FSGS Recurrence Modeling Using Induced Pluripotent Stem Cell (iPSC)-Derived Podocytes in Patients with Idiopathic Nephrotic Syndrome

Journal of the American Society of Nephrology, vol. 34, pp. 1007

Abstract

Background: Clinical outcome is highly variable, often resulting in renal failure, in patients with idiopathic Nephrotic syndrome and disease returns after transplantation (Tx) in about 50% of patients. Proposed circulating permeability factors (CPFs) are as of yet few and unvalidated in larger cohorts. In vitro assays to detect podocyte damage result in heterogeneous outcomes. Taken together, there are potential patient- and donor-specific characteristics that influence disease outcome after Tx. Here, we modelled FSGS recurrence using iPSC-derived podocytes. Methods: We included 5 patient-donor couples with known outcomes of FSGS recurrence after Tx (3x recurrence, 2x non-recurrence) and generated iPSCs out of PBMCs. We subsequently exposed iPSC-derived podocytes to suspected CPF-containing plasmas and measured podocyte damage using various previously published in vitro damage assays. Results: Using an optimized hybrid directed differentiation protocol, we successfully created iPSC-derived podocytes showing podocytes-specific markers. We were able to model primary FSGS using patients' iPSC-derived podocytes exposed to pre-Tx plasma (patient-specifically) mimicking the in vivo situation. We also modelled FSGS recurrence using donor iPSC-derived podocytes exposed to post-Tx plasma (patient-specifically) (Figure 1) again according to the in vivo situation. Differences in damage response between iPSC-derived podocyte cellines suggest we found proof for donor-specific characteristics that may influence disease recurrence after Tx using a crossmatching experiment. Conclusions: iPSC-derived podocytes can be used to model primary FSGS and FSGS recurrence. Data suggests that currently unknown donor-specific characteristics may influence disease outcome after Tx in patients with idiopathic Nephrotic syndrome. We aim to further study these potential donor-specific characteristics. Funding: Government Support - Non-U.S.

Authors 5

1. Bartholomeus T. van den Berge

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   RadboudUMC department of Nephrology, Nijmegen, Netherlands;

   RadboudUMC department of Pathology, Nijmegen, Netherlands;

2. Jitske Jansen Aachen

   Radboud University Nijmegen · Radboud University Medical Center · RWTH Aachen University

   Affiliation as printed

   RWTH Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany

   RadboudUMC department of Pathology, Nijmegen, Netherlands;

3. Jack F.M. Wetzels

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   RadboudUMC department of Nephrology, Nijmegen, Netherlands;

4. Bart Smeets

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   RadboudUMC department of Pathology, Nijmegen, Netherlands;

5. Rutger J. H. Maas

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   RadboudUMC department of Nephrology, Nijmegen, Netherlands;