基于“因加而发”理论探讨细胞焦亡在糖尿病肾病发生发展中的作用机制及证治策略

Mechanisms of Pyroptosis in the Initiation and Progression of Diabetic Kidney Disease and Related Syndrome Differentiation and Treatment Strategies: An Exploration Based on the “Yin Jia Er Fa” Theory

摘要: 糖尿病肾病(DKD)起病隐匿、渐进加重、遇诱暴发，与中医学“因加而发”理论所揭示的新故合邪、因加致病规律高度契合。该病病机总属本虚标实，以脾肾气阴亏虚为本，糖浊、脂浊、瘀毒内伏为宿邪；外感、劳倦、情志失调、血糖波动等新邪引动宿邪，正邪交争加剧，则蛋白尿骤增、肾功能急转直下。细胞焦亡是以NLRP3炎症小体-caspase-1-GSDMD信号轴为核心的炎性程序性死亡方式，贯穿DKD肾小球内皮细胞、足细胞、系膜细胞及肾小管上皮细胞的损伤过程，可能是“宿邪久伏”与“新邪引动”之间重要的细胞分子事件之一，细胞焦亡是中医“浊毒”病理状态在细胞层面的重要表现形式与关键驱动机制之一。基于“因加而发”理论，DKD防治宜分阶段干预：消渴期健脾益肾以绝宿邪之源，微量白蛋白尿期清热化浊以救其于芽，临床蛋白尿期化瘀泄浊、抑制焦亡以截断病势，肾功能衰竭期攻补兼施以防传变，全程调摄防新邪引动，达到“无加可发”之目的。该分期证治策略体现中医学“治未病”“既病防变”思想，与靶向焦亡的现代治疗理念相契合，可为中西医结合防治DKD提供参考。

Abstract: Diabetic kidney disease (DKD) is characterized by insidious onset, progressive aggravation, and trigger-induced flares, which is consistent with the TCM theory of “Yin Jia Er Fa” (no onset without superimposed pathogenic factors) reflecting the combination of new and pre-existing pathogens. Its pathogenesis is root deficiency with branch excess: spleen-kidney qi-yin deficiency as the root, and latent sugar turbidity, lipid turbidity, and stasis toxin as pre-existing pathogens. Newly contracted factors, such as exogenous infection, overexertion, emotional disturbance, and glucose fluctuation, may trigger these latent pathogens, as the struggle between healthy qi and pathogens intensifies, leading to sharp increases in proteinuria and rapid renal function decline. Pyroptosis, an inflammatory form of programmed cell death mediated by the NLRP3 inflammasome-caspase-1-GSDMD axis, is involved throughout the injury processes involving glomerular endothelial cells, podocytes, mesangial cells, and tubular epithelial cells. It may be a key cellular event linking latent pathogens with newly contracted triggers, and may represent an important cellular manifestation and key driver of the TCM pathological state of “turbid toxin”. Guided by the “Yin Jia Er Fa” theory, DKD management should be staged: in the Xiaoke stage, fortify the spleen and kidney to eliminate the source of latent pathogens; in the microalbuminuria stage, clear heat and resolve turbidity; in the clinical proteinuria stage, transform stasis, drain turbidity, and inhibit pyroptosis; and in the renal failure stage, combine attack and tonification. Throughout treatment, triggering factors should be avoided to achieve “Wu Jia Ke Fa” (no onset without superimposed pathogenic factors). This strategy reflects the TCM concepts of preventive treatment and preventing deterioration, aligns with modern pyroptosis-targeted therapy, and may provide a reference for integrated Chinese-Western medicine in DKD management.