GlycoCheck - Published research

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Ways and Means of Cellular Reconditioning for Kidney Regeneration

Ishiko S. · Goligorsky M.S.
American Journal of Nephrology, Vol. 53, No. 2-3, April 2022

Abstract

Background: Mitochondrial, lysosomal, and peroxisomal dysfunction; defective autophagy; mitophagy; and pexophagy, as well as the loss of glycocalyx integrity are known contributors to initiation and progression of diverse kidney diseases. Those cellular organelles are tightly interactive in health, and during development of a disease, damage in one may propagate to others. By extension, it follows that restoring an individual defect may culminate in a broader restorative spectrum and improvement of cell and organ functions.

Summary: A novel strategy of reconditioning cellular organellar dysfunction, which we define as refurbishment of pathogenically pivotal intra- or extracellular elements, damaged in the course of disease and impeding restoration, is briefly outlined in this overview. Individual therapeutic reconditioning approaches targeting selected organelles are cataloged. We anticipate that the proposed reconditioning strategy in the future may enrich the arsenal of regenerative medicine and nephrology.

Key Message: The arsenal of regenerative medicine and nephrology consisting of organ transplantation, use of stem cells, cell-free approaches, cell reprogramming strategies, and organ engineering has been enriched by the reconditioning strategy. The latter is based on the recognition of two facts that (a) impairment of diverse cellular organelles contributes to pathogenesis of kidney disease and (b) individual organelles are functionally interactively coupled, which explains the “domino effect” leading to their dysfunction. Reconditioning takes advantage of these facts and, while initially directed to restore the function of individual cellular organelles, culminates in the propagation of a therapeutic intervention to account for improved cell and organ function. Examples of such interventions are briefly summarized along the presentation of defective cellular organelles contributing to pathogenesis of kidney disease.

Excerpt from section Therapeutic Interventions to Preserve and Repair Glycocalyx

Another potentially promising therapeutic approach is represented by Endocalyx ProTM (Microvascular Health Solutions, Salt Lake City, [UT], USA), a combination of natural products each endowed with individual properties to accelerate restoration and prevent excessive degradation of glycocalyx. It contains brown seaweed extract called Laminaria japonica, rich in fucoidan sulfate – a hybrid of HS and CS. The fucoidan repairs the glycocalyx and prevents its breakdown by inhibiting heparanase activity. Another component is a high molecular weight hyaluronan. It is supplemented with glucosamine sulfate, providing the building blocks for glycocalyx synthesis. Further components include a proprietary blend of polyphenol and flavonoids with added superoxide dismutase and catalase (both from bitter melon concentrate).

Mutations in the heparan sulfate backbone elongating enzymes EXT1 and EXT2 have no major effect on endothelial glycocalyx and the glomerular filtration barrier

Ramzi Khalil, Margien G. S. Boels, PALGA Group, Bernard M. van den Berg, Jan A. Bruijn, Ton J. Rabelink, Pancras C. W. Hogendoorn & Hans J. Baelde
Molecular Genetics and Genomics 01 February 2022

Abstract

In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology.

Microvascular rarefaction in patients with cerebrovascular events

Patricia P. Wadowski, Christian Schörgenhofer,Thomas Rieder, Sebastian Ert, Joseph Pultar, Wolfgang Serles, Thomas Sycha, Florian Mayer, Renate Koppensteiner, Thomas Gremmel, Bernd Jilma
ScienceDirect 23 December 2021

Abstract

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing post-stroke brain reorganization. We hypothesized that microcirculatory changes during acute cerebrovascular events could be reflected systemically and visualized sublingually.

In a prospective observational trial in vivo sublingual sidestream darkfield videomicroscopy was performed in twenty-one patients with either acute stroke (n = 13 ischemic, n = 1 ischemic with hemorrhagic transformation and n = 2 hemorrhagic stroke) or transitory ischemic attacks (n = 5) within 24 h after hospital admission and compared to an age- and sex-matched control group. Repetitive measurements were performed on the third day and after one week.

Functional and perfused total capillary density was rarefied in the overall patient group (3060 vs 3717 μm/mm2, p = 0.001 and 5263 vs 6550 μm/mm2, p = 0.002, respectively) and in patients with ischemic strokes (2897 vs. 3717 μm/mm2, p < 0.001 and 5263 vs. 6550 μm/mm2, p = 0.006, respectively) when compared to healthy controls. The perfused boundary region (PBR), which was measured as an inverse indicator of glycocalyx thickness, was markedly related to red blood cell (RBC) filling percentage (regarded as an estimate of microvessel perfusion) in the overall patient group (r = −0.843, p < 0.001), in patients with ischemic strokes (r = −0.82, p = 0.001) as well as in healthy volunteers (r = −0.845, p < 0.001).

In addition, there were significant associations between platelet count or platelet aggregation values (as measured by whole blood impedance aggregometry) and microvascular parameters in the overall patient collective, as well as in patients with ischemic strokes.

In conclusion, cerebrovascular events are associated with altered systemic microvascular perfusion.

Endothelial glycocalyx and microvascular perfusion are associated with carotid intima-media thickness and impaired myocardial deformation in psoriatic disease

Ignatios Ikonomidis, George Pavlidis, Vaia Lambadiari, Pinelopi Rafouli-Stergiou, George Makavos, John Thymis, Gavriella Kostelli, Maria Varoudi, Konstantinos Katogiannis, Konstantinos Theodoropoulos, Pelagia Katsimbri, John Parissis & Evangelia Papad
Journal of Human Hypertension 25 November 2021

Abstract

Psoriatic disease is associated with vascular and myocardial dysfunction. We aimed to evaluate endothelial glycocalyx barrier properties and microvascular perfusion in psoriatic patients, as well as their correlation with carotid intima-media thickness (cIMT) and markers of left ventricular (LV) myocardial deformation. We examined 297 psoriatic patients and 150 controls, adjusted for age, sex, and atherosclerotic risk factors. The severity of psoriatic disease was estimated using the psoriasis area and severity index (PASI). Perfused boundary region (PBR), a marker of glycocalyx barrier function, was measured non-invasively in sublingual microvessels with a diameter 5–25 μm using Sidestream Dark Field camera (Microscan, GlycoCheck). Increased PBR indicates reduced glycocalyx thickness. Indexes of microvascular perfusion, including red blood cells filling (RBCF) and functional microvascular density, were also calculated. We measured cIMT, coronary flow reserve (CFR) and markers of myocardial deformation by speckle-tracking imaging, namely global longitudinal strain (GLS) and percentage changes between peak twisting and untwisting at mitral valve opening (%dpTw-UtwMVO). Compared to controls, psoriatic patients had higher PBR5-25μm (2.13 ± 0.29μm versus 1.78 ± 0.25μm, p < 0.001) and lower RBCF and functional microvascular density (p < 0.001). Increased PASI was associated with elevated PBR and more impaired cIMT and GLS (p < 0.05). There was an inverse association of PBR with RBCF and functional microvascular density (p < 0.001). In psoriatic population, increased PBR was related to increased cIMT, reduced CFR, impaired GLS and decreased %dpTw-UtwMVO (p < 0.001). Glycocalyx thickness is reduced in psoriatic patients, which in turn impairs microvascular perfusion, and is associated with carotid IMT and impaired coronary and myocardial function.

Association of Gestational Diabetes With Subclinical Cardiovascular Disease on Echocardiogram and Endothelial Function Testing

Anum Minhas , Malamo E Countouris , Chiadi E Ndumele , Elizabeth Selvin , Arthur J Vaught , Robin Gandley , Allison Hays , Pamela Ouyang , Wendy L Bennett , Janet M Catov and Erin Michos
Circulation (American Heart Association) 8 Nov 2021

Abstract

Introduction: Gestational diabetes mellitus (GDM) increases risk for cardiovascular disease (CVD). The subclinical cardiovascular structural and functional changes that contribute to long-term cardiovascular risk are unclear.

Hypothesis: We hypothesized that GDM is associated with adverse cardiovascular remodeling, diastolic function abnormalities, and endothelial dysfunction at approximately a decade after delivery, thereby increasing CVD risk.

Methods: We conducted a cross-sectional analysis of women from an existing cohort with abstracted clinical pregnancy data. Women attended a follow-up visit at a median of 9 years after delivery. Echocardiograms, Peripheral Arterial Tonometry (EndoPAT), glycocalyx analysis (GlycoCheck) and laboratory testing were conducted at the follow-up visit.

Results: Among 217 women who attended the follow-up visit, 53 (24%) had history of GDM. After adjusting for age, race, preeclampsia history or preterm delivery, women with prior Compared to women without GDM, women with prior GDM had higher interventricular septal and left ventricular (LV) posterior wall thickness and lower septal e’ velocity (Table; Model 2). They also had worse endothelial function with lower reactive hyperemia index (RHI) and adverse GlycoCheck parameters. Measures of hypertrophy were attenuated by additional adjustment for body mass index, hypertension, and diabetes (Model 3), but findings of adverse LV diastology, RHI and GlycoCheck parameters remained significant.

Conclusions: Women with GDM were more likely to have increased LV wall thickness, adverse diastology and endothelial dysfunction nearly a decade postpartum. Adjusting for traditional cardiovascular risk factors attenuated some but not all parameters. These findings suggest that subclinical structural and functional cardiac and vascular changes may be a mechanism by which GDM causes increased risk of CVD.

Impaired Endothelial Glycocalyx Predicts Adverse Outcome in Subjects Without Overt Cardiovascular Disease: a 6-Year Follow-up Study

Ignatios Ikonomidis, John Thymis, Panagiotis Simitsis, Georgia-Angeliki Koliou, Spiridon Katsanos, Charilaos Triantafyllou, Foteini Kousathana, George Pavlidis, Aikaterini Kountouri, Eftihia Polyzogopoulou, Konstantinos Katogiannis, Dimitrios Vlastos,
Journal of Cardiovascular Translational Research 28 Oct 2021

Abstract

We investigated whether disturbance of glycocalyx integrity is related with increased cardiovascular risk. In 600 healthy subjects, we measured perfused boundary region (PBR), a marker of glycocalyx integrity, in sublingual microvessels with diameter ranging 5–25 µm using a dedicated camera (Sideview Darkfield Imaging). Increased PBR indicates reduced glycocalyx thickness. We prospectively monitored the occurrence of cardiovascular events (MACE-death, myocardial infarction, and stroke) during a 6-year follow-up. Fifty-seven MACE were documented. Increased values of PBR5-25 predicted higher risk for MACE in a model including sex, age, hyperlipidemia, diabetes, hypertension, smoking, family history of coronary disease, treatment with ACEi/ARBs, or lipid-lowering agents (hazard ratio (HR), 6.44, p = 0.011; net reclassification improvement (NRI), 28%; C-statistic: 0.761). PBR5-25 was an independent and additive predictor of outcome when added in a model including the European Heart SCORE, diabetes, family history of CAD, and medication (HR, 4.71; NRI: 39.7%, C-statistic from 0.653 to 0.693; p < 0.01).Glycocalyx integrity is an independent and additive predictor to risk factors for MACE at 6-year follow-up in individuals without cardiovascular disease. ClinicalTrials.govIdentifier:NCT04646252.