Am Soc Nephrol. 2016 Oct;27(10)
- 9. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 11. N Engl J Med. 2009 Jul 2;361(1)
- 12. N Engl J Med. 2009 Jul 2;361(1)
- 13. Anti-PLA2R antibodies have been identified in 57, 74, 75, 78, 80, and 82 percent of patients with primary membranous nephropathy J Am Soc Nephrol. 2015 Oct;26(10) Kidney Int. 2013;83(5) J Am Soc Nephrol. 2012 Oct;23(10) Clin J Am Soc Nephrol. 2011;6(6) J Am Soc Nephrol. 2011;22(6) N Engl J Med. 2011;364(7):689
- 14. Anti-PLA2R Auto-antibodies Is it only related to Idiopathic MN? J Am Soc Nephrol 22: 1137–1143, 2011.
- 15. J Cent South Univ. 2016 Oct 28;41(10)
- 16. J Cent South Univ. 2016 Oct 28;41(10)
- 17. • PLA2R has been detected in the immune deposits of some patients with secondary MN due to: –HCV, HBV –Neoplasms –Sarcoidosis –Other inflammatory & autoimmune diseases Am J Nephrol. 2015 ; 41(4-5) Medicine (Baltimore). 2015 ; 94(30)
- 18. Secondary MN with positive anti-PLA2R, how? Associated conditions may represent a disease- precipitating “second hit” in a patient genetically and immunologically predisposed to develop MN Anti-PLA2R Is it only related to Idiopathic MN? Am J Kidney Dis. 2016 Jul;68(1)
- 19. Any patient with nephrotic syndrome who tests positive for anti-PLA2R is almost certain to have MN
- 20. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 21. Am J Kidney Dis. 2016 Jul;68(1)
- 22. Int Urol Nephrol. 2016 Jun;48(6):845-9
- 23. Luminex (ALBIA) Detecting PLA2R autoantibodies on an addressable laser bead immunoassay J Immunol Res. 2014; 2014: 143274.
- 24. J Immunol Res. 2014; 2014: 143274.
- 25. J Immunol Res. 2014; 2014: 143274.
- 26. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 27. J Am Soc Nephrol. 2014 Jun;25(6)
- 28. Clin J Am Soc Nephrol. 2011 Jun;6(6)
- 29. Indian J Nephrol. 2016 Jul-Aug;26(4) Association of serum anti-PLA2R antibodies with proteinuria
- 30. n = 118 The clinical end point: increase of serum creatinine by ≥ 25% and serum creatinine reaching ≥ 1.3 mg/dl anti-PLA2R antibody titer measured within 6 months of kidney biopsy and prior to any immunosuppressive therapy Clin J Am Soc Nephrol. 2014 Nov 7;9(11)
- 31. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 32. J Am Soc Nephrol. 2012 Oct;23(10)
- 33. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 34. J Am Soc Nephrol. 2014 Jun;25(6) patients treated with immunosuppressive therapy (n=101)
- 35. J Am Soc Nephrol. 2014 Jun;25(6) P < 0.05
- 36. J Am Soc Nephrol. 2014 Jun;25(6)
- 37. J Am Soc Nephrol. 2014 Jun;25(6)
- 38. J Am Soc Nephrol. 2015 Oct;26(10)
- 39. Patients % who achieved partial or complete remission Antiphosphlipase A2 antibody titers 82 % <87 RU/mL 59 % 87 to 204 RU/mL 37 % >204 RU/mL J Am Soc Nephrol. 2015 Oct;26(10)
- 40. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 41. Clin J Am Soc Nephrol. 2011 Jun;6(6)
- 42. Kidney Int. 2013 May;83(5)
- 43. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 45. Transplantation. 2015 Aug;99(8) anti-PLA2R levels (cut-off of 45 U/mL) during the pretransplantation period accurately predicted pMN recurrence, with a sensitivity of 85.3%, specificity of 85.1%
- 47. • Other factors that may affect post Tx recurrence: – anti-PLA2R antibody titer – Donor and recipient relatedness, class II major histocompatibility complex interactions – Potency of transplant immunosuppression therapy Transplantation. 2015;99(8) Nephrol Dial Transplant. 2014;29(12) Am J Transplant. 2012;12(1) Probability of recurrence of MN after kidney Tx is not only affected by anti-PLA2R antibody seropositivity level at the time of transplantation
- 48. Recurrence of MN after kidney Tx despite a negative pre-transplantation test result for anti- PLA2R antibodies Am J Kidney Dis. 2016 Jul;68(1) Transplantation. 2013;95(10) Cause Post-transplantation anti-PLA2R ab awakening of memory cells Positive anti-THSD7A antibodies Negative De Novo MN Negative
- 49. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 50. J Am Soc Nephrol. 2016 Oct;27(10)
- 51. J Am Soc Nephrol. 2016 Oct;27(10)
- 52. J Am Soc Nephrol. 2016 Oct;27(10)
- 53. J Am Soc Nephrol. 2016 Oct;27(10)
- 54. N Engl J Med. 2011 Feb 17;364(7)
- 55. N Engl J Med. 2011 Feb 17;364(7)
- 56. Am J Kidney Dis. 2016 Jul;68(1)
- 57. Kidney Int. 2016 Jun;89(6):1399
- 58. Kidney Int. 2016 Jun;89(6):1399 This does not support the hypothesis that antibodies could only be detected once the buffer capacity of the kidney is exceeded
- 59. PLA2R deposit in kidney Is it only related to Idiopathic MN? Nephrol Dial Transplant. 2013 Jul;28(7)
- 60. PLA2R deposit in kidney Is it only related to Idiopathic MN? J Am Soc Nephrol. 2011;22(6) Also a few patients with secondary MN to lupus and cancer have positive PLA2R immunostaining in kidney biopsy
- 61. Secondary MN with positive PLA2R in kidney biopsy, how? Associated conditions may represent a disease- precipitating “second hit” in a patient genetically and immunologically predisposed to develop MN PLA2R deposit in kidney Is it only related to Idiopathic MN? Am J Kidney Dis. 2016 Jul;68(1)
- 62. Talk Outline • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 63. J Am Soc Nephrol. 2016 Oct 24
- 64. J Am Soc Nephrol. 2016 Oct 24
- 65. J Am Soc Nephrol. 2016 Oct 24
- 66. J Am Soc Nephrol. 2016 Oct 24
- 67. J Am Soc Nephrol. 2016 Oct 24
- 68. Home Messages • Molecular character • anti-PLA2R autoantibodies – Diagnosis: • Primary vs Secondary • Immunoassays used for diagnosis – Correlation with: • Disease presentation: – Proteinuria and disease severity – Progression of renal failure • Remission: – Spontaneous – Remission after therapy: » Immunosuppression » Rituximab • Relapse • Post kidney transplantation recurrence • Glomerular PLA2R antigen detection • A proposal for serology based approach
- 69. Gawad Thank You
Notes de l'éditeur
- This is important in patients for whom kidney biopsy poses a high risk, such as those needing anticoagulation for thromboembolic disease and patients with a single kidney.
- Western blotting, which is both sensitive and very specific for the detection of anti- PLA2R when recombinant human PLA2R is used as the antigen. However, the technique is costly, labor intensive, and impractical for routine clinical use. compared with the Western blot assay for anti-PLA2R, the commercial IIFA and ELISA tests are highly specific for primary MN versus secondary MN and other forms of glomerular disease, although the ELISA is somewhat less sensitive using the recommended cutoff for positivity. Although the IIFA is relatively high throughput, anti-PLA2R titers are semiquantitative and observer dependent, and reactivity with other baseline cell antigens may occasionally predispose to equivocal results. It is generally used as an initial screening assay, much like antineutrophil cytoplasmic antibody assays, before proceeding to the highthroughput and more quantitative and specific ELISA.
- Control: 50 normal healthy controls, 41 nephrotic disease controls (patients presenting with nephrotic syndrome in which biopsy revealed underlying cause different from IMN
- Control: 50 normal healthy controls, 41 nephrotic disease controls (patients presenting with nephrotic syndrome in which biopsy revealed underlying cause different from IMN
- Control: 50 normal healthy controls, 41 nephrotic disease controls (patients presenting with nephrotic syndrome in which biopsy revealed underlying cause different from IMN
- PLA2R antibody levels associated with clinical disease activity (proteinuria) in patients with immunosuppressive therapy (n=101) or supportive care (n=32).
- Serum levels of PLA2R-Ab were first measured by an indirect immunofluorescence test (8,13). After development of an ELISA (14) by EUROIMMUN AG, we continued measurements of total IgG and IgG4 subclass PLA2R-Ab by ELISA. the ELISA results were considered positive at a level .20 units/ml for IgG PLA2R-Ab and .0.259 units/ml for IgG4 PLA2R-Ab.
- Within 3 months after the start of the immunosuppressive therapy (0 months), proteinuria decreases by 39% and PLA2R antibody levels by 81%. Proteinuria continuously declines during the further follow-up, whereas PLA2R antibody levels remained low. *P < 0.05, statistically significant difference between the single time point and the start of immunosuppression (0 months
- higher anti-PLA2R titers within two years of diagnosis predicted substantially greater progression of kidney function decline over the subsequent five years of follow-up
- De Novo: most likely the result of alloantibodies in the transplant rather than the autoantibodies responsible for recurrent primary MN. associated with evidence of antibody-mediated rejection and circulating donor specific antibodies.80-82 Whereas IgG4 is usually the dominant or codominant IgG subclass deposited in recurrent MN, the IgG1 subclass predominates in de novo MN.83 Assays for circulating anti-PLA2R antibodies or staining for PLA2R on kidney biopsy specimens almost always gives negative results in patients with de novo MN.84 PLA2R positivity is an ideal tool for differentiating between recurrent and de novo MN in patients in whom the original cause of ESRD was unknown.
- a minority of patients who are seropositive for anti-PLA2R antibodies exhibit no staining for PLA2R within the immune deposits of their corresponding biopsy specimens. This may represent masking by autoantibodies of epitopes recognized by the commercial antibody used for IF staining, but has not yet been fully explored.
- a minority of patients who are seropositive for anti-PLA2R antibodies exhibit no staining for PLA2R within the immune deposits of their corresponding biopsy specimens. This may represent masking by autoantibodies of epitopes recognized by the commercial antibody used for IF staining, but has not yet been fully explored.