Isoprostanes and asthma

Isoprostanes are prostaglandin (PG)-like compounds generated in vivo following oxidative stress by non-enzymatic peroxidation of polyunsaturated fatty acids, including arachidonic acid. They are named based on their prostane ring structure and by the localization of hydroxyl groups on the carbon side chain; these structural differences result in a broad array of isoprostane molecules with varying biological properties. Generation of specific isoprostanes is also regulated by host cell redox conditions; reducing conditions favor F₂-isoprostane production while under conditions with deficient antioxidant capacity, D₂- and E₂-isoprostanes are formed. F₂-isoprostanes (F₂-isoP) are considered reliable markers of oxidative stress in pulmonary diseases including asthma. Importantly, F₂-isoP and other isoprostanes function as ligands for PG receptors, and potentially other receptors that have not yet been identified. They have been reported to have important biological properties in many organs. In the lung, isoprostanes regulate cellular processes affecting airway smooth muscle tone, neural secretion, epithelial ion flux, endothelial cell adhesion and permeability, and macrophage adhesion and function. In this review, we will summarize the evidence that F₂-isoP functions as a marker of oxidative stress in asthma, and that F₂-isoP and other isoprostanes exert biological effects that contribute to the pathogenesis of asthma. This article is part of a Special Issue entitled Biochemistry of Asthma.     

Plasma F2-isoprostanes are elevated in newborns and inversely correlated to gestational age

F(2)-isoprostanes, prostaglandin F(2)-like compounds formed by free radical-catalyzed lipid peroxidation, are considered the most reliable markers of oxidative stress. It has been repeatedly suggested that newborns are exposed to conditions of oxidative stress resulting from the change from a low oxygen pressure in utero to a high oxygen pressure at birth. We measured the levels of F(2)-isoprostanes in plasma of newborns by gas chromatography/mass spectrometry and we found that F(2)-isoprostanes are significantly higher in term newborns compared to healthy adults. The greatest values were found in preterm newborns in whom F(2)-isoprostanes are even higher than in term babies. Moreover a significant inverse correlation was found between the plasma levels of isoprostanes and the gestational age. A quite normal level of isoprostanes was found in the mothers both at delivery and during pregnancy. Placental total F(2)-isoprostanes (sum of free plus esterified) were significantly higher in preterm compared to term deliveries and such a difference might account for the difference in plasma isoprostanes. Plasma non-protein-bound iron is higher in preterm than in term newborns, even if no correlation was found with plasma F(2)-isoprostanes. Erythrocyte desferrioxamine-chelatable iron content (0 time) and release (24 h of aerobic incubation) are higher in newborns than in adults and in preterm than in term newborns, but again no correlation was found with plasma F(2)-isoprostanes. The marked increase in plasma isoprostanes suggests that oxidative stress is a feature of the physiopathological changes seen in the perinatal period.     

Isoprostanes and hepatic fibrosis

After a brief introduction to oxidative stress, the discovery of F(2)-isoprostanes as specific and reliable markers of oxidative stress is described. Isoprostanes are also agonists of important biological effects. Since a relation between oxidative stress and collagen hyperproduction has been previously suggested and since lipid peroxidation products have been proposed as possible mediators of liver fibrosis, we investigated whether collagen synthesis is induced by F(2)-isoprostanes the most proximal products of lipid peroxidation. In a rat model of carbon tetrachloride-induced hepatic fibrosis, plasma isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content was also increased. When hepatic stellate cells from normal liver were cultured up to activation (expression of alpha-smooth muscle-alpha actin) and then treated with F(2)-isoprostanes in the concentration range found in the in vivo studies (10(-9)-10(-8)M), a striking increase in DNA synthesis, in cell proliferation and in collagen synthesis was observed. Moreover, F(2)-isoprostanes increased the production of transforming growth factor-beta1 by U937 cells, assumed as a model of Kupffer cells or liver macrophages. The data suggest the possibility that F(2)-isoprostanes generated by lipid peroxidation in hepatocytes mediate hepatic stellate cell proliferation and collagen hyperproduction seen in hepatic fibrosis.     

ReviewIsoprostanes: Novel Bioactive Products of Lipid Peroxidation

Isoprostanes, are a novel group of prostaglandin-like compounds that are biosynthesised from esterified polyunsaturated fatty acid (PUFA) through a non-enzymatic free radical-catalysed reaction. Several of these compounds possess potent biological activity, as evidenced mainly through their pulmonary and renal vasoconstrictive effects, and have short half-lives. It has been shown that isoprostanes act as full or partial agonists through thromboxane receptors. Both human and experimental studies have indicated associations of isoprostanes and severe inflammatory conditions, ischemia-reperfusion, diabetes and atherosclerosis. Reports have shown that F²-isoprostanes are authentic biomarkers of lipid peroxidation and can be used as potential in vivo indicators of oxidant stress in various clinical conditions, as well as in evaluations of antioxidants or drugs for their free radical-scavenging properties.

Higher levels of F²-isoprostanes have been found in the normal human pregnancy compared to non-pregnancy, but their physiological role has not been well studied so far. Since bioactive F²-isoprostanes are continuously formed in various tissues and large amounts of these potent compounds are found unmetabolised in their free acid form in the urine in normal basal conditions with a wide inter-individual variation, their role in the regulation of normal physiological functions could be of further biological interest, but has yet to be disclosed. Their potent biological activity has attracted great attention among scientists, since these compounds are found in humans and animals in both physiological and pathological conditions and can be used as reliable biomarkers of lipid peroxidation.     

Variability of oxidative stress biomarkers in hemodialysis patients

Abstract

Oxidative stress biomarkers may have a role in the future to assist clinical decisions regarding the use of antioxidant therapies and their efficacy. The aims of this study were to evaluate the within and between-individual variability of plasma oxidative stress biomarkers and investigate factors affecting their variability. Plasma F2-isoprostanes and protein carbonyls were measured in 14 hemodialysis patients every 2 weeks for 10 weeks. Within-individual coefficients of variation (CVs) were isoprostanes?=?30.4% (range?=?6.1–66.7%) and protein carbonyls?=?16.3% (8.4–29.5%). Between-individual CVs were isoprostanes?=?34.4% (28.9–40.2%) and protein carbonyls?=?19.5% (15.6–24.5%). There were no significant (p?>?0.05) relationships between the oxidative stress biomarkers and dietary antioxidant intake, medications, clinical and demographic parameters.     

Isoprostanes in amniotic fluid: a predictive marker for fetal growth restriction in pregnancy

Isoprostanes are markers of free radical-catalyzed lipid peroxidation. Evidence suggests that oxidative stress occurs in pregnancies with fetal growth restriction (FGR). The aim of this study was to analyze F2-isoprostanes in amniotic fluid of FGR pregnancies. We tested the hypothesis that F2-isoprostanes are reliable markers to distinguish FGR pregnancies from normal ones and appropriate-for-gestational-age (AGA) from small-for-gestational-age (SGA) newborns. F2-isoprostanes levels were measured by colorimetric enzyme immunoassay in the amniotic fluid of 77 pregnancies with normal fetal growth (group I) and 37 with FGR (group II). Fetal biometry and Doppler measurements were obtained using an ATL HDI 3000 ultrasound system. Isoprostanes were higher in group II than group I. The ROC curve distinguished group I from group II, showing 100% sensitivity and 88.3% specificity at a cutoff of 94 pg/ml. There were no statistical differences in isoprostanes levels between AGA and SGA newborns in group II. The area under the ROC curve drawn to distinguish AGA and SGA newborns showed a sensitivity of 100% and a specificity of 72.3% at a cutoff of 94 pg/ml. The relative risk index indicated a 8.05 times higher risk of birth weight below the 3rd percentiles in group II than in group I. High isoprostanes concentrations can be detected in the amniotic fluid of FGR pregnancies and the assay of isoprostanes in amniotic fluid is a reliable assessment of fetal oxidative stress. Common use of this predictive marker in obstetrics will improve the ability of clinicians to identify those fetuses who will be born SGA or with a birth weight below the 25th percentile.     

Determinants of F2-isoprostane biosynthesis and inhibition in man

Several cardiovascular risk factors are characterized by the coexistence of low-grade inflammation, enhanced oxidative stress and lipid peroxidation. It has been hypothesized that F2-isoprostanes, a product of in vivo lipid peroxidation, may transduce the effects of metabolic and hemodynamic abnormalities into increased cardiovascular risk. Thus, the formation of these compounds, including urinary 8-iso-Prostaglandin (PG) F2alpha, has been investigated in clinical settings putatively associated with oxidant stress. Enhanced lipid peroxidation together with increased in vivo platelet activation have been found in association with the major cardiovascular risk factors. Thus, F2-isoprostanes may transduce the effects of oxidant stress associated with complex metabolic disorders into specialized forms of cellular activation. In particular, the low-grade inflammatory state characterizing metabolic disorders such as obesity, hypercholesterolemia, type 2 diabetes mellitus, and homozygous homocystinuria may be the primary trigger of thromboxane-dependent platelet activation mediated, at least in part, through enhanced lipid peroxidation. Moreover, oxidative stress may promote endothelial dysfunction through increased production of reactive oxygen species that inactivate nitric oxide. Accumulation and activation of leukocytes plays a key role in atherosclerosis and its complications. Interestingly, neutrophil adhesion induced by minimally modified low-density lipoproteins is mainly mediated by F2-isoprostanes. Although epidemiological studies suggest an inverse relationship between antioxidant vitamin intake and cardiovascular disease, several clinical trials have obtained conflicting results on the effects of vitamin E supplementation on the risk of cardiovascular events. On the other hand, the use of F2-isoprostane formation as a biochemical end-point for dose-finding studies of vitamin E supplementation has helped clarifying the unique features of its pharmacodynamic effects on lipid peroxidation. This information could be extremely valuable in the selection of the appropriate patient subgroups that may benefit from antioxidant interventions.     

Oxidative Stress,Inflammation, and Diabetic Vasculopathies: The Role of Alpha Tocopherol Therapy

The diabetic state confers an increased propensity to accelerated atherogenesis. In addition to the established risk factors, there is evidence for increased oxidative stress and inflammation in diabetes. Increased oxidative stress is manifested by increased lipid peroxidation (e.g. increased F 2 -isoprostanes) and increased DNA damage. Evidence for increased inflammation includes increased monocyte superoxide and pro-inflammatory cytokine release (IL-1, IL-6, and TNF- &#102 ), increased monocyte adhesion to endothelium and increased levels of plasma C-reactive protein, the prototypic marker of inflammation. Most importantly, alpha tocopherol therapy, especially at high doses, clearly shows a benefit with regards to LDL oxidation, isoprostanes and a decrease in inflammatory markers such as C-reactive protein, pro-inflammatory cytokines and PAI-1 levels. Thus, it appears that, in diabetes, alpha tocopherol therapy could emerge as an additional therapeutic modality.     

Oxidative stress,inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy

The diabetic state confers an increased propensity to accelerated atherogenesis. In addition to the established risk factors, there is evidence for increased oxidative stress and inflammation in diabetes. Increased oxidative stress is manifested by increased lipid peroxidation (e.g. increased F2-isoprostanes) and increased DNA damage. Evidence for increased inflammation includes increased monocyte superoxide and pro-inflammatory cytokine release (IL-1, IL-6, and TNF-alpha), increased monocyte adhesion to endothelium and increased levels of plasma C-reactive protein, the prototypic marker of inflammation. Most importantly, alpha tocopherol therapy, especially at high doses, clearly shows a benefit with regards to LDL oxidation, isoprostanes and a decrease in inflammatory markers such as C-reactive protein, pro-inflammatory cytokines and PAI-1 levels. Thus, it appears that, in diabetes, alpha tocopherol therapy could emerge as an additional therapeutic modality.     

The biochemistry of the isoprostane, neuroprostane, and isofuran pathways of lipid peroxidation

F2-isoprostanes are prostaglandin F2-like compounds that are formed nonenzymatically by free radical mediated peroxidation of arachidonic acid. Intermediate in the pathway of the formation of isoprostanes are labile prostaglandin H2-like bicyclic endoperoxides (H2-isoprostanes), which are reduced to F2-isoprostanes and also undergo rearrangement in vivo to form E-ring and D-ring isoprostanes, isothromboxanes, and highly reactive acyclic gamma-ketoaldehdyes (isoketals). Docosahexaenoic acid (C22:6omega3) is highly enriched in neurons in the brain and is highly susceptible to oxidation. Free radical mediated oxidation of docosahexaenoic acid results in the formation of isoprostane-like compounds (neuroprostanes). F4- and E4/D4-neuroprostanes as well as neuroketals have been shown to be produced in vivo. Finally, we recently discovered a new pathway of lipid peroxidation that forms compounds with a substituted tetrahydrofuran ring (isofurans). Oxygen concentrations differentially modulate the formation of isoprostanes and isofurans; at elevated oxygen concentrations, the formation of isofurans is favored whereas the formation of isoprostanes is disfavored.     

Analysis of oxidative stress and wound-inducible dinor isoprostanes F(1) (phytoprostanes F(1)) in plants

Isoprostanes F(2) are arachidonate autoxidation products in mammals that have been shown to be induced during several human disorders associated with enhanced free-radical generation. Isoprostanes F(2) represent not only extremely reliable markers of oxidative stress in vivo, but they also exert potent biological effects. Therefore, it has been postulated that isoprostanoids are mediators of oxidant injury in vivo. Higher plants, however, do not synthesize arachidonic acid or isoprostanes. Here we show that a series of isoprostane F(2) analogs termed phytoprostanes F(1) (previously dinor isoprostanes F(1)) are formed by an analogous pathway from alpha-linolenate in plants. High-performance liquid chromatography and gas chromatography-mass spectrometry methods using [(18)O](3)phytoprostanes F(1) as internal standard have been developed to quantify phytoprostanes F(1). In fresh peppermint (Mentha piperita) leaves, phytoprostanes F(1) were found in free form (76 ng/g of dry weight) and at about 150-fold higher levels esterified in lipids. It is notable that these levels of phytoprostanes F(1) are more than two orders of magnitude higher than the basal levels of isoprostanes F(2) in mammalian tissues. Furthermore, wounding, as well as butyl hydroperoxide or cupric acetate stress triggered a dramatic increase of free and esterified phytoprostanes F(1). Thus phytoprostanes F(1) may represent a sensitive measure of oxidative damage in plants similar to isoprostanes in mammals. However, one of the most exciting issues to be clarified is the possibility that linolenate-derived phytoprostanes F(1) exert biological activities in plants and/or animals.     

Augmentation of monocyte intracellular ascorbate in vitro protects cells from oxidative damage and inflammatory responses

Ascorbic acid is present as a primary antioxidant in plasma and within cells, protecting both cytosolic and membrane components of cells from oxidative damage. The effects of intracellular ascorbic acid on F(2)-isoprostanes (biomarkers of oxidative stress) and monocyte chemoattractant protein-1 (marker of inflammatory responses) production in monocytic THP-1 cells were investigated under conditions of 2,2'-Azobis(2-methylpropionamidine)dihydrochloride (AAPH) induced oxidative stress. Cells cultured under normal conditions have extremely low ascorbate levels and the intracellular ascorbate can be augmented significantly by adding ascorbate to the culture medium. While AAPH treatment reduced cell viability, increased F(2)-isoprostanes and MCP-1 production, the presence of intracellular ascorbic acid maintained high cell viability and attenuated both F(2)-isoprostanes and MCP-1 production. Measurement of intracellular ascorbic acid and its oxidised products showed that intracellular ASC was oxidised to a significantly greater extent during AAPH treatment and may be utilised to protect the cells under conditions of oxidative stress. This study demonstrates the importance of intracellular ascorbate, which may be lacking under normal cell culture conditions, under conditions of increased oxidative stress.     

F2-isoprostanes as biomarkers of lipid peroxidation in patients with chronic renal failure

Chronic renal failure patients on long-term hemolysis are found to be under increased oxidative stress, caused by antioxidant deficiency, neutrophil activation during hemodialysis (HD), platelet activation and/or chronic inflammation. Increased levels of oxidants (e.g. malondialdehyde, 4-hydroxynonenal, hydrocarbons, lipohydroperoxides, oxycholesterols, carbonyls) in HD patients are thought to play an important role in the development of endothelial dysfunction, atherogenesis and cardiovascular disease, which is a frequent condition in end-stage renal disease. F2-isoprostanes have been established as chemically stable, highly specific and reliable biomarkers of in vivo oxidative stress which can very sensitively measured by gas chromatography-mass spectrometry (Morrow et al. [17]). An up to 6-fold increase of plasma F2-isoprostanes in HD patients is accompanied by an enhanced formation of indicators of inflammation (e.g. C-reactive protein) and decreases of endogenous antioxidants (e.g. ascorbate, alpha-tocopherol). In their esterified form F2-isoprostanes may be a useful criteria to evaluate the effectiveness of clinical interventions to diminish oxidant stress and associated inflammation. Furthermore, F2-isoprostanes possess potent biological activities (e.g. 8-iso-PGF2alpha is known as a renal vasoconstrictor) suggesting that they may also act as mediators of the cellular effects of oxidative stress and inflammation.     

Separation and identification of F2-isoprostane regioisomers and diastereomers by novel liquid chromatographic/mass spectrometric methods

Isoprostanes are isomers of prostaglandins that are generated from free radical-initiated autoxidation of arachidonic acid. Quantification of F(2)-isoprostanes is regarded as the "gold standard" to assess oxidative stress in various human diseases. There are 32 possible racemic isoprostane isomers that exist as four sets of regioisomers. Each regioisomer is composed of eight diastereomers. We report liquid chromatographic/mass spectrometric methods to separate and identify F(2)-isoprostane stereoisomers. These methods have been applied to the analysis of F(2)-isoprostanes derived from tissues of rats exposed to an oxidative stress and are useful to assess the relative formation of various regioisomers and stereoisomers generated in vitro and in vivo. The delineation of the more abundant isomers formed will allow for studies to examine the biological relevance of selected compounds in vivo.     

Bioactive eicosanoids: Role of prostaglandin F2α and F2-isoprostanes in inflammation and oxidative stress related pathology

Oxidative stress and inflammation are supposed to be the key players of several acute and chronic diseases, and also for progressive aging process. Eicosanoids, especially prostaglandin F_2α (PGF_2α) and F₂-isoprostanes are endogenous compounds that are involved both in physiology and the above mentioned pathologies. These compounds are biosynthesized mainly from esterified arachidonic acid through both enzymatic and non-enzymatic free radical-catalysed reactions in vivo, respectively. They have shown to possess potent biological activities in addition to their application as biomarkers of oxidative stress and inflammation. Recent advancement of methodologies has made it possible to quantify these compounds more reliably and apply them in various in vivo studies successfully. Today, experimental and clinical studies have revealed that both PGF_2α and F₂-isoprostanes are involved in severe acute or chronic inflammatory conditions such as rheumatic diseases, asthma, risk factors of atherosclerosis, diabetes, ischemia-reperfusion, septic shock and many others. These evidences promote that assessment of bioactive PGF_2α and F₂-isoprostanes simultaneously in body fluids offers unique non-invasive analytical opportunity to study the function of these eicosanoids in physiology, oxidative stress-related and inflammatory diseases, and also in the determination of potency of various radical scavengers, anti-inflammatory compounds, drugs, antioxidants and diet.     

Oxidative stress in human hypertension: association with antihypertensive treatment, gender, nutrition, and lifestyle

There is growing evidence that oxidative stress contributes to the pathogenesis of hypertension. Our aim was to measure markers of oxidative stress in hypertensive subjects, and assess the potential confounding influences of antihypertensive therapy, other cardiovascular risk factors, gender, lifestyle, and nutrition. Markers of oxidative stress, including plasma and 24 h urinary F2-isoprostanes, were measured in 70 untreated (men = 43, women = 27) and 85 treated (men = 43, women = 42) hypertensive subjects and 40 normotensive controls (men = 20, women = 20). Overall, F2-isoprostanes were not elevated in hypertensive subjects compared with controls. However, urinary and plasma F2-isoprostanes were significantly lower in treated compared with untreated hypertensive men, but not women. In hypertensive men, the number of antihypertensive drugs taken was inversely associated with both urinary and plasma F2-isoprostanes (p <.05). Self-reported alcohol intake and biomarkers of alcohol consumption (gamma-glutamyl transpeptidase and high-density lipoprotein cholesterol) were positively associated with plasma but not urinary, F2-isoprostanes in men. Several nutrients were independently associated with plasma and urinary F2-isoprostanes in women. The results do not support the hypothesis that treated or untreated hypertensive subjects are under increased oxidative stress compared with normotensive controls.     

Thromboxane receptor signalling in renal ischemia reperfusion injury

F(2)-isoprostanes are formed by oxidative modification of arachidonic acid and are the gold standard for detection of oxidative stress in vivo. F(2)-isoprostanes are biologically active compounds that signal through the thromboxane A(2) (TP) receptor; infusion of F(2)-isoprostanes reduces glomerular filtration in the kidney by constricting afferent arterioles. This study investigated whether endogenous F(2)-isoprostanes contribute to the pathogenesis of ischemic acute kidney injury, which is associated with oxidative stress and reduced glomerular filtration. TP receptor knockout mice-that lack F(2)-isoprostanes and thromboxane A(2) signalling-and wild-type control mice underwent 30 min of renal ischemia and 24 h of reperfusion. Kidney dysfunction, histological injury and the number of infiltrated neutrophils were similar between the two mouse strains, whereas TP receptor knockout mice had significantly more apoptotic cells and tissue lipid peroxidation than their wild-type counterparts. F(2)-isoprostanes and thromboxane B(2) were readily detectable in urine collections after surgery. The findings indicate that F(2)-isoprostanes and thromboxane A(2) signalling do not contribute critically to the pathogenesis of ischemic acute kidney injury and more generally provide evidence against a prominent role for F(2)-isoprostanes signalling in exacerbating acute disease states associated with oxidative stress.     

Isoprostanes in fetal and neonatal health and disease

Isoprostanes are prostaglandin-like bioactive molecules generated via nonenzymatic peroxidation of lipid membrane-derived arachidonic acid by free radicals and reactive oxygen species. Their cognate receptors, biological actions, and signaling pathways are poorly understood. Aside from being sensitive and specific biomarkers of oxidative stress, E- and F-ring isoprostanes have important biological functions and likely mediate many of the disease-related pathological changes for which they are used as indicators. The biochemical pathways involved in isoprostane formation, their pathogenetic relevance to adult disease states, and their biological function are addressed. Developmentally, plasma and tissue content data show that isoprostane levels are highest during fetal and early neonatal life, when compared with adults. As such, the available data suggesting that isoprostanes play an important biological role, as well as possibly actively participate in the regulation of pulmonary vascular tone and the transition from fetal to postnatal life, are here reviewed. Lastly, the association between isoprostanes and certain neonatal clinical conditions is addressed. Although its existence has been recognized for almost 20 years, little is known about the critical importance of isoprostanes during fetal life and immediate neonatal period. This review is an attempt to bridge this knowledge gap.     

Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases

F2-isoprostanes are produced in vivo by nonenzymatic peroxidation of arachidonic acid esterified in phospholipids. Increased urinary and plasma F2-isoprostane levels are associated with a number of human diseases. These metabolites are regarded as excellent markers of oxidant stress in vivo. Isoprostanes are initially generated in situ, i.e. when the arachidonate precursor is esterified in phospholipids, and they are subsequently released in free form. Although the mechanism(s) responsible for the release of free isoprostanes after in situ generation in membrane phospholipids is, for the most part, unknown, this process is likely mediated by phospholipase A2 activity(ies). Here we reported that human plasma contains an enzymatic activity that catalyzes this reaction. The activity associates with high density and low density lipoprotein and comigrates with platelet-activating factor (PAF) acetylhydrolase on KBr density gradients. Plasma samples from subjects deficient in PAF acetylhydrolase do not release F2-isoprostanes from esterified precursors. The intracellular PAF acetylhydrolase II, which shares homology to the plasma enzyme, also catalyzes this reaction. We found that both the intracellular and plasma PAF acetylhydrolases have high affinity for esterified F2-isoprostanes. However, the rate of esterified F2-isoprostane hydrolysis is much slower compared with the rate of hydrolysis of other substrates utilized by these enzymes. Studies using PAF acetylhydrolase transgenic mice indicated that these animals have a higher capacity to release F2-isoprostanes compared with nontransgenic littermates. Our results suggested that PAF acetylhydrolases play key roles in the hydrolysis of F2-isoprostanes esterified on phospholipids in vivo.     

Oxidative stress contributes to muscle atrophy in chronic kidney disease patients

Abstract

Objectives

Patients with chronic kidney disease have impaired muscle metabolism, resulting in muscle atrophy. Oxidative stress has previously been identified as a significant contributor to muscle atrophy in other populations, but the contribution in chronic kidney disease is unknown. The aim of this study was to investigate the association between oxidative stress, grip strength, and lean mass in patients with chronic kidney disease.

Methods

This is a cross-sectional study of 152 participants with stage 3 or 4 chronic kidney disease. Outcome measures include grip strength, lean mass, plasma total F2-isoprostanes, inflammation, peak oxygen uptake, and standard clinical measures.

Results

Thirty four (22.4%) chronic kidney disease patients had elevated oxidative stress levels (plasma F2-isoprostanes >250 pg/ml), with 82% of patients below age-predicted grip strength normative values. There was a significant negative association between plasma F2-isoprostanes and grip strength (r = ?0.251) and lean mass (r = ?0.243). There were no associations with inflammation markers. Multiple linear regression identified plasma F2-isoprostanes as a significant predictor of grip strength independent of other predictors: sex, diabetes status, body mass index, body fat percent, and phosphate (adjusted r² = 69.5, P < 0.001).

Discussion

Plasma F2-isoprostanes were independently associated with reduced strength in chronic kidney disease patients.