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Huuskes BM, DeBuque RJ, Kerr PG, Samuel CS, Ricardo SD. The Use of Live Cell Imaging and Automated Image Analysis to Assist With Determining Optimal Parameters for Angiogenic Assay in vitro. Front Cell Dev Biol 2019; 7:45. [PMID: 31024908 PMCID: PMC6468051 DOI: 10.3389/fcell.2019.00045] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 03/15/2019] [Indexed: 11/16/2022] Open
Abstract
Testing angiogenic potential and function of cells in culture is important for the understanding of the mechanisms that can modulate angiogenesis, especially when discovering novel anti- or pro-angiogenic therapeutics. Commonly used angiogenic assays include tube formation, proliferation, migration, and wound healing, and although well-characterized, it is important that methodology is standardized and reproducible. Human endothelial progenitor cells (EPCs) are critical for post-natal vascular homeostasis and can be isolated from human peripheral blood. Endothelial colony forming cells (ECFCs) are a subset of EPCs and are of interest as a possible therapeutic target for hypoxic diseases such as kidney disease, as they have a high angiogenic potential. However, once ECFCs are identified in culture, the exact timing of passaging has not been well-described and the optimal conditions to perform angiogenic assays such as seeding density, growth media (GM) concentrations and end-points of these assays is widely varied in the literature. Here, we describe the process of isolating, culturing and passaging ECFCs from patients with end-stage renal disease (ESRD), aided by image analysis. We further describe optimal conditions, for human bladder endothelial cells (hBECs), challenged in angiogenic assays and confirm that cell density is a limiting factor in accurately detecting angiogenic parameters. Furthermore, we show that GM along is enough to alter the angiogenic potential of cells, seeded at the same density. Lastly, we report on the success of human ECFCs in angiogenic assays and describe the benefits of live-cell imaging combined with time-lapse microscopy for this type of investigation.
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Affiliation(s)
- Brooke M Huuskes
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Ryan J DeBuque
- Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Peter G Kerr
- Department of Nephrology, Monash Medical Centre, Monash University, Melbourne, VIC, Australia
| | - Chrishan S Samuel
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Sharon D Ricardo
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
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Ozkok A, Yildiz A. Endothelial Progenitor Cells and Kidney Diseases. Kidney Blood Press Res 2018; 43:701-718. [PMID: 29763891 DOI: 10.1159/000489745] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 05/03/2018] [Indexed: 01/12/2023] Open
Abstract
Endothelial progenitor cells (EPC) are bone marrow derived or tissue-resident cells that play major roles in the maintenance of vascular integrity and repair of endothelial damage. Although EPCs may be capable of directly engrafting and regenerating the endothelium, the most important effects of EPCs seem to be depended on paracrine effects. In recent studies, specific microvesicles and mRNAs have been found to mediate the pro-angiogenic and regenerative effects of EPCs on endothelium. EPC counts have important prognostic implications in cardiovascular diseases (CVD). Uremia and inflammation are associated with lower EPC counts which probably contribute to increased CVD risks in patients with chronic kidney disease. Beneficial effects of the EPC therapies have been shown in studies performed on different models of CVD and kidney diseases such as acute and chronic kidney diseases and glomerulonephritis. However, lack of a clear definition and specific marker of EPCs is the most important problem causing difficulties in interpretation of the results of the studies investigating EPCs.
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Affiliation(s)
- Abdullah Ozkok
- University of Health Sciences, Umraniye Training and Research Hospital, Department of Nephrology, Istanbul, Turkey,
| | - Alaattin Yildiz
- Istanbul University, Istanbul Faculty of Medicine, Department of Nephrology, Istanbul, Turkey
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Lee HJ, Kim W, Kim WS, Woo JS, Kim YG, Moon JY, Lee SH, Ihm CG, Lee TW, Jeong KH. Circulating Endothelial Progenitor Cell Levels Predict Cardiovascular Events in End-Stage Renal Disease Patients on Maintenance Hemodialysis. Nephron Clin Pract 2015; 130:151-8. [PMID: 26089157 DOI: 10.1159/000430471] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 04/13/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The number of circulating endothelial progenitor cells (EPCs) has been identified as a surrogate biologic marker for vascular function and cumulative cardiovascular (CV) risk in the general population. Patients with end-stage renal disease (ESRD) on hemodialysis (HD) have markedly decreased EPC counts and function. We hypothesized that the number of circulating EPCs predicts death from all causes and CV events in patients with ESRD on HD. METHODS We quantified the EPCs in blood samples from 70 patients with ESRD on HD. Circulating EPCs were counted by flow cytometry as the number of CD45(low)CD34(+)VEGFR2(+) cells. Death from all causes and CV events served as outcome variables over a median follow-up period of 20 months. RESULTS It has been postulated that the number of circulating EPCs at baseline ranged from 1 to 350 cells/200 μl, with a mean of ± standard deviation (SD) of 26.0 ± 48.2 cells/200 μl. The median, lowest and highest tertiles of EPC counts were 11.0, 9.0, and 17.0 cells/200 μl, respectively. Patients with the lowest tertile EPC counts had significantly higher rates of CV events, but mortality was similar between the two groups. After adjusting for these risk factors, HbA1c and the lowest tertile EPC count remained as independent predictors of CV events. A cutoff value of 9.5 cells/200 μl maximized the power of the EPC count to predict future CV events as determined by ROC curve analysis. CONCLUSIONS Reduced circulating EPC counts independently predicted CV events in 70 patients with ESRD on maintenance HD. Circulating EPCs may play a role in vascular repair, thereby affecting the clinical course of CV events.
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Affiliation(s)
- Hong Joo Lee
- Department of Nephrology, Seoul Red Cross Hospital, Seoul, South Korea
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Treatment of antibody-mediated rejection including immunoadsorption during first year after renal transplantation--Clinical results and regulation of endothelial progenitor cells. ATHEROSCLEROSIS SUPP 2015; 18:67-73. [PMID: 25936307 DOI: 10.1016/j.atherosclerosissup.2015.02.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Antibody-mediated rejection (AMR) is associated with poor allograft survival. Therefore, effective treatment strategies are required. Extracorporeal strategies are increasingly included in treatment of antibody-mediated rejection to eliminate the detrimental alloantibodies. Yet, other mechanisms contributing to the beneficial effect of apheresis besides the removal of antibodies are under consideration. METHODS We retrospectively analyzed data of 427 transplant patients from 2006 to 2013 with special focus on occurrence, treatment - always including immunoadsorption - and 12-months outcome of antibody-mediated rejection. Besides, we prospectively monitored how the number and phenotype of endothelial progenitor cells in four patients experiencing antibody-mediated rejection changed during the treatment course of 6-20 sessions of immunoadsorption in comparison to seven patients subjected to immunoadsorption because of preparation for ABO-incompatible transplantation. RESULTS 24 patients were diagnosed with acute AMR and treated with immunoadsorption resulting in patient and allograft survival of 100% and 87.5%, respectively. In patients with antibody-mediated rejection, the endothelial progenitor cell number after successful immunoadsorption therapy was always transiently decreased and the adhesive and migratory ability improved. This regulation of circulating endothelial precursor cells was not seen in patients undergoing repetitive immunoadsorptions before ABO-incompatible transplantation. CONCLUSION Combined therapy with immunoadsorption allows a successful treatment of AMR. Treatment seems to be associated with a transient regulation of circulating endothelial precursor cells.
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Zumrutdal A. Role of β 2-microglobulin in uremic patients may be greater than originally suspected. World J Nephrol 2015; 4:98-104. [PMID: 25664251 PMCID: PMC4317633 DOI: 10.5527/wjn.v4.i1.98] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 09/03/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
The role of beta2-microglobulin (β2M) in dialysis-related amyloidosis as a specific amyloid precursor was defined in the 1980s. Studies in those years were largely related to β2M amyloidosis. In 2005, for what was probably the first time in the available literature, we provided data about the association between β2M and early-onset atherosclerosis in hemodialysis patients without co-morbidities. In recent years, the role of uremic toxins in uremic atherosclerosis and the interest in β2M as a marker of cardiovascular (CV) and/or mortality risk have grown. In the current literature, clinical studies suggest that β2M is an independent, significant predictor of mortality, not only in dialysis patients, but also in predialysis patients and in the high-risk portion of the general population, and it seems to be a factor strongly linked to the presence and severity of CV disease. It is still unknown whether β2M is only a uremic toxin marker or if it also has an active role in vascular damage, but data support that it may reflect an increased burden of systemic atherosclerosis in a setting of underlying chronic kidney disease. Thus, although there have been some inconsistencies among the various analyses relating to β2M, it promises to be a novel risk marker of kidney function in the awareness and detection of high-risk patients. However, more research is required to establish the pathophysiological relationships between retained uremic toxins and further biochemical modifications in the uremic milieu to get answers to the questions of why and how. In this review, the recent literature about the changing role of β2M in uremic patients will be examined.
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Roura S, Gálvez-Montón C, Bayes-Genis A. The challenges for cardiac vascular precursor cell therapy: lessons from a very elusive precursor. J Vasc Res 2013; 50:304-23. [PMID: 23860201 DOI: 10.1159/000353294] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 05/01/2013] [Indexed: 11/19/2022] Open
Abstract
There is compelling evidence that cardiovascular disorders arise and/or progress due mainly to endothelial dysfunction. Novel therapeutic strategies aim to generate new myocardial tissue using cells with regenerative potential, either alone or in combination with biomaterials, cytokines and advanced monitoring devices. Among the human adult progenitor cells used in such methods, those historically termed 'endothelial progenitor cells' show promise for vascular growth and repair. Asahara et al. [Science 1997;275:964-967] initially described putative endothelial cell precursors in 1997. Subsequently, distinct cell populations termed endothelial colony-forming units-Hill, circulating angiogenic cells and endothelial colony-forming cells were identified that varied in terms of phenotype, vascular homeostasis contribution and purity. Notably, most of these cells are not genuine vascular precursor cells belonging to the endothelial lineage. This review provides a broad overview of the main properties of the endothelium, focusing on the basis governing its growth and repair. We discuss efforts to identify true vascular precursors, a matter of debate for the past 15 years, as well as recent methodological advances in identifying new hierarchies of more homogeneous, clonogenic and proliferative vascular endothelial-lineage precursors. Consideration of these issues provides insights that may help develop more effective therapies against human diseases that involve vascular deficits.
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Affiliation(s)
- Santiago Roura
- ICREC Research Program, Health Research Institute Germans Trias i Pujol-IGTP, University Hospital Germans Trias i Pujol, Badalona, Spain.
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Ariza F, Merino A, Carracedo J, Alvarez de Lara MA, Crespo R, Ramirez R, Martín-Malo A, Aljama P. Post-dilution high convective transport improves microinflammation and endothelial dysfunction independently of the technique. Blood Purif 2013; 35:270-8. [PMID: 23689471 DOI: 10.1159/000350611] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 03/05/2013] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS We examined the effects of different online hemodiafiltration techniques on microinflammation and endothelial damage/repair. METHODS The study was designed as a prospective crossover study. Flow cytometry was used to measure CD14(+)CD16(+) monocytes, apoptotic endothelial microparticles (EMPs), and endothelial progenitor cells (EPCs). RESULTS Patients treated with high-flux hemodialysis showed a marked chronic inflammatory state (HF-HD 11 ± 2) versus healthy subjects (HS 3.9 ± 2.3; p < 0.05). High convective transport, independent of the technique used, improves microinflammatory parameters (OL-HDF 7.3 ± 2.1 or MID 6.5 ± 3.4; p < 0.05) and the endothelial damage/repair balance compared to HF-HD (EPCs HF-HD 0.3 ± 0.2), with no differences found between the two modalities (EPCs OL-HDF 0.6 ± 0.1, MID 0.6 ± 0.2; p < 0.05). CONCLUSION An increase in convective transport improves the microinflammatory state and the endothelial damage/repair of these patients independently of the technique used.
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Affiliation(s)
- Francisco Ariza
- Reina Sofia University Hospital, Nephrology Unit, Córdoba, Spain
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Makulska I, Szczepańska M, Drożdż D, Polak-Jonkisz D, Zwolińska D. Skin autofluorescence as a marker of cardiovascular risk in children with chronic kidney disease. Pediatr Nephrol 2013; 28:121-8. [PMID: 22976887 PMCID: PMC3505501 DOI: 10.1007/s00467-012-2280-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Revised: 07/13/2012] [Accepted: 07/13/2012] [Indexed: 01/20/2023]
Abstract
BACKGROUND We examined skin autofluorescence (sAF) in chronic kidney disease children (CKD) in relation to renal function and dialysis modality. METHODS Twenty children on hemodialysis (HD), 20 on peritoneal dialysis (PD), 36 treated conservatively, and 26 healthy subjects were enrolled into the study. In all children sAF, pulse-wave velocity indexed to height (PWV/ht), left ventricular mass index (LVMI), blood pressure (BP), serum lipid profile, phosphate (P), calcium (Ca), and homocysteine were measured. RESULTS sAF was significantly elevated in CKD groups vs. controls and was significantly associated with PWV/ht, LVMI, BP, P, Ca × P product and homocysteine. sAF in HD and PD groups was positively correlated with dialysis vintage, and in the predialysis group negatively correlated with glomerular filtration rate (eGFR). Multiple regression analysis showed significant association of sAF with LVMI and P in the CKD patient group, and with dialysis treatment duration and BP in dialyzed children. CONCLUSIONS In CKD children, tissue accumulation of advanced glycation end-products (AGEs) was observed. This was aggravated as eGFR declined and was related to early cardiovascular changes and some biochemical cardiovascular disease (CVD) risk markers. sAF as a non-invasive method may be a useful tool for identification of a clinical risk factors of cardiovascular disease in CKD children.
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Affiliation(s)
- Irena Makulska
- Department of Pediatric Nephrology, Wrocław Medical University, ul. Borowska 213, Wrocław, Poland
| | - Maria Szczepańska
- Pediatric Dialysis Unit, Zabrze, Medical University of Silesia, Katowice, Poland
| | - Dorota Drożdż
- Dialysis Unit, Jagiellonian University Medical College, Kraków, Poland
| | - Dorota Polak-Jonkisz
- Department of Pediatric Nephrology, Wrocław Medical University, ul. Borowska 213, Wrocław, Poland
| | - Danuta Zwolińska
- Department of Pediatric Nephrology, Wrocław Medical University, ul. Borowska 213, Wrocław, Poland
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Yuen DA, Gilbert RE, Marsden PA. Bone marrow cell therapies for endothelial repair and their relevance to kidney disease. Semin Nephrol 2012; 32:215-23. [PMID: 22617771 DOI: 10.1016/j.semnephrol.2012.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Endothelial injury is a characteristic finding in chronic kidney disease and is associated with both markedly increased cardiovascular risk and chronic kidney disease progression. The past decade has seen a remarkable surge of interest in the role of bone marrow-derived cells for the protection, repair, and regeneration of injured endothelium. In particular, despite controversies regarding their mechanisms of action, endothelial progenitor cells have garnered considerable attention, with multiple reports suggesting that these cells exhibit remarkable pro-angiogenic effects. Recent advances in our understanding of how the bone marrow responds to endothelial injury now suggest that multiple bone marrow cell populations, including both endothelial progenitor cells and a novel group of cells called early outgrowth cells, promote endothelial repair and regeneration through different, yet complementary, mechanisms. Moreover, certain subsets of bone marrow-derived cells also appear to have novel, potent, angiogenesis-independent tissue-protective properties. The bone marrow should thus now be viewed not only as a hematopoiesis organ, but also as a rich reservoir of cells capable of protecting and even regenerating nonhematopoietic tissues such as the kidney. To harness the prognostic and therapeutic potential of the bone marrow, the renal community must be aware of recent advances in our understanding of the nature and therapeutic potential of these cells.
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Affiliation(s)
- Darren A Yuen
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
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Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P. Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction. Semin Dial 2011; 24:327-37. [PMID: 21682773 DOI: 10.1111/j.1525-139x.2011.00925.x] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro-inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.
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Is secondary hyperparathyroidism-related myelofibrosis a negative prognostic factor for kidney transplant outcome? Med Hypotheses 2011; 77:557-9. [DOI: 10.1016/j.mehy.2011.06.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 06/12/2011] [Indexed: 12/21/2022]
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Cianciolo G, La Manna G, Cappuccilli ML, Lanci N, Della Bella E, Cuna V, Dormi A, Todeschini P, Donati G, Alviano F, Costa R, Bagnara GP, Stefoni S. VDR expression on circulating endothelial progenitor cells in dialysis patients is modulated by 25(OH)D serum levels and calcitriol therapy. Blood Purif 2011; 32:161-73. [PMID: 21757895 DOI: 10.1159/000325459] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 02/08/2011] [Indexed: 12/29/2022]
Abstract
BACKGROUND/AIMS Vitamin D deficiency is associated with endothelial dysfunction in uremic patients, possibly by the impairment in the number and function of endothelial progenitor cells (EPCs). In 89 hemodialysis patients, we investigated the factors associated with the number of circulating EPCs (CD34+/CD133+/KDR+ and CD34+/CD133-/KDR+ cells), the presence of VDR and the determinants of VDR expression on EPCs, in particular in calcitriol therapy. METHODS EPC counts, percentages of VDR-positive EPCs and VDR expression were assessed by flow cytometry. Cells isolated from a subgroup of patients were cultured to analyze colony-forming units, specific markers expression and a capillary-like structure formation. RESULTS/CONCLUSIONS Our study demonstrates the presence of VDR on EPCs. In our dialysis patients, the parameters studied on both CD34+/CD133+/KDR+ and CD34+/CD133-/KDR+ cells, in particular VDR expression, seem to be influenced by uremia-related factors, including anemia, inflammation, diabetes, 25(OH)D serum levels and calcitriol therapy.
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Affiliation(s)
- Giuseppe Cianciolo
- Nephrology Dialysis and Renal Transplantation Unit, S. Orsola University Hospital, Bologna, Italy
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Brunet P, Gondouin B, Duval-Sabatier A, Dou L, Cerini C, Dignat-George F, Jourde-Chiche N, Argiles A, Burtey S. Does uremia cause vascular dysfunction? Kidney Blood Press Res 2011; 34:284-90. [PMID: 21691132 DOI: 10.1159/000327131] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Vascular dysfunction induced by uremia has 4 main aspects. (1) Atherosclerosis is increased. Intima-media thickness is increased, and animal studies have established that uremia accelerates atherosclerosis. Uremic toxins are involved in several steps of atherosclerosis. Leukocyte activation is stimulated by guanidines, advanced glycation end products (AGE), p-cresyl sulfate, platelet diadenosine polyphosphates, and indoxyl sulfate. Endothelial adhesion molecules are stimulated by indoxyl sulfate. Migration and proliferation of vascular smooth muscle cells (VSMC) are stimulated by local inflammation which could be triggered by indoxyl sulfate and AGE. Uremia is associated with an increase in von Willebrand factor, thrombomodulin, plasminogen activator inhibitor 1, and matrix metalloproteinases. These factors contribute to thrombosis and plaque destabilization. There is also a decrease in nitric oxide (NO) availability, due to asymmetric dimethylarginine (ADMA), AGE, and oxidative stress. Moreover, circulating endothelial microparticles (EMP) are increased in uremia, and inhibit the NO pathway. EMP are induced in vitro by indoxyl sulfate and p-cresyl sulfate. (2) Arterial stiffness occurs due to the loss of compliance of the vascular wall which induces an increase in pulse pressure leading to left ventricular hypertrophy and a decrease in coronary perfusion. Implicated uremic toxins are ADMA, AGE, and oxidative stress. (3) Vascular calcifications are increased in uremia. Their formation involves a transdifferentiation process of VSMC into osteoblast-like cells. Implicated uremic toxins are mainly inorganic phosphate, as well as reactive oxygen species, tumor necrosis factor and leptin. (4) Abnormalities of vascular repair and neointimal hyperplasia are due to VSMC proliferation and lead to severe reduction of vascular lumen. Restenosis after coronary angioplasty is higher in dialysis than in nondialysis patients. Arteriovenous fistula stenosis is the most common cause of thrombosis. Uremic toxins such as indoxyl sulfate and some guanidine compounds inhibit endothelial proliferation and wound repair. Endothelial progenitor cells which contribute to vessel repair are decreased and impaired in uremia, related to high serum levels of β(2)-microglobulin and indole-3 acetic acid. Overall, there is a link between kidney function and cardiovascular risk, as emphasized by recent meta-analyses. Moreover, an association has been reported between cardiovascular mortality and uremic toxins such as indoxyl sulfate, p-cresol and p-cresyl sulfate.
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Yuen DA, Kuliszewski MA, Liao C, Rudenko D, Leong-Poi H, Chan CT. Nocturnal hemodialysis is associated with restoration of early-outgrowth endothelial progenitor-like cell function. Clin J Am Soc Nephrol 2011; 6:1345-53. [PMID: 21597025 DOI: 10.2215/cjn.10911210] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Angiogenesis is a key response to tissue ischemia that may be impaired by uremia. Although early-outgrowth endothelial progenitor-like cells promote angiogenesis in the setting of normal renal function, cells from uremic patients are dysfunctional. When compared with conventional hemodialysis, it was hypothesized that nocturnal hemodialysis would improve the in vivo angiogenic activity of these cells in a well described model of ischemic vascular disease. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS Early-outgrowth endothelial progenitor-like cells were cultured from healthy controls (n = 5) and age- and gender-matched conventional hemodialysis (12 h/wk, n = 10) and nocturnal hemodialysis (30 to 50 h/wk, n = 9) patients. Cells (5 × 10(5)) or saline were injected into the ischemic hindlimb of athymic nude rats 1 day after left common iliac artery ligation. RESULTS Although conventional dialysis cell injection had no effect versus saline, nocturnal hemodialysis and healthy control cell injection significantly improved ischemic hindlimb perfusion and capillary density. Nocturnal hemodialysis cell injection was also associated with significant increases in endogenous angiopoietin 1 expression in the ischemic hindlimb compared with saline and conventional dialysis cell injection. CONCLUSIONS In contrast to a conventional dialytic regimen, nocturnal hemodialysis is associated with a significantly improved ability of early-outgrowth endothelial progenitor-like cells to promote angiogenesis and thus restore perfusion in a model of ischemic vascular disease.
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Affiliation(s)
- Darren A Yuen
- Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
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15
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From kidney development to drug delivery and tissue engineering strategies in renal regenerative medicine. J Control Release 2011; 152:177-85. [DOI: 10.1016/j.jconrel.2011.01.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 01/28/2011] [Indexed: 01/05/2023]
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Perin L, Da Sacco S, De Filippo RE. Regenerative medicine of the kidney. Adv Drug Deliv Rev 2011; 63:379-87. [PMID: 21145933 DOI: 10.1016/j.addr.2010.12.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Revised: 11/23/2010] [Accepted: 12/01/2010] [Indexed: 01/19/2023]
Abstract
End stage renal disease is a major health problem in this country and worldwide. Although dialysis and kidney transplantation are currently used to treat this condition, kidney regeneration resulting in complete healing would be a desirable alternative. In this review we focus our attention on current therapeutic approaches used clinically to delay the onset of kidney failure. In addition we describe novel approaches, like Tissue Engineering, Stem cell Applications, Gene Therapy, and Renal Replacement Therapy that may one day be possible alternative therapies for patients with the hope of delaying kidney failure or even stopping the progression of renal disease.
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Ueno H, Koyama H, Fukumoto S, Tanaka S, Shoji T, Shoji T, Emoto M, Tahara H, Tsujimoto Y, Tabata T, Nishizawa Y. Dialysis modality is independently associated with circulating endothelial progenitor cells in end-stage renal disease patients. Nephrol Dial Transplant 2009; 25:581-6. [PMID: 19628645 DOI: 10.1093/ndt/gfp358] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Numbers of endothelial progenitor cells (EPC) have been shown to be decreased in subjects with end-stage renal disease (ESRD). It is not clear, however, whether dialysis modality affects circulating EPCs in ESRD subjects. METHODS We examined the number of circulating EPCs in 67 continuous ambulatory peritoneal dialysis (CAPD) patients and age- and gender-matched 142 haemodialysis (HD) patients, and 78 subjects without chronic kidney disease. Arterial stiffness was analysed as pulse-wave velocity (PWV) for these patients, and their mutual relationship with circulating EPCs was examined. EPCs were measured as CD34(+) CD133(+) CD45(low) VEGFR2(+) cells determined by flow cytometry. RESULTS The EPC numbers exhibited a strong correlation (R(2) = 0.866) with endothelial-colony forming units on culture assay. The levels of EPCs in HD or CAPD subjects were significantly lower than those in control subjects. Among ESRD subjects, the levels of EPC were significantly higher in CAPD subjects than those in HD subjects. In ESRD subjects, PWV levels tended to be associated with EPCs (Rs = -0.131, P = 0.058). However, the significant relationship between dialysis modality and circulating EPCs was independent of the levels of PWV. The association of circulating EPCs with dialysis modality was significant even after adjusting for other potential confounders, including age, gender, blood pressure, history of cardiovascular diseases, presence of diabetes, blood haemoglobin level and treatments with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker or statin. CONCLUSIONS CAPD treatment could be a positive regulator of number of circulating EPCs in subjects with ESRD, with the relationship independent of the status of arteriosclerosis.
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Affiliation(s)
- Hiroki Ueno
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
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Generating New Blood Flow: Integrating Developmental Biology and Tissue Engineering. Trends Cardiovasc Med 2008; 18:312-23. [DOI: 10.1016/j.tcm.2009.01.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2008] [Revised: 01/20/2009] [Accepted: 01/27/2009] [Indexed: 11/23/2022]
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19
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Coppolino G, Buemi A, Bolignano D, Lacquaniti A, La Spada M, Stilo F, De Caridi G, Benedetto F, Loddo S, Buemi M, Spinelli F. Perioperative iloprost and endothelial progenitor cells in uremic patients with severe limb ischemia undergoing peripheral revascularization. J Surg Res 2008; 157:e129-35. [PMID: 19589539 DOI: 10.1016/j.jss.2008.07.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2008] [Revised: 07/13/2008] [Accepted: 07/14/2008] [Indexed: 01/13/2023]
Abstract
The incidence of severe limb ischemia (SLI) is high among haemodialysis (HD) patients. Limb rescue rate after surgical revascularization is relatively poor compared with patients with normal renal function. Prostanoids are an interesting category as adjuvants to revascularization. New vessel growth develops not exclusively by proliferation of endothelial cells in vascular extremities but also by cells mobilized from the bone marrow (HSC), transformed into endothelial progenitor cells (EPC) contributing to both re-endothelialization and neovascularization. Basal number of HSC and EPC is significantly reduced in HD patients and correlated with a subsequent defective neovascularization. The aim of this study was to evaluate the effects of perioperative treatment with iloprost in uremic patients with acute ischemia of lower limbs, undergoing surgical revascularization, on endothelial progenitor cells, hypothesizing a possible biological mechanism induced by the prostanoids. A search was also made for vascular remodeling processes through the analysis of the concentrations of soluble adhesion molecules (i-CAM, v-CAM, e-selectin), biochemical markers of endothelial activation. Thirty HD patients with SLI undergoing peripheral revascularization were enrolled (15 were treated with iloprost and 15 with a placebo). Iloprost was administered as an intra-arterial bolus of 3000 ng over 1 to 3 min immediately after revascularization and in the same affected artery. Serum samples were taken before revascularization (T0), at 6 (T6) and 24 h (T24) after infusion to measure sICAM-1, sE-selectin, and sVCAM-1, and for quantification of HSC and EPC. Progenitors were identified by specific surface markers CD34+, CD133+ and VEGFR2+. Count was conducted using PROCOUNT performed in a TRUCOUNT tube and with a FACSort flow cytometer. Before revascularization, all patients showed a decreased number of HSC and EPC. After 6 h, HSC augmented significantly compared with T0 in both groups. The iloprost group attained a significant increase compared with the placebo group. HSC levels reduced drastically at T24. EPC augmented significantly compared with basal level after 24 h. In the iloprost group, the increase was considerable compared with the placebo group. A close negative correlation, assessed by Pearson coefficient (r), was found between HSC and EPC at T24 in the iloprost group (R = 0.82 P < 0.01). Adhesion molecules had increased levels at T6 and T24 in both groups. Moreover, a close positive correlation, assessed by Pearson coefficient, was found between EPC and adhesion molecules in both groups but the iloprost group maintained a better statistical association. Revascularization stimulated HSC and EPC release from bone marrow but at a different time: HSC increased suddenly at 6 h and diminished to a minimal amount at T24, conversely, EPC increased significantly only at T24. Iloprost treatment was able to amplify this mechanism validating recent findings (North TE et al., [31]). Adhesion molecules as markers of endothelial activation and vascular development confirmed this tendency.
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20
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Surdacki A, Marewicz E, Wieteska E, Szastak G, Rakowski T, Wieczorek-Surdacka E, Dudek D, Pryjma J, Dubiel JS. Association between endothelial progenitor cell depletion in blood and mild-to-moderate renal insufficiency in stable angina. Nephrol Dial Transplant 2008; 23:2265-73. [DOI: 10.1093/ndt/gfm943] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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21
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Schlieper G, Hristov M, Brandenburg V, Kruger T, Westenfeld R, Mahnken AH, Yagmur E, Boecker G, Heussen N, Gladziwa U, Ketteler M, Weber C, Floege J. Predictors of low circulating endothelial progenitor cell numbers in haemodialysis patients. Nephrol Dial Transplant 2008; 23:2611-8. [DOI: 10.1093/ndt/gfn103] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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22
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Coppolino G, Bolignano D, Campo S, Loddo S, Teti D, Buemi M. Circulating Progenitor Cells after Cold Pressor Test in Hypertensive and Uremic Patients. Hypertens Res 2008; 31:717-24. [DOI: 10.1291/hypres.31.717] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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23
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Vanholder R, Baurmeister U, Brunet P, Cohen G, Glorieux G, Jankowski J. A bench to bedside view of uremic toxins. J Am Soc Nephrol 2008; 19:863-70. [PMID: 18287557 DOI: 10.1681/asn.2007121377] [Citation(s) in RCA: 235] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Reviewing the current picture of uremic toxicity reveals its complexity. Focusing on cardiovascular damage as a model of uremic effects resulting in substantial morbidity and mortality, most molecules with potential to affect the function of a variety of cell types within the vascular system are difficult to remove by dialysis. Examples are the larger middle molecular weight molecules and protein-bound molecules. Recent clinical studies suggest that enhancing the removal of these compounds is beneficial for survival. Future therapeutic options are discussed, including improved removal of toxins and the search for pharmacologic strategies blocking responsible pathophysiologic pathways.
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Affiliation(s)
- Raymond Vanholder
- Nephrology Section, Department of Internal Medicine, OK12, University Hospital, De Pintelaan 185, B9000 Gent, Belgium.
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24
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Tongers J, Losordo DW. Frontiers in Nephrology: The Evolving Therapeutic Applications of Endothelial Progenitor Cells. J Am Soc Nephrol 2007; 18:2843-52. [DOI: 10.1681/asn.2007050597] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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25
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Sturiale A, Coppolino G, Loddo S, Criseo M, Campo S, Crascì E, Bolignano D, Nostro L, Teti D, Buemi M. Effects of haemodialysis on circulating endothelial progenitor cell count. Blood Purif 2007; 25:242-51. [PMID: 17429198 DOI: 10.1159/000101697] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Accepted: 01/26/2007] [Indexed: 11/19/2022]
Abstract
During haemodialysis (HD) the endothelium is the first organ to sense and to be impaired by mechanical and immunological stimuli. We hypothesized that a single HD session induces mobilization of endothelial progenitor cells (EPCs) and that cardiovascular risk factors may influence this process. We quantified EPCs at different maturational stages (CD34+, CD133+/VEGFR2+) in blood samples from 30 patients, during HD and on the interdialytic day, and in 10 healthy volunteers. Samples were drawn at the start of HD, 1, 2 and 3 h after, at the end of HD and at 24 h on the interdialytic day. Patients were divided into two groups based on a recent risk scoring system (SCORE project): low-risk (LR) and high-risk groups (HR). HD patients showed a significantly reduced basal number of EPCs with respect to healthy volunteers. In contrast, we observed increasing EPCs during HD whereas they diminished on the interdialytic day. The EPC number was directly correlated with HD time progression. The EPC number during HD was increased in the HR group with respect to the LR group. We had a direct correlation between risk score and number of EPCs. Cardiovascular risk factors influenced the mobilization of stem cells from the bone marrow. This feature could be the direct consequence of an augmented request of stem cells to respond to the most important endothelial impairment but could also show a defective capacity of EPCs to home in and repair the sites of vascular injury.
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Affiliation(s)
- Alessio Sturiale
- Department of Internal Medicine, University of Messina, Messina, Italy
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Herbrig K, Gebler K, Oelschlaegel U, Pistrosch F, Foerster S, Wagner A, Gross P, Passauer J. Kidney transplantation substantially improves endothelial progenitor cell dysfunction in patients with end-stage renal disease. Am J Transplant 2006; 6:2922-8. [PMID: 17061996 DOI: 10.1111/j.1600-6143.2006.01555.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Endothelial progenitor cells (EPC) are involved in endothelial repair and maintenance. Dysfunction of EPC may contribute to accelerated arteriosclerosis in chronic kidney disease. Kidney transplantation (KTx) improves both survival and endothelial function of dialysis patients. In a prospective study, we tested to which extent KTx changes EPC biology. We studied number and function (migratory activity, adhesion to extracellular matrix proteins and to mature endothelial cells [EC]) of EPC in 20 patients during dialysis and 3, 6, 9 and 12 months after KTx. Twenty-two healthy volunteers served as matched controls. Circulating precursor populations were measured by flow cytometric analysis. Cytokines relevant for EPC mobilization were monitored. Compared to the dialysis state, KTx increased the migration of EPC to approximately 2-fold. Adhesion to fibronectin and to collagen type IV was significantly increased after KTx. An improved adhesion rate of EPC to mature EC was observed. The number of EPC decreased. The amount of precursor populations showed no difference compared to the pretransplant state. Our study shows an improved function of EPC after KTx. This finding indicates an improved potential for endothelial repair which in turn may contribute to enhanced endothelial function and reduced cardiovascular morbidity after KTx.
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Affiliation(s)
- K Herbrig
- Nephrology, Department of Internal Medicine III, Technical University of Dresden, Dresden, Germany.
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Roberts MA, Hare DL, Ratnaike S, Ierino FL. Cardiovascular Biomarkers in CKD: Pathophysiology and Implications for Clinical Management of Cardiac Disease. Am J Kidney Dis 2006; 48:341-60. [PMID: 16931208 DOI: 10.1053/j.ajkd.2006.06.005] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2006] [Accepted: 06/05/2006] [Indexed: 12/31/2022]
Abstract
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with all forms of chronic kidney disease (CKD). The underlying pathological state is caused by a complex interplay of traditional and nontraditional risk factors that results in atherosclerosis, arteriosclerosis, and altered cardiac morphological characteristics. This multifactorial disease introduces new challenges in predicting and treating patients with CVD sufficiently early in the course of CKD to positively alter patient outcome. Asymptomatic individuals with progressive CVD are a group of patients that deserve focused attention because early detection and intervention may provide the best opportunity for improved outcome. However, identifying CVD in asymptomatic patients with CKD or end-stage renal disease remains a significant hurdle in the management of these patients. Recently, a number of cardiovascular biomarkers were identified as predictors of patient outcome in individuals with CVD and, with additional research, may be used to guide the early diagnosis of and therapy for CVD in patients with CKD. This review examines the pathophysiological characteristics and potential clinical role of these novel cardiovascular biomarkers in risk stratification, risk monitoring, and selection of preventive therapies for patients with CKD.
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Affiliation(s)
- Matthew A Roberts
- Department of Nephrology, Division of Laboratory Medicine, Austin Health, University of Melbourne, Victoria, Australia
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Abstract
It is being increasingly recognized that cardiovascular disease (CVD) and its complications are the most important cause of morbidity and mortality in patients with chronic kidney disease (CKD) and dialysis patients. If outcomes for these patients are to be improved, therapeutic strategies at all stages of CKD will have to target the etiologies and mechanisms that lead to CVD. In this review, we focus on the central role of endothelial dysfunction as the critical precursor of CVD. We argue that a better understanding of endothelial dysfunction by nephrologists and dialysis physicians is necessary if there is to be success in limiting the CVD epidemic that kills and maims our patients. The extensive studies to explain the high prevalence of vascular disease in patients with CKD have shown the close relationship among endothelial dysfunction, inflammation, and atherosclerosis. The pathogenesis starts with endothelial cell injury from any of many possible causes, and strategies to reduce the burden of CVD in uremic and dialysis patients must be directed at restoring normal endothelial function or, at the least, preventing aggravation of endothelial damage. At the center of the exploration of endothelial dysfunction and atherosclerosis are oxidative stress and inflammation. Of these, which is the chicken and which is the egg is unknown, but in the setting of uremia, endothelial injury because of free radical, oxidative stress is likely to precede inflammation. The issues raised here are highly complex and most renal practitioners may not have been adequately exposed to the background research underlying current thinking of the pathogenesis of vascular disease. Clearly, progress in management of CVD in patients with CKD will require collaboration with experts in the research and treatment of vascular disease. Nephrologists seeking optimum outcomes for patients with CKD will need to become "endotheliologists" or, at the least, subscribe to a mission "to protect the endothelium."
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Affiliation(s)
- Jose A Diaz-Buxo
- Fresenius Medical Care North America, Lexington, Massachusetts, USA.
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Rodríguez-Ayala E, Yao Q, Holmén C, Lindholm B, Sumitran-Holgersson S, Stenvinkel P. Imbalance between detached circulating endothelial cells and endothelial progenitor cells in chronic kidney disease. Blood Purif 2005; 24:196-202. [PMID: 16373998 DOI: 10.1159/000090519] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2005] [Indexed: 12/29/2022]
Abstract
BACKGROUND Patients with chronic kidney disease (CKD) display endothelial dysfunction and are at a high risk for atherosclerotic cardiovascular disease (CVD). Recent studies suggest that circulating detached endothelial cells (CECs) and stimulated endothelial progenitor cells (EPCs) from the bone marrow may reflect endothelial damage. METHODS We correlated the levels of CECs expressing the endothelial cell inflammation marker (MICA+ cells) and EPCs (Tie-2+ or VEGFR-2+ cells) in a population of 19 (55 +/- 3 years; 42% males) patients with advanced CKD (median glomerular filtration rate 8 ml/min). In addition, the levels of CD-31+ cells were investigated. Twenty healthy age- (49 +/- 2 years) and gender- (50% men) matched subjects served as controls. RESULTS CECs expressing MICA were increased (7.6 +/- 2.7 vs. 1.6 +/- 0.3%; p < 0.05) in CKD patients, however EPCs expressing Tie-2 or VEGFR-2 were significantly decreased (0.16 +/- 0.07 vs. 0.53 +/- 0.15%; p < 0.05, and 0.42 +/- 0.10 vs. 2.80 +/- 0.72%; p < 0.01, respectively) as compared to controls. Furthermore, we also found that the levels of CD-31+ cells were significantly elevated (22.8 +/- 4.2 vs. 9.4 +/- 0.8%; p < 0.01) in CKD patients. Patients on angiotensin-converting enzyme (ACE) inhibitors tended (p = 0.06) to have higher levels of VEGFR-2+ cells (0.57 +/- 0.14 vs. 0.16 +/- 0.11%). CONCLUSION Our results suggest that there is a marked imbalance between the CEC and EPC numbers in patients with CKD. Further research is needed to evaluate the independent role of inflammatory endothelial markers as well as the effects of ACE inhibitors on mobilization of EPCs in patients with advanced CKD.
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Affiliation(s)
- Ernesto Rodríguez-Ayala
- Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden
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