Membranous GN

How does it happen?

Build up of immune complexes along the GBM –> lost of podocyte foot processes –> thickening of the GBM –> sclerosis & hyalinisation of glomeruli

membranous-immunecomplex.pngImage from UNC Kidney Centre


What is seen on light microscopy?

Thickening of the GBM with little or no cellular proliferation or infiltration. As the disease progresses – chronic sclerosing glomerular and tubulointerstitial changes develop.


Image from

Long arrows show thickened GBM compared to short arrows showing tubular wall. *=mesangial expansion


Silver stain


Image from

Arrow showing ‘spikes’ along the GBM, which are new basement membrane growing in between the sup epithelial deposits.



IF ?

Diffuse granular pattern of IgG or C3 staining along the GBM.


Image from 

Diffuse granular IgG along the capillary walls


Subepithelial electron dense deposits on the outer aspect of the GBM, effacement of the foot processes of the overlying podocyte, and expansion of the GBM by deposition of new extracellular matrix between the deposits – known as ‘spikes’.

Primary/Idiopathic Membranous

  • electron dense deposits are exclusively sub epithelial and intramembranous.
  • tubular basement membrane staining is rare
  • IgG deposits are mostly IgG4
  • Staining for PLA2R and C1q
  • Staining for IgG1 and IgG3 and leukocyte invasion of the glom tuft is more in keeping with secondary MN


Causes of MN

  1. Specific targets
    1. Transmembrane receptor expressed in podocytes
      • Phospholipase A2 Receptor Ab – PLA2R Ab
      • Thrombospondin type-1 domain containing 7A (THSD7A)
    2. Peptides expressed by podocytes
      • neutral endopeptidase (from mom to child)
    3. Abs directed against other antigens
      • IgG4 against PLA2R etc
  2. Genetics
    1. PLA2R on chromosome 2q24
    2. HLA-DQA1 on chromosome 6p21
  3. SLE
    1. Stains for IgA,M and C1q with sub endothelial and sub epithelial deposits and tubuloreticular structures in the glomerular endothelial cells
  4. Drugs
    1. Penicillamine
    2. Gold
    3. Anti TNF agents
    4. NSAIDS
  5. Infections
    1. Hepatitis B with hypocomplementanaemia
    2. Hep C but less so
    3. Syphillis
  6. Malignancy
    • mostly solid tumours – prostate/lung/GI tract
    • less commonly haematological malignancy – CLL
      • deposition of tumor antigens in the glomeruli promotes antibody deposition and complement activation, leading to epithelial cell and GBM injury, and consequent proteinuria
      • in situ binding of antibodies to podocyte antigens – THSD7A & PLA2R
  7. IgG4 disease


and lastly MN can also be seen in conjunction with:

  1. Diabetes
  2. Crescentic GN – ANCA/GBM
  3. FSGS
  4. IgA
  5. Lupus


Tests to be carried out if kidney biopsy shows MN

  1. PLA2R Ab tires
  2. Complement (should be normal in just MN, but affected in SLE/Hepatitis)
  3. ANCA/dsDNA
  4. Malignancy screen


ACEi/ARB first

IS only if nephrotic AND AT LEAST ONE OF:

  1. UPCR > 400 + 50% over baseline value that has not improved since starting ACEi/ARBs AFTER 6 months
  2. Life threatening complications with nephrotic sydrome
  3. Creat increase >30% in 6-12 months AND GFR remains 25-30 with changes not explained by superimposed complications

1st line: Treat with Ponticelli regimen :

  • 6 months
  • alternative oral/IV steroids and oral CYC (preferred) or chlorambucil
  • After 6 months, manage conservatively for another 6 months
  • Can use continuous daily oral CYC/chlorambucil

2nd line (if 1st line contra indicated or resistant):

  • CNI  – CyA /Fk
    • For at least 6 months
    • IF fail : STOP CNI
    • IF remission : decrease CNI every 4-8 weeks to 50% of starting dose and continue for 1 year

– use initial therapy that worked to achieve remission
– Ponticelli can only be repeated ONCE. Do not use more than once in children




Focal segmental glomerulosclerosis – a histologic lesion which is due to injury to visceral epithelial cell or podocyte which is attached to the GBM via foot processes. Can also involve injury to parietal epithelial cells.

How is FSGS formed in the kidney?

  1. Podocyte injury


2. Sclerosis



  1. Insidious onset of nephrotic syndrome
  2. Microscopic haematuria with varying ranges of proteinuria
  3. Hypertension
  4. Renal insufficiency

Primary/Idiopathic FSGS

  • most often presents with nephrotic syndrome
    • Causes postulated:
      • High level of suPAR (soluble urokinase plasminogen activating receptor)
        • induces FSGS in mice
      • Expression of microRNA in podocytes leading to down regulation of Wilms Tumour protein (important for a variety of genes involved in podocyte function) may be an intracellular mechanism responsible
        • found in glomeruli of patients with acquired (non genetic) FSGS

Secondary FSGS

  • normally non-nephrotic range proteinuria with some CKD
  • result from scarring due to a previous injury
    • Focal proliferative GN, e.g. active IgA, lupus nephritis, vasculitis
    • Hereditary nephritis, e.g. Alport’s
    • Membranous
    • TMA
  • refers to FSGS due to adaptive response/compensation to hyper filtration or glomerular hypertrophy
    • Disorders with reduced renal mass and/or renal vasodilation, e.g. unilateral renal agenesis, CAN
    • Renal vasodilatation e.g. in diabetes, sickle cell anaemia, Type 1 glycogen storage disorders, familial autonomic insufficiency
    • Intraglomerular hypertrophy/hyperfiltration e.g. due to severe pre eclampsia, anabolic steroid use, interferon use and obesity
    • Prior nephron loss e.g. reflux nephropathy
    • Ischaemia e.g. in benign hypertensive nephrosclerosis
  • Infections/Virus Associated
    • HIV (HIVAN)
    • Parvovirus B19
  • Toxins/drugs
    • CyA, pamidronate/alendronate, heroin, interferon-a, Lithium
  • Genetic abnormalities/Familial
    • Autosomal dominant with variable penetrance.
    • Normally steroid resistant
    •  NPHS1 – nephrin (can be tested), NPHS2 – podocin (can be tested), alpha-actinin-4, the TRPC6 ion channel, CD2AP
    • 2ndy FSGS familial forms copy
    • Microsoft Word - cqn_61_Figures
      Parts of the podocyte where genetics can cause podocytopathy
  • renal atherothromboembolic disease
  • Malignancy
    • Lymphoma

Differentiation between primary and secondary FSGS

  • Primary normally presents with acute or subacute onset of nephrotic syndrome; secondary will have non nephrotic range proteinuria, presenting with increasing proteinuria and rising Cr over a period of time
  • Histologically, primary FSGS has diffuse foot process fusion; in secondary FSGS, this tends to be focal and limited to the sclerotic areas
  • Treatment wise, 50-60% of primary FSGS respond to steroids while aim of treating secondary FSGS is to reduce intraglomerular pressure, i.e. with the use of ACEi.

Diff FSGS copy

And as if that isn’t enough, someone decided that FSGS can also be subdivided to their histologic variants.


  • fsgs_4-types

Collapsing variant associated with

  • Parvovirus
  • APOL1 gene
  • Bisphosphonate therapy

APOL1 – Apolipoprotein L1 gene

  • An important gene to talk about.
  • Polymorphism in the region of MYH9 on chromosome 22
  • Common in African Americans vs European (60% vs 4%)
  • Increase risk of FSGS and HIVAN
  • Defense against a subspecies of Trypanosomes, conferring an advantage against the sleeping sickness


KDIGO Definition of FSGS in Adults

Classification Definition
Complete remission <0.3g/d proteinuria

Normal Cr

Albumin >35

Partial remission 0.3-3.5g/d

Cr change <25% OR


Decrease > 50% Cr and change in Cr <25%

Relapse >3.5g/d after complete remission
Frequent relapse Not defined
Steroid dependent 2 relapses during therapy OR

within 2 weeks of completing steroid therapy

Steroid resistant Persistence of proteinuria despite pred 1mg/kg/d or 2mg/kg/d alt day for >4months

Initial treatment

Only FSGS with nephrotic syndrome – steroids/IS therapy

1st line therapy : Steroids to be given at 1mg/kg/d (max 80mg) or 2mg/kg/d alt days (max 120mg)

Treatment continuation for steroids

  • Min 4 weeks to max 16 weeks, as tolerated
    • Until remission has been achieved or 16 weeks, whichever is earlier
  • Tapered over 6 months when remission achieved
  • If steroids CI e.g. diabetes/osteoporosis/psychiatric condition
    • 1st line therapy : CNIs


  • 1st line : oral cyclophosphamide 2-2.5mg/kg/d for 8 weeks
  • 2nd line: relapse despite cyclo/wish to protect fertiliity : CNI; Fk 0.05-0.1mg/kg/d or CyA 3-5mg/kg/d in divided doses
  • 3rd line : if not tolerant of steroids/cyclo/CNIs : MMF 500-1g BD for 1-2 years

Steroid resistant FSGS

  • CyA 3-5mg/kg/d in divided doses for 4-6 months
    • if partial/complete remission, continue with slow taper for at least 12 months
  • If CyA NOT tolerated
    • MMF and high dose dexamethasone


Membranoproliferative glomerulonephritis, i.e. mesangiocapillary glomerulonephritis.

What a bloody mouthful.

Again, one of the GNs that just sound difficult in medical school and needs some thinking into it. The problem is that the definitions and classifications have been changed multiple times throughout the years and what I learned 10 years ago is probably not relevant anymore now.

Anyhow, I digress.

Firstly – MPGN has characteristic changes on LIGHT MICROSCOPY.

  • Immune complex/complement factors deposit onto the GBM, leading to thickening of the GBM. This then leads to inter positioning of the mesangium & endothelial cells  with the GBM leading to laying down of new GBM; hence double contouring of the glomerular capillary walls.
  •  This also leads to mesangial hypercellularity and endocapillary proliferation, causing a lobular appearance of the glomerular tuft.

Electron microscopy (EM) in immunoglobulin-positive MPGN typically demonstrates subendothelial and mesangial deposits. EM does not differentiate immune complex or complement mediated MPGN.

MPGN can be classified into 2 separate entities:

Immune complex mediated – c3 and Ig staining along capillary wall in a granular pattern vs linear pattern in anti GBM  :


i)chronic infections (HCV : shows granular deposition of IgM, C3, and both kappa and lambda light chains +/- IgG; HBV, TB, coxiella, brucella, nocardia) or carrier state (mycoplasma, Neisseria, strep) -> this causes chronic low grade Ab production.

ii)Monoclonal gammopathies like MGUS (deposition of monotypic kappa or lambda light chains but not both), and less likely, myeloma, Non Hodgkin’s lymphoma and CLL.

iii) Autoimmune diseases :  typically characterized by the “full house” pattern of immunoglobulin deposition, including IgG, IgM, IgA, C1q, C3, and kappa and lambda light chains. Most common is SLE, followed by Sjogren’s and then RA

Recurrence of MPGN with monoclonal IgG deposits has been described in transplanted kidneys (idiopathic immune complex mediated MPGN)

Complement mediated – dysregulation and persistent activation of the alternative complement pathway. Immunoflorescence demonstrates bright c3 staining (No Ig in the mesangium and capillary walls). Complement can be low or not, especially in the chronic phase of DDD and C3GN


Dense Deposit Disease – activation of the alternative complement pathway (negative staining for C1q and C4 which is the classical complement pathway)

EM shows characteristic sausage-shaped, wavy, densely osmophilic deposits along the glomerular basement membranes (GBM) and mesangium.

Aetiology is likely due to an absence of a constitutive inhibitor of the alternative complement pathway (factor H) or the presence of a circulating autoantibody (C3 nephritic factor; CNefs) that binds to and prevents inactivation of the alternative pathway C3 convertase (80% have elevated levels).

External manifestations:

  • drusen in Bruch’s membrane of the retina (like macular deposits in age related macular degeneration, however, drusen in DDD occurs at a much younger age).
  • Acquired partial lipodystrophy characterized by loss of subcutaneous fat in the upper half of the body

DDD is also occasionally diagnosed in older adults, some of whom have been found to have an underlying monoclonal gammopathy

Age of onset 5-15 years
ESRF in 50% by 10 years

C3 glomerulonephritis

C3GN has also been reported in association with monoclonal gammopathies and anti-factor H activity, as well as with inherited disease due to mutations in the CFHR5 gene (CFHR5 nephropathy) and a mutation producing a CFHR1-CFHR3 hybrid gene.

Similar appearances in light microscopy and immunoflorescence BUT EM demonstrates deposits that are similar to those seen with immune complex-mediated MPGN but does not show the typical sausage-shaped intramembranous and mesangial deposits observed in DDD

CFHR5 nephropathy – a familial form of C3GN, in cypriot families  due to a mutation in the gene for complement factor H-related protein 5. Autosomal dominant with 90% penetrance. Can reoccur in transplanted kidney.
IgA like phenotype, Greek Cypriot patient can present with haematuria after a LRTI

What if one gets sub epithelial deposits and sub endothelial deposits too ? If they are both complement + and Ig + , post infections GN is what is happening. What if its complement + but Ig – ? It could be resolving post infections GN, OR undiagnosed C3GN – check their complement pathway!!

And finally, MPGN features but negative for complement or immunoglobulins?

  • TMA : TTP, HUS, drug induced
  • Antiphospholipid Ab Syndrome
  • Nephropathy associated with bone marrow transplantation
  • Chronic renal allograft nephropathy
  • Radiation nephritis
  • Malignant hypertension


Treatment, according to KDIGO

Treat if:

  1. Nephrotic syndrome AND
  2. progressive decline in GFR AND OR
  3. Crescents

With immunosuppression, COMBINED

ie steroids + MMF or CYC

Therapy < 6 months