Kidney Pathology of Megalin Deficiency in Adulthood

This is the authors' abstract. We don't add key points for this paper.

Megalin belongs to the large LDL receptor-related protein subfamily and is pivotal in the tubular reabsorption of low molecular-weight proteins freely filtered through glomerular filter. Megalin deficiency is an ultra-rare inherited disease (faciooculoacousticorenal or Donnay-Barrow syndrome (FOAR/DB)) mostly diagnosed in childhood. Here, we report an exceptional case of biallelic mutations of LRP2 , the gene encoding the endocytic receptor megalin, diagnosed in a 51-year-old woman and characterized by chronic kidney disease with incomplete proximal tubule dysfunction, moderate sensorineural hearing loss, severe myopia and convergent strabismus. Kidney biopsy showed mild interstitial fibrosis with tubular atrophy but severe glomerulosclerosis. Other causes of chronic kidney disease were ruled out. This case highlights that, (1) while megalin is mainly recognized as a key actor of proximal tubule physiology, megalin deficiency was associated with predominantly glomerular scarring lesions in human, promoting slowly progressive CKD similar to mouse models; (2) megalin can contribute to podocyte physiology; and (3) LRP2 should be included in kidney gene panels for the evaluation of nephropathy of unknown origin, even in adulthood.