Human kidney organoids as models for personalized congenital nephrotic syndrome

Posted on: 23/07/2024

Nephrotic syndrome

Nephrotic syndrome (NS) is a kidney disorder caused by glomerular injury and more specifically podocytes damage also known as podocytopathy. This glomerular dysfunction induces a severe proteinuria. Podocytes play a major role in the glomerular filtration via their interdigitating foot processes. These processes are linked by a protein complex containing, amongst others nephrin (NPHS1) and podocin (NPHS2). A mutation in the genes coding for these proteins leads to Congenital Nephrotic Syndrome. NS can also be caused by an increased concentration of circulating permeability factors. However, when the cause of NS cannot be determined, the pathology is termed ‘idiopathic NS’.


Modelling of nephrotic syndrome

In the past, several animal and in vitro models have been used to study NS. However, both type of models failed at recapitulating molecular mechanisms underlying glomerular injury. 2D in vitro models consisting of podocyte cell lines or derived from stem cells have the advantage of standardized culture conditions, but do not contain the protein complexes implicated in filtration. Thus, organoid models have been introduced and show more convincing characteristics and the presence of important protein complexes. However, until recently, organoid models were still lacking a functional glomerular filtration barrier.


Development of new 3D models

In 2018, a team of Japanese researchers developed a new kidney organoid model for congenital NS which has a mutation for the gene coding for the nephrin (NPHS1 mutant). This is a good model as it mimics the glomerular filtration defect and expresses the defective protein.

In 2022, a team of researchers from the Netherlands developed two other organoid models:

  • Congenital NS kidney organoid model with the NPHS2 mutation,
  • Idiopathic NS models.

Their study also indicates that iPSC-derived kidney organoids are a better model for NS than 2D iPSC-derived podocytes or podocyte cell lines. Indeed, the organoids also exhibit the cellular signalling cascade induced upon injury.  After repair of the genetic defect by using CRISPR/Cas9 technique, filtration process was restored in organoids.



These new 3D kidney organoid models will allow to have a better understanding of congenital and idiopathic NS and to evaluate new potential therapies.



Human kidney organoids as models for personalized congenital nephrotic syndrome