Glomerulonephritis

Yes, I'm skipping ahead to another pathology lecture. Yes, I know that I've written more about pathology than about any other field this year. Unfortunately, pathology is the area that I've been struggling with the most, so it's the area I'm writing about the most, and unless anyone comments asking for me to cover a different topic, I'm just going to keep ploughing ahead.

This lecture was long, but it only had one learning outcome: "Classify glomerulonephritis with reference to aetiology, pathogenesis, clinical presentation, key morphological findings and natural history." I will be using my own headings for this post instead.

Clinical Presentations of Renal Disease

There are four (or five, depending on how you count them) main presentations of renal disease: acute renal failure, chronic renal failure, nephritic syndrome, and nephrotic syndrome. There is also rapidly-progressing glomerulonephritis, which is a subset of nephritic syndrome. Renal diseases are very common: around 40% of adults over 75 will have indicators of chronic kidney disease, and this number is even higher in Indigenous populations.

Acute renal failure

Acute renal failure is characterised by azotaemia, which is a rapid rise in serum urea and/or creatinine (a marker of renal function). There may also be uraemia, which is essentially just symptomatic azotaemia (symptoms include lethargy, decreased appetite, shortness of breath, peripheral neuropathy, and oedema). Other symptoms include oliguria (reduced urine output), or maybe even anuria (no urine output). Symptoms arise over days to weeks and may completely resolve (though there is a chance of progressing to chronic renal failure).

Causes of renal failure can be classified into three categories: pre-renal, renal, and post-renal. Pre-renal causes encompass basically anything that affects the blood supply to the kidneys. Renal failure encompasses intrinsic kidney diseases, and post-renal causes encompass anything that affects urine outflow.

Chronic renal failure

Chronic renal failure is basically the same as acute renal failure, but it is over a longer period of time (months to years). Furthermore, chronic renal failure is irreversible and will eventually progress to end-stage renal failure, defined as a glomerular filtration rate of less than 5% of normal. Treatment of chronic renal failure aims to delay progression.

Nephritic syndrome

Nephritic syndrome is a set of symptoms that includes azotaemia/uraemia, oliguria, macroscopic haematuria (blood in the urine that you can see), mild/moderate proteinuria, and hypertension. It is usually caused by glomerulonephritis (disease that affects the glomerulus). Rapidly-progressive glomerulonephritis (RPGN) is a subset of nephritic syndrome in which the rise in serum urea and creatinine is very rapid. RPGN is usually due to a subset of glomerulonephritis called crescentic glomerulonephritis.

Nephrotic syndrome

Nephrotic syndrome is a set of symptoms that includes proteinuria (>3.5g/24h), hypoalbuminaemia, peripheral oedema, hyperlipidaemia, and lipiduria. Nephrotic syndrome, like nephritic syndrome, is usually due to glomerulonephritis. If glomerulonephritis increases the permeability of glomerular capillaries, proteins can leak out into the urine, resulting in proteinuria. Since protein is leaving the body through the urine, there is low protein in the serum, leading to hypoalbuminaemia and a reduced serum oncotic pressure, which in turn can lead to peripheral oedema. At the same time, there is increased hepatic lipid synthesis, leading to hyperlipidaemia and eventually lipiduria.

Glomerulonephritis

I've mentioned glomerulonephritis before, but what is it exactly? Well, glomerulonephritis refers to a range of diseases that affect the glomeruli of the kidneys. Most of these diseases are mediated by the formation of immune complexes or structural issues. Diagnostic tools for glomerulonephritis include light microscopy, immunofluorescence, and electron microscopy. Glomerulonephritis can be iether primary or secondary: primary glomerulonephritis has no identifiable cause, whereas secondary glomerulonephritis is due to a recognisable cause (e.g. drugs, infections, etc.).

Glomerulonephritis can present in different ways, depending on the specific disease. Some types of glomerulonephritis have a presentation resembling nephrotic syndrome, whereas others have a presentation resembling nephritic syndrome. In this post, I'll be starting with the most "nephrotic" types of glomerulonephritis and working my way towards the most "nephritic" types of glomerulonephritis.

Minimal change disease

Minimal change disease is a type of glomerulonephritis that mainly affects children and presents with nephrotic syndrome. It is a disease mediated by structural changes, in particular of the podocytes surrounding glomerular capillaries. As you can guess by the name, there are minimal changes in the diagnostic tests. Light microscopy and immunofluorescence both look normal: you have to use electron microscopy to see the difference. Normal podocytes have "slit diaphragms" between the foot processes, and these "slit diaphragms" have the negative charge that repels proteins and stops them from getting into the urine. In minimal change disease, foot processes are effaced and fused together, meaning that the slit diaphragms and the repulsive negative charge are lost, allowing proteins to leak into the urine, resulting in nephrotic syndrome.

Prognosis of minimal change disease is very good in children, as it responds well to steroids in this population. The response in adults, however, is less predictable.

Membranous nephropathy

Membranous nephropathy mainly affects adults and results in nephrotic syndrome. It is mediated by immune complexes that deposit in the subepithelial space (i.e. under the podocytes but outside the basement membrane... I think). Basement membrane "spikes" (thickening of the basement membrane) appear between the deposits of immune complexes. Immunofluorescence shows granular IgG and C3.

Unlike with other forms of glomerulonephritis, primary membranous nephropathy now has an identifiable cause. Primary membranous nephropathy is due to autoantibodies to the podocyte phospholipase A2 receptor. Secondary membranous nephropathy can be all the usual suspects: drugs, infections, autoimmune diseases, etc.

Prognosis of membranous nephropathy is quite variable. 40% of patients will go into pontaneous remission. However, 40% of patients will progress to chronic renal failure. The remaining 20% of patients will have stable disease.

Focal segmental glomerulosclerosis (FSGS)

Focal segmental glomerulosclerosis (FSGS) is focal, meaning that less than 50% of all glomeruli are affected, and segmental, meaning that less than 50% of an individual glomerulus is affected. (Just for comparison: diffuse means that more than 50% of all glomeruli are affected, whereas global means that more than 50% of individual glomeruli are affected). FSGS is the most common cause of nephrotic syndrome in adults and is due to structural abnormalities in the podocytes.

As the "sclerosis" part of the name suggests, there is scarring involved in FSGS. Scarring can be seen under both light and electron microscopy. FSGS is not immune-mediated, but due to scarring, larger antibodies such as IgM may be trapped and can be identified under immunofluorescence. Sometimes, complement molecules such as C3 may be also be activated by the trapping of IgM.

Prognosis of FSGS is not the worst, but it's not the best either. Around 30% of patients respond to steroids, but the rest progress to chronic renal failure.

IgA nephropathy (a.k.a. Berger's disease)

IgA nephropathy is the most common cause of glomerulonephritis worldwide and usually affects young adults. It is immune-complex mediated and presents with nephritic syndrome (note: this is the first type of glomerulonephritis I've spoken about so far that presents with nephritic, rather than nephrotic, syndrome). Under light microscopy, there is mesangial matrix expansion and hypercellularity, and under electron microscopy, the immune-complexes can be seen. Immunofluorescence reveals granular IgA (hence why this disease is called IgA nephropathy).

Prognosis of IgA nephropathy follows the "Rule of Thirds": around 1/3 resolve spontaneously, 1/3 have stable disease, and 1/3 progress to FSGS and/or chronic renal failure.

Post-infectious glomerulonephritis (a.k.a. acute proliferative glomerulonephritis or post-streptococcal glomerulonephritis)

Post-infectious glomerulonephritis usually affects children around 1-4 weeks after a bout of cellulitis or pharyngitis. It is immune-complex mediated and is often a response to streptococcal pyrogenic exotoxin B, which is why this disease is sometimes called post-streptococcal glomerulonephritis. (Note, however, that Streptococcus species are not the only species that can cause this disease.) Post-infectious glomerulonephritis presents with nephritic syndrome. Microscopy reveals inflammation and immune-complex deposits, whereas immunofluorescence reveals granular IgG and C3.

There is no such thing as primary post-infectious glomerulonephritis: it is always secondary to infection (hence the "post-infectious" in the name). As mentioned before, it is usually due to Streptococcus, but not always. Prognosis is very good in children, with nearly all children recovering with only conservative treatment. However, prognosis is not so good in adults: around 40% of adults with post-infectious glomerulonephritis progress to chronic renal failure.

Crescentic glomerulonephritis

As mentioned earlier, crescentic glomerulonephritis is a subset of glomerulonephritis that can present with rapidly progressive glomerulonephritis (a subset of nephritic syndrome). Crescentic glomerulonephritis is not a diagnosis- it is simply a histological pattern with an underlying cause that needs to be identified.

The "crescents" in crescentic glomerulonephritis are formed by a proliferation of parietal epithelial cells, which are epithelial cells lining Bowman's capsule. The crescents can fill up Bowman's space and block it, leading to chronic renal failure within weeks to months. There are three main categories of crescentic glomerulonephritis. Type I crescentic glomerulonephritis is characterised by anti-glomerular basement membrane (anti-GBM) autoantibodies, type II is immune complex mediated, and type III is "pauci-immune" (which I think means that there is minimal evidence of hypersensitivity).

Type I crescentic glomerulonephritis

Type I crescentic glomerulonephritis, or anti-GBM disease, involves autoantibodies against the α3 chain of the Type IV collagen in the glomerular basement membrane. These autoantibodies may cross-react with the basement membranes of other tissues, notably in the lung, resulting in a syndrome called pulmonary-renal syndrome. Pulmonary-renal syndrome is also known as Goodpasture syndrome.

Type II crescentic glomerulonephritis

Type II crescentic glomerulonephritis is immune-complex mediated and includes several types of glomerulonephritis that I've already written about above, including post-infectious glomerulonephritis and IgA nephropathy.

Type III crescentic glomerulonephritis

Type III crescentic glomerulonephritis, or pauci-immune glomerulonephritis, involves an antibody called ANCA. ANCA stands for anti-neutrophil cytoplasmic antibody, and as the name suggests, it acts against cytoplasmic enzymes in neutrophils. Type III crescentic glomerulonephritis is associated with small-vessel vasculitis, including Wegener's granulomatosis (a.k.a. granulomatosis with polyangiitis, or GPA), and Churg-Strauss syndrome (a.k.a. eosinophilic granulomatosis with polyangiitis, or EGPA). GPA involves necrotising granulomatous inflammation of the respiratory tract and kidney. EGPA is similar, but there may also be asthma and eosinophil-rich granulomas.