Olof Heimbürger

Emerging Biomarkers for Evaluating Cardiovascular Risk in the Chronic Kidney Disease Patient: How Do New Pieces Fit into the Uremic Puzzle?

Premature cardiovascular disease (CVD), including stroke, peripheral vascular disease, sudden death, coronary artery disease, and congestive heart failure, is a notorious problem in patients with chronic kidney disease (CKD). Because the presence of CVD is independently associated with kidney function decline, it appears that the relationship between CKD and CVD is reciprocal or bidirectional, and that it is this association that leads to the vicious circle contributing to premature death. As randomized, placebo-controlled trials have so far been disappointing and unable to show a survival benefit of various treatment strategies, such a lipid-lowering, increased dialysis dose and normalization of hemoglobin, the risk factor profile seems to be different in CKD compared with the general population. Indeed, seemingly paradoxical associations between traditional risk factors and cardiovascular outcome in patients with advanced CKD have complicated our efforts to identify the real cardiovascular culprits. This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification. Each of these is not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population. However, a causal relationship between these new markers and CVD in CKD patients remains to be established. Finally, two novel disciplines, proteomics and epigenetics, will be discussed, because these tools may be helpful in the understanding of the discussed vascular risk factors.

Associations between circulating inflammatory markers and residual renal function in CRF patients

BACKGROUND Circulating levels of cytokines and other inflammation markers are markedly elevated in patients with chronic renal failure. This could be caused by increased generation, decreased removal, or both. However, it is not well established to what extent renal function per se contributes to the uremic proinflammatory milieu. The aim of the present study is to analyze the relationship between inflammation and glomerular filtration rate (GFR) in 176 patients (age, 52 +/- 1 years; GFR, 6.5 +/- 0.1 mL/min) close to the initiation of renal replacement therapy. METHODS Circulating levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), hyaluronan, and neopterin were measured after an overnight fast. Patients subsequently were subdivided into two groups according to median GFR (6.5 mL/min). RESULTS Despite the narrow range of GFR (1.8 to 16.5 mL/min), hsCRP, hyaluronan, and neopterin levels were significantly greater in the subgroup with lower GFRs, and significant negative correlations were noted between GFR and IL-6 (rho = -0.18; P < 0.05), hyaluronan (rho = -0.25; P < 0.001), and neopterin (rho = -0.32; P < 0.0005). In multivariate analysis, although age and GFR were associated with inflammation, cardiovascular disease and diabetes mellitus were not. CONCLUSION These results show that a low GFR per se is associated with an inflammatory state, suggesting impaired renal elimination of proinflammatory cytokines, increased generation of cytokines in uremia, or an adverse effect of inflammation on renal function.

Icodextrin Improves the Fluid Status of Peritoneal Dialysis Patients: Results of a Double-Blind Randomized Controlled Trial

Worsening fluid balance results in reduced technique and patient survival in peritoneal dialysis. Under these conditions, the glucose polymer icodextrin is known to enhance ultrafiltration in the long dwell. A multicenter, randomized, double-blind, controlled trial was undertaken to compare icodextrin versus 2.27% glucose to establish whether icodextrin improves fluid status. Fifty patients with urine output <750 ml/d, high solute transport, and either treated hypertension or untreated BP >140/90 mmHg, or a requirement for the equivalent of all 2.27% glucose exchanges, were randomized 1:1 and evaluated at 1, 3, and 6 mo. Members of the icodextrin group lost weight, whereas the control group gained weight. Similar differences in total body water were observed, largely explained by reduced extracellular fluid volume in those receiving icodextrin, who also achieved better ultrafiltration and total sodium losses at 3 mo (P < 0.05) and had better maintenance of urine volume at 6 mo (P = 0.039). In patients fulfilling the studys inclusion criteria, the use of icodextrin, when compared with 2.27% glucose, in the long exchange improves fluid removal and status in peritoneal dialysis. This effect is apparent within 1 mo of commencement and was sustained for 6 mo without harmful effects on residual renal function.

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 patients 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.

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.

Low Serum Testosterone Increases Mortality Risk among Male Dialysis Patients

Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease.

Plasma Pentosidine Is Associated with Inflammation and Malnutrition in End-Stage Renal Disease Patients Starting on Dialysis Therapy

Pentosidine is an advanced glycation end-product (AGE), formed by glycosylation and oxidation, that accumulates markedly in end-stage renal disease (ESRD). It has been speculated that AGE and carbonyl stress contributes to long-term complications such as cardiovascular disease (CVD) in ESRD patients. This study determined plasma levels of pentosidine as well as the presence of inflammation (CRP > or = 10 mg/L), clinical CVD (CVD(clin)), and malnutrition (subjective global assessment [SGA] > 1) in a cohort of 191 ESRD patients, median age of 55 yr (range, 23 to 70 yr) and median GFR = 7 ml/min (range, 2 to 17 ml/min), close to start of renal replacement therapy. Fifty-one elderly subjects, median age of 82 yr (range, 71 to 110 yr), with mild renal impairment, median GFR = 67 ml/min (range, 38 to 113 ml/min), were also studied for comparative analysis of plasma pentosidine. The plasma pentosidine content was elevated in all patients compared with the levels in the elderly subjects and were negatively correlated with GFR both in the ESRD patients (Rho = -0.24; P < 0.01; n = 159) and in the elderly subjects (Rho = -0.31; P < 0.05). Moreover, the plasma pentosidine content was correlated with age in the ESRD patients (Rho = 0.26; P < 0.001) and in the elderly subjects (Rho = 0.44; P < 0.001). The 63 malnourished ESRD patients (35%) had a significantly higher (P < 0.05) median plasma pentosidine than the well-nourished patients (39 versus 27 pmol/mg albumin). Similarly, 73 inflamed patients (38%) had a significantly higher (P < 0.001) median pentosidine content compared with 118 non-inflamed patients (37 versus 24 pmol/mg albumin). Also, the plasma pentosidine content showed weak but significant positive correlations with CRP (Rho = 0.28; P < 0.0001), fibrinogen (Rho = 0.23; P < 0.01; n = 126), IL-6 (Rho = 0.22; P < 0.01; n = 169), and soluble vascular cellular adhesion molecule-1 (Rho = 0.38; P < 0.001; n = 74). On the other hand, no significant differences in plasma pentosidine content were noted between the patients with and those without CVD(clin) (32 versus 27 pmol/mg albumin, respectively). Analyses of all-cause mortality, by Kaplan-Meier, showed that mortality was not linked to the plasma pentosidine content. Moreover, survival analysis by the Cox regression model showed that age (P < 0.001), diabetes mellitus (P < 0.01), malnutrition (P < 0.01), and CVD(clin) (P < 0.01) independently predicted poor outcome, whereas an elevated plasma pentosidine content did not. The present study shows that an elevated plasma pentosidine content in ESRD patients is significantly associated with both inflammation and malnutrition and confirms that low residual renal function and high age further contribute to an increased plasma pentosidine content. However, in this small cohort, the plasma pentosidine content did not predict outcome. Thus, accumulation of plasma pentosidine is unlikely to be an appropriate clinically useful marker to predict mortality in ESRD patients.

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

Abstract.  Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR, Bárány P, Heimbürger O, Suliman ME, Alvestrand A, Lindholm B, Stenvinkel P (Karolinska Institutet, Stockholm; and Karo Bio AB, Novum, Huddinge; Sweden). Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007; 262: 690–701.

Do ACE-inhibitors suppress tumour necrosis factor-α production in advanced chronic renal failure?

Abstract. Stenvinkel P, Andersson P, Wang T, Lindholm B, Bergström J, Palmblad J, Heimbürger O, Cederholm T (Huddinge University Hospital and Karolinska Institute, Stockholm; Sweden). Do ACE‐inhibitors suppress tumour necrosis factor‐α production in advanced chronic renal failure? J Intern Med 1999; 246: 503–507.

Abdominal fat deposition is associated with increased inflammation, protein–energy wasting and worse outcome in patients undergoing haemodialysis

OBJECTIVE The role of obesity in promoting or preventing the complications of haemodialysis patients remains unclear, with several studies suggesting that obesity may even be beneficial. We tested the hypothesis that abdominal fat deposition in HD patients is a risk factor associated with both increased inflammation and protein-energy wasting (PEW), as well as elevated mortality risk. METHODS A cross-sectional study with mortality follow-up [median 41 (interquartile range 25-47) months] of haemodialysis patients [n = 173, 100 men, aged 65 (51-74) years]. Abdominal fat deposition was assessed by means of a conicity index (Ci), which estimates fat accumulation in the abdomen as the deviation of body shape from a cylindrical towards a double-cone shape (i.e. two cones with a common base at the waist level). The Ci was studied with regard to baseline inflammatory, anthropometric and nutritional markers, including subjective global assessment (SGA). RESULTS Across increasing tertiles of the Ci, patients were older, fatter and more inflamed (P < 0.01 for all). At the same time, they presented a higher prevalence of PEW (SGA >1), reduced handgrip strength and lower S-creatinine (P < 0.01 for all). An increased abdominal fat deposition was associated with worse outcome independently of age, sex, comorbidities and dialysis vintage [Cox HR 1.93 (95% CI = 1.06-3.49)], but the predictive value disappeared following adjustment for interleukin-6 (IL-6) and PEW. CONCLUSION Abdominal fat deposition in haemodialysis patients is linked to both inflammation and PEW, resulting in an increased mortality risk. Our results support the idea that regional differences in adiposity accumulation may have diverse implications on patient outcome.