Introduction:
Patients with CKD and ESKD suffer from aggressive dialysis vascular access stenosis within the venous segment of AVFs and AVGs. They also suffer from a huge burden of vascular disease, which responds poorly to interventions such as angioplasty. Despite the huge morbidity, mortality, and economic costs associated with both dialysis vascular access dysfunction and peripheral vascular disease in CKD and ESKD patients, the pathogenetic pathways responsible for this remain unclear. Our group has previously developed and validated a uremic pig model which we now plan to use to investigate differential gene expression and pathway analyses following angioplasty injury of the femoral artery and vein in uremic and control pigs. We believe that these studies could result in the future identification of uremia specific pathways responsible for the response to vascular injury in CKD and ESKD patients.
Methods:
Pigs were made uremic (creatinine = 4-8mg/dL) by performing a right sided nephrectomy followed by a selective ligation of the branches of the left renal artery, such that only 5-7% of the left kidney was still perfused. Following documentation of a creatinine of at least 4-8mg/dL for 2 weeks we performed an angioplasty of the femoral artery and vein on one side, with the contralateral side serving as a control (no angioplasty). Animals were sacrificed two weeks post angioplasty, and arterial and venous samples from the femoral artery and vein on both sides were collected for RNA extraction and bulk RNA sequencing. The serum creatinine at sacrifice was documented to be between 4-8mg/dL. An identical set of experiments was performed on a non-uremic pig.
Results:
Differential expression gene (DEG) analysis revealed that uremia up-regulated 21 genes in the control artery but only 7 genes in the control vein (no angioplasty). In contrast, 177 genes were up-regulated in injured vein (angioplasty) but only 1 gene was up-regulated in the injured artery (angioplasty). In addition, angioplasty injury up-regulated 510 genes in normal vein but only 56 genes in normal artery. Additional pathway enrichment studies revealed differentially enriched pathways in different groups. For example, olfactory receptor activity, positive regulation of immune system process and interferon gamma response were the 3 maximally enriched pathways in uremic control artery whereas neuropeptide receptor activity, neuropeptide signaling pathway and molecular transducer activity were the 3 maximally enriched pathways in uremic control vein.
Conclusions:
Our results, although preliminary, suggest that all three variables, uremia, angioplasty injury, and vessel type (artery vs vein) contribute to the differential gene expression and pathway analyses that we observed in our experiments. Interestingly uremia per se, had more impact (greater DEG) on arteries as compared to veins, while angioplasty injury had a greater impact on veins as compared to arteries. From a future therapeutic perspective, our data suggests that the optimal therapy to reduce restenosis following angioplasty of the venous segment of an AVF in an ESKD may be very different from that needed to reduce restenosis following arterial angioplasty injury for peripheral arterial disease in a CKD/ESKD patient, with the latter being very different from that needed to reduce restenosis following arterial angioplasty injury in a patient without CKD/ESKD.
Portions of this data were presented at ASN Kidney Week 2024
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.