In acute glomerulonephritis, the kidneys are normal in size or enlarged and oedema to us, and the surface of the kidney may show punctate haemorrhages. In long-standing progressive chronic glomerulonephritis the kidneys may be normal in size or small with finely granular cortical scarring.
Different immunological insults may induce similar or identical histological changes. For example, the immune complex-mediated glomerulonephritis in mumps is not distinguishable from that following ,B-haemolytic streptococcal infection. Conversely, different histological responses may occur in the same disease process in different individuals, e.g. in SLE .
The histological response to immune complex deposition probably depends on the size of the complexes, their rate of deposition and the efficiency of host clearance mechanisms.
Renal tissue, obtained at transcutaneous renal biopsy, is examined by:
LIGHT MICROSCOPY to assess the extent and histological type of disease.
ELECTRON MICROSCOPY to define the type of disease and to correlate with immunofluorescence, e.g. to see the exact sites of deposits.
IMMUNOFLUORESCENCE to assess the type of immunological injury. Immunoperoxidase methods may also be applied.
All three methods of examination are necessary for proper histopathological assessment. Immune complex deposition results in a diffuse granular pattern of staining, with IgG, IgM, IgA, components of the complement system and, in addition, fibrin and fibrinogen all present.
The presence of anti-GBM antibody produces a smooth linear pattern of staining for IgG on immunofluorescence.
There is not a complete correlation between the histopathological types and the clinical features of the disease the commonest associations.
PROLIFERATIVE GLOMERULONEPHRITIS. Proliferative changes occur in many immune complex-mediated nephritides and also in anti-GBM nephritis. It has the following subtypes:
1 Diffuse proliferative glomerulonephritis. All the glomeruli are similarly affected; shows the typical histological appearances. There is proliferation of endothelial and mesangial cells and several polymorphonuclear leucocytes are present. The glomerulus is swollen, packed with cells and bulges into the opening of the proximal tubule. A normal glomerulus is shown in Fig. 9.11 for comparison. Electron microscopy of the lesions shows subepithelial humps present on the glomerular basement membrane and immunofluorescence shows granular deposits of immunoglobulin and C3.
This type of glomerulonephritis, presenting as an acute nephritis, is commonly seen after a streptococcal infection .
2 Focal segmental glomerulonephritis. Only some of the glomeruli here show proliferative changes whilst others are normal, hence the term focal. The affected glomeruli show segmental involvement of the tufts, i.e. changes are present in one or more parts of the glomerulus.
This condition may occur as a primary renal clisease, but it is also seen in SLE, subacute infective endocarditis, with infected atrioventricular shunts (shunt nephritis), and in disorders with IgA deposits, e.g. Henoch-Schonlei purpura and IgA nephropathy. A severe focal necrotizing form is seen in polyarteritis nodosa and Wegener’s granulomatosis. Special subtypes (IgA nephropathy and focal glomerulosclerosis) are discussed below.
3 Proliferative glomerulonephritis with crescent formation (rapidly progressive glomerulonephritis; RPGN) or crescentic glomerulonephritis . The term ‘crescent’ is applied to an aggregate of macro phages and epithelial cells in Bowman’s space. Crescents are associated with severe damage to the glomerular tuft and are seen in occasional glomeruli in several types of glomerulonephritis.
However, if most glomeruli show crescents the glomerulonephritis is usually placed in this subtype, as clinical progression to renal failure is rapid.
This condition is seen in both immune complex and anti-GBM antibody-mediated nephritis. It particularly occurs in polyarteritis nodosa, Wegener’s granulomatosis and Goodpasture’s syndrome. 4 Mesangiocapillary (membranoproliferative) glomerulonephritis (MCGN). In type 1 there is mesangial cell proliferation,
with mainly subendothelial immune complex deposition and apparent splitting of the capillary basement membrane, giving a ‘tram-line’ effect. It may be idiopathic or may occur with shunt nephritis. It can be associated with persistently reduced levels of C3 and normal levels of C4.
In type 2 there is mesangial cell proliferation with electron-dense, linear intramembranous deposits that usually stain for C3 only. This type may be idiopathic or may occur after measles. Partial lipodystrophy (loss of subcutaneous fat in various parts of the body) may be seen. MCGN affects young adults. Patients present with haematuria, proteinuria, the nephrotic syndrome or renal failure. Most patients eventually go on to develop renal failure over several years.
MEMBRANOUS GLOMERULONEPHRITIS. Thickening of the capillary basement membrane due to immune complex deposition is the main feature of this disease. In the majority of patients the antigenic component of the complex is unknown. Associations include SLE (where the antigen is host DNA), malignancy of the bowel and bronchus (tumour-derived antigen) and penicillamine therapy. Plasmodium malariae is a common cause in the tropics. A strong association with HLA-DR3 has been found.
This condition occurs mainly in adults, predominantly in males. Patients present with proteinuria or frank nephrotic syndrome. Approximately one-third of patients develop end-stage renal failure within 10-20 years of diagnosis. Younger patients, females and those with asymptomatic proteinuria of modest degree at the time of presentation do best. Spontaneous remission occurs in about one-third of patients, particularly females. Controversy exists as to the value or otherwise of corticosteroid and immunosuppressive treatment with, for example, chlorambucil, azathioprine and cyclophosphamide, which is not surprising in view of the fact that a significant proportion of patients are destined to do well without specific treatment. It may well be that a subgroup of patients who develop progressive renal impairment benefit from such treatment.
MINIMAL CHANGE GLOMERULAR LESION (MINIMAL CHANGE NEPHROPATHY). This is not a true glomerulonephritis and is included here for convenience. In this condition the glomeruli appear normal on light microscopy. The only abnormality seen on electron microscopy is fusion of the foot processes of epithelial cells (podocytes). This is a non-specific finding and is seen in many conditions associated with proteinuria. Neither immune complexes nor anti-GBM antibody can be demonstrated by immunofluorescence. However, the immunological pathogenesis of this condition is suggested by three factors:
1 Its response to steroids and immunosuppressive drugs
2 Its occurrence in Hodgkin’s disease, with remission following successful treatment
3 Patients with the condition and family members having a higher incidence of asthma and eczema-remission following desensitization or antigen avoidance has been described. A suggested explanation for the proteinuria is the production by lymphocytes of a factor that increases glomerular permeability to protein.
Minimal change nephropathy is commonest in children, particularly males, accounting for the large majority of cases of nephrotic syndrome in childhood. The condition accounts for 20-25% of cases of adult nephrotic syndrome. It does not lead to chronic renal failure. Specific treatment is with corticosteroids, cyclophosphamide
IGA NEPHROPATHY. This disease consists of focal proliferative glomerulonephritis and mesangial deposits of IgA. In some cases IgG, IgM or C3 and properdin may also be seen in the glomerular mesangium. Glomerulonephritis in Henoch-Schonlein purpura has a similar pathological picture and is sometimes regarded as the same condition.
IgA nephropathy tends to occur in children and young males. They present with asymptomatic microscopic haematuria or recurrent macroscopic haematuria, which issometimes related to upper respiratory infection. Proteinuria occurs and 5% can be nephrotic. The prognosis is usually good especially in those with normal blood pressure, normal renal function and absence of proteinuria at presentation. Surprisingly, recurrent macroscopic haematuria is a good prognostic sign. There is no specific treatment. Up to 20% of patients eventually develop renal failure.
HENOCH-SCHONLEIN SYNDROME. This clinical syndrome comprises a characteristic skin rash, abdominal colic, joint pain and glomerulonephritis. The rash is of purpuric type and the synonym Henoch-Schonlein purpura is often used. It occurs at all ages and in both sexes, but is mainly a disease of early childhood. Males are twice as often affected as females. A recent history of infection, often respiratory) is common. The disease is rare in adults. Serum concentrations of IgA are increased in about half the patients during the first 3 months of the disease and IgA-containing immune complexes have been detected in serum in a high proportion of cases. The renal lesion is a focal segmental proliferative glomerulonephritis, sometimes with mesangial hypercellularity. Epithelial crescents may be present. Immunoglobulin deposition, mainly of IgA, is seen in the glomerular mesangium and to a lesser extent in the capillary walls on immunofluorescence. IgG, IgM and components of the complement system may also be detectable. Electrondense deposits, presumably immune complexes, are seen in the mesangium and subendothelial position on electron microscopy. No treatment is of proven benefit.
FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS).
This is a disease of unknown pathogenesis. It is particularly prone to recur in kidneys transplanted into affected individuals, sometimes within days of transplantation. A circulating factor may be involved. It presents as proteinuria or nephrotic syndrome and is usually resistant to steroid therapy. All age groups are affected. On light microscopy, segmental glomerulosclerosis is seen, which later progresses to global sclerosis. The deep glomeruli at the corticomedullary junction are affected first. These may be missed on transcutaneous biopsy, leading to a mistaken diagnosis of minimal change glomerular lesion. Immunofluorescence may show deposits of C3 and IgM in affected portions of the glomerulus, but non-specific fixation to damaged tissue, rather than immune complex deposition, may well be the explanation for this. About 50% of patients progress to end-stage renal failure within 10 years of diagnosis.