Randomized controlled clinical trial of Shenzhuo Formula in the treatment of macroalbuminuria in diabetic kidney disease and its inflammation-modulating mechanisms

Background Shenzhuo Formula (SZF), a modified Didang Tang, is used for diabetic kidney disease (DKD), though high-quality evidence is limited. Methods In a randomized, double-blind, double-dummy, active-controlled, multicenter trial, irbesartan (IRB) was the control. A Bayesian model assessed efficacy. Mechanistic studies included Olink inflammation proteomics, single-cell RNA sequencing (scRNA-seq) of KK-Ay mouse kidneys, and in vivo experiments. Results A total of 120 DKD patients with macroalbuminuria were randomized (SZF n = 57, IRB n = 63). At 24 weeks, 24 h urinary total protein change was −0.03 (−0.24 to 0.18) g/24 h in the SZF group and 0.08 (−0.30 to 0.14) g/24 h in the IRB group (P = 0.61). Estimated glomerular filtration rate improved with SZF by 5.91 (1.80 to 10.01) mL/min/1.73m² but declined with IRB by −1.67 (−5.18 to 1.84) mL/min/1.73m² (P < 0.01). Serum creatinine decreased with SZF by −5.15 (−9.73 to −0.56) μmol/L but increased with IRB by 3.39 (−0.84 to 7.61) μmol/L (P < 0.01). Traditional Chinese medicine syndrome response was higher with SZF (89.47% vs. 63.49%, P < 0.01). Safety and metabolic parameters were comparable. Bayesian analysis favored SZF for renal benefit. Mechanistically, SZF downregulated CX3CL1 in endothelial cells and MCP-1 in mesangial and tubular cells, suggesting anti-inflammatory effects restoring endothelial function and attenuating fibrosis. Conclusions SZF matched IRB in proteinuria reduction but was superior in preserving renal function and improving traditional Chinese medicine symptoms in DKD, with good safety. Benefits may involve suppression of CX3CL1/MCP-1-mediated inflammation.