Objective: The paper is aimed to establish a method for renal injury in rats with kidney yang deficiency syndrome (KYDS) of the stable by comparing different model establishment methods and optimize the final modeling method.Method: In order to mimic water metabolism disorder of KYDS- a diagnostic pattern in traditional Chinese medicine (TCM), we made a comparison of hydrocortisone-induced, adenine-induced, dexamethasone combined with adriamycin-induced KYDS rat model according to testing general behavior, detecting Hypothalamus-pituitary-adrenal (HPA) axis function and renal function also making use of drug action. Additionally, the effect of adenine at a dose of 100 mg/kg, 150 mg/kg, and 200 mg/kg, respectively, on establishment of KYDS model was investigated in rats. Finally, Shenqi Wan (SQW, 3 g/kg) was used to estimate the deterioration of adenine that is associated with KYDS. Result: Three KYDS model rats all exhibited weight loss, anal temperature drop, reduced food intake and dysfunction of the Hypothalamus-pituitary-adrenal (HPA) axis, which could be alleviated by SQW. However, different from other two methods, adenine-induced rats were prominently manifested as water and fluid metabolism disorders (sharply increased water intake and urine volume). Renal injury in adenine-induced rats was more obvious than it in hydrocortisone-induced rats and dexamethasone combined with adriamycin-induced rats. And renal toxicity caused by adenine was reversible by SQW treatment. Water metabolism disorder in adenine-induced rats was more closer to clinical symptoms of patients with KYDS. Subsequently, we found different dose of adenine gavage (100, 150, 200 mg/kg) for 14 days result in general behavior change, dysfunction of HPA axis and renal function damage. But only medium-dose of adenine induced toxicity could be reversed by SQW treatment for 21 days.Conclusion: The result of the comparison between the three modeling methods showed that adenine-induced was more effective to establish the KYDS model, and only a medium-dose of adenine for inducing renal poison could be recovered by SQW treatment. Therefore, a medium-dose of adenine was optimal for the establishment of the KYDS rat model.Trial registration : This is an animal experiment, trial registration is not necessary.