Kidney Pathology of Megalin Deficiency in Adulthood

Megalin belongs to the large low-density lipoprotein receptor--related protein subfamily and is pivotal in the tubular reabsorption of low-molecular-weight proteins freely filtered through the glomerular filter. Megalin deficiency is an ultrarare inherited disease (faciooculoacousticorenal or Donnay-Barrow syndrome) mostly diagnosed in childhood. In this study, we report an exceptional case of biallelic mutations in LRP2, the gene encoding the endocytic receptor megalin, diagnosed in a 51-year-old woman and characterized by chronic kidney disease (CKD) 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 CKD were ruled out. This case highlights the following aspects: (1) although megalin is mainly recognized as a key factor of proximal tubule physiology, megalin deficiency was associated with predominantly glomerular scarring lesions in humans, 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.