Lipids, blood pressure and kidney update 2014

Accepted Manuscript Title: Lipids, blood pressure and kidney update 2014 Author: Maciej Banach Wilbert S. Aronow Corina Serban Amirhossein Sahabkar Jacek Rysz Luminita Voroneanu Adrian Covic PII: DOI: Reference:

S1043-6618(15)00048-1 http://dx.doi.org/doi:10.1016/j.phrs.2015.03.009 YPHRS 2797

To appear in:

Pharmacological Research

Received date: Revised date: Accepted date:

23-2-2015 14-3-2015 15-3-2015

Please cite this article as: Banach M, Aronow WS, Serban C, Sahabkar A, Rysz J, Voroneanu L, Covic A, Lipids, blood pressure and kidney update 2014, Pharmacological Research (2015), http://dx.doi.org/10.1016/j.phrs.2015.03.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

LIPIDS, BLOOD PRESSURE AND KIDNEY UPDATE 2014

Maciej Banach1, Wilbert S. Aronow2, Corina Serban3,

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Amirhossein Sahabkar4,5, Jacek Rysz1, Luminita Voroneanu6, Adrian Covic6 Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of

Department of Functional Sciences, Discipline of Pathophysiology, “Victor Babes” University

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Lodz, Poland; 2Department of Medicine, New York Medical College, Valhalla, NY, USA;

of Medicine and Pharmacy, Timisoara, Romania; 4Biotechnology Research Center, Mashhad

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University of Medical Sciences, Mashhad, Iran; 5Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth,

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Australia; 6Nephrology Clinic, Dialysis and Renal Transplant Center, C.I. Parhon University

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*Corresponding author:

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Hospital and Grigore. T. Popa, University of Medicine and Pharmacy, Iasi, Romania.

Prof. Maciej Banach, MD, PhD, FNLA, FAHA, FESC, FASA, FRSPH. Head, Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113; 90-549 Lodz, Poland. Phone: +48 42 639 37 71; Fax: +48 42 639 37 71; E-mail: [email protected]

Conflict of Interest Disclosures: None Number of words: 10539

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ABSTRACT This paper is an effort to review all the most important studies and guidelines in the topics of lipid, blood pressure and kidney published in 2014. Irrespective of advances, the options for

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improving simultaneous hypercholesterolemia and hypertension management (as well as its complication – chronic kidney disease) remain a problem. Recommending hypolidemic,

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hypotensive and kidney disease drugs to obtain therapy targets in cardiovascular, diabetic,

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elderly and kidney disease (=high risk) patients might strengthen risk factor control, improve compliance and the therapy efficacy, and in the consequence reduce the risk of cardiovascular

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events and mortality rate. That is why the authors have decided to summary and discuss the

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recent scientific achievements in the field of lipid, blood pressure and kidney.

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statin intolerance statin myopathy

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Keywords: Blood pressure, Cholesterol, Dyslipidemia, Hypertension, Lipids, Renal disease,

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LIPIDS UPDATE 2014 Year 2014 was very important taking into account lipid research. There was a continuation of discussion concerning recommendations of optimal dyslipidemia management, several

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important studies and trials were also presented and published [1-4]. The latest International Atherosclerosis Society (IAS) position paper comprising global recommendations for the

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management of dyslipidemia, introduced the new concept of total risk referring to a sum of all

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risk existing factors in a person, adjusted for age, as a promising therapeutic strategy [5]. The National Lipid Association (NLA) established a selection of recommendations for control of

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dyslipidemia in clinical practice and defined a new patient-centered approach, referring to the active participation of the patients in clinical and therapeutic decisions making and a novel term

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of atherogenic cholesterol, comprising low-density lipoprotein cholesterol (LDL-C) and non-

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high-density lipoprotein cholesterol (non HDL-C) as the primary targets for therapies [6].

Statin intolerance – a myth or reality?

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Statins are usually well tolerated possessing a good safety profile [7], although dose dependent side effects of statins might be associated with myopathy, new onset of diabetes, increased levels of transaminases, and cognitive disorders [8-12]. One should also remember that there are many other possible statin therapy adverse effects, including headaches, joint pains, and abdominal pain, peripheral neuropathy, sleep problems, sexual function problems, fatigue, weight change, breast enlargement, dry skin, rashes, nausea, upset stomach, as well as hair loss and pseudo-lupus syndrome [13]. It has been shown that approximately 3% to even 20% of statin users experience the phenomena of statin intolerance, and since recent guidelines extended their use [14], side-effects of statins tend to be an escalating challenge [15]. The large differences 3

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between the studies concerning the prevalence of statin intolerance is connected to the fact that patients with side effects after statin therapy were excluded from all statin trials (that is why the prevalence was usually up to 5%), and the much higher prevalence have been observed in the

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observational studies (even up to 20%) [16-18]. The problem might be also connected with the lack of clear definition of statin intolerance. The first attempts were at the design of proprotein

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convertase subtilisin/kexin 9 (PCSK9) inhibitors trials dedicated to such population (GAUSS 1-3

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trials with evolocumab and ODYSSEY ALTERNATIVE with alirocumab) [19-21]. Working within International Lipid Expert Panel it seems that statin intolerance should be defined as: (1)

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inability to tolerate ≥2 statins at any dose or any increase in dose, (2) intolerance associated with confirmed, intolerable statin-related adverse effect(s) or significant biomarker abnormalities, (3)

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symptom or biomarker changes resolution or significant improvement upon dose decrease or

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discontinuation, and (4) symptoms or biomarker changes not attributable to established

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predispositions such as drug-drug interactions and recognized conditions increasing the risk of statin intolerance [22]. Being just published European Atherosclerosis Society (EAS) statement

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on statin-associated muscle symptoms has not attempted to define statin intolerance [23]. Analyzing current definitions for statin-associated muscle adverse events, a myalgia clinical index score was suggested by the National Lipid Association's Muscle Safety Expert Panel [24]. There might be many different causes and risk factors of statin intolerance, including genetic predisposition [25]. The confirmed genetic factors related to elevated statin muscle levels is a mitochondrial enzyme (GATM), the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), an influx transporter (SLCO1B1 – located on chromosome 12 is probably the most common genetic risk factor of statin intolerance) and the efflux transporters (ABCB1 and ABCG2) [26]. Recently, it has been shown that statin-induced mitophagy, the 4

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phenomena of losing of mitochondria, could have also an important role in the progression of muscle myopathy during statin therapy [27]. NLA also presented a clear recommendation how to manage with statin intolerant patients [10], there have been also recently published meta-

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analyses analyzing the association between vitamin D (VitD) levels and coenzyme Q(10) supplementation and statin induced myalgia (SIM). The authors working within the Lipid and

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Blood Pressure Meta-Analysis Collaboration (LBPMC) Group showed that there is strong

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significant association between low levels of VitD and SIM, and they did not find such link between CoQ(10) supplementation and SIM, although the available randomized controlled trials

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evaluated only CoQ(10) doses up to 400 mg/day [28,29].

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Optimal lipid lowering therapy – looking for new (old) agents…

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Year 2014 was also completely dedicated to continous discussion around the optimal lipid

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lowering therapy [30-34]. The first strategy for development of novel therapies against dyslipidemia include the further reduction of LDL-C levels using monoclonal antibodies to

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inhibit PCSK9, antisense oligonucleotide to restrict the production of apolipoprotein B (ApoB), and acyl-coenzyme A cholesterol acyl transferase inhibitors and microsomal transfer protein (MTP) inhibitors [35]. It has been shown that PCSK9 is an enzyme with a crucial function in lipid metabolism [36,37]. The inhibition of PCSK9 using monoclonal antibodies, mimetic peptides, genetic knockdown of PCSK9, gene-repair techniques, gene silencing or silencing RNA appears useful not only in patients with high cardiovascular (CV) risk without optimal LDL-C levels despite statin therapy (in monotherapy and as add-on therapy), but it seems to be crucial in patients with familial hypercholesterolemia (FH) or those intolerant to statins [38,39]. Generally, PCSK9 inhibitors realize nearly 70% decrease of LDL-C levels (MENDEL-2, 5

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GAUSS-2, ODYSSEY COMBO, ODYSSEY ALTERNATIVE trials), even in severe FH patients (RUTHERFORD-2 and ODYSSEY FH trials), with very beneficial safety profile in 52week trials (DESCARTES and ODYSSEY LONG-TERM trials) [19,20,40-44]. Latest results

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published on evolocumab showed a 30% decrease of serum LDL-C levels in homozygous FH patients (TESLA trial) [45]. Moreover, if PCSK9 inhibitors are combined with a statin, the

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results obtained reach the targets recommended by current EAS 2011 guidelines [46,47], even in

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severe FH patients. In 2014 two PCSK9 trials with statin intolerant patients were published. Besides mentioned GAUSS-2 trial with evolocumab [20], ODYSSEY ALTERNATIVE, a

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randomized phase 3 trial was presented during American Heart Association (AHA) congress in Chicago [48]. The investigators compared the efficacy and safety of alirocumab and ezetimibe in

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314 intolerant patients to minimum 2 statins, one being at minimum starting dose. They showed

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significant reduction of LDL-C after 24 weeks of therapy with alirocumab as compared to

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ezetimibe (45% vs. 14.6%). Alirocumab group had also significantly reduced muscle side effects compared to atorvastatin group (32.5% vs 46%, p = 0.042), but no significant difference was

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observed between groups treated with PCSK9 inhibitors. The myalgia rates and the discontinuation rates of statins were comparable between groups [48]. Similarly important results were obtained in ODYSSEY LONG-TERM trial [49], which is presented during European Society of Cardiology (ESC) Congress in Barcelona. The study aimed to assess safety, tolerability and efficacy of alirocumab in patients at high CV risk (including 17.7% of patients with HeFH) for 18 months. All patients had LDL-C ≥70 mg/dL and were receiving a maximally tolerated stable statin dose. Patients were randomized to either alirocumab 150 mg or placebo subcutaneously every two weeks for 78 weeks. At Week 24, LS mean changes of LDL-C from baseline were -61.0% and +0.8% for alirocumab and placebo, respectively, and 81% of the 6

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alirocumab-treated patients reached prespecified LDL-C treatment levels according to their level of CV risk. LDL-C reduction with alirocumab was maintained to week 52. Treatment-emergent adverse events (TEAEs) occurred in 78.6% alirocumab and 80.6% of placebo patients. TEAEs

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led to discontinuation in 6.2% and 5.5% of alirocumab and placebo patients, respectively. No marked imbalance was observed in the frequency of TEAEs. Treatment-emergent CV events

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were positively adjudicated in 4.0% and 4.4% of the alirocumab and placebo patients,

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respectively. It is also worth mentioning that for the first time the researchers made the analysis of TEAEs for the patients who obtained LDL-C level <25 mg/dl, showing lack of increase of any

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side effects associated with such low level of LDL-C.

Mentioned above PCSK9 inhibitors trials as well as presented at AHA Scientific Sessions

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2014 - the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-

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IT) confirmed not only the efficacy of “lower the better” approach as well as safety of intensive

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LDL lowering. The study included more than 18 000 after acute coronary syndrome (ACS) (<10 days). Patients were randomized to one of two treatment strategies: simvastatin 40 mg alone or

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simvastatin 40 mg plus ezetimibe 10 mg. At baseline, the mean LDL-C level among the ACS patients was 95 mg/dL in both treatment arms. With simvastatin 40 mg, LDL-C levels were reduced to 69.9 mg/dL at 1 year. The addition of ezetimibe 10 mg to simvastatin further lowered LDL-cholesterol levels, to 53.2 mg/dL at 1 year. Over 7 years, there remained a significant difference between the two treatments in the achieved LDL-cholesterol levels. The investigators showed the largest relative reduction in the combined end point of coronary heart disease death, myocardial infarction (MI), and urgent coronary revascularization (18.9% event rate in the simvastatin arm vs 17.5% in the ezetimibe/simvastatin arm; P=0.016). Over a period of 7 years, the addition of ezetimibe to simvastatin 40 mg reduced the primary end point by 6.4. The 7

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number-needed-to-treat to prevent one event was 50 when measured over a median time of 7 years, and the absolute reduction in risk over 7 years was 2.0%, with 32.7% in the ezetimibe/simvastatin arm experiencing a primary end point compared with 34.7% in the

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simvastatin arm. In terms of individual components of the primary end point, the reduction was driven by a statistically significant reduction in the risk of MI and ischemic stroke. All-cause

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mortality was not affected by treatment [50].

Lipoprotein a – an undervalued risk factor?

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Recent opinions take into consideration lipoprotein(a) [Lp(a)] as a possible target for dyslipidemia, since Mendelian randomization studies identified Lp(a) as a causal factor in the

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mechanism of atherosclerosis [51]. Lp(a) is independent from all other risk factors, predictor of

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cardiovascular disease (CVD), what has been confirmed in many available epidemiological

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studies [52]. Moreover, Lp(a) has been involved in premature aortic stenosis [53] and it appears to strengthen the atherosclerotic plaque by partially suppressing the fibrinolitic process.

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Recently, a cross sectional study with 1960 FH patients showed that Lp(a) was an independent predictor of CVD, impartial of the LDLR transformation [54]. Furthermore, the levels of Lp(a) did not vary as a reaction to normal food consumption, but were raised if the levels of C-reactive protein (CRP) were increased [55]. After genotyping, the investigators from the Precocious Coronary Artery Disease (PROCARDIS) case-control trial, discovered an association between the LPA null allele (rs41272114) and decreased Lp(a) levels and coronary artery disease (CAD) risk [56]. A recent analysis from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial has shown that Lp(a) is a considerable determinant of residual risk in patients treated with potent statin therapy [36]. 8

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Niacin produces a reduction up to 30% of circulating Lp(a) levels [57]. A recent study evaluated the effect of evolocumab on Lp(a) from a pooled analysis on 1,359 patients of 4 phase II trials, and a significant dose-related reductions of circulating Lp(a) levels by 30-35% was observed

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(what was a confirmation of the other available trials with PCSK9 inhibitors) [58]. However, there is a discussion connected with this effect, as it has been shown that the level of reduction

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depends on the baseline values of Lp(a), and there is no clear mechanism how PCKS9 inhibition

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effects Lp(a). Another double-blind, randomized, placebo-controlled, phase 2 study showed a significant reduction of circulating Lp(a) levels using alirocumab at dose 150 mg every 2 weeks,

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in statin-treated patients with hypercholesterolemia [59].

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LDL-C lowering with ETC-1002 – what we really know?

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Discussing the recent achievements in further LDL-lowering therapy ETC-1002 needs to be

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mentioned. ETC-1002 is a new investigational LDL-C-lowering agent (Esperion Therapeutics, Inc.), which is a dicarboxylic acid derivative with a novel mechanism of action targeting two

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hepatic enzymes: adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase, inhibiting sterol and fatty acid synthesis and promoting mitochondrial long-chain fatty acid oxidation [60]. This agent is currently in phase II clinical research, however, the available data suggests that ETC-1002 significantly decreased LDL-C levels (up to 32%) in both patients with normal and elevated baseline TGs levels [60]. The levels of apolipoprotein B (apoB) and non-HDL-C were also reduced with very beneficial effect on inflammatory markers, blood pressure and body weight. Taking into account the available data it seems that ETC-1102 might be a very effective agent hypercholesterolemic subjects who are statin intolerant or as addon therapy in those who are unable to reach the LDL-C goals despite being on statin therapy. The 9

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safety and tolerability of ETC-1002 needs to be also confirmed in ongoing and future studies [60].

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Hypertriglyceridemia – the debate continues

The second strategy for development of novel therapies against dyslipidemia comprises the

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reduction of triglyceride-rich lipoproteins levels using ω-3 fatty acids, microsomal triglyceride

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transfer protein (MTP) inhibitors, and diacylglycerol acyl transferase-1 (DGAT-1) inhibitors [61,62]. It has been shown that ω-3 fatty acids decrease blood pressure and platelet aggregation,

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stabilize the atherosclerotic plaque and reduce the risk of critical arrhythmias [63]. Recently, the Food and Drug Administration (FDA), based on results obtained in phase 3 Epanova for

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Lowering Very High Triglycerides (EVOLVE) trial, approved Epanova (ω-3 carboxylic acids) as

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an adjunct to diet to lower severe hypertriglyceridemia (TG levels >500 mg/dL) [64]. However,

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the European Medicines Agency (EMA) has authorized the use of ω-3 fatty acids supplementation only as a complement therapy after myocardial infarction.

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Icosapent ethyl (IPE) (Vascepa, formerly AMR101, Amarin), a new synthetic ω-3 fatty acid drug, substantially reduced the levels of TG, non-HDL-C and apoB, without increasing LDL-C levels in patients with high TG levels [65]. OM3-FFA, another ω-3 fatty acid formulation, has shown even more increased bioavailability than ethyl ester forms and decrease TG levels in patients with severe hypertriglyceridemia [66]. The Reduction of Cardiovascular Events with EPA-Intervention (REDUCE-IT) trial is a new randomized trial launched by Amarin. High-risk patients on statin therapy will receive Vascepa and the primary end point will be the cardiovascular events [67].

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It needs to be mentioned that year 2014 was a time of high discussion around the usage of fibrates (fenofibrate) in patients with diabetes. It started with American College of Cardiology (ACC)/American Heart Association (AHA) lipid guidelines (presented in November 2014),

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when, based on the results of the Fenofibrate Intervention and Event Lowering of Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials, no

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combination therapy was recommended [68,69]. Next, similar recommendations were presented

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by NICE 2014 guidelines [70]. It seems, however, that the presented approach has at least few limitations. First of all, one should not base the recommendations on such trials like FIELD and

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ACCORD, as they were essentially methodologically limited, what was connected to the fact that the populations included to these studies were without any indications for fenofibrate

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therapy (with too optimal lipoprotein parameters), and in the FIELD trial statins were used two

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times more often in the placebo group than in the fenofibrate one. Finally, the experts from

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ACC/AHA as well as from NICE did not take into account very important and positive results of fibrates in diabetic patients from prospective and genetic studies, where the strong association

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between TG decrease and CV risk reduction was observed [10,71-73]. Therefore in our everyday clinical practice we should follow EAS/ESC 2011 recommendations, and always consider fenofibrate in diabetic patients, especially with high TGs levels and very low HDL levels (however the later is less important in the time of debate on HDL-C functionality in diabetic patients).

HDL-C – is it still a therapy target? Finally, the third strategy for development of novel therapies against dyslipidemia include the increase of high-density-lipoprotein cholesterol (HDL-C) levels, HDL functionality and HDL 11

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particle numbers, using microRNAs (miRNAs), apolipoprotein AI mimetic peptides, cholesteryl ester transfer protein (CETP) inhibitors (we have been still waiting for the results of trials with anacetrapib and evacetrapib) and HDL-derived agents [35,74]. miRNAs are considered

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important regulators of lipoprotein metabolism, controlling the expression of the genes related to HDL-C metabolism, such as the scavenger receptor SRB1, and the ATP transporters, ABCA1

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and ABCG1 [75-77]. Recently it was discovered that HDL-C is dependent on scavenger receptor

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class B type I and is involved in the mechanism of intercellular communication by transporting miRNAs from a tissue and delivering to another one [78]. The deficiency [79] and antagonism

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[80] of miR-33 increase the macrophage cholesterol efflux and the levels of HDL-C and reduces progression of atherosclerosis.

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Another issue still concerns the research on the functionality of HDL-C, as based on the

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results of available studies published in last few years, it seems that not the quantity, and quality

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of HDL-C is important [81-87]. It has been recently showed that HDL-C retrieved from human atheroma is dysfunctional and substantial oxidized by myeloperoxidase (MPO) [88]. The Dallas

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Heart study measured HDL-particle levels, HDL-C levels and cholesterol-efflux capacity in 2924 healthy patients [89]. It was observed that cholesterol-efflux capacity was inversely linked with atherosclerotic CVD, confirming the hypothesis that measuring HDL levels does not indicate HDL functionality [89]. Furthermore, cholesterol-efflux capacity was not associated with body composition, insulin resistance, adiposity and lipid levels, while the cholesterol-efflux capacity was not influenced by sex and race [89]. However there is still discussion on the gold standard method to measure subfractions/subpopulations of HDL-C, and which HDL particles are more prone to be dysfunctional. There have been also attempts to find a direct method of measurement of dysfunctional HDL (currently it is mainly based on MPO measurements) with specific 12

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miRNA transferred in these particles, what would allow starting a development of new drugs (as only this hypothesis is confirmed), which would reduce only HDL-C with impaired functionality

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[90].

BLOOD PRESSURE UPDATE 2014

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What is new in JNC8 recommendations?

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The 2014 guidelines report from the Eighth Joint National Committee (JNC 8) on management of high blood pressure in adults made 9 recommendations [91,92]. The first

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recommendation was to use antihypertensive drug therapy in patients aged 60 years and older without chronic kidney disease or diabetes mellitus to lower the systolic blood pressure (SBP) to

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less than 150 mm Hg and the diastolic blood pressure to less than 90 mm Hg [91]. We agree

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with the diastolic blood pressure goal but disagree with the SBP goal recommendation as does a

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minority report from JNC 8 which recommends that the SBP goal in patients younger than 80 years with hypertension without chronic kidney disease or diabetes mellitus should be less than

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140 mm Hg [93].

Older persons have the lowest rates of adequate blood pressure control and the highest incidence of cardiovascular events [94,95]. Blood pressure is adequately controlled in 36% of men and 28% of women between ages 60-79 years and in 38% of men and 23% of women aged 80 years and older [96]. We are very concerned that the higher SBP goal in older persons recommended by Eighth Joint National Committee (JNC 8) will lead to a higher incidence of cardiovascular events and mortality. The second recommendation from JNC 8 was to use antihypertensive drug therapy in patients younger than 60 years to lower the diastolic blood pressure goal to less than 90 mm Hg [97]. The third recommendation from JNC 8 was to use 13

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antihypertensive drug therapy in patients younger than 60 years to lower the SBP goal to less than 140 mm Hg [93]. The fourth recommendation from JNC 8 was to use antihypertensive drug therapy in patients aged 18 years and older with chronic kidney disease to lower the blood

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pressure to less than 140/90 mm Hg [97]. The fifth recommendation from JNC 8 was to use antihypertensive drug therapy in patients aged 18 years and older with diabetes mellitus to lower

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the blood pressure to less than 140/90 mm Hg [97]. The sixth recommendation from JNC 8 in the

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general nonblack population including diabetics was to use as initial antihypertensive therapy a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme (ACE)

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inhibitor, or angiotensin receptor blocker (ARB) [91,98]. A meta-analysis of 147 randomized trials including 464,000 persons with hypertension showed that except for the extra protective

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effect of beta blockers given after myocardial infarction and a minor additional effect of CCBs in

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preventing stroke, beta blockers, ACE inhibitors, ARBs, diuretics, and CCBs cause a similar

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reduction in coronary events and stroke for a given reduction in blood pressure [99]. The choice of specific antihypertensive drugs used depends on efficacy, tolerability, presence of associated

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comorbidities, and cost [94,95]. The seventh recommendation from JNC 8 in the general black population including diabetics was to use as initial antihypertensive therapy a thiazide-type diuretic or CCB [97]. The eighth recommendation from JNC 8 states that in adults aged 18 years and older with chronic kidney disease, initial or add-on antihypertensive drug therapy should include an ACE inhibitor or ARB to improve renal outcomes [97]. This includes all patients with hypertension and chronic kidney disease regardless of race and presence or absence of diabetes mellitus. Compared with amlodipine, ramipril reduced progression of chronic kidney disease in African-Americans with hypertensive nephrosclerosis without diabetes mellitus and an estimated glomerular filtration rate between 20 to 65 ml/minute/1.73 m2 [100]. The ninth recommendation 14

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from JNC 8 states that the main goal of antihypertensive drug treatment is to achieve and maintain the blood pressure goal [97]. If the goal blood pressure is not achieved in 1 month, increase the dose of the initial antihypertensive drug or add a second drug from one of the classes

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of drug listed in recommendation 6. If the goal blood pressure is still not achieved, add a third class of drug. Do not use an ACE inhibitor plus an ARB together as you will not increase

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efficacy but will increase adverse effects [101]. If a fourth antihypertensive drug is indicated, we

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would consider use of an aldosterone antagonist if the serum potassium level is ≤ 4.5 mmol/L [102,103]. Referral to a specialist in hypertension may be needed if the goal blood pressure

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cannot be achieved.

Among 8,354 patients aged 60 years and older with coronary artery disease in the INVEST

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(International Verapamil SR-Trandolapril) Study, a baseline SBP of ≥150 mm Hg, and 22,308

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patient years of follow-up, 57% had a SBP <140 mm Hg, 21% had a SBP of 140 to 149 mm Hg,

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and 22% had a SBP of ≥150 mm Hg [104]. The primary outcome of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke occurred in 9.36% of patients with a SBP <140 mm Hg,

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in 12.71% of patients with a SBP of 140-149 mm Hg, and in 21.3% of patients with a SBP ≥150 mm Hg (p<0.0001) [104]. Using propensity score analyses, compared with a SBP <140 mm Hg, a SBP of 140 to 149 mm Hg increased cardiovascular mortality 34% (p =0.04), total stroke 89% (p = 0.002), and nonfatal stroke 70% (p = 0.03)[104]. Compared with a SBP of <140 mm Hg, a SBP ≥150 mm Hg increased the primary outcome 82% (p<0.0001), all-cause mortality 60% (p<0.0001), cardiovascular mortality 218% (p<0.0001), and total stroke 283% (p<0.0001) [104]. Older persons are currently being undertreated for hypertension [96,105]. If the JNC 8 panel recommendations are implemented, 6 million USA adults aged 60 years and older would not be eligible for antihypertensive drug therapy, and treatment intensity would be reduced for an 15

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additional 13.5 million older persons [106], leading to increased incidences of coronary events, stroke, heart failure, cardiovascular mortality, and other adverse events associated with poor control of hypertension. The JNC 8 guidelines raising the threshold for initiating

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antihypertensive drug treatment and SBP goal for older persons places high-risk women, especially African-American women at unnecessary excess risk for cardiovascular morbidity and

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mortality [107].

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The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is an observational study of stroke incidence of persons living in the stroke belt and stroke buckle

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regions of the United States [108]. This study included 4,181 persons aged 55-64 years, 3,737 persons aged 65-74 years, and 1,839 patients aged 75 years and older (mean age 79.3 years)

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taking antihypertensive drugs. Median follow-up was 4.5 years for CVD (coronary heart disease

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or stroke) and coronary heart disease, 5.7 years for stroke, and 6.0 years for all-cause mortality.

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This study showed that among persons aged 55 years and older taking antihypertensive medication, a SBP between 120 and 139 mm Hg was significantly associated with a lower risk

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for cardiovascular and all-cause mortality outcomes [108], and BP reduction below 120 mmHg might be associated with the increased risk of CV events (J-curve phenomenon) [109,110]. At the 2014 ESC meeting, data were presented from the REGARDS study showing in 13, 948 older patients on antihypertensive drug therapy that the diastolic blood pressure should be between 70 and 90 mm Hg [111]. Data from the REGARDS study were presented showing in 10,893 patients aged 55 to 74 years without hypertension that the recommended level of SBP should be less than 140 mm Hg if tolerated, and due to significant stroke reduction it should also be considered for the oldest patients [112]. Results were also presented of a meta-analysis of 11 randomized placebo-controlled trials which included 40,325 older patients that antihypertensive 16

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drug therapy significantly reduced all-cause mortality 13% (95% CI, 7% to 19%), cardiovascular death 18% (95% CI, 7% to 27%), cardiovascular events 21% (95% CI, 13% to 27%), stroke 30%

ASH/ISH 2014 guidelines – any additional information to JNC8?

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(95% CI, 23% to 37%), and fatal stroke 33% (95% CI, 95 to 50%) [113].

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The 2014 American Society of Hypertension (ASH)/International Society of Hypertension

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(ISH) guidelines recommend reducing the blood pressure to less than 140/90 mm Hg in adults younger than 80 years [114]. In adults aged 80 years and older, these guidelines recommend

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reducing the blood pressure to less than 150/90 mm Hg unless these patients have diabetes mellitus or chronic kidney disease when a goal of less than 140/90 mm Hg can be considered

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[114]. In patients with a blood pressure of ≥ 160/100 mm Hg, drug treatment should be started

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immediately after diagnosis usually with a 2-drug combination. Nonpharmacologic treatment

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includes weight loss in patients who are overweight or obese, salt reduction, regular aerobic exercise, limiting alcohol consumption to 2 drinks a day in men and 1 drink a day in women, and

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stopping smoking [114].

If hypertension is the only or main condition in blacks at all ages, the first drug should be a CCB or thiazide diuretic [114]. If a second drug is needed, an ARB or ACE inhibitor is recommended. If a third antihypertensive drug is needed, a CCB plus ACE inhibitor or ARB plus thiazide diuretic is recommended. If hypertension is the only or main condition in white and other non-black patients younger than 60 years, the first drug should be an ARB or ACE inhibitor [114]. If a second drug is needed, a CCB or thiazide diuretic is recommended. If a third antihypertensive drug is needed, a CCB plus ACE inhibitor or ARB plus thiazide diuretic is recommended. If hypertension is the only or main condition in white and other non-black 17

Page 17 of 51

patients aged 60 years and older, the first drug should be a CCB or thiazide diuretic although an ARB or ACE inhibitor is usually effective [114]. If a second drug is needed, an ARB or ACE inhibitor is recommended or CCB or thiazide diuretic is recommended if the first drug is an ARB

ip t

or ACE inhibitor. If a third antihypertensive drug is needed, a CCB plus ACE inhibitor or ARB plus thiazide diuretic are recommended. If the patient with hypertension has diabetes mellitus,

cr

the first drug should be an ARB or ACE inhibitor [114]. However, the first drug may be a CCB

us

or thiazide diuretic if the patient is black. If a second drug is needed, a CCB or thiazide diuretic is indicated. In black patients, if the first drug was a CCB or thiazide diuretic, the second drug

an

should be an ARB or ACE inhibitor. If a third drug is needed, the patient should be treated with an ARB or ACE inhibitor plus a CCB plus a thiazide diuretic. If the patient with hypertension

M

has chronic kidney disease, the first drug should be an ARB or ACE inhibitor [114]. If a second

d

drug is needed, a CCB or thiazide diuretic is recommended. If a third antihypertensive drug is

te

needed, an ACE inhibitor or ARB plus a CCB plus a thiazide diuretic are recommended. If the patient with hypertension has clinical coronary artery disease, the first drug should be a beta

Ac ce p

blocker plus an ARB or ACE inhibitor [114]. If a second drug is needed, a CCB

or thiazide

diuretic is recommended. If a third antihypertensive drug is needed, a beta-blocker plus an ACE inhibitor or ARB plus a thiazide diuretic or CCB is recommended. If the patient with hypertension has a history of stroke, the first drug should be an ARB or ACE inhibitor [114]. If a second drug is needed, a CCB or thiazide diuretic is recommended. If a third antihypertensive drug is needed, an ACE inhibitor or ARB plus CCB plus a thiazide diuretic are recommended. Patients with symptomatic heart failure should be treated with an ACE inhibitor or ARB plus a beta-blocker plus a diuretic plus spironolactone if indicated regardless of blood pressure [114,115]. If the estimated glomerular filtration rate is less than 40 ml/minute, a loop diuretic 18

Page 18 of 51

(furosemide or torsemide) is needed. A dihydropyridine CCB can be added if needed for blood pressure control. For patients with hypertension not controlled with 3 drugs including a thiazide diuretic

ip t

(treatment resistant hypertension), add a mineralocorticoid antagonist such as spironolactone, a beta blocker, a centrally acting agent, an alpha blocker, or a direct vasodilator [114]. Check

cr

whether these patients are taking other drugs which can interfere with their hypertension

us

treatment such as nonsteroidal anti-inflammatory drugs, cold remedies, and some antidepressants. Check to make sure they are actually taking their medications. Check their

an

sodium intake [114]. Consider secondary causes of hypertension [114,116]. In the absence of randomized control data, the American Heart Association (AHA) 2007

M

guidelines recommended that patients with hypertension at high risk for coronary events

d

including those with diabetes mellitus or chronic kidney disease should have their blood pressure

te

reduced to less than 130/80 mm Hg [117]. On the basis of clinical trial data from studies including the INVEST trial [118], the ACCORD trial [119], and the ONgoing Telmisartan

the

Ac ce p

Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) trial [120,121], American College of Cardiology (ACC)/AHA 2011 expert consensus document on

hypertension in the elderly [105], the 2013 European Society of Hypertension guidelines [122], the American Diabetes Society 2013 guidelines [123], the 2014 JNC 8 guidelines [97], and the 2014 ASH/ISH guidelines [114] recommended that the goal blood pressure in patients with diabetes mellitus should be less than 140/90 mm Hg. The American Diabetes Society 2013 guidelines recommend that the drug regimen should include an ACE inhibitor or ARB unless the patient is pregnant [123].

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A meta-analysis [124] was performed of the 2,272 patients, mean age 55 years (up to age 70 years), with hypertensive chronic kidney disease without diabetes mellitus in the African American Study of Kidney Disease and Hypertension (AASK) [125], the Modification of Diet

ip t

in Renal Disease (MDRD) [126], and the Ramipril Efficacy in Nephropathy 2 (REIN-2) [127] trials. This meta-analysis demonstrated that a blood pressure of less than 125/75 to 130/80 mm

cr

Hg did not improve clinical outcomes more than a target blood pressure of less than 140/90 mm

us

Hg [124]. Whether a blood pressure of less than 130/80 mm Hg benefits patients with proteinuria greater than 300 to 1,000 mg per day suggested by a subgroup analysis from the AASK trial

an

[125] requires further study [124].

The ACC/AHA 2011 expert consensus document on hypertension in the elderly

M

[105,128,129], the 2013 European Society of Hypertension guidelines [122], the 2014 JNC 8

d

guidelines [97], and the 2014 ASH/ISH guidelines [114] recommend that the goal blood pressure

te

in patients with chronic kidney disease should be less than 140/90 mm Hg. The International Society of Nephrology 2012 guidelines for management of blood pressure in patients with non-

Ac ce p

dialysis-dependent chronic kidney disease recommend that patients with chronic kidney disease without diabetes mellitus [130] or with diabetes mellitus [131] with hypertension and albuminuria less than 30 mg per 24 hours should have their SBP lowered to less than 140 mm Hg with a class I B indication. If albuminuria greater than 30 mg per 24 hours is present, the SBP may be lowered to less than 130 mm Hg with a class II D indication [130,131]. These guidelines do not recommend the choice of antihypertensive drug in patients with albuminuria less than 300 mg per 24 hours but recommend the use of an ACE inhibitor or ARB in patients with chronic kidney disease with or without diabetes mellitus if the urine albumin excretion is greater than 300 mg per 24 hours in patients who need antihypertensive drug therapy [130,131]. 20

Page 20 of 51

Renal denervation – what was new in 2014? The commonest cause of secondary hypertension in older patients is renal artery stenosis. Despite 2 randomized trials in patients with atherosclerotic renal artery stenosis showing no

ip t

clinical benefit of renal artery revascularization plus medical therapy versus medical therapy alone and serious procedure-related complications associated with revascularization [132,133],

cr

the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study was performed

us

[134]. The CORAL study randomly assigned 947 patients, mean age 69 years, with atherosclerotic renal artery stenosis and either systolic hypertension while taking 2 or more

an

antihypertensive drugs or chronic kidney disease to medical therapy plus renal artery stenting or to medical therapy alone [134]. Patients were followed for a composite endpoint of death from

M

cardiovascular or renal causes, myocardial infarction, stroke, and hospitalization for congestive

d

heart failure, progressive renal insufficiency, or the need for renal replacement therapy. Median

te

follow-up was 43 months. The primary composite endpoint occurred in 35.1% of patients who underwent stenting in addition to receiving medical therapy and in 35.8% of patients who

Ac ce p

received medical therapy alone (p not significant). There were no significant differences between the 2 groups in the rates of the individual components of the primary endpoint or in all-cause mortality. The SBP decreased 2.3 mm Hg more in the stented group (p = 0.03) [134]. There was no significant benefit in the primary endpoint in stented patients with renal artery stenosis of greater than 80% [134].

Prior unblinded studies have suggested that catheter-based renal artery denervation lowers blood pressure in patients with resistant hypertension [135,136]. The updated European Society of Hypertension position paper summarized current evidence on use of renal denervation to treat resistant hypertension in hypertension excellence centers [137]. The SYMPLICITY HTN-3 trial 21

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randomized 535 patients, mean age 57 years, with resistant hypertension in a 2:1 ratio to undergo renal denervation or a sham procedure [138]. The mean reduction in office SBP at 6 months was 14 mm Hg in the renal denervation group versus 12 mmHg in the sham control group (p not

ip t

significant). The mean reduction in 24-hour ambulatory SBP at 6 months was 7 mmHg in the renal denervation group versus 5 mm Hg in the sham control group (p not significant) [138]. The

cr

24-hour ambulatory SBP was 2 mm Hg lower in the renal denervation group (p not significant)

us

[139]. The daytime ambulatory SBP change was 1.1 mm Hg lower in the renal denervation group (p not significant [139]. The nocturnal ambulatory SBP change was 3.3 mm Hg lower in

an

the renal denervation group (p not significant [139]. The percent of nondippers converted to dippers was 21% in the renal denervation group versus 15% in the sham control group (p not

M

significant) [139]. The 2014 ESC meeting reported data from SYMPLICITY HTN-3, which

d

stated that at 1-year follow-up, there was no significant difference in lowering of office and 24-

te

hour ambulatory blood pressures between the renal denervation, crossover to renal denervation, and non-crossover groups. Renal denervation procedures that do not account for asymmetries in

Ac ce p

renal periarterial nerve and ganglia distribution may miss targets and fall below the critical threshold for effect [140]. The ultimate fate of use of renal denervation to treat resistant hypertension remains unknown [141]. Alternate techniques that are more effective in causing sympathetic renal denervation may be developed [141].

KIDNEY UPDATES 2014 Acute kidney injury (AKI) – a large challenge for nephrologists The incidence of AKI requiring dialysis in hospitalized patients is increasing [142]; the hospitalized patients who recover from AKI requiring dialysis are at increased risk of stroke and 22

Page 22 of 51

death. In a recent study Wu et al. included 4315 patients in the AKI - recovery group and matched 4315 control subjects as the non-AKI control-group. After a median follow-up period of 3.36 years, the incident stroke rate was 15.6 per 1000 person-years. The AKI-recovery group had

ip t

a higher risk (hazard ratio: 1.25; p=0.037) and higher severity of stroke events than the non-AKI group, regardless of progression to subsequent chronic kidney disease. Furthermore, the risk of

cr

mortality in the AKI-recovery group was higher than in the non-AKI group (hazard ratio: 2.4;

us

p<0.001) [143].

Moreover, AKI might be an unrecognized determinant of short-term hospital readmission,

an

especially for cardiovascular-related conditions, such as heart failure and myocardial infarction. In a recent study including 22001 hospitalized adults, AKI was independently associated with

M

higher odds of 30-day hospital readmission (OR, 1.21; 95% CI, 1.08-1.36), which persisted at 60

d

(OR, 1.15; 95% CI, 1.03-1.27) and 90 days (adjusted OR, 1.13; 95% CI, 1.02-1.25). The AKI

te

group was more likely prone to be readmitted to the hospital within 30 days for cardiovascular-

[144].

Ac ce p

related conditions, mainly heart failure (p < 0.001) and acute myocardial infarction (p = 0.01)

Fenoldopam mesylate, a selective dopamine receptor D1 agonist has been used for the prevention and therapy of acute kidney injury. It induces vasodilatation of the renal, mesenteric, peripheral, and coronary arteries [145]. Unlike dopamine, fenoldopam has no significant affinity for D2 receptors; thus, hypothetically, it can induce greater vasodilatation in the renal medulla than in the cortex. Previous data were contradictory – so that treatment with fenoldopam was not recommended by AKI guidelines. Recently the largest double blind, placebo-controlled RCT on fenoldopam in patients with AKI after cardiac surgery was published. The authors randomly assigned 667 total patients admitted to intensive care units with early acute kidney injury after 23

Page 23 of 51

cardiac surgery to either fenoldopam (n = 338) or saline placebo (n = 329). Compared to placebo, fenoldopam did not decrease death (23% in the fenoldopam group vs 22% in the placebo group – p = .86) or the need for dialysis (20% in the fenoldopam group vs 18% in the

ip t

placebo group – p = .47) at 30 days follow-up. The trial was stopped by the safety committee following interim analyses for ineffectiveness. Furthermore, the fenoldopam group had

cr

significantly higher rates of hypotension (26%, compared with 15% among the placebo group,

us

p = 0.001) [146].

Similarly, neither aspirin nor clonidine administered before and after non-cardiac surgery

an

decreased the risk of AKI. The supposed major mechanism of perioperative acute kidney injury is a reduced kidney perfusion and ischemia, with activation of inflammatory mediators, adhesion

M

molecules, platelets, and thromboxane [147]. Aspirin decreases platelet aggregation and

d

microembolization, potentially improving GFR at a time of poor kidney perfusion. Moreover,

te

aspirin reduces might reduce urinary thromboxane, a strong vasoconstrictor. Clonidine, a centrally α2-adrenergic agonist, decreases the central sympathetic outflow and has analgesic,

Ac ce p

anxiolytic, and anti-inflammatory effects [148]. In a 2 × 2 factorial randomized, blinded, clinical trial of 6905 patients undergoing no cardiac surgery from 88 centers in 22 countries patients were assigned to take aspirin (200 mg) or placebo 2 to 4 hours before surgery and then aspirin (100 mg) or placebo daily up to 30 days after surgery, and oral clonidine (0.2 mg) or placebo 2 to 4 hours before surgery, followed by a transdermal clonidine patch (which provided clonidine at 0.2 mg/d) or placebo patch that remained until 72 hours after surgery. Neither aspirin nor clonidine reduced the risk of AKI (13.4% for aspirin vs 12.3% for placebo; 13.0% for clonidine vs 12.7% for placebo). Moreover, aspirin amplified the risk of major bleeding, and this was connected with an increased risk of AKI (23.3% when bleeding was present vs. 12.3% when 24

Page 24 of 51

bleeding was absent). Clonidine increased the risk of clinically significant hypotension, which was associated with an increased risk of AKI (14.3% when hypotension was present vs. 11.8% when hypotension was absent) [149].

ip t

In hospitalized patients, anemia is an independent risk factor for AKI [150]. Recently, Mehta et al. studied 1,946 hospitalized patients; 18% of them experienced AKI during their hospital

cr

stay. The AKI group had significantly lower average hemoglobin (Hb) levels during

us

hospitalization compared with patients who did not have AKI. Additionally, aggravation of anemia was more significant in AKI than non-AKI patients from admission to discharge (decline

an

of 1.05 vs. 0.69 mg/dl). Of the 348 patients with AKI, 69% recovered completely, 23% had a partial recovery, and 8% had no recovery. Higher mean and baseline hemoglobin levels

M

predicted a full or partial recovery of kidney function. Increasing quintiles of Hb level at baseline

d

were linked with increased likelihood of complete or partial recovery. Compared with patients in

te

the lowest quintile (9.24 mg/dl or less), those in the third, fourth, and fifth quintiles (10.51– 11.60, 11.61–12.80, and 12.81 mg/dl or higher, respectively) had a significant 5.0, 4.9, and 5.6

Ac ce p

times increased odds of complete or partial recovery. In adjusted analyses, Hb levels below 10 mg/dl independently predicted a significant 82% increased odds of AKI [151]. If anemia per se is the reason for AKI, or if the underlying cause of anemia is the cause of more severe kidney injury is still not known. Of note, previous studies failed to demonstrate that correction of anemia with EPO is clearly beneficial.

New definition of chronic kidney disease In June, the National Institute for Health and Care Excellence (NICE) of the United Kingdom released its new 2014 guidance for Chronic Kidney Disease (CKD). NICE was one of 25

Page 25 of 51

the first to subdivide CKD stage 3 (eGFR 30-59ml/min/1.73m2) into 3A (eGFR 4559ml/min/1.73m2) and 3B (eGFR 30-44 ml/min/1.73m2) and to add proteinuria (defined as a urinary albumin to creatinine ratio - UACR >30 mg/mmol) using the Kidney Disease Outcomes

ip t

Quality Initiative (KDOQI) 2002 classification schema as its base [152]. NICE 2014 included four new recommendations:

cr

 The UACR threshold for CKD was reduced from 30 mg/mmol to 3 mg/mmol;

us

 The CKD-EPI creatinine equation - using isotope dilution mass spectrometry (IDMS) standardized serum creatinine values and after adjustments for black vs. non-black race and

an

gender) was recommended as the standard way for determining eGFR.

 The eGFR- cystatin C should be used to confirm or rule out CKD in people with an eGFR-

M

creatinine of 45-59ml/min/1.73m2 and an UACR of < 3 mg/mmol. The current eGFR

d

measurements based on creatinine have come under criticism for diagnosing too many people

te

with CKD stage 3, mainly elderly people. As a result of extensive over diagnosis, NICE has recommended the new test – eGFR cystatinC – which would be used for patients with an initial

Ac ce p

creatinine-based eGFR of 45-59 ml/min per 1.73 m2 but no proteinuria, as indicated by an ACR of less than 3 mg/mmol, to confirm a diagnosis of G3a (formerly stage 3a) CKD.  An “opportunistic screening” for CKD in patients at increased risk of CKD (such as diabetes, hypertension, CV disease, multisystem disease or a family history of CKD) should be considered. However, older age per se is not regarded as a sufficient reason for such testing. This differs dramatically from recommendations from US organizations, such as the National Kidney Foundation.

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CKD progression and dialysis initiation – the questions still exist… CKD progression was defined historically by doubling of serum creatinine; both US FDA and the European Medicines Agency (EMA) have recognized that requiring a doubling in serum

ip t

creatinine from baseline as a marker of CKD progression is a major problem for clinical trials in nephrology and agreed that there is an imperative need to have a more readily attainable end

cr

point to define CKD progression. In a recent meta-analysis including almost 1.7 million

us

participants in the Chronic Kidney Disease Prognosis Consortium the association between the decrease in eGFR over 1, 2, and 3 years and the risk for ESRD and mortality was examined

an

[153]. The optimal level of eGFR decline as a surrogate end-point appeared to be 30% over 2 years. Over 2 years, more patients had a decrease of at least 30% than a doubling in serum

M

creatinine (6.9% vs 0.79%). The cumulative population-attributable risk over 2 years was higher

d

when the 30% threshold was used than when the doubling threshold was used (44% vs 10%).

te

Mortality risk was just about 10-fold when the 30% threshold was used. Dialysis initiations in patients with CKD should be based on symptoms and complications

Ac ce p

and not on laboratory tests, according to the new guidelines published by the Canadian Society of nephrology [154]. CKD patients with eGFR <15 ml.min/1.73 m² should be closely monitored; they should not begin dialysis until their eGFR drops to 6 mL/minute per 1.73 m² or less or if clinical indications emerge. The society based its recommendations on 23 studies, including the Initiating Dialysis Early and Late (IDEAL) study, a large recent clinical trial conducted in Australia and New Zealand that looked at survival rates, costs, and other factors in early vs deferred start of dialysis.

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Renoprotection - what was new in 2014? The use of the mineralocorticoid receptor antagonists (MRAs) in CKD patients was associated with renoprotection and cardioprotection. The beneficial CV effects of MRAs have

ip t

been attributed to several mechanisms, including their effects on CV remodeling, collagen turnover, oxidative stress and endothelial function [155,156]. A recently published double blind,

cr

randomized, placebo-controlled trial included 314 hypertensive patients with albuminuria

us

(urinary albumin-to-creatinine ratio of 30-599 mg/g), and an eGFR of 50 mL/min per 1.73 m2 or more, treated with angiotensin converting enzyme inhibitors and/or angiotensin receptor

an

blockers. Subjects were randomly assigned to either an MRA or placebo. Addition of low-dose eplerenone to renin-angiotensin system inhibitors further reduced albuminuria in hypertensive

M

patients with non-diabetic chronic kidney disease compared with placebo (absolute difference

d

−27·6% [-51·15 to -3·96]; p=0.022), without serious safety concerns [157].

te

Hyperkaliemia is particularly common in patients with medications that interfere the renin– angiotensin–aldosterone system (RAAS) or/and with MRA’s. Two different oral medications

Ac ce p

that lower plasma potassium levels have been recently studied. Patiromer is a dry powder that binds potassium when mixed in small amounts of water. It exchanges potassium for calcium in the colon; hypercalcemia could be of considerable concern if the drug were to be absorbed. In a recent trial, patients with CKD who were receiving RAAS inhibitors and had serum potassium levels of 5.1 to 6.5 mmol/liter received patiromer (at an initial dose of 4.2 g or 8.4 g twice a day) for 4 weeks (initial treatment phase). 76% of the patients had normal potassium levels at the end of this phase. Eligible patients at the end of week 4 (those with a baseline hyperkalemia and K levels decreased by phase 1 treatment to 3.8 - 5.1 mmol/liter) (N-107 pts) entered a 8-week phase 2 randomized withdrawal study, in which they were randomly assigned to continue patiromer or 28

Page 28 of 51

switch to placebo; the primary efficacy end point was the between-group difference in the median change in serum potassium level over the first 4 weeks. Hyperkalemia recurred in 60% of the patients who were switched to placebo, as compared to 15% of those who continued

ip t

patiromer. The most common adverse event was constipation (in 11% of the patients), and hypokalemia (in 3% of the patients). The adverse effects appear to have been mild, but the study

cr

was short: 12 weeks [158]. The second drug - ZS-9 is a compound with a crystalline lattice

us

structure that traps potassium preferentially; in vitro, it traps about 10 times as much potassium as Kayexalate. In a multicenter, two-stage, double-blind, phase 3 trial, Packman et al. assigned

an

753 patients with hyperkalemia to receive either ZS-9 (at a dose of 1.25 g, 2.5 g, 5 g, or 10 g) or placebo three times daily for 48 hours. Patients with normokalemia (serum potassium level, 3.5

M

to 4.9 mmol per liter) at 48 hours were randomly assigned to receive either ZS-9 or placebo once

d

daily on days 3 to 14. The primary end point was the exponential rate of change in the mean

te

serum potassium level at 48 hours. Potassium levels decreased in patients receiving the active drug from 5.3 mmol/l at baseline to 4.9 mmol/l, 4.8 mmol/l, and 4.6 mmol/l at 48 hours in the

Ac ce p

groups receiving 2.5 g, 5 g, and 10 g of the drug, respectively (p<0.001 for all comparisons), as compared with a rate of 5.1 mmol/l at 48 hours in the group that received placebo and in the group that received 1.25 g of the drug. In the second phase of the study, patients who received 5 g and 10 g maintained serum potassium at levels of 4.7 mmol/l and 4.5 mmol/l, respectively, during days 3 to 15, as compared with a level of more than 5.0 mmol/l in the placebo group (p< 0.01 for all comparisons). It is important to note that almost 75% of the participants had an eGFR < 60 ml per minute/1.73 m2 of body-surface area, 60% had diabetes, and 40% had heart failure; in addition, 65% were receiving RAAS-inhibitor therapy, throughout the study [159].

29

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Both studies excluded patients with serum potassium levels greater than 6.5 mmol/l or electrocardiographic changes, hospitalized patients, and patients undergoing dialysis. In addition, the decrease in potassium, especially with patiromer therapy appears to be gradual, so how well

ip t

this agent would perform in acute situations is still unclear. Both agents appear to offer some promise for the treatment of hyperkalemia in patients with CKD and cardiac disease; the long-

cr

term durability and side-effect profile of these agents is also unclear, given the relatively short

us

span of the two studies. Whether these agents will be permissive for long-term administration of

an

renoprotective and cardioprotective agents that block the RAAS remains unanswered [160].

ANCA associated vasculitis

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The field of ANCA-associated vasculitis therapy is at this time undergoing probably the

d

most significant change since the effectiveness of CYC was revealed in the early 1970’s. In the

te

last 10 years several small observational studies have reported the efficacy of the chimeric monoclonal anti-CD20 antibody rituximab against granulomatosis with polyangiitis, microscopic

Ac ce p

polyangiitis and Churg–Strauss syndrome. In 2010, two randomized clinical trials, Rituximab in ANCA-associated vasculitis (RAVE) [161] and Rituximab versus cyclophosphamide in ANCAassociated vasculitis (RITUXVAS) [162] were published, providing the first controlled evidence for rituximab as an effective and safe as conventional immunosuppressive therapy for polyangiitis. Recently, new evidence related to maintenance phase in ANCA associated vasculitis was provided. Patients with newly diagnosed or relapsing ANCA-associated vasculitis in complete remission after a cyclophosphamide–glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry (57 patients) or daily azathioprine (58 patients) until month 22. The primary end 30

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point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both). At month 28, more patients had

ip t

sustained remission with rituximab than with azathioprine (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; p = 0.002). Most importantly, the frequencies of severe

us

cr

adverse events were similar in the two groups [163].

Cardiovascular disease in CKD – two inseparable conditions

an

Morbidity and mortality rates in CKD patients are tremendously elevated, approaching 1520% annually [164]. Almost 40% of this mortality is attributable to CV disease; thus the

M

prevention of CVD is crucial in this population. Recent data suggest that a coronary artery

d

calcium score was able to predict the risk for CV events in CKD patients [165]. Among 6553

te

participants (1284 people with and 5269 without CKD), and no prior CV disease from the MultiEthnic Study of Atherosclerosis cohort, the investigators compared the performance of the

Ac ce p

calcium score with two others measures of subclinical atherosclerosis - carotid intima-media thickness and ankle-brachial index, as predictors for CV disease (including coronary heart disease, stroke, heart failure, and peripheral artery disease). In Cox proportional hazards models adjusted for Framingham predictors, each subclinical measure was independently associated with CV outcomes, but with larger adjusted hazard ratios for the coronary artery calcium score. When each CVD subtype was analyzed separately, CAC was superior to IMT and ABI for CHD and HF prediction, regardless of CKD status [165].

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Hypertension and kidney diseases – the never-ending story As it has been mentioned above, in patients with renal artery stenosis stenting offers no advantages over best medical therapy in reducing hard clinical events. The CORAL trial

ip t

included 947 patients with renal-artery atherosclerosis (stenosis >60%) who had either systolic hypertension and were taking two or more blood pressure-lowering drugs or chronic kidney

cr

disease. They were randomized equally to medical therapy alone or medical therapy plus renal-

us

artery stenting. At a median follow-up of 43 months, the rate of the primary composite end point (death from CV or renal causes, MI, stroke, hospitalization for congestive heart failure,

an

progressive renal insufficiency, or need for kidney replacement) was no different between groups (35% of patients in each group). Similarly, there were also no differences in rates of individual

M

components of the end point or in rates of all-cause mortality. A very modest difference in SBP

d

was seen between groups (–2.3 mmHg in the stenting group), but this clearly did not translate

te

into clinically meaningful differences. Even more, 11 patients suffered an arterial dissection in the stenting group [134]. Shelley Wood, in a nice Medscape commentary pointed out that “The

Ac ce p

study results are in line with other randomized trials that have looked at blood-pressure effects or kidney function and should markedly curtail the number of procedures being performed” [166]. In ADPKD hypertension occurs early and is associated with larger total kidney volume as well as activation of the renin–angiotensin–aldosterone system and the progression of kidney disease progression to ESRD and CV death [167]. It has been suggested that management with multiple agents that block the RAAS (dual therapy) might improve outcomes by circumventing compensatory feedback processes that generate more angiotensin II when a single blocker is used [168]. The HALT-PKD trials included young (15 to 49 years of age), hypertensive patients with ADPKD and preserved kidney function. They were randomly assigned to receive lisinopril 32

Page 32 of 51

plus telmisartan versus lisinopril alone and were randomly assigned to standard blood-pressure control (120/70 to 130/80 mm Hg) or rigorous blood-pressure control (95/60 to 110/75 mm Hg). However, dual therapy did not show an advantage, as compared with lisinopril alone, with regard

ip t

to the change in total kidney volume or estimated GFR [169]. Moreover, low BP target attenuated the annual rate of increase in total kidney volume by 14.2%, was associated with

cr

reduced urinary albumin excretion and a superior decline in left ventricular mass index. A

us

similar study was performed in older patients (18 to 64 years of age) with moderate-advanced CKD (eGFR 25-60 ml/min). The authors compared the effects of dual versus single blockade but

an

did not compared standard versus rigorous BP control [170]. The dual blockade did not showed an advantage in primary composite outcome (time to death, ESRD or halving of the baseline

M

estimated GFR) compared with single RAAS blockade alone.

d

Lowering BP too much may be harmful, in CKD patients. In a recent published study

te

including nearly 77,800 U.S. veterans with CKD who had uncontrolled hypertension at baseline, the death rate for patients with SBPs below 120 mmHg was 80.9 per 1,000 patient years, versus

Ac ce p

41.8 per 1,000 for the 120 to 139 mm Hg group [171]. All-cause mortality was 70% higher for CKD patients with SBP below 120 mm Hg compared with those with SBPs between 120 and 139 mm Hg.

Unidentified, clinically unapparent volume expansion is an important cause for hypertension. In CKD stage 3-4 patients, a low sodium diet (100 mmol/day) was associated with substantial reduction (9.7/3.9 mm Hg) in BP, in antihypertensive medication and in extracellular volume by 0.8 l [172], while diuretics significantly reduce BP via volume contraction, in CKD subjects with poorly controlled hypertension [173]. The administration of 25 mg chlorthalidone decreased BP similarly in both groups (low kidney function and control: systolic pressure, −20 33

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and −23; 95% confidence interval, −22/−18 and −26/−19; diastolic pressure, −9 and −10, −11/−7, and −13/−8) with similar adverse events (15.0% and 16.7%). In both groups, posttreatment changes were a decrease for eGFR and serum potassium and an increase in serum uric

ip t

acid. The study had no placebo group, but the authors pointed out that "use of placebo in highrisk patients with uncontrolled hypertension was inadmissible [173]. These data are in contrast

cr

with previous suggestion of reduced efficiency of chlorthalidone with low kidney function but

us

require long-term trials detailing chlorthalidone properties in chronic kidney disease. Occult volume overload is a common problem in general and CKD population and is present

an

in more than 20% of the cases [174]. Clinical assessment of hydration status is an inaccurate clinical science. The use of natriuretic peptides as markers of hydration status is limited in

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patients with CKD or with severely compromised heart function [174]. Bioimpedance provides a

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noninvasive and reliable, simple, reproducible technology for diagnosing subclinical fluid

te

accumulation. Bioimpedance guided fluid management was associated with an improvement in BP control, intradialytic symptoms, left ventricular mass index or arterial stiffness. Onofriescu et

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al. [175] showed in a randomized controlled parallel group trial including 136 HD patients follow-up for 2.5 years that strict volume control guide by bioimpedance is associated with better survival rate (p = 0.03). After 2.5 years, there was a greater decline in arterial stiffness (PWV −2.78 m/s; (95% CI, −3.75 to 1.80) m/s; p<0.001); and systolic BP (−2.43 mm Hg; (95% CI, −7.70 to 2.84) p=0.4) in the bioimpedance group than the clinical-methods group. Lung ultrasound is a novel, validated technique that has been increasingly applied to estimate water content of the lung interstitium (that is strictly dependent on the filling pressure of the left ventricle) in patients with heart disease, with acute respiratory failure or in dialysis patients. Patients with increased pulmonary congestion had a higher risk of cardiac events and death 34

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compared with those having mild or no pulmonary congestion [176]. In a prospective observational study, Siriopol et al. enrolled 96 patients from a single HD unit undergoing thrice weekly HD [177]. They used three different methods of evaluation: lung ultrasonography (pre-

ip t

and post-dialysis), bioimpedance spectroscopy (pre- and post-dialysis) and echocardiography (pre-dialysis). The lung comet score emerged as the best predictor for mortality, independently

cr

of bioimpedance-derived parameters in this population. Notwithstanding, the multivariate

us

survival analysis in this cohort was internally confirmed by a bootstrapping technique and the number of events in this study was quite small (n = 13); therefore, further observations in larger

an

cohorts and longer follow-up in this Romanian cohort are necessary to definitively confirm the

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independent relationship of lung water with mortality in ESKD [178].

d

Mineral metabolism in CKD

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Two different oral phosphate binders have been recently studied. Velphoro (PA21 sucroferric oxyhydroxide) is a chewable, calcium-free, iron-based phosphate binder that

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was approved by the U.S. Food and Drug Administration to treat hyperphosphatemia in patients on dialysis in November 2013. In a recent open-label, randomized, active-controlled phase III study, PA 21 in a dose of 3-4 tablets per day (one tablet per meal), was as effective in lowering and maintaining serum phosphorus in dialysis patients as sevelamer carbonate with 8-9 tablets per day (-0.71 mmol/l (PA21) and -0.79 mmol/l (sevelamer). Patients treated with Velphoro had a comparable tolerability (the percentage of patients that reported at least one treatment-emergent adverse event was 83.2% with PA21 and 76.1% with sevelamer) [179]. Similarly, a new oral phosphate binder that replenished iron stores in patients with CKD stage 3-5 and anemia was recently reported. A ferrum citrate based complex for 12 weeks caused a significantly increase in 35

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transferrin saturation (from 22% to 32%) and a decrease in serum phosphate (from 4.5 to 3.9 mg/dL) [180]. Additionally, hemoglobin increased by 0.5 g/l (p<.001), urinary phosphate decreased by 39% (p < .001), and intact FGF23 deceased by 119 RU/ml (p < .017).

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Uncontrolled secondary hyperparathyroidism (sHPT) in patients with ESRD is a risk factor for calciphylaxis. A post-hoc analysis of data from 3,861 hemodialysis patients included in the

cr

EVOLVE Trial, reported that 24 experienced calciphylaxis: 6 in the cinacalcet arm and 18 in the

us

placebo arm - a difference that translated into a significant 75% decreased risk of calciphylaxis [181]. By multivariable analysis, other factors associated with CUA included female sex (male

an

patients had a 67% decreased risk), higher body mass index, higher diastolic BP (each 10 mm increment was associated with a significant 50% increased risk), and history of dyslipidemia or

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Survival in CKD

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M

parathyroidectomy (a significant 5.8 times increased risk).

The survival rate in CKD patients is substantially lower in contrast to the general population

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[182]; new data suggests that physical activity is associated with improved quality of life, lesser rates of depression and mortality in these patients. Walking appears associated with improvements in cardio respiratory and physical fitness, BP control, in malnutritioninflammation complex syndrome, and overall improved quality of life in patients with CKD. Recently, walking was also associated with lower risk of overall mortality and inferior risk of renal replacement therapy. In a 6363 patients with CKD stage 3-5, walking, independent of patients’ age, renal function, and co-morbidities, was connected to lower overall mortality (adjusted sub distribution hazard ratio (SHR) of walking was 0.67 (95% confidence interval [95% CI], 0.53 to 0.84; p<0.001)) and lower RRT risk (0.79 (95% CI, 0.73 to 0.85; p<0.001)) in 36

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the multivariate competing-risks regression [183]. The same favorable effects of physical activity were reported in hemodialysis patients. In a study including 5763 patients from the DOPPS cohort, aerobic exercise was correlated with lower mortality rates (infrequently active had an

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11% reduction in mortality (hazard ratio [HR], 0.89; 95% CI, 0.72 - 1.10), sometimes-active patients had a 16% reduction (HR, 0.84; 95% CI, 0.67 - 1.05), often-active patients had a 19%

cr

reduction (HR, 0.81; 95% CI, 0.68 - 0.96), and very active patients had a 40% reduction (HR,

us

0.60; 95% CI, 0.47 – 0.77; p for trend < .001) [184]. Additionally, higher levels of aerobic activity were also associated with better scores on quality-of-life outcomes and with lower scores

an

for symptoms of depression. It is accepted that depression is a significant risk factor for mortality particularly in the early dialysis time period. Furthermore, in patients with diabetes and major

M

depression the risk of developing ESRD is elevated. In a recent study including 3886

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participants, during a median follow-up of 8.8 years, patients with major depression had a higher

symptoms [185].

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risk for ESRD (HR 1.85; 95% CI 1.02 – 3.33) compared with patients with minor depressive

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Beta-blockers improve survival in the general population [186,187]; by extension, they are also used, with the same recommendation in dialysis patients. There are two distinct types of beta-blockers: with high dialyzability (removed from the circulation by hemodialysis, like acebutolol, atenolol, and metoprolol and with low dialyzability (bisoprolol and propranolol). Weir et al. in a retrospective cohort study showed a significantly higher risk for death in patients receiving high dialyzability beta blockers (relative risk, 1.4; 95% CI, 1.1 - 1.8; p = 0.006). The authors did not found the same association among patients not receiving dialysis (RR, 1.0; 95% CI, 0.9 to 1.3; p=0.71) [188]. The mechanism of death did not appear to be related to an excess risk of myocardial infarction or heart failure among the high-dialyzability β-blocker group; 37

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however, the authors point out that bisoprolol has a high degree of beta-1 selectivity, which might play a role in its superior safety profile in the dialysis population. The current study did not evaluate carvedilol. Although carvedilol is an important beta blocker for patients receiving

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hemodialysis, it was not included in the study because access to the medication is restricted in

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the study jurisdiction.

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48 Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara‐Dinet MT, Gipe D. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of odyssey alternative, a randomized phase 3 trial. Journal of Clinical Lipidology 2014 49 Jennifer G. Robinson MF, Michel Krempf, Jean Bergeron, Gérald Luc, Maurizio Averna, Erik Stroes, Gisle Langslet, Frederick J. Raal, Mahfouz El Shahawy, Michael J. Koren, Norman Lepor, Christelle Lorenzato, Robert Pordy, Umesh Chaudhari, John J.P. Kastelein. Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: First results from the odyssey long term study in 2,341 patients. ESC Hot Line Session Barcelona 2014 50 CP C. Improve-it trial: A comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. American Heart Association 2014 Scientific Sessions; November 17; Chicago, IL 2014 51 Koschinsky M, Boffa M. Lipoprotein (a) as a therapeutic target in cardiovascular disease. Expert opinion on therapeutic targets 2014:1-11. 52 Kronenberg F. Genetic determination of lipoprotein(a) and its association with cardiovascular disease: Convenient does not always mean better. Journal of internal medicine 2014;276:243-247. 53 Hung M-Y, Tsimikas S. What is the ultimate test that lowering lipoprotein (a) is beneficial for cardiovascular disease and aortic stenosis? Current opinion in lipidology 2014;25:423-430. 54 Alonso R, Andres E, Mata N, Fuentes-Jiménez F, Badimón L, López-Miranda J, Padró T, Muñiz O, Díaz-Díaz JL, Mauri M. Lipoprotein (a) levels in familial hypercholesterolemia: An important predictor of cardiovascular disease independent of the type of ldl receptor mutation. Journal of the American College of Cardiology 2014;63:1982-1989. 55 Langsted A, Kamstrup PR, Nordestgaard BG. Lipoprotein(a): Fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 2014;234:95-101. 56 Kyriakou T, Seedorf U, Goel A, Hopewell JC, Clarke R, Watkins H, Farrall M. A common lpa null allele associates with lower lipoprotein (a) levels and coronary artery disease risk. Arteriosclerosis, thrombosis, and vascular biology 2014;34:2095-2099. 57 Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353-361. 58 Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM. Reduction in lipoprotein (a) with PCSK9 monoclonal antibody evolocumab (amg 145): A pooled analysis of more than 1,300 patients in 4 phase ii trials. Journal of the American College of Cardiology 2014;63:1278-1288. 59 Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand A-C, Ginsberg HN, Stein EA. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein (a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). The American journal of cardiology 2014;114:711-715. 60 Nikolic D, Mikhailidis DP, Davidson MH, Rizzo M, Banach M. Etc-1002: A future option for lipid disorders? Atherosclerosis 2014;237:705-710. 61 Rached FH, Chapman MJ, Kontush A. An overview of the new frontiers in the treatment of atherogenic dyslipidemias. Clinical Pharmacology & Therapeutics 2014;96:57-63. 62 Derosa G, Limas C, Macías P, Estrella A, Maffioli P. Dietary and nutraceutical approach to type 2 diabetes. Archives of medical science: AMS 2014;10:336-344. 63 Khawaja OA, Gaziano JM, Djoussé L. N-3 fatty acids for prevention of cardiovascular disease. Current atherosclerosis reports 2014;16:1-7. 64 Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN, Kling D, Davidson MH. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: The epanova for lowering very high triglycerides (evolve) trial. Journal of clinical lipidology 2014;8:94-106. 65 Jacobson TA. Perspectives on a new prescription omega-3 fatty acid, icosapent ethyl, for hypertriglyceridemia. Clinical Lipidology 2014:1-13.

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66 Maki KC, Orloff DG, Nicholls SJ, Dunbar RL, Roth EM, Curcio D, Johnson J, Kling D, Davidson MH. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the esprit trial). Clinical therapeutics 2013;35:1400-1411. e1403. 67 Hiatt WR, Smith RJ. Assessing the clinical benefits of lipid-disorder drugs. New England Journal of Medicine 2014;370:396-399. 68 Katsiki N, Nikolic D, Montalto G, Banach M, Mikhailidis DP, Rizzo M. The role of fibrate treatment in dyslipidemia: An overview. Curr Pharm Design 2013;19:3124-3131. 69 Stone N, ROBINSON J, Lichtenstein A. 2013 acc/aha guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the american college of cardiology/american heart association task force on practice guidelines. J am coll cardiol 2013 nov 12 [epub ahead of print]. Correction. Journal of the American College of Cardiology 2014;63:3024-3025. 70 Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: Summary of updated nice guidance. Bmj 2014;349:g4356. 71 Rizzo M, Barylski M, Rizvi AA, Montalto G, P Mikhailidis D, Banach M. Combined dyslipidemia: Should the focus be ldl cholesterol or atherogenic dyslipidemia? Curr Pharm Design 2013;19:3858-3868. 72 Filippatos TD, Rizos EC, Gazi IF, Lagos K, Agouridis D, Mikhailidis DP, Elisaf MS. Differences in metabolic parameters and cardiovascular risk between american diabetes association and world health organization definition of impaired fasting glucose in european caucasian subjects: A cross-sectional study. Archives of medical science: AMS 2013;9:788-795. 73 Filippatos TD, Rizos EC, Gazi IF, Lagos K, Agouridis D, Mikhailidis DP, Elisaf MS. Differences in metabolic parameters and cardiovascular risk between american diabetes association and world health organization definition of impaired fasting glucose in european caucasian subjects: A cross-sectional study. Archives of medical science: AMS 2013;9:788-795. 74 Barylski M, Toth PP, Nikolic D, Banach M, Rizzo M, Montalto G. Emerging therapies for raising high-density lipoprotein cholesterol (hdl-c) and augmenting HDL particle functionality. Best Practice & Research Clinical Endocrinology & Metabolism 2014;28:453-461. 75 Canfrán-Duque A, Ramírez CM, Goedeke L, Lin C-S, Fernández-Hernando C. Micrornas and hdl life cycle. Cardiovascular Research 2014:cvu140. 76 Mao Y, Mohan R, Zhang S, Tang X. Micrornas as pharmacological targets in diabetes. Pharmacological Research 2013;75:37-47. 77 Dávalos A, Fernández-Hernando C. From evolution to revolution: Mirnas as pharmacological targets for modulating cholesterol efflux and reverse cholesterol transport. Pharmacological Research 2013;75:60-72. 78 Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. Micrornas are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nature cell biology 2011;13:423-433. 79 Horie T, Baba O, Kuwabara Y, Chujo Y, Watanabe S, Kinoshita M, Horiguchi M, Nakamura T, Chonabayashi K, Hishizawa M. Microrna-33 deficiency reduces the progression of atherosclerotic plaque in apoe−/− mice. Journal of the American Heart Association 2012;1:e003376. 80 Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y. Antagonism of mir-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. The Journal of clinical investigation 2011;121:2921-2931. 81 Dodani S, Dong L, Guirgis F, Reddy S. Carotid intima media thickness and low high-density lipoprotein (HDL) in south asian immigrants: Could dysfunctional HDL be the missing link? Archives of medical science: AMS 2014;10:870-879.

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139 Bakris GL, Townsend RR, Liu M, Cohen SA, D’Agostino R, Flack JM, Kandzari DE, Katzen BT, Leon MB, Mauri L. Impact of renal denervation on 24-hour ambulatory blood pressure: Results from symplicity htn-3. Journal of the American College of Cardiology 2014 140 Tzafriri AR, Mahfoud F, Keating JH, Markham PM, Spognardi A, Wong G, Fuimaono K, Böhm M, Edelman ER. Innervation patterns may limit response to endovascular renal denervation. Journal of the American College of Cardiology 2014;64:1079-1087. 141 DeMaria AN. Reflections on renal denervation. Journal of the American College of Cardiology 2014;63:1452-1453. 142 Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu C-y. Temporal changes in incidence of dialysisrequiring aki. Journal of the American Society of Nephrology 2013;24:37-42. 143 Wu VC, Wu PC, Wu CH, Huang TM, Chang CH, Tsai PR, Ko WJ, Chen L, Wang CY, Chu TS, Wu KD, Group TNTUSGoARF. The impact of acute kidney injury on the long‐term risk of stroke. Journal of the American Heart Association 2014;3 144 Koulouridis I, Price LL, Madias NE, Jaber BL. Hospital-acquired acute kidney injury and hospital readmission: A cohort study. American Journal of Kidney Diseases 2014 145 Adluri RKP, Singh AV, Skoyles J, Robins A, Hitch A, Baker M, Mitchell IM. The effect of fenoldopam and dopexamine on hepatic blood flow and hepatic function following coronary artery bypass grafting with hypothermic cardiopulmonary bypass. European Journal of Cardio-Thoracic Surgery 2009;35:988-994. 146 Landoni M. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery a randomized clinical trial. 2014 147 Gerrah R, Ehrlich S, Tshori S, Sahar G. Beneficial effect of aspirin on renal function in patients with renal insufficiency postcardiac surgery. The Journal of cardiovascular surgery 2004;45:545-550. 148 Wu C-T, Jao S-W, Borel CO, Yeh C-C, Li C-Y, Lu C-H, Wong C-S. The effect of epidural clonidine on perioperative cytokine response, postoperative pain, and bowel function in patients undergoing colorectal surgery. Anesthesia & Analgesia 2004;99:502-509. 149 Garg AX, Kurz A, Sessler DI, Cuerden M, Robinson A, Mrkobrada M, Parikh CR, Mizera R, Jones PM, Tiboni M. Perioperative aspirin and clonidine and risk of acute kidney injury: A randomized clinical trial. JAMA 2014 150 Shema-Didi L, Ore L, Geron R, Kristal B. Is anemia at hospital admission associated with inhospital acute kidney injury occurrence? Nephron Clinical Practice 2010;115:c168-c176. 151 Montecucco F, Burger F, Pelli G, Poku NK, Berlier C, Steffens S, Mach F. Statins inhibit creactive protein-induced chemokine secretion, icam-1 upregulation and chemotaxis in adherent human monocytes. Rheumatology 2009;48:233-242. 152 Akasaki Y, Matsuda S, Nakayama K, Fukagawa S, Miura H, Iwamoto Y. Mevastatin reduces cartilage degradation in rabbit experimental osteoarthritis through inhibition of synovial inflammation. Osteoarthritis and Cartilage 2009;17:235-243. 153 Coresh J, Turin T, Matsushita K, Sang Y, Ballew S, Appel L, Arima H, Chadban S, Cirillo M, Djurdjev O. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA: the journal of the American Medical Association 2014 154 Nesrallah GE, Mustafa RA, Clark WF, Bass A, Barnieh L, Hemmelgarn BR, Klarenbach S, Quinn RR, Hiremath S, Ravani P. Canadian society of nephrology 2014 clinical practice guideline for timing the initiation of chronic dialysis. Canadian Medical Association Journal 2014;186:112-117. 155 Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nature Reviews Nephrology 2013;9:459-469. 156 Impellizzeri D, Esposito E, Attley J, Cuzzocrea S. Targeting inflammation: New therapeutic approaches in chronic kidney disease (ckd). Pharmacological Research 2014;81:91-102.

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157 Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa Y, Fujita T, Group ES. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: A doubleblind, randomised, placebo-controlled trial. The Lancet Diabetes & Endocrinology 2014 158 Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-Schmidt H, Berman L, Pitt B. Patiromer in patients with kidney disease and hyperkalemia receiving raas inhibitors. New England Journal of Medicine 2014 159 Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B. Sodium zirconium cyclosilicate in hyperkalemia. New England Journal of Medicine 2014 160 Ingelfinger JR. A new era for the treatment of hyperkalemia? New England Journal of Medicine 2014 161 Falk RJ, Jennette JC. Rituximab in anca-associated disease. The New England journal of medicine 2010;363:285. 162 Jones RB, Cohen Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P. Rituximab versus cyclophosphamide in anca-associated renal vasculitis. New England Journal of Medicine 2010;363:211-220. 163 Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P. Rituximab versus azathioprine for maintenance in anca-associated vasculitis. New England Journal of Medicine 2014;371:1771-1780. 164 Floer M, Binion DG, Nelson VM, Manley S, Wellner M, Sadeghi S, Behmaram B, Sewell C, Otterson MF, Kucharzik T, Rafiee P. Role of muts homolog 2 (msh2) in intestinal myofibroblast proliferation during crohn's disease stricture formation. American Journal of Physiology-Gastrointestinal and Liver Physiology 2008;295:G581-G590. 165 Matsushita K, Sang Y, Ballew SH, Shlipak M, Katz R, Rosas SE, Peralta CA, Woodward M, Kramer HJ, Jacobs DR. Subclinical atherosclerosis measures for cardiovascular prediction in ckd. Journal of the American Society of Nephrology 2014:ASN. 2014020173. 166 Funk JL, Chen J, Downey KJ, Clark RA. Bone protective effect of simvastatin in experimental arthritis. Journal of Rheumatology 2008;35:1083-1091. 167 Chapman AB, Stepniakowski K, Rahbari-Oskoui F. Hypertension in autosomal dominant polycystic kidney disease. Advances in chronic kidney disease 2010;17:153-163. 168 Schrier R, McFann K, Johnson A, Chapman A, Edelstein C, Brosnahan G, Ecder T, Tison L. Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: Results of a seven-year prospective randomized study. Journal of the American Society of Nephrology 2002;13:1733-1739. 169 Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Bae KT, Moore CG, Chapman AB. Blood pressure in early autosomal dominant polycystic kidney disease. New England Journal of Medicine;0:null. 170 Torres VE, Abebe KZ, Chapman AB, Schrier RW, Braun WE, Steinman TI, Winklhofer FT, Brosnahan G, Czarnecki PG, Hogan MC, Miskulin DC, Rahbari-Oskoui FF, Grantham JJ, Harris PC, Flessner MF, Moore CG, Perrone RD. Angiotensin blockade in late autosomal dominant polycystic kidney disease. New England Journal of Medicine;0:null. 171 Kovesdy CP, Lu JL, Molnar MZ, et al. Observational modeling of strict vs conventional blood pressure control in patients with chronic kidney disease. JAMA Internal Medicine 2014;174:1442-1449. 172 McMahon EJ, Bauer JD, Hawley CM, Isbel NM, Stowasser M, Johnson DW, Campbell KL. A randomized trial of dietary sodium restriction in ckd. Journal of the American Society of Nephrology 2013;24:2096-2103. 173 Cirillo M, Marcarelli F, Mele AA, Romano M, Lombardi C, Bilancio G. Parallel-group 8-week study on chlorthalidone effects in hypertensives with low kidney function. Hypertension 2014;63:692697.

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174 Hung S-C, Kuo K-L, Peng C-H, Wu C-H, Lien Y-C, Wang Y-C, Tarng D-C. Volume overload correlates with cardiovascular risk factors in patients with chronic kidney disease. Kidney international 2013 175 Onofriescu M, Hogas S, Voroneanu L, Apetrii M, Nistor I, Kanbay M, Covic AC. Bioimpedanceguided fluid management in maintenance hemodialysis: A pilot randomized controlled trial. American Journal of Kidney Diseases 2014 176 Zoccali C, Torino C, Tripepi R, Tripepi G, D’Arrigo G, Postorino M, Gargani L, Sicari R, Picano E, Mallamaci F. Pulmonary congestion predicts cardiac events and mortality in esrd. Journal of the American Society of Nephrology 2013:ASN. 2012100990. 177 Siriopol D, Hogas S, Voroneanu L, Onofriescu M, Apetrii M, Oleniuc M, Moscalu M, Sascau R, Covic A. Predicting mortality in haemodialysis patients: A comparison between lung ultrasonography, bioimpedance data and echocardiography parameters. Nephrology Dialysis Transplantation 2013;28:2851-2859. 178 Zoccali C, Puntorieri E, Mallamaci F. Lung congestion as a hidden threat in end-stage kidney disease: A call to action. Nephrology Dialysis Transplantation 2013;28:2657-2660. 179 Floege J, Covic AC, Ketteler M, Rastogi A, Chong EM, Gaillard S, Lisk LJ, Sprague SM. A phase iii study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients. Kidney international 2014 180 Block GA, Fishbane S, Rodriguez M, Smits G, Shemesh S, Pergola PE, Wolf M, Chertow GM. A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with ckd stages 3-5. American Journal of Kidney Diseases 2014 181 Marai I, Shoenfeld Y. The beneficial effects of statins in autoimmune disease therapy. Drug News & Perspectives 2007;20:165-169. 182 Xu H, Liu P, Liang L, Danesh FR, Yang X. Rhoa-mediated, tumor necrosis factor alpha-induced activation of nf-kappa b in rheumatoid synoviocytes - inhibitory effect of simvastatin. Arthritis and rheumatism 2006;54:3441-3451. 183 Chen I-R, Wang S-M, Liang C-C, Kuo H-L, Chang C-T, Liu J-H, Lin H-H, Wang I-K, Yang Y-F, Chou C-Y. Association of walking with survival and rrt among patients with ckd stages 3–5. Clinical Journal of the American Society of Nephrology 2014:CJN. 09810913. 184 Lacson E, Bruce L, Li N-C, Mooney A, Maddux FW. Depressive affect and hospitalization risk in incident hemodialysis patients. Clinical Journal of the American Society of Nephrology 2014:CJN. 01340214. 185 Margaret KY, Weiss NS, Ding X, Katon WJ, Zhou X-H, Young BA. Associations between depressive symptoms and incident esrd in a diabetic cohort. Clinical Journal of the American Society of Nephrology 2014:CJN. 08670813. 186 Franczyk-Skóra B, Gluba A, Banach M, Rysz J. Treatment of non-st-elevation myocardial infarction and st-elevation myocardial infarction in patients with chronic kidney disease. Archives of Medical Science: AMS 2013;9:1019-1027. 187 Bielecka-Dabrowa A, S Aronow W, Rysz J, Banach M. Current place of beta-blockers in the treatment of hypertension. Current vascular pharmacology 2010;8:733-741. 188 Weir MA, Dixon SN, Fleet JL, Roberts MA, Hackam DG, Oliver MJ, Suri RS, Quinn RR, Ozair S, Beyea MM. Β-blocker dialyzability and mortality in older patients receiving hemodialysis. Journal of the American Society of Nephrology 2014:ASN. 2014040324.

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*Graphical Abstract (for review)

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Lipid, blood pressure and kidney update 2014

Statin intolerance – a myth or reality?

ASH/ISH 2014 guidelines – any additional information to JNC8?

ce pt

– looking for new (old) agents…

ed

Optimal lipid lowering therapy

What is new in JNC8 recommendations?

Lipoprotein a – an undervalued risk factor?

Ac

LDL-C lowering with ETC-1002 – what we really know? Hypertriglyceridemia – the debate continues

HDL-C – is it still a therapy target?

Acute kidney injury (AKI) – a large challenge for nephrologists New definition of chronic kidney disease

Renal denervation – what was new in 2014?

CKD progression and dialysis initiation – the questions still exist…

HTN and kidney diseases – the never-ending story

ANCA associated vasculitis

Mineral metabolism in CKD

Cardiovascular disease in CKD – two inseparable conditionsPage 51 of 51

Survival in CKD