Biomedical subjects

Vaidyanathapuram S Balakrishnan

Publications and source records attributed to Vaidyanathapuram S Balakrishnan.

At least 19 recordsLinked to original sources

PubMed2006

NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure.

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.

Acute Kidney Injury↗

PubMed2006

A systematic review of the effect of the Excebrane dialyser on biomarkers of lipid peroxidation.

BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anaemia. We conducted a systematic review and meta-analysis to examine the effect of Excebrane, a vitamin E-coated cellulose-based dialyser, on circulating biomarkers of lipid peroxidation, as surrogate markers of oxidative stress. METHODS: The primary sources used to identify candidate studies included PubMed, the Cochrane Central Register of Controlled Trials, a bibliography provided by the dialyser manufacturer, and a manual search of abstracts from proceedings of scientific meetings and review articles. Studies were selected for analysis if their design included a comparator group (primarily within patient comparison, i.e. pre- and post-study evaluations). For the meta-analysis, we computed the overall change of the outcome from baseline using a random-effects model. A supplemental analysis was performed in which the absolute levels of these biomarkers of lipid peroxidation were converted to a common unit by calculating standardized effect sizes. RESULTS: Fourteen peer-reviewed articles met the criteria. The studies consisted of 11 single arm, one randomized crossover and two randomized controlled trials, with a total of 37 to 158 evaluable patients, according to the outcome of interest analysed. Due to the paucity of randomized trials, the meta-analysis was limited to the Excebrane arm of each study. When the studies were combined according to similar measurement units, the overall mean decrease in malondialdehyde (MDA) level was -0.3 mM (95% CI, -0.5 to -0.1 mM; seven studies) and -0.8 nmol/mg low-density lipoprotein (LDL) (95% CI, -1.3 to -0.4 nmol/mg LDL; three studies), respectively. The summary estimate revealed a non-significant decrease in pre-dialysis thiobarbituric acid reactive substances (TBARS) level of 0.4 microM (95% CI, -1.2 to 0.4 microM; three studies). When the MDA and TBARS studies were combined using the standardized effect size, the mean decrease in these biomarkers of lipid peroxidation was statistically significant at -1.7 units (95% CI, -2.7, -0.7 units; 13 studies). A meta-analysis on the effect of Excebrane on pre-dialysis levels of oxidized-LDL could not be performed due to study heterogeneity. CONCLUSION: The conversion of dialysis patients to a vitamin E-coated dialyser is associated with an improvement in circulating biomarkers of lipid peroxidation, which is of potential clinical benefit.

Antioxidants↗

PubMed2006

The kidney disease wasting: inflammation, oxidative stress, and diet-gene interaction.

The 350,000 maintenance hemodialysis (MHD) patients in the United States have an unacceptably high mortality rate of >20%/year. Almost half of all deaths are assumed to be cardiovascular. Markers of kidney disease wasting (KDW) such as hypoalbuminemia, anorexia, body weight and fat loss, rather than traditional cardiovascular risk factors, appear to be the strongest predictors of early death in these patients. The KDW is closely related to oxidative stress (SOX). Such SOX markers as serum myeloperoxidase are associated with pro-inflammatory cytokines and poor survival in MHD patients. Identifying the conditions that modulate the KDW/SOX-axis may be the key to improving outcomes in MHD patients. Dysfunctional lipoproteins such as a higher ratio of the high-density lipoprotein inflammatory index (HII) may engender or aggravate the KDW, whereas functionally intact or larger lipoprotein pools, as in hypercholesterolemia and obesity, may mitigate the KDW in MHD patients. Hence, a reverse epidemiology or "bad-gone-good" phenomenon may be observed. Diet and gene and their complex interaction may lead to higher proportions of pro-inflammatory or oxidative lipoproteins such as HII, resulting in the aggravation of the SOX and inflammatory processes, endothelial dysfunction, and subsequent atherosclerotic cardiovascular disease and death in MHD patients. Understanding the factors that modulate the KDW/SOX complex and their associations with genetic polymorphism, nutrition, and outcomes in MHD patients may lead to developing more effective strategies to improve outcomes in this and the 20 to 30 million Americans with chronic disease states such as individuals with chronic heart failure, advanced age, malignancies, AIDS, or cachexia.

Cardiovascular Diseases↗

PubMed2005

Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients.

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.

Adolescent↗

PubMed2005

Polymorphism of host response genes: implications in the pathogenesis and treatment of acute renal failure.

Acute inflammatory disorders are the result of an interaction between genetic and environmental factors, and are often characterized by an imbalance between pro- and anti-inflammatory host immune responses. Over the past decade, polymorphisms of host response genes have been explored as genetic risk and prognostic markers in the course and severity of acute inflammatory disorders. Increasing evidence supports an important role for inflammatory mechanisms in the pathogenesis of acute renal failure (ARF) following both ischemic and nephrotoxic injury. The use of genetic epidemiology may become a useful tool to identify patients with an altered susceptibility to developing hospital-acquired ARF, and stratify those who may benefit from preventive therapies that modulate host immune responses in a favorable way. This review summarizes the existing experimental and clinical studies supporting the role of inflammation in ARF and critically appraises studies that have examined polymorphism of immune response genes as potential determinants of susceptibility to and severity of acute inflammatory disorders. Conclusions are drawn on the application of genetic epidemiology to the field of ARF and the rationale for further research on the role of genetic markers in ARF.

Acute Kidney Injury↗

PubMed2004

Relationship of urine output to dialysis initiation and mortality in acute renal failure.

BACKGROUND: A non-oliguric state is considered a good prognostic indicator in acute renal failure (ARF), and may lead to withholding renal replacement therapy in anticipation of recovery. The present study explores the relationship between urine volume and the start of dialysis and hospital mortality in patients with ARF. METHODS: In a non-concurrent cohort of patients with ARF treated exclusively with intermittent hemodialysis (IHD), demographic, clinical and laboratory characteristics were collected at the time of the first nephrology consultation and at the start of dialysis. Multiple linear and logistic regression analyses were used to identify factors associated with the time to initiation of dialysis and hospital mortality, respectively. RESULTS: Urine volume correlated with the time from admission to start of dialysis (r = 0.60; p < 0.001). Higher urine volume, lower serum creatinine and lower APACHE II score were independently associated with increased time from admission to start of dialysis. Hospital mortality was independently associated with a higher urine volume (odds ratio, OR 3.8, 95% confidence interval, CI, 1.1-12.8, p = 0.03), a higher MOF score (OR 4.9, 95% CI 1.1-21.6, p = 0.03) and a higher number of dialysis treatments performed in the 1st week (OR 3.7, 95% CI 1.2-11.3, p = 0.03). CONCLUSIONS: Among patients with ARF requiring IHD, increased urine output is associated with higher mortality. This observation may reflect physician bias toward later initiation of dialysis in non-oliguric ARF. Further research is needed to help identify patients with non-oliguric ARF who require early dialytic support.

Acute Kidney Injury↗

PubMed2004

Iron storage indices: novel predictors of bacteremia in hemodialysis patients initiating intravenous iron therapy.

Bacterial sepsis is the second leading cause of death among hemodialysis (HD) patients. Iron overload and intravenous iron therapy are linked to bacterial infection. This study examined iron stores, intravenous iron dosing, and bacteremic risk in HD patients. Retrospectively, 132 HD patients receiving their first course of intravenous iron were studied. Baseline laboratory values, including transferrin saturation (TSAT) value and ferritin level, were measured before initiating intravenous iron therapy. Patients were followed for up to 1 year after the initiation of iron therapy for the outcome of bacteremia by Cox proportional hazards regression analysis. Iron-replete patients (those with a TSAT value > or =20% and a ferritin level > or =100 ng/mL) had a significantly higher risk of bacteremia (hazard ratio [HR], 2.5). Venous catheter users (HR, 4.9) and those with diabetes mellitus (HR, 2.2) were also at increased risk. Modest iron storage levels may increase the risk of bacteremia among HD patients initiating intravenous iron therapy. Additional studies are needed to confirm these relationships.

Bacteremia↗

PubMed2004

Cytokine gene promoter polymorphisms and mortality in acute renal failure.

BACKGROUND: Although cytokines play a pivotal role in the inflammatory responses that mediate the severity of acute renal failure (ARF), the importance of pro- and anti-inflammatory cytokine gene promoter polymorphisms has been unexplored. METHODS: We prospectively evaluated the relationship of single nucleotide polymorphism in the promoter region of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) to mortality in 61 patients with ARF requiring intermittent hemodialysis. Cytokine genotyping was performed on leukocytes using PCR techniques. Cox proportional-hazards regression analysis was used to explore these relationships. RESULTS: The mean (+/-SD) APACHE II score was 24 +/- 7, MOF score 2 +/- 1, and 64% had sepsis. The TNF-alpha high producer genotype (-308 A-allele carrier) was associated with a higher risk of death after adjustment for the APACHE II score (HR=2.5; P=0.04), and the IL-10 intermediate/high producer genotype (-1082 G-allele carrier) was associated with a lower risk of death after adjustment for the MOF score (HR=0.36; P=0.03). Considering combinations of genotypes, the TNF-alpha high and IL-10 low producer genotype combination was associated with a approximately 6-fold increased risk of death compared to the TNF-alpha-low and IL-10 intermediate/high producer genotype combination, after adjustment for either APACHE II (P=0.004), MOF score (P=0.004) or sepsis (P=0.006). CONCLUSIONS: TNF-alpha and IL-10 gene polymorphisms are related to the risk of death among patients with ARF who require dialysis. Larger studies are needed to confirm these relationships.

Acute Kidney Injury↗

PubMed2004

Dialyzer membrane type and reuse practice influence polymorphonuclear leukocyte function in hemodialysis patients.

BACKGROUND: Polymorphonuclear leukocyte (PMNL) production of reactive oxygen species (ROS) has been linked to hemodialysis (HD) associated morbidity. The effect of dialyzer membrane type and reuse on PMNL function has not been clearly defined. METHODS: The present report is a cross-sectional study undertaken in a cohort of patients undergoing regular HD, at enrollment into the Hemodialysis (HEMO) Study, to study the association between patient and dialysis-related factors and PMNL function. PMNL function was assessed by measuring PMA- and N-formyl methionyl-leucyl-phenylalanine (fMLP) -induced respiratory burst, and phagocytic activity toward Staphylococcus aureus. RESULTS: PMNL from patients dialyzed with polysulphone (PS) or cuprophane (CU) membranes showed higher PMA-induced respiratory burst activity compared with those exposed to substituted cellulose (cellulose acetate, cellulose triacetate, CA/CT) membranes, regardless of dialyzer reuse. The use of bleach as a cleansing agent during reuse was associated with higher PMA-induced PMNL superoxide production, as was the use of renalin when compared to aldehydes. In a subgroup of patients using PS dialyzers, reuse itself was associated with higher fMLP-induced superoxide production. The type of bleach-germicide combination during reuse showed that use of renalin as a germicide was also associated with higher PMNL phagocytosis index. The number of years on HD correlated inversely with PMA-induced PMNL superoxide response. Weaker PMNL response to fMLP was associated with greater comorbidity and poor functional status as quantified by Index of Coexisting Diseases (ICED) and Karnofsky scores, respectively. CONCLUSION: Our results indicate that dialyzer membrane type and the reuse process influence the oxidative response of PMNL among HD patients. The implications of these observations on clinical morbidity need to be further evaluated in prospective studies.

Aged↗

PubMed2004

Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin.

BACKGROUND: Cytokine-orchestrated chronic inflammation plays a major role in long-term morbidity and mortality in patients with end-stage renal disease (ESRD) on hemodialysis (HD). In this cross-sectional study, we evaluated the association between specific alleles/genotypes and combinations of genotypes of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), and IL-10 with indices of comorbidity, functional status, and other biological markers in a cohort of 183 ESRD patients recruited to the Hemodialysis (HEMO) Study from two Boston centers. METHODS: Genotyping was performed for single nucleotide polymorphisms in the promoter region of IL-6 (-174 G-->C), TNF-alpha (-308 G-->A), and IL-10 (-1082 G-->A). The relationship of specific genotypes to the index of coexistent disease (ICED) score (an index of comorbidity), Karnofsky Index (a measure of functional status), serum albumin, and nutritional indices (anthropometric measurements, body mass index, normalized protein catabolic ratio) were studied. Plasma IL-6 levels, as well as TNF-alpha and IL-10 production by endotoxin-stimulated peripheral blood mononuclear cells (PBMC), were also measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with the high producer genotypes for the proinflammatory cytokines IL-6 (G/G and G/C) and TNF-alpha (G/A and A/A) had significantly higher comorbidity (ICED scores of > or =2) and lower functional scores (Karnofsky Index) compared with patients with the low producer genotypes for these cytokines (C/C and G/G, respectively). In contrast, patients with the high and intermediate producer genotypes (G/G and G/A) for the anti-inflammatory cytokine IL-10 had a higher Karnofsky Index compared with those with the low producer genotype (A/A). Serum albumin levels were lower in patients with the TNF-alpha high producer genotype (G/A and A/A) compared with those with the low producer genotype (G/A and A/A). On multivariate analysis, the IL-6 high producer genotypes were associated with an odds ratio (OR) of 4.87 for higher comorbidity (ICED scores > or =2) (P= 0.02), and 4.9 for lower Karnofsky Index (lower functional status) (P= 0.04) compared with patients with the low IL-6 producer genotypes. Similarly, the TNF-alpha high producer genotype was associated with increased odds for a higher ICED score, lower Karnofsky Index, and lower serum albumin compared with patients with the low producer genotype for this cytokine. In contrast, the IL-10 high/intermediate producer genotype was associated with increased odds for a higher Karnofsky Index (P= 0.05). Cytokine genotype combinations-the TNF-alpha high producer and IL-6 high producer genotype combination, and the IL-6 high producer and IL-10 low producer genotype combination-were independently associated with a higher ICED score. These genotype combinations, as well as the TNF-alpha high producer and IL-10 low producer genotype combination, were also associated with a lower Karnofsky Index. CONCLUSION: In ESRD patients on long-term HD, single nucleotide polymorphisms in the promoter region of the proinflammatory cytokines IL-6 and TNF-alpha, and the regulatory monokine IL-10, show a strong association with indices of comorbidity and function, and biological and nutritional markers.

Aged↗

PubMed2004

Transforming growth factor-beta 1 gene polymorphisms and cardiovascular disease in hemodialysis patients.

BACKGROUND: Atherosclerotic vascular disease is a leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD). Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that inhibits the atheromatous process. We studied coding region polymorphisms of the TGF-beta1 gene (+869 T --> C at codon 10 and +915 G --> C at codon 25) as genetic susceptibility factors for prevalent vascular disease and cardiac outcomes in a cohort of HD patients enrolled in the HEMO Study. METHODS: Genotyping was carried out using polymerase chain reaction-sequence specific primer (PCR-SSP) methods with a cytokine genotyping tray. Prevalent vascular disease was coded from the Index of Disease Severity (IDS) scores for ischemic heart disease (IHD), peripheral vascular disease (PVD), cerebrovascular disease (CVD), and congestive heart failure (CHF), 0 indicating absence, and 1 to 3 increasing grades of severity. The presence of any vascular disease (VD) (i.e., any degree of IHD/PVD/CVD), and the number of coexistent vascular system diseases per patient were derived. Cardiac outcomes, one of the secondary outcomes of the HEMO Study, were expressed as a composite of the first hospitalization for, or death from, cardiac causes. RESULTS: The cohort consisted of 183 patients at enrollment, 56% male, 44% African American (AA), and 40% diabetic. The mean age was 62.4 +/- 12.2 years, and median dialysis vintage 2.02 years. The most frequent genotype at codon 10 was T/C (67%), and at codon 25 was G/G (72%). IHD was present in 52% of patients; 65% had at least one vascular system involvement, and 31% had 2 or more. On both univariate and multivariate analysis, the G/C genotype at codon 25 was significantly associated with the presence and extent of vascular disease at enrollment. The median time to cardiac outcome, defined as a composite of the first hospitalization for, or death from, cardiac causes, was 411 days in patients with the G/C genotype compared with 851 days in those with the G/G genotype (P= 0.03). Patients with the G/C genotype had a 1.6-fold increased hazard for cardiac outcomes after adjustment for baseline covariates (P= 0.04). CONCLUSION: The G/C substitution at codon 25 was associated with an increased risk for prevalent vascular disease, new onset cardiac morbidity, and cardiac mortality in HD patients, and may be a genetic susceptibility factor for the development of atherosclerosis. Further studies are required to evaluate the role of TGF-beta1 as a candidate gene.

Aged↗

PubMed2004

Factors associated with urea reduction ratio in acute renal failure.

Prescription and delivery of hemodialysis (HD) in acute renal failure (ARF) may be affected by patient-related factors such as hemodynamic instability, catabolism, variable extracellular fluid volume, and coagulation disturbances. This study was undertaken in a cohort of patients with ARF requiring HD, to quantify patient- and dialysis-related variables that influence dialysis delivery. The urea reduction ratio (URR) was calculated for each HD session. Patient-related variables included age, gender, weight, mean arterial pressure, and Acute Physiological and Chronic Health Evaluation (APACHE) II and Multiple Organ Failure (MOF) scores. Dialysis-related variables were dialyzer characteristics (membrane type, surface area, KoA, and K(UF)), blood flow rate (Qb), session length, anticoagulant use, vascular access, and ultrafiltration volume. The analysis of factors associated with URR was performed using mixed linear statistical models. The cohort consisted of 81 adult patients with ARF who underwent 419 consecutive dialysis sessions. Mean (+/- SD) age was 60 +/- 18 years; 57% were male. At dialysis initiation, APACHE II score was 23 +/- 8 and MOF score 2 +/- 1. The number of HD treatments averaged 5.5 +/- 6.1/patient and 0.8 +/- 0.2/patient/day, mean URR was 54 +/- 15%, and session length 3.2 +/- 1.1 h; 58% used a femoral venous catheter, and 92% polysulfone dialyzers. Among patient-related variables, the only independent predictor of delivered dose of dialysis, as measured by URR was the predialysis weight (P < 0.01). Among the dialysis-related variables, treatment time (P < 0.01), dialyzer surface area (P < 0.01), dialyzer K(UF) (P = 0.04), blood flow rate (P < 0.01), and the use of a femoral venous catheter (P < 0.01) were also independently associated with URR. An interaction between vascular access site and blood flow rate was also found to be significant (P < 0.01). This study underscores the importance of the dialysis prescription parameters and vascular access site in influencing the dialysis dose in critically ill patients, and argues against the importance of patient-related characteristics such as disease severity.

APACHE↗

PubMed2004

Polymorphism of immunomodulatory cytokine genes: implications in acute renal failure.

Experimental studies have incriminated cytokines and other immunoregulatory molecules as important mediators of tissue injury in acute renal failure (ARF). The relative importance of genetic factors, e.g. polymorphisms involving cytokine genes, in influencing susceptibility to and severity of ARF is unknown. This review summarizes the existing experimental and clinical studies supporting the role of inflammation in ARF, and critically examines human studies that have examined polymorphism of two critical cytokine genes, tumor necrosis factor-alpha and interleukin-10, as potential determinants of susceptibility to and severity of acute infectious and inflammatory diseases. Conclusions are drawn on the application of genetic epidemiology to the field of ARF and the rationale for further research on the role of genetic markers in ARF.

Acute Kidney Injury↗

PubMed2004

Reprocessed (high-flux) Polyflux dialyzers resist trans-membrane endotoxin passage and attenuate inflammatory markers.

BACKGROUND: Bacterial contamination of dialysis water can contribute to the chronic microinflammatory state observed in dialysis patients. This study characterized the selective permeability of new and peroxyacetic acid/acetic acid/hydrogen peroxide (Renalin) reprocessed high-flux, polyarylethersulfone-polyvinylpyrrolidone (Polyflux-17R) dialyzers after exposure to endotoxin-contaminated dialysate during in vitro dialysis. Clinical correlation with pre-dialysis levels of systemic markers of inflammation, and clearance of middle molecules was also assessed in vivo. METHODS: Six hemodialysis (HD) patients were enrolled in the study. After reuses 0, 1, 5, 10, and 15, the dialyzers were reclaimed and submitted to an in vitro dialysis circuit using standard dialysate and blood from healthy volunteers. New and reprocessed dialyzers were sequentially exposed to escalating doses of Pseudomonas aeruginosa endotoxin in the dialysate compartment, and whole blood tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production was used as an index of reverse passage of endotoxin. In vivo, IL-6, C-reactive protein (CRP) and serum amyloid A (SAA) levels were measured to assess the impact of reprocessing on the systemic inflammatory response. Finally, pre- and post-dialysis samples were collected to measure urea and beta(2)-microglobulin (beta(2)-M) clearances. RESULTS: During in vitro dialysis, blood-side endotoxin levels were undetectable following dialysate contamination. TNF-alpha production remained unchanged (p = NS), and IL-6 production fell significantly on reuses 0, 1, 10, and 15 (p = 0.03) suggesting membrane adsorption, as a result of reuse-dependent surface binding. In vivo, whereas IL-6 and SAA levels did not significantly differ (p = 0.90 and 0.59, respectively), CRP levels fell near significantly, over the course of 15 reuses (p = 0.06). In vivo, beta(2)-M clearance was not affected by the reuse technique (p = 0.28). CONCLUSIONS: This study provides in vitro and in vivo evidence arguing that high-flux Polyflux dialyzers provide more than adequate dialysis, while preventing the in vitro back-diffusion of bacterial endotoxin despite 15 reuses with Renalin. Clinically, this may translate into an attenuation of the microinflammatory milieu.

Aged↗

PubMed2004

Cytokine single nucleotide polymorphism. Role in acute renal failure.

Although the pathogenesis of ARF is heterogeneous and results from a combination of different environmental influences and host responses, there is overwhelming data to suggest a common pathway that involves pro- and anti-inflammatory molecules, which in turn, determines the extent of tissue injury. The number of recognized cytokine gene polymorphisms is growing daily. The development of cytokine gene mapping may help identify patients in whom an excessive systemic inflammatory response may follow a therapeutic intervention (e.g. CABG, contrast administration), and who may be at increased risk for developing acute organ dysfunction. Through these advances, tools may be developed to better understand, prevent and treat ARF. Genetic epidemiology studies may help characterize the importance of genetic markers in the development of ARF. This would require large prospective cohort studies aimed at examining associations between genetic markers, urinary (urine KIM-1 and NAG) and circulating (serum creatinine) markers of kidney injury. Once firmly established, the association of a particular genetic profile and outcome could be used to risk stratify patients for the development of ARF (fig. 4). Ultimately, cytokine-modulating therapies could be employed on the basis of genotypic risk stratification with the goal to prevent kidney injury or minimize its deleterious effects on patient outcome.

Acute Kidney Injury↗

PubMed2003

Effect of a novel adsorbent on cytokine responsiveness to uremic plasma.

BACKGROUND: Middle molecules such as beta2-microglobulin (beta2M) and advanced glycation end products (AGE)-modified proteins contribute to inflammation in uremia. The BetaSorb column is a new adsorptive device, which contains copolymeric beads, suitable for removal of beta2M and other middle molecules. We assessed the effect of this column on the bioreactivity of uremic plasma, as measured by cytokine responsiveness. METHODS: Uremic plasma was perfused in vitro through the column (10 mL/min) and samples were collected after 10 to 30 passes. Endotoxin-stimulated tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) production by THP-1-derived monocytes was measured following brief exposure to uremic plasma. beta2M levels were measured. The contribution of AGE-modified proteins to the bioreactivity of uremic plasma was explored. RESULTS: TNF-alpha and IL-10 production markedly decreased after 30 passes (629 +/- 78 vs. 144 +/- 62 pg/mL; 207 +/- 25 vs. 117 +/- 23 pg/mL; P=0.04). The column removed beta2M efficiently with a marked decline in plasma levels by 99% after 30 passes. Neutralization of AGE receptor (RAGE) resulted in a further reduction in the bioreactivity of uremic plasma. This was observed with nonperfused, as well as perfused, uremic plasma, suggesting that AGE-modified proteins were biologically active and still present after perfusion. CONCLUSION: The sorbent beads removed uremic solute(s) that prime monocytes to enhanced cytokine production. Removal of beta2M was efficient, and of native and AGE-modified middle molecules likely.

Antibodies↗

PubMed2003

Antioxidant and oxidative stress indices in dialysis-dependent acute renal failure.

BACKGROUND: Experimental animal models and in vitro studies have established a role for reactive oxygen species and the therapeutic potential for free radical scavengers in acute renal failure (ARF). Little is known of the effects of hemodialysis and other clinical variables on antioxidant defenses and oxidative stress among patients with ARF. METHODS: We examined antioxidant defenses and oxidative stress status in 24 patients with ARF requiring hemodialysis (HD). Blood samples were drawn prior to the first dialysis session (baseline), as well as before and after the third and sixth dialysis sessions. At each time point, the following parameters were measured: plasma alpha-tocopherol (vitamin E), plasma glutathione peroxidase (GSH-Px), serum total oxygen radical absorbance capacity (ORAC), plasma thiobarbituric acid reactive substances (TBARS), plasma tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10). Multivariate linear regression analyses were performed to examine clinical/laboratory variables associated with antioxidant/oxidative stress indices. The changes in antioxidant/oxidative stress indices over time after initiation of hemodialysis was evaluated in a subgroup of patients (n = 11) who completed six dialysis sessions. Intradialytic changes in antioxidant/oxidative stress indices and the differential impact of cellulose acetate vs. polysulfone dialyzers were also evaluated. RESULTS: Factors associated with alpha-tocopherol level were serum albumin (301 microg/dl upward arrow for each 1 g/dl upward arrow in albumin) and ORAC (188 microg/dl upward arrow for each 1,000 micromol Trolox Eq/l upward arrow in ORAC). Age was independently associated with plasma GSH-Px levels (55 U/l downward arrow for each 10-year age upward arrow ). Factors associated with ORAC were alpha-tocopherol (85 micromol Trolox Eq/l upward arrow for each 100 microg/dl upward arrow in alpha-tocopherol) and total bilirubin (30 micromol Trolox Eq/l downward arrow for each 1 mg/dl upward arrow in total bilirubin). Total bilirubin was independently associated with TBARS (0.2 microM upward arrow for each 1 mg/dl upward arrow in total bilirubin). GSH-Px and ORAC levels declined over time between baseline and the sixth dialysis session (p < 0.05 for both). Finally, there was a significant intradialytic decline in ORAC levels, which appeared to be more pronounced with use of cellulose acetate compared with polysulfone dialyzer membranes (p < 0.05). CONCLUSIONS: These observations indicate that antioxidant and oxidative stress indices in ARF patients are associated with several clinical and laboratory variables as well as the dialysis procedure. Further studies are needed to investigate the therapeutic role of anti-oxidant therapy in these patients.

Acute Kidney Injury↗

PubMed2002

Defective interleukin-10 synthesis by peripheral blood mononuclear cells among hemodialysis patients.

BACKGROUND: Interleukin-10 (IL-10), a potent regulatory monokine produced by activated mononuclear cells, provides an efficient autocrine mechanism for controlling proinflammatory cytokine synthesis. We hypothesized that defective synthesis of IL-10 could contribute to the inflammatory state in hemodialysis (HD) patients due to impaired feedback inhibition of proinflammatory cytokine production. METHODS: We compared peripheral blood mononuclear cell (PBMC) synthesis and transcription of IL-10 and TNF-alpha in 12 patients with end-stage renal disease on long-term maintenance HD and a control group of 10 healthy subjects. RESULTS: The synthesis of IL-10 by unstimulated PBMC was detectable in 5 of 12 (42%) HD patients as compared to 7 of 10 (70%) controls (p = 0.02). IL-10 synthesis in response to endotoxin (ET) by PBMC from HD patients was significantly lower when compared to the robust response in the control group (p = 0.008). Among the HD patients, there was a positive correlation between ET-stimulated IL-10 synthesis and the duration of time on dialysis. Unstimulated and ET-stimulated synthesis of TNF-alpha by PBMC did not differ between the 2 groups. In the HD patients, there was an inverse correlation between TNF-alpha and IL-10 synthesis by ET-stimulated PBMC, suggesting a regulatory effect of IL-10 on PBMC TNF-alpha synthesis. There was also an inverse correlation between plasma albumin and ET-stimulated TNF-alpha synthesis by PBMC among HD patients. TNF-alpha mRNA expression did not differ in HD patients relative to healthy controls. In contrast, when IL-10 mRNA from ET-stimulated PBMC was quantified, there was marked difference between the 2 groups indicating a transcriptional defect in IL-10 synthesis in PBMC from HD patients. CONCLUSION: Our observations indicate a marked abnormality in IL-10 synthesis by PBMC from HD patients probably related to a transcriptional defect. Low PBMC IL-10 synthesis may contribute to a chronic inflammatory state in these patients by defective feedback inhibition of proinflammatory cytokine production.

Adult↗