Abstract
Primary focal segmental glomerulosclerosis (pFSGS) is an acquired kidney disorder that frequently leads to kidney failure and confers an elevated risk of recurrence after kidney transplantation, termed recurrent pFSGS. Unfortunately, there is no diagnostic method to foresee recurrence of pFSGS after kidney transplantation. Progress in developing assays to test disease activity is hampered by few preclinical models to replicate disease and inability of in vitro cultured primary podocytes to remain terminally differentiated. In recent years, advancements in kidney organoid biology have led to the development of kidney tissues with glomeruli and major nephron segments including podocytes. To develop a pFSGS model, we studied the effect of plasma from patients diagnosed with pFSGS on kidney organoids differentiated from human pluripotent stem cells. The pFSGS plasma treatment induced podocytopathy, extracellular matrix protein deposition, fibrosis and apoptosis within organoids, whereas non-recurrent plasma did not affect organoid structure. pFSGS plasma also led to loss of normal expression patterns of podocyte specific proteins, nephrin and podocin within podocytes. Further, cytokine array profiling revealed that pFSGS plasma induced secretion of cytokines associated with inflammation and angiogenesis. Additionally, kidney organoids treated with plasma obtained after therapeutic plasma exchange for recurrent pFSGS led to lower cell death in organoids after sequential exchanges with the final exchange showing the least apoptotic cells without morphological abnormality. Overall, our results demonstrate the potential of kidney organoids in advancing kidney disease modeling. These insights could be applied in clinical settings to assist in gauging FSGS recurrence risk prior to kidney transplantation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 888-902 |
| Number of pages | 15 |
| Journal | Kidney international |
| Volume | 107 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2025 |
Funding
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Congressionally Directed Medical Research Program under Award No. W81XWH-18-1-0748. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. Additionally, this work was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number F30DK123985 to Bilal A. Naved and R01DK113168 to Jason A. Wertheim and training grant T32GM008152. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to acknowledge and thank Paula M Tonino for help with electron microscopy at the University of Arizona Imaging Cores-Electron (RRID: SCR_023279 ), and Patty Jansma and Doug Cromey for assistance with fluorescent imaging at the University of Arizona Imaging Cores-Optical Core Facility (RRID: SCR_023355 ). This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Congressionally Directed Medical Research Program under award number W81XWH-18-1-0748. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. Additionally, this work was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award numbers F30DK123985 (BAN) and R01DK113168 (JAW) and training grant T32GM008152. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to acknowledge and thank Paula M. Tonino for help with electron microscopy at the University of Arizona Imaging Cores\u2013Electron (Research Resource Identifier: SCR_023279), and Patty Jansma and Doug Cromey for assistance with fluorescent imaging at the University of Arizona Imaging Cores\u2013Optical Core Facility (Research Resource Identifier: SCR_023355). AKG, JAW, and LG conceived the study. AKG, EM, KMK, and BAN performed the experiments, acquired data, and wrote the manuscript. LS-B and LG prepared plasma samples. AKG, EM, KMK, JAW, and LG analyzed scientific data. LG and JAW contributed to study supervision and funding acquisition. AKG, EM, KMK, BAN, LS-B, JAW, and LG reviewed, edited, finalized, and approved the manuscript. Supplementary material is available online at www.kidney-international.org.
Keywords
- extracellular matrix
- glomerulus
- human plasma
- kidney organoids
- podocytes
- primary focal segmental glomerulosclerosis
ASJC Scopus subject areas
- Nephrology
