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BACKGROUND: Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). METHODS: We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by level of glomerular filtration (serum cystatin C and creatinine) and tubular injury (urinary NAG, KIM-1, α-GST, and π-GST) markers, in 262 hospitalized adults. RESULTS: In unadjusted analyses, compared with the GG genotype, the TNFA GA and AA genotype groups tended to have higher enrollment (p = 0.08), peak (p = 0.004), and discharge (p = 0.004) serum creatinine levels, and the AA genotype tended to have a higher enrollment serum cystatin C level (p = 0.04). Compared with the GG genotype, the TNFA GA and AA genotype groups tended to have a higher urinary KIM-1 level (p = 0.03), and the AA genotype group tended to have a higher urinary π-GST level (p = 0.03). After adjustment for sex, race, age, baseline estimated glomerular filtration rate, sepsis, and dialysis requirement, compared with the GG genotype, the TNFA minor A-allele group had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; p = 0.001) and a higher urinary KIM-1 (relative ratio: 1.73; 95% CI: 1.16, 2.59; p = 0.008). The TNFA minor A-allele group also had a higher Multiple Organ Failure score of 0.26 (95% CI: 0.03, 0.49; p = 0.024) after adjustment for sex, race, age, and sepsis. CONCLUSIONS: The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Larger studies are needed to confirm these relationships.

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CONTEXT: Urinary α-GST and π-GST are renal tubular leakage markers. OBJECTIVE: To evaluate the performance characteristics of these markers for the early detection of acute kidney injury (AKI). MATERIALS AND METHODS: Multicenter prospective cohort study of 252 adults undergoing cardiopulmonary bypass (CPB). RESULTS: AKI developed in 72 patients. The 2 h post-CPB π-GST level modestly predicted the development of AKI, including higher stages of severity, whereas α-GST did not. DISCUSSION: Small number of events and absence of subsequent post-operative biomarker measurements. CONCLUSIONS: Among adults undergoing CPB, urinary π-GST outperformed α-GST for predicting AKI, but neither marker displayed good discrimination.

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Myeloperoxidase (MPO) is a lysosomal enzyme that may be involved in oxidative stress-mediated kidney injury. Using a two-step approach, we measured the association of four polymorphisms across the length of the MPO gene with systemic markers of oxidative stress: plasma MPO and urinary 15-F(2t)-isoprostane levels. Adverse outcomes were measured in a primary cohort of 262 adults hospitalized with acute kidney injury, and a secondary cohort of 277 adults undergoing cardiac surgery with cardiopulmonary bypass and at risk for postoperative acute kidney injury. Dominant and haplotype multivariable logistic regression analyses found a genotype-phenotype association in the primary cohort between rs2243828, rs7208693, rs2071409, and rs2759 MPO polymorphisms and both markers of oxidative stress. In adjusted analyses, all four polymorphic allele groups had 2-3-fold higher odds for composite outcomes of dialysis or in-hospital death or a composite of dialysis, assisted mechanical ventilation, or in-hospital death. The MPO T-G-A-T haplotype copy-number was associated with lower plasma MPO levels and lower adjusted odds for the composite outcomes. Significant but less consistent associations were found in the secondary cohort. In summary, our two-step genetic association study identified several polymorphisms spanning the entire MPO gene locus and a common haplotype marker for patients at risk for acute kidney injury.

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BACKGROUND: Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI). METHODS: We first evaluated the potential role of functional multiallelic KLK1 promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C-rich repeat region of the proximal KLK1 promoter was determined by direct Sanger/capillary resequencing. RESULTS: 16 alleles were identified in a complex, polymorphic G/C-rich region of the KLK1 proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the KLK1 risk-allele (I or G) carrier state was associated with the composite of ≥2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The KLK1 risk-allele carrier state was also marginally associated with the composite of ≥2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06). CONCLUSIONS: KLK1 promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings.

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CONTEXT: Urinary α-glutathione S-transferase (α-GST) and π-glutathione S-transferase (π-GST) are promising proximal and distal tubular leakage markers for early detection of acute kidney injury (AKI). OBJECTIVE: To examine the performance of these markers for predicting the composite of dialysis requirement or in-hospital death in patients with an established diagnosis of AKI. MATERIALS AND METHODS: Prospective cohort study of 245 adults with AKI. A single urinary α-GST and π-GST measurement was obtained at time of nephrology consultation. RESULTS: Overall, urinary π-GST performed better than α-GST for prediction of dialysis requirement (AUC 0.59 vs. 0.56), and the composite outcome (AUC 0.58 vs. 0.56). In subgroup analyses, π-GST displayed better discrimination for prediction of dialysis requirement in patients with baseline eGFR <60 mL/min/1.73 m(2) (AUC 0.61) and oliguria (AUC 0.72). Similarly, α-GST performed better in patients with stage-1 (AUC 0.66) and stage-2 AKI (AUC 0.80). CONCLUSIONS: In patients with an established diagnosis of AKI, a single urinary π-GST measurement performed better than α-GST at predicting dialysis requirement or death, but neither marker had good prognostic discrimination.

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BACKGROUND: NADPH oxidase is an important enzyme involved in the generation of reactive oxygen species in acute kidney injury (AKI). Its key subunit, p22(phox), is encoded by the highly polymorphic CYBA gene. METHODS: We examined the associations of CYBA gene polymorphisms across the CYBA locus (rs8854, rs3794624, rs4673, rs4782390, and rs1049255) with dialysis requirement or in-hospital death in 256 hospitalized adults with AKI. Dominant and haplotype multivariable logistic regression analyses were performed, adjusted for sex, race, age, and severity of illness. RESULTS: The baseline characteristics of the patients were not different among genotype groups with the exception of a lower prevalence of sepsis and shock in the CYBA rs8854 A-allele group; a higher prevalence of shock in the CYBA rs4782390 T-allele group, and a higher APACHE II score in the CYBA rs1049255 G-allele group. The CYBA rs8854 A-allele had an adjusted odds ratio (OR) of 0.41 (95% confidence interval, CI, 0.18-0.96) for the outcome of dialysis requirement or in-hospital death. The CYBA rs4673 T-allele and rs1049255 G-allele had unadjusted ORs of 1.69 (95% CI 1.03-2.79) and 1.66 (95% CI 1.01-2.73) for the composite outcome, respectively, which became non-significant after multivariable adjustment. The remaining 2 polymorphisms were not associated with the outcomes of interest. Finally, the presence of the CYBA A-A-G-G haplotype (generated from rs4782390, rs4673, rs3794624, and rs8854, all in Hardy-Weinberg equilibrium) was associated with an elevated OR of 1.81 (95% CI 1.07-3.08) for dialysis requirement or in-hospital death, which was attenuated after multivariable adjustment (OR 1.80; 95% CI 0.99-3.29). CONCLUSION: This study identifies several polymorphisms spanning the entire CYBA gene locus and a common haplotype as risk markers for dialysis requirement or in-hospital death in patients with AKI. Additional studies are needed to validate these findings.

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BACKGROUND AND OBJECTIVES: Little is known about the performance of plasma cystatin C (CysC) in patients undergoing cardiopulmonary bypass (CPB) and its utility in the early diagnosis of acute kidney injury (AKI). In this post hoc analysis, the goal was to determine whether plasma cystatin C, measured 2 hours after the conclusion of CPB, is a reliable marker of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma CysC was measured in 150 patients undergoing CPB at the following times: preoperatively, 2 hours after the conclusion of CPB, postoperative day 1, and postoperative day 2. Plasma CysC levels were related to the development of AKI as defined by an increase in serum creatinine of >or=50% or >or=0.3 mg/dl from baseline up to 3 days postoperative. Mixed linear models were used to evaluate the relationship of serial plasma CysC values with AKI. The discriminatory capacity of plasma CysC was estimated using receiver operating characteristic curves. Logistic regression was utilized to assess the adjusted relationship between plasma CysC and subsequent AKI. RESULTS: AKI developed in 47 (31.3%) patients. Plasma CysC was higher at all times among patients who developed AKI compared with those who did not (P < 0.0001). The discriminatory capacity of plasma CysC measured preoperatively and 2 hours after the conclusion of CPB was modest. CONCLUSIONS: Serial measures of plasma CysC are highly correlated with the development of AKI. However, the discriminatory capacity of plasma CysC as an early marker of AKI remains limited.

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BACKGROUND/AIMS: The catecholaminergic pathway is important in the physical stress response; however, its role is not well understood in acute kidney injury (AKI). We studied single nucleotide polymorphisms (SNPs) of phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholaminergic pathway, and their association with adverse outcomes in AKI. METHODS: We performed a case-control study of 961 Caucasian subjects (194 with AKI and 767 controls). The PNMT promoter G-161A (rs876493) and coding A+1543G (rs5638) SNPs were genotyped and haplotypes generated. The outcomes of interest were the development of AKI, in-hospital mortality, dialysis requirement, oliguria, and hemodynamic shock. Urine catecholamines were measured in cases to explore genotype-phenotype correlations. RESULTS: The PNMT +1543 G allele was associated with AKI [odds ratio (OR) 2.19, 95% confidence interval (CI): 1.04-4.60]. For AKI cases, each PNMT -161 A allele was associated with lower mortality (OR 0.58, 95% CI: 0.35-0.99) and hemodynamic shock (OR 0.63, 95% CI: 0.40-1.00). The PNMT +1543 G allele was associated with oliguria (OR 3.35, 95% CI: 1.13-9.95). Urine adrenaline was associated with increased hemodynamic shock and mortality, but was lowest in PNMT -161 A/A carriers. CONCLUSION: In Caucasians, PNMT SNPs are associated with the development of AKI, disease severity, and in-hospital mortality. The adrenergic pathway provides another area of focus in the study of AKI.

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Chronic inflammation is highly prevalent in patients with chronic kidney disease (CKD), and is associated with increased cardiovascular morbidity and mortality. There are numerous causes of inflammation in CKD, including the potential exposure to bacterial lipopolysaccharide (LPS) in the bloodstream from the intestinal tract as a result of uremia-related increases in intestinal permeability. Sevelamer, a commonly prescribed non-calcium, non-metal-based phosphate binder in CKD, also possesses putative anti-inflammatory properties, as its use has been associated with a reduction in systemic markers of inflammation. Emerging studies have provided direct evidence that sevelamer shows in vitro LPS-binding properties. Indirect clinical evidence suggests that sevelamer might also limit translocation of LPS from the intestinal lumen into the bloodstream. This review focuses on bacterial LPS as a source of chronic inflammation in CKD, and proposes that sevelamer might possess novel anti-inflammatory properties as a result of LPS binding in the intestinal tract. The proposed hypothesis that intestinal LPS-binding by sevelamer may lower circulating LPS, and in turn systemic inflammation, requires further evaluation in a clinical trial.

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BACKGROUND: Cardiopulmonary bypass (CPB) elicits an inflammatory response mediated partly by neutrophils, which are activated and recruited by interleukin-8 (IL-8). We hypothesized that acute kidney injury (AKI) following CPB might be mediated by IL-8 and examined the association of perioperative plasma IL-8 levels with AKI in a prospective cohort. METHODS: Plasma IL-8 was measured before, and 2, 24 and 48 h following CPB. Two AKI definitions, a serum creatinine increase of > or = 0.3 mg/dl or 50% (AKI Network [AKIN] stage-1) or > or = 50% alone (AKI-50%), within the first 72 h, were used. Area under the receiver operator characteristic curves (AUCs) were generated and multivariable logistic regression analyses performed. RESULTS: A total of 143 patients were enrolled. The baseline mean serum creatinine was 1.1 mg/ dl (SD = 0.3), the CPB perfusion time was 112 min (SD = 43). Twenty-nine percent of the patients developed AKIN stage-1 and 13% AKI-50%. The plasma IL-8 level 2 h after CPB was higher in AKIN stage-1 (p = 0.03) and AKI-50% (p < 0.01), and predicted AKIN stage-1 (AUC = 0.62; p = 0.02) and AKI-50% (AUC = 0.72; p < 0.01). On multivariable analysis, the 2-hour plasma IL-8 level was associated with 1.36- and 1.59-fold higher odds for AKIN stage-1 and AKI-50%, respectively (p = 0.05). CONCLUSION: Plasma IL-8 predicts the development of AKI following CPB, supporting a potential involvement for this chemokine in the pathogenesis of AKI.

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BACKGROUND: Serum cystatin C has emerged as a new and potentially more reliable marker of kidney function. However, its utility and performance in patients with acute kidney injury (AKI), particularly for the prediction of dialysis requirement, is not well known. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Adult patients with AKI enrolled at 2 academic medical centers, at time of nephrology consultation. PREDICTORS: Serum cystatin C (primary predictor), serum creatinine, and serum urea nitrogen levels and 24-hour urine output measured at enrollment. OUTCOMES: The composite of dialysis requirement or in-hospital death. COVARIATES: Acute Physiology and Chronic Health Evaluation II (APACHE II) score, liver disease, sepsis, and mechanical ventilation. RESULTS: 200 participants were enrolled for this analysis. Mean age was 65 years, 55% were men, and mean APACHE II score was 20. In unadjusted analyses, increases in serum cystatin C (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.36 to 2.59), serum creatinine (OR, 1.53; 95% CI, 1.12 to 2.09), and serum urea nitrogen levels (OR, 1.84; 95% CI, 1.34 to 2.54) were associated with a higher odds (per 1-SD increase) for the composite outcome, whereas greater urine output (OR, 0.56; 95% CI, 0.39 to 0.80) was associated with lower odds. These associations persisted after adjustment for APACHE II score. The addition of serum cystatin C, serum creatinine, and serum urea nitrogen levels or urine output to a basic model entailing APACHE II score, liver disease, sepsis, and assisted mechanical ventilation improved its prediction, evidenced by increases in areas under a receiver operator characteristic curve from 0.816 to 0.829, 0.826, 0.837, and 0.836, respectively. However, there was no significant difference between each of these models. LIMITATIONS: Observational study, single serum cystatin C measurement. CONCLUSION: In patients with AKI, serum cystatin C level performs similarly to serum creatinine level, serum urea nitrogen level, and urine output for predicting dialysis requirement or in-hospital death. Larger studies are needed to confirm these findings.

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The purpose of this study was to compare the performance of six candidate urinary biomarkers, kidney injury molecule (KIM)-1, N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, cystatin C and alpha-1 microglobulin, measured 2 h following cardiopulmonary bypass (CPB) for the early detection of acute kidney injury (AKI) in a prospective cohort of patients undergoing cardiac surgery. A total of 103 subjects were enrolled; AKI developed in 13%. Urinary KIM-1 achieved the highest area under-the-receiver-operator-characteristic curve (AUC 0.78, 95% confidence interval 0.64-0.91), followed by IL-18 and NAG. Only urinary KIM-1 remained independently associated with AKI after adjustment for a preoperative AKI prediction score (Cleveland Clinic Foundation score; p = 0.02), or CPB perfusion time (p = 0.006). In this small pilot cohort, KIM-1 performed best as an early biomarker for AKI. Larger studies are needed to explore further the role of biomarkers for early detection of AKI following cardiac surgery.

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OBJECTIVE: There is a growing interest in the potential anti-inflammatory properties of sevelamer hydrochloride, a commonly used phosphate binder for patients with chronic kidney failure. This study explores the hypothesis that sevelamer hydrochloride binds bacterial endotoxin in the intestinal tract, leading to lower circulating endotoxin levels, and offering a novel anti-inflammatory mechanism. METHODS: We performed a cross-sectional study in medically stable patients with chronic kidney failure undergoing maintenance hemodialysis. Blood samples were collected before 2 consecutive dialysis sessions, and plasma was tested for endotoxin, interleukin-6 and C-reactive protein. Linear regression analyses were used to examine patient-related and dialysis-related factors associated with plasma endotoxin level. RESULTS: Forty-six patients met our eligibility criteria. Their mean age was 62 years, 41% were diabetic, and 65% reported the use of sevelamer hydrochloride. The mean plasma endotoxin level was significantly lower in patients using sevelamer hydrochloride compared with those who were not (0.23 +/- 0.01 vs. 0.30 +/- 0.01 EU/mL, P = .001). However, plasma interleukin-6 and C-reactive protein levels were not significantly different between the two groups. According to multivariate analysis, the use of sevelamer hydrochloride was associated with a lower plasma endotoxin level after adjustment for race, gender, age, dialysis vintage, total cholesterol level, and white blood cell count. CONCLUSIONS: This proof-of-concept pilot study demonstrates that the use of sevelamer hydrochloride is associated with a lower plasma endotoxin level, supporting the hypothesis that this agent binds to endotoxin in the intestinal lumen. Although this may be an important mechanism by which sevelamer hydrochloride attenuates systemic inflammation, a clinical trial is required to test this hypothesis.

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Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that mediates many cellular responses to tissue hypoxia, a common feature of acute kidney injury (AKI). Here we studied 241 patients with AKI and determined the relationship to adverse outcome of a non-synonymous polymorphism in the coding region of the HIF-1alpha gene where a C to T substitution occurs at position +85 in exon 12, a change known to enhance transactivation. The baseline characteristics of the patients were not different among genotype groups except for a significantly higher prevalence of shock and number of failed organs in T-allele carriers. A significant genotype-phenotype association was found for plasma levels of vascular endothelial growth factor-A but not angiopoietin-2, two downstream targets of HIF-1alpha. Compared to the CC genotype, T-allele carriers had significantly higher adjusted odds for dialysis requirement or in-hospital death; assisted mechanical ventilation or dialysis requirement; and the composite of assisted mechanical ventilation, dialysis requirement or in-hospital death. The trend for higher plasma angiopoietin-2 levels was associated with significantly higher adjusted odds for in-hospital death; dialysis requirement or in-hospital death; and the composite outcome of assisted mechanical ventilation, dialysis, or in-hospital death. Despite the limited cohort size, our study found this particular HIF-1alpha genetic variant to be associated with disease severity and adverse outcomes in AKI. Larger studies are needed to confirm these relationships.

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BACKGROUND: Sevelamer hydrochloride has been shown to attenuate circulating biomarkers of inflammation in patients with chronic kidney failure. We hypothesize that sevelamer hydrochloride binds bacterial endotoxin (ET) resulting in a decrease in ET levels and cytokine production. METHODS: To assess the ET-binding affinity of sevelamer hydrochloride, purified Escherichia coli ET was incubated with sevelamer hydrochloride (0-50 mg/ml). After incubation, ET was measured in supernatants. In addition, THP-1-derived monocytes were co-incubated with supernatants of sevelamer hydrochloride and ET. After 24-hour incubation, TNF-alpha was measured. The effect of pH on the ET-binding affinity of sevelamer hydrochloride, as well as cooperative binding between ET and phosphate for sevelamer hydrochloride were assessed. RESULTS: Sevelamer hydrochloride exhibited time- and dose-dependent binding affinity for ET, resulting in a marked reduction in free ET levels. The 1-hour dose-dependent ET-binding effect of sevelamer hydrochloride translated into a marked reduction in TNF-alpha levels. Varying the pH conditions did not affect the ET-binding affinity of sevelamer hydrochloride. The addition of phosphate (0-50 mM) resulted in a further reduction in free ET levels, translating into a further increase in the binding affinity of sevelamer hydrochloride for ET. CONCLUSIONS: This study demonstrates that sevelamer hydrochloride binds to ET, thereby reducing free ET and cytokine levels. Positive cooperative binding was also noted between phosphate and ET for sevelamer hydrochloride. This study supports the hypothesis that sevelamer hydrochloride might bind to ET in the intestinal lumen and reduce systemic inflammation. Animal and human studies are required to examine this hypothesis.

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We recently demonstrated that melatonin, N-acetylserotonin (NAS), and N-acetyldopamine (NAD) attenuate the synthesis of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) and the generation of oxidant radicals. In this study, we examined whether acetyl and methyl derivatives of dopamine modulate LPS-stimulated TNF-alpha synthesis and LPS- and iron-induced lipid peroxidation. Differentiated THP-1-derived human monocytes were coincubated with Escherichia coli and rising concentrations of NAS, NAD, N-methyldopamine (NMD), or 4-O-methyldopamine (4-O-MD). After 24 h, TNF-alpha was measured in cell supernatants. In addition, lipid peroxidation was induced by adding FeCl(2) solution to mouse brain tissue homogenates in the presence of rising concentrations of NAS, NAD, NMD, or 4-O-MD. Incubating THP-1-derived monocytes with rising concentrations of NAS, NAD, NMD, or 4-O-MD markedly decreased LPS-stimulated TNF-alpha production, which was dose dependent and on the order of 96%-98%. Rising concentrations of NMD markedly inhibited lipid peroxidation by 59%-98%. Our results indicated that the inhibitory effect of NAS, NAD, NMD, or 4-O-MD on LPS-induced TNF-alpha production and FeCl(2)-stimulated lipid peroxidation is robust and dose dependent.

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The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.

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Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.

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Melatonin and N-acetylserotonin (NAS) have antioxidant properties. In the present study, we examined whether melatonin, NAS, and N-acetyldopamine (NAD) have a modulatory effect on tumor necrosis factor-alpha (TNF-alpha) synthesis and superoxide production. Differentiated THP-1-derived human monocytes were coincubated with Escherichia coli lipopolysaccharide (LPS) and rising concentrations of melatonin, NAS, or NAD. After 24 h, TNF-alpha was measured in cell supernatants. In addition, the production of superoxide by HL-60-derived human neutrophils upon stimulation with 4-beta-phorbol 12-beta-myristate 13-alpha-acetate (PMA) or N-formyl methionyl-leucyl-phenylalanine (fMLP) and increasing concentrations of melatonin, NAS, or NAD was determined. Incubation of THP-1-derived monocytes with increasing concentrations of melatonin, NAS, or NAD resulted in a marked decrease in LPS-stimulated TNF-alpha production, which was dose-dependent and on the order of 96-98%. Incubation of HL-60-derived neutrophils with increasing concentrations of melatonin, NAS, or NAD resulted in a modest decrease in PMA-stimulated superoxide production, which was dose-dependent. At the 100 microM dose, melatonin, NAS, or NAD resulted in a 14 +/- 4%, 30 +/- 1%, and 29 +/- 1% decrease in PMA-stimulated superoxide production, respectively. Coincubation of HL-60 cells with melatonin, NAS, or NAD also resulted in a modest dose-dependent decrease in fMLP-stimulated superoxide production. At the 100 microM dose, melatonin, NAS, or NAD resulted in a 13 +/- 1%, 14 +/- 1%, and 14 +/- 1% decrease in superoxide production, respectively. Our results indicate that the inhibitory effect of melatonin, NAS, or NAD on LPS-induced TNF-alpha production is robust and dose-dependent. These compounds are equally effective in attenuating the generation of oxidant radicals, although to a lesser degree.

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BACKGROUND: Interleukin-6 (IL-6) is a mediator and marker of the chronic inflammatory process that is responsible for much of the morbidity and mortality seen in hemodialysis (HD) patients. This study evaluated circulating plasma IL-6 as a predictor of all-cause mortality and cardiovascular mortality and studied its relationship to prevalent comorbidity and hypoalbuminemia, in a cohort of stable HD patients enrolled in the HEMO study. METHODS: Clinical data included demographic, medical, and routine laboratory parameters. Comorbidities were graded using the Index of Co-Existing Diseases (ICED). Outcomes of interest were all-cause mortality and cardiovascular mortality. Blood samples were drawn at enrollment and annually, and plasma IL-6 levels measured with high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Median plasma IL-6 level in 206 patients was 7.9 pg/mL (range, 0.1 to 90.3 pg/mL) and was higher in patients with vascular disease ( P = 0.03), higher ICED scores ( P = 0.01), and lower Karnofsky indices ( P < 0.01). Serum albumin was inversely related to plasma IL-6 levels ( P = 0.03, r = -0.16). Unadjusted median survival time was 1,209 days in the lowest quartile of plasma IL-6 and 806 days in the highest ( P = 0.02, log rank test). A 1-log increase in plasma IL-6 was associated with a 1.19-fold higher adjusted risk for all-cause mortality ( P = 0.04; 95% confidence interval, 1.01 to 1.40) and a 1.43-fold higher adjusted risk of cardiovascular mortality ( P = 0.02; 95% confidence interval, 1.06 to 1.92). Hazard ratio estimates were higher when IL-6 levels over time were incorporated as a time-dependent covariate. CONCLUSION: Plasma IL-6 levels are strongly associated with comorbidity in HD patients and are a powerful predictor of cardiovascular and all-cause mortality.

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