The susceptibility of the kidney to alternative pathway activation-A hypothesis

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• The alternative pathway (AP) of the complement system is crucial for immune defense but its dysregulation drives kidney diseases.
• Atypical hemolytic uremic syndrome (AHUS) and C3 glomerulopathy (C3G) are severe kidney diseases linked to AP dysregulation.
• Predisposing factors include genetic variants in complement regulators and autoantibodies targeting AP proteins or convertases.

Purpose of the Study:

• To review pre-clinical and clinical data on molecular causes of aberrant AP control leading to glomerular activation.
• To explore the reasons for the specific targeting of the glomerulus in AP-mediated kidney diseases.
• To propose a model explaining kidney tropism in AP defects and discuss prevention strategies.

Main Methods:

• Review of existing pre-clinical and clinical data.
• Analysis of molecular defects in AP regulation.
• Examination of the interaction between AP proteins and glomerular structures.

Main Results:

• Systemic AP defects predominantly manifest as kidney pathology, specifically in glomerular capillaries.
• Evidence links molecular causes of aberrant AP control to activation within the glomerulus.
• A model is proposed to explain the kidney's unique susceptibility to AP-mediated damage.

Conclusions:

• Aberrant alternative pathway activation is a key driver of glomerular diseases like AHUS and C3G.
• The glomerulus possesses unique properties that attract and localize complement activation.
• Understanding these mechanisms may lead to novel strategies for preventing kidney damage in AP-related disorders.