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

Effect of a novel adsorbent on cytokine responsiveness to uremic plasma

Effect of a novel adsorbent on cytokine responsiveness to uremic plasma.BackgroundMiddle molecules such as β2-microglobulin (β2M) 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 β2M and other middle molecules. We assessed the effect of this column on the bioreactivity of uremic plasma, as measured by cytokine responsiveness.MethodsUremic 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-α (TNF-α) and interleukin-10 (IL-10) production by THP-1–derived monocytes was measured following brief exposure to uremic plasma. β2M levels were measured. The contribution of AGE-modified proteins to the bioreactivity of uremic plasma was explored.ResultsTNF-α 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 β2M 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.ConclusionThe sorbent beads removed uremic solute(s) that prime monocytes to enhanced cytokine production. Removal of β2M was efficient, and of native and AGE-modified middle molecules likely

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

Dialyzer membrane type and reuse practice influence polymorphonuclear leukocyte function in hemodialysis patients.BackgroundPolymorphonuclear 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.MethodsThe 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.ResultsPMNL 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.ConclusionOur 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

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-β, 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