12. Talk Outline
Steps of Management of MN
(Diagnosis & Treatment)
Evaluation
of secondary causes
Therapy:
Secondary: Treat the cause
Idiopathic: Specific
Treatment
To go through evaluation of secondary causes
we have to discuss first Clinically applied
Pathophysiology of MN
Kidney Int Suppl. 2012;2:139-274
13. 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
14. 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
15. Animal Model - Heymann nephritis
Megalin
Quigg RJ. Kidney Int 2003; 64:2318.
16. Congenital MN have been shown to be mediated by an antibody to neutral endopeptidase
(NEP), an antigen expressed on the podocyte membrane. In these cases, mothers with a
hereditary absence of NEP become sensitized during pregnancy and passively transfer anti-NEP
IgG to the infant, who is born with congenital nephrotic syndrome caused by MN through an
alloimmune mechanism
Human Podocyte Antigens
Neutral Endopeptidase
18. Human Podocyte Antigens
Thrombospondin type - 1 domain -
containing 7A (THSD7A)
• A transmembrane protein expressed on podocytes.
• Responsible Ab in 10% of primary MN with negative
anti-PLA2R Ab.
Gödel M et al. N Engl J Med 2015; 372:1073.
Iwakura T et al. PLoS One 2015; 10:e0138841.
19. Mechanism of primary MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.
20. Mechanism of primary MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.
Qu Z et al. Nephrol Dial Transplant 27: 1931–1937, 2012
21. Mechanism of primary MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.
22. Characteristics of Primary MN
Pathogenesis
• Anti PLAR2 Ab.
• Th2 Humoral immunity.
• IgG4 subclass.
• C5b9 (MAC)
23. Characteristics of Primary MN
Pathogenesis
• Anti PLAR2 Ab.
• Th2 Humoral immunity.
• IgG4 subclass.
• C5b9 (MAC)
24.
25.
26.
27. Serum PLA2R auto antibodies test is a
good +ve but not good -ve marker for
MN.
Anti-PLA2R Titers Clinical Significance
(1)
28. Anti-PLA2R Titers Clinical Significance
(2)
• anti-PLA2R titers strongly correlated with
clinical status
• lower anti-PLA2R titers were associated with a
higher rate of spontaneous remission
• a decline in anti-PLA2R predicted the clinical
response to immunosuppressive therapy
Hofstra JM et al. Clin J Am Soc Nephrol 2011; 6:1286.
Hofstra JM et al. J Am Soc Nephrol 2012; 23:1735.
Ruggenenti P et al. J Am Soc Nephrol 2015; 26:2545.
29.
30. Anti-PLA2R
Is it only related to Idiopathic MN?
J Am Soc Nephrol 22: 1137–1143, 2011.
31. Anti-PLA2R Titers Clinical Significance
(3)
• Highly suggestive of primary MN
• But does not exclude the coexistence of:
–hepatitis virus infection,
–malignancy,
–another associated rheumatologic or
inflammatory disease.
J Am Soc Nephrol 22: 1137–1143, 2011.
33. Membranous Nephropathy
(Part 2)
Diagnosis (Primary vs Secondary)
Mohammed Abdel Gawad
Nephrologist – Alexandria - Egypt
Founder & Chairman of NephroTube
drgawad@gmail.com
34. Talk Outline
Steps of Management of MN
(Diagnosis & Treatment)
Evaluation
of secondary causes
Therapy:
Secondary: Treat the cause
Idiopathic: Specific
Treatment
Kidney Int Suppl. 2012;2:139-274
35. 1- Biopsy
1ry MN
Subepithelial
IgG subclass 4
Anti PLA2R
2ry MN
- Ig other than IgG (e.g. IgA, IgM),
particularly in mesangium,
subendothelial, tubular BM
deposits.
- C1q deposits
- tubuloreticular structures in the
glomerular endothelial cells
36. Serum anti PL
3- Age
4th to 5th decade
(suggesting 1ry pathology, but not
excluding 2ry causes)
- ANA - Anti dsDNA
- HBsAg - HCV Ab
- Cryoglobulins - RF
- C3 - C4
- ESR - CRP
If not 4th to 5th decade
(suggesting 2ry pathology, but not
excluding 1ry causes)
Tumor screening:
When to screen ?
How to screen?
Laurence H Beck, Richard J Glassock. UpTodate. Oct 21, 2015.
37. Serum anti PL
3- Age
4th to 5th decade
(suggesting 1ry pathology, but not
excluding 2ry causes)
- ANA - Anti dsDNA
- HBsAg - HCV Ab
- Cryoglobulins - RF
- C3 - C4
- ESR - CRP
If not 4th to 5th decade
(suggesting 2ry pathology, but not
excluding 1ry causes)
Tumor screening:
When to screen ?
How to screen?
Laurence H Beck, Richard J Glassock. UpTodate. Oct 21, 2015.
Serum complement
is usually normal in
idiopathic MN
38. Serum anti PL
3- Age
4th to 5th decade
(suggesting 1ry pathology, but not
excluding 2ry causes)
- ANA - Anti dsDNA
- HBsAg - HCV Ab
- Cryoglobulins - RF
- C3 - C4
- ESR - CRP
If not 4th to 5th decade
(suggesting 2ry pathology, but not
excluding 1ry causes)
Tumor screening:
When to screen ?
How to screen?
Take care of what is called
PURE MEMBERANOUS
LUPUS NEPHROPATHY
where no clinical or
serological evidence of SLE.
Laurence H Beck, Richard J Glassock. UpTodate. Oct 21, 2015.
39. Malignancy Screening
When to screen?
If the anti-PLA2R antibody test is negative
+ the kidney histology is consistent with secondary MN
+ there is no other clear cause of secondary MN
+ risk factors or alarm signs:
• extensive smoking history,
• guaiac-positive stools,
• unexplained anemia or weight loss
Laurence H Beck, Richard J Glassock. UpTodate. Oct 21, 2015.
41. Malignancy Screening
How to screen?
Examination:
- LN.
- Systemic exam for any mass.
- CXR
- USS Abd & Pelvis
- CBC
- Occult blood in stool
Male > 50 = PSA Female > 50 = Mammogram
Body CT Scan (± other imaging) if cause is
not evident
42. Malignancy Screening
Frequency of screening
Cancer screening should continue for a period of
five to ten years after the diagnosis of MN
(since cancers associated with MN are typically diagnosed within
this time frame.)
Laurence H Beck, Richard J Glassock. UpTodate. Oct 21, 2015.
45. Talk Outline
Steps of Management
(Diagnosis & Treatment)
Evaluation
of secondary causes
Therapy:
Secondary: Treat the cause
Idiopathic: Specific
Treatment
Kidney Int Suppl. 2012;2:139-274
46. Spontaneous complete
remission of proteinuria
5 to 30 % at five years
Spontaneous partial remission 25 to 40 % at five years
End-stage renal disease in
untreated patients
14 % at five years,
35 % at 10 years,
41 % at 15 years
Possibility of Remission
Jha V et al. J Am Soc Nephrol 2007; 18:1899.
47. MN - Risk Categories
Low Risk Medium Risk High Risk
Serum
creatinine
and creatinine
clearance
Normal Normal or
near-normal
Deteriorating
renal function
Proteinuria <4 g/day 4-8 g/day >8 g/day
Supportive
treatment
period
over 6 months
of supportive
care
over 6 months
of supportive
care
over 3-6
months
of supportive
care
Fernando C. Clin J Am Soc Nephrol 3: 905-919, 2008
48. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)
49. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)
50. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)
51. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)
52. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.
53. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)