Page created on March 8, 2019. Last updated on November 15, 2021 at 22:23
Nephrotic syndrome is a renal syndrome which includes the following clinical features:
- Features which are always present:
- Nephrotic-range proteinuria (> 3,5 g/day)
- Hypoproteinaemia, hypoalbuminaemia
- Oedema (periorbital/leg oedema, anasarca, ascites, hydrothorax)
- Features which are often present:
- Hypercoagulability (loss of anticoagulant proteins)
- Increased risk of infections
- Shrinkage of kidneys
Protein loss of 3,5 g/day is referred to as nephrotic-range proteinuria.
Nephrotic syndrome is a possible clinical manifestation of glomerular disease.
Nephrotic syndrome can be caused by several glomerular diseases. The most important are:
- Minimal change disease/nephropathy
- Focal segmental glomerulosclerosis (FSGS)
- Membranous glomerulonephritis/nephropathy
- Diabetic nephropathy
- Amyloid nephropathy
In adults, membranous glomerulonephritis and FSGS are the most common causes.
In children, minimal change disease accounts for almost all cases of nephrotic syndrome.
Hypoalbuminaemia and oedema are obvious symptoms of massive proteinuria. The latter two symptoms need more explanation. The simple explanation is that the liver can’t produce more albumin without producing more apolipoproteins; synthesis of these two are interconnected and can’t be separated. As the body loses proteins and albumin will the liver increase the albumin production, to which the apolipoprotein production follows. These apolipoproteins aren’t “wasted” but instead bind lipids to form lipoproteins and are then released into the blood.
Proteinuria may be either selective or non-selective which indicates whether very large proteins are lost as well.
Patients with nephrotic syndrome lose antibodies in the urine, which may increase the risk of infection. They also lose antithrombin III and other anticoagulant factors, which increases their risk for thrombosis.
Minimal change disease
Minimal change disease is the most common cause of nephrotic syndrome in children. The name comes from the fact that the glomeruli appear normal under light microscope, however loss of podocytes’ feet can be seen under electron microscope.
Affected patients have no other symptoms of renal disease like hypertension or decreased renal function. More than 90% of affected children respond well to a short course of corticosteroid therapy, so the prognosis is good.
The proteinuria in minimal change disease is selective in that very large proteins like globulins aren’t lost.
Membranous nephropathy is the most common cause of nephrotic syndrome in white populations. It’s a chronic, slowly progressive disease that mostly affect middle-aged adults.
In 85% of cases it’s primary due to autoantibodies against the phospholipase A2 receptor on podocytes. The remaining 15% of cases are secondary to infections, cancer, autoimmune disease, etc.
The pathomechanism involves in situ immune complex formation in the glomeruli against glomeruli antigens (the A2 receptor) or against planted antigens. The damage in membranous nephropathy doesn’t occur from inflammatory cells but rather from the complement system. The membrane attack complex (MAC) attacks mesangial cells and podocytes that causes the proteinuria.
Histologically, the main feature is diffuse thickening of the capillary wall, which is visible with PAS staining under light microscope.
Electron microscopy shows subepithelial deposits which leans against the glomerular basement membrane. They are separated from each other by spike like protrusions of the GBM, this characteristic pattern is called “spike and dome apperance”.
Immunofluoresence microscopy shows granular deposits along the glomerular basement membrane.
The disease progresses slowly and doesn’t show symptoms until the later stages. Treatment is with corticosteroids, but 60% of patients with the disease are not cured of the proteinuria. 40% of patients progress into chronic renal failure.
Focal segmental glomerulosclerosis
The name focal segmental glomerulosclerosis refers to the fact that not all glomeruli are involved (focal), not all parts of the glomeruli are involved (segmental), and that interstitial tissue accumulate in the glomeruli (glomerulosclerosis). It’s the most common cause of nephrotic syndrome in black populations. It may be primary (idiopathic) or secondary to:
- HIV infection
- Heroin use
- Sickle cell disease
The pathomechanism involves some circulating factors that increases the glomerular epithelial cell’s protein permeability, which causes them to take in more proteins. These proteins are eventually deposited as hyaline and cause sclerosis.
Like the name (focal segmental) suggests are only certain glomeruli affected, and only certain segment of them. Segmental sclerosis and hyalinization of glomeruli is visible on light microscopy. Loss of podocytes’ feet can be seen under electron microscope, like in minimal change disease.
Unlike minimal change disease is the proteinuria here non-selective. FSGS doesn’t respond well to corticosteroids and commonly progresses into chronic glomerulonephritis. 50% of sufferers develop end-stage renal failure within 10 years.
Membranoproliferative glomerulonephritis (MPGN) is characterised by a proliferation of glomerular cells. Two types of MPGN exist:
- MPGN type I – immune complex-mediated type
- MPGN type II or dense deposit disease – complement-mediated type
Type I is associated with SLE, hepatitis B and C, endocarditis, HIV and certain tumors. Type II is very rare and affects 2-3 per million people.
The pathogenesis of MPGN type I involves immune complex deposition in the glomeruli. The immune complexes can be circulating or formed in situ. The inciting antigen is not known. Type I accounts for 80% of cases.
The pathogenesis of MPGN type II involves a dysregulation of the complement system that causes overactivation of it.
The light microscopy is similar for both types. The glomeruli are large and hypercellular. The glomerular basement membrane is thickened. The GBM has a “tram track” apperance which is charactheristic for this disease.
The electron microscopy is different for the two types. In type I are there subendothelial deposits. In type II is the lamina densa and subendothelial space of the glomerular basement membrane transformed into an irregular, ribbon-like dense structure.
MPGN manifests mostly as nephrotic syndrome but may have components of nephritic syndrome as well. It usually presents in older children or young adults. The prognosis of both types is poor but type II is worse. MPGN recurs in kidney transplanted patients. Basically no patients enter complete remission, and 50% progress into end-stage renal failure within 10 years.
19. Glomerulonephritis. Classification according to clinical symptoms. Histologic alterations in glomerulonephritides.
21. Nephritic syndrome (acute poststreptococcal glomerulonephritis). Rapidly progressive glomerulonephritis. Diabetic nephropathy.
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