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Uremic Toxicity of Advanced Glycation End Products in CKD

† ‡ ‡ Andréa E.M. Stinghen,* Ziad A. Massy,* Helen Vlassara, § Gary E. Striker, § and | Agnès Boullier*

*Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France; †Division of Nephrology, Ambroise Paré University Medical Center, Assistance Publique-Hôpitaux de Paris (APHP), University of Paris Ouest, University Versailles-Saint Quentin, Boulogne Billancourt/Paris, France; ‡Division of Experimental Diabetes and Aging, Departments of Geriatrics and Palliative Care and Medicine and §Division of Experimental Diabetes and Aging, Department of Geriatrics and Aging and Division of Nephrology, Department of Medicine, Icahn School of Medicine, New York, New York; and |Biochemistry Laboratory, Amiens University Medical Center, Amiens, France

ABSTRACT Advanced glycation end products (AGEs), a heterogeneous group of compounds include the 1,2-dicarbonyl compounds formed by nonenzymatic glycation reactions between reducing sugars and amino glyoxal and methylglyoxal (MG), a highly acids, lipids, or DNA, are formed not only in the presence of hyperglycemia, but also in reactive dicarbonyl compound.7 At least diseases associated with high levels of oxidative stress, such as CKD. In chronic renal 20 different types of AGE have been de- failure, higher circulating AGE levels result from increased formation and decreased scribed: N-carboxymethyllysine (CML), renal clearance. Interactions between AGEs and their receptors, including advanced pentosidine, and hydroimidazolone are glycation end product–specific receptor (RAGE), trigger various intracellular events, among the best characterized, are rela- such as oxidative stress and inflammation, leading to cardiovascular complications. tively nonreactive, and serve as markers Although patients with CKD have a higher burden of cardiovascular disease, the re- ofAGEaccumulationinseveraltis- lationship between AGEs and cardiovascular disease in patients with CKD is not fully sues.8,9 AGEs can be degraded by en- characterized. In this paper, we review the various deleterious effects of AGEs in CKD zymes, such as glyoxalase I (Glo-1) and that lead to cardiovascular complications and the role of these AGEs in diabetic ne- II (Glo-2).10 Glo-1 detoxifies reactive phropathy. We also discuss potential pharmacologic approaches to circumvent these a-oxoaldehyde, removing deleterious deleterious effects by reducing exogenous and endogenous sources of AGEs, increas- species, such as MG.11 AGEs can also be ing the breakdown of existing AGEs, or inhibiting AGE-induced inflammation. Finally, modified by innate defense machineries, we speculate on preventive and therapeutic strategies that focus on the AGE-RAGE such as lysozyme, which sequesters AGEs axis to prevent vascular complications in patients with CKD. and accelerates their renal excretion in vivo,12 and receptor-dependent uptake J Am Soc Nephrol 27: 354–370, 2016. doi: 10.1681/ASN.2014101047 and degradation.13

Receptors for AGEs Advanced glycation end products (AGEs) formation of an unstable, freely reversible Advanced glycation end products receptor 1 constitute a heterogeneous group of com- Schiff base. This base can be rearranged to (AGER1) binds AGEs14 and leads to their pounds derived from the nonenzymatic form a more stable intermediate called an sequestration and detoxification, thus glycationofproteins,lipids,andnuclear Amadori product, which in the presence acids through a complex sequence of ofatransitionmetal,isoxidizedtoyieldthe reactionsreferredtoastheMaillard final AGE (Figure 1) (reviewed in ref. 3). Published online ahead of print. Publication date reaction.1,2 AGEs can also be formed by autoxida- available at www.jasn.org. tion of glucose and oxidative stress. Hu- Correspondence: Dr. Agnès Boullier, INSERM U-1088, Generation of AGEs mans are exposed to exogenous sources of Université de Picardie Jules Verne (UPJV), Centre Hos- pitalier Universitaire (CHU) Sud, Avenue Laënnec-Salouel, 4 5 Protein glycation is initiated by a nucle- AGE (diet and cigarette smoke )anden- F-80054 Amiens Cédex 1, France. Email: agnes. ophilic addition reaction between a free dogenous sources of AGE when the or- [email protected] aminogroupfromaproteinandacarbonyl ganism is exposed to high levels of glucose, Copyright © 2016 by the American Society of group from a reducing sugar, with the such as in diabetes.6 AGE precursors Nephrology

354 ISSN : 1046-6673/2702-354 J Am Soc Nephrol 27: 354–370, 2016 www.jasn.org BRIEF REVIEW

proinflammatory chemokines. Signaling through full-length RAGE is known to be essential for both physiologic and path- ologic processes.8,24–27 sRAGE acts as a decoy for RAGE ligands and modulates activation or signaling through RAGE.28

PATHOPHYSIOLOGIC EFFECTS OF AGES

Mechanisms Accumulation of AGEs in patients with CKD has been shown to result from inflammation, oxidative stress, and diet (Figure 2).29,30 AGEs are proinflamma- tory and pro-oxidative compounds that play a role in the high prevalence of en- dothelial dysfunction and subsequent cardiovascular disease (CVD) in patients with CKD.31

Figure 1. Main steps in AGE formation. Oxidative Stress The oxidative stress induced by reactive oxygen species (ROS) is associated with atherosclerosis and cardiovascular morbid- reducing AGE levels in the intracellular space, where it can sequester AGEs. ity in patients with CKD.32 AGEs increase and extracellular spaces, resulting in High sRAGE levels are associated with the levels of ROS33 through activation of antioxidant properties.15,16 Advanced an increased incidence of CKD before NADPH oxidase34 and mitochondrial glycation end product–specific receptor but not after adjustment for baseline kid- pathways in both a receptor-dependent (RAGE), another well characterized recep- ney function,21 suggesting that either cir- manner (i.e.,throughRAGE)35 and a tor for AGEs, is a multiligand transmem- culating sRAGE levels are directly affected receptor-independent manner. In patients brane cell surface receptor that belongs to by an impaired kidney filtration as as- with type 2 diabetes mellitus, circulating the Ig protein superfamily17,18 and binds sessed by GFR or inversely, circulating AGE levels are correlated with RAGE many ligands, including AGEs.19 In the sRAGE directly affects kidney function. mRNA expression and oxidative markers, absence of disease, RAGE is usually ex- Additional studies are needed to elucidate such as protein carbonyl formation, ad- pressed at very low levels in various cell the mechanisms of the association be- vanced oxidation protein product genera- types (smooth muscle cells, macrophages, tween sRAGE and kidney disease. tion, and lipid peroxidation.36 Reciprocally, and endothelial cells). In several dis- high levels of ROS lead to increased levels eases, such as diabetes and autoimmune/ Signaling through RAGE of AGEs,37 because another cause of AGE inflammatory diseases, RAGE expression RAGE was first identified as a signal formationinuremiaistheincreasedoxi- is elevated,20 whereas AGER1 levels are de- transduction receptor for AGEs linked to dative stress generated by an imbalance creased, resulting in suppression of the an- proteins or lipids.22 RAGE can also in- between oxidized glutathione and GSH tioxidant defense system and increased teract with advanced oxidation protein levels as well as changes in antioxidant levels of pro-oxidant mechanisms. The products, supporting the hypothesis systems, such as superoxide dismutase soluble truncated form of RAGE lacks that ligands generated by oxidative stress (SOD)/peroxidase.5 In fact, oxidative the full–length transmembrane domain may signal through RAGE.23 Full-length stress is closely linked to glycation, be- of the receptor. Soluble advanced glycation RAGE contains a single transmembrane cause GSH depletion also decreases the end product–specific receptor (sRAGE) region and a short intracellular domain. in situ activity of Glo-1, thereby increasing can be produced by alternative splicing Upon binding to RAGE, AGEs activate glyoxal and MG concentrations.10 Inter- (endogenous secretory advanced glycation several signaling pathways, including estingly, AGER1 is downregulated by ele- end product–specific receptor [esRAGE]) NF-kB, mitogen-activated protein kina- vated AGE levels.38 Furthermore, AGEs or proteolytic cleavage mediated by ses, and Jun N-terminal kinase, which in have been shown to increase the oxidation metalloproteinase (sRAGE). It is conse- turn, regulate the transcription of pro- of LDLs39—a key stage in the develop- quently released into the extracellular teins, such as adhesion molecules and ment of atherosclerosis.40 Glycated LDLs

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Figure 2. Pathophysiologic effects of AGEs. cGMP, cyclic guanosine monophosphate; ECM, extracellular matrix; eNOS, endothelial NO 2 2 synthase; EPC, endothelial progenitor cell; O2 °, superoxide anion; ONOO , peroxynitrite. are, therefore, more susceptible to oxida- translocates to the nucleus to induce the Inflammation tion,41 are less effectively cleared from the expression of genes encoding antioxidant AGEs have been shown to amplify inflam- circulation, and also, promote the forma- and detoxifying molecules by binding to matory responses in patients with CKD50,51 tion of antibodies that bind AGEs local- the antioxidant response element region through RAGE,52,53 because the RAGE- ized in the vessel wall, which amplifies the of their promoter. Moreover, it has been AGE interaction activates the redox– development of vascular inflammation shown that targeting Nrf2 ameliorates ox- sensitive transcription factor NF-kB, which and atherosclerosis.42 Overexpression of idative stress.45 Several studies have shown leads to gene expression and the release of Glo-1 in an animal model has been shown that some Nrf2 target antioxidant genes proinflammatory molecules, such as IL- to have beneficial vascular effects, decrease (SOD and glutathione peroxidase) are de- 1a,IL-6,andTNF-a.54,55 The in vitro use ROS,43 and protect against formation of creased in animal models of CKD46 and of human recombinant lysozyme sig- atherogenic LDL. patients with CKD,47 which may conse- nificantly reduced AGE–induced IL-6 Numerous studies have shown that quently aggravate oxidative stress and in- mRNA.56 It has recently been shown the nuclear factor erythroid 2–related flammation. MG induces oxidative stress that targeting Nrf2 ameliorates inflamma- factor (Nrf2) plays an important role in partly by negatively affecting Nrf2.48 In- tion by inhibiting the NF-kBpathway45 the antioxidant response. Under basal terestingly, one of the targets of the Nrf2/ and probably, increasing Glo-1, which 2 2 conditions, Nrf2 is associated in the cyto- Keap system is Glo-1. In Nrf2 / mice, detoxifies reactive oxoaldehydes, such plasm with the repressor kelch like ECH- Glo-1 mRNA is decreased, whereas MG asMG.RAGEexpressionbyactivated associated protein1 (Keap1), which urine excretion is increased.49 Transcrip- endothelium also promotes leukocyte promotes its ubiquitination for degrada- tional control of Glo-1 by Nrf2, therefore, recruitment.57–60 Moreover, AGEs de- tion.44 However, in response to oxidative provides protection against dicarbonyl lay spontaneous apoptosis of mono- stress, Nrf2 is released from Keap1 and glycation. cytes and consequently, contribute to the

356 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 354–370, 2016 www.jasn.org BRIEF REVIEW development of inflammatory responses.61 expression.63 AGE-RAGE–induced oxida- role in the vasculature and is involved in A recent prospective study of patients with tive stress is central to VCAM-1 induction, the development of atherosclerosis.100 Se- AKI and sepsis showed that the association because anti-RAGE antibodies, sRAGE, rum levels of ET-1 are markedly elevated of RAGE and inflammatory mediators and N-acetylcysteine inhibit VCAM-1 ex- in patients with chronic renal failure, contributes to endothelial dysfunction.62 pression.79 It has recently been shown that 101,102 and ET-1 is involved in both the Moreover, exposure of the endothelium chronic CML ingestion induced RAGE– development and progression of to uremic plasma results in a time- and dependent endothelial dysfunction in CKD.103 Odetti et al.101 observed a signif- CKD stage–dependent increase in expres- mice.80 Furthermore, Glo-1 overexpres- icant positive correlation between pento- sion of monocyte chemoattractant sion decreases endothelial dysfunction sidine and ET-1 plasma levels in subjects protein-1 and IL-8, suggesting the presence in a diabetic rat model.81 undergoing chronic hemodialysis (HD). of a link between systemic inflammation In patients with CKD, endothelial dys- Recently, it has been shown that ET-1 and uremic toxicity.63 In addition to its an- function results from increased endothelial transcription in cultured bovine aortic en- tioxidant properties, AGER1, by increasing injury and decreased endothelial repair82 dothelial cells is controlled by the AGE– the degradation of AGEs, is a negative reg- caused by a decreased endothelial progen- inducible, redox–sensitive transcription ulator of the inflammatory response in in- itor cell (EPC) count.83–89 Furthermore, factor NF-kB.104 AGEs, therefore, play flammatory and parenchymal cells, such as circulating EPC levels in patients with an important role in endothelial dysfunc- vascular smooth muscle and glomerular ESRD are negatively correlated with skin tion by (1) decreasing levels of two impor- mesangial cells.64 autofluorescence (a marker of tissue- tant endothelium–dependent relaxing bound AGEs) but not with serum pento- factors (NO and PGI2) and (2)increasing Cardiovascular Effects of AGEs sidine levels.89,90 Recent studies have endothelial production of the potent va- Patients with CKD have a higher CVD shown that AGEs impair EPC survival, dif- soconstrictor ET-1.104 burden than the general population, and ferentiation, migration, and function.91–93 Another important role of the endo- renal failure is associated with elevated One of the endothelium’smostim- thelium is its function as a selective levels of circulating AGEs.65,66 AGEs have portant functions is the synthesis and barrier between the blood and the sur- an important cardiovascular effect, because release of endothelium–derived relaxing rounding tissues. AGEs have been shown AGE accumulation leads to endothelial factors, such as nitric oxide (NO) and to be associated with increased perme- dysfunction, arterial stiffness, myocardial prostaglandin I2 (PGI2). Patients with ability of the endothelial layer.105,106 changes, immune system dysregulation, CKD display impaired endothelium– and atherosclerosis progression. Studies dependent vasodilation.94 AGEs have been Arterial Stiffness of the relationship between AGEs and shown to impair NO production partly Arterial stiffening occurs because of loss CVDinESRDhaveyieldedconflicting by downregulating NO synthase34,39,95 of compliance of the vessel wall107,108 and results.67–75 It is noteworthy that many dif- through increased mRNA degrada- is an important independent risk factor ferent AGEs have been identified with tion.96 In vitro studies show that sera for cardiovascular mortality in patients widely varying tissue localization and com- from patients with CKD suppress endo- with CKD. position, which could, therefore, explain thelial NO synthase activity in cultured CKD not only accelerates the develop- these conflicting results. However, recent vascular endothelial cells.97,98 This in- ment of atherosclerosis but also, leads to studies have shown a strong link between hibition of endothelial NO synthase ac- excessive vascular calcification resulting serum sRAGE levels and cardiovascular tivity is mediated by RAGE activation of fromtheinflammation andoxidative stress risk factors and disease.29,76 The main del- peripheral mononuclear cells in pa- present in patients with CKD.109–113 Vas- eterious effects of AGEs in the cardiovas- tients with CKD.31 AGEs also inhibit cular calcification is an independent pre- cular system are described below. NO by increasing NADPH oxidase ex- dictor of cardiovascular mortality,114,115 pression, establishing a link between and one of its consequences is altered aor- Endothelial Dysfunction RAGE and chronic endothelial dysfunc- tic compliance.116 AGE levels117 as well as Endothelial dysfunction, an early marker tion.34,39,95 PGI2 has also been shown to tissue AGEs118 are associated with vascular of atherosclerosis,77 is predictive of the be decreased by AGEs, such as glycated calcification in patients with CKD, sug- occurrence of cardiovascular events. In albumin in cultured microvascular endo- gesting that increased AGE may contribute CKD, endothelial dysfunction begins thelial cells.99 to vascular calcification. It has recently early in the course of the disease inde- Endothelial dysfunction is defined as been shown, in an animal model, that pendently of traditional cardiovascular an imbalance between vasodilating and AGE-induced calcification is mediated by risk factors.78 vasoconstricting substances produced RAGE and oxidative stress.119 Moreover, Plasma levels of endothelial cell acti- by or acting on the endothelium. The intra- lower sRAGE levels were recently associ- vation markers are elevated in advanced cellular signaling molecule endothelin-1 ated with carotid plaque calcification.76 CKD, and exposure of the endothelium (ET-1), best known as a potent endoge- Arterial stiffness has a major role not to uremic plasma increases soluble vascu- nous vasoconstrictor peptide produced only in the increase in systolic BP and lar cell adhesion molecule-1 (VCAM-1) by endothelial cells, has an important pulse pressure, but also in the decrease

J Am Soc Nephrol 27: 354–370, 2016 Uremic Toxicity of AGEs in CKD 357 BRIEF REVIEW www.jasn.org in diastolic BP. This BP alteration leads to AGEs reduces the severity of the early in patients with CKD.142 As mentioned left ventricular hypertrophy and abnormal manifestations of DN,56 suggesting that above, AGEs are generated during the pulse wave velocity (PWV), both of which AGEs play an important role in the path- thermal processing and storage of are apparent at the early stages of CKD.120 ogenesis of DN.134,135 Immunohisto- foods.4 A recent clinical study in patients Measurement of PWV, a noninvasive chemical studies in patients with DN with CKD showed that reducing dietary method for assessing arterial wall stiffness have shown that AGEs accumulate in the AGEs may lower oxidative stress and in- related to vascular calcification,121 is a mesangium and glomerular capillary flammation, restore AGER1 levels, and strong independent predictor of cardio- wall.136 Horie et al.137 showed that patients protect against innate immune dysfunc- vascular mortality in patients with with advanced DN exhibit enhanced CML tion.130 Dietary restriction is, therefore, ESRD.122,123 Several studies suggest that accumulation in the expanded mesangial an effective, feasible, and economic AGEs are involved in arterial stiffness.124 matrix and a thicker glomerular capillary method to reduce the levels of toxic For example, chronic CML ingestion in- wall in early nodular lesions and arterial AGEs and possibly, the associated car- duced RAGE–dependent arterial stiffness walls (relative to the healthy kidney). Sim- diovascular mortality.143 in mice.80 Zhou et al.125 showed a positive ilar results were found with the AGE correlation between arterial stiffness and imidazole.138 Inhibition of Gastrointestinal Absorption serum pentosidine levels. Moreover, skin Accumulation of AGEs may be caused Another option to reduce the intake autofluorescence (a marker of AGE accu- by both decreased clearance and increased of exogenous AGEs is to block or inhibit mulation) is associated with arterial PWV endogenous AGE formation or higher the gastrointestinal absorption of dietary (and therefore, arterial stiffness) in pa- dietary intake.139 In addition to glomeru- AGEs. Several compounds have been tients with ESRD.126 This may be caused laraccumulationofAGESinDN,the widely studied, including the spherical by the formation of irreversible cross- AGE-RAGE interaction can also trigger carbon adsorbent AST-120 and sevelamer links between the end products and premature cell senescence, a key process carbonate. long–lived structural proteins, such as col- in DN, in response to endoplasmic retic- Administration of the oral adsorbent lagen and elastin. ulum stress, partly through p21 signaling AST-120 before initiating dialysis has been activation.140 shown to not only improve the survival Immune System Dysregulation rate inpatientsonHD144,145 but also, delay The immune system plays an important the onset of HD in patients with CKD.146 role in the development and progression of THERAPEUTIC INTERVENTIONS AST-120 is also associated with a reduc- CVD. It has been shown that dysregulation tion in carotid intima media thickness and of the immune system contributes to In view of the many harmful effects of arterial stiffness in patients with CKD and atherosclerosis in patients on HD.127,128 AGEs on cell function, it is essential to without diabetes.147 However, recent ran- – Several studies have suggested that AGEs develop strategies designed to counteract domized placebo controlled Evaluating can amplify local immune reactions in the their effects. Several pharmacologic Prevention of Progression In CKD kidney.Otherstudiesinhumanshave treatment strategies targeting the AGE- (EPPIC) Trials of AST-120 in CKD did fi shownthatAGEformationandaccumu- RAGE system have been studied in vitro not support the bene t of adding AST- lation are partially responsible for the ob- and in vivo for their potential to prevent 120 to standard therapy.148 AST-120 has served immune system dysregulation. AGE formation or local AGE accumula- been shown to bind AGE and effectively Friedlander et al.129 showed a positive as- tion.141 These therapeutic compounds decrease plasma AGE levels.144 In a recent sociation between serum pentosidine and can be divided into several classes as a animal study, AST-120 was shown to re- – monocyte activation, which may contrib- function of their mechanism of action duce the indoxyl sulfate induced decrease ute to elevated complication rates. It has (Figure 3, Table 1): AGE absorption in- of Nrf2,149 which may, therefore, decrease also been shown that decreased AGE intake hibitors, AGE formation inhibitors, AGE formation of AGEs, such as MG, by in- protects against loss of innate immunity.130 cross–link breakers, RAGE antagonists, creasing Glo-1. and AGE binders, such as sRAGE. Al- Sevelamer carbonate is a nonabsorb- – Diabetic Nephropathy though many compounds are currently able, noncalcium based compound fre- Diabetic nephropathy (DN) is the leading being studied, only a few have entered quently used to lower blood phosphorus cause of ESRD and the most common clinical trials, and none have yet been levels in patients with advanced CKD or indication for RRT.131 The kidney has an approved for clinical use in patients ESRD. It has recently been shown that importantroleinthemetabolismof with CKD. sevelamer can act as a pleiotropic drug AGEs, because renal proximal tubule cells by sequestering cytotoxic AGEs in the absorb AGEs from the glomerular filtrate Decreasing Exogenous Sources of gut and thus, preventing their uptake. and catabolize them.132,133 GFR is nega- AGEs Moreover, sevelamer decreases CML tively correlated with not only serum AGE Decreased Dietary AGE Intake levels, oxidative stress, and inflammation levels but also, RAGE mRNA expression Dietary AGE content is an important and increases AGER1 expression.150–153 in PBMCs.31 Lysozyme that sequesters contributor to serum AGE accumulation The results of a randomized trial in

358 Journal of the American Society of Nephrology J Am Soc Nephrol 27: 354–370, 2016 www.jasn.org BRIEF REVIEW

Figure 3. Potential strategies for counteracting the effects of AGEs. GPX, glutathione peroxidase; miRNA, microRNA. patients on HD showed that sevelamer Decreasing Endogenous Sources of Lin et al.167 showed that online hemo- slows calcification and suppresses pento- AGEs diafiltration, a combination of both HF sidine accumulation.154 Although long– Dialysis and HD, for .6 months in patients with term clinical studies in patients with CKD Several dialysis techniques are currently uremia leads to a significant reduction in have not yet been performed, a short-term used, such as HD, hemofiltration (HF), serum AGE levels. A recent study showed comparison of sevelamer with calcium hemodiafiltration, and peritoneal dialy- that convective therapies not only effec- carbonate showed that it lowered serum sis (PD). tively cleared uremic toxins but also, de- AGEs in patients on HD.150 Sirtuin1, an A conventional HD session typically creased levels of inflammatory markers, NAD+–dependent histone deacetylase reduces blood AGE levels by #20%, and such as IL-6.168 that has anti–inflammatory, antiapoptotic, only low–molecularmassAGEs(,10- PD, an important alternative to HD, and antioxidant properties155 and prevents kDa AGE peptide) are efficiently removed also reduces AGEs formation.169,170 Ad- calcification156 and endothelial senes- from the blood.160 However, this efficiency vantageously, serum concentrations of cence,157 is decreased by AGEs, such as can be enhanced by increasing the fre- AGEs, such as pentosidine, are lower in MG.158 In a recent clinical study in pa- quency or duration of HD sessions.161–163 patients on PD than in patients on tients with type 2 diabetes mellitus In HF, molecules are removed from blood HD.171 However, despite higher levels and stages 2–4 diabetic kidney disease, by ultrafiltration of a large blood volume of AGE excretion in patients on PD, sevelamer significantly increased anti- under high hydrostatic pressure through a free AGE levels in the PD effluent were oxidant molecules, such as AGER1, Nrf2, larger–pore size membrane. Membranes elevated because of increased synthesis of and Sirtuin1, while decreasing pro– with high permeability can, therefore, de- free AGEs. Conventional PD fluid con- oxidant molecules, such as RAGE and crease blood AGEs by up to 60%164 and up tains supraphysiologic concentrations AGEs.159 to 80% with high-flux polysulfone.165,166 of glucose and glucose degradation

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Table 1. Clinical studies to decrease levels of AGEs in patients with CKD Therapy and Ref. Patient Characteristics Design Outcome Measures Results Decreasing exogenous sources of AGEs Dietary restriction 130 9 Patients with stage 3 Interventional study: an AGEs: CML, MG, and Reduction of AGEs (CML CKD isocaloric low–AGE (30%– VCAM-1; PMNC: and MG) inflammation 50% reduction) or regular RAGE and AGER1; and oxidative stress; diet for 4 wk OS: 8-isoprostanes restore levels of AGER1 and protect against immune dysfunction 143 26 Patients without Prospective and randomized 4- AGEs: CML and MG Reduction of AGEs (CML diabetes and with wk study: high- or low-AGE and MG), CML LDL, CML renal failure on diet ApoB, dialysate CML, maintenance PD (18 and MG completed the study) Gastrointestinal absorption inhibition Oral adsorbent AST-120 144 10 Patients withCRF and 2 g AST-120 three times per Serum levels of AGEs Significant decrease of chronic GN (n=8) or day for 3 mo (CML) before and serum AGEs in patients nephrosclerosis (n=2) after AST-120 without diabetes and treatment with CRF SC 153 Patients with diabetes Single–center, randomized, 2- AGEs: CML and MG; Decrease CML and MG and stages 2–4CKD mo, open–label, intention to OS: 8-isoprostanes levels, oxidative stress, treat, cross–over study and inflammation and comparing SC with CC increase AGER1 treatment expression 154 183 Adult patients on Randomized trial with parallel- CACS; AGEs: Decrease calcification and maintenance HD group design: 12 mo of pentosidine at study suppress pentosidine treatment with SC (n=91) or entry, 6 mo, and study accumulation CC (n=92) completion 159 117 Patients with type 2 Two–center, randomized, Antioxidants: RAGE1, SC treatment: reduce AGE diabetes mellitus and intention to treat, open– sirtuin1, and Nrf2; levels, improve innate stages 2–4DKD label study comparing SC pro-oxidants: AGEs defense homeostasis, (n=57) with CC treatment (CML and MG), RAGE, improve inflammation, (n=60) and 8-isoprostanes and reduce chronic OS Decreasing endogenous sources of AGEs Dialysis 163 32 Patients on chronic Cross-sectional study: Measurement of DHD: better control of AGE HD (21 with comparison group of ESRD glycation indexes on produced in ESRD normoglycemia and with patients not yet on plasma by HPLC: 11 with diabetes) and dialysis; comparison of two furosine, bound and 11 patients without different dialysis schedules: free pentosidine, and diabetes and with 4 h three times per week two classes of LMM uremia not yet on (SHD) and 2 h six times per AGE peptides dialysis week (DHD) 164 10 Patients with ESRD Treatment: three times each Kinetics of AGE removal Both high-flux dialyzers with DIAPES and HF60, two by fluorescence were equally effective to different synthetic, high–flux spectroscopy and remove low–molecular HD membranes ELISA AGE products

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Table 1. Continued

Therapy and Ref. Patient Characteristics Design Outcome Measures Results 166 126 Patients on HD 29 Patients on HD with low-flux Protein–linked and free Similar clearance of free cellulose, 57 patients with plasma pentosidine pentosidine with all high-flux polysulfone, 25 by HPLC membranes; reduction patients with levels of protein-linked polymenthylmethacrylate, pentosidine to control and 15 patients with AN69 levels for three patients who were switched from AN69 to polysulfone 167 81 Patients with chronic Three groups: conventional Serum AGE levels by Significant reduction in uremia HD, high-flux HD, and online ELISA pre- and predialysis serum AGE HDF postdialysis and after levels for patients with 6 mo; AGE clearance uremia treated with online HDF for .6mo Kidney transplantation 183 HD, CAPD, and renal Clearance of Palb and Pfree by Plasma levels of Palb Renal transplantation: best transplantation different modalities of RRT and Pfree therapeutic modality to normalize both Palb and Pfree levels 184 10 Patients on dialysis, 8 Immunohistochemical study Immunohistochemistry Reduction of AGE patients with renal on cardiac tissues from with antibodies accumulation in cardiac transplants, 7 autopsies against CML- tissues in patients with controls, 8 patients modified AGE renal transplants with mild renal compared with patients insufficiency and on dialysis without diabetes 185 66 Patients with renal Comparison between three Tissue AGEs by skin Reduction of tissue AGE transplants, 1707 groups of patients autofluorescence accumulation in patients patients with CKD with renal transplants (stage 3), and 115 compared with patients patients on dialysis on dialysis and similar to (53 on HD and 62 on patients with CKD stage 3 PD) Other approaches Calcium channel blockers 221 30 Patients with Single–center, randomized, 6- sRAGE, AGEs OS: Azelnidipine treatment but hypertension and mo, comparison of urinary 8-OH dG not amlodipine nondiabetic stage 1 treatment with azelnidipine decreases circulating or 2 CKD (16 mg daily) and AGEs and sRAGE amlodipine (5 mg daily) Antidiabetic drugs 222 66 Patients with type 2 6-mo Open–label study: Serum pentosidine at Serum pentosidine levels diabetes metformin (n=22), baseline and 6 mo significantly decreased at pioglitazone (n=22), or after each treatment 6 mo after treatments in control (n=22) both groups 223 64 Patients with type 2 Randomized, open–label, Serum total sRAGE and Increase of circulating diabetes parallel group study: esRAGE (before and sRAGE and esRAGE comparison of 6-mo after 6 mo of levels in the rosiglitazone treatments with treatment) group; significant rosiglitazone or sulfonylurea reduction of AGEs levels in both groups

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Table 1. Continued

Therapy and Ref. Patient Characteristics Design Outcome Measures Results Statins 225 70 Patients with type 2 Simvastatin (40 mg daily; Simvastatin inhibits plaque diabetes enlisted to n=35); diet alone (n=35) RAGE expression by undergo carotid decreasing MPO– endarterectomy dependent AGE generation SC, sevelamer carbonate; CRF, chronic renal failure; DKD, diabetic kidney disease; CAPD, continuous ambulatory peritoneal dialysis; CC, calcium carbonate; SHD, standard hemodialysis; DHD, daily hemodialysis; DIAPES; HF60; AN69; HDF, hemodiafiltration; Palb, albumin-linked pentosidine; Pfree, free form of pentosidine; PMNC, peripheral mononuclear cells; OS, oxidative stress; CACS, coronary artery calcification score; LMM, low molecular mass; 8-OH dG, 8 hydroxy deoxyguanosine; esRAGE, endogenous secretory advanced glycation end product–specific receptor; ApoB, apolipoprotein B; MPO, myeloperoxidase. products (GDPs; generated during ster- and/or oxidative stress by sequestration that leads to DN.198 Inhibitors of the ilization by heating of dialysis fluid) that of metal ions, reactive dicarbonyl com- renin-angiotensin axis can improve can increase the formation of AGEs.172–174 pounds, ROS, and reactive nitrogen spe- glomerular hyperfiltration and are In patients on PD, high levels of AGE cies. Thus, the use of antioxidants, such known to decrease the severity of DN deposition in tissue correlate with glu- as vitamin E, vitamin A, and lipoic acid, in animal and clinical studies.199 Sev- cose exposure.175 Nonglucose PD solu- has been studied in vitro to counteract eral angiotensin receptor blockers (in- tions or solutions containing low-GDP AGE effects.186 cluding olmesartan, telmisartan,200,201 levels, such as icodextrin, may, there- and irbesartan202) have been shown to – fore, minimize AGE formation.176 179 Reactive Dicarbonyl Scavengers decrease plasma CML and pentosidine The acidic pH and the hyperosmolality Several compounds can trap reactive levels in patients on HD203 and act as of conventional PD fluid can also damage carbonyl intermediates (AGE precursors) antioxidants against AGE.202 Sebeková the peritoneum and consequently, impair and quench ROS.187,188 For example, the et al.204 found that the angiotensin– its function as a dialyzing membrane. strongly nucleophilic Pimagedine (2- converting enzyme inhibitor ramipril Other alternatives (such as neutral pH aminoguanidine) can scavenge reactive significantly decreased levels of fluores- and low–GDP peritoneal solutions180) carbonyl intermediates in the Maillard cent AGEs but not CML. can also be used to decrease AGE forma- reaction189,190 and also, decrease VCAM-1 tion during conventional PD.181 expression in endothelial cells.191 Admin- fl Aldose Reductase Inhibitors Continuous ow PD is another op- istration of aminoguanidine to patients Aldose reductase is a multifunctional tion that also effectively reduces AGE with ESRD also led to a reduction of cir- enzyme that reduces aldehydes, and it is formation.170 culating LDL levels.39 involved in the polyol pathway of AGE The vitamin B6 derivative pyridox- formation. Inhibiting aldose reductase, amine (registered as Pyridorin) is a post- Kidney Transplantation therefore, reduces levels of AGE precursors Because AGEs are mainly excreted by the Amadori inhibitor192 that traps reactive and decreases AGE accumulation.205 Ad- kidneys, serum AGE levels increase with carbonyl and dicarbonyl compounds de- ministration of the aldose reductase in- declining kidney function.182 Kidney rived from Amadori compounds, thereby hibitor eparlestat decreases serum AGE fi 193,194 transplantation is, therefore, an ef cient reducing AGE accumulation. Pyri- levels in patients with diabetes.206 way of decreasing levels of uremic toxins, doxamine also scavenges ROS and che- including AGEs. Thus, pentosidine levels lates metal ions (oxidation catalysts). In started to fall within 4 weeks of kidney diabetic rats, pyridoxamine has been Increasing the Breakdown of AGEs transplantation and reached normal val- shown to decrease AGE and calcifica- Agents that break AGE cross-links (re- ues after 6 months.183 Studies showed that tion.195 Polizzi et al.196 showed that a com- viewed in ref. 207) have been shown to kidney transplantation decreases AGE ac- bination of vitamins B1 and B6 decreases improve arterial compliance in hu- cumulation in tissues,184,185 which was as- DNA glycation in patients with DN. How- mans.208 Animal and human studies sessed by skin autofluorescence, thereby ever, an 8-week randomized, placebo– have shown that AGE cross–link break- significantly reducing cardiovascular controlled study in 50 patients on HD ers, such as ALT-711 and alagebrium, events in recipients of transplants com- found that the combination of pyridoxine decrease AGE levels209,210 and tissue pared with patients on dialysis.185 and thiamine had no effect on plasma lev- AGEs,211,212 reverse their effects,213–216 els of AGEs and pentosidine.197 such as aortic stiffness, calcification,195 Antioxidants and extracellular matrix accumula- To decrease endogenous sources of Renin-Angiotensin System Inhibitors tion,212 and improve renal function by AGEs, several compounds have been The renin-angiotensin system plays an facilitating urinary excretion of the end developed to attenuate glyoxidation important role in the disease processes products.

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RAGE Inhibitors be reduced in AGE–induced endothelial subjects, suggesting that they could be Many different animal studies have cell apoptosis.238,239 AGEs also strongly beneficial for the treatment of CKD. shown that RAGE blockade by decreas- increased miR214 in monocytes from pa- Bardoxolone methyl, a synthetic Nrf2 ing RAGE expression215,217,218 or RAGE tients with chronic renal failure, which in activator, has been tested as a therapeutic competition reduces oxidative stress195 turn, abolished AGE–induced cell sur- agent in clinical trials.246 Despite promis- and endothelial dysfunction. Thus, vival,61 thereby limiting the inflammatory ing results in phase II trials, a recent study sRAGE prevents the development of response. Identifying specific miRs that showed that it contributes to higher rates structural and functional characteristics target the AGE-RAGE axis is, therefore, of cardiovascular events in susceptible pa- of nephropathy in db/db mice.29,219 of interest to correct their expression by tients with an increased risk of heart fail- Recently, a receptor-based bioadsorbent in vivo delivery of miR mimics to restore ure at baseline.247 Additional studies are, designed to target AGE gave promising miR levels or inhibitors to block miR therefore, needed to evaluate the safety of results to selectively deplete serum function. Chen et al.240 have recently these compounds. However, Nrf2 activa- AGEs from human blood.220 This shown that miR29b, which inhibits DN tors seem to be a promising new thera- sRAGE–based extracorporeal therapy in db/db mice, was downregulated in re- peutic strategy to improve or delay kidney could be useful to selectively decrease se- sponse to AGEs and that its overexpression dysfunction. rum AGEs and decrease inflammation in by gene therapy attenuated diabetic kidney patients with diabetes and/or CKD. disease. miRs have consequently emerged as a promising novel therapeutic strategy CONCLUSION Other Approaches for the treatment of CKD. However, miR Other therapeutic approaches, such as delivery and safety require additional in- AGEs have been widely described in calcium channel blockers,221 antidiabetic vestigation before clinical application. hyperglycemic conditions, such as diabe- drugs,93,217,222,223 statins,224,225 and lyso- tes; however, they can also be generated in zyme,56,226 have also been used. Recent Nrf2 and Glo-1 Inducers conditions associated with elevated levels studies have also described the use of al- Nrf2 signaling has been shown to have a of oxidative stress, such as CKD. The ternative medicines with antiglycation protective role in renal injuries. Several kidney has an important role in AGE activities,227,228 such as extracts from cer- Nrf2 target antioxidant genes, such as metabolism, because CKD is associated tain plants like Moutan cortex229–231 and SOD, are decreased in CKD. Pharmaco- with AGE accumulation with declining Azadirachta indica,232 which exert reno- logic interventions activating Nrf2 could, kidney function. In this review, we de- protective effects by inhibition of the therefore, be beneficial to protect the scribe the mechanisms of AGE formation AGE-RAGE axis (Table 1). This section kidney in CKD, partly by ameliorating and the various pathologic effects of will focus on emerging therapeutic oxidative stress.45 Because another target AGEs. The experimental data available approaches, such as microRNAs of Nrf2 is Glo-1,49 targeting Nrf2 can to date emphasize the harmful effects of (miRs) and Nrf2 and Glo-1 inducers. also decrease AGEs, such as MG. Natu- AGEs on vascular function (with endo- rally occurring Nrf2 activators have been thelial dysfunction, elevated oxidative MiRs described in animal studies (reviewed in stress, and arterial stiffness) and the There is growing evidence that miRs play a ref. 241). For example, ankaflavin, a nat- immune system. We also describe the key role in kidney physiology and con- ural peroxisome proliferator-activated various potential therapeutic strategies tribute to both the induction and progres- receptor g agonist, has been shown to designed to decrease exogenous and en- sion of CKD.233,234 miRs are ubiquitously upregulate Nrf2 and protect against dogenous sources of AGE precursors or expressed short noncoding RNAs com- MG-induced diabetes in vivo.242 Monascin, increase the breakdown of AGEs. A large prising 20–22 nucleotides that regulate obtained from Monascus-fermented prod- body of evidence has shown that the key biologic pathways and cellular func- ucts, has recently been shown to possess interaction between AGEs and RAGE tions by inhibiting gene expression anti–inflammatory and antioxidant plays a key role in vascular damage. through post-transcriptional repression properties by decreasing RAGE and in- Inhibiting the AGE-RAGE axis by means of their target mRNAs.235 For example, creasing heme oxigenase 1 by upregulation of RAGE inhibitors could become a novel miR21 has been shown to be a key thera- of Nrf2.48,243 Dimerumic acid, another therapeutic strategy. Of interest are the peutic target for renal injury in a mouse product extracted from Monascus, has an recent new potential therapeutic strate- model of type 2 diabetes.236 Several other inhibitory effect on CML–induced RAGE gies emerging from in vitro and in vivo miRs have also been implicated in the signals by Nrf2-mediated attenuation of studies, such as Nrf2 and Glo-1 inducers process of vascular calcification.111 In- oxidative stress in hepatic cells.244 It also as well as miRs regulation. terestingly, recent studies have shown decreases hepatic Glo, thereby decreasing Weprovideanoverviewofthepatho- the involvement of miRs in the regulation serum and hepatic AGEs in MG-treated biology of AGEs and information on how of AGE/RAGE signaling (reviewed in ref. mice.245 These widely used plant–derived AGE accumulation is involved in vascular 237). For example, miR200b/miR200c Nrf2 activators have been shown to be safe damage in patients with CKD. Addi- and miR223 levels have been shown to with shown health benefits in human tional preclinical and clinical studies are,

J Am Soc Nephrol 27: 354–370, 2016 Uremic Toxicity of AGEs in CKD 363 BRIEF REVIEW www.jasn.org nevertheless, needed to (1) determine the oxidative stress: A role in cytotoxicity. Bio- 24. Xie J, Méndez JD, Méndez-Valenzuela V, – relevance of targeting AGEs to reduce the chem Pharmacol 58: 641 648, 1999 Aguilar-Hernández MM: Cellular signalling 11. Vander Jagt DL, Hunsaker LA: Methylglyoxal of the receptor for advanced glycation end complications of CKD and (2) identify metabolism and diabetic complications: products (RAGE). Cell Signal 25: 2185– new therapeutic interventions that may Roles of aldose reductase, glyoxalase-I, 2197, 2013 reduce or delay morbidity and mortality betaine aldehyde dehydrogenase and 2- 25. Ott C, Jacobs K, Haucke E, Navarrete in this population. oxoaldehyde dehydrogenase. Chem Biol Santos A, Grune T, Simm A: Role of ad- Interact 143-144: 341–351, 2003 vanced glycation end products in cellular 12. Zheng F, Cai W, Mitsuhashi T, Vlassara H: signaling. 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