Innovative application of kidney organoids in acute kidney injury

Abstract

BACKGROUND: In recent years, the application of kidney organoid technology in acute kidney injury has gradually become a research hotspot. Traditional animal models have species differences from humans, and physiological and pathological processes of their kidneys cannot fully represent the human situation. Kidney organoid technology forms 3D kidney models through stem cell culture, which can simulate the complex structure and function of human kidneys. It has shown great potential in disease modeling and mechanism exploration of acute kidney injury, prediction of drug nephrotoxicity, and exploration of regeneration and repair mechanisms. OBJECTIVE: To summarize the application progress of kidney organoids in acute kidney injury research, providing new technical means and research strategies for the prevention and treatment of acute kidney injury. METHODS: Literature related to organoids and acute kidney injury was searched in CNKI and PubMed databases. Chinese search terms included "acute kidney injury, organoid, pluripotent stem cells, 3D bioprinting, kidney-on-a-chip, regenerative medicine, kidney transplantation"; English search terms included "acute kidney injury, organoid, pluripotent stem cells, 3D bioprinting, kidney-on-a-chip, regenerative medicine, kidney transplantation". All retrieved literature were original research articles and relevant reviews, with the search time limit from database inception to April 2025. Finally, 99 articles were screened for analysis and summary. RESULTS AND CONCLUSION: (1) The cell sources for inducing kidney organoid formation reported in the literature mainly include pluripotent stem cells, embryonic stem cells, and urine-derived stem cells. These induced kidney organoids play important roles in in vitro drug screening, kidney development, and disease modeling. (2) 3D bioprinting and kidney-on-a-chip technology are emerging techniques for constructing kidney organoids. 3D bioprinting can precisely and specifically construct complex multicellular structures, while kidney-on-a-chip technology has characteristics such as high gas permeability, sensitivity, and low cost, which can extend organoid lifespan, increase biocompatibility, and are suitable for preclinical drug development and toxicity screening. (3) The combination of gene editing technology with kidney organoid models brings new perspectives and tools for kidney disease research, drug development, and regenerative medicine. It can construct kidney organoids with specific reporter genes or sensitive indicators, and amplify and classify specific kidney cell types in kidney organoids. (4) Kidney organoids show unique advantages in disease simulation, drug evaluation, and exploration of regenerative therapeutic strategies for acute kidney injury. They can serve as in vitro models to study the toxicity mechanisms of drugs such as cisplatin, doxorubicin, and red yeast rice supplements that cause acute kidney injury, screen high-throughput drugs and therapeutic targets, and also play an important role in the field of renal transplantation regenerative medicine.

1. Introduction

Acute kidney injury is a clinical syndrome characterized by a sudden and prolonged decline in renal function, primarily defined by a decrease in glomerular filtration rate, with serum creatinine ≥26.5 μmol/L (0.3 mg/dL) within 48 hours, or an increase in serum creatinine to at least 1.5 times baseline, known or presumed to have occurred within 7 days. Additionally, urine output less than 0.5 mL/(kg·h) for 6 hours suggests acute kidney injury. Acute kidney injury may manifest as oliguria (defined as urine output less than 400 mL per 24 hours or 17 mL/h) or anuria (defined as urine output less than 100 mL per 24 hours) [1]. Established risk factors for acute kidney injury include advanced age, hypertension, diabetes, high percentage of total body surface area burned, elevated abbreviated burn severity index, inhalation injury, rhabdomyolysis, surgical intervention, elevated sequential organ failure assessment score, sepsis, hypoalbuminemia, specific genetic polymorphisms, and drug-induced factors [2-3]. Current therapeutic strategies for kidney disease mainly include two approaches: one is to repair the damaged organ to restore function, and the other is to replace therapy with cells, bioengineered devices, or engineered tissues.

Kidney organoids are complex, autonomous 3D cell aggregates that mimic the structure, function, and cellular complexity of the human kidney, providing a powerful platform for studying human kidney development and disease mechanisms, enabling in vitro drug screening and exploration of regenerative therapies [4] (Figure 1). The formation of kidney organoids mainly involves three stages: stem cells first differentiate into primitive streak mesoderm, then migrate upward to form intermediate mesoderm, which further differentiates into two key renal progenitor populations: metanephric mesenchyme and ureteric bud, which respectively form nephrons and collecting ducts. TAGUCHI et al. [5] generated mouse kidney organoids by combining mouse embryonic stem cell-derived nephron progenitor cells, ureteric bud, and stromal progenitor cells (including glomeruli, tubules, and collecting ducts) isolated from mouse embryos. Human renal epithelial cells isolated from kidney tissue of nephrectomized patients can form kidney organoids without 3D scaffolds.