Membranous nephropathy (MN) is a glomerular disease characterized by subepithelial immune deposits causing nephrotic syndrome in many cases. It can be primary or secondary. Evaluation of secondary causes includes screening for autoimmune diseases, viral infections, malignancies and other underlying conditions. Treatment involves treating any identified secondary cause. For primary MN, supportive care is initially recommended, with immunosuppressive therapy considered for persistent high-risk disease. Treatment options include steroids, calcineurin inhibitors and alkylating agents. Close monitoring of response is important to guide management.

1. Membranous Nephropathy
Management Algorithm
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria – EGY
drgawad@gmail.com
ESNT Outreach Program: Sohag 3-5 Dec 2015

2. To download the lecture with full
animations please contact me
drgawad@gmail.com

3. Membranous Nephropathy
• Glomerular disease:
–Nephrotic syndrome in 60% to 70%
–Normal or mildly elevated blood pressure at
presentation
–Urine:
• Benign urinary sediment
• Nonselective proteinuria
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

4. Membranous Nephropathy
• Subepithelial Immune deposits of IgG and
complement
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

5. Membranous Nephropathy
• Etiology:
Primary
(two third of cases)
Secondary
Kidney Int Suppl. 2012;2:139-274

6. Membranous Nephropathy
• Etiology:
Secondary
Kidney Int Suppl. 2012;2:139-274

7. Membranous Nephropathy
• Etiology:
Secondary
Kidney Int Suppl. 2012;2:139-274

8. Membranous Nephropathy
• Etiology:
Secondary
Kidney Int Suppl. 2012;2:139-274

9. My Starting Point
A biopsy proven diagnosis of
Membranous Nephropathy (MN)

10. 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

11. 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

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.

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 MN

15. 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 MN

16. 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 MN

17. 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

18. 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

19. Animal Model - Heymann nephritis
Megalin
Quigg RJ. Kidney Int 2003; 64:2318.

20. 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

21. Human Podocyte Antigens
Phospholipase A2 Receptor

22. Human Podocyte Antigens
Thrombospondin type - 1 domain -
containing 7A (THSD7A)
• A transmembrane protein expressed on podocytes.
• Responsible Ab in 10% of idiopathic 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.

23. Mechanism of idiopathic MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

24. Mechanism of idiopathic MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.
Qu Z et al. Nephrol Dial Transplant 27: 1931–1937, 2012

25. Mechanism of idiopathic MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

26. Mechanism of idiopathic MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

27. Mechanism of idiopathic MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

28. Mechanism of idiopathic MN
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

29. Characteristics of Idiopathic MN
Pathogenesis
• Anti PLAR2 Ab.
• Th2 Humoral immunity.
• IgG4 subclass.
• C5b9 (MAC)

30. Characteristics of Idiopathic MN
Pathogenesis
• Anti PLAR2 Ab.
• Th2 Humoral immunity.
• IgG4 subclass.
• C5b9 (MAC)

34. Serum PLA2R auto antibodies test is a
good +ve but not good -ve marker for
MN.
Anti-PLA2R Titers Clinical Significance
(1)

35. 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.

37. Anti-PLA2R
Is it only related to Idiopathic MN?
J Am Soc Nephrol 22: 1137–1143, 2011.

38. 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.

39. 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

40. Diagnostic Algorithm
Zeng CH et al. Am J Kidney Dis 2008; 52: 691–698.
To Exclude Secondary Causes

41. 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

42. 2- 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.

43. 2- 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.

44. 2- 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.

45. 2- 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

46. 2- 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.

47. 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.

48. Malignancy Screening
How to screen?
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

49. 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

50. 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.

52. 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

53. Definitions
Kidney Int Suppl. 2012;2:139-274
Jha V et al. J Am Soc Nephrol 2007; 18:1899–1904.
Urinary protein (confirmed by two
values at least 1 week apart)
Serum
albumin
S.Cr.
Complete
Remission
- Urinary protein excretion < 0.3 g/d
- uPCR < 300 mg/g or < 30 mg/mmol
Normal
Partial
Remission
- Urinary protein excretion < 3.5 g/d
- uPCR < 3500 mg/g or <350 mg/mmol
+
50% or greater reduction from peak
values

54. 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.

55. General Supportive Therapy
• Angiotensin inhibition
• Lipid lowering
• Anticoagulation (if serum albumin <2.5 g/dl and
additional risks for thrombosis)
• Diuretics to control edema, Salt restriction
• Maintenance of adequate nutrition
Laurence H Beck, Richard J Glassock. UpTodate. Oct 21, 2015.
Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

56. 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

57. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

58. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

59. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

60. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

61. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

62. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

63. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

64. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

65. IMN – Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

66. The ‘‘Ponticelli Regimen’’
Kidney Int Suppl. 2012;2:139-274

67. CNI-based Regimens
Kidney Int Suppl. 2012;2:139-274

68. Claudio Ponticelli, Richard J. Glassock. CJASN. 2014 Mar;9(3):609-16.

69. Repeat Kidney Biopsy
Kidney Int Suppl. 2012;2:139-274

72. 1- Biopsy
1ry MN
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

73. 2- 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
- Syphilis serology
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.

74. Serum complement is usually normal in
idiopathic MN
Take care of what is called PURE
MEMBERANOUS LUPUS NEPHROPATHY
where no clinical or serological evidence of SLE.

75. 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

76. Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

77. Treatment Algorithm
Kidney Int Suppl. 2012;2:139-274
Hofstra, J. M. et al. Nat. Rev. Nephrol. 9, 443–458 (2013)

78. Gawad
Thank You