Alexander Combes, PhD

Acute kidney injury (AKI) management remains limited to supportive care, and no pharmacologic therapy is approved specifically to prevent injury or accelerate recovery after an ischaemic insult in clinical practice. Biopsy studies increasingly implicate specific cellular and molecular pathways in AKI and its progression to chronic kidney disease (CKD), but testing which pathways actually drive injury or recovery requires a controllable human system. Animal models remain essential but are difficult to scale for drug screening, and species differences limit direct translation of findings to human AKI biology.

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

.¹ The model identified cellular, molecular, and metabolic signatures of AKI and persistent post-injury states, providing targets investigators can test experimentally rather than relying only on biopsy correlations across acute and chronic timepoints. Combes' lab is also developing a higher throughput organoid format designed for multiwell drug screening, aiming to identify candidates able to protect kidney tissue or improve recovery after injury.

For nephrologists, the approach offers a route to prioritize candidate therapies before animal testing, screening both approved drugs for repurposing and compound libraries with defined mechanisms of action, potentially shortening the path to clinical testing. "Our goal is to use these models to find treatments that could protect the kidney or improve recovery after injury," Combes said in a statement.² Combes spoke with HCPLive about how the platform could be used to screen and repurpose therapies for AKI.

Q&A: Using Kidney Organoids to Screen AKI Therapies

 Does this research move the needle on AKI's lack of targeted therapies?

 Clinical biopsy studies are increasingly identifying the cellular and molecular pathways associated with AKI and persistent kidney injury, but we need human experimental models in which we can test which of those pathways actually drive injury or recovery. Animal models remain essential, but they are difficult to use for large-scale screening and there can be important species differences. In this study, we used a suite of profiling technologies to identify which cellular, molecular and metabolic signatures of AKI and persistent injury are reproduced in human kidney organoids. That gives us a platform where we can now target those processes experimentally and test potential therapies. My lab is also developing new ways to produce kidney organoids that are much better suited to high-throughput screening. Together, this puts us in a strong position to identify and prioritise candidate therapies for further testing in animal models and, ultimately, clinical studies.

 What would you want a practicing nephrologist to take away from this work?

 The main message is that kidney organoids reproduce important aspects of human AKI biology, including persistent injury-associated epithelial states linked to the transition from AKI to chronic kidney disease. They don't capture the functional changes or systemic context of AKI, and there are challenges in modelling adult injury in developmentally immature kidney tissue. However, the core injury and repair responses are sufficiently conserved to provide a meaningful human model for mechanistic and therapeutic studies. By combining organoids with what we are learning from patient biopsies and biomarkers, we can begin to test the mechanisms driving acute injury and incomplete recovery in a human system. We think this can improve our understanding of injury biology in both adult and neonatal AKI and provide a platform for therapeutic development.

 What would the process of screening approved drugs for repurposing look like from here?

 We're developing a higher-throughput version of the organoid model that allows us to generate kidney tissue reproducibly in multiwell formats. We can then expose these organoids to a defined injury and screen for protective therapies by looking for reductions in acute tubular injury markers, or for therapies that enhance repair by assessing persistent injury and inflammatory markers after recovery. We plan to screen both approved drugs and broader libraries of compounds with known mechanisms of action. The latter can help identify new pathways that control injury and repair, while repurposing approved drugs offers a potentially faster route to clinical translation. If we find a strong effect with a drug that already has established safety, dosing and pharmacology in patients, there may be fewer barriers to testing it for AKI than developing an entirely new drug. Promising candidates would still require rigorous validation in more complex models and ultimately clinical trials.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

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

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

Articles

Human kidney organoids modelling ischaemic AKI reproduce key cellular, molecular, and metabolic features seen in patient biopsies, including persistent epithelial injury states implicated in AKI-to-CKD transition and macrophage–epithelial crosstalk. The system enables causal testing of candidate pathways driving injury versus recovery in a controllable human context, addressing limitations of biopsy correlation and species differences in animal models. A higher-throughput, multiwell organoid format is being developed to support scalable screening, prioritizing repurposed approved drugs and mechanistically annotated compound libraries.

Alexander Combes, PhD, discusses how kidney organoids could be used to screen and repurpose drugs for acute kidney injury.

Kidney Organoids May Speed AKI Drug Screening, With 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.

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.