Acute on chronic bilateral renal vein thrombosis in the setting of remission of class V lupus nephritis: A case report and literature review.

Renal vein thrombosis (RVT), defined as the presence of a thrombus in the major renal vein or one of its tributaries, can present acutely or go unnoticed resulting in acute kidney injury or chronic kidney disease. RVT is associated with multiple etiologies, including nephrotic syndrome, thrombophilia, autoimmune disorders, and malignancy. Patients with systemic lupus erythematosus (SLE), a multiorgan autoimmune disorder, are predisposed to coagulopathy and thus are at a higher risk of venous and arterial thromboembolism. We describe the case of a 41-year-old man with SLE and biopsy-proven membranous glomerulonephritis (WHO class V lupus nephritis) in clinical remission with no evidence of nephrotic range proteinuria who presented with macroscopic hematuria and was diagnosed with acute-on-chronic bilateral RVT. We discuss the different causes of RVT and compare the clinical presentation, diagnostic imaging findings, and management of acute and chronic RVT.

Malignancy-induced lactic acidosis in adult lymphoma.

Malignancy-induced lactic acidosis (MILA), a rare paraneoplastic phenomenon, is mostly described with hematologic malignancies (lymphomas and leukemias) but has also been reported with solid tumors. It is a subset of type B lactic acidosis being mediated without evidence of tissue hypoperfusion. Lymphoma-induced lactic acidosis is often considered an oncologic emergency and is associated with an increased risk of mortality and poor prognosis. It has a complex pathophysiology centered in the "Warburg effect," i.e., the programming of cancer cells to depend on aerobic glycolysis for promotion of their proliferation and anabolic growth. The treatment of lymphoma-induced lactic acidosis is focused on prompt administration of chemotherapy. The role of alkali therapy in this setting is controversial and has limited proven benefit with a potential for worsening the lactic acidosis. If alkali therapy is used in the presence of severe acidemia to optimize cardiovascular status, it should be administered judiciously.

Inflammation and Progression of CKD: The CRIC Study.

BACKGROUND AND OBJECTIVES: CKD is a global public health problem with significant mortality and morbidity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-ß, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants. RESULTS: Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant. CONCLUSIONS: Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

Plasma adiponectin levels and clinical outcomes among haemodialysis patients.

BACKGROUND: Adiponectin (ADPN) levels are consistently elevated among patients with advanced chronic kidney disease, but its relationship with cardiovascular outcomes in this population remains controversial. METHODS: We measured baseline and yearly plasma ADPN in 182 prevalent haemodialysis patients recruited to the Haemodialysis (HEMO) Study from two Boston centres. Plasma ADPN at baseline and during follow-up was studied in relation to prevalent cardiovascular disease (CVD) and cardiovascular and all-cause mortality. RESULTS: Baseline plasma ADPN levels were found to be approximately twofold higher than in the general population and correlated inversely with (log-transformed) CRP levels and (log-transformed) body mass index (BMI). Levels measured over time showed a gradual increase (0.95 microg/mL, 95% CI = 0.12-1.78 microg/mL; P = 0.03) by year, although this difference became non-significant after adjustment for covariates. Baseline ADPN levels were lower among patients with pre-existing CVD (adjusted OR of 0.67; P = 0.03). They also predicted all-cause mortality (P < 0.01) and the composite outcome of 'cardiovascular events/cardiovascular mortality' (P < 0.01); levels measured over time predicted the composite outcome of 'cardiovascular events and all-cause mortality' (P < 0.01). These relationships were non-linear (quadratic) with the hazard for each outcome increasing in the lower and upper ranges of the distribution of ADPN, and strengthened after adjustment for baseline covariates including serum albumin, CVD and the flux and dialysis dose categorization of the HEMO study. CONCLUSIONS: In summary, low plasma levels of ADPN were associated with inflammation and pre-existing CVD; ADPN levels predicted cardiovascular and mortality outcomes, the relationship being extensively confounded by multiple patient-related factors.

Genetics and reverse epidemiology among patients on chronic hemodialysis.

A reversal in the association between traditional and nontraditional risk factors and clinical outcomes is often encountered in patients with chronic illness, including among those with advanced chronic kidney disease (CKD) on maintenance hemodialysis (MHD). The effects of the malnutrition-inflammation complex syndrome (MICS) may play a significant role in the reversal of this risk factor-outcomes association. the MICS, this syndrome complex is not universal in its prevalence among MHD patients. The significant inter- and intra-individual differences in the prevalence of inflammation, oxidative stress, and malnutrition, indicates the influence of genetic factors in this variability. In recent years, enormous advancement in the field of molecular genetics, genomics and bioinformatics, have revolutionized studies of the genetic epidemiology of several diseases. However, genetic association studies are at a preliminary stage in the population with advanced CKD (Table 1). Preliminary studies of the impact of polyphisms in inflammation and oxidative stress-related genes and genes affecting body composition and metabolism suggest that genetic variation may indeed affect the phenotype of the MHD population. Further, some of these gene polymorphisms may also contribute to a reversal of the association between traditional risk factors, such as BMI, blood pressure, and cholesterol and clinical outcomes in this vulnerable patient population. Genetic studies in patients with advanced CKD pose enormous challenges, including recruitment of sufficient numbers of patients to achieve adequate statistical power, resolution of immense genotypic and phenotypic heterogeneity, and gene-environment and gene-gene interactions. However, well-designed adequately powered studies with carefully defined phenotypes may potentially allow definition of risk profiles characterized by combinations of relevant Single nucleotide polymorphisms in the setting of given environmental factors. Accurate risk stratification that takes into account genetic information would allow more informed targeting of pharmacologic intervention and better refined clinical trial methodologies.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Iron storage indices and risk of bacterial infections in hemodialysis patients.

BACKGROUND: Infection is the second leading cause of death among hemodialysis (HD) patients. Because iron overload may be a risk factor for bacterial infection, concerns about excessive use of intravenous (IV) iron have arisen. In this retrospective analysis, we explored the relationship between target iron storage indices, as outlined in the Dialysis Outcomes Quality Initiative (DOQI) guidelines, and the incidence of bacterial infections. METHODS: We reviewed the charts of 87 HD patients who received their first course of IV iron at our dialysis unit between 1997 and 2001. Transferrin saturation (TSAT) rate, ferritin level, and other clinical/laboratory measures were recorded at baseline. Patients were followed for up to 2 years for the outcomes of bacteremia and bacterial pneumonia and censored at death, end-of-study observation, or kidney transplantation. Cox proportional hazards regression was used to evaluate the relationship of bacterial infections to iron storage indices. RESULTS: Thirty-two patients had at least one episode of bacterial infections. In multivariate analyses, after adjusting for sex and venous catheter use, iron-replete state (ferritin > 100 ng/mL and TSAT > 20%) was associated with a threefold higher risk of bacterial infections (95% CI 1.3-6.6; p = 0.01). Although diabetes mellitus and lower serum albumin had a nonsignificant trend toward an increased risk of bacterial infections, no such relationship was seen with the first 3-month cumulative IV iron dose. CONCLUSIONS: This study suggests an increased risk for bacterial infections at modest levels of iron stores (ferritin > 100 ng/mL and TSAT > 20%) among HD patients initiating IV iron. Large prospective studies are needed to confirm these relationships.

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.

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.

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.