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Abstract: SA-PO1007

Changes in the Human Kidney Cellular Architecture During Fibrosis

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Quinn, Ghazal Z., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Abedini, Amin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Sheng, Xin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Gao, Guannan, Boehringer Ingelheim International GmbH, Ridgefield, Connecticut, United States
  • Vuong, Lynda, Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Palmer, Matthew, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
  • Hill, Jonathan, Boehringer Ingelheim International GmbH, Ridgefield, Connecticut, United States
  • Pullen, Steven S., Boehringer Ingelheim International GmbH, Ridgefield, Connecticut, United States
  • Hakimi, A. Ari, Memorial Sloan Kettering Cancer Center, New York, New York, United States
  • Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background

Chronic diabetic and hypertensive kidney disease account for more than 75% of all end stage renal disease cases. The underlying mechanisms of disease progression are poorly understood. We hypothesized that changes in the cellular composition of kidney tissue might highlight disease-causal cell types or mechanisms.

Methods

We analyzed human kidney tissue samples (n=593) of patients with diabetic and hypertensive kidney disease or controls. We obtained associated clinical and histolopathological information and generated corresponding bulk RNA sequencing information from kidney tissue. Histopathologic features such interstitial fibrosis were scored by a renal pathologist. Human kidney single cell gene expression was generated to obtain cell type-specific gene expression changes. We used in silico deconvolution (CIBERSORTx) to estimate cell proportions in bulk tissue RNA sequencing data. We validated changes in immune cell fractions using flow cytometry analyses.

Results

We found strong correlations between kidney proximal tubule (PT) cells, regulatory T cells, Natural Killer cells, effector T cells and the degree of kidney dysfunction including interstitial fibrosis (r2=0.51, p <0.001) and estimated glomerular filatration rate (eGFR, r2=0.39, p <0.001). In silico deconvolution and flow cytometric analyses highlighted the association between T cells and eGFR. We found patients with low PT cell fractions (i.e., <45% PT cells) had significantly higher immune cell types such as Th17 cells, and more rapid eGFR decline over time (p<0.05).

Conclusion

In summary, kidney fibrosis is characterized by marked changes in kidney proximal tubules. Changes in immune and lymphocyte fractions are a key feature of diabetic and hypertensive CKD. Cell fraction changes predict the rate of kidney function decline.

Funding

  • NIDDK Support