Bengt Lindholm

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.

Plasma Pentraxin 3 in Patients with Chronic Kidney Disease: Associations with Renal Function, Protein-Energy Wasting, Cardiovascular Disease, and Mortality

BACKGROUND AND OBJECTIVES Plasma protein pentraxin 3 concentrations are elevated in a wide range of diseased states. However, no study has evaluated protein pentraxin 3 in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Plasma protein pentraxin 3 concentrations were analyzed in relation to GFR, inflammation, cardiovascular disease, and protein-energy wasting in 71 patients with stages 3 to 4 chronic kidney disease, 276 patients with stage 5 chronic kidney disease, and 61 control subjects. Survival (5 yr) in patients with stage 5 chronic kidney disease was analyzed in relation to protein pentraxin 3 levels. RESULTS Both patient groups with chronic kidney disease had higher protein pentraxin 3 concentrations than control subjects, with the highest concentration in patients with stage 5 chronic kidney disease. In all patients with chronic kidney disease, protein pentraxin 3 correlated negatively with GFR and positively with inflammatory markers. Patients with protein-energy wasting, inflammation, and cardiovascular disease had higher concentrations of protein pentraxin 3 than their counterparts. Patients with high protein pentraxin 3 levels had higher all-cause and cardiovascular mortality. After adjustment for age, gender, C-reactive protein, and cardiovascular disease, all-cause mortality was still significantly higher in patients with high protein pentraxin 3. Finally, protein pentraxin 3 showed a predictive value of mortality similar to that of IL-6 and better than C-reactive protein. CONCLUSION Plasma protein pentraxin 3 increases as GFR declines and is associated with the presence of cardiovascular disease and protein-energy wasting. Furthermore, in patients with chronic kidney disease, elevated protein pentraxin 3 predicted 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.

Comparative Associations of Muscle Mass and Muscle Strength with Mortality in Dialysis Patients

BACKGROUND AND OBJECTIVES Reduced muscle mass and strength are prevalent conditions in dialysis patients. However, muscle strength and muscle mass are not congruent; muscle strength can diminish even though muscle mass is maintained or increased. This study addresses phenotype and mortality associations of these muscle dysfunction entities alone or in combination (i.e., concurrent loss of muscle mass and strength/mobility, here defined as sarcopenia). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study included 330 incident dialysis patients (203 men, mean age 53±13 years, and mean GFR 7±2 ml/min per 1.73 m(2)) recruited between 1994 and 2010 and followed prospectively for up to 5 years. Low muscle mass (by dual-energy x-ray absorptiometry appendicular mass index) and low muscle strength (by handgrip) were defined against young reference populations according to the European Working Group on Sarcopenia in Older People. RESULTS Whereas 20% of patients had sarcopenia, low muscle mass and low muscle strength alone were observed in a further 24% and 15% of patients, respectively. Old age, comorbidities, protein-energy wasting, physical inactivity, low albumin, and inflammation associated with low muscle strength, but not with low muscle mass (multivariate ANOVA interactions). During follow-up, 95 patients (29%) died and both conditions associated with mortality as separate entities. When combined, individuals with low muscle mass alone were not at increased risk of mortality (adjusted hazard ratio [HR], 1.23; 95% confidence interval [95% CI], 0.56 to 2.67). Individuals with low muscle strength were at increased risk, irrespective of their muscle stores being appropriate (HR, 1.98; 95% CI, 1.01 to 3.87) or low (HR, 1.93; 95% CI, 1.01 to 3.71). CONCLUSIONS Low muscle strength was more strongly associated with aging, protein-energy wasting, physical inactivity, inflammation, and mortality than low muscle mass. Assessment of muscle functionality may provide additional diagnostic and prognostic information to muscle-mass evaluation.

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin

BACKGROUND Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). METHODS We performed a cross-sectional study of 85 incident patients (51 +/- 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor (<500 mg/day; n = 40) or severe (>/=500 mg/day; n = 45) proteinuria. Clinical and anthropometric data, along with ultrasonographic flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thicknesses (CIMT), were recorded in each group. Circulating NAMPT/visfatin, adiponectin (normalized to BMI), AHSG/fetuin-A and hsCRP levels were also measured using commercial ELISA. RESULTS Plasma NAMPT/visfatin, CIMT, HOMA index and hsCRP levels were all significantly higher in diabetics than in control subjects, and all but CIMT correlated with proteinuria (rho = 0.46; P < 0.001, rho = 0.54; P > 0.05, rho = 0.32; P = 0.003, rho = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (rho = -0.54; P < 0.001, rho = -0.56; P < 0.001, rho = -0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r(2) = -0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r(2) = -0.33, P = 0.006) were independently related to FMD. CONCLUSIONS The present study suggests that the presence of proteinuria, regardless of the degree of renal function impairment, is an important predictor of endothelial dysfunction in early diabetic nephropathy and that it is associated with altered circulating levels of NAMPT/visfatin and adiponectin.

Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease

BACKGROUND Abnormally low serum testosterone levels were recently associated with an increased mortality risk in male dialysis patients. However, the prevalence of testosterone deficiency in end-stage renal disease (ESRD) is not well defined. We hereby explore the prevalence and correlates of clinical testosterone deficiency in a large cohort of ESRD male patients. METHODS Two hundred and sixty ESRD men [median age 59 (25th-75th percentile 48-67)  years] were included. Testosterone concentration and testosterone deficiency (<10 nmol/L) were studied in relation to clinically evident cardiovascular disease and markers of inflammation at baseline as well as deaths registered during the following 36 months. RESULTS Testosterone deficiency was present in 44% of the patients, while 33% showed testosterone insufficiency (10-14 nmol/L), and only 23% had normal testosterone values (>14 nmol/L). Testosterone was strongly and inversely correlated to inflammatory markers (CRP, IL-6 and fibrinogen), even after correction for age and sex hormone-binding globulin. In a crude spline curve, low testosterone concentrations were associated with worse outcome. A clinical condition of testosterone deficiency was independently associated with cardiovascular co-morbidity [odds ratio (OR) 2.51; 95% confidence interval (CI) 1.32-4.76] and death (OR 2.00; 95% CI 1.01-3.97) in logistic regression analyses. CONCLUSIONS Testosterone deficiency is a common finding among male ESRD patients, and it is independently associated with inflammation, cardiovascular co-morbidity and outcome. Future studies are needed to determine the potential adverse effects of male hypogonadism in ESRD and the possibility of improving risk profile, quality of life, and ultimately outcome with testosterone supplementation in these patients.

Mediterranean Diet, Kidney Function, and Mortality in Men with CKD

BACKGROUND AND OBJECTIVES Adherence to a Mediterranean diet may link to a better preserved kidney function in the community as well as a favorable cardiometabolic profile and reduced mortality risk in individuals with manifest CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Dietary habits were determined by 7-day dietary records in a population-based cohort of 1110 Swedish men (age 70 years) from 1991 to 1995, 506 of whom were considered to have CKD because of a GFR<60 ml/min per 1.73 m(2). A Mediterranean Diet Score was calculated, and participants were categorized as having low, medium, or high adherence. Adequate dietary reporters were identified with Goldberg cutoffs (n=597). Deaths were registered during a median follow-up of 9.9 years. RESULTS Compared with low adherents, medium and high adherents were 23% and 42% less likely to have CKD, respectively (adjusted odds ratio [95% confidence interval]=0.77 [0.57 to 1.05] and 0.58 [0.38 to 0.87], respectively, P for trend=0.04). Among those individuals with CKD, phosphate intake and net endogenous acid production were progressively lower across increasing adherence groups. No differences were observed regarding other cardiometabolic risk factors across adherence groups. As many as 168 (33%) CKD individuals died during follow-up. Compared with low adherents, proportional hazards regression associated medium and high adherents to a 25% and 23% lower mortality risk, respectively (adjusted hazard ratio [95% confidence interval]=0.75 [0.52 to 1.06] and 0.77 [0.44 to 1.36], respectively, P for trend=0.10). Sensitivity analyses showed significant and stronger associations when only adequate dietary reporters were considered. CONCLUSIONS Adherence to a Mediterranean dietary pattern is associated with lower likelihood of CKD in elderly men. A greater adherence to this diet independently predicted survival in those patients with manifest CKD. Clinical trials are warranted to test the hypothesis that following such a diet could improve outcomes (independent of other healthy lifestyles) in CKD patients.

Inflammation contributes to low plasma amino acid concentrations in patients with chronic kidney disease

BACKGROUND Inflammation and malnutrition are common in chronic kidney disease (CKD) patients, and plasma concentrations of free amino acids (AAs) in these patients are often abnormal. Malnutrition contributes to alterations in AA concentrations. OBJECTIVE The objective was to study the effects of inflammation on plasma AA concentrations. DESIGN Concentrations of plasma AAs, serum albumin, and several inflammatory markers were analyzed in 200 fasting, nondiabetic CKD patients who were close to the start of renal replacement therapy. The nutritional status of these patients was assessed by a subjective global assessment. RESULTS The patients with inflammation [C-reactive protein (CRP) concentrations >10 mg/L] or malnutrition had lower AA concentrations than did the patients with no inflammation or malnutrition. The presence of both inflammation and malnutrition was associated with more marked reductions in AA concentrations than was malnutrition alone. Significant inverse correlations were observed between the plasma concentrations of most of the essential and nonessential AAs and inflammatory markers, whereas serum albumin concentrations were positively correlated with several AA concentrations. A stepwise multivariate regression analysis showed that serum CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs. An analysis of all-cause mortality with a Kaplan-Meier test showed that the patients with higher AA concentrations had significantly better survival than did the patients with lower AA concentrations. CONCLUSIONS Plasma AA concentrations are low in CKD patients with inflammation and are inversely correlated with concentrations of inflammatory markers. Although inflammation and malnutrition are closely related, CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs, which suggests an independent role of inflammation as a cause of low plasma AA concentrations in CKD patients.

Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease.

Background The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population. Objective To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality. Methods Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3–5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed. Results GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3–5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32–14.2; p = 0.016). Conclusion Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3–5 patients.

C-reactive protein in end-stage renal disease: are there reasons to measure it?

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in end-stage renal disease (ESRD) patients. As traditional risk factors cannot alone explain the unacceptable high prevalence and incidence of CVD in this population, inflammation (a common phenomenon in ESRD), and other non-traditional risk factors are likely to contribute. Among several inflammatory biomarkers used to assess inflammation, high-sensitivity C-reactive protein (hs-CRP) has attracted the most interest. Indeed, in the general population the consistency of prognostic data for hs-CRP and the practicality of its use have led to suggestions that CRP should be used as a clinical criterion for global cardiovascular risk prediction. As CRP is so strongly associated with vascular disease, it has been suggested that this protein is not only a marker, but also a mediator, of atherogenesis. Indeed, recent in vitro data from studies on endothelial cells, monocytes-macrophages and smooth muscle cells support a direct role for CRP in atherogenesis. In ESRD, hs-CRP has been proven to be a strong predictor of both cardiovascular and all-cause mortality, and associated with oxidative stress, vascular calcification and endothelial dysfunction. As recent studies suggest that interleukin-6 may be a somewhat better outcome predictor than hs-CRP, comparative studies are needed to evaluate which inflammation biomarker is the most cost-effective predictor of outcome in the ESRD patient population.