Modeling Principle

The Pig Acute Kidney Injury Model is a SCI gold-standard large-animal pathological model of acute kidney injury established by unilateral/bilateral renal pedicle ischemia-reperfusion (I/R) injury combined with short-term hypoxic intervention. It accurately recapitulates the complete pathological progression of clinical hospital-acquired acute kidney injury (AKI), including renal cortical ischemia and hypoxia, renal tubular epithelial cell apoptosis and necrosis, sharp decline in glomerular filtration function, renal interstitial inflammatory infiltration, oxidative stress burst and rapid renal failure, and compensates for the experimental defects of rodent small animals with huge differences from humans in renal anatomical structure, nephron density, renal hemodynamics and renal metabolic rhythm.

The renal anatomical structure, corticomedullary proportional hierarchy, renal tubular arrangement pattern, renal microcirculation framework, renal oxidative stress and inflammatory regulatory pathways, and liver-kidney metabolic coupling mechanism of minipigs are highly homologous to humans. The temporal sequence of transient oliguria, soaring serum creatinine and urea nitrogen, renal tubular brush border shedding, interstitial edema and inflammatory infiltration, and progressive deterioration of renal function after ischemia-reperfusion injury is fully consistent with the clinical course of acute kidney injury induced by surgery, shock and ischemia hypoxia. Standardized renal pedicle clamping blocks renal blood flow, causing severe renal cortical ischemia and hypoxia, mitochondrial dysfunction and massive release of ROS reactive oxygen species, triggering a renal oxidative stress cascade response. Sustained ischemic injury induces DNA damage and apoptosis of renal tubular epithelial cells, destroying tubular reabsorption and filtration barrier function. Secondary inflammatory stress bursts after blood reperfusion, activating the classic NF-κB/TLR4 inflammatory pathway and releasing a large number of pro-inflammatory factors such as IL-1β, IL-6 and TNF-α, inducing infiltration of neutrophils and macrophages in renal interstitium, further aggravating renal tubular necrosis, renal interstitial edema and sharp decline in glomerular filtration rate, and gradually forming typical acute renal dysfunction phenotype, which fully recapitulates the classic pathogenic cascade of human acute kidney injury: ischemia hypoxia-oxidative stress burst-inflammatory cascade reaction-renal tubular necrosis-filtration failure-acute kidney injury.

Minipigs have large kidney volume, clear corticomedullary boundary, stable vascular anatomy and wide modeling field of vision. The progression of AKI lesions is rapid and stable with minimal individual differences and no spontaneous renal lesions. It can clearly distinguish three-stage pathological phenotypes: ischemic stress stage, reperfusion inflammatory peak stage and stable renal dysfunction stage, serving as a standardized large-animal gold-standard model for preclinical translational research on AKI pathogenesis, renoprotective drug screening, renal tubular repair and regeneration, renal antioxidant and anti-inflammatory preparations, and clinical renal injury prevention and treatment.

Modeling Success Criteria

Macroscopic Renal Function and General Phenotype

Animals in the blank control group had good mental state, normal food and water intake and stable urine volume. The kidneys were ruddy in color, uniform in texture and clear in corticomedullary boundary without congestion, edema or organic damage. At 24 h after reperfusion, animals in the model group showed listlessness, decreased food and water intake and significantly reduced 24 h urine volume. Anatomically, the kidneys were swollen and congested with pale edematous cortex and obvious medullary congestion, with typical macroscopic acute ischemic injury phenotype and extremely significant difference from the blank group, confirming preliminary successful model construction.

Quantitative Biochemical Gold-Standard Indexes of Serum and Urine

Serum renal function indexes Scr, BUN and UA in the model group were extremely significantly higher than those in the blank group; urine renal tubular specific injury markers NGAL, KIM-1 and urine protein content were sharply upregulated; the accumulation of ROS and MDA in renal tissues and serum increased, while the antioxidant activities of SOD and GSH-Px decreased significantly; pro-inflammatory factors TNF-α, IL-1β and IL-6 were massively released, fully matching the core biochemical diagnostic characteristics of clinical acute kidney injury: sharp decline in renal function, specific renal tubular necrosis, oxidative stress imbalance and acute inflammatory burst.

Renal Histopathological Characteristics

Combined HE, PAS and Masson staining of renal tissues showed characteristic temporal pathological changes of acute kidney injury:

1. Early stage at 6 h after reperfusion: mild edema of renal tubular epithelial cells, a small amount of brush border shedding and mild renal interstitial edema with a small number of inflammatory cell infiltration;

2. Peak stage at 12 h after reperfusion: extensive edema and vacuolar degeneration of renal tubular epithelial cells, massive brush border shedding, stenosis and occlusion of tubular lumen, aggravated renal interstitial edema and diffuse inflammatory cell infiltration;

3. Terminal stage at 24 h after reperfusion: large-area necrosis and shedding of renal tubular epithelial cells with karyopyknosis and fragmentation, disordered and collapsed renal tubular structure, congested and swollen glomeruli and massive inflammatory infiltration in renal interstitium without obvious fibrosis, which perfectly recapitulates the characteristic pathological injury grading of human acute ischemic renal injury.

Core Oxidative Stress and Inflammatory Pathway Indexes

The TLR4/NF-κB inflammatory pathway of the model group was significantly activated with cascade release of downstream pro-inflammatory factors; the renal oxidative stress pathway was overactivated with inhibited antioxidant system and massive accumulation of oxygen free radicals; the renal tubular injury and apoptosis pathway was abnormally activated with specific high expression of NGAL/KIM-1 injury markers, which accurately conforms to the complete pathogenic mechanism induced by ischemia-reperfusion: ischemic hypoxic injury-oxidative stress imbalance-inflammatory cascade burst-renal tubular apoptosis and necrosis-acute renal failure, serving as the core academic criterion for confirming successful modeling.

Model Advantages

This model is a well-recognized exclusive large-animal gold-standard model for ischemia-reperfusion-induced acute kidney injury in nephrology SCI field. Standardized modeling with 45 min ischemia + 24 h reperfusion rapidly and stably forms acute renal failure, renal tubular necrosis and oxidative inflammatory injury phenotypes highly homologous to human clinic. The renal anatomy, renal hemodynamics, renal tubular metabolism and oxidative inflammatory regulation mechanism of minipigs are highly consistent with humans, with uniform and consistent acute injury sequence and functional deterioration gradient, extremely low intra-group data dispersion and far higher reproducibility than rodent models. The modeling mechanism completely simulates hospital-acquired acute kidney injury caused by clinical surgery, shock and ischemia hypoxia without non-specific interference of drug-induced and toxin-induced modeling, which accurately fits the real clinical pathogenesis. It can dynamically monitor the temporal changes of renal function, suitable for preclinical pharmacodynamic evaluation of renoprotective drugs, antioxidant and anti-inflammatory preparations, renal tubular repair materials and renal targeted preparations. Large-animal renal tissue samples are sufficient with comprehensive detection dimensions, and the clinical transformation credibility of data is extremely high with high recognition in high-score nephrology and urology SCI journals, suitable for National Natural Science Foundation, master/doctor project opening, graduation thesis of nephrology/urology and translational medical research of renal injury regeneration.

Research Applications

The Pig Acute Kidney Injury Model is corely applied to basic research on renal ischemia-reperfusion-induced oxidative stress burst, TLR4/NF-κB-mediated acute renal inflammation, renal tubular epithelial cell apoptosis and necrosis, sharp decline in glomerular filtration function and acute renal failure. It is specially used for screening and evaluating renoprotective small-molecule drugs, natural active extracts, renal targeted preparations, intraoperative protective consumables and medical repair biomaterials with effects of inhibiting renal oxidative stress, blocking intrarenal inflammatory cascade reaction, protecting renal tubular epithelial cells, improving renal microcirculation, repairing renal function and reducing renal tissue edema and inflammatory infiltration. It is widely adopted for excavation of pathogenic targets of acute kidney injury, elucidation of renal oxidative inflammation regulatory network and large-animal preclinical in-vivo pharmacodynamic verification of acute kidney injury prevention and treatment drugs, serving as a scarce and essential standardized large-animal gold-standard model in the fields of nephrology critical care medicine, urology and renal regenerative repair pharmacology research.

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