Membranous Nephropathy : Types, Epidemiology and Investigation

Definition Of Membranous Nephropathy

IgG and Complement beneath the podocyte on the subepithelial surface of the glomerular capillary wall. Podocyte Injury - increases the permeability of protein through GBN.

Types Of Membranous Nephropathy

• Primary Membranous Nephropathy
  • The antigen is present in the kidney. 
  • Anti-PLA₂R associated (70 -80%)( MOST COMMON)
  • Idiopathic (20-30%)
  • Anti -THSD7A( up to 5%)
  • Some New antigens:
    • NELL-1
    • Semaphorin 3B
• Secondary Membranous Nephropathy

• Alloimmune Membranous Nephropathy(very rare):
  • Graft-versus-host disease after hematopoietic stem cell transplantation.
  • De novo membranous nephropathy in renal allograft.
  • Fetomaternal Alloimmunization to neutral endopeptidase.

Human Membranous Nephropathy   

1. Neutral endopeptidase - podocyte protein
   • Mother is deficient in NEP
   • Anti-NEP antibodies 
   • Transmitted Transplacentally to the fetus 
   • Antenatal MN.
2. MN in chronic GVHD and allogeneic hematopoietic stem cell transplant.
3. Antibodies against M-type Phospholipase A2 receptor (Anti PLA₂R)
   • PLA₂R - Mannose Receptor Family
   • 75- 80% of primary MN
4. Antibodies against Thrombospondin type 1 domain-containing 7A-THSD7A (5-10%)
5. Antibodies against reductase, enolase, and SOD2.

• Two types of antigens:
  • Intrinsic Podocyte Antigens (already present on the podocyte membrane)
  • Extrinsic Planted Antigens (present in blood cells and then get deposited in the GBM)- cBSA

Epidemiology Of  Membranous Nephropathy

• Common in adults - Primary MN has a peak incidence in the 4^th to 5^th decades.
• Children's - rare - secondary (HBV)
• Males > Females

Clinical and Serological Manifestation

• Nephrotic syndrome - 60-70%
• Normal or mildly elevated blood pressure - 10-20 %
• Complications secondary to Nephrotic syndrome
• Features of secondary disease
• Once extensive podocyte loss, despite immunological remission - proteinuria continues( because of complement-mediated injury to GBM/podocyte)

Investigations In Membranous Nephropathy

• Benign Urinary sediment
• Nonselective proteinuria
• Microscopic Haematuria - 30-40%
• RBC cast - rare
• Serum Complement - Normal
• Increase in creatinine - <10%

Pathology Of Membranous Nephropathy

• Light Microscopy
  • Stage 1: Glomeruli and Interstitium - normal - early
  • Stage 2:
    • Homogeneous thickening of the capillary wall
    • Spike-like configuration - projections in GBM - silver methenamine
  • Stage 3 - Lucencies in GBM.
    • Leukocyte infiltration is absent, with changes in podocyte and basement membrane and no hypercellularity.
• Immunohistochemistry
  • Finely Granular capillary wall lgG - subepithelial side
  • Predominant is lgG4
  • Other lg - secondary causes
  • C3 breakdown products are present
  • Strong C1q staging - lupus-associated MN
  • PLA2r staining in immune deposits is positive - only positive glomerular stain and negative serology are possible.  
• Electron Microscopy
  • Subepithelial electron-dense deposits.
    • Stage 1 - Little change in GBM, Effacement of foot process
    • Stage 2 - Basement membrane laid down between deposits and spikes.
    • Stage 3 - Deposition of new basement membrane-like material around deposits.
    • Stage 4 - Thickened basement membrane, lucent deposit, spikes are less apparent.
  • Tubuloreticular inclusion - Lupus-associated MN

Histopathology Differentiating Primary and Secondary Membranous Nephropathy

Workup in Patients Of Membranous Nephropathy

Secondary Membranous Nephropathy

• Seen in 20-30% of patients.
• Adults malignancy is an important cause of colon, kidney, lung - solid tumors
• Hep B associated:
  • Affects adults and children - carriers 
  • Endemic area
  • With/without liver disease
  • Children - Benign course
  • Adults - progressive renal impairment amenable to treatment
• Drugs - recovers after discontinuation
  • NSAIDs - recovers after one week
  • Gold and penicillamine - recover in a longer time

Clinical Course Of Secondary Membranous Nephropathy

• Spontaneous Remission - 30%
• Female Gender, Lower level of proteinuria
• Patients with subnephrotic proteinuria - a 50% likelihood of progressing to a Nephrotic state in the next 2 years.

Predictors of Poor Outcome

Risk Categories

Significance of Anti PLA₂R

• Used for Diagnosis
• Predict spontaneous remission
• Disease activity
• Response to treatment
• Risk of Progression
• Stopping Treatment

Relapse after complete/ Partial Remission

• 25-40% - Complete Remission
• 50% - Partial Remission
• Majority - subnephrotic proteinuria, stable long-term kidney function

Treatment Of Membranous Nephropathy

• Non Immunosuppressive Therapy 
  • Control of Edema - Diuretics
  • Hypertension - RAS INHIBITORS
  • Hyperlipidemia - Statins
  • Proteinuria - RAS INHIBITORS - 30% proteinuria reduction. The effect occurs within 3 months of therapy.
  • Coagulopathy - Proteinuria > 10 gm , Serum Albumin <2.5
• Immunosuppressive Therapy
  • Persistent nephrotic-range proteinuria (>4 g/day)
  • Proteinuria has not declined more than 50% from baseline over a minimum observation period of 6 months despite maximum antihypertensive and antiproteinuric therapy.
  • Severe Disabling or life-threatening symptoms related to the nephrotic syndrome
  • Rising serum creatinine greater than 30% within 1-2 months.
  • High levels of antiPLA₂R. 
  • Ponticelli/ Modified Ponticelli Regimen
    • Alternative to Steriods + Alkylating agents.
      • Steroid:- Methylprednisolone - 1 g pulse dose x 3 days.
      • Followed by Oral -0.5mg/kg/day x 27 days.
      • Given in 1st,2nd,3rd month.
    • Alkylating agent -
      • Chlorambucil is used in the Ponticelli regimen. It is oral and given in the 2nd, 4th, and 6th months.
      • Cyclophosphamide(2-2.5mg/kg/day) - Used in Modified Ponticelli regimen -Oral, given in 2nd, 4th,6th month.

Pharmacotherapy used:

• CORTICOSTEROIDS - No use as monotherapy
• CYCLOSPORINE + STEROIDS 
  • The remission rate is 75%, which will increase to 85% by 12 months.
  • Relapse 38% within 6 months of discontinuation of therapy
  • At least 25% reduction in proteinuria takes place in 3-4 months
• TACROLIMUS + STEROIDS
  • Remission rate of 76%, Relapse rate of 50%
  • Adverse effects of CNI
  • Summary - Beneficial in long-term treatment, increases nephrotoxicity
• MMF - might not work as monotherapy
• RITUXIMAB 
  • Remission - 60-7-%
  • It can be used in patients with previously failed immunosuppressive therapy.
  • Action can be monitored by a decline in Anti PLA₂R - which causes immunological remission.
  • Lesser adverse effect

KDIGO 2012 Guidelines

• These define the appropriate investigation to rule out secondary
• Initial Therapy

1. Urinary protein excretion persistently exists at 4 g/d and remains at over 50% of the baseline value, and does not show a progressive decline during antihypertensive and antiproteinuric therapy of at least 6 months.
2. Presence of severe, disability, or life-threatening symptoms related to the nephrotic syndrome.
3. SCr has given by 30% or more within 6 to 12 months from the time of diagnosis but the GFR is not less than 25 -30 ml/min per 1.73m2 and this change is not explained by superimposed complications.

• Do not use immunosuppression if creatinine >3.5
• Prophylactic Anticoagulation when albumin <2.5
• Remission

1. Complete Remission: Urinary protein excretion <0.3 g/d ( uPCR < 300 mg/g or <30 mg/mmol), confirmed by two values at least 1 week apart, accompanied by a normal serum albumin concentration and a normal SCr.
2. Partial Remission: Urinary protein excretion <3.5 g/d ( uPCR < 3500 mg/g or <350 mg/mmol) 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 concentration and stable SCr.

• Ponticelli Regime/ Modified Ponticelli - KDIGO 2012 Guideline
  • Month 1: IV Methylprednisolone ( 1g) daily for 3 doses, then oral methylprednisolone (0.5 mg/kg/d) for 27 days
  • Month 2: Oral Chlorambucil (0.15-0.2 mg/kg/d) or 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

KDIGO 2012 - Risk and Benefit of Ponticelli Regime

KDIGO 2012 - Contraindications for Ponticelli Regimen

• Untreated Infection ( HIV, Hepatitis B and C, Tuberculosis, Fungal Infection, etc.)
• Neoplasia ( Lungs, skin[ except  squamous cell], breast, colon, etc.)
• Urinary Retention
• Inability to comply with monitoring
• Pre-existing leukopenia( <4000 leukocytes/mm³)
• SCr >3.5 mg/dl (>309 umol/l)

KDIGO PUBLIC DRAFT GUIDELINE - Risks 

KDIGO 2012 Guideline In Case Of Treatment Relapse

Hope you found this blog helpful for your NEET SS Nephrology Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.