Metabolic Intensification in Limb Salvage: A Doubly Robust Dual-Center Study Establishing 37.9 g/L as the Physiological Requirement for Diabetic Foot Ulcer Regeneration.

Abstract

BackgroundClinical guidelines conventionally define nutritional adequacy using a 35 g/L serum albumin threshold. However, its biological sufficiency for driving diabetic foot ulcer (DFU) regeneration remains unvalidated. This investigation utilized a structural modeling framework to interrogate the non-linear relationship between albumin and DFU repair and to identify the precise physiological threshold required for active healing.MethodsThis prospective, dual-center cohort study of 733 DFU patients utilized a 20-week observation window anchored to baseline enrollment (Time Zero, T0). To isolate the independent metabolic effect of albumin from systemic inflammatory confounding, we implemented a doubly robust framework integrating generalized propensity score (GPS) weighting with restricted cubic spline (RCS) modeling. The primary endpoint was Percentage Area Reduction (PAR) at 20 weeks.ResultsBaseline albumin was identified as a significant independent driver of wound reduction (β = 3.25; 95% CI: 0.76-5.73; P = 0.01) and a protective factor against major amputation (OR = 0.89; 95% CI: 0.79-0.99; P = 0.037). RCS analysis revealed a highly significant non-linear trajectory (P for non-linearity < 0.001) with a biological inflection point at 37.9 g/L. No significant regenerative progress occurred within the 31.4-37.9 g/L stagnation plateau. Sensitivity analysis confirmed the conventional 35 g/L cutoff failed to differentiate healing outcomes (P = 0.869), resulting in 45.8% of normoalbuminemic patients being misclassified within a state of regenerative arrest. The calculated E-value of 3.40 confirms profound robustness against unmeasured confounding.ConclusionsThe conventional 35 g/L albumin threshold is clinically inadequate to sustain the metabolic demands of DFU repair. To breach the identified stagnation plateau and transition the wound bed toward active regeneration, clinicians should prioritize a new physiological target of 37.9 g/L (clinically operationalized as ≥ 38 g/L). This necessitates a strategic shift toward metabolic intensification in limb salvage protocols.