Archives of Nephrology ISSN: 2639-3573 Volume 2, Issue 1, 2018, PP: 06-14 Accelerated in the Setting of Chronic Kidney Disease Allison B. Reiss*, Amy D. Glass, Heather A. Renna, David J. Grossfeld, Daniel S. Glass, Lora J. Kasselman, Joshua De Leon Department of Medicine, NYU Winthrop Hospital, Mineola, New York. [email protected] *Corresponding Author: Allison B. Reiss, Department of Medicine, Biomedical Research Institute, NYU Winthrop Hospital, 101 Mineola Boulevard, Mineola, New York.

Abstract Between 35% and 50% of deaths among patients with chronic kidney disease (CKD) can be attributed to . Even after adjusting for traditional cardiovascular risk factors, cardiovascular mortality risk is substantially increased in a linear fashion with decreasing glomerular filtration rate in CKD. Uremic toxins, oxidative stress and are critical factors found in CKD that can accelerate the atherosclerotic process. Although the precise mechanistic link(s) between CKD and cardiovascular disease are not yet fully defined, this review will discuss the current state of our knowledge. Lack of effective treatment for cardiovascular disease in CKD is a major unmet clinical need that can only be resolved with greater insight into the unique molecular and cellular mechanisms underlying cardiovacular disease pathogenesis in CKD. Keywords: Atherosclerosis, Ckd, Statin, Inflammation, Oxidative Stress, Microbiome.

Introduction with risk and severity of atherosclerosis (3, 4). Atherosclerosis demonstrates several properties Chronic kidney disease (CKD), the gradual loss of kidney function over time, is associated with disease compared to the general population. One specific to the population of patients with kidney 1 in 10 people globally (1, 2).Cardiovascular disease in this population (5, 6). Controlling for traditional reduced life expectancy and affects approximately is the leading cause of death in patients with kidney atheroscleroticmajor difference risk is factors,that atherogenesis the presence is ofaccelerated CKD is a major risk factor for and independent predictor of the development of atherosclerosis (7-9)(Table 1). diseaseand degree of renal insufficiency measured asTable worsening 1. Cardiovascular glomerular Risk filtration in CKD. rateAggravating correlates factors. Atherosclerotic Risk Factors: CKD Traditional Non-Traditional Age Gender Cytokines Inflammation Obesity Oxidative Stress Diabetes Uremic toxins Smoking Endothelial dysfunction Decreased glomerular filtration rate Infection Physical inactivity Abnormal gut microbiome

Archives of Nephrology V2 . I1 . 2019 6 Accelerated Atherosclerosis in the Setting of Chronic Kidney Disease cell proliferation and migration in culture (30, 31). patients with CKD compared to the general population Indoxyl sulfate also makes cultured isThe incompletely mechanism understood by which atherogenesis and is presently differs under in more adhesive to by increasing active investigation. Amongst the abnormalities seen chemoattractant protein 1, E-selectin and intercellular adhesio mmatory uremic toxins are regarded as keyfactors promoting in CKD, enhanced inflammation and accumulation of atherosclerosis (10, 11). For example, patients with necro n molecule 1 (32-34). The infla remic CKD have been shown to manifest signs of increased cytokines interleukin (IL)-1β, IL-18, IL-6 and tumor oxidative stress (12-14). Hypertension, a known uremicsis toxins factor involved (TNF)α in canatherogenesis be considered are advanced u contributor to cardiovascular risk, is common in glycatiotoxins thatn end may productsbe -promoting (AGEs) and (35-38).Other leptin. AGEs, CKDand likely participates in atherosclerosis in generated nonenzymatically by the Maillard reaction CKD (15,16).Histologically, atherosclerotic lesions that binds reducing sugars with the free amino groups in CKD patients are similar in composition to those in proteins, lipids or nucleic acids, cause tissue damage observed in persons with normal kidney function (17). Thisbrief review will explore how the unique 41). AGEs inhibit nitric oxide synthase, leading to endothelialand oxidative damage stress and and dysfunction are pro-inflammatory (42). Leptin, (39- a atherosclerotic process and discuss strategies for peptide hormone produced by white adipose tissue, cardiovasinflammatorycular environmentdisease prevention in CKD and affectstreatment the can also induce endothelial dysfunction, oxidative in CKD. stre Inflammation, Oxidative Stress and proliferation and platelet Uremic Toxins in CKD activationssand (43, inflammation 44). while also promoting CKD is also associated with dysbiosis of the gut as supported by several lines of evidence including microbiome withan increasedratio of pathogenic thInflammatione observation appears that to premature play a role in atherosc atherogenesislerotic cardiovascular disease occurs more frequently in (45). Pathogens that colonize the intestines enhance patients with systemic lupus erythematosus and proteinand pro-inflammatory fermentation, producing flora over waste symbiotic metabolites species rheumatoid arthritis, both examples of chronic such as microbial-derived uremic toxins. Further, a immunologically-mediated diseases characterized by by these microbes can allow breach of the intestinal that occurs in CKD may be attributed to a number barrierlocal inflammatory so that toxins response more easily to endotoxins enter the circulation. produced ofinflammation factors including (18-20).The increased chronic production, inflammatory slowed state These toxins are poorly excreted when kidney function degradation and compromised clearance of pro- y cytokines, elevated levels of reactive ) (Figure 1). oxygen species and chronic, recurrent infections (21). is insufficient and can then add to the build up to inflammator Uremic toxins are solutes excreted by healthy kidneys harmfulTreatment levels in of CKD Atherosclerosis (46-48 in CKD that are not removed adequately in CKD and cause In CKD patients, cardiovascular disease is often 22). Theyarepro-atherogenic due to underdiagnosed and may be undertreated (49). multiple actions such as enhancement of oxidative Management of conventional risk factors for adverse effects ( stress, and promotion of vascular smooth muscle and atherosclerotic cardiovascular disease that are endothelial dysfunction (23-27).Oxidative stress in prevalent in CKD patients is generally by well- CKD results from impaired defenses as well as higher established methods including medication to manage rates of pro-oxidant activity. There is excess formation dyslipidemia, control and reduce of reactive oxygen and nitrogen species and increased hyperglycemia (50) (Table 2). However, traditional oxidative burden in the kidney and vasculaturewith Framingham risk factors are inaccurate predictors con of of cardiovascular prognosis in CKD (51).Other non- comitant inflammation and production conventional atherosclerotic risk factors in CKD such oxidativelyThe uremic modified solute indoxyl atherogenic sulfate lipids has been (13, 28,shown 29). t o induce oxidative stress and inhibit endothelial treatments (52). as chronic inflammation do not yet have definitive 7 Archives of Nephrology V2 . I1 . 2019 Accelerated Atherosclerosis in the Setting of Chronic Kidney Disease

Fig 1. Dysbiosis in CKD. An abnormal gut microbiome may contribute to cardiovascular risk in CKD. Increased permeability of the gut epithelial barrier results in systemic translocation of bacterial-derived uremic toxins. These toxins induce oxidative stress and damage. Table 2. Strategies to Reduce Cardiovascular Risk in CKD. Standard and innovative approaches. Prevention and Treatment of Atherosclerotic Cardiovascular Disease in CKD tandard Non-standard Control blood pressure Control blood sugar Reduce oxidative Stress Reduce inflammation Manage lipids MicroRNA targeting Program of physical activity Change gut microbiome - probiotics Smoking cessation Cytokine neutralization: monoclonal antibodies

Atherogenic dyslipidemia, characterized by increased Another problem with statins is that they primarily triglycerides and decreased HDL levels, is commonly target low density (LDL) which documented in persons with reduced renal function is not as strongly associated with cardiovascular risk (53, 54).High triglycerides are likely a consequence in CKD patients as in the general population (59, 60). of impaired clearance and reduced activity of lipoprotein lipase and hepatic triglyceride lipase (55, disease population treated by dialysis. In this group, Statins show even less efficacy in the end stage renal 56).Statin drugs are mainstay therapy for dyslipidemia statin therapy does not appear to measurably impact with demonstrated impact on atherosclerosis in development of atherosclerotic complications and various populations who are at risk for cardiovascular may not be recommended for them. Another class of lipid lowering drugs, proprotein of major atherosclerotic events in patients with convert asesubtilisin/kexin type 9 (PCSK9) inhibitors, disease.They are effective in decreasing the incidence moderate-to-severe CKD when combined with work by slowing LDL receptor degradationand it has s (57). Unfortunately, statins and especially been suggested that they may be useful in CKD due to st tate developmenfibrate t of myopathy and rhabdomyolysis, size, skewing toward larger, possibly less atherogenic atins combined with fibrates, may precipi particlestheir effects (61, 62).on distribution of HDL and LDL particle

whichArchives are of already Nephrology more likelyV2 . I1 to . 2019occur in CKD (58). 8 Accelerated Atherosclerosis in the Setting of Chronic Kidney Disease Elevated blood pressure among populations with Conclusions CKD is a chronic multisystemic disorder associated with accelerated atherosclerosis and enhanced 2017CKD is guidelines, a major modifiable the American cardiovascular College of Cardiologyrisk factor cardiovascular risk (90). Traditional risk factors recomwith estimatedmends that prevalence adults of with 67–86% CKD (63). should In their be alone cannot explain the cardiovascular mortality in CKD. It is likely that the uremic environment mmHg (64, 65). Guidelines recommend blockade s pathological atherosclerotic processes oftreated the renin–angiotensin to a target blood pressure system (RAS) less than by using 130/80 an through production of uremic toxins, exacerbation of angiotensin-converting enzyme inhibitor (ACEi) amplifie or an angiotensin-receptor blocker (ARB)because lipid accumulation and endothelial dysfunction they provide additional blood pressure-independent contributeinflammation to andinitiation increased and oxidativeprogression stress. of atheroma Oxidized renopro ACEi, ARB, beta-blockers formation. Treatments include diet and lifestyle and calcium channel blockersareamong the drugs tection (66-68). tions, encouraging physical activity and commonly used to control blood pressure because smoking cessation. Medications are used to control lifest 69). bloodmodifica pressure, blood sugar and dyslipidemia. Newer Diuretics are often added as part of combination yle changes alone are rarely sufficient ( to optimize the gut microbiome and to limit oxidative approaches that are still experimental include efforts drug therapy in CKD and offer antihypertensive and Diet ey spec at cardioprotective benefits (70, 71). stress and inflammation. In the future, targeting of components in cardioprotection in CKD (72- 74). post-transcriptionally regulate gene expression, may ary and lifestyle modifications are also k be appliedific microRNAs, to restore functionssmall non-coding related to endothelialRNAs th drug treatments (75). Diet is important and impacts integrity and other processes adversely impacted by Smoking may interfere with effectiveness of some the CKD milieu. Such studies are already underway 77). in murine models (91, 92). Therapy with monoclonal uremicblood sugar, toxins lipid and profile change and the the gut microbiome microbiome (76, are antibodies to reduce cytokine activity is another Newer approaches to reduce inflammation and intriguing possibility since these drugs, including supplementbeing explored that (78, may 79). target Resistant the gut starch,microbiome a soluble in a for autoimmune disorders (93).An early study of IL- anti-TNF and anti-IL-1β biologics, are already in use wayfiber that and reduces prebiotic, uremic has been toxins proposed ( as a dietary such as N-acetylcysteine are also in early stages of cardiovascular disease in CKD remains a persistent 1β inhibition looks promising (94). Unfortunately, consideration for their ability to improve80). Anti-oxidants endothelial and urgent problem with no major breakthroughs on the horizon at this time. References function (52,81). that reduces cardiovascular risk in rheumatoid [1] Hsu PK, Powe NR. Recent trends in the prevalence arthritMethotrexate,is, was a tried powerful unsuccessfully anti-inflammatory in non -auto drug of chronic kidney disease: not the same old song.

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Citation: Allison B. Reiss, Amy D. Glass, Heather A. Renna, et al. Accelerated Atherosclerosis in the Setting of Chronic Kidney Disease. Archives of Nephrology. 2018; 2(1): 06-14. Copyright: © 2018 Allison B. Reiss, Amy D. Glass, Heather A. Renna, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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