Synergistic Effects of Diabetic Neuropathy and Kidney Function Decline on Second Metatarsal Skeletal Health and Foot Function: a Pilot Study

Abstract A discouraging increase in diabetes-related nontraumatic lower-extremity amputations (NLEA) has occurred over the last decade. Individuals with diabetic neuropathy (DMPN) and chronic kidney disease (CKD) are at the highest risk for NLEA. Despite the critical implications, little is known about the factors that initiate the cascade of events leading to NLEA, limiting early and effective interventions. We aimed to develop and implement a technique for quantifying metatarsal bone density and microstructure using high-resolution peripheral quantitative computed tomography (HR-pQCT). Twelve participants were enrolled: n=3 who were healthy controls (CON; 57±4 years, BMI 30±13 kg/m2, eGFR 106±4 mL/min/1.73m2), n=3 who had type 2 diabetic neuropathy with eGFR stage 1 (DMPN; 66±2 years, BMI 27±3 kg/m2, eGFR 96±2 mL/min/1.73m2), and n=6 who had type 2 diabetic neuropathy with eGFR defined stages 2-4 (DMPN+eGFR2-4; 69±10 years, BMI 28±3 kg/m2, eGFR 64±20 mL/min/1.73m2). Participants underwent assessments including HR-pQCT of the second metatarsal, dynamic plantar pressure measurements, and multi-segment foot biomechanics analysis during gait. Between-group and pooled correlational analyses were performed. The DMPN+eGFR2-4 group exhibited the highest cortical porosity at the mid-diaphysis, the highest pressure-time integrals at the hindfoot and for the total foot, the lowest intersegmental foot excursions, and lowest maximum ankle power. Correlation analyses revealed strong relationships between estimated glomerular filtration rate (eGFR) and cortical porosity (r=-0.868, p.001), stance hindfoot excursion (r=0.662, p=.027), swing toe excursion (r=0.759, p=.007), swing forefoot excursion (r=0.823, p=.002), swing hindfoot excursion (r=0.745, p=.007), and ankle power (r=0.717, p=.013). Skeletal deterioration, abnormal loading, and poor biomechanics underscore the compounded effects of DMPN and eGFR decline on foot health, likely a consequence of CKD-mineral bone disorder syndrome. These findings suggest potential targets for intervention to prevent NLEAs in this high-risk population. Further research is needed to explore the interaction between DMPN and CKD and targeted therapeutic strategies to improve clinical outcomes.