Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling.

Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.

The Impact of Gitelman Syndrome on Cardiovascular Disease: From Physiopathology to Clinical Management.

Gitelman syndrome (GS), or congenital hypokalemic hypomagnesemia hypocalciuria with metabolic alkalosis, is a congenital inherited tubulopathy. This tubulopathy is associated with disorders of water-electrolyte homeostasis, such as metabolic alkalosis, hypokalemia, hyponatremia, hypomagnesemia and hypocalciuria. GS has an autosomal recessive inheritance. The loss-of-function mutation involves the gene that codifies for thiazide-sensitive sodium-chloride co-transporter located in the distal convoluted tubule. The physiopathology of the syndrome is characterized by activation of the renin-angiotensin-aldosterone system (RAAS) with a low plasmatic concentration of angiotensin-II. Despite hyper-activation of RAAS, average or low blood pressure is detected in association with low peripheral resistance and reduced response to vasopressors. Clinical findings are brief episodes of fatigue, syncope, vertigo, ataxia and blurred vision; sudden cardiac death might occur. This review aims to give insight into cardiovascular implications and management of GS.