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Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease.

ABSTRACT: Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here.

SUBMITTER: Diaz-Ricart M

PROVIDER: S-EPMC7354562 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease.

Diaz-Ricart Maribel M Torramade-Moix Sergi S Pascual Georgina G Palomo Marta M Moreno-Castaño Ana Belen AB Martinez-Sanchez Julia J Vera Manel M Cases Aleix A Escolar Gines G

Toxins 20200601 6

Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of t ...[more]

PMID: 32492843

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Project description:BACKGROUND. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and there is an established association between vasculopathy affecting the kidney and eye. Optical coherence tomography (OCT) is a novel, rapid method for high-definition imaging of the retina and choroid. Its use in patients at high cardiovascular disease risk remains unexplored. METHODS. We used the new SPECTRALIS OCT machine to examine retinal and retinal nerve fiber layer (RNFL) thickness, macular volume, and choroidal thickness in a prospective cross-sectional study in 150 subjects: 50 patients with hypertension (defined as a documented clinic BP greater than or equal to 140/90 mmHg (prior to starting any treatment) with no underlying cause identified); 50 with CKD (estimated glomerular filtration rate (eGFR) 8-125 ml/min/1.73 m2); and 50 matched healthy controls. We excluded those with diabetes. The same, masked ophthalmologist carried out each study. Plasma IL-6, TNF-? , asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1), as measures of inflammation and endothelial function, were also assessed. RESULTS. Retinal thickness, macular volume, and choroidal thickness were all reduced in CKD compared with hypertensive and healthy subjects (for retinal thickness and macular volume P < 0.0001 for CKD vs. healthy and for CKD vs. hypertensive subjects; for choroidal thickness P < 0.001 for CKD vs. healthy and for CKD vs. hypertensive subjects). RNFL thickness did not differ between groups. Interestingly, a thinner choroid was associated with a lower eGFR (r = 0.35, P <0.0001) and, in CKD, with proteinuria (r = -0.58, P < 0.001) as well as increased circulating C-reactive protein (r = -0.57, P = 0.0002), IL-6 (r = -0.40, P < 0.01), ADMA (r = -0.37, P = 0.02), and ET-1 (r = -0.44, P < 0.01). Finally, choroidal thinning was associated with renal histological inflammation and arterial stiffness. In a model of hypertension, choroidal thinning was seen only in the presence of renal injury. CONCLUSIONS. Chorioretinal thinning in CKD is associated with lower eGFR and greater proteinuria, but not BP. Larger studies, in more targeted groups of patients, are now needed to clarify whether these eye changes reflect the natural history of CKD. Similarly, the associations with arterial stiffness, inflammation, and endothelial dysfunction warrant further examination. TRIAL REGISTRATION. Registration number at www.clinicalTrials.gov: NCT02132741. SOURCE OF FUNDING. TR was supported by a bursary from the Erasmus Medical Centre, Rotterdam. JJMHvB was supported by a bursary from the Utrecht University. JRC is supported by a Rowling Scholarship. SB was supported by a Wellcome Trust funded clinical research fellowship from the Scottish Translational Medicine and Therapeutics Initiative, and by a Rowling Scholarship, at the time of this work. ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994).

Project description:BackgroundHaemodialysis (HD) patients are predisposed to dysregulated fluid balance leading to extracellular water (ECW) expansion. Fluid overload has been closely linked with outcome in these patients. This has mainly been attributed to cardiac volume overload, but the relation between abnormalities in fluid status with micro- and macrovascular dysfunction has not been studied in detail. We studied the interaction of macro- and microvascular factors in states of normal and over- hydration in HD-dependent CKD.MethodsFluid compartments [total body water (TBW) and ECW] and overhydration index (OH) were measured with Multifrequency bio-impedance (BCM). Overhydration was defined as OH/ECW>7%. Overhydration was also assessed using the ECW/TBW ratio. Macrocirculation was assessed by pulse-wave velocity (PWV) and mean arterial pressure (MAP) measurements while microcirculation through sublingual capillaroscopy assessment of the Perfused Boundary Region of the endothelial glycocalyx (PBR 5-25mcg). A panel of pro-inflammatory and vascular serum biomarkers and growth factors was analysed.ResultsOf 72 HD participants, 30 were in normohydration (N) range and 42 overhydrated according to the OH/ECW ratio. Average ECW/TBW was 0.48±0.03. Overhydrated patients had higher MAP (122.9±22.5 v 111.7±22.2mmHg, p = 0.04) and comorbidities (median Davies score 1.5 v 1.0, p = 0.03). PWV (p = 0.25) and PBR 5-25mcg (p = 0.97) did not differ between the 2 groups. However, Vascular Adhesion Molecule (VCAM)-1, Interleukin-6 and Thrombomodulin, and reduced Leptin were observed in the overhydrated group. Elevation in VCAM-1 levels (OR 1.03; 95% CI 1.01-1.06; p = 0.02) showed a strong independent association with OH/ECW>7% in an adjusted logistic regression analysis and exhibited a strong linear relationship with ECW/TBW (Bata = 0.210, p = 0.03) in an also adjusted model.ConclusionExtracellular fluid overload is significantly linked to microinflammation and markers of endothelial dysfunction. The study provides novel insight in the cardiovascular risk profile associated with overhydration in uraemia.

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Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease.

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Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease.

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