Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) Syndrome in the Diabetic, Neuropathic Foot

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Project Summary/Abstract Non-traumatic lower extremity amputations (NLEA) in people with diabetic peripheral neuropathy (DPN) have devastating consequences, most notable a 3-year mortality rate of up to 71%. Data from our previous award cycle support a foot bone and vascular pathway culminating in NLEA in people with DPN. Bone and vascular deterioration were significantly related to key risk factors for NLEA in the insensate foot; foot deformity, fracture, and delayed wound healing. However, the current bone and vascular pathway does not explain why the highest rate of NLEA occurs in individuals with DPN and end-stage chronic kidney disease (CKD). We believe that CKD-mineral bone disorder (CKD-MBD) is the missing link in the foot bone and vascular pathway to DPN-associated NLEA. CKD-MBD is recognized, in the hip and coronary/aortic vessels, to induce a bone-vascular paradox with loss of skeletal bone volume and strength and vascular calcification. However, the contribution of CKD-MBD to DPN-associated NLEA is unknown. Thus, this renewal application will extend our discoveries and test the central hypothesis that CKD-MBD synergistically combines with DPN in the foot bone and vascular deterioration pathway to place the DPN foot at the highest risk for NLEA. This application will employ a multi-site, cross-sectional (n=216) and longitudinal (n=114), study of people with Type 2 DPN across all stages of CKD: stage 1(No CKD) to 5. Through this project we aim to: 1) quantify the effect of CKD severity and progression on pedal bone quality & quantity and vessel calcification (Aim 1), 2) determine the effect of CKD, mediated through bone quantity and quality and foot vessel calcification, on clinically relevant foot outcomes (Aim 2), 3) explore the ability of CKD, bone quality and quantity, and vascular calcification variables to predict risk for clinically relevant poor foot outcomes. The investigative team from Washington University in St. Louis, High Point University, and University of California San Francisco represents a unique and powerful combination of collective and individual clinical research expertise in DPN tissue deterioration, imaging, and CKD-MBD. This project uses highly innovative cutting-edge technology and processing to measure individual foot bone quantity & quality and pedal vessel calcification with computed tomography and hidden changes in foot bone cortical and trabecular micro- architecture that are not reflected in global measures of BMD using high resolution peripheral quantitative computed tomography (HR-pQCT). Finally, in our NLEA risk prediction aim we include a CKD-MBD serum marker (sclerostin), a critical step in translating CKD-MBD research from bench to bedside. Understanding the pathway to NLEA will improve preventative care and management of people with DPN to reduce the risk of NLEA by making CKD prevention and treatment indispensable, identifying pharmaceutical targets, and identifying risk factors of NLEA, allowing early intervention.