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
Terry Hao-Yu Qin, Atiqah Aziz, Xiu-Wen Ling, Amber Haseeb, Eva Mahirah Zulkifli, Tunku Kamarul, Han-Ling Tan, Aiden Yi-Fei WangBackground
Clinical 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.
Methods
This 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.
Results
Baseline 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.
Conclusions
The 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.