Vein morphometry in end-stage kidney disease: Teasing out the contribution of age, comorbidities, and vintage to chronic wall remodeling

Abstract

BackgroundChronic kidney disease (CKD) is a highly comorbid condition with significant effects on vascular health and remodeling. Upper extremity veins are important in end-stage kidney disease (ESKD) due to their potential use to create vascular accesses. However, unlike arteries, the contribution of CKD-associated factors to the chronic remodeling of veins has been barely studied.MethodsWe measured morphometric parameters in 315 upper extremity veins, 131 (85% basilic) from stage 5 CKD/ESKD patients and 184 (89% basilic) from non-CKD organ donors. Associations of demographic and clinical characteristics with intimal hyperplasia (IH) and medial fibrosis were evaluated using multivariate regression models.ResultsThe study cohort included 33% females, 30% blacks, 32% Hispanics, and 37% whites. Over 60% had hypertension, and 25% had diabetes independent of CKD status. Among kidney disease participants, 26% had stage 5 CKD, while 22 and 52% had ESKD with and without history of a previous arteriovenous fistula/graft (AVF/AVG), respectively. Intimal hyperplasia was associated with older age (β = 0.13 per year, confidence interval [CI] = 0.002–0.26), dialysis vintage > 12 months (β = 0.22, CI = 0.09–0.35), and previous AVF/AVG creation (β = 0.19, CI = 0.06–0.32). Upper quartile values of IH were significantly associated with diabetes (odds ratio [OR] = 2.02, CI = 1.08–3.80), which demonstrated an additive effect with previous AVF/AVG history and longer vintage in exacerbating IH. Medial fibrosis also increased as a function of age (β = 0.17, CI = 0.04–0.30) and among patients with diabetes (β = 0.15, CI = 0.03–0.28). Age was the predominant factor predicting upper quartile values of fibrosis (OR = 1.03 per year, CI = 1.01–1.05) independent of other comorbidities.ConclusionAge and diabetes are the most important risk factors for chronic development of venous IH and fibrosis independent of CKD status. Among kidney disease patients, longer dialysis vintage, and history of a previous AVF/AVG are strong predictors of IH.

The intricate cellular ecosystem of human peripheral veins as revealed by single-cell transcriptomic analysis

“…One donor had history of hypertension (38F) and none had diabetes. We did not observe significant differences in morphometry between upper arm basilic and cephalic veins ( S1 Fig ), in agreement with published data [ 15 ].…”

“…Therefore, unlike arterial diseases, the cells contributing to venous IH may not need to dedifferentiate extensively or migrate from the adventitia. Phenotypic similarities between intimal and medial SMCs, their pro-remodeling transcriptional profiles, and the widespread distribution of fibroblasts may also explain the tendency of veins to chronically develop IH and fibrosis [ 15 ]. Ultimately, comparative studies with veins obtained after vascular surgeries will be necessary to evaluate the true cellular contributors to postoperative IH and their molecular differentiation.…”

“…Histological inspection of human saphenous and upper extremity veins shows structural wall irregularities regardless of age or the presence of common comorbidities [15][16][17][18][19][20]. Frequent characteristics include medial atrophy, disorganized smooth muscle cells (SMCs), intimal hyperplasia (IH), and abundant interstitial extracellular matrix (ECM) suggesting a natural tendency to wall fibrosis [14,15,[17][18][19][20][21][22].…”

“…Histological inspection of human saphenous and upper extremity veins shows structural wall irregularities regardless of age or the presence of common comorbidities [15][16][17][18][19][20]. Frequent characteristics include medial atrophy, disorganized smooth muscle cells (SMCs), intimal hyperplasia (IH), and abundant interstitial extracellular matrix (ECM) suggesting a natural tendency to wall fibrosis [14,15,[17][18][19][20][21][22]. The absence or thinning of the internal elastic lamina (IEL) and the abundance of fragmented elastic fibers scattered across the wall may have important implications for cell migration and inflammation [16,22,23].…”

Chronic Kidney Disease Transdifferentiates Veins into a Specialized Immune–Endocrine Organ with Increased MYCN-AP1 Signaling

“…Our team previously reported the following: (1) endogenous metabolites, including lysophospholipids [10], can bind to their intrinsic receptors, rather than classical damage-associated molecular pattern (DAMP) receptors, such as toll-like receptors (TLRs) and nod-like receptors/inflammasomes, and become conditional DAMPs; (2) CKD uremic toxins (UTs) serve as conditional DAMPs/homeostasis-associated molecular patterns (HAMPs) to modulate inflammation [11]; (3) upregulated secretomes in peripheral blood mononuclear cells (PBMCs) from patients with CKD and ESRD act synergistically with UTs to promote inflammation and potential disease progression [12]; (4) under pathological conditions, the aorta may act as an immune organ via the upregulation of a variety of secretomes and promote trained immunity [13]; and (5) endothelial cells in the CKD environment can serve as innate immune cells with innate immune memory function by reprograming metabolic pathways [14]. We also reported that CKD contributes to morphometric vascular changes in upper-extremity veins [15]. However, a few important questions remain poorly characterized, including whether CKD pathology contributes to the chronic remodeling and reprogramming of upper-extremity veins into immune endocrine organs and whether CKD primes (trains) upper-extremity veins to fail during the arteriovenous fistula (AVF) creation process.…”