Modeling Principle

The pig kidney stone model is a SCI gold-standard large-animal calcium oxalate nephrolithiasis pathological model constructed by compound induction of oxalic acid combined with high-calcium diet, which accurately simulates the whole process of crystal deposition, renal tubular injury, renal interstitial inflammation and stone formation of clinical primary and metabolic kidney stones, and completely compensates for the significant research defects of rodent small animals in renal anatomical structure, metabolic rhythm and stone formation mechanism compared with humans. Porcine renal anatomical structure, nephron quantity, renal tubule distribution, urinary physicochemical properties, calcium-oxalate metabolic pathways and renal oxidative stress response mechanisms are highly homologous to humans. Urine osmotic pressure, acid-base buffer system and crystal supersaturation threshold are highly consistent with the human urinary system. The formation location, growth rule and composition of stones are completely identical to clinical human calcium oxalate kidney stones, making it the non-human mammalian gold-standard large-animal model with the highest clinical fitting degree in urolithiasis translational medical research. Long-term exogenous oxalic acid intake combined with high-calcium diet intervention continuously increases the concentration of calcium ions and oxalate ions in the urine of experimental pigs, breaks the urinary crystal dissolution balance, and forms a calcium oxalate supersaturated urine environment. Tiny calcium oxalate crystals are first deposited in the renal tubular lumen and epithelial surface, continuously inducing oxidative stress injury, mitochondrial dysfunction and apoptosis of renal tubular epithelial cells, activating NF-κB, NLRP3 inflammasome and TGF-β fibrosis pathways, and triggering local chronic inflammatory infiltration, interstitial edema and fibrotic remodeling in renal tissues. Deposited crystals continuously aggregate, adhere and grow, gradually forming microcalculi and further developing into macroscopic renal calculi, which fully recapitulates the classic pathological process of human nephrolithiasis: metabolic disorder-urine supersaturation-crystal deposition-renal tubular injury-inflammatory fibrosis-stone formation. With high stone formation rate, stable modeling cycle, uniform pathological phenotype and minimal individual differences, and no spontaneous renal calculi and congenital renal metabolic abnormalities, this model serves as an authoritative SCI standardized large-animal model for the elucidation of nephrolithiasis pathogenesis, prevention and control of stone recurrence, renal protection intervention, and preclinical evaluation of new litholytic and anti-lithogenic drugs and urological dressings.

Modeling Success Criteria

Renal Macroscopic and Stone Phenotypes

The kidneys of the blank control group were ruddy in color, uniform in texture, smooth in surface without swelling and congestion, with clear renal pelvis and calyx structure, no crystal adhesion and no stone formation. The kidneys of the model group showed mild swelling, dull color and slightly rough surface. A large number of white crystals adhered to the renal pelvis, renal papilla and renal tubular collecting system, with scattered or clustered microcalculi and formed stones visible, and mild hydronephrosis and dilatation were observed in partial renal calyces. The renal organ coefficient was significantly higher than that of the blank group with typical macroscopic stone phenotypes, confirming the preliminary formation of the nephrolithiasis model.

Quantitative Urinary and Serum Metabolic Indexes

The 24-hour urinary calcium and urinary oxalic acid concentrations of the model group were extremely significantly increased, the number of urinary crystals was greatly elevated, and the urine showed an obvious supersaturated state; serum renal function indexes Scr, BUN and UA were significantly upregulated, presenting the phenotype of renal tubular injury and mild renal function abnormality. The characteristics of metabolic disorder are highly consistent with the core serological and urinary diagnostic criteria of hypercalciuria, hyperoxaluria and mild renal function injury in clinical nephrolithiasis patients, serving as the core quantitative gold standard for successful modeling.

Renal Histopathological Characteristics

HE staining and Von Kossa crystal staining of renal tissues showed characteristic pathological injuries of nephrolithiasis: renal tubular lumen dilatation, swelling, degeneration, shedding and necrosis of epithelial cells, and a large number of calcium oxalate crystals deposited in the lumen blocking the tubules; massive inflammatory cell infiltration and obvious tissue edema were observed in the renal interstitium; Masson staining showed abnormal proliferation of renal interstitial collagen fibers and significantly aggravated fibrosis, which fully recapitulates the classic pathological injury chain of human nephrolithiasis: crystal deposition-tubular obstruction-epithelial injury-interstitial inflammation-renal fibrosis, with highly specific pathological phenotypes and stable modeling effect.

Core Inflammatory and Oxidative Stress Indexes

The levels of oxidative damage products ROS and MDA in renal tissues of the model group were significantly increased, while the antioxidant capacities of SOD and GSH-Px were significantly decreased, resulting in severe imbalance of renal tubular oxidative stress homeostasis. Core pro-inflammatory factors TNF-α, IL-6 and IL-1β were highly expressed, the NLRP3 inflammasome and NF-κB pathways were continuously activated, and the TGF-β-mediated fibrosis pathway was abnormally activated, which fully conforms to the core pathogenic mechanism of nephrolithiasis: oxidative damage-inflammation outbreak-crystal adhesion-fibrotic remodeling, serving as the core academic basis for successful model construction.

Model Advantage

As a SCI-certified exclusive large-animal gold-standard model for calcium oxalate nephrolithiasis, it completely breaks through the species defects of rodent small animals such as fast renal metabolic rate, easy crystal excretion, low stone formation rate and great differences in pathological phenotypes from humans. Porcine renal anatomical structure, urinary metabolic characteristics, crystal deposition mechanism and inflammatory fibrosis response are highly homologous to humans, and the stone composition, growth location and pathological injury process are completely consistent with clinical primary calcium oxalate kidney stones. The compound metabolic induction modeling method combining diet and drugs has no surgical trauma and no exogenous mechanical damage, with pure modeling mechanism and high conformity to the real pathogenesis of clinical metabolic stones. It has a moderate modeling cycle, stable stone formation, uniform crystal deposition, minimal inter-group differences and excellent reproducibility. It can completely simulate the whole pathogenic chain of urine supersaturation, crystal adhesion, renal tubular injury, inflammatory activation and renal interstitial fibrosis, and is specially suitable for large-animal preclinical translational evaluation of new drugs for nephrolithiasis prevention, litholysis, anti-inflammation, anti-oxidation and anti-fibrosis. With clear project mechanism, extremely high translational value and high recognition in high-score SCI journals, it is fully applicable for fund declaration, project opening, master and doctoral theses and translational medical research of urinary calculi.

Research Applications

The pig kidney stone model is corely applied to basic research on renal crystal deposition, renal tubular oxidative stress injury, NLRP3 inflammasome activation and renal interstitial inflammatory fibrosis caused by high oxalic acid and high calcium metabolic disorder. It is specially used for screening and evaluating traditional Chinese medicine compounds, natural active ingredients, small chemical molecules and urinary system targeted preparations with effects of inhibiting urinary crystal supersaturation, blocking crystal adhesion and deposition, protecting renal tubular epithelium, anti-inflammation and anti-oxidation, improving renal fibrosis, and preventing and controlling stone formation and recurrence. It is widely used in the exploration of nephrolithiasis pathogenic targets, elucidation of renal metabolic disorder mechanisms and large-animal preclinical translational verification of anti-lithogenic and litholytic drugs, serving as a scarce and essential standardized large-animal gold-standard model in the fields of urinary calculi, renal injury protection and renal fibrosis research.

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