How does podocyte effacement cause proteinuria?

From the Guidelines

Podocyte effacement causes proteinuria by disrupting the glomerular filtration barrier, leading to a loss of the normal interdigitated architecture and disruption of the slit diaphragm, resulting in the leakage of plasma proteins into the urine. This process is central to the pathophysiology of many glomerular diseases. The molecular basis involves dysregulation of the actin cytoskeleton within podocytes and altered expression of key proteins like nephrin, podocin, and synaptopodin that maintain the slit diaphragm integrity 1.

Key Factors Contributing to Proteinuria

• Disruption of the slit diaphragm
• Loss of the normal interdigitated architecture of podocytes
• Dysregulation of the actin cytoskeleton within podocytes
• Altered expression of key proteins like nephrin, podocin, and synaptopodin

Clinical Implications

In patients with IgAN, such as the 28-year-old Caucasian male patient, the degree of proteinuria is a critical factor in determining prognosis, with a threshold level of proteinuria of 1 g/day being associated with a higher risk of progression to renal failure 1. The use of ACEi or ARB has been associated with proteinuria reduction and a reduction in GFR decline in patients with proteinuria ≥1 g/day, and should be instituted in all IgAN patients who are at higher risk for progression 1.

Management of Proteinuria

• Reduction of proteinuria to <1 g/day is associated with a more favorable prognosis
• Use of ACEi or ARB to reduce proteinuria and slow GFR decline
• Strict BP targets, with a target BP of <125/75 mm Hg in patients with proteinuria ≥1 g/day 1

From the Research

Podocyte Effacement and Proteinuria

• Podocyte effacement, characterized by the loss of foot process architecture, results in urinary protein loss 2, 3, 4, 5, 6
• The change in podocyte shape is not a passive process, but rather a complex interplay of proteins that comprise the molecular anatomy of podocytes 3, 4
• Podocyte injury is typically associated with marked proteinuria, as podocytes form the final barrier to protein loss 4

Mechanisms of Podocyte Effacement

• Disruption of the actin cytoskeletal network in podocytes leads to foot process effacement 4
• Rac1 activation is sufficient and necessary for podocyte foot process effacement, and is mediated by Four-and-a-half LIM domains protein 2 (FHL2) in hypertensive nephropathy 5
• Angiotensin II-induced podocyte cytoskeleton reorganization via FAK-Rac1 axis is also involved in podocyte effacement 5

Consequences of Podocyte Effacement

• Podocyte effacement leads to proteinuria, which can progress to glomerulosclerosis and end-stage renal disease 3, 6
• Reduction in podocyte number can also contribute to proteinuria and glomerulosclerosis, due to the relative inability of podocytes to proliferate, detach, and undergo apoptosis 3