Post-streptococcal glomerulonephritis

I’ve had a lot of emails about glomerulonephritis lately. Most people seem to want help simplifying the mechanisms and types of glomerular diseases (this section in Robbins is looooong). So that’s what this post is about: a short (well, sort of), simplified explanation of glomerular diseases.

Before we launch into the different kinds of glomerulonephritis, it’s worth mentioning that while diseases involving other parts of the kidney have multiple causes (like toxins, hypoxia, and drug reactions), diseases involving the glomeruli are by and large immune-related. Sometimes an antibody is directed against the glomerulus; other times antigen-antibody complexes implant themselves in the glomerulus. T-cell mechanisms probably play a minor role, if any.

Most types of glomerulonephritis present with either nephrotic or nephritic syndrome – so we’ll discuss them under those two headings. A third type of glomerulonephritis, rapidly-progressive glomerulonephritis, is so nasty and fast-acting that it doesn’t really belong under either nephrotic or nephritic syndrome, so it gets its own category.

Nephrotic syndrome
Some glomerular diseases present with nephrotic syndrome, which is characterized by massive proteinuria, leading to hypoalbuminemia and edema (see Nephrotic vs. Nephritic Syndrome for a way to remember the components of nephrotic syndrome). The mechanism that ties all these glomerular diseases together is a derangement in the walls of the capillaries (which causes proteins to slip out of the blood into the urinary space). Usually, there is something wrong with the podocytes (those epithelial cells that stick their little foot process down onto the outside of the capillaries); often they are effaced (flattened down). This seems kind of counter-intuitive: if the foot processes are lost, and the cell is flat up against the capillary, wouldn’t it be harder for protein to get out into the urinary space? It turns out that as the podocytes change shape, the little filtration slits between adjacent podocytes are also damaged, making it easier for proteins to escape.

There are four diseases that account for most cases of primary nephrotic syndrome (other diseases, like diabetes, can cause nephrotic syndrome, but we’ll limit our discussion to primary diseases of the glomeruli):

  • Minimal change disease. This is a fairly benign glomerular disease that’s more common in children (in fact, it’s the most common cause of nephrotic syndrome in kids). You really don’t see any changes under the microscope (hence the name “minimal change”) – but if you look on electron micrographs, the foot processes are effaced (there are fewer actual foot processes – the whole podocyte appears to be flattened over the outside of the capillaries). Most children with minimal change disease respond well to steroids, but some relapse, and a few develop chronic renal disease as adults.
  • Focal segmental glomerulosclerosis. This disease is named the way it is because only some (focal) glomeruli are involved, and usually only a portion (segment) of the glomerulus is damaged. Focal segmental glomerulosclerosis (FSGS) can be primary (idiopathic), or it can be related to other conditions like HIV infection or heroin abuse. Some cases arise from other forms of glomerulonephritis, and rare cases are hereditary. Nobody seems to know what exactly causes FSGS, but one thing appears clear: the initiating event is podocyte injury. Proteins leak out of the blood, and for some reason, they tend to collect in places, forming masses of hyaline (pink) material that can encroach on (or even obliterate) capillary lumens. The prognosis is poor; most patients don’t respond well to corticosteroids.
  • Membranous nephropathy (or membranous glomerulonephritis). In this disease, antibodies react to antigens (either endogenous or planted) in the glomerulus, forming antigen-antibody complexes that deposit themselves along the glomerular basement membrane (GBM). This makes the capillary walls look thick, especially later on in the disease, as the immune complexes continue to accumulate. This also seems weird: if the capillary walls are so thick, how come protein can leak out? It turns out that there is a ton of complement around the areas of damage. It’s probably this complement that’s doing the damage, attacking podocytes, which respond by releasing proteases and oxidants that damage the capillary walls (causing loss of permeability).  Most cases of membranous nephropathy are idiopathic, and the clinical course is variable but often mild.
  • Membranoproliferative glomerulonephritis. There are two types of membranoproliferative glomerulonephritis (MPGN): type I (which is characterized by subendothelial – and occasionally subepithelial or mesangial – immunoglobulin and complement deposits) and type II (which is characterized by deposits of complement in the basement membrane proper). Both types show a thickened glomerular basement membrane on light microscopy; if you do a silver stain, it looks like the GBM is split into two (because mesangial cells and inflammatory cells get stuck in there). Some cases are associated with infections; others are idiopathic. The prognosis is generally poor.

Nephritic syndrome
Some glomerular diseases present with nephritic syndrome, which is characterized by hematuria, oliguria, proteinuria and hypertension (take a look at Nephrotic vs. Nephritic Syndrome to see how you might remember all these symptoms). The mechanism that ties all these glomerular diseases together is proliferation of the cells within the glomeruli, along with inflammation in the glomerulus. The inflammatory cells damage capillary walls, allowing red cells to leak out. It’s harder to pump blood through the glomerulus when it’s all stuffed full of cells, so the glomerular filtration rate goes down (leading to oliguria).

There are three main primary glomerular diseases that commonly present with nephritic syndrome:

  • Acute infectious (post-streptococcal) glomerulonephritis. This disease is pretty common. It usually happens in children after a bout of group A strep infection. The body makes antibodies to some part of the bacterium (probably), and the resulting antigen-antibody complexes get stuck in the glomerulus, irritating the glomerulus and making the cells proliferate. By light microscopy, the glomeruli look big and hypercellular. Most children recover, but some develop rapidly progressive glomerulonephritis (see below). Adults don’t fare quite as well.
  • IgA nephropathy (Berger disease). This disease is also common (it’s the most common glomerular disease worldwide). Following an upper respiratory infection, the patient (usually a child or young adult) develops hematuria, which resolves – but then comes back later and recurs every few months. Many of these patients seem to produce more IgA than normal – so after an infection of the upper respiratory tract, there is a ton of IgA around. It gets stuck in the mesangium, where it activates complement, which damages the glomerulus. The light microscopic appearance varies a lot, but if you do immunofluorescence, you can see a ton of IgA stuck in the mesangial regions of the glomerulus. Despite having recurrent episodes of hematuria, most patients do pretty well.
  • Hereditary nephritis. There are a group of hereditary diseases that have mutations in GBM proteins. The best known of these is Alport syndrome, which consists of glomerulonephritis plus deafness and eye disorders. In Alport syndrome, changes don’t show up under the microscope until late in the disease, when interstitial cells start looking foamy, glomeruli become sclerotic, tubules atrophy, and the interstitium becomes fibrotic. Most cases of Alport syndrome are X-linked and caused by a mutation in a gene encoding type IV collagen. Most male patients present with hematuria as children or young adults; renal failure usually occurs between the ages of 20 and 50 (females are usually carriers, and are often asymptomatic).

Rapidly-progressive (crescentic) glomerulonephritis
Rapidly-progressive glomerulonephritis (RPGN) is a clinical syndrome in which patients become severely oliguric and develop renal failure within a few weeks or months. It is somewhat like nephritic syndrome, in that patients are oliguric – but the rapid loss of renal function sets it apart from nephritic syndrome. There are a bunch of different causes, most of which are immune-mediated. Whatever the cause, the glomeruli in this syndrome show crescent-shaped masses of proliferating cells and leukocytes within the glomerular tuft itself. There are three main types of RPGN:

  • Type I (anti-GBM antibody). In this type of RPGN, there is linear deposition of IgG and sometimes complement on the GBM. In some patients, the IgG also binds to the GBM in lung capillaries; these patients have Goodpasture syndrome. Plasmapheresis can be helpful (it removes the nasty antibodies).
  • Type II (immune-complex-mediated). In this type of RPGN, immune complexes are found along the GBM and/or mesangium. Some cases are idiopathic, but others evolve from post-streptococcal GN, lupus, IgA nephropathy, or Henoch-Schonlein purpura. Plasmapheresis doesn’t seem to help these patients much.
  • Type III (pauci-immune). There aren’t any anti-GBM antibodies or immune complexes in this type of RPGN. Instead, there are antineutrophil cytoplasmic antibodies (ANCAs) in the serum. Some cases are idiopathic, but others are associated with vasculitides that typically have ANCAs, like microscopic polyangiitis or Wegener granulomatosis. Some of these patients have so much proteinuria that it kind of starts to look like nephrotic syndrome. Plasmapheresis is sometimes helpful.