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


Anti GBM Disease

Goodpasture’s Syndrome in old terms.

Again, one of these very renal specific diseases that can likewise cause pulmonary haemorrhage in 40-60% of cases.

Sometimes, it is easier to understand the mechanism of the disease in the first instance.

So, for whatever reason : idiopathic; a chest infection that causes damage to the pulmonary lining – hence revealing an epitope that triggers the Ab to be formed; damage to the GBM with urinary tract obstruction or lithotripsy; genetic susceptibility : HLA-DR15 (confirmed in Chinese and Japanese population and DR4 appear to be at increased risk, while those with DR1 and DR7 are at lesser risk; causes anti GBM Ab (typically IgG 1 or 3 but can also be IgA or IgM) to be made which targets type 4 collagen. If you really want to know – the NC1 domain of the alpha 3 chain -stop being a nerd. Well, they bind most strongly to alpha-3(IV) NC, but the majority also recognized alpha-5(IV) and, to a lesser extent, alpha-4(IV).

So these tiny bastards are floating around your body looking for any basement membrane to bind to and damage it – namely the GBM in your kidneys or alveolar basement membranes in your lungs. BUT!!  Patients without alveolar haemorrhage were found to also carry similar autoAb against alpha-3(IV) NC hence some sort of increase in alveolar permeability is required for access to the alveolar basement membrane. Patients with pulmonary haemorrhage were found to have some underlying lung damage – smoking, cocaine inhalation, infections, hydrocarbon exposure —- time to pack them ciggies away and  kick the coke habit.

So a patient pitches up – they can become completely anuric and alarm bells should start to ring..

Urine dip can show proteinuria (but not in the nephrotic range) and microscopy show dysmorphic red cells, white cells, red and granular casts.

Chest XRays can show pulmonary haemorrhage and a raised KCO due to increase diffusion across the alveoli because of bleeding.

You panic, stuff in a catheter,  get an urgent US to ensure they haven’t completely thrombosesd off their vasculature, take some bloods and send them off for an acute nephritic screen. And the results come back showing raised anti GBM titres but also a positive ANCA. Up to 1/3 of patient with anti GBM have a positive ANCA- mostly MPO-ANCA and blood tests of a batch of military men (they keep their blood many years in advance, why?!) who went on to develop anti GBM disease later showed that they had low levels of ANCA in the past. Mechanism moi? Not sure.

A kidney biopsy is done (of course, ain’t nephrologists for nothing) and light microscopy normally shows a crescentic GN and immunofluorescence – the pathognomonic features of linear IgG deposition along the glomerular capillaries or the distal tubules,

How to treat?

Principle 1 is to get rid of the circulating antibodies. The most efficient way is via plasmapheresis. Quick to do, stick a line in and start.

Principle 2 is to immune suppress. Steroids at 1mg/kg and taper when remission is induced or cyclophosphamide at 2mg/kg and consider azathioprine in the longer term. Of course, our good friend rituximab has also shown to be anecdotally useful.

As a general finding, those with < 30% crescents and a plasma creatinine below 265 micromol/L did well, while those with severe crescentic involvement and a plasma creatinine 354 micromol/L did poorly.

KDIGO guidelines recommend that treatment should be initiated in all patients with

  • pulmonary haemorrhage independent of kidney involvement
  • anti GBM GN at presentation UNLESS they are dialysis dependant or have 100% crescents on biopsy and do not have pulmonary haemorrhage
  • no maintenance IS for anti GBM GN
  • to consider transplantation after anti GBM Ab remain undetectable for 6 months

The predictors of kidney survival in anti-GBM GN are

  • SCr at presentation
  • the need for dialysis at presentation, and the
  • percentage of glomerular crescents

Like all autoimmune diseases, this is a shitty one to have as it is aggressive, treatment options aren’t great and although most patients spontaneously go into remission in 12 months, it can reoccur and once ESRF sets it, very few patients come of dialysis.