PodoNet

The PodoNet project was initiated to establish coordinated clinical, genetic and experimental research activities in steroid-resistant nephrotic syndrome (SRNS), a rare but important kidney disorder.SRNS may be caused either by hereditary abnormalities of the podocyte, the kidney cell forming the filtration barrier, or by alterations of the immune system leading to podocyte damage. While some patients respond to intensified immunosuppressive therapy, many patients prove multidrug resistant and gradually progress to end-stage kidney disease. Due to the rarity and heterogeneity of the disorder, information regarding causative genetic and non‐genetic abnormalities, the short‐ and long‐term efficacy of existing therapeutic concepts and the prognosis of individual genetic forms is scarce. The majority of genes causing SRNS is probably unknown. Finally, no causal therapeutic strategies directed at correcting the deficient function of mutated podocyte proteins in genetic forms of SRNS.

The PodoNet project set out to develop diagnostic and therapeutic guidelines for SRNS management, collect the critical mass of patients and biological samples to establish the relative frequency of genetic and non-genetic forms of SRNS, provide genotype-phenotype correlations, search for novel disease-causing genes, and establish in vitro and in vivo models aimed at developing novel molecular therapies for the most common genetic form of SRNS.

We established a Web Portal providing diagnostic and therapeutic practice guidelines and created an online SRNS patient registry. Since August 2009, 1469 patients were registered and detailed clinical, family history, genetic, histopathology, biochemical and medication-related information was entered by 65 pediatric nephrology centers in 21 countries. In addition, a central biobank for DNA, serum and urine samples was created that serves as a unique resource for genetic and biomarker studies.
We found major differences in the efficacy of different immunosuppressive treatment protocols. A genetic cause was found in one third of the multidrug resistant patients. Genetic causes were uncommon in patients in whom SRNS first manifested in the second decade of life. Whereas long- term kidney survival was excellent in patients in whom proteinuria responded to initial immunosuppressive therapy, multidrug resistant patients – both with and without detectable genetic cause – steadily progressed to end-stage kidney disease within 15 to 20 years.

PodoNet partners identified and characterized the function of two novel disease causing genes in families with isolated SRNS, and a third new gene was detected in a syndromic form of SRNS. In the experimental part of the project, we developed a cell-based assay to screen drug candidate compound libraries for activity in overcoming the genetic defect of the most common hereditary form of SRNS, i.e. impaired cellular trafficking and accelerated degradation of the podocyte membrane protein podocin. A first promising compound increasing the abundance of podocin protein was identified.
Finally, an inducible ‘knock-in mouse’ model carrying the most common human mutation was developed that allows to induce nephrotic syndrome closely resembling human disease. Preliminary results indicate that angiotensin antagonists (ACE inhibitors and angiotensin receptor blockers), established nephroprotective therapies in acquired proteinuric disorders, effectively lower proteinuria, reduce glomerulosclerosis and improve renal survival also in this inherited structural podocytopathy.