Part Three Endothelial Cell Dysfunction And Increased Cardiovascular Risk in Patients With Chronic Kidney Disease

2. Oxidative Stress

Oxidative stress is defined as the imbalance between prooxidants and antioxidants. An increase in pro-oxidants and the generation of reactive oxygen species (ROS) and reactive nitrogen species affects the metabolism of cells and can trigger severe cell damage and apoptosis.122 It can be caused by mitochondrial dysfunction resulting in increased superoxide levels, increased activity of NOX (NADPH oxidase) leading to increased hydrogen peroxide levels as well as through eNOS uncoupling resulting in peroxynitrite production.122

In the vasculature, NOX is the major contributor to the generation of ROS.123 Of the 7 NOX isoforms, endothelial cells express 4: NOX-1 (NADPH oxidase 1), NOX-2, NOX-4, and NOX-5, with NOX-4 being the most prominently expressed subtype in endothelial cells.123,124 Especially NOX-2 and NOX-4 are often linked to the initiation and progression of cardiovascular complications.124 Extended NOX activation, e.g. through stimulation by inflammatory mediators such as TNF-α, increases ROS production in endothelial cells and thereby mediates NF-κB signaling, enhancing vascular inflammation and inducing a vicious circle of inflammation and oxidative stress.125,126 Also, a range of uremic toxins has been described to trigger inflammation and prolonged NOX activation to lead to oxidative stress in endothelial cells.127 For an extensive overview of the different NOX isoforms in CVD, we refer to a detailed review by Zhang et al.128

Lately, ROS-induced ROS release, a form of intracellular communication between ROS derived from NOX enzymes and mitochondria, has been presented as a feedforward mechanism to maintain and amplify ROS signaling.123 In the context of CKD with increased systemic AGE levels, endothelial cells stimulated with AGEs showed increased levels of NOX-2, cytosolic and mitochondrial ROS but decreased levels of mitochondrial sirtuin-3, with analysis of sirtuin-3 blockade suggesting a role for mitochondrial ROS in cytoplasmic ROS production.129

In addition, uncoupling of eNOS is induced through CKD-mediated posttranslational modifications of LDL (low-density lipoprotein) and HDL (high-density lipoprotein), resulting in increased endothelial ROS production130–132 (posttranslational modifications described in more detail below). Finally, a reduction in antioxidative mechanisms could increase the overall oxidative stress level. For example, patients with advanced CKD display a reduction in NRF-2 (nuclear factor erythroid 2-related factor-2), a cellular protector from oxidative stress.133,134 Inducing the NRF-2 pathway in endothelial cells could therefore be a novel therapeutic approach to treating inflammatory diseases such as atherosclerosis by protecting the endothelium from oxidative damage as shown in.135

Based on these disturbances in the pro-/antioxidative balance also in the context of CKD,122 oxidative stress is believed to be an important contributor to cardiovascular morbidity in the general population as well as in CKD patients.122,136

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3. Uremic Toxins

Uremic toxins are broadly defined as substances of organic or inorganic origin that accumulate in the circulation due to kidney function decline and/or increased production, with harmful effects on the body. Currently >140 of such solutes have been identified.137 Overall, the uremic milieu triggers proinflammatory effects (eg, VCAM-1 and C-C motif chemokine ligand 2 expression), NOX expression, and ROS production, as well as reduced antioxidant enzyme activity in endothelial cells, as demonstrated upon incubation of endothelial cells with uremic serum in vitro (Table 2).127,145 Furthermore, uremic serum collected from patients with CKD gradually reduces the endothelial glycocalyx height along with increasing CKD stage and increases the stiffness of the glycocalyx as well as of the actin-rich cortex beneath the plasma membrane in vitro. This, as well as uremic serum-induced reduction of eNOS and NO production in vitro, could be counteracted by blocking the mineralocorticoid receptors and the epithelial Na+ channel as its downstream target.146

The recent systematic review by Harlacher et al127 described in detail known uremic toxins with detrimental effects on the endothelium. This revealed that uremic toxins such as p-cresyl sulfate, indoxyl sulfate, cyanate, AGEs, asymmetric dimethylarginine, and uric acid induce oxidative stress (ROS production, NOX activation) and inflammation and promote the adhesion of inflammatory leukocytes to the endothelium.127,145 Furthermore, a subset of these uremic toxins reduces the proliferative capacity of endothelial cells and can trigger cell death. Also, cyanate enhances the prothrombotic effects of the endothelium by triggering the expression of TF and PAI-1.127 As underlying mechanisms, these uremic toxins activate MAPK [mitogen-activated protein kinase]/ NF-κB, RAGE, CREB (cAMP response element-binding protein)/ATF1 (AMP-dependent transcription factor 1) and AhR (aryl hydrocarbon receptor)-dependent pathways in endothelial cells (Table 2),127,145 which are known to induce among others oxidative stress and inflammation. Indoxyl sulfate also upregulates the endothelial expression of solute carrier family 22 member 6 (OAT1 [organic anion transporter 1]), a membrane transporter molecule mediating cellular uptake of p-cresyl sulfate and indoxyl sulfate.145

Furthermore, AGEs were shown to enhance endothelial permeability and induce endothelial senescence as indicated by senescence-associated β-galactosidase staining and expression of the senescence-associated proteins p53, p21, and p16.152 p-Cresylsulfate, indoxyl sulfate, cyanate, AGEs, and uric acid reduced the expression and activity of eNOS, thereby decreasing NO bioavailability and increasing vascular stiffness.127 Along the same line, the uremic toxin kynurenine triggered an increase of superoxide production in the vasculature at least partly via AhR-dependent signaling in endothelial cells, thereby reducing NO-mediated vasorelaxation.144 In patients with CKD, the plasma concentration of kynurenine positively correlated with sICAM-1, sVCAM-1, vWF, and thrombomodulin as markers of endothelial cell dysfunction.153

Combined, this suggests an important contribution of uremic toxins to cardiovascular risk in patients with CKD. Meta-analysis studies concluded a significant association of the uremic toxin p-cresyl sulfate with cardiovascular risk in patients with CKD,154 whereas indoxyl sulfate and asymmetric dimethylarginine correlated with overall mortality but not cardiovascular mortality in CKD.154,155

4. Posttranslational Modifications

Uremic toxin accumulation and oxidative stress in CKD not only trigger proinflammatory signaling but also induce posttranslational modifications, which may alter the function of the targeted proteins as well as lipoprotein particles. For example, triggered by increased urea concentrations in patients with CKD, the intracellular sorting receptor sortilin is carbamylated in CKD. Carbamylated sortilin promotes VSMC calcification in vitro and is associated with increased coronary artery calcification in CKD patients.156 Also, PTMs have been identified to negatively affect lipoprotein particle function in CKD, with a negative impact on endothelial health. Both LDL and HDL particles are oxidized and carbamylated in patients with CKD,157 triggered by increased oxidative stress and plasma urea concentrations in CKD, respectively. oxLDL is well known for its proinflammatory effects in both CVD and CKD patients.157,158 Carbamylated LDL, but not native LDL, impaired endothelium-dependent vascular relaxation and enhanced ROS production through NADPH oxidase activation and eNOS uncoupling through the LOX-1 receptor.130 Carbamylated LDL was also shown to induce autophagy, cell death, and DNA fragmentation in endothelial cells.159 Furthermore, it enhanced thrombin generation and injury-induced thrombus formation in a mouse model, as well as increasing the production of TF and PAI-1 in endothelial cells through LOX-1.160

Whereas HDL exerts anti-inflammatory and pro-proliferative effects in endothelial cells,130,161 oxHDL (oxidized HDL) triggered NOX2-mediated ROS production as well as proinflammatory NF-κB signaling and cytokine expression in endothelial cells through LOX-1.131 Along this line, carbamylated HDL reduced endothelial migration and proliferation.161 Also, HDL from patients with CKD showed enrichment in the proinflammatory protein SAA (serum amyloid A) as well as in the uremic toxin SDMA. SDMA-enriched HDL and CKD-HDL increased ROS through NADPH oxidase activation and reduced endothelial NO production via TLR2 in vitro. In contrast to HDL from healthy donors, SDMA-enriched HDL and CKD-HDL did not support endothelial repair after injury of the carotid artery in a mouse model.132

In summary, CKD-induced alterations of lipoprotein particles make LDL an even more noxious particle and convert HDL from a protective to a damaging lipoprotein particle. For more details and additional alterations in lipoprotein particles in CKD, we refer to a recent detailed review by Noels et al.157

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5. Metabolic Acidosis

With a prevalence of 39% in predialysis patients with a glomerular filtration rate <20, chronic metabolic acidosis is a common complication in patients with advanced CKD,162 although it is consistently underdiagnosed and undertreated.163 It is caused by reduced excretion of metabolically produced acids, leading to decreased systemic bicarbonate levels. Metabolic acidosis in CKD has been associated with CKD progression as well as with an increased risk of adverse cardiovascular events, including heart failure.164,165 On a molecular level, chronic metabolic acidosis has been shown to induce ammonia genesis and to increase the production of angiotensin II, aldosterone, and endothelin-1, to enhance net acid excretion.166 However, sustained upregulation of these mediators exerts proinflammatory and profibrotic effects on the kidney, thus again contributing to CKD progression. Furthermore, these mediators exert proinflammatory and vasoconstrictive effects on the endothelium.167,168 Also, in vitro studies revealed acidosis to trigger proinflammatory NF-κB signaling, endoplasmic reticulum stress, and the unfolded protein response in the endothelium via the proton-sensing receptor GPR4.169,170 Specifically extracellular acidification inhibited store-operated Ca2+ entry through divalent cation channels and thereby interfered with agonist-mediated production of the protective factors NO and prostaglandin I 2 by endothelial cells.171 A pilot study identified an improvement of endothelial function in CKD stage 3b-4 patients upon sodium bicarbonate treatment for 6 weeks, as detected by a 1.8% increase in brachial artery flow-mediated dilation. Overall effects on cardiovascular outcomes were not examined.172

6. Sympathetic Nerve Activity

Sympathetic nerve activity—for example, as measured by plasma levels of norepinephrine or catecholamines— increases along with kidney function decline, potentially triggered by increased renin-angiotensin-aldosterone system signaling, reduced NO bioavailability, and increased oxidative stress, among other factors.173,174 Increased sympathetic nerve activity contributes to hypertension, but also independent of blood pressure effects, high sympathetic nerve activity is associated with CKD progression as well as with increased cardiovascular risk in both predialysis and dialysis CKD patients.173,175,176 Sympathetic nerve activation reduces endothelial-dependent vasodilation and increases vascular stiffness, as discussed in detail by Kaur et al.173 In animal models, blocking sympathetic nerve activity reduced microvascular rarefaction.49 Furthermore, in vitro studies showed that high levels of catecholamine neurotransmitters trigger endothelial adrenergic receptors, leading to endothelial permeability and glycocalyx loss in endothelial cells.177 Combined, these findings suggest also a contribution of increased sympathetic nerve activity to endothelial dysfunction in CKD.

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7. Vascular Aging

Although aging is a natural process, in the case of CKD, it is accelerated. An indicator of cellular aging and subsequent decline in function is telomere length. A reduction in telomere length can drive endothelial cells into senescence, characterized by a stable arrest in cell growth and a proinflammatory phenotype.178 Although telomere shortening has been observed in CKD independent of age,179 a recent meta-analysis indicated a paradoxical association between CKD and telomere length. As such, the authors postulated that the shortening of telomeres associated with a declining kidney function is likely offset by cellular telomere reparative mechanisms in patients who survive longer with CKD,180 but more research is needed. Moreover, to what extent telomere shortening occurs in the endothelial layer as a consequence of reduced kidney function is unclear.

Premature aging takes place partially due to systemic inflammation (“inflammageing”).79 The other way around, senescent cells can develop a senescence-associated secretory phenotype to release, among others, proinflammatory cytokines, growth factors, and soluble receptors contributing to local as well as systemic inflammation, which accelerates tissue damage in patients with CKD.80

Furthermore, patients with CKD display a reduction in Klotho due to impaired kidney function. Klotho is a protective protein with antioxidant, antiapoptotic, and anti-senescent effects, also toward endothelial cells,181 and its depletion is a crucial contributor to premature vascular aging in CKD.80,182,183 Animal studies by Shi et al linked a reduction in Klotho to a reduction in autophagy. Early αKlotho administration increased autophagic flux induction upon acute kidney injury and protected from kidney damage progression into CKD, suggesting the administration of Klotho as a potential treatment after acute kidney injury to reverse kidney failure.184 A disturbed autophagic flux is additionally induced by uremic toxins such as indoxyl sulfate, p-cresyl sulfate, and indole acetic acid, leading to the accumulation of oxidized proteins and organelles and increasing the sensitivity of endothelial cells toward oxidative stress.185

A depletion of Klotho in aortic endothelial and smooth muscle cells is accompanied by a significant reduction in SIRT1 (sirtuin-1). Similar to Klotho, SIRT1 is anti-inflammatory, antioxidative, antiapoptotic, and anti-senescent; it inhibits the activation of NADPH oxidases and prohibits the production of ROS in endothelial cells.186 Blocking of SIRT1 triggered a proinflammatory phenotype illustrated by an increased ROS production in aortic endothelial cells and reduced endothelial-dependent vascular relaxation through impaired NO production.187,188 Beyond counteracting inflammation, oxidative stress, and senescence, SIRT1 also protects from CKD-associated fibrosis and vascular calcification, suggesting SIRT1 is a potential future therapeutic target for CKD.186

8. Smooth Muscle—Endothelium Interaction and Vascular Calcification

Within the vasculature, endothelial cells and VSMCs can bidirectionally communicate.189 About VSMC communication to endothelial cells, endothelial cells cocultured with VSMCs express increased levels of MMP-2 and MMP-9.190 Synthetic VSMCs produce proinflammatory IL-1β and IL-6, which induced NF-κB activation and E-selectin expression in cocultured endothelial cells.191 Also, mechanical stress-induced microparticle production by VSMCs induced proinflammatory responses in endothelial cells.192 Despite these findings, the overall contribution of VSMC changes to endothelial cell dysfunction in CVD remains unclear. This is also true in the context of CKD. CKD patients frequently display medial vascular calcification, for example, identified in 88% of dialysis patients aged 20 to 30 years old.193 Medial vascular calcification is associated with increased vascular stiffness as well as cardiovascular mortality in CKD patients.194,195 Whereas the impact of vascular calcification on endothelial function has not been studied to our knowledge, a dysfunctional endothelial cell layer does contribute to medial calcification. For example, NO produced by endothelial cells counteracts VSMC calcification.196 Also, inhibition of eNOS-mediated NO production by L-NAME increases warfarin-induced medial calcification in rats,197 with warfarin triggering vascular calcification by interfering with the activation of the calcification inhibitor matrix GLA protein. As discussed above, in CKD, endothelial cells show a reduced eNOS expression and activation resulting in a reduced NO bioavailability, for example, triggered by uremic toxins as well as hyper- and hypophosphatemia.127 Further, uremic toxins can trigger endothelial inflammation,127 with inflammatory mediators such as TNF-α and IL-1β reported to be able to sensitize endothelial cells to BMP-induced osteogenic differentiation into osteoprogenitor cells, which could contribute to vascular calcification.198

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IMPACT OF PHARMACOLOGICAL INTERVENTIONS ON ENDOTHELIAL CELL DYSFUNCTION IN CKD

Considering the function of the endothelium as the gatekeeper of vascular health, maintaining its integrity by pharmacological intervention could contribute to alleviating the cardiovascular risk of patients with CKD. Drugs administered to patients with CKD to treat comorbidities such as hypertension, hyperlipidemia, and diabetes have been extensively examined in light of endothelial cell function. Consequently, direct and indirect endothelial protective effects of antihypertensive, lipid-lowering (statins), and antihyperglycemic drugs have been well documented.199 For an extensive review of the mechanisms responsible for these beneficial effects on the endothelium, we refer to the recent review by Xu et al.199 Also in the context of CKD, endothelial protective effects of antihypertensive drugs with or without statin add-on therapy have been observed,200,201 although it needs to be noted that ACE inhibitors—but not angiotensin receptor blockers— increased proinflammatory asymmetric dimethylarginine levels in hemodialysis patients.202

In recent years, SGLT2 (sodium-glucose cotransporter-2) inhibitors received much attention due to their cardiovascular and kidney protective effects. Also, in patients with CKD, SGLT2 inhibitors were associated with an improvement in cardiovascular and kidney health, irrespective of diabetes status.203 In terms of endothelial protective effects, a recent meta-analysis showed that treatment with the SGLT2 inhibitor dapagliflozin resulted in an improved FMD in patients with type 2 diabetes.204 The clinical trial PROCEED is currently ongoing to determine whether SGLT2 inhibitors are also capable of improving endothelial function in patients with diabetes and CKD.205 Interestingly, treatment of human cardiac microvascular endothelial cells with the SGLT2 inhibitor empagliflozin could counteract the increase in oxidative stress and the reduction in endothelial nitric oxide bioavailability caused by uremic serum exposure, but the underlying mechanisms remain unclear.206

Mineralocorticoid receptor antagonists, being potassium-sparing diuretics, have been shown to have endothelial protective effects as well. In patients with stable mild to moderate chronic heart failure, spironolactone treatment improved endothelium-dependent vasodilation and increased NO bioactivity.207 Also in the context of CKD, endothelial protective effects of mineralocorticoid receptor antagonists have been observed. In a small cohort of stable chronic hemodialysis patients, spironolactone treatment for 4 months resulted in an improvement of endothelial function as assessed by venous occlusion plethysmography.208 In animal models of kidney dysfunction, spironolactone, and finer enone ameliorated endothelial dysfunction by enhancing NO bioavailability and reducing oxidative stress.129,209,210

In terms of drugs targeting inflammation, blocking IL-1α/β with rilonacept for 12 weeks in patients with CKD3-4 improved FMD of the brachial artery and reduced systemic levels of hsCRP as well as endothelial expression of NADPH oxidase.211 Allopurinol, a xanthine oxidase inhibitor used to treat hyperuricemia, has contrasting results on its endothelial effects, with studies reporting no effect212,213 to studies showing an improvement in endothelial function in terms of vasodilatory responses in patients with CKD treated with allopurinol for 8 weeks or 9 months.214,215 Similarly, conflicting results have been published on the endothelial protective effects of Vitamin D. Whereas clinical trials have shown improvements in endothelial function upon Vitamin D supplementation,216,217 other trials observed no change.218–220

In recent years, many other clinical trials have been initiated investigating the effect of a wide range of pharmacological interventions or dietary supplements and/or adaptations (eg, endothelin receptor antagonism, antioxidant molecule mitoQ, low-AGE diet, plant-derived supplements or prebiotics) on endothelial function in CKD; however, outcomes were not always clear or were not yet reported (based on a search of the www.clinicaltrials. gov database for clinical trials in CKD measuring endothelial function). As the effects of CKD on the endothelium are multifactorial and the CKD patient population is very heterogeneous, protecting and maintaining endothelial integrity might require an early and multifactorial approach as well.

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CONCLUSIONS

A healthy endothelial layer is a crucial gatekeeper counteracting CVD development. Patients with CKD display an impaired endothelial protective function due to the proinflammatory, prothrombotic, and uremic environment caused by their decline in kidney function, which contributes to the increased cardiovascular risk of these patients. Over the past decade, studies have started to reveal cellular and molecular mechanisms that underlie endothelial cell dysfunction in CKD, identifying a role for detrimental inflammatory and uremic mediators that are upregulated in CKD in contrast to the downregulation of protective factors. Clinical trials evaluating the effect of selected pharmacological interventions on endothelial function specifically in patients with CKD have been initiated and are ongoing, for example with a focus on targeting reduced endothelial nitric oxide bioavailability as well as increased inflammation and oxidative stress, and are expected to provide additional insights on patient level in the upcoming years. Additionally, preclinical and clinical studies should further support the development of new therapeutic options by unraveling novel disease mechanisms of increased cardiovascular risk specifically in this CKD population. This should also include a further focus on the level of immune-thrombosis interactions with the endothelium as the gatekeeper of cardiovascular health. Overall, these efforts should support further cardiovascular risk reduction in this specific vulnerable patient population.

REFERENCES

122. Daenen K, Andries A, Mekahli D, Van Schepdael A, Jouret F, Bammens B. Oxidative stress in chronic kidney disease. Pediatr Nephrol. 2019;34:975– 991. doi: 10.1007/s00467-018-4005-4

123. Fukai T, Ushio-Fukai M. Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells. 2020;9:1849. doi: 10.3390/cells9081849

124. Drummond GR, Sobey CG. Endothelial NADPH oxidases: which NOX to target in vascular disease? Trends Endocrinol Metab. 2014;25:452–463. doi 10.1016/j.tem.2014.06.012

125. Vaziri ND. The causal link between oxidative stress, inflammation, and hypertension. Iran J Kidney Dis. 2008;2:1–10.

126. Zhao W, Feng H, Guo S, Han Y, Chen X. Danshenol A inhibits TNFalpha-induced expression of intercellular adhesion molecule-1 (ICAM- 1) mediated by NOX4 in endothelial cells. Sci Rep. 2017;7:12953. doi: 10.1038/s41598-017-13072-1

127. Harlacher E, Wollenhaupt J, Baaten C, Noels H. Impact of uremic toxins on endothelial dysfunction in chronic kidney disease: a systematic review. Int J Mol Sci. 2022;23:531. doi: 10.3390/ijms23010531

128. Zhang Y, Murugesan P, Huang K, Cai H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets. Nat Rev Cardiol. 2020;17:170–194. doi: 10.1038/s41569-019-0260-8

129. Wang CC, Lee AS, Liu SH, Chang KC, Shen MY, Chang CT. Spironolactone ameliorates endothelial dysfunction through inhibition of the AGE/RAGE axis in a chronic renal failure rat model. BMC Nephrol. 2019;20:351. doi: 10.1186/s12882-019-1534-4

130. Speer T, Owala FO, Holy EW, Zewinger S, Frenzel FL, Stähli BE, Razavi M, Triem S, Cvija H, Rohrer L, et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur Heart J. 2014;35:3021–3032. doi: 10.1093/eurheartj/ehu111

131. Pérez L, Vallejos A, Echeverria C, Varela D, Cabello-Verrugio C, Simon F. OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells. Lab Invest. 2019;99:421–437. doi: 10.1038/s41374-018-0151-3

132. Speer T, Rohrer L, Blyszczuk P, Shroff R, Kuschnerus K, Kränkel N, Kania G, Zewinger S, Akhmedov A, Shi Y, et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity. 2013;38:754–768. doi 10.1016/j.immuni.2013.02.009

133. Aranda-Rivera AK, Cruz-Gregorio A, Pedraza-Chaverri J, Scholze A. Nrf2 activation in chronic kidney disease: promises and pitfalls. Antioxidants (Basel). 2022;11:1112. doi: 10.3390/antiox11061112

134. Juul-Nielsen C, Shen J, Stenvinkel P, Scholze A. Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: alterations, interventions, and relation to morbidity. Nephrol Dial Transplant. 2022;37:904–916. doi: 10.1093/ndt/gfab031

135. Chen XL, Dodd G, Thomas S, Zhang X, Wasserman MA, Rovin BH, Kunsch C. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol. 2006;290:H1862–H1870. doi: 10.1152/ajpheart.00651.2005

136. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62:1524–1538. doi: 10.1046/j.1523-1755.2002.00600.x

137. Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A; European Uremic Toxin Group. Normal and pathological concentrations of uremic toxins. J Am Soc Nephrol. 2012;23:1258–1270. doi: 10.1681/ASN.2011121175

138. Tumor Z, Shimizu H, Enomoto A, Miyazaki H, Niwa T. Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stress-induced NF-kappaB activation. Am J Nephrol. 2010;31:435–441. doi: 10.1159/000299798

139. Masai N, Tatebe J, Yoshino G, Morita T. Indoxyl sulfate stimulates monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells by inducing oxidative stress through activation of the NADPH oxidase-nuclear factor-kB pathway. Circ J. 2010;74:2216–2224. doi 10.1253/circa.cj-10-0117

140. El-Gamal D, Holzer M, Gauster M, Schicho R, Binder V, Konya V, Wadsack C, Schuligoi R, Heinemann A, Marsche G. Cyanate is a novel inducer of endothelial cam-1 expression. Antioxid Redox Signal. 2012;16:129–137. doi 10.1089/ars.2011.4090

141. Saum K, Campos B, Celdran-Bonafonte D, Nayak L, Sangwung P, Thakar C, Roy-Chaudhury P, Owens Iii AP. Uremic advanced glycation end products and protein-bound solutes induce endothelial dysfunction through suppression of Krüppel-like factor 2. J Am Heart Assoc. 2018;7:e007566. doi: 10.1161/JAHA.117.007566

142. Guo ZJ, Niu HX, Hou FF, Zhang L, Fu N, Nagai R, Lu X, Chen BH, Shan YX, Tian JW, et al. Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxid Redox Signal. 2008;10:1699–1712. doi 10.1089/ars.2007.1999

143. Ito S, Osaka M, Edamatsu T, Itoh Y, Yoshida M. Crucial role of the aryl hydrocarbon receptor (AhR) in indoxyl sulfate-induced vascular inflammation. J Atheroscler Thromb. 2016;23:960–975. doi 10.5551/jat.34462

144. Nakagawa K, Kobayashi F, Kamei Y, Tawa M, Ohkita M. Acute kynurenine exposure of rat thoracic aorta induces vascular dysfunction via superoxide anion production. Biol Pharm Bull. 2022;45:522–527. doi: 10.1248/bpb.b21-01079

145. Stafim da Cunha R, Gregório PC, Maciel RAP, Favretto G, Franco CRC, Gonçalves JP, de Azevedo MLV, Pecoits-Filho R, Stinghen AEM. Uremic toxins activate CREB/ATF1 in endothelial cells related to chronic kidney disease. Biochem Pharmacol. 2022;198:114984. doi: 10.1016/j.bcp.2022.114984

146. Fels B, Beyer A, Cazaña-Pérez V, Giraldez T, Navarro-González JF, Alvarez de la Rosa D, Schaefer F, Bayazit AK, Obrycki L, Ranchin B, et al. Effects of chronic kidney disease on nanomechanics of the endothelial glycocalyx are mediated by the mineralocorticoid receptor. Int J Mol Sci. 2022;23:10659. doi: 10.3390/ijms231810659

147. Davel AP, Anwar IJ, Jaffe IZ. The endothelial mineralocorticoid receptor: mediator of the switch from vascular health to disease. Curr Opin Nephrol Hypertens. 2017;26:97–104. doi: 10.1097/MNH.0000000000000306

148. Yang K, Nie L, Huang Y, Zhang J, Xiao T, Guan X, Zhao J. Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein. Toxicol Lett. 2012;215:77–83. doi: 10.1016/j.toxlet.2012.10.004

149. El-Gamal D, Rao SP, Holzer M, Hallström S, Haybaeck J, Gauster M, Wadsack C, Kozina A, Frank S, Schicho R, et al. The urea decomposition product cyanate promotes endothelial dysfunction. Kidney Int. 2014;86:923– 931. doi 10.1038/ki.2014.218

150. Linden E, Cai W, He JC, Xue C, Li Z, Winston J, Vlassara H, Uribarri J. Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation. Clin J Am Soc Nephrol. 2008;3:691–698. doi: 10.2215/CJN.04291007

151. Li P, Zhang L, Zhang M, Zhou C, Lin N. Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: a mechanism for uric acid-induced endothelial dysfunction. Int J Mol Med. 2016;37:989– 997. doi: 10.3892/ijmm.2016.2491

152. Cheng M, Yang Z, Qiao L, Yang Y, Deng Y, Zhang C, Mi T. AGEs induce endothelial cells senescence and endothelial barrier dysfunction via miR-1-3-p/MLCK signaling pathways. Gene. 2023;851:147030. doi 10.1016/j.gene.2022.147030

153. Pawlak K, Mysliwiec M, Pawlak D. Kynurenine pathway - a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients. Adv Med Sci. 2010;55:196–203. doi: 10.2478/v10039-010-0015-6

154. Lin CJ, Wu V, Wu PC, Wu CJ. Meta-analysis of the associations of cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS One. 2015;10:e0132589. doi: 10.1371/journal.pone.0132589

155. Zhang H, Xiang S, Dai Z, Fan Y. Asymmetric dimethylarginine level as biomarkers of cardiovascular or all-cause mortality in patients with chronic kidney disease: a meta-analysis. Biomarkers. 2021;26:579–585. doi: 10.1080/1354750X.2021.1954694

156. Jankowski V, Saritas T, Kjolby M, Hermann J, Speer T, Himmelsbach A, Mahr K, Augusto Heuschkel M, Schunk SJ, Thirup S, et al. Carbamylated sortilin associated with cardiovascular calcification in patients with chronic kidney disease. Kidney Int. 2022;101:574–584. doi: 10.1016/j.kint.2021.10.018

157. Noels H, Lehrke M, Vanholder R, Jankowski J. Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations. Nat Rev Nephrol. 2021;17:528–542. doi: 10.1038/s41581-021-00423-5

158. Soppert J, Lehrke M, Marx N, Jankowski J, Noels H. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Adv Drug Deliv Rev. 2020;159:4–33. doi: 10.1016/j.addr.2020.07.019

159. Bose C, Shah SV, Karaduta OK, Kaushal GP. Carbamylated LowDensity Lipoprotein (cLDL)-mediated induction of autophagy and its role in endothelial cell injury. PLoS One. 2016;11:e0165576. doi: 10.1371/journal.pone.0165576

160. Holy EW, Akhmedov A, Speer T, Camici GG, Zewinger S, Bonetti N, Beer JH, Lüscher TF, Tanner FC. Carbamylated low-density lipoproteins induce a prothrombotic state via LOX-1: impact on arterial thrombus formation in vivo. J Am Coll Cardiol. 2016;68:1664–1676. doi 10.1016/j.jacc.2016.07.755

161. Sun JT, Yang K, Lu L, Zhu ZB, Zhu JZ, Ni JW, Han H, Chen N, Zhang RY. Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function. Am J Physiol Renal Physiol. 2016;310:F511–F517. doi: 10.1152/ajprenal.00508.2015

162. Moranne O, Froissart M, Rossert J, Gauci C, Boffa JJ, Haymann JP, M’Rad MB, Jacquot C, Houillier P, Stengel B, et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol. 2009;20:164–171. doi: 10.1681/ASN.2008020159

163. Whitlock RH, Ferguson TW, Komenda P, Rigatto C, Collister D, Bohm C, Reaven NL, Funk SE, Tangri N. Metabolic acidosis is undertreated and underdiagnosed: a retrospective cohort study. Nephrol Dial Transplant. 2022:gfac099. doi: 10.1093/ndt/gfac299

164. Dobre M, Yang W, Chen J, Drawz P, Hamm LL, Horwitz E, Hostetter T, Jaar B, Lora CM, Nessel L, et al. Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study. Am J Kid Dis. 2013;62:670–678. doi: 10.1053/j.ajkd.2013.01.017

165. Collister D, Ferguson TW, Funk SE, Reaven NL, Mathur V, Tangri N. Metabolic acidosis and cardiovascular disease in CKD. Kid Med. 2021;3:753–761. e1. doi 10.1016/j.xkme.2021.04.011

166. Wesson DE, Buysse JM, Bushinsky DA. Mechanisms of metabolic acidosis-induced kidney injury in chronic kidney disease. J Am Soc Nephrol. 2020;31:469–482. doi: 10.1681/ASN.2019070677

167. Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol. 2007;292:C82–C97. doi: 10.1152/ajpcell.00287.2006

168. Chen ZW, Tsai CH, Pan CT, Chou CH, Liao CW, Hung CS, Wu VC, Lin YH. Endothelial dysfunction in primary aldosteronism. Int J Mol Sci. 2019;20:5214. doi: 10.3390/ijms20205214

169. Dong L, Li Z, Leffler NR, Asch AS, Chi JT, Yang LV. Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLoS One. 2013;8:e61991. doi: 10.1371/journal.pone.0061991

170. Dong L, Krewson EA, Yang LV. Acidosis activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. Int J Mol Sci. 2017;18:278. doi: 10.3390/ijms18020278

171. Asai M, Takeuchi K, Saotome M, Urushida T, Katoh H, Satoh H, Hayashi H, Watanabe H. Extracellular acidosis suppresses endothelial function by inhibiting store-operated Ca2+ entry via non-selective cation channels. Cardiovasc Res. 2009;83:97–105. doi: 10.1093/cvr/cvp105

172. Kendrick J, Shah P, Andrews E, You Z, Nowak K, Pasch A, Chonchol M. Effect of treatment of metabolic acidosis on vascular endothelial function in patients with CKD: a pilot randomized cross-over study. Clin J Am Soc Nephrol. 2018;13:1463–1470. doi: 10.2215/CJN.00380118

173. Kaur J, Young BE, Fadel PJ. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int J Mol Sci. 2017;18:1682. doi: 10.3390/ijms18081682

174. Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, Esler MD, Lambert GW. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009;20:933–939. doi: 10.1681/ASN.2008040402

175. Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FA, Tripepi G, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation. 2002;105:1354–1359. doi: 10.1161/hc1102.105261

176. Penne EL, Neumann J, Klein IH, Oey PL, Bots ML, Blankestijn PJ. Sympathetic hyperactivity and clinical outcome in chronic kidney disease patients during standard treatment. J Nephrol. 2009;22:208–215.

177. Lopez Garcia de Lomana A, Vilhjalmsson AI, McGarrity S, Sigurethardottir R, Anuforo O, Viktorsdottir AR, Kotronoulas A, Bergmann A, Franzson L, Halldorsson H, et al. Metabolic response in endothelial cells to catecholamine stimulation is associated with increased vascular permeability. Int J Mol Sci. 2022;23:3162. doi: 10.3390/ijms23063162

178. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–1217. doi 10.1016/j.cell.2013.05.039

179. Park S, Lee S, Kim Y, Cho S, Kim K, Kim YC, Han SS, Lee H, Lee JP, Joo KW, et al. A mendelian randomization study found causal linkage between telomere attrition and chronic kidney disease. Kidney Int. 2021;100:1063–1070. doi 10.1016/j.kint.2021.06.041

180. Ameh OI, Okpechi IG, Dandara C, Kengne AP. Association between telomere length, chronic kidney disease, and renal traits: a systematic review. OMICS. 2017;21:143–155. doi 10.1089/omi.2016.0180

181. Ikushima M, Rakugi H, Ishikawa K, Maekawa Y, Yamamoto K, Ohta J, Chihara Y, Kida I, Ogihara T. Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun. 2006;339:827–832. doi 10.1016/j.bbrc.2005.11.094

182. Buendía P, Carracedo J, Soriano S, Madueño JA, Ortiz A, Martín-Malo A, Aljama P, Ramírez R. Klotho prevents NFkB translocation and protects the endothelial cell from senescence induced by uremia. J Gerontol A Biol Sci Med Sci. 2015;70:1198–1209. doi: 10.1093/gerona/glu170

183. Izquierdo MC, Perez-Gomez M, Sanchez-Niño MD, Sanz AB, Ruiz-Andres O, Poveda J, Moreno JA, Egido J, Ortiz A. Klotho, phosphate and inflammation/aging in chronic kidney disease. Nephrol Dial Transplant. 2012;27:iv6–iv10. doi: 10.1093/ndt/gfs426

184. Shi M, Flores B, Gillings N, Bian A, Cho HJ, Yan S, Liu Y, Levine B, Moe OW, Hu MC. altho mitigate the progression of AKI to CKD through the activation of autophagy. J Am Soc Nephrol. 2016;27:2331–2345. doi: 10.1681/ASN.2015060613

185. Rodrigues SD, Santos SS, Meireles T, Romero N, Glorieux G, Pecoits-Filho R, Zhang DD, Nakao LS. Uremic toxins promote the accumulation of oxidized protein and increased sensitivity to hydrogen peroxide in endothelial cells by impairing the autophagic flux. Biochem Biophys Res Commun. 2020;523:123–129. doi 10.1016/j.bbrc.2019.12.022

186. Yan J, Wang J, He JC, Zhong Y. Sirtuin 1 in chronic kidney disease and therapeutic potential of targeting sirtuin 1. Front Endocrinol (Lausanne). 2022;13:917773. doi 10.3389/fend.2022.917773

187. Gao D, Zuo Z, Tian J, Ali Q, Lin Y, Lei H, Sun Z. Activation of SIRT1 attenuates klotho deficiency-induced arterial stiffness and hypertension by enhancing AMP-activated protein kinase activity. Hypertension. 2016;68:1191–1199. doi: 10.1161/HYPERTENSIONAHA.116.07709

188. Zarzuela MJ, López-Sepúlveda R, Sánchez M, Romero M, GómezGuzmán M, Ungvary Z, Pérez_Vizcaíno F, Jiménez R, Duarte J. SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. Biochem Pharmacol. 2013;85:1288–1296. doi: 10.1016/j.bcp.2013.02.015

189. Zhang YX, Tang RN, Wang LT, Liu BC. Role of crosstalk between endothelial cells and smooth muscle cells in vascular calcification in chronic kidney disease. Cell Prolif. 2021;54:e12980. doi 10.1111/cpr.12980

190. Meng F, Zhao Y, Wang B, Li B, Sheng Y, Liu M, Li H, Xiu R. Endothelial cells promote calcification in aortic smooth muscle cells from spontaneously hypertensive rats. Cell Physiol Biochem. 2018;49:2371–2381. doi: 10.1159/000493837

191. Chiu JJ, Chen LJ, Lee CI, Lee PL, Lee DY, Tsai MC, Lin CW, Usami S, Chien S. Mechanisms of induction of endothelial cell E-selectin expression by smooth muscle cells and its inhibition by shear stress. Blood. 2007;110:519–528. doi: 10.1182/blood-2006-08-040097

192. Jia LX, Zhang WM, Li TT, Liu Y, Piao CM, Ma YC, Lu Y, Wang Y, Liu TT, Qi YF, et al. ER, stress-dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection. Clin Sci (Lond). 2017;131:1287–1299. doi: 10.1042/CS20170252

193. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478–1483. doi: 10.1056/NEJM200005183422003

194. Chen Y, Zhao X, Wu H. Arterial stiffness: a focus on vascular calcification and its link to bone mineralization. Arterioscler Thromb Vasc Biol. 2020;40:1078–1093. doi: 10.1161/ATVBAHA.120.313131

195. Himmelsbach A, Ciliox C, Goettsch C. Cardiovascular calcification in chronic kidney disease - therapeutic opportunities. Toxins (Basel). 2020;12:181. doi: 10.3390/toxins12030181

196. Kanno Y, Into T, Lowenstein CJ, Matsushita K. Nitric oxide regulates vascular calcification by interfering with TGF- signaling. Cardiovasc Res. 2008;77:221–230. doi: 10.1093/cvr/cvm049

197. Van den Bergh G, Van den Branden A, Opdebeeck B, Fransen P, Neven E, De Meyer GRY, D’Haese PC, Verhulst A. Endothelial dysfunction aggravates arterial media calcification in warfarin administered rats. FASEB J. 2022;36:e22315. doi 10.1096/fj.202101919R

198. Zhang L, Yao J, Yao Y, Boström KI. Contributions of the endothelium to vascular calcification. Front Cell Dev Biol. 2021;9:620882. doi: 10.3389/fcell.2021.620882

199. Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, Luo S, Li Z, Liu P, Han J, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev. 2021;73:924–967. doi: 10.1124/pharmrev.120.000096

200. Yilmaz MI, Saglam M, Sonmez A, Caglar K, Cakir E, Kurt Y, Eyileten T, Tasar M, Acikel C, Oguz Y, et al. Improving proteinuria, endothelial functions and asymmetric dimethylarginine levels in chronic kidney disease: ramipril versus valsartan. Blood Purif. 2007;25:327–335. doi: 10.1159/000107410

201. Han SH, Kang EW, Yoon HS, Lee HC, Yoo TH, Choi KH, Han DS, Kang SW. Combined vascular effects of HMG-CoA reductase inhibitor and angiotensin receptor blocker in non-diabetic patients undergoing peritoneal dialysis. Nephrol Dial Transplant. 2011;26:3722–3728. doi: 10.1093/ndt/gfr108

202. Gamboa JL, Pretorius M, Sprinkel KC, Brown NJ, Ikizler TA. Angiotensin-converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis -- a randomized cross-over study. BMC Nephrol. 2015;16:167. doi: 10.1186/s12882-015-0162-x

203. Nuffield Department of Population Health Renal Studies G and Consortium SiM-AC-RT. Impact of diabetes on the effects of sodium-glucose cotransporter-2 inhibitors on kidney outcomes: a collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400:1788–1801. doi: 10.1016/S0140-6736(22)02074-8

204. Patoulias D, Papadopoulos C, Kassimis G, Vassilikos V, Karagiannis A, Doumas M. Meta-analysis addressing the effect of sodium-glucose cotransporter 2 inhibitors on flow-mediated dilation in patients with type 2 diabetes mellitus. Am J Cardiol. 2022;165:133–135. doi: 10.1016/j.amjcard.2021.11.003

205. Tanaka A, Shimabukuro M, Okada Y, Sugimoto K, Kurozumi A, Torimoto K, Hirai H, Node K; PROCEED trial investigators. Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial. Cardiovasc Diabetol. 2020;19:85. doi: 10.1186/s12933-020-01065-w

206. Juni RP, Al-Shama R, Kuster DWD, van der Velden J, Hamer HM, Vervloet MG, Eringa EC, Koolwijk P, van Hinsbergh VWM. Empagliflozin restores chronic kidney disease-induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction. Kidney Int. 2021;99:1088– 1101. doi 10.1016/j.kint.2020.12.013

207. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000;101:594–597. doi 10.1161/01.cir.101.6.594

208. Flevari P, Kalogeropoulou S, Drakou A, Leftheriotis D, Panou F, Lekakis J, Kremastinos D, Vlahakos DV. Spironolactone improves endothelial and cardiac autonomic function in nonheart failure hemodialysis patients. J Hypertens. 2013;31:1239–1244. doi: 10.1097/HJH.0b013e32835f955c

209. Gil-Ortega M, Vega-Martin E, Martin-Ramos M, Gonzalez-Blazquez R, Pulido-Olmo H, Ruiz-Hurtado G, Schulz A, Ruilope LM, Kolkhof P, Somoza B, et al. Finerenone reduces intrinsic arterial stiffness in Munich Wistar from rats, a genetic model of chronic kidney disease. Am J Nephrol. 2020;51:294– 303. doi: 10.1159/000506275

210. Gonzalez-Blazquez R, Somoza B, Gil-Ortega M, Martin Ramos M, Ramiro-Cortijo D, Vega-Martin E, Schulz A, Ruilope LM, Kolkhof P, Kreutz R, et al. Finerenone attenuates endothelial dysfunction and albuminuria in a chronic kidney disease model by a reduction in oxidative stress. Front Pharmacol. 2018;9:1131. doi: 10.3389/par.2018.01131

211. Nowak KL, Chonchol M, Ikizler TA, Farmer-Bailey H, Salas N, Chaudhry R, Wang W, Smits G, Tengesdal I, Dinarello CA, et al. IL-1 inhibition and vascular function in CKD. J Am Soc Nephrol. 2017;28:971–980. doi: 10.1681/ASN.2016040453

212. Jalal DI, Decker E, Perrenoud L, Nowak KL, Bispham N, Mehta T, Smits G, You Z, Seals D, Chonchol M, et al. Vascular function and uric acid-lowering in stage 3 CKD. J Am Soc Nephrol. 2017;28:943–952. doi: 10.1681/ASN.2016050521

213. Rutherford E, Ireland S, Mangion K, Stewart GA, MacGregor MS, Roditi G, Woodward R, Gandy SJ, Houston JG, Jardine AG, et al. A randomized, controlled trial of the effect of allopurinol on the left ventricular mass index in hemodialysis patients. Kidney Int Rep. 2020;6:146–155. doi: 10.1016/j.ekir.2020.10.025

214. Kao MP, Ang DS, Gandy SJ, Nadir MA, Houston JG, Lang CC, Struthers AD. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol. 2011;22:1382–1389. doi: 10.1681/ASN.2010111185

215. Yelken B, Caliskan Y, Gorgulu N, Altun I, Yilmaz A, Yazici H, Oflaz H, Yildiz A. Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. Clin Nephrol. 2012;77:275–282. doi: 10.5414/cn107352

216. Zoccali C, Curatola G, Panuccio V, Tripepi R, Pizzini P, Versace M, Bolignano D, Cutrupi S, Politi R, Tripepi G, et al. Paricalcitol and endothelial function in chronic kidney disease trial. Hypertension. 2014;64:1005– 1011. doi: 10.1161/HYPERTENSIONAHA.114.03748

217. Chitalia N, Ismail T, Tooth L, Boa F, Hampson G, Goldsmith D, Kaski JC, Banerjee D. Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PLoS One. 2014;9:e91363. doi: 10.1371/journal.pone.0091363

218. Thethi TK, Bajwa MA, Ghanim H, Jo C, Weir M, Goldfine AB, Umpierrez G, Desouza C, Dandona P, Fang-Hollingsworth Y, et al. Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease. J Diabetes Complications. 2015;29:433–437. doi: 10.1016/j.jdiacomp.2015.01.004

219. Kendrick J, Andrews E, You Z, Moreau K, Nowak KL, Farmer-Bailey H, Seals DR, Chonchol M. Cholecalciferol, calcitriol, and vascular function in CKD: a randomized, double-blind trial. Clin J Am Soc Nephrol. 2017;12:1438– 1446. doi: 10.2215/CJN.01870217

220. Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, Light RP, Agarwal R. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension. 2008;52:249–255. doi: 10.1161/HYPERTENSIONAHA.108.113159

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