Association between levels of pentraxin 3 and incidence of chronic kidney disease in the elderly.

OBJECTIVE: Higher levels of the novel inflammatory marker pentraxin 3 (PTX3) predict cardiovascular mortality in patients with chronic kidney disease (CKD). Yet, whether PTX3 predicts worsening of kidney function has been less well studied. We therefore investigated the associations between PTX3 levels, kidney disease measures and CKD incidence. METHODS: Cross-sectional associations between serum PTX3 levels, urinary albumin/creatinine ratio (ACR) and cystatin C-estimated glomerular filtration rate (GFR) were assessed in two independent community-based cohorts of elderly subjects: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 768, 51% women, mean age 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 651, mean age 77 years). The longitudinal association between PTX3 level at baseline and incident CKD (GFR <60 mL(-1) min(-1) 1.73 m(-2) was also analysed (number of events/number at risk: PIVUS 229/746, ULSAM 206/315). RESULTS: PTX3 levels were inversely associated with GFR [PIVUS: B-coefficient per 1 SD increase -0.16, 95% confidence interval (CI) -0.23 to -0.10, P < 0.001; ULSAM: B-coefficient per 1 SD increase -0.09, 95% CI -0.16 to -0.01, P < 0.05], but not ACR, after adjusting for age, gender, C-reactive protein and prevalent cardiovascular disease in cross-sectional analyses. In longitudinal analyses, PTX3 levels predicted incident CKD after 5 years in both cohorts [PIVUS: multivariable odds ratio (OR) 1.21, 95% CI 1.01-1.45, P < 0.05; ULSAM: multivariable OR 1.37, 95% CI 1.07-1.77, P < 0.05]. CONCLUSIONS: Higher PTX3 levels are associated with lower GFR and independently predict incident CKD in elderly men and women. Our data confirm and extend previous evidence suggesting that inflammatory processes are activated in the early stages of CKD and drive impairment of kidney function. Circulating PTX3 appears to be a promising biomarker of kidney disease.

Immunoglobulin (Ig)M antibodies against oxidized cardiolipin but not native cardiolipin are novel biomarkers in haemodialysis patients, associated negatively with mortality.

The risk of premature death is high in haemodialysis (HD) patients. Antibodies against cardiolipin (anti-CL) are thrombogenic in diseases such as systemic lupus erythematosus (SLE). CL is easily oxidized (Ox) and plays a role in apoptosis. In this work we studied immunoglobulin (Ig)M anti-CL and anti-OxCL in HD-patients. We conducted an observational study with a prospective follow-up examining the relationship between anti-CL, anti-OxCL and mortality risk in a well-characterized cohort of 221 prevalent HD patients [56% men, median age 66 (interquartile range 51-74) years, vintage time 29 (15-58) months] with a mean follow-up period of 41 (20-48 months). According to the receiver operator characteristic (ROC) analysis, anti-OxCL [area under the curve (AUC) 0·62, P < 0·01], but not anti-CL (AUC 0·52, P = 0·2), is associated with mortality. In crude and adjusted Cox analysis, every log increase in anti-OxCL inversely predicted all-cause [adjusted hazard ratios (HR) 0·62 (0·43-0·89)] and CVD-related [adjusted HR 0·56 (0·32-0·98)] mortality. Patients with anti-OxCL levels below median also had increased all-cause and cardiovascular disease (CVD)-related mortality. Although anti-OxCL and anti-phosphorylcholine (PC) were related positively to each other (ρ = 0·57, P < 0·01), patients with one or two of these autoantibody levels below the median were associated with an incrementally increased death risk. Anti-OxCL were co-factor ß2-GPI-independent; anti-CL from patients with anti-phospholipid antibody syndrome were ß2-GPI-dependent, while sera from HD-patients less so. Sera from healthy donors was not ß2-GPI-dependent. Anti-OxCL IgM is ß2-glycoprotein 1 (GPI)-independent and a novel biomarker; low levels are associated with death among HD patients (and high levels with decreased risk). Combination with anti-PC increases this association. Putative therapeutic implications warrant further investigation.

Clinical determinants and mortality predictability of stearoyl-CoA desaturase-1 activity indices in dialysis patients.

BACKGROUND: Stearoyl-CoA desaturase-1 (SCD-1) converts dietary saturated fatty acids to monounsaturated fatty acids. Elevated SCD-1 activity thus signifies impaired fatty acid metabolism and excess saturated fat intake. In the general population, increased SCD-1 activity is associated with cardiovascular disease and mortality. The determinants and implications of SCD-1 activity in dialysis patients are unknown. SUBJECTS: A total of 222 dialysis patients (39% women) with prospective follow-up, median age of 57 years and an average of 12 months of dialysis. DESIGN: Fatty acid compositions in plasma phospholipids and free fatty acids (FFAs) were assessed by gas-liquid chromatography. SCD-1 activity indices were calculated as the product-to-precursor fatty acid ratio (palmitoleic acid/palmitic acid) in each fraction to reflect SCD-1 activities in the liver and adipose tissue. RESULTS: Median hepatic and adipose tissue SCD-1 activity indices were 0.016 and 0.150, respectively. In multivariate analyses, SCD-1 was positively associated with age, female sex and serum interleukin-6 level. During 18.4 (interquartile range 5.5-37.3) months of follow-up, there were 61 deaths and 115 kidney transplants. The cut-off level for high SCD-1 indices was determined by receiver operating characteristic curve analyses. In fully adjusted competing risk models, patients with high SCD-1 indices in both phospholipids and FFAs had more than twofold increased mortality risk before kidney transplantation [hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.28-4.11 and HR 2.36, 95% CI 1.38-4.03, respectively], compared with patients with low SCD-1 indices. CONCLUSIONS: Both hepatic and adipose tissue SCD-1 activity indices independently predict mortality in dialysis patients. Further studies are warranted to determine whether reducing SCD-1 activity by dietary intervention (limiting saturated fat) could improve survival in dialysis patients.

Increased expression of pro-inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients.

OBJECTIVES: Low-grade systemic inflammation, oxidative stress and peripheral insulin resistance are intimately associated and contribute to the increased risk of cardiovascular complications in advanced chronic kidney disease (CKD). Because altered adipose tissue activities have previously been linked to pathophysiological processes in various inflammatory and metabolic diseases we hypothesized that the uraemic milieu in patients with CKD may interact with the adipose tissue, provoking an unfavourable shift in its transcriptional output. DESIGN: Twenty-one adipokine mRNAs were quantified in abdominal subcutaneous adipose tissue (SAT) biopsies and serum/plasma concentrations of inflammatory markers and related protein products were measured. SETTING: The study was conducted at the Karolinska University Hospital, Huddinge, and Karolinska Institutet, Stockholm, Sweden. SUBJECTS: Thirty-seven patients with CKD [15 women, median 58 (interquartile range 49-65) years] and nine nonuraemic individuals [four women, age 62 (45-64) years] were recruited prior to initiation of peritoneal dialysis catheter insertion or elective hernia repair/laparoscopic cholecystectomy, respectively. RESULTS: Even after correction for body mass index, SAT from patients showed a significant upregulation of inflammatory pathway genes interleukin 6 (3.0-fold, P=0.0002) and suppressor of cytokine signalling 3 (2.5-fold, P=0.01), as well as downregulation of leptin (2.0-fold, P=0.03) and the oxidative stress genes uncoupling protein 2 (1.5-fold, P=0.03) and cytochrome b-245, alpha polypeptide (1.5-fold, P=0.005), in relation to controls. CONCLUSIONS: These gene expression differences suggest that inflammatory and oxidative stress activities may be important features of the intrinsic properties of uraemic adipose tissue, which may have significant effects on the uraemic phenotype.

Temporal discrepancies in the association between the apoB/apoA-I ratio and mortality in incident dialysis patients.

BACKGROUND: In the general population, a high apoB/apoA-I ratio is a strong risk factor for cardiovascular disease and mortality. However, whether this is the case in chronic kidney disease (CKD) patients is currently unknown. STUDY DESIGN: The apoB/apoA-I ratio was evaluated in 391 incident CKD stage 5 patients examined close to dialysis initiation, and again after 1 year of dialysis in a subgroup of 182 patients, subsequently followed for up to 3 years. RESULTS: Baseline values of the apoB/apoA-I ratio as well as changes in the ratio during the first year of dialysis correlated with body mass index (BMI) and fat mass. The baseline apoB/apoA-I ratio showed no association with 4-year mortality. However, after adjustment for confounders, a high apoB/apoA-I ratio (>0.9) predicted short-term (first year) survival [hazard ratio (HR): 0.35; 95% confidence interval (CI): 0.13-0.85)] and long-term (next 3 years) mortality (HR: 1.72; 95% CI: 1.01-2.96). An increase in the apoB/apoA-I ratio during the first year of dialysis was linked to a survival advantage thereafter (HR: 0.48; 95% CI: 0.22-0.98). However, this association lost its significance (HR: 0.62; 95% CI: 0.26-1.36) after adjustment for indices of protein-energy wasting. CONCLUSIONS: A high apoB/apoA-I ratio and an increase in this ratio during the first year on dialysis were associated with short-term survival advantage in CKD patients. This paradoxical relationship represents an example of the so-called reverse epidemiology phenomenon in CKD patients and suggests that the apoB/apoA-I ratio should always be interpreted with caution in this patient population.

Low serum fetuin-A concentration predicts poor outcome only in the presence of inflammation in prevalent haemodialysis patients.

BACKGROUND: Fetuin-A, a negative acute phase protein that inhibits vascular calcification, has a controversial association with mortality in chronic kidney disease (CKD) patients. Chronic inflammation, which is common in CKD, may promote vascular calcification. MATERIALS AND METHODS: We investigated the impact of inflammation on the relationship between serum fetuin-A and mortality (42 months) in 222 prevalent haemodialysis (HD) patients. RESULTS: Serum fetuin correlated negatively with comorbidity score (assessed by Davies score) and circulating inflammatory markers. Patients with low fetuin-A levels (< median) had higher mortality (Hazard ratio 'HR' 2.2; CI 1.4-3.5, P < 0.001), but this association was lost after adjustment for age, gender, comorbidities score, dialysis vintage and inflammation (CRP > median). In inflamed patients with low fetuin a significantly independent association with mortality (HR 2.3; CI 1.2-4.5, P = 0.01) was observed compared to non-inflamed patients with high fetuin-A, after adjusting for the same variables. Non-inflamed patients with low fetuin-A and inflamed patients with high fetuin-A did not have increased mortality compared to non-inflamed patients with high fetuin-A. CONCLUSIONS: The results show that low levels of serum fetuin-A are associated with increased mortality in HD patients only in the presence of inflammation. This suggests that coexistence of a low serum fetuin-A level and low-grade inflammation exerts an additive effect on the risk of death in HD patients.

The long pentraxin PTX-3 in prevalent hemodialysis patients: associations with comorbidities and mortality.

BACKGROUND: Pentraxin (PTX)-3, a new candidate marker for inflammation is expressed in a variety of cell types. Recently, we have shown that increase in PTX-3 level is associated with clinical outcome in incident CKD stage 5 patients at start of renal replacement therapy. However, no data are available on PTX-3 and its relationship with clinical outcome in prevalent dialysis patients. METHODS: We analyzed plasma PTX-3 concentrations in relation to comorbidities (Davies score), protein-energy wasting (PEW) and inflammation markers in 200 prevalent hemodialysis (HD) patients, aged 64 +/- 14 years, who had been on HD treatment for a median period of 36 months. Survival (42 months) was analyzed in relation to PTX-3 levels (high PTX-3 tertile vs. low two tertiles). RESULTS: Plasma PTX-3 correlated positively with C-reactive protein and interleukin-6, and negatively with s-albumin and fetuin-A. Patients with cardiovascular disease (CVD) and PEW had higher levels of PTX-3 than their counterparts and PTX-3 was associated with comorbidity score. In multiple logistic regression analysis, the high comorbidity score and PEW were the significant predictive variables of high PTX-3. In unadjusted analysis high PTX-3 was significantly associated with all-cause mortality. After adjustment for sex, age, dialysis vintage, comorbidity score, PEW and CRP using the multivariate Cox regression analysis, death rate was still significantly higher in patients with high PTX-3 (HR 1.7; CI 1.1-2.7, P = 0.03). CONCLUSION: Markedly increased levels of PTX-3 were found in HD patients with signs of CVD and PEW. In addition, the concentration of PTX-3 was associated with inflammation markers and comorbidity score. Our data also shows that high PTX-3 level was independently associated with all-cause mortality.

Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients.

INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months. RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.

Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease.

OBJECTIVES: In this study, we explore the associations of decreased thyroid hormone levels with inflammation, wasting and survival in biochemically euthyroid patients with end-stage renal disease (ESRD). DESIGN: After exclusion of 23 patients with thyroid-stimulating hormone (TSH) values outside the normal range (0.1-4.5 mIU L(-1)), 187 clinically and biochemically euthyroid incident ESRD stage 5 patients starting dialysis were followed for a median of 20 (range 1-60) months. Measurements of total and free forms of thyroid hormones, s-albumin, hs-CRP, interleukin (IL)-6, vascular adhesion molecule (VCAM)-1 and insulin-like growth factor 1 (IGF-1) were performed at baseline. RESULTS: In this population, 17 out of 210 patients (8%) were defined as subclinically hypothyroid. Multivariate analysis, according to receiver operating characteristic (ROC) curves, showed that mortality was best predicted by total triiodothyronine (T3). When using the cut-off levels derived from ROC, low T3 levels were associated with increased inflammation (higher hs-CRP, IL-6 and VCAM-1) and lower concentration of both s-albumin and IGF-1. Finally, low T3 but not low free triiodothyronine was associated with worse all-cause (Likelihood ratio = 45.4; P < 0.0001) and cardiovascular mortality (Likelihood ratio = 47.8; P < 0.0001) after adjustment for confounding factors. CONCLUSION: This study showed that low T3 levels are independent predictors of all-cause and also cardiovascular disease mortality in biochemically euthyroid patients, perhaps due to an intimate association with inflammation. Based on these results, the use of T3 levels in studies assessing the relationship between thyroid dysfunction and mortality risk is recommended.

Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?

OBJECTIVE: The lifespan of dialysis patients is as short as in patients with metastatic cancer disease, mainly due to cardiovascular disease (CVD). DNA methylation is an important cellular mechanism modulating gene expression associated with ageing, inflammation and atherosclerotic processes. DESIGN: DNA methylation was analysed in peripheral blood leucocytes from three different groups of chronic kidney disease (CKD) populations (37 CKD stages 3 and 4 patients, 98 CKD stage 5 patients and 20 prevalent haemodialysis patients). Thirty-six healthy subjects served as controls. Clinical characteristics (diabetes mellitus, nutritional status and presence of clinical CVD), inflammation and oxidative stress biomarkers, homocysteine and global DNA methylation in peripheral blood leucocytes (defined as HpaII/MspI ratio by the Luminometric Methylation Assay method) were evaluated. CKD stage 5 patients (n=98) starting dialysis treatment were followed for a period of 36 +/- 2 months. RESULTS: Inflamed patients had lower ratios of HpaII/MspI, indicating global DNA hypermethylation. Analysis by the Cox regression model demonstrated that DNA hypermethylation (HpaII/MspI ratio

Plasma pentosidine and total homocysteine levels in relation to change in common carotid intima-media area in the first year of dialysis therapy.

BACKGROUND: Homocysteine and advanced glycation end-products (AGEs), which accumulate in chronic kidney disease (CKD), are recently proposed cardiovascular risk factors. In this study, we evaluated the association between changes in calculated intima media (cIM) area of the common carotid artery during the first year of dialysis therapy and plasma total homocysteine (tHcy) level as well as circulating AGEs such as plasma pentosidine level. METHODS: We studied 63 CKD patients (38 males) aged 52 +/- 12 years at a time-point close to start of dialysis treatment and after 12 months of dialysis treatment (41 on peritoneal and 22 on hemodialysis). The tHcy and plasma pentosidine levels were measured by HPLC. Change in cIM area was evaluated by non-invasive B mode ultrasonography. Malnutrition was assessed by subjective global assessment (SGA). RESULTS: At basal, 70% of the patients had carotid plaques, 32% had symptomatic CVD, 38% had malnutrition, 30% had inflammation (CRP > or = 1 mg/dl) and 23% had diabetes mellitus, respectively. At baseline, the mean plasma pentosidine levels were similar in the patients with and without carotid plaques (36 +/- 21 vs 36 +/- 19 pmol/mg albumin, respectively), whereas the median plasma tHcy was significantly lower in the patients with carotid plaques than in the patients without carotid plaques (32 +/- 21 vs 52 +/- 42 pmol/l, p < 0.01, respectively). The prevalence of hyperhomocysteinemia (tHcy level > 13.7 micromol/l) was 95%. In univariate analysis, the change in cIM area during the first year of dialysis was significantly correlated with basal plasma pentosidine level (p = 0.31, p = 0.01), but not with basal tHcy (p = -0.11). However, neither pentosidine nor tHcy levels were correlated with cIM area at basal or at 12 months. In a stepwise multiple regression model, age and plasma pentosidine content, but not the tHcy level, associated with changes in the cIM area. CONCLUSION: Progression of atherosclerosis, as indicated by changes in carotid intima-media area during the course of dialysis treatment, was associated with pentosidine, but not with tHcy, levels at baseline in these CKD patients. This suggests that the accumulation of AGEs in CKD patients may have a role in the pathogenesis of CVD in these patients. Since almost all CKD patients have hyperhomocysteinemia, this finding, however, does not exclude a role ofhomocysteine as a risk factor for CVD in CKD patients.

Place of genotyping and phenotyping in understanding and potentially modifying outcomes in peritoneal dialysis patients.

With the landmark publication of the human genome sequence and its subsequent division into haplotype blocks, the characterization of genetic variations is becoming a feasible approach to study both the pathophysiology and risk factors of complex traits. A number of strategies are available today for identifying candidate genes or polymorphisms associated with pertinent phenotypes. For Mendelian diseases with high penetrance owing to mutations in a single gene, such as polycystic kidney disease, linkage studies have been very successful in mapping the disease loci owing to the availability of families with multiple affected members. In contrast to monogenic conditions, complex diseases such as end-stage renal disease (ESRD) and complex traits such as individual variations in membrane transport and complications during the course of peritoneal dialysis (PD) therapy have a number of competing determinants and inhibitors, both genetic and environmental. Current results reflect this complexity, with few studies showing a large effect of any single risk factor on survival or outcome on PD. However, these studies have so far been small (less than 500 patients) and have not utilized bioinformatics or novel technologies (e.g., multiplex genotyping equipment). In the following review, we outline current approaches for using genetic data in clinical studies as well as highlight some of the most promising results in ESRD patients, particularly those on PD.

Are insulin-like growth factor and its binding proteins 1 and 3 clinically useful as markers of malnutrition, sarcopenia and inflammation in end-stage renal disease?

INTRODUCTION: Malnutrition is common in end-stage renal disease (ESRD) and affects both morbidity and mortality. The growth hormone-dependent insulin-like growth factor (IGF)-I may be a good marker of malnutrition because of its short half-life. In the present study, we investigate the influence of decreasing residual renal function as well as of chronic inflammation on the IGF system to assess its usefulness in this patient group. PATIENTS AND METHODS: Cross-sectional analysis of 220 ESRD patients (140 males) with a mean age of 52+/-1 years. Biochemical analyses of insulin, IGF-I, IGFBP-1, IGFBP-3, IL-6, high sensitivity (hs)-CRP and other routine markers. Malnutrition status was recorded using subjective global assessment (SGA), body mass index, estimated protein intake from nitrogen appearance (nPNA), handgrip strength (HGS) and insulin resistance (HOMA-IR). Dual energy X-ray absorptiometry was used to assess body composition. RESULTS: Both IGF-I and IGFBP-1 showed significant and opposite correlations with most markers of nutritional status, including SGA (rho=-0.29 and 0.27; P<0.001), nPNA (rho=0.18 and -0.22; P<0.05), S-creatinine (rho=0.19 and -0.19; P<0.01) and HGS (rho=0.21 and -0.25; P<0.01). IFG-I was strongly correlated with IGFBP-3 (rho=0.62; P<0.001) and inversely correlated with IGFBP-1 (rho=0.44; P<0.001). Both IGF-I and IGFBP-3, but not IGFBP-1, were significantly correlated with age (rho=-0.25 for IGF-I and -0.35 for IGFBP-3; P<0.001) and hsCRP (rho=-0.21 and -0.32; P<0.01). In multivariate analysis, SGA and s-albumin were independent predictors of both IGF-I and IGFBP-1. CONCLUSION: Both IGF-I and IGFBP-1 appear to correlate well with markers of protein-energy malnutrition and sarcopenia. However, IGF-I is also influenced by age, whereas IGFBP-1 is influenced by glucose metabolism. IGFBP-3 does not correlate with nutritional status in ESRD, perhaps because of a strong association with inflammation.

Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance.

In the present study, we explore the role of decreased renal function and a genetic polymorphism on the recently discovered protein resistin, apparently able to inhibit hepatic insulin action in mice. We also investigate possible links with inflammation and the insulin resistance present in patients with chronic kidney disease (CKD). This is a post hoc, cross-sectional study comparing 239 prevalent CKD patients with varying degrees of renal function impairment with an age- and gender-matched randomly selected control group of 25 individuals. Glomerular filtration rate (GFR) was estimated by the mean of urea and creatinine clearance (24-h urine samples) (n=204) or by iohexol clearance (n=60). Plasma analysis of blood lipids, insulin, glucose, inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, vascular cellular adhesion molecule, intercellular adhesion molecule) and resistin (kit from LINCO Research, St Charles, MS) was performed using commercially available assays or routine methods. Insulin resistance was estimated by quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment for insulin resistance (HOMA-IR) and body composition by dual-energy X-ray absorptiometry. Genotyping of a C/G promoter single nucleotide polymorphism (n=168) at position -180 of the resistin gene was performed by PyroSequencing. Serum levels of resistin were markedly elevated in the CKD patients with both advanced (39.9+/-1.3 ng/ml) and mild to moderate (23.2+/-1.0 ng/ml) renal function impairment, as compared to controls (8.5+/-0.7 ng/ml; P<0.001). In a multiple linear regression model in patients (adjusted r(2)=0.60), only GFR (beta=3.4; P<0.0001), lean body mass (beta=2.2; P<0.001) and the inflammatory markers were independently associated with circulating resistin levels. There was a weak but significant impact of -180 C/G genotype on plasma levels of resistin (median 43.0+/-2.4 ng/ml in CC, 37.5+/-2.0 ng/ml in CG, and 41.1+/-4.9 ng/ml in GG; P<0.05). Univariate analysis of non-diabetic patients and controls showed that serum resistin was associated with markers of glucose metabolism. However, in a multiple regression model, resistin, as well as all the measured markers of inflammation, was only associated with insulin resistance if GFR was not taken into account. Circulating resistin levels are strongly associated with both GFR and inflammatory biomarkers in CKD. As the significant relationship between plasma resistin levels and insulin resistance was lost following the correction for GFR, resistin is not a likely mediator of insulin resistance in patients with CKD. Renal function is an important factor to take into account in clinical studies relating insulin sensitivity to inflammatory biomarkers in CKD as well as in patients with diabetes mellitus, who often have an impaired renal function.

Fluid and solute transport in CAPD patients before and after permanent loss of ultrafiltration capacity.

BACKGROUND: Two major types of permanent loss of ultrafiltration capacity (UFC) were previously distinguished among patients treated with CAPD: 1) type HDR with high diffusive peritoneal transport rate of small solutes and low osmotic conductance,but with normal fluid absorption rate, and 2) type HAR with high fluid absorption rate, but with normal diffusive peritoneal transport rate of small solutes and normal osmotic conductance. However, the detailed pattern of changes in peritoneal transport parameters in patients developing loss of ultrafiltration capacity is not known. OBJECTIVE: Analysis of solute and fluid transport parameters in the same patient before and after UFC loss. PATIENTS: Seven CAPD patients who had undergone repeated dwell studies,which were carried out before and/or after the onset of UFC loss. METHODS: Dialysis fluids (2 L) with glucose or a mixture of amino acids as osmotic agent at three basic tonicities were applied during 6 hour dwell studies. Fluid and solute transport parameters were previously shown not to be affected by these dialysis solutions (except by hypertonic amino acid-based solution). Intraperitoneal dialysate volume and fluid absorption rate were assessed using radiolabeled human serum albumin (RISA). Osmotic conductance (a(OS))was estimated by a mathematical model as ultrafiltration rate induced by unit osmolality gradient. Diffusive mass transport coefficients, K(BD), for glucose,urea,and creatinine were estimated using the modified Babb-Randerson-Farrell model. RESULTS: Five patients had increased K(BD) for small solutes after the onset of UFC loss,and three of them had decreased a(OS),whereas two patients had normal a(OS). In one of them, a(OS) decreased with time after the onset of UFC loss with concomitant normalization of glucose absorption. In all studies of these five patients the fluid absorption rate was within the normal range. Two other patients had increased fluid absorption rate (about 5 ml/min),and one of them also had increased K(BD) for small solutes,in two consecutive dwell studies in each patient with the second study being carried out at 1 and 7 months respectively after the first one. In all four studies in these two patients, the a(OS) was within the normal range. The sodium dip during dialysis with 3.86% glucose-based solution was lost, not only among most patients with UFC loss related to reduced osmotic conductance, but also in patients with increased K(BD). CONCLUSIONS: The occurrence of two major types of UFC loss was confirmed. However, a case of a mixed type of UFC loss with high fluid absorption rate and high K(BD) for small solutes, but normal osmotic conductance, and with normalization of initially high K(BD) for small solutes, linked with decreasing initially normal osmotic conductance,was also found. As a reduced sodium dip with hypertonic glucose solution is not only seen in patients with reduced osmotic conductance, it cannot reliably be used as a single measure of decreased aquaporin function. Permanent ultrafiltration capacity loss may be a dynamic phenomenon with a variety of alterations in peritoneal transport characteristics.

Peroxisome proliferator-activated receptor gamma polymorphisms affect systemic inflammation and survival in end-stage renal disease patients starting renal replacement therapy.

BACKGROUND: Inflammation may contribute to the markedly increased cardiovascular morbidity and mortality in end-stage renal disease (ESRD). However, the prevalence of inflammation varies in different ESRD populations. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is an important nuclear signaling protein that may regulate inflammatory response, and recent studies have revealed genetic polymorphisms that have significant effect on PPAR-gamma signaling. The aim of this study was to clarify whether the PPAR-gamma 161C/T and PPAR-gamma2 Pro12Ala single-nucleotide polymorphisms (SNPs) influence the inter-individual variance of inflammation and mortality in ESRD patients. METHODS: The present prospective study included 229 incident Caucasian ESRD patients (62% males) just prior to starting renal replacement therapy and 207 healthy controls (62% males). Blood samples were taken for measuring systemic inflammatory (CRP, TNF-alpha, IL-6) and nutritional (S-albumin) parameters. The presence of diabetes mellitus, malnutrition (subjective global assessment (SGA)) and cardiovascular disease (CVD) were also assessed. Genotyping of the two PPAR-gamma SNPs was performed using Pyrosequencing. During follow-up (1621+/-63 days), both all-cause and CVD-mortality were investigated. RESULTS: ESRD patients had a higher prevalence of both the PPAR-gamma 161 CC and PPAR-gamma2 Pro12Pro genotypes than the general population (p<0.01). Whereas the Pro12Pro genotype was associated with higher median serum levels of both hs-CRP (p<0.05) and TNF-alpha (p<0.01) the 161CC genotype was associated with a significantly higher (6.6 mg/L versus 3.3 mg/L; p<0.01) median hs-CRP level. Following adjustment for age, gender, SGA and CVD a significantly higher mortality rate was observed in patients with the Pro12Pro genotype. CONCLUSION: This study demonstrates significant differences in PPAR-gamma genotype distribution between ESRD patients and healthy controls. Furthermore, as the PPAR-gamma2 Pro12Pro genotype was associated with both higher levels of biomarkers of inflammation as well as shorter survival, genetic polymorphisms seem to play a role in determining systemic inflammatory status and outcome in this patient group.

The role of peritoneal dialysis in renal replacement therapy: an update on medical aspects.

In this brief review, we discuss various medical factors that are of importance for the role of peritoneal dialysis (PD) in renal replacement therapy (RRT), whereas the complex role of non medical factors will only be mentioned briefly. The aim of any RRT, including hemodialysis, PD and renal transplantation, is to normalize the volume and composition of the body fluids, to remove uremic toxins, and to improve clinical outcome. In the following, we will focus on adequacy, preservation of residual renal function, fluid balance, infections, nutrition, cardiovascular disease and systemic inflammation in PD as these factors are strong predictors of clinical outcome in end stage renal disease patients.

Systemic inflammation in dialysis patients with end-stage renal disease: causes and consequences.

Despite rapid improvements in dialysis technology during the last 20 years, the mortality rate in end-stage renal disease (ESRD) patients treated with dialysis is still unacceptably high and comparable to that of many cancer patients with metastases. The main cause of the increased mortality in ESRD patients is cardiovascular disease (CVD), which is twice as common and advances at twice the rate already in patients with earlier stages of chronic kidney disease as compared to the general population. Although traditional risk factors are common in dialysis patients, they can only in part explain the very high prevalence of CVD in this patient group. Recent evidence demonstrates that chronic inflammation, a non-traditional risk factor which is a commonly observed in dialysis patients, may cause malnutrition and progressive atherosclerotic CVD by several pathogenetic mechanisms. Available data suggest that pro-inflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. While the long-term effects of chronic inflammation may be most important in the pathogenesis of CVD, the acute-phase reaction may also be a direct cause of acute vascular injury by several pathogenetic mechanisms. The cause(s) of inflammation in dialysis are multifactorial and include both dialysis-related and unrelated factors. Thus, it could be speculated that suppression of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. As there are currently no established guidelines for the treatment of chronic inflammation in ESRD patients, studies on the long-term effects of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome in this patient group are warranted.

Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality.

OBJECTIVES: Cardiac troponin T (cTnT) is a highly sensitive and specific marker of myocardial damage. It has been shown that elevated serum concentrations of cTnT in haemodialysis (HD) patients are associated with poor prognostic outcome. The aim of the present study was to investigate the predictive value of cTnT in samples from predialysis patients and to investigate associations between cTnT and inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6). DESIGN: Cohort, follow-up study. SETTING: Huddinge University Hospital, Sweden. SUBJECTS: A total of 115 (62% males, 28% diabetic patients) end-stage renal disease (ESRD) patients (52 +/- 1 years), of which 29% had cardiovascular disease (CVD), were studied shortly before the onset of dialysis therapy. Sixty-four patients started peritoneal dialysis (PD) as renal replacement therapy, whilst 49 started HD during the follow-up. MAIN OUTCOME MEASURES: The cTnT was analysed with the third generation TnT assay on Elecsys 2010. The prognostic value was calculated for cTnT, IL-6, age, CVD, malnutrition, diabetes mellitus (DM) and gender. Survival analyses were made with Kaplan-Meier and Cox regression analyses, with all-cause mortality as the clinical end point (mean follow-up period 2.7 +/- 0.1 years). RESULTS: Significant correlations were found between cTnT and CKMB (rho = 0.52, P < 0.0001), IL-6 (rho = 0.23, P < 0.05), CRP (rho = 0.30, P < 0.05), and serum albumin (rho = -0.31, P < 0.001), respectively. Diabetic patients had higher median serum cTnT level (0.09 microg L-1; range <0.01-0.51 vs. 0.04 microg L-1; range <0.01-0.67 microg L-1; P < 0.005) compared with nondiabetic patients. Likewise, patients with CVD had a significantly higher median level (0.08 microg L-1; range <0.01-0.67 microg L-1 vs. 0.04 microg L-1; range <0.01-0.61 microg L-1; P < 0.01) of cTnT compared with patients without CVD. Patients with cTnT > or =0.10 microg L-1 had a higher cumulative mortality rate than patients with cTnT < 0.10 microg L-1 (chi2 = 7.04; P < 0.01). Whilst age, CVD, malnutrition, DM, IL-6, cTnT and male gender were associated with poor outcome in the univariate analysis, only DM (P < 0.05) and cTnT (P < 0.05) were independently associated with mortality in a multivariate analysis. CONCLUSIONS: The present study demonstrates that serum concentrations of cTnT > or =0.10 microg L-1 is a significant predictor of mortality in patients starting dialysis. Moreover, the positive correlations between cTnT and IL-6, and CRP, respectively, suggest an association between inflammation and cTnT levels. Finally, the results of the present study suggest that cTnT is an independent predictor of mortality in ESRD patients starting dialysis.

Soluble leptin receptors and serum leptin in end-stage renal disease: relationship with inflammation and body composition.

BACKGROUND: Elevated serum leptin (S-leptin) levels have been reported in patients with end-stage renal disease (ESRD). Apart from the decreased glomerular filtration rate (GFR), body composition and inflammation may affect leptin levels in ESRD. Leptin circulates both free of and bound to soluble leptin receptors (sOB-R), which are the main determinants of leptin activity and have not been described in ESRD until now. DESIGN: To analyze the association between S-leptin, sOB-R, and inflammation and body composition, we studied 149 (62% males) normal weight (BMI 24.7 +/- 0.4 kg m(-2)) ESRD patients (51 +/- 1 years old) shortly before the start of dialysis (GFR 7.0 +/- 0.2 mL min(-1)). sOB-R and plasma interleukin-6 (IL-6; n= 113) levels were evaluated using ELISA, S-leptin using RIA, and body composition was assessed by X-ray absorptiometry (n = 139). Forty-one healthy subjects age (51 +/- 1 years), BMI (23.6 +/- 0.5 kg m(-2)) and gender-matched (59% males) were used as controls. RESULTS: Median S-leptin was higher in the ESRD patients (10.0 ng mL(-1)) compared with the controls (3.9 ng mL(-1)) (P < 0.001). The median sOB-R did not differ significantly between the ESRD patients (44 U mL-1) and the controls (37 U mL-1). Thus, the sOB-R/S-leptin ratio was lower in the ESRD patients (9.5 +/- 1.2 vs. 12.3 +/- 1.8; P < 0.01) than the controls. A negative correlation was observed between S-leptin and sOB-R (Rho = -0.42; P < 0.0001) in the ESRD patients, a positive correlation was observed between lean body mass and the sOB-R/S-leptin ratio (Rho = 0.33, P = 0.0001) whereas fat mass was negatively correlated to both sOB-R (Rho = -0.26, P = 0.002), and the sOB-R/S-leptin ratio (Rho = -0.62, P < 0.0001). Positive correlations were observed between IL-6 and S-leptin (Rho = 0.19; P < 0.05) and weak but significant body fat mass (Rho = 0.20; P < 0.05), respectively. CONCLUSIONS: This study demonstrates that despite markedly elevated S-leptin levels in the ESRD patients, sOB-R did not differ from the controls. In view of the anorexigenic and pro-atherogenic effects of leptin, further elucidation of the consequences of free bioactive leptin in the development of complications such as malnutrition and cardiovascular disease in ESRD patients is required.