Publications by authors named "Diego Celdran-Bonafonte"

5 Publications

  • Page 1 of 1

Functional analysis of arteriovenous fistulae in non-contrast magnetic resonance images.

Comput Methods Programs Biomed 2022 Jul 13;222:106938. Epub 2022 Jun 13.

Department of Mechanical Engineering, University of Maryland, College Park, MD, USA. Electronic address:

Background And Objective: Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis vascular access and their successful maturation is critical to reduce patient morbidity, mortality, cost, and improve quality of life. Peri-anastomotic venous segment stenosis is the primary cause of AVF maturation failure. The objective is to develop a software protocol for the functional analysis of arteriovenous fistula.

Method: We have developed a standard protocol for the anatomical analysis of the AVF to better understand the mechanisms involved in AVF stenosis and to identify future imaging biomarkers for AVF success or failure using non-contrast magnetic resonance imaging (MRI). The 3D model of the AVF is created using a polar dynamic programming technique. Analysis has been performed on six Yorkshire cross domestic swine, but techniques can be applied into clinical settings.

Results: Differences in AVF angles and vein curvature are associated with significant variability of venous cross-sectional area. This suggests that the pattern of stenosis is likely to be dependent upon hemodynamic profiles which are largely determined by AVF anatomical features and could play an important role in AVF maturation.

Conclusions: This protocol enables us to visualize and study the hemodynamic profiles indirectly allowing early stratification of patients into high and low risk groups for AVF maturation failure. High risk patients could then be targeted with an enhanced process of care or future maturation enhancing therapies resulting in a much-needed precision-medicine approach to dialysis vascular access.
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http://dx.doi.org/10.1016/j.cmpb.2022.106938DOI Listing
July 2022

A pig model of tunneled dialysis catheter (TDC) infection and dysfunction: Opportunities for therapeutic innovation.

J Vasc Access 2021 Sep 23:11297298211046751. Epub 2021 Sep 23.

UNC Kidney Center, Chapel Hill, NC, USA.

Background: Although tunneled dialysis catheters (TDC) are far from ideal, they still represent the main form of vascular access for most patients beginning dialysis. Catheters are easy to place and allow patients instant access to dialysis, but regardless of these benefits, catheters are associated with a high incidence of significant complications like bloodstream infections, central venous stenosis, thrombosis, and dysfunction. In the present study, we aim to describe and characterize a swine model of catheter dysfunction and bloodstream infection, that recreates the clinical scenario, to help to serve as a platform to develop therapeutic innovations for this important clinical problem.

Methods: Six Yorkshire cross pigs were used in this study. Non-coated commercial catheters were implanted in the external jugular recreating the main features of common clinical practice. Catheters were aseptically accessed twice a week for a mock dialysis procedure (flushing in and out) to assess for and identify catheter dysfunction. Animals were monitored daily for infections; once detected, blood samples were collected for bacterial culture and antibiograms. Study animals were euthanized when nonresponsive to treatment. Tissue samples were collected in a standardized fashion for macroscopic inspection and histological analysis.

Results: The data analysis revealed an early onset of infection with a median time to infection of 9 days, 40% of the isolates were polymicrobial, and the average time to euthanasia was 20.16 ± 7.3 days. Median time to catheter dysfunction onset was 6 days post-implantation. Postmortem dissection revealed external fibrin sheath and internal thrombosis as the main causes of catheter dysfunction. There was also evidence of central venous stenosis with positive cells for αSMA, CD68, Ki67, Smoothelin, and Vimentin within the venous neointima.

Conclusions: The described model represents a reliable and reproducible large animal model of catheter dysfunction and bloodstream infection, which recreates all the main complications of TDC's and so could be used as a validated large animal model to develop new therapies for TDC related infection, thrombosis/dysfunction and central venous stenosis.
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http://dx.doi.org/10.1177/11297298211046751DOI Listing
September 2021

A coming of age for vascular access research: the good, the bad, and the ugly!

Kidney Int 2019 06;95(6):1294-1295

University of North Carolina Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Southern Arizona VA Health Care System (SAVAHCS), Tucson, Arizona, USA. Electronic address:

Dialysis vascular access dysfunction remains an important clinical problem with a very significant morbidity, mortality, and socio-economic cost. Despite the magnitude of the clinical problem, there are currently no truly effective therapies for vascular access dysfunction. Through a high-quality scientific investigation, Liang et al. have identified a number of novel biological pathways responsible for "mouse" arteriovenous fistula stenosis. We hope that the identification of these druggable pathways (targets) will allow for the development of new and effective therapies for vascular access dysfunction, through the creation of an innovation substrate for dialysis vascular access.
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http://dx.doi.org/10.1016/j.kint.2019.02.035DOI Listing
June 2019

Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression of Krüppel-Like Factor 2.

J Am Heart Assoc 2018 01 4;7(1). Epub 2018 Jan 4.

Division of Cardiovascular Health and Disease, The University of Cincinnati College of Medicine, Cincinnati, OH

Background: Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease. The accumulation of uremic solutes in this patient population is associated with endothelial dysfunction and accelerated cardiovascular disease. In this study, we examined the impact of the uremic milieu on the endothelial transcription factor, Krüppel-like factor 2 (KLF2), a key regulator of endothelial function and activation.

Methods And Results: Using serum from uremic pigs with chronic renal insufficiency, our results show that KLF2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically, KLF2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine-modified albumin, an advanced glycation end product (AGE) known to induce endothelial dysfunction. AGE-mediated suppression of KLF2 is dependent on activation of the receptor for AGE, as measured by small interfering RNA knockdown of the receptor for AGE. Furthermore, KLF2 suppression promotes endothelial dysfunction, because adenoviral overexpression of KLF2 inhibits reactive oxygen species production and leukocyte adhesion in human umbilical vein endothelial cells. In addition, the application of hemodynamic shear stress, prolonged serum dialysis, or treatment with the receptor for AGE antagonist azeliragon (TTP488) is sufficient to prevent KLF2 suppression in vitro. To decipher the mechanism by which uremic AGEs suppress KLF2 expression, we assessed the role of the receptor for AGE in activation of nuclear factor-κB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of IκBα, we show that translocation of p65 to the nucleus is necessary for KLF2 suppression after treatment with uremic AGEs.

Conclusions: These data identify KLF2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.
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http://dx.doi.org/10.1161/JAHA.117.007566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778969PMC
January 2018

The topical administration of rhEGF-loaded nanostructured lipid carriers (rhEGF-NLC) improves healing in a porcine full-thickness excisional wound model.

J Control Release 2015 Jan 6;197:41-7. Epub 2014 Nov 6.

NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country, Vitoria, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Spain. Electronic address:

The development of an effective treatment able to reduce the healing time of chronic wounds is a major health care need. In this regard, our research group has recently demonstrated the in vivo effectiveness of the topical administration of rhEGF-loaded lipid nanoparticles in healing-impaired db/db mice. Here we report the effectiveness of rhEGF-NLC (rhEGF loaded nanostructured lipid carriers) in a more relevant preclinical model of wound healing, the porcine full-thickness excisional wound model. The rhEGF-NLC showed a particle size of around 335nm, negative surface charge (-27mV) and a high encapsulation efficiency of 94%. rhEGF plasma levels were almost undetectable, suggesting that no systemic absorption occurred, which may minimise potential side effects and improve treatment safety. In vivo healing experiments carried out in large white pigs demonstrated that 20μg of rhEGF-NLC topically administered twice a week increased the wound closure and percentage of healed wounds by day 25, compared with the same number of intralesional administrations of 75μg free rhEGF and empty NLC. Moreover, rhEGF-NLC improved the wound healing quality expressed in terms of number of arranged microvasculature, fibroblast migration and proliferation, collagen deposition and evolution of the inflammatory response. Overall, these findings demonstrated that topically administered rhEGF-NLC may generate de novo intact skin after full thickness injury in a porcine model, thereby confirming their potential clinical application for the treatment of chronic wounds.
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http://dx.doi.org/10.1016/j.jconrel.2014.10.033DOI Listing
January 2015
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