Sequential emergence of hematuria and proteinuria in autosomal dominant Alport syndrome: a pathophysiological perspective.

Autosomal dominant Alport syndrome (ADAS) is characterized by pathogenic variants in COL4A3 or COL4A4 and typically presents with persistent microscopic hematuria, while clinically detectable proteinuria often emerges later in the disease course. The pathophysiological basis for this sequential pattern remains incompletely understood. From a structural and biophysical perspective, erythrocyte impermeability represents a more stringent requirement of the glomerular filtration barrier than protein impermeability. Glomerular basement membrane thinning alone is unlikely to permit red blood cell passage, suggesting that microscopic hematuria may reflect focal full-thickness disruption of the filtration barrier at a limited number of sites. In contrast, clinically detectable proteinuria may require a substantially greater reduction in effective filtration barrier integrity and surface area, potentially involving both glomerular basement membrane and podocyte injury. We therefore propose that the common clinical sequence of isolated hematuria followed by proteinuria can be interpreted as a continuum of increasing glomerular fragility in a genetically vulnerable filtration barrier. Although alternative explanations, including age-dependent expression and variable penetrance, should be considered, this model offers a plausible pathophysiological framework for understanding disease progression.

conclusionPersistent hematuria in children with ADAS may therefore represent an early marker of ongoing glomerular vulnerability rather than a completely benign finding, highlighting the importance of longitudinal monitoring before the development of overt proteinuria. WHAT IS KNOWN: • Hematuria is usually the earliest manifestation of autosomal dominant Alport syndrome. • Proteinuria is associated with a higher risk of kidney disease progression. WHAT IS NEW: • Sequential emergence of hematuria and proteinuria may reflect progressive impairment of the glomerular filtration barrier in autosomal dominant Alport syndrome. • A pathophysiological model based on injury to the three components of the glomerular filtration barrier-the endothelium, glomerular basement membrane, and podocytes-is proposed.