Alexander Combes, PhD

Acute kidney injury (AKI) remains managed largely through supportive care, without approved therapies aimed directly at the underlying injury and repair processes. The condition contributes to up to 20% of hospital admissions and can progress toward 

when recovery is incomplete.¹ Few experimental systems allow investigators to control an ischaemic insult in human kidney tissue and then track how individual cell populations respond and recover, particularly across the acute and post-injury phases.

Alexander Combes, PhD, head of the Development and Disease Laboratory at Monash Biomedicine Discovery Institute, led development of a human kidney organoid model reproducing ischaemic AKI, published August 19, 2026, in 

.² Incorporating human macrophages alongside nephron cell types, the model used single-cell and spatial profiling to show injury disrupted normal cell identity, though podocyte and distal tubule markers largely recovered after reoxygenation. Proximal tubule cells showed a more heterogeneous response, with some populations retaining injury-associated and inflammatory programs instead of returning to baseline, and macrophages exposed to the model shifted toward activated inflammatory states.

For nephrologists, the model offers a human platform to investigate why proximal tubule cells are disproportionately prone to incomplete repair, a pattern implicated in progression from AKI to CKD. "By recreating these responses in miniature human kidneys, we can investigate what drives healthy recovery versus persistent damage, and identify ways to intervene," Combes said in a statement.¹ 

Combes spoke with HCPLive about the organoid model, the biology driving incomplete proximal tubule repair, and what it means for future AKI therapies.

Q&A: Modeling AKI injury and recovery in kidney organoids

 What gap in AKI research were you trying to address with this model?

 Much of what we know about AKI comes from clinical studies and animal models, both of which are essential, but there are relatively few experimental human systems where we can control the injury and then follow how different kidney cell types respond and recover. We wanted to determine whether human kidney organoids could fill some of that gap by reproducing clinically relevant features of ischaemic AKI in a system where we can study the underlying mechanisms and, ultimately, test potential therapies.

 What would you say are the most important findings from this study?

 Previous studies had shown that kidney organoids can reproduce generic features of AKI. We extended this into a defined ischaemic injury model and found that, importantly, the organoids did not fully recover after injury. Instead, they retained persistent injury-associated epithelial states linked to the transition from AKI to chronic kidney disease. Capturing both the acute injury phase and these persistent post-injury states is important because it creates opportunities to screen for drugs that either prevent injury in the first place or improve recovery afterwards. We also incorporated human macrophages and found that injury drove them towards activated inflammatory states, providing a way to study interactions between injured kidney cells and the immune system.

 Why did proximal tubule cells recover less completely than podocytes or the distal tubule after injury?

 We used single-cell and spatial profiling to look at individual kidney cell populations during injury and recovery. Hypoxia initially disrupted normal cell identity and function across nephron cell types. After return to normal oxygen conditions, markers of podocyte and distal tubule identity largely recovered. In contrast, proximal tubule cells showed a more heterogeneous response: some recovered towards their normal state, while others retained injury-associated and inflammatory programs. That is interesting because the proximal tubule is particularly vulnerable in human AKI and is thought to play an important role in determining whether the kidney successfully repairs or progresses towards persistent dysfunction. Organoids do not recreate that entire clinical process, but it gives us a human experimental system to investigate why some tubular cells recover while others remain in an altered state.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools. Combes reported no relevant disclosures.

Monash University. Miniature kidneys could accelerate new treatments for acute kidney injury. News release. August 20, 2026. Accessed September 8, 2026. 

https://www.eurekalert.org/news-releases/1140789

Nunez-Nescolarde AB, et al. Modelling ischaemic AKI in human kidney organoids reveals injury-associated epithelial states and macrophage-epithelial crosstalk. Genome Med. 2026;doi:10.1186/s13073-026-01712-z

Articles

Acute kidney injury lacks disease-modifying therapies and often progresses to CKD when repair is incomplete, underscoring the need for controllable human experimental systems. A human kidney organoid platform was engineered to model ischaemic AKI with reoxygenation recovery, integrating macrophages and leveraging single-cell and spatial profiling. Hypoxia disrupted nephron identity broadly, with podocyte and distal tubule programs largely restoring after reoxygenation. Proximal tubules recovered heterogeneously; subsets persisted in injury-associated inflammatory states. Macrophages adopted activated inflammatory phenotypes, enabling study of immune–epithelial crosstalk and therapeutic screening.

 Human kidney organoids reveal why proximal tubule cells resist full recovery after AKI, aiding drug screening research.