Update info on Membranous Nephropathy from KDIGO, uptodate and other renouned textbook reference.

1. NEPHROLOGY MORNING SESSION
BY: DR. K. M. NAHID UL HAQUE
DEM STUDENT
Membranous
Nephropathy

2. Membranous Nephropathy
Membranous nephropathy (MN) is among the most
common causes of the nephrotic syndrome in
nondiabetic adults accounting for up to one-third of
biopsy diagnoses. (Uptodate19.2)

3. Membranous Nephropathy
Membranous GN may be Idiopathic or Secondary.
IMN is more common in adults approximately 75 %
of cases /uptodate 19.2
Secondary MN is more common in children (75%)
than adults (25%) /KDIGO
MN is typically a disease of adults (fewer than 3% of
cases are found in children) and primary cause of
Nephrotic syndrome in adults. /KDIGO

4. Why Called Membranous ???
Primary pathology involved in thickening of
glomerular basement membrane due to sub
epithelial deposits.

5. Clinical Features
The commonest presentation of IMN is nephrotic
syndrome with preserved kidney function.
The disease course may be punctuated with
spontaneous remissions and relapses.
KDIGO

6. About 80% of adults
with IMN have
nephrotic syndrome at
presentation.
About 50% of patients
with persistent high-
grade proteinuria
eventually progress to
ESRD.
About 20 % adults
presets with
subnephrotic
proteinuria.
KDIGO
Clinical Features

7. Clinical Features
Because the underlying pathology is due to the
gradual accumulation of subepithelial deposits and
resultant podocyte damage, the features of the
nephrotic syndrome, especially weight gain and
lower extremity edema, develop at a slower pace
than that observed in patients with minimal change
disease or primary FSGS; thus, the precise onset of
disease is less likely to be noticed by the patient or
clinician.
Uptodate 19.2

8. Clinical Features
Approximately 70 percent of patients have normal
blood pressure and glomerular filtration rate (GFR)
at presentation.
 Acute renal failure (ARF) is uncommon, and may be
due to hypovolemia due to aggressive diuresis, acute
interstitial nephritis due to diuretics or other
offending drugs or rarely from acute renal vein
thrombosis leading to renal infarction.

9. Clinical Features

10. Natural History
Spontaneous complete remission of proteinuria
occurs in 5 to 30 percent at five years.
Spontaneous partial remission (≤2 g of proteinuria
per day) occurs in 25 to 40 percent at five years.
The occurrence of ESRD in untreated patients is
approximately 14 percent at five years, 35 percent at
10 years, and 41 percent at 15 years.
Uptodate 19.2

11. Differential Diagnosis
Minimal change disease.
Membranoproliferative glomerulonephritis.
Focal segmental glomerulosclorosis.
Medscap

12. Pathology
Diagnostic features include capillary wall thickening
but normal cellularity.
Thickening of the capillary walls is due to gradual
accumulation of subepithelial deposits (IgG and C3)
and resultant podocyte damage.
In some cases the injury is focal and segmental.
KDIGO

13. Diagnosis - MN
The diagnosis of MN is made on kidney biopsy.
 On light microscopy: Features include capillary wall
thickening, normal cellularity.
On immunofluorescence: IgG and C3 deposition
along the capillary walls. In IMN, deposition of the
IgG4 subclass of IgG is dominant, whereas other IgG
subclasses dominate in secondary forms of MN
On electron microscopy: Subepithelial deposits.

14. Membranous Vs Normal Glomeruli

15. Fluresence Microscopy

16. Electron Microscopy

17. Idiopathic Vs Secondary
The diagnosis of IMN is made by exclusion of
secondary causes using-
 History
 Physical exam
 Apppropriate laboratory tests (e.g., serology, imaging) and
 By careful examination of the kidney biopsy by light,
immunofluorescence, and electron microscope.

18. Why Idiopathic Vs Secondary diagnosis is necessary?
Distinguishing secondary MN from IMN is very
important, since the therapy in the former must be
directed at the underlying cause.
Some of the treatments for IMN ( e.g.
immunosuppressive agents) are potentially toxic
both to the patient and for the kidney.
Perform appropriate investigations to exclude
secondary causes in all cases of biopsy-proven
MN.

19. Phospholipage A2 Autoantibodies
A recent study has shown that about 70–80% of
IMN patients exhibit circulating antibodies of IgG4
subtype against the M-type phospholipase A2
receptor.
Such autoantibodies appear to be absent or very
uncommon in patients with secondary MN.
Studies are needed to validate the utility of antibody
against M-type phospholipase A2 receptor in terms
of its accuracy in separating primary from secondary
MN.

20. Phospholipage A2 Autoantibodies
If the absence of autoantibodies to phos-pholipase
A2 receptor in secondary MN is validated and a
sensitive and specific assay for autoantibodies
becomes available, it could become a valuable
marker to positively identify (‘‘rule in’’) IMN.
 The IgG4 subclass dominates in the deposits of
IMN, while IgG1, IgG2, and/or IgG3 dominate in
secondary forms of MN.

21. Secondary causes
Autoimmune
Infection
Malignancy
Drugs

22. Autoimmune
 SLE
 Rheumatoid arthritis
 Mixed connective tissue
disease
 Dermatomyositis
 Systemic sclerosis
 Myasthenia gravis
 Bullous pemphigoid
 Autoimmune thyroid disease
 Sjogren’s syndrome
 Crohn’s disease
 Graft-versus-host disease
 Ankylosing spondylitis

23. Infections
 Hepatitis B
 Hepatitis C
 Human immunodeficiency
 Malaria
 Schistosomiasis
 Filariasis
 Syphilis
 Enterococcal endocarditis
 Hydatid disease
 Leprosy

24. Malignancies
 Carcinomas
 Lung
 Esophageal
 Colon
 Leukemia
 Breast
 Stomach
 Mesothelioma
 Melanoma
 Ovary
 Prostate
 Oropharynx

25. Drugs/ Toxins:
 Penicillamine
 Lithium
 Probencid
 Murcury
 NSAID
 Captopril
 Clopidogrel
 COX-2 inhibitor
 Formaldehyde
 Hydrocarbon

26. Common Causes
 Systemic lupus (in younger women)
 Chronic hepatitis B infection(especially in East Asia)
 Drugs (such as NSAID, penicillamine, gold and mercury).
 Malignancy- esp. over the age of 65 years.

27. Prognosis
1/3 Rule:
Third of the case will go spontaneous remission.
Third of the case will continue heavy proteinuria but
normal kidney function.
Third of the cases will develops ESRD.
Ref:Pocket Tutor Renal Medicine/By Oliveria

28. Prognosis
Complete remission of nephrotic syndrome predicts
excellent long-term kidney function & patient
survival.
A partial remission also significantly reduces the risk
of progression to ESRD.
The primary aims of treatment, therefore, are to
induce a lasting reduction in proteinuria.
KDIGO

29. Definitions of complete and partial remission
Complete Remission: Urinary protein excretion <0.3
g/d confirmed by two values at least 1 week apart,
accompanied by a normal serum albumin
concentration, and a normal SCr.
Partial Remission: Urinary protein excretion <3.5 and
a 50% or greater reduction from peak values;
confirmed by two values at least 1 week apart,
accompanied by an improvement or normalization of
the serum albumin concentrationand stable SCr.
KDIGO

30. All currently used treatment modalities have
significant toxicity; therefore, selecting
patients at high risk of progression is
important so that exposure to treatment-
related adverse events is minimized.
Treatment

31. Treatment
Non immunosuppressive therapy
Immunosuppressive therapy
Uptodate 19.2

32. Non Immunosuppressive Therapy
1. Angiotensin inhibition
2. Control of blood pressure
3. Lipid lowering agents
4. Anticoagulation
Uptodate 19.2

33. Non immunosuppressive therapy
1. Angiotensin inhibition:
 The evidence for a renal protective effect with an ACE inhibitor or an
ARB is relatively weak among patients with MN.
 Possible benefits with use of an ACE inhibitor or ARB were noted in
a study from the Spanish Group for the Study of Glomerular Disease
(GLOSEN), which retrospectively examined the outcomes of 328
patients with MN and nephrotic range proteinuria (>3.5 g/day).
 Although none were treated with immunosuppressive medication, 67
percent of patients received either an ACE inhibitor or ARB and 32
percent developed complete or partial remission.
Uptodate 19.2

34. Angiotensin Inhibition cont…
 However, because this was not a randomized controlled trial, it is not
possible to draw definitive conclusions about the benefit of ACE
inhibitors or ARBs on the frequency of spontaneous remission.
 Furthermore there was a significant rise in the serum creatinine
among patients who did not remit in this study, suggesting that there
is a significant hazard associated with withholding
immunosuppressive therapy in all patients while waiting for
spontaneous remission.
Uptodate 19.2

35. Non immunosuppressive therapy
2. Goal blood pressure:
 The goal blood pressure in patients with any form of proteinuric
chronic kidney disease is less than 130/80 mmHg, or perhaps lower.
Uptodate 19.2

36. Non immunosuppressive therapy
3. Lipid-lowering :
 Hyperlipidemia, with often dramatic elevations in the serum
cholesterol concentration, is commonly present in patients with
membranous nephropathy.
 The mainstay of therapy for such hypercholesterolemia is statins.
Uptodate 19.2

37. Non immunosuppressive therapy
4. Anticoagulation:
 Patients with MN, are at increased risk for thrombotic events,
such as deep vein and renal vein thrombosis or pulmonary
embolism.
 All patients who have a thromboembolic event should be
treated initially with low molecular weight or unfractionated
heparin, followed by oral anticoagulation (eg, warfarin).
Uptodate 19.2
 Patients with IMN with marked reduction in serum albumin
(o2.5 g/dl) and additional risks for thrombosis, be considered
for prophylactic anticoagulant therapy, using oral warfarin.
KDIGO

38. Immunosuppressive Therapy
Selection of adult patients with IMN to be considered for
treatment with immunosuppressive agents when at least one
of the following conditions is met:
 Urinary protein excretion persistently exceeds 4 g/d & remains at
over 50% of the baseline value & does not show progressive decline,
during antihypertensive and antiproteinuric therapy during an
observation period of at least 6 months.
 The presence of severe, disabling, or life-threatening symptoms
related to the nephrotic syndrome.
 SCr has risen by 30% or more within 6 to 12 months from the time of
diagnosis but the eGFR is not less than 25–30 ml/min per 1.73 m2
&
this change is not explained by superimposed complications.
KDIGO

39. Immunosuppressive Therapy cont..
Do not use immunosuppressive therapy in patients with a
 S. Cr persistently 3.5 mg/dl (430µlmol/l)
eGFR <30 ml/min per 1.73 m2
Reduction of kidney size on ultrasound (e.g. <8 cm in length)
Those with concomitant severe or potentially life-threatening infections.
KDIGO

40. Immunosuppressive Therapy
Corticosteroid mono-therapy is not recommended
for initial therapy of IMN.
KDIGO

41. Ponticelli Regimen
Month 1: i.v. methylprednisolone (1 g) daily for three
doses, then oral methyprednisolone (0.5 mg/kg/d)
for 27 days.
Month 2: oral cyclophosphamide (2.0 mg/kg/d) for
30 days
Month 3: Repeat Month 1
Month 4: Repeat Month 2
Month 5: Repeat Month 1
Month 6: Repeat Month 2
Latest KDIGO recommendation

42. Other Agents
Oral chlorambucil
 Cyclosporine
Tacrolimus
Rutiximab
ACTH – on trial.

43. Risk Benefits
 Opportunistic infection
 Reactivation of viral hepatitis
 Alopecia
 Gonadal damage
 Hemorrhagic cystitis
(cyclophosphamide only)
 Neoplasia
 Transitional cell carcinoma of
the bladder, ureter or pelvis
 Toxic hepatitis
 Prevention of CKD and ESRD
 Avoidance of complications of
nephrotic syndrome
(thrombosis, accelerated
atherogenesis)
 Prolongation of life; improved
quality of life
KDIGO
Immunosuppressive Therapy

44. Relapsing patients
KDIGO suggest that relapses of nephrotic syndrome
in IMN be treated by reinstitution of the same
therapy that resulted in the initial remission.

45. Resistant cases
Patient who fail to response to cyclical
cyclophosphamide/corticosteroid therapy a trail of
Rutiximab/other agent can be given.
Uptodate 19.2

46. Thank you all