Dialysis modality and nutritional status are associated with variability of inflammatory markers.

BACKGROUND: Inflammation is a common feature in dialysis patients and is associated with cardiovascular complications and poor outcome. Measuring the variability of inflammatory markers may help in understanding underlying factors triggering inflammation. Whether the inflammatory pattern in hemodialysis (HD) and peritoneal dialysis (PD) patients differs has scarcely been studied. Here we explored factors associated with the magnitude and variability of inflammation markers in HD and PD patients. METHODS: In two 3-month, prospective cohort studies comprising 228 prevalent HD and 80 prevalent PD patients, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP) were measured in blood samples drawn each month and every week, respectively. Information on comorbidity, protein-energy wasting (PEW) and medications was gathered at baseline, and information on symptoms potentially related to inflammation was gathered weekly. A mixed-effect model was used for multivariate analysis of factors linked to CRP and IL-6 variation. RESULTS: IL-6 and CRP levels were higher and showed higher variability in HD versus PD patients [median IL-6 8.3 (interquartile range, IQR, 5.3-14.5) versus 6.7 (IQR 4.2-10.0) pg/mL, P < 0.001 and median CRP 6.1 (IQR 2.5-14.0) versus 5.4 (IQR 1.6-9.0) mg/L, P < 0.001). PEW predicted increased inflammation variability after correcting for age, sex, dialysis vintage, modality and comorbidity. Increased comorbidity predicted IL-6, but not CRP, variability. CONCLUSIONS: Circulating concentrations as well as variability of IL-6 and CRP levels were higher in HD as compared with PD patients. In HD and PD patients, short-term variability of IL-6 and CRP levels associated strongly with PEW, while comorbidity was related to IL-6 but not to CRP variability.

Determinants of N-terminal pro-brain natriuretic peptide variation in hemodialysis patients and prediction of survival.

BACKGROUND/AIMS: N-Terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor of cardiac events and death in the general population and in chronic kidney disease. There is limited information on how natriuretic peptides vary in dialysis patients. The aim of this study was to analyze NT-proBNP variability, factors predicting its variability and survival related to NT-proBNP variability. METHODS: A prospective 3-month observational study of prevalent hemodialysis patients with monthly measurements of NT-proBNP was carried out. A total of 211 hemodialysis patients were included, and mortality was recorded during 52 months of follow-up. RESULTS: Inflammation was the strongest predictor of NT-proBNP variability. Patients with constantly high NT-proBNP had an increased risk of death adjusting for age, sex, dialysis vintage and comorbidity but not when also adjusting for nutritional status. CONCLUSIONS: Longitudinal changes in NT-proBNP are associated with changes in inflammation, nutritional status, age and comorbidity. Due to strong interactions with predictors of mortality such as nutritional status, we were unable to confirm NT-proBNP as an independent marker for mortality in dialysis patients.

Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factor-α are similarly associated with survival in haemodialysis patients.

BACKGROUND: The impact of intra-individual changes of inflammatory markers [other than C-reactive protein (CRP)] on mortality in haemodialysis (HD) patients is unknown. We therefore studied survival in relation to trimestral variations of CRP, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). METHODS: In 201 prevalent HD patients from the Mapping of Inflammatory Markers in Chronic Kidney Disease cohort, serum CRP, IL-6 and TNF-α were measured 3 months apart and survival was assessed during follow-up. Based on fluctuations along tertiles of distribution, four patterns were defined for each inflammatory marker: stable low, decrease, increase and stable high. Hazard ratios were calculated by the Cox proportional hazard model, and Pearson's test was used to correlate changes. CRP analyses were replicated in 472 incident HD patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. RESULTS: Patients with persistently elevated CRP values had the worst mortality in crude [HR 2.98 (95% CI 1.71-5.20)] and adjusted [2.79 (1.58-4.94)] Cox models, together with those who increased in their CRP levels [crude 3.27 (1.91-5.60); adjusted 3.13 (1.79-5.45)]. Similar survival patterns were observed for IL-6 and TNF-α variation categories. Correlations among these changes were, however, not strong. In the replication cohort, individuals with persistently elevated CRP values also showed the highest mortality risk [crude 3.38 (2.31-4.94); adjusted 2.33 (1.58-3.45)]. CONCLUSIONS: Trimestral variations of TNF-α, IL-6, and CRP are similarly associated with survival in HD patients. The agreement between changes of these biomarkers was low, suggesting that different pathways may trigger each of these markers.

High-sensitivity troponins in dialysis patients: variation and prognostic value.

BACKGROUND: Dialysis patients have a high prevalence of cardiovascular mortality but also elevated cardiac troponins (cTns) even without signs of cardiac ischaemia. The study aims to assess variation and prognostic value of high-sensitivity cTnI and cTnT in prevalent dialysis patients. METHODS: In 198 prevalent haemodialysis (HD) and 78 peritoneal dialysis (PD) patients, 4-monthly serum troponin I and T measurements were obtained. Reference change values (RCVs) were used for variability assessment and competing-risk regression models for survival analyses; maximal follow-up was 50 months. RESULTS: HD and PD patients had similar troponin levels [median (interquartile range) troponin I: 25 ng/L (14-43) versus 21 ng/L (11-37), troponin T: 70 ng/L (44-129) versus 67 ng/L (43-123)]. Of troponin I and T levels, 42% versus 98% were above the decision level of myocardial infarction. RCVs were +68/-41% (troponin I) and +29/-23% (troponin T). Increased variability of troponins related to higher age, male sex, protein-energy wasting and congestive heart failure, but not ischaemic heart disease or dialysis form. Elevated troponin T, but not troponin I, predicted death after adjusting for confounders. CONCLUSIONS: A large proportion of prevalent dialysis patients without current established or ongoing cardiac events have elevated levels of high-sensitivity cTns. Mortality risk was doubled in patients with persistently high troponin T levels. The large intraindividual variation of cTns suggests that serial measurements and reference change levels may be used to improve diagnostic utility. However, evidence-based recommendations require more data from large studies of dialysis patients with cardiac events.

Comorbidity and acute clinical events as determinants of C-reactive protein variation in hemodialysis patients: implications for patient survival.

BACKGROUND: Patients with chronic kidney disease stage 5 have high comorbidity and are prone to inflammation that may contribute to the high cardiovascular mortality risk. STUDY DESIGN: Three-month observational cohort study of prevalent hemodialysis patients. SETTINGS & PARTICIPANTS: 228 hemodialysis patients (44% women) were included, median age of 66 years, median time on dialysis therapy of 29 months. PREDICTORS & OUTCOMES: In part 1, comorbidity and intercurrent illness were predictors and C-reactive protein (CRP) level was the outcome. In part 2, serial CRP values were predictors and survival was the outcome. MEASUREMENTS: High-sensitivity CRP was measured weekly and interleukin 6 (IL-6), tumor necrosis factor alpha, and IL-10 were measured monthly. Data for comorbidity were collected from patient records to calculate Davies comorbidity score, and self-reported clinical events were recorded weekly. RESULTS: Median baseline CRP level was 6.7 mg/L (25th to 75th percentiles, 2.5 to 21 mg/L). Baseline CRP level correlated with time-averaged CRP (Spearman rho = 0.76) and individual median of serial CRP values (rho = 0.78; both P < 0.001). Part 1: comorbidity score was significantly associated with greater CRP and IL-6 levels. Age, sex, comorbidity, and 7 of 12 clinical events had significant effects on CRP level variation. Part 2: during a mean follow-up of 29 months, 38% of patients died. Median and mean serial CRP levels were associated with a greater hazard ratio for death (1.013; 95% confidence interval, 1.004 to 1.022) and 1.012 (95% confidence interval, 1.004 to 1.020) than baseline, maximum, and minimum CRP values during the study. Other significant covariates were age, Davies risk group, dialysis vintage, and albumin level. LIMITATIONS: The study is based on observational data for prevalent dialysis patients. CONCLUSIONS: Comorbidity and clinical events are strongly associated with inflammation in hemodialysis patients. Despite variability over time, inflammation assessed by using CRP level is a strong predictor of mortality. Serial measurements provide additional information compared with a single measurement.

N-terminal pro-brain natriuretic peptide independently predicts protein energy wasting and is associated with all-cause mortality in prevalent HD patients.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) has been demonstrated to be associated with cardiovascular disease (CVD) and mortality in end-stage renal disease patients. We hypothesized that common confounders, such as protein-energy wasting (PEW) and inflammation could modulate this relationship. METHODS: NT-proBNP was measured in 222 prevalent hemodialysis (HD) patients (55.4% male, mean age 66 years, range 51-74) using commercial ELISA. Levels were related to clinical characteristics, biochemical markers and survival. RESULTS: NT-proBNP levels were positively associated with IL-6 (rho = 0.37, p <0.001) and C-reactive protein (rho = 0.25, p <0.001), but negatively associated with serum IGF-1 (rho = -0.34, p < 0.001), handgrip strength (rho = -0.30, p <0.001) and body weight (rho = -0.20, p < 0.001). In multivariate analysis, an NT-proBNP level above the cutoff of the receiver-operating curve (9,761 pg/ml) was associated with PEW (odds ratio = 2.30, p = 0.008) even following adjustment for age, dialysis vintage, inflammation and the Davies score. As expected, NT-proBNP predicted clinical CVD (odds ratio = 1.90, p = 0.05) and all-cause mortality (Cox regression hazard ratio = 1.57, p = 0.03) also after adjustment for confounders. Patients with an NT-proBNP above the cutoff also exhibited a higher mortality (Kaplan-Meier chi(2) = 13.95, p < 0.001). CONCLUSION: We demonstrate a novel association between NT-proBNP and PEW, which may be part of the explanation for the strong links between NT-proBNP and mortality in HD patients.

The higher mortality associated with low serum albumin is dependent on systemic inflammation in end-stage kidney disease.

BACKGROUND: The correlation of low serum albumin with mortality in patients with chronic kidney disease (CKD) is partly linked to its association with systemic inflammation. However, it is not clear to what extent albumin's correlation with mortality depends on concomitant systemic inflammation. Here we addressed this question in patients with CKD stage 5. METHODS: Serum albumin (S-Alb), systemic inflammation (high-sensitive C-reactive protein, hsCRP), cardiovascular disease (CVD) and nutritional status (subjective global assessment, SGA) were assessed at baseline in 822 patients: 523 incident dialysis patients, 212 prevalent hemodialysis (HD) and 87 prevalent peritoneal dialysis (PD) patients. Patients were divided into four groups according to hsCRP and S-Alb in each cohort: Group 1 -normal S-Alb and normal hsCRP (reference); Group 2 -low S-Alb and normal hsCRP; Group 3-normal S-Alb and high hsCRP; Group 4-low S-Alb and high hsCRP. Survival over 60 months was analyzed. RESULTS: In Cox analysis, Group 4 had an increased mortality risk (adjusted Hazard ratio (95% confidence interval): 1.62 (1.06-2.47); p = 0.02) whereas the augmented mortality risks for Groups 2 and 3 in univariate analyses were not significant after adjustments for age, gender, blood pressure, diabetes mellitus, smoking, SGA, renal function and renal replacement technique. CONCLUSIONS: Whereas mortality risk was increased in CKD stage 5 patients with low S-Alb and high CRP, it was not increased in patients with low S-Alb and normal CRP. Our observation suggests that inflammatory status should be taken into account when using S-albumin for risk assessment in CKD stage 5 patients.

Increased Levels of Modified Advanced Oxidation Protein Products Are Associated with Central and Peripheral Blood Pressure in Peritoneal Dialysis Patients.

UNLABELLED: ♦ BACKGROUND AND AIMS: Oxidative stress plays an important role in the pathogenesis of cardiovascular disease (CVD). Central blood pressure (BP) is thought to be more relevant than peripheral BP for the pathogenesis of CVD. Advanced oxidation protein products (AOPP) are markers of oxidative stress. This study investigated the relationship between AOPP and central BP in peritoneal dialysis (PD) patients. ♦ METHODS: In a cross-sectional study of 75 PD patients (67% men), we analyzed two oxidative stress markers, AOPP (modified assay, mAOPP, correcting for the impact of triglycerides) and pentosidine, three inflammation markers, interleukin-6 (IL-6), tumor necrosis factor (TNF), and high-sensitivity C-reactive protein (hs-CRP). All patients underwent measurement of central systolic blood pressure (SBP) and diastolic blood pressure (DBP) by applanation tonometry. ♦ RESULTS: Patients with mAOPP levels above the median had a higher central SBP and DBP than those below the median values. In univariate analysis, the levels of mAOPP associated with central SBP and central DBP. Multiple regression analysis, adjusting for age, gender, diabetes, CVD, protein-energy wasting (PEW), hs-CRP and extracellular water by multi-frequency bioimpedance or N-terminal prohormone of brain natriuretic peptide (NT-proBNP), confirmed independent associations between mAOPP and central SBP and central DBP respectively. ♦ CONCLUSIONS: The mAOPP level is independently associated with the central SBP and DBP in PD patients. This finding suggests that oxidative stress may be involved in the pathogenesis of hypertension or that hypertension itself or factors associated with hypertension such as fluid overload may have an additional effect on oxidative stress in PD patients.

Three-month variation of plasma pentraxin 3 compared with C-reactive protein, albumin and homocysteine levels in haemodialysis patients.

BACKGROUND: Inflammatory markers vary considerably over time in haemodialysis (HD) patients, yet the variability is poorly defined. The aim of the study was to assess changes of plasma levels of pentraxin-3 (PTX-3), C-reactive protein (CRP), albumin and homocysteine (Hcy) over 3 months and the association between the changes in these biomarkers and mortality. METHODS: In 188 prevalent HD patients, inflammatory markers were measured at inclusion and after 3 months. Mortality was recorded during a median follow-up of 41 months. The changes of the biomarker levels were categorized according to change in tertile for the specific biomarker. The variation was calculated as the intra-class correlation (ICC). Mortality was analysed by Kaplan-Meier and Cox proportional hazards model. The predictive strength was calculated for single measurements and for the variation of each inflammatory marker. RESULTS: The intra-individual variation (low ICC) was largest for PTX-3 [ICC 0.44; 95% confidence interval (CI): 0.33-0.55], albumin (ICC 0.58; 95% CI: 0.49-0.67) and CRP (ICC 0.59; 95% CI: 0.51-0.68) and lowest for Hcy (ICC 0.81; 95% CI: 0.77-0.86). During follow-up, 88 patients died. CONCLUSIONS: PTX-3 measurements are less stable and show higher variation within patients than CRP, albumin and Hcy. Persistently elevated PTX-3 levels are associated with high mortality. Moreover, in multivariate logistic regression we found that stable high PTX-3 adds to the mortality risk, even after inclusion of clinical factors and the three other biomarkers. The associations of decreasing albumin levels as well as low Hcy levels with worse outcome reflect protein-energy wasting.

Additive effects of soluble TWEAK and inflammation on mortality in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, primarily due to cardiovascular disease. Reduced soluble TNF-like weak inducer of apoptosis (sTWEAK) plasma levels have been reported both in patients with subclinical atherosclerosis and CKD. DESIGN, PARTICIPANTS, & MEASUREMENTS: A cross-sectional study was conducted in 218 prevalent patients (121 men; 63 +/- 14 yr) undergoing hemodialysis (HD). sTWEAK levels in relation with the patients' outcome were studied. RESULTS: sTWEAK plasma levels were 208 [(165 to 272) pg/ml, median interquartile range], significantly lower than healthy controls (P < 0.0001). sTWEAK was negatively associated with inflammatory markers, such as C-reactive protein and IL-6. Overall mortality was assessed after an average follow-up of 31 mo, during which 81 patients died. After controlling for potential confounding variables, patients in the upper tertile of sTWEAK plasma levels had an increased risk of cardiovascular and all-cause mortality. A significant interaction effect between sTWEAK and IL-6 levels was found [synergy index: 2.19 (0.80, 5.93)]. Thus, the association of sTWEAK with mortality was strongest in patients with inflammation (defined as IL-6 > 7.0 pg/ml), in whom high sTWEAK strongly predicted cardiovascular and all-cause mortality. These results were confirmed in a second cohort of HD patients. CONCLUSIONS: The concurrent presence of elevated sTWEAK plasma concentrations and an inflammatory environment have additive effects on mortality in HD patients. Further studies on the potential different role of sTWEAK in health and disease are warranted.

Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients.

BACKGROUND & AIMS: Muscle wasting is considered the best marker of protein-energy wasting in end-stage renal disease (ESRD). We tested the usefulness of a simple observer subjective muscle atrophy (MA) grading in relation to morbidity and mortality in ESRD patients. METHODS: In two different ESRD cohorts (265 incident patients starting dialysis and 221 prevalent hemodialysis patients), each patient's degree of MA was visually graded by a trained nurse on a scale from 1 to 4 as part of the subjective global assessment. This score was confronted with inflammatory and nutritional indexes as well as objective measurements of muscle atrophy. Patients were then prospectively followed for up to four or six years, depending on the cohort. RESULTS: Thirty percent of the incident and 39% of the prevalent patients presented signs of MA. Across worsening MA scale, nutritional and anthropometric markers of muscle loss were incrementally poorer. Inflammation markers as well as the proportion of women became progressively higher. Female sex, presence of cardiovascular disease, inflammation and low insulin-like growth factor-1 levels were associated with increased significant odd ratios of MA in each cohort. After adjustment for age, sex, inflammation, diabetes, cardiovascular disease, glomerular filtration rate and/or time on hemodialysis, the hazard ratio of death for moderate/severe MA was 2.62 (95% CI: 1.34, 5.13; p=0.001) and 3.04 (95% CI: 1.61, 5.71; p=0.0001) in the incident and prevalent cohorts respectively. CONCLUSION: Increased MA is more common in female dialysis patients and associated with inflammation, poor nutritional and anthropometric status, as well as a 3-fold increased 4-6 year mortality. Our data support the use of frequent MA and/or nutritional assessments in the clinical practice.

C-reactive protein is elevated 30 years after eclamptic pregnancy.

Women with a history of preeclampsia or eclampsia (seizure during preeclamptic pregnancy) are at increased risk for cardiovascular disease after pregnancy for reasons that remain unclear. Prospective studies during pregnancy suggest that inflammation, dyslipidemia, and insulin resistance are associated with increased risk of preeclampsia. Elevated serum C-reactive protein (CRP >3 mg/L) is an indicator of inflammation and cardiovascular risk. We hypothesized that Icelandic postmenopausal women with a history of eclampsia would manifest higher concentrations of serum CRP than Icelandic postmenopausal controls with a history of uncomplicated pregnancies. We also asked whether elevated CRP is associated with the dyslipidemia and insulin resistance previously identified in this cohort. CRP, measured by high-sensitivity enzyme-linked immunoassay, was higher in women with prior eclampsia (n=25) than controls (n=28) (median mg/L [interquartile range]: 9.0 [0.9 to 13.2] versus 2.0 [0.3 to 5.1]; P<0.03). This difference remained significant after adjustment for body mass index, smoking, hormone replacement, and current age. Women with prior eclampsia clustered into either high CRP (range 8.97 to 40.6 mg/L, n=13) or lower CRP (median 1.0, range 0.05 to 3.77, n=12) subsets. The prior eclampsia/high CRP subset displayed significantly elevated systolic blood pressures, lower high-density lipoprotein (HDL) cholesterol, higher apolipoprotein B, and higher fasting insulin and homeostasis model of insulin resistance (HOMA) values compared to controls, whereas the prior eclampsia/low CRP subset differed from controls only by marginally increased apolipoprotein B. The triad of inflammation, low HDL, and insulin resistance may elevate risk for both preeclampsia/eclampsia and cardiovascular disease in later life.