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.