Glomerulonephritis

Clinic

• A glomerulus, a functional unit that represents the first step in the filtration of blood and generation of urine.
• GN refers to an inflammation of the glomerulus, which is the unit involved in filtration in the kidney.
• GN typically results in one or both of the nephrotic or nephritic syndromes.
• It may present with
  • Hematuria
  • Proteinuria
  • Nephrotic syndrome
  • Nephritic syndrome

• GN is a group of disease that are categorized into
  • Non-proliferative
  • Proliferative types
• Primary causes are intrinsic to the kidney. Secondary causes are associated with certain infections (bacterial, viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis), or diabetes.

Nephrotic syndrome

• Edema due to Proteinuria and decreased protein in the blood, with increased fat in the blood.
• Inflammation that affects the cells surrounding the glomerulus, podocytes, increases the permeability to proteins, resulting in an increase in excreted proteins. When the amount of proteins excreted in the urine exceeds the liver's ability to compensate, fewer proteins are detected in the blood – in particular albumin, which makes up the majority of circulating proteins.
• With decreased proteins in the blood, there is a decrease in the oncotic pressure of the blood. This results in edema, as the oncotic pressure in tissue remains the same. Although decreased intravascular oncotic (i.e. osmotic) pressure partially explains the patient's edema, more recent studies have shown that extensive sodium retention in the distal nephron (collecting duct) is the predominant cause of water retention and edema in the nephrotic syndrome. This is worsened by the secretion of the hormone aldosterone by the adrenal gland, which is secreted in response to the decrease in circulating blood and causes sodium and water retention.
• Hyperlipidemia is thought to be a result of the increased activity of the liver.

Nephritic syndrome

• Podocytes, cells which line the glomerulus, are negatively charged and have small gaps, preventing the filtration of large molecules. When damaged by inflammation, this can result in an increased permeability to proteins
• The nephritic syndrome is characterized by
  • Hematuria (especially Red blood cell casts with dysmorphic red blood cells)
  • Decrease in the amount of urine
  • Hypertension. In this syndrome, inflammatory damage to cells lining the glomerulus are thought to result in destruction of the epithelial barrier, leading to blood being found in the urine. At the same time, reactive changes, e.g. proliferation of mesangial cells,^[which?] may result in a decrease in kidney blood flow, resulting in a decrease in the production of urine.
  • Renin–angiotensin system may be subsequently activated, because of the decrease in perfusion of juxtaglomerular apparatus, which may result in hypertension.

Types

Nonproliferative

This is characterized by forms of glomerulonephritis in which the number of cells is not changed. These forms usually result in the nephrotic syndrome. Causes include:

Minimal change disease

Minimal change disease is characterised as a cause of nephrotic syndrome without visible changes in the glomerulus on microscopy. Minimal change disease typically presents with edema, an increase in proteins passed from urine and decrease in blood protein levels, and an increase in circulating lipids (i.e., nephrotic syndrome) and is the most common cause of the nephrotic syndrome in children. Although no changes may be visible by light microscopy, changes on electron microscopy within the glomeruli may show a fusion of the foot processes of the podocytes (cells lining the basement membrane of the capillaries of glomerulus). It is typically managed with corticosteroids and does not progress to chronic kidney disease.

Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis is characterised by a sclerosis of segments of some glomeruli. It is likely to present as a nephrotic syndrome. This form of glomerulonephritis may be associated with conditions such as HIV and heroin abuse, or inherited as Alport syndrome. The cause of about 20–30% of focal-segmental glomerulosclerosis is unknown. On microscopy, affected glomeruli may show an increase in hyalin, a pink and homogenous material, fat cells, an increase in the mesangial matrix and collagen. Treatment may involve corticosteroids, but up to half of people with focal segmental glomerulonephritis continue to have progressive deterioration of kidney function, ending in kidney failure.

Membranous glomerulonephritis

Membranous glomerulonephritis may cause either nephrotic or a nephritic picture. About two-thirds are associated with auto-antibodies to phospholipase A2 receptor, but other associations include cancers of the lung and bowel, infections such as hepatitis B and malaria, drugs including penicillamine, and connective tissue diseases such as systemic lupus erythematosus. Individuals with cerebral shunts are at risk of developing shunt nephritis, which frequently produces MGN.^{[citation needed]}

Microscopically, MGN is characterized by a thickened glomerular basement membrane without a hyperproliferation of the glomerular cells. Immunofluorescence demonstrates diffuse granular uptake of IgG. The basement membrane may completely surround the granular deposits, forming a "spike and dome" pattern. Tubules also display the symptoms of a typical Type III hypersensitivity reaction, which causes the endothelial cells to proliferate, which can be seen under a light microscope with a PAS stain.

Prognosis follows the rule of thirds: one-third remain with MGN indefinitely, one-third remit, and one-third progress to end-stage kidney failure. As the glomerulonephritis progresses, the tubules of the kidney become infected, leading to atrophy and hyalinisation. The kidney appears to shrink. Treatment with corticosteroids is attempted if the disease progresses.

In extremely rare cases, the disease has been known to run in families, usually passed down through the females. This condition, similarly, is called Familial Membranous Glomerulonephritis. There have only been about nine documented cases in the world.

Thin basement membrane disease

Main article: Thin basement membrane disease

Thin basement membrane disease is an autosomal dominant inherited disease characterized by thin glomerular basement membranes on electron microscopy. It is a benign condition that causes persistent microscopic hematuria. This also may cause proteinuria which is usually mild and overall prognosis is excellent.^{[citation needed]}

Fibronectin glomerulopathy

Fibronectin glomerulopathy is a rare form of glomerulopathy characterised by enlarged glomeruli with deposits in the mesangium and subendothelial space. The deposits have been shown to be fibronectin. This condition is inherited in an autosomal dominant fashion. About 40% of cases are due to mutations in the fibronectin (FN1) gene located on chromosome 2 (2q34).

Proliferative

Proliferative glomerulonephritis is characterised by an increased number of cells in the glomerulus. These forms usually present with a triad of blood in the urine, decreased urine production, and hypertension, the nephritic syndrome. These forms usually progress to end-stage kidney failure (ESKF) over weeks to years (depending on type).

IgA nephropathy

IgA nephropathy, also known as Berger's disease, is the most common type of glomerulonephritis, and generally presents with isolated visible or occult hematuria, occasionally combined with low grade proteinuria, and rarely causes a nephritic syndrome characterised by proteinuria, and visible blood in the urine. IgA nephropathy is classically described as a self-resolving form in young adults several days after a respiratory infection. It is characterised by deposits of IgA in the space between glomerular capillaries.

Henoch–Schönlein purpura refers to a form of IgA nephropathy, typically affecting children, characterised by a rash of small bruises affecting the buttocks and lower legs, with abdominal pain.

Post-infectious

• It classically occurs after infection with the bacteria Streptococcus pyogenes.

Membranoproliferative

• Also known as mesangiocapillary glomerulonephritis, is characterised by an increase in the number of cells in the glomerulus, and alterations in the glomerular basement membrane. These forms present with the nephritic syndrome, hypocomplementemia, and have a poor prognosis. Three subtypes:
  • Type 1 MPGN is caused by immune complex deposition in the mesangium and subendothelial space, typically secondary to SLE, HBV and HCV, or other chronic or recurring infections. Circulating immune complexes may activate the complement system, leading to inflammation and an influx of inflammatory cells.
  • Type 2 MPGN, also known as Dense Deposit Disease, is characterized by an excessive activation of the complement system. The C3 Nephritic Factor autoantibody stabilizes C3-convertase, which may lead to an excessive activation of complement. Type 2 MPGN is a subgroup of C3 glomerulopathy, a newly proposed diagnosis which also encompasses C3 Glomerulonephritis (C3GN).
  • Type 3 MPGN, which is caused by immune complex deposition in the subepithelial space.

Rapidly progressive glomerulonephritis

• Crescentic glomerulonephritis induced by infective endocarditis on PAS staining and immunofluorescence. PAS staining (left) demonstrated circumferential and cellular crescent formation with interstitial nephritis. Immunofluorescence (right) demonstrated C3 positive staining in mesangial area.
• Also known as crescentic GN, is characterized by a rapid, progressive deterioration in kidney function.
• They may present with a nephritic syndrome.
• Three main subtypes are recognised:
  1. Goodpasture syndrome, an autoimmune disease also affecting the lung. In Goodpasture syndrome, IgG antibodies directed against the glomerular basement membrane trigger an inflammatory reaction, causing a nephritic syndrome and the coughing up of blood.
  2. Immune-complex-mediated damage, and may be associated with SLE, post-infective glomerulonephritis, IgA nephropathy, and IgA vasculitis
  3. Also called pauciimmune type, is associated with causes of vascular inflammation including
     1. Granulomatosis with polyangiitis (GPA) and
     2. Microscopic polyangiitis. No immune deposits can be seen on staining, however blood tests may be positive for the ANCA antibody.