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Nephritic end of the spectrum

Educational resources for renal medicine

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In preparation ...

Now to the other end of the spectrum. , There are again 3+2 causes.

Nephritis and nephritic syndrome Causes - Manifestations

The description of nephritic synrome in all the textbooks is of an acute diseease with smokey or red urine, oliguria, hypertension and oedema. It comes from post-infectious or post-streptococcal glomerulonephritis, which may still be the most common of all these diseases worldwide, but which is now a rare disease in Western Europe, just like that other post-streptococcal syndrome, rheumatic fever.

Causes

It is still very common though in the third world, and some Eastern European countries that experienced economic collapse at the end of the 20th century saw big increases in incidence then.

The other rare disease on this list is anti-GBM disease, although this remains the archetypal aggressive and destructive disease, the immunology of which has taught us a lot about how glomeruli are damaged. The target antigen is also present in the alveolar basement membrane, so some patients present with teh combination of alveolar haemorrhage and rapidly progressive renal disease known as Goodpasture syndrome. [needs pics] However small vessel vasculitis is a more common cause of simultaneous aggressive nephritis and lung haemorrhage.

IgA immunofluorescence

... In Western Europe, typical acute nephritic syndrome is now more likely to be due to an exacerbation of IgA nephropathy, but this is just one of several presentations. This deposition of immunoglobulin A is the shared by all presentations, and the commonest appearance on a renal biopsy is an expansion of the mesangial matrix, and increase in the number of mesangial cells, as seen here. [get pic]

IgA nephropathy text - map

IgA nephropathy is the commonest type of glomerulonephritis in western Europe, and is also extremely common worldwide, although as this figure shows, its incidence varies enormously. The figures show the proportion of renal biopsies with IgA disease as the diagnosis, and this can be influenced by how aggressively you biopsy people with relatively mild renal disease. There seem to be strong genetic influences though, for example the condition seems to be rare not just in Africa, but also in African Americans in the USA, as shown by the 2% figure in brackets.

Presentations graph

An important feature of IgA nephropathy is that it is usually a very slowly evolving disease, grumbling over years and decades. It may present at any age, but the typical presentation varies at different ages.

Henoch Schonlein purpura is most often a childhood illness with rash, abdominal pain and haematuria.

The haematuria is caused by glomerulonephritis, and in children is usually mild. When this condition occurs in adults the glomerular disease is usually more severe. In both though, it is accompanied by IgA deposition in the mesangium. The disease is in fact a small vessel vasculitis and we will mention it again.

Students and others in their 20s who have this disease may notice red urine with a respiratory infection, and during these exacerbations they may also have hypertension and oedema, and renal impairment, just like post-streptococcal nephritis. Unlike childhood Henoch Schonlein purpura though, the urinary abnormalities and sometimes the hypertension and renal impairment do not completely resolve.

The next presentation is associated with pre-employment or pre-insurance medical examinations, when asymptomatic urinary abnormalities, with or without hypertension, are picked up. This group usually has no symptoms.

Alternatively the disease may be diagnosed a decade or several decades later by which time glomerular filtration rate has often been lost, and sometimes the patient may be near endstage renal failure, but still show haematuria and proteinuria.

Are these patients all the same? They certainly overlap, although most who present late give no history of red urine, or Henoch-Schonlein type rash, and neither are all those who present early necessarily fated to develop endstage renal failure. They are at increased risk of it though.

 

Vasculitis and FNGN

In this biopsy, there is a segmental lesion of the glomerulus at 12 o'clock. However there are no normal nuclei in it apart from the fragments associated with dying cells. This segment of glomerulus is necrotic - focal necrotising glomerulonephritis, caused by small vessel vasculitis within glomeruli. Even more obviously, the interstitium around the glomerulus is very inflamed too.

... crescent beginning

Severe nephritic disease like this can trigger an important chain of events that is just beginning in this picture. You can see a fibrin thrombus in two capillary loops, and in the lower one the fibrin is leaking into Bowman's space, where it has caused parietal epithelial cells to proliferate - the beginning of crescent formation. Crescents are a feature of the most aggressive nephritic diseases.

Severe crescentic nephritis

In this much more advanced example, all glomeruli have been affected by a catastrophic disease that has caused fragmentation of GBM in some glomeruli, and also rupture of Bowman's capsules, which seems to reduce the chances of healing.

Causes of crescents

Here is a short list of conditions that cause crescentic nephritis. Any nephritic, GBM-breaking type of nephritis can cause it if it is behaving at its most aggressive, but these are the most common causes.

They can cause renal function to deteriorate over days to weeks.

Top of the list of causes is vasculitis, inflammation of blood vessels.

Vasculitis classification diagram

Vasculitis is classified by the size of vessels it affects, so the types we're talking about that affect glomeruli are causes of small vessel vasculitis, towards the right of this diagram. Sometimes vasculitis occurs in other diseases, but most commonly glomeruli are affected by the primary types of small vessel vasculitis.

HSP pic again

Henoch Schonlein purpura, which we mentioned as a variant of IgA nephropathy earlier, is one of these.

This patient also had a vasculitic skin rash caused by exactly the same kind of process.

However the major group comprises the ANCA-associated types of vasculitis. The subtypes are not so important, as initial appearances and management are the same, but the most common are microscopic polyangiitis and Wegener's granulomatosis.

ANCA pic

ANCA are anti-neutrophil cytoplasm antibodies - as shown here, these bind to targets in the cytoplasm of normal neutrophils: in fact to the neutrophil granule enzymes myeloperoxidase and proteinase 3. They are very useful but not infallible guides to diagnosis in small vessel vasculitis.

Systemic vasculitis text

Systemic vasculitis can affect any organ with blood vessels in it - so that's any organ. It can occur in association with other diseases such as rheumatoid arthritis or systemic lupus erythematosus, but most that affect the kidney are primary. Most important of all, they are highly treatable.

Diagnosis of vasculitis text

They often present as a systemic illness that begins very non-specifically, may evolve to include arthralgia or arthritis, and weight loss is common.

I mentioned that ANCA can be very useful, but they aren't always positiv, and sometimes can be positive in other circumstances, particularly infection. Infection is an important differential diagnosis as conditions such as endocarditis may cause similar symptoms and signs and yet need very different treatments.

FNGN biopsy again

Biopsies of affected organs are very useful. In ANCA-associated vasculitis there is evidence of involvement of small blood vessels with little or no antibody deposition - so-called 'pauci-immune' glomerulonephritis. In Henoch Schonlein purpura you see IgA deposits in the mesangium.

Therapy graph

This is why it's important to make the diagnosis: here is a patient who presented with rapidly deteriorating renal function caused by crescentic nephritis, and high titres of anti-myeloperoxidase antibodies, in other words of antineutrophil cytoplasm antibodies, ANCA. Immunosuppression with cyclophosphamide and prednisolone, and plasma exchange, salvaged renal function and probably also prevented the patient from dying from vasculits affecting other organs.

Renal disease may be grumbling but is often progressing rapidly before the diagnosis can be made. Involvement of glomeruli is often associated with similar involvement of alveoli, leading to the combination of alveolar haemorrhage with rapidly progressive renal failure.

SLE histology ... immunofluorescence

The last condition is this one. You can see a glomerulus with far too many cells, proliferative glomerulonephritis, and with some capillary loops that are grossly thickened by immune deposits, as shown at two o'clock.

Immunofluorescence shows deposition of multiple immunoglobulins.

Lupus nephritis text

This is lupus nephritis. Systemic lupus erythematosus, SLE, most commonly affects young women, causing predominantly arthritis and systemic illness, and multiple other possible autoimmune manifestations. Antibodies to double-stranded DNA are characteristic. Significant renal disease is regarded as a marker of more severe lupus, though minor urinary abnormalities are probably common. Hypertension is usual but other manifestations, and histological appearances, are very useful. You just saw an example of diffuse proliferative glomerulonephritis, which responds to fairly heavy immunosuppression with cyclophosphamide along with prednisolone. Cyclophosphamide is usually given in monthly pulses, to keep side effects down, for up to a year. Alternative agents are being developed. Lupus is generally a chronic disease and there is a high risk of recurrent disease which means that most patients need to remain on immunosuppressive treatment for years.

 
Page last modified 04.03.2012, 23:18 by Neil Turner. edrep and edren are produced by the Renal Unit at the Royal Infirmary of Edinburgh and Univ. Edinburgh. CAUTIONS and Contact us. Note that the information published here is primarily intended for education, not for clinical care.