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.
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).
A new study using GlycoCheck, and co-authored by GlycoCheck Chief Science Officer, Dr. Hans Vink, reports new findings of research on patients with sepsis. The study, titled “Identification of novel sublingual parameters to analyze and diagnose microvascular dysfunction in sepsis: the NOSTRADAMUS study” was published in Critical Care. Critical Care is a high-quality, peer-reviewed, international clinical medical journal that provides a comprehensive overview of the intensive care field.
“For the first time, we can now determine quantitative microvascular scores that correlate very well with accepted clinical parameters in individual sepsis patients for a wide range of clinical severities,” said Dr. Vink, Co-Founder of GlycoCheck.
“The new GlycoCheck software system represents a significant upgrade for researchers and healthcare practitioners,” said Robert Long, CEO and Co-Founder of GlycoCheck and Microvascular Health Solutions. “For several years, GlycoCheck has been used globally in groundbreaking research to understand the complex nature of the endothelial glycocalyx.”
The study concludes that new important diameter-specific quantification and differentiated analysis of RBC kinetics is a key to understand microvascular dysfunction in sepsis. MVHSdynamic, which has a broad bandwidth to detect micro-vascular (dys-) function, might serve as a valuable tool to detect microvascular impairment in critically ill patients.
Large elastic artery stiffening and endothelial dysfunction, and associated reductions in nitric oxide (NO) bioavailability, are central features of vascular aging. We have recently demonstrated that the glycocalyx, a gel-like structure that is bound to the luminal surface of the vascular endothelium, is dysfunctional in the aged vasculature. The glycocalyx has several functions that are critical for the maintenance of a healthy vasculature. We sought to determine if chronic dietary supplementation of glycocalyx precursors (glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan) could restore glycocalyx function, while concomitantly ameliorating age-related vascular dysfunction. Young (Y: 7 mo) and old (O: 30 mo) male B6D2F1 mice consumed a control (C) or glycocalyx precursor (GP: 37 mg/kg encapsulated chow provided courtesy of MicroVascular Health Solutions, Inc. [U.S. Patent Serial No. 9,943,572]) diet ad libitum for 10 weeks. Glycocalyx barrier function (perfused boundary region [PBR]) was evaluated in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. PBR was ~13% higher in OC compared to YC, suggestive of an age-related impairment in glycocalyx barrier function, and this was normalized in OGP mice (Both P<0.05; Figure 1). At baseline, aortic pulse wave velocity (PWV), a measure of large artery stiffness, was higher in OC and OGP compared with YC mice (Both P<0.05; Figure 2). However, after the dietary intervention, PWV decreased by ~13% in OGP (P<0.05), whereas, PWV was unchanged in OC and YC mice after the 10 week period (P>0.05). We assessed endothelial function by endothelium-dependent dilation (EDD, maximal response to acetylcholine [ACh]) in the carotid artery. Carotid artery EDD was higher in YC and OGP compared to OC mice (92.5±2.4 and 90.7±2.3 vs. 69.0±4.9%, respectively, P<0.05). EDD of OGP was similar to YC mice (P>0.05). After incubation with the nitric oxide (NO) synthase inhibitor, L-NAME, the dilatory response did not differ between groups (P>0.05). NO bioavailability (max ACh dilation – max ACh+L-NAME dilation) was ~10–14 fold higher in YC and OGP compared to OC mice (Both P<0.05; Figure 3). Endothelium-independent dilation (vasodilation to sodium nitroprusside) was not different between groups (P>0.05). In young mice, GP diet did not affect any of the aforementioned measurements (P>0.05). In conclusion, 10 weeks of dietary GP supplementation in old mice restores glycocalyx barrier function that is accompanied by reduced aortic stiffness and augmented EDD and NO bioavailability, suggesting that the glycocalyx may be an effective therapeutic target for vascular dysfunction in older adults.
6.3.2 Food supplement
A pilot study was conducted among 13 healthy volunteers receiving the Endocalyx food supplement. After 3 months, the Microvascular Health Index measured by SDF imaging improved by 31%. After 4 months, the Microvascular Health Index in the volunteers improved by 50%. This showed the beneficial effects of the food supplement on the microvasculature as it significantly increased capillary density and red blood cell filling percentage, and reduced the perfused boundary region (unpublished data, H. Vink).
6.4.2 Food supplement
In the pilot study with Endocalyx, no serious adverse effects were reported. One side effect that was reported was dizziness, as the Endocalyx supplement lowered the systolic blood pressure. The supplement is already used in general practitioners’ offices in the United States and to date; no one reported any major side effects. Studies conducted with the individual ingredients also did not report any serious adverse effects. A possible side effect may be an unknown allergic reaction to one of the ingredients of the supplement. Benefits of the Endocalyx food supplement in diabetic patients remain to be established but are mainly improving microvascular health by supporting endothelial glycocalyx function.
Leiden University Medical Center
Dutch Kidney Foundation
Health Holland (Dutch Top Sector Life Sciences & Health)
Laan van Nieuw Oost-Indië 334,
2593 CE Den Haag
Dutch Kidney Foundation
Groot Hertoginnelaan 34
1405 EE, Bussum
Leiden University Medical Center, The Netherlands
Radboud University Medical Center, The Netherlands
To investigate whether intervention with the dietary supplement Endocalyx™ improves the
Microvascular Health Index between baseline and 3 months in type 2 diabetic South Asian patients with
microalbuminuria in comparison to the placebo group.
Background: Deterioration of the endothelial glycocalyx (eGC), a protective carbohydrate-rich layer lining the luminal surface of the endothelium, plays a key role in vascular barrier dysfunction and eventually organ-failure in systemic inflammatory response syndrome and sepsis. Early detection of glycocalyx damage could thus become an important goal in critical care. This study was designed to determine the feasibility and reproducibility of quantitative, real-time glycocalyx measurements performed at bedside in the emergency room (ER) and intensive care unit (ICU).
Methods: The observational study included 70 patients admitted to the ER or ICU of a university hospital. A physician and the nurse in charge of the patient performed sublingual microcirculatory measurements using sidestream dark field (SDF) imaging. A novel data acquisition and analysis software (GlycoCheck™) was used to analyze the perfused boundary region (PBR), an inverse parameter of endothelial glycocalyx dimensions in vessels with diameters of between 5 and 25 μm.
Results: The method showed a good intra-observer reproducibility. Specifically, intraclass correlation coefficient analysis showed an excellent reproducibility between the physician’s measurements (0.77 [CI 95%: 0.52-0.89]). The bias between the two PBRs was – 0.077 ± 0.24 μm. Moreover, there were no significant differences in the PBR values obtained by the nurses when compared to those reported by the physician (regarded as the “gold standard” measurement). Intraclass correlation coefficient analysis showed excellent reproducibility between the nurses’ and physician’s PBRs (0.75 [95% CI: 0.52-0.87]). The mean difference between the two PBRs (i.e., the bias) was 0.007 ± 0.25 μm. The nurses’ PBR assessment had a 90% sensitivity (95% CI: 60-99%) and 90% specificity (95% CI: 80-93%) to identify a severely impaired glycocalyx.
Conclusion: Glycocalyx dimensions can be measured at patients’ bedside precisely by non-invasive assessment of the PBR. This assessment could become part of standard monitoring and contribute to clinical decision-making and resuscitation protocols in clinical trials and daily practice.