aopps are a family of oxidized , dityrosine - containing , crosslinked protein compounds formed by the reaction of plasma proteins with chlorinated oxidants . in vivo , the generation of chlorinated oxidants is a feature of phagocytic cells that possess myeloperoxidase , the only enzyme that is able to generate a chlorinated oxidant . in vitro , aopps can be formed by exposure of albumin to hypochlorous acid . the formation of aopps is correlated to the concentration of chlorinated oxidant added , indicating that aopps result from the interaction between oxidants and plasma proteins . in uremic patients , the oxidative activity of circulating neutrophils corresponded with the concentration of plasma aopps , suggesting that neutrophils , which possess high content of myeloperoxidase , might be involved in plasma aopp formation . in 1996 , witko - sarsat et al . first reported elevated plasma level of aopps in uremic patients . the highest level of aopps is detected in patients on maintenance hemodialysis , followed by those on peritoneal dialysis . notably , patients with advanced chronic renal failure not yet on dialysis had almost three times higher aopp levels than healthy subjects . end - stage renal failure may occur within 5 years of presentation , or conversely , more than 20 years later . therefore , identification of factors predictive of subsequent outcome at an earlier stage of the disease should be of great interest , particularly if these factors can effectively guide treatment decisions . a prospective cohort study reveals that elevated plasma level of aopp at the early stage of igan is one of the most potent independent risk factors for poor renal outcome ( start of dialysis ) . consistent with this finding , another study that included 62 igan patients with a mean follow - up of 4.46 ( range 310 ) years shows that aopps are strongly associated with proteinuria at sampling and the rate of renal function decline during follow - up . these studies suggest that aopps may serve as a surrogate marker for a bad prognosis in igan , and elevated plasma level of aopps at the early stage of the disease may warrant more aggressive intervention . besides elevated plasma level of aopps , increased aopps in renal tissues are detected in patients with diabetic nephropathy , membranous nephropathy , and igan patients ( unpublished data ) . figure 1 gives an example of the histological distribution of aopps in renal tissue in a patient with igan . aopp accumulation in the kidney appears multifactorial and may be because of trapping of aopps from the circulation , increased local generation of new aopps , or pathologically decreased aopp turnover . renal trapping of aopps has been demonstrated by steady intravenous infusion of aopp - modified albumin into unilateral nephrectomized rats . after 3 weeks of infusion , the aopp content in the kidneys was significantly increased in both glomeruli and tubules . it is believed that ros increases in patients with acute kidney injury ( aki ) . a prospective cohort study to compare aopp levels between aki and non - aki patients revealed that the levels of aopps are significantly higher in aki patients than healthy controls . patients with the most severe aki ( rifle class failure ) have markedly elevated aopp levels compared with rifle class risk and injury patients . clinical studies provide convincing evidence for an association between elevated aopp levels and kidney injury , suggesting aopps may be important predictors of the prognosis of kidney disease . in addition , the pathogenic role of aopps in kidney damage is supported by a number of experimental observations . cell culture and animal studies show that most resident renal cells are adversely affected by aopps . for example , given the importance of podocytes in maintaining glomerular filtration barrier , we find that chronic loading of aopps causes podocyte apoptosis via the p53-bax apoptotic pathway , leading to proteinuria . in addition , aopps upregulate the expression of fibronectin and collagen i in cultured mesangial cells via nad(p)h oxidase - dependent o2 production , and when endothelial cells in the kidney are stimulated by aopps , the pro - inflammatory mediators such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 are released . these detrimental cellular events caused by aopps ultimately lead to renal function perturbations such as an increase in urinary protein excretion , decreased creatinine clearance , and an aggravated glomerulosclerosis and interstitial fibrosis . for instance , by activating nf-b , a redox - sensitive transcription factor that regulates expression of pro - inflammatory cytokines and chemokines , oxidative stress promotes recruitment and activation of leukocytes and resident cells , thereby eliciting inflammation . it is known that nuclear translocation of nf-b subunits p50 and p65 is significantly greater in the peripheral mononuclear cells of patients with igan than healthy control . aopps as mediators of inflammation are known to be involved in monocyte activation , and aopps formed in vitro are potent mediators of monocyte activation , triggering both their respiratory burst and tumor necrosis factor- synthesis . likewise , aopps derived from the plasma of hemodialysis patients have the capacity to trigger respiratory burst of monocytes . consistent with clinical finding , animal studies demonstrate that chronic loading of aopps in streptozotocin - induced diabetes or unilateral nephrectomy rats results in the activation of nf-b and in the upregulation of pro - inflammatory and pro - fibrotic factors such as monocyte chemoattractant protein-1 and tgf-1 . however , emerging studies reveal that aopps are also capable of promoting ros production , leading to an inexorable positive feedback loop . aopps activate nad(p)h oxidase through the protein kinase c - dependent pathway that leads to an excessive generation of intracellular superoxide in various renal cells including podocyte , endothelial cells , mesangial cells , and tubular epithelial cells . significantly , the effect of aopp - modified albumin on ros generation is 100 times that of native albumin . in conditions with increased protein oxidative damage such as ckd and diabetes , increased aopp - modified albumin in the lumen of renal tubules might cause a more dramatic renal injury than unaltered albumin . in addition to the involvement in renal damage , aopps are also implicated in the pathogenesis of atherosclerosis and cardiovascular events ( cvds ) in ckd . report that aopp levels are independent predictors of cvd in non - diabetic ckd patients in the predialysis phase . our most recent study indicates that the plasma aopp level is an independent risk factor for cvd in patients on hemodialysis . a clinical study showed that aopps are independently correlated with flow - mediated dilatation% and nitrate - mediated dilatation% , and therefore can predict endothelial function of peritoneal dialysis patients . 
 in vitro studies reveal that aopps induce vascular endothelial cells - dysfunction by activating nf-b and p38 mitogen - activated protein kinase signaling . karand colleagues shows that in vitro generated aopp - modified albumin binds with high affinity to the high - density lipoprotein ( hdl ) scavenger receptor class b type i ( sr - bi ) , and competitively inhibits hdl association to sr - bi and thus decreases sr - bi - mediated cholesterol ester uptake and results in depressed plasma clearance of hdl - cholesterol . third , aopps have been shown to inhibit cholesterol efflux from human macrophage foam cells by downregulating the expression of atp - binding membrane cassette transporter a-1 and liver x receptor  , and thus may promote macrophage foam cell formation . our group found that intravenous infusion of aopp - modified albumin also significantly increases macrophage infiltration in atherosclerotic plaques in hypercholesterolemic rabbits . the presence of aopp - modified proteins in tissues and the biological effects associated with their accumulation have stimulated an intensive search for cellular surface molecules that recognize aopps and activate downstream cellular responses . receptor for advanced glycation end products ( rage ) on the surface of endothelial cells was first discovered as a receptor of aopp - modified albumin . further research also identified cd36 as being capable of binding aopp - modified albumin . in the kidney , physiological expression of rage is found on podocyte at a very low concentration but is significantly enhanced by chronic loading of aopps . ros generated by this mechanism in turn leads to p53 upregulation , bax and caspase 3 activation , and podocyte apoptosis . interestingly , although both rage and cd36 are found in tubular epithelia , knocking down cd36 by small interfering rna shows a more dramatic inhibition on aopp - induced intrarenal ras activation . similarly to that of rage , cd36 mediates aopp  human serum albumin ( hsa)-induced intracellular ros generation via a mechanism that involves protein kinase c and membrane nad(p)h oxidase signaling pathways , and the secretion of tgf-1 in cultured proximal tubular cells . in addition , cd36 mediates aopp  albumin endocytic uptake and subsequent lysosomal degradation in proximal tubular cells . whether rage mediates aopp  albumin endocytosis remains to be further analyzed . aopp accumulation is associated with renal function decline in ckd patients and therefore may be a target for intervention . a clinical study shows that angiotensin ii type 1 receptor blocker ( arb ) candesartan can reduce the plasma aopp level when administered to non - diabetic patients on peritoneal dialysis . in addition , a cross - sectional study reveals that , in elderly people with impaired glucose metabolism , the vitamin d status is inversely associated with plasma levels of aopps , especially in subjects with hypovitaminosis d , suggesting a role for vitamin d in preventing aopp - related pathologies . as many effects of aopps are mediated by rage activation , antagonism of this receptor appears to be an appropriate therapeutic concept . indeed , direct blockade of rage with an antibody or silencing its expression by small interfering rna prevented aopp - induced podocyte apoptosis and intrarenal ras activation in animal models . there is increasing evidence supporting a pathogenic role of aopps in the initiation and progression of ckd . intensive studies have also led to a better understanding of the cellular and molecular mechanisms by which aopps exert their pathogenic actions . figure 2 summarizes the mechanism and effect of aopps on renal cells and presents an integrated picture for understanding a pathogenic role of aopps in ckd . clearly , aopps are a leading candidate target for future ckd treatment , and more studies are needed to develop new therapeutic strategies for the prevention of aopp - associated renal injury in ckd patients .
advanced oxidation protein products ( aopps ) are the dityrosine - containing and crosslinking protein products formed during oxidative stress by reaction of plasma protein with chlorinated oxidants , and often carried by albumin in vivo . 
 accumulation of plasma and renal aopps is a common pathologic finding in chronic kidney disease ( ckd ) patients . 
 moreover , aopp accumulation is an independent risk factor for cardiovascular events ( cvds ) in ckd . 
 clinical and experimental studies indicate that aopps are involved in the structural changes of progressive nephropathies such as glomerulosclerosis , interstitial fibrosis , and tubular atrophy via the redox - dependent pathway . 
 mounting evidence supports the role of aopps as a new class of renal pathogenic mediators in the progression of ckd . 
 this mini review describes the formation of aopps , the involvement of aopps in ckd pathogenesis , and the underlying mechanisms .