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Histopathological Assessment of Precision-Cut Kidney Slices: A Live Human Tissue-Based Model of Renal Fibrosis
Andreas Riishede1, Camilla Merrild1, Seulgi Hyun1
1Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Abstract:
Chronic kidney disease (CKD) is characterized by a progressive decline of renal function. A major challenge in CKD drug development is the low success rate of drug candidates, with fewer than 10% of drugs entering Phase I clinical trials demonstrating clinical benefit. Traditional in vitro and in vivo models, while valuable, do not fully recapitulate human kidney complexity. To address this, we utilized human precision-cut kidney slices (PCKS), an ex vivo model that preserves human cellular diversity and organ architecture. Although this model lacks factors such as blood flow and osmotic gradients, it enables controlled induction of fibrosis through TGF-β treatment. To assess potential therapeutic interventions, we adapted a histopathological scoring system that was originally developed for human kidney biopsies. Our findings demonstrate that PCKS exhibit progressive fibrosis and tubular atrophy during culture up to 48 h, with TGF-β treatment further exacerbating these effects at the 48 h time-point. In contrast to PCKS from healthy patients, 48 h incubation of PCKS from CKD patients did not induce additional fibrosis or tubular atrophy. Thus, our scoring system provides a robust method for assessing fibrosis and tubular atrophy in human PCKS and may serve as a promising tool in preclinical drug screening.
Insights
Human precision-cut kidney slices (PCKS) offer a novel ex vivo model for studying chronic kidney disease (CKD) drug development. A new scoring system effectively assesses fibrosis and tubular atrophy in PCKS, aiding preclinical screening.
Area of Science:
- Nephrology
- Drug Development
- Biomedical Engineering
Background:
- Chronic kidney disease (CKD) poses significant challenges in drug development due to high failure rates of clinical candidates.
- Existing in vitro and in vivo models do not fully replicate human kidney complexity, limiting their predictive power.
- Human precision-cut kidney slices (PCKS) represent an ex vivo model that retains human kidney cellular diversity and architecture.
Purpose of the Study:
- To evaluate the utility of human precision-cut kidney slices (PCKS) as an ex vivo model for studying chronic kidney disease (CKD) pathogenesis and drug development.
- To adapt and validate a histopathological scoring system for assessing fibrosis and tubular atrophy in PCKS.
- To investigate the potential of PCKS for controlled induction of fibrosis using TGF-β stimulation.
Main Methods:
- Human precision-cut kidney slices (PCKS) were cultured ex vivo.
- Fibrosis and tubular atrophy were induced using TGF-β treatment.
- A histopathological scoring system, adapted from human kidney biopsies, was used to quantify pathological changes.
- PCKS from both healthy donors and CKD patients were analyzed.
Main Results:
- PCKS exhibited progressive fibrosis and tubular atrophy during culture up to 48 hours.
- TGF-β treatment significantly exacerbated fibrosis and tubular atrophy in PCKS at 48 hours.
- PCKS from CKD patients did not show additional fibrosis or tubular atrophy after 48 hours of incubation compared to healthy controls.
- The adapted scoring system proved robust for assessing fibrosis and tubular atrophy in PCKS.
Conclusions:
- Human precision-cut kidney slices (PCKS) serve as a valuable ex vivo model for studying kidney fibrosis.
- The developed histopathological scoring system is a reliable tool for evaluating fibrosis and tubular atrophy in PCKS.
- This model and scoring system show promise for preclinical drug screening in chronic kidney disease (CKD) research.