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PH-RN03

Nephrotic syndrome

How injury to the podocytes lets large amounts of protein through the glomerular filtration barrier, and why this causes low albumin, oedema, high lipids and a tendency to clot.

By the end, you can

  • Describe the three layers of the glomerular filtration barrier and what each holds back.
  • Explain how podocyte injury and foot-process effacement let albumin leak into the urine.
  • Explain how hypoalbuminaemia and renal salt retention together cause oedema.
  • Relate the loss of plasma proteins and the liver’s response to hyperlipidaemia, thrombosis and infection.
  • Outline how the main causes differ in what injures the podocyte.
  • Recognise the classic tissue and urine findings, classifications and tests of nephrotic syndrome, and explain how its main treatments act on the mechanism.

What it is

Nephrotic syndrome is the combination of heavy proteinuria, a low serum albumin and oedema, usually with hyperlipidaemia, caused by leakage of protein through a damaged glomerular filtration barrier. It is a pattern rather than one disease: diseases of the podocyte itself, immune deposits and systemic diseases such as diabetes and amyloidosis can all produce it.

4 types to tell apart
Minimal change disease
The commonest cause in children. Glomeruli look normal under the light microscope; electron microscopy shows widespread foot-process effacement without immune deposits. It often remits but can relapse.
Membranous nephropathy
A common cause in adults. Antibodies, often against the podocyte protein PLA2R, form deposits beneath the podocytes and activate complement; it can also be secondary to infections, autoimmune disease, cancers or drugs.
Focal segmental glomerulosclerosis (FSGS)
A pattern of scarring in segments of some glomeruli after podocyte loss. Causes include circulating factors, genetic variants in podocyte proteins, obesity, hyperfiltration and some viral infections.
Secondary to systemic disease
Diabetic kidney disease, the commonest cause of nephrotic-range proteinuria in adults, and amyloidosis damage the barrier as part of a wider disease.

US spelling: oedema → edema, hyperlipidaemia → hyperlipidemia.

Normal function

The glomerular filtration barrier

Blood in the is separated from the by three layers. The capillary endothelium is that hold back blood cells. The glomerular basement membrane (GBM) is a of type IV collagen, laminin and negatively charged proteoglycans. Outside it, podocytes in interlocking , and the narrow slits between them are bridged by the slit diaphragm, such as nephrin and podocin.

Water, salts, glucose and small molecules pass freely; cells and most proteins do not. Albumin, a medium-sized, negatively charged protein, is almost entirely held back. In the usual explanation the slit diaphragm is the final size barrier and negative charge helps repel albumin, though their relative contributions are debated. The little albumin filtered is reclaimed by the proximal tubule, so healthy urine holds less than about 150 mg of protein a day.

Podocytes rarely divide in adults, so those lost are not readily replaced.

Point to it on the model