Tissue level of advanced glycation end products is an independent determinant of high-sensitivity C-reactive protein levels in haemodialysis patients

Aim: C‐reactive protein (CRP) level predicts future cardiovascular events in patients on haemodialysis (HD). Advanced glycation end products (AGE) play a role in cardiovascular disease (CVD) in HD patients. However, which variables including tissue AGE levels are independently associated with CRP remains unknown. Therefore, whether tissue AGE and CRP levels were correlated with atherosclerosis in HD patients was examined. Methods: Fifty‐four HD patients underwent determinations of blood chemistries and tissue AGE. Tissue AGE levels were evaluated by measuring skin autofluorescence. Pulsatility index (PI) in the carotid artery was measured using a Doppler ultrasonography. Results: Univariate analyses showed that age, white blood cells, serum albumin (inversely), alkaline phosphatase (inversely), tartrate‐resistant acid phosphatase 5b (TRAP5b) (inversely) and skin AGE levels were significantly correlated with high‐sensitivity CRP (hsCRP). Multiple stepwise regression analysis revealed that serum albumin, TRAP5b and skin AGE levels were independent determinants of hsCRP. Further, PI was highest among HD patients with high skin AGE and high hsCRP levels. Conclusion: The present study suggests that tissue AGE level is one of the independent determinants of hsCRP in HD patients. Tissue AGE and hsCRP levels may be correlated with each other, which could in concert contribute to the progression of atherosclerosis in these subjects.     

Diabetes Mellitus,Hyperhomocystinemia and Atherosclerotic Vascular Disease in Taiwanese Chronic Hemodialysis Patients: A Retrospective Study

Aim: Diabetic patients with hemodialysis (HD) have a high mortality rate from atherosclerotic vascular disease (ASVD). However, the extent of the role of hyperhomocystinemia as a risk factor of ASVD is uncertain in diabetic HD patients. We investigated whether there was an association with ASVD events in diabetics and non‐diabetics where these were chronic hyperhomocystinemia HD patients. Methods: Two hundred patients undergoing HD were included in the study. About 50% of the patients had diabetes mellitus (DM). They had predialysis blood work performed for total homocysteine. A history of DM was elicited using information from the patients' questionnaires and verified by careful inpatient and outpatient chart review. Results: A total of 196 patients had hyperhomocystinemia and were enrolled this study. Mean homocysteine concentration was 29.7 ± 6.6 µmol/L overall. DM was present in 50.0% of patients. The mean homocysteine concentration was 29.4 ± 9.5 µmol/L and 29.9 ± 9.7 µmol/L in diabetic HD patients (n = 98) and non‐diabetic HD patients (n = 98), respectively (P = 0.71). There was no association with hyperhomocystinemia between diabetic and non‐diabetic in chronic HD patients. There were significant differences including age, sex, HDL cholesterol, triglycerides, hypertension, smoking, serum creatinine, dialysis duration and glucose intolerance in the two groups (P < 0.05). There were also significant differences in ASVD (P = 0.0027) and CVD (P = 0.0017) between diabetics and non‐diabetics in cases of chronic hyperhomocystinemia HD patients. The adjusted odds ratio for ASVD was 3.02 (95%CI, 1.63 to 5.59) for those subjects with a DM in the highest quartile compared with the lowest 3 quartiles. Conclusions: There were associations with ASVD and CVD in diabetics and non‐diabetics in cases of chronic hyperhomocystinemia HD patients. There was no association with hyperhomocystinemia between diabetic and non‐diabetic in Taiwanese chronic HD patients. This study found that the presence of DM and advanced age were the major determinants for ASVD events in chronic HD patients, rather than the levels of homocysteine.     

Evaluation of advanced glycation end products accumulation, using skin autofluorescence, in CKD and dialysis patients

Purpose

Advanced glycation end products (AGE), biomarkers of metabolic stress, are frequently encountered in chronic kidney disease (CKD) patients with cardiovascular disease. Our aim was to evaluate tissue accumulation of AGEs in CKD patients and possible correlations with traditional and non-traditional cardiovascular risk factors.

Methods

Skin AF was measured using AGE Reader in 310 patients: 157 haemodialysis patients (HD) (mean age 60?years, dialysis vintage 29 months, 19.1% diabetic), 102 peritoneal dialysis patients (PD) (mean age 56.3?years, dialysis vintage 16 months, 17.6% diabetic), 32 CKD patients (mean age 68?years, CKD duration 30 months, 34.4% diabetic) and 19 type 2 diabetic patients, without renal failure (mean age 59?years and median duration of diabetes 36 months).

Results

HD patients have higher AGE levels compared to PD ones. Dialysis patients have the highest skin AF values compared to CKD patients (P?P?P?P?P?Conclusions CKD patients have higher AGE values depending on duration (disease, RRT) and GFR (dialysis adequacy and RRF). Other important determinants were diabetes and age.     

Increased levels of serum matrix metalloproteinase-3 in haemodialysis patients with dialysis-related amyloidosis

Background: It is recognized that matrix metalloproteinase‐3 (MMP‐3) is abundantly expressed in active rheumatoid synovium, and that serum level of MMP‐3 is a useful marker for diagnosis of rheumatoid arthritis and for evaluation of prognosis in joint destruction. Little is known about serum MMP‐3 levels in haemodialysis (HD) patients, and thus, the association between serum MMP‐3 and dialysis‐related amyloidosis (DRA) has yet to be elucidated. Methods: Serum levels of MMP‐3 were measured by enzyme immunoassay in 150 HD patients, 90 without DRA and 60 with DRA, before HD. Simple regression analysis was performed to investigate the relationship between serum level of MMP‐3 and clinical parameters, including age, HD duration, C‐reactive protein and β2 microglobulin (BMG). Results: Serum levels of MMP‐3 were significantly higher in HD patients with DRA than in HD patients without DRA (258.2 ± 118.1 vs 201.5 ± 98.4 pg/mL, P = 0.0017), and both levels were significantly higher than those of healthy subjects (45.6 ± 13.4 pg/mL, P < 0.0001). Serum MMP‐3 levels significantly correlated with serum levels of BMG (r = 0.197, P = 0.0164) and HD duration (r = 0.168, P = 0.0427). Moreover, serum MMP‐3 levels significantly correlated with serum BMG levels in HD patients without DRA (r = 0.341, P = 0.0012), but not in HD patients with DRA. Conclusion: Our results suggest that matrix metalloproteinase activity increases in HD patients, which may be associated with BMG and DRA.     

Asymmetric Dimethylarginine in Hemodialysis,Hemodiafiltration, and Peritoneal Dialysis

Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction. Production and elimination of ADMA may be affected by the type of renal replacement therapy used and oxidative stress. Plasma ADMA, advanced glycation end products (AGE), and homocysteine were assessed in 59 subjects: 20 hemodialysis (HD) patients, 19 patients undergoing peritoneal dialysis (PD), and 20 controls. Results were compared between the groups. The effect of 8 weeks of HD and high‐volume predilution hemodiafiltration (HDF) was compared in a randomized study. HD patients showed higher ADMA (1.20 [0.90–1.39 µmol/L]) compared to controls (0.89 [0.77–0.98], P < 0.01), while ADMA in PD did not differ from controls (0.96 [0.88–1.28]). AGE and homocysteine were highest in HD, lower in PD (P < 0.01 vs. HD), and lowest in controls (P < 0.001 vs. HD and PD). PD patients had higher residual renal function than HD (P < 0.01). The decrease in ADMA at the end of HD (from 1.25 [0.97–1.33] to 0.66 [0.57–0.73], P < 0.001) was comparable to that of HDF. Switching from HD to HDF led to a decrease in predialysis homocysteine level in 8 weeks (P < 0.05), while ADMA and AGE did not change. Increased ADMA levels in patients undergoing HD, as compared to PD, may be caused by higher oxidative stress and lower residual renal function in HD. Other factors, such as diabetes and statin therapy, may also be at play. The decrease in ADMA at the end of HD and HDF is comparable. Switching from HD to HDF decreases in 8 weeks the predialysis levels of homocysteine without affecting ADMA.     

Effect of l‐carnitine on oxidative stress and platelet activation after major surgery

Background: The surgical/anesthesia trauma is associated with an increased production of reactive oxygen species (ROS). This enhanced oxidative stress leads to cell damage resulting in various complications such as sepsis, myocardial injury and increased mortality. The aim of this study was to investigate the role of antioxidant treatment with l‐ carnitine in oxidative stress and platelet activation in patients undergoing major abdominal surgery. Methods: Forty patients scheduled for abdominal surgery were randomly allocated to l‐ carnitine, administered with a rapid infusion (0.05 g/kg) diluted in 250 ml of saline solution, vs. placebo treatment just before the surgical intervention. At baseline and after treatment, oxidative stress was evaluated by detection of circulating levels of soluble NOX2‐derived peptide (sNOX2‐dp), a marker of NADPH oxidase activation, and by analyzing platelet ROS formation. Platelet activation was studied by dosing sCD40L. Results: We observed an increase of soluble sNOX2‐dp, sCD40L and ROS production in the placebo group compared with the baseline after the surgical intervention. Conversely, in the l‐ carnitine‐treated group, sNOX2‐dp, sCD40L and ROS production did not significantly differ from the baseline. A linear correlation analysis showed that Δ of ROS correlated with Δ of sNOX2 (R_s=0.817; P<0.001) and Δ of sCD40L (R_s=0.780; P<0.001). Multiple linear regression analysis showed that the only independent predictive variable associated with Δ of ROS was Δ of serum NOX2 levels (SE=0.05; standardized coefficient β=1.075; P<0.001). Conclusion: Our findings suggest that l‐ carnitine could be helpful in modulating oxidative stress and platelet activation during major abdominal surgery‐dependent oxidative damage.     

Benefits of first-half intensive haemodiafiltration for the removal of uraemic solutes

Aim: Haemodiafiltration (HDF) is the most efficient blood purification method and can remove a wide spectrum of solutes of different molecular weights (MW). The purpose of this study was to investigate whether the removed amounts of solutes, especially the larger molecules, could be increased by changing the HDF filtration procedure. Methods: A new first‐half intensive HDF treatment (F‐HDF) was designed, whereby convective clearance is intensively forced during the first half of a HDF session. We compared the removed amounts of solutes in the same group of nine patients treated by F‐HDF, constant rate‐replacing HDF (C‐HDF) and a high‐flux haemodialysis (HD). Results: F‐HDF can remove significantly larger amounts of α₁‐microglobulin (MG), molecular weight (MW) 33 000, compared with HD and C‐HDF (30.1 ± 15.1 vs 12.4 ± 0.3, 15.0 ± 3.1 mg, P < 0.01). Regarding the removal amounts and clear space of β₂MG, MW 11 800, there were no significant differences between the three treatment modalities. Regarding amounts of creatinine, urea nitrogen and phosphorus, there were no significant differences between the three treatment modalities. Conclusion: In post‐replacement HDF with a high‐flux membrane dialyzer, the method used in the present study in which replacement is completed during the first half of the process, is associated with a greater rate of larger molecule removal than the conventional uniform replacement method.     

RELATIONS BETWEEN OXIDATIVE STRESS,HEPATOCYTE GROWTH FACTOR,AND LIVER DISEASE IN HEMODIALYSIS PATIENTS

Background: Hepatocyte growth factor (HGF) and copper/zinc superoxide dismutase (Cu/Zn SOD) protect against tissue injury, including that due to oxidative stress (SOX). We studied whether they could be associated with each other, SOX markers, prevalence of viral hepatitis, and cardiovascular disease (CVD) and their laboratory surrogates in maintenance hemodialysis (HD) patients. Methods: In 24 patients, pre-dialysis serum HGF, plasma Cu/Zn SOD, total lipid peroxides, and serum autoantibodies against oxidized LDL were measured by ELISAs. Viral hepatitis B and C markers were determined by third generation microparticle ELISAs, and CVD was identified on a clinical basis. Results: In HD patients, circulating HGF, Cu/Zn SOD, and the other SOX markers were higher than in healthy controls, and HGF directly correlated with Cu/Zn SOD levels (P = 0.0006). Both HGF (P = 0.021) and Cu/Zn SOD (P = 0.017) were positively associated with prevalence of viral hepatitis and serum alanine aminotransferase activity (P = 0.021 and P = 0.040, respectively). Presence of CVD directly correlated with HGF (P = 0.001) but not with Cu/Zn SOD levels (P = 0.087). Circulating HGF positively related to serum C-reactive protein (P = 0.043). In patients without viral hepatitis and CVD, both HGF and Cu/Zn SOD were lower than in those with, and higher than in healthy controls. CVD (P = 0.003) and viral hepatitis (P = 0.024) were independent predictors of increased HGF, while positive viral hepatitis marker predicted increased Cu/Zn SOD levels (P = 0.019) in HD patients. There were no associations between HGF and the SOX markers in controls. Conclusions: In maintenance HD patients, circulating Cu/Zn SOD and HGF levels are increased, likely as a part of the reparatory reaction against liver damage. Viral hepatitis status and liver function should be considered in further studies of Cu/Zn SOD in these subjects.     

Association of Serum Pentosidine With Arterial Stiffness in Hemodialysis Patients

Pentosidine is an advanced glycation end product (AGE). The present study was undertaken to investigate the association of serum pentosidine with carotid distensibility as a measure of arterial stiffness in hemodialysis patients. One hundred and three patients on maintenance hemodialysis were recruited. The distensibility coefficient of the common carotid artery was evaluated by an ultrasonic phase‐locked echo‐tracking system. Serum pentosidine was measured by competitive enzyme‐linked immunosorbent assay. Serum albumin, lipid profile, calcium, phosphorus, intact parathyroid hormone (iPTH), high‐sensitivity C‐reactive protein (hs‐CRP), and oxidized low‐density lipoprotein (ox‐LDL) levels were also measured. Correlation was determined by linear and multiple stepwise regression analysis. Serum pentosidine level studied in hemodialysis patients was 0.54 ± 0.13 µg/mL. No significant difference in serum pentosidine level was noted between patients with and without diabetes (0.59 ± 0.10 µg/mL vs. 0.53 ± 0.13 µg/mL, P = 0.062) as well as between patients with and without prior cardiovascular disease (CVD) history (0.56 ± 0.14 µg/mL vs. 0.53 ± 0.12 µg/mL, P = 0.206). In multivariate regression analysis, only age (β = 0.363, P < 0.001) and ox‐LDL (β = 0.262, P = 0.004) were identified as independent determinants for serum pentosidine. Serum pentosidine was significantly correlated with carotid distensibility (r = ?0.387, P < 0.001), as well as age, ox‐LDL, and hs‐CRP. After adjustment for age, blood pressure, history of diabetes, prior CVD history, lipid profile, calcium, phosphorus, iPTH, hs‐CRP, and ox‐LDL, serum pentosidine was still negatively correlated with distensibility (β = ?0.175, P = 0.044). Serum pentosidine was independently associated with carotid distensibility in hemodialysis patients. This finding suggested that the accumulation of AGE might be an important pathway in the development of arterial stiffness in end‐stage renal disease.     

Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.     

Smaller low-density lipoprotein size as a possible risk factor for the prevalence of coronary artery diseases in haemodialysis patients: associations of cholesteryl ester transfer protein and the hepatic lipase gene polymorphism with low-density lipoprotein size

Aim: Smaller low‐density lipoprotein (LDL) size has recently been reported as a non‐traditional lipid risk factor for coronary artery disease (CAD). Cholesteryl ester transfer protein (CETP) and the C/T hepatic lipase (HL) gene polymorphism may promote LDL size reduction via the CETP‐mediated exchange of CE for triglyceride (TG) and subsequent HL‐mediated TG hydrolysis in LDL. However, little is known about LDL size status and its relationship with CAD prevalence in haemodialysis (HD) patients who are at high risk for atherosclerosis. Methods: CETP levels, HL genotypes and LDL size were determined, and the determinants of LDL size and its association with CAD prevalence in HD patients (n = 236) aged over 30 years were investigated. Results: The HD patients had a similar LDL size to the healthy subjects. In the HD group, high‐density lipoprotein cholesterol was an independent positive determinant of LDL size, while log₁₀ (TG) was an independent negative determinant in the high (≥2.1 µg/mL) but not low (<2.1 µg/mL) CETP group. In the patients with hypertriglyceridemia, the high CETP group had a significantly smaller LDL size than the low CETP group. Among the patients with above‐median TG levels, the CC genotype and CETP were independent negative determinants of LDL size. In the whole group and the high CETP group, the patients with CAD had a significantly smaller LDL size than those without CAD. Finally, DM and smaller LDL size were identified as independent risk factors for CAD prevalence. Conclusion: These suggest that a smaller LDL size, which is associated with higher levels of TG and CETP and the HL/CC genotype, may serve as a risk factor for CAD in HD patients.     

Plasma Pentraxin 3 is Associated with Cardiovascular Disease in Hemodialysis Patients

Abstract

This cross-sectional study evaluates the associations of Pentraxin 3 (PTX3) and cardiovascular disease (CVD) in hemodialysis (HD) patients. Plasma was obtained from 98 maintenance HD patients before and after a session of HD and 50 age-matched healthy subjects. We measured plasma PTX3 levels by enzyme-linked immunosorbent assay. Our results showed that plasma PTX3 levels were significantly higher in HD patients compared with controls (1.87 vs. 1.11 ng/mL, p < 0.001), and increased acutely after a single HD session (post-HD 2.18 ng/mL vs. pre-HD 1.87 ng/mL, p < 0.001). Patients with CVD had higher plasma PTX3 levels than those without CVD (2.18 vs. 1.76 ng/mL, p < 0.05). Plasma PTX3 levels correlated positively with cardiac troponin T (ρ = 0.287, p = 0.007) and carotid artery intima-media thickness (ρ = 0.294, p = 0.043). High plasma PTX3 (>1.87 ng/mL) level was positively and independently associated with CVD (OR = 3.15, p = 0.024). Receiver operator characteristics analysis showed the correlation between PTX3 and CVD more closely than high sensitivity C-reactive protein (hs-CRP) in patients whose hs-CRP were higher than 3 mg/L. The area under the curve for PTX3 and hs-CRP was 0.655 (p = 0.047) and 0.562 (p = 0.458), respectively. Moreover, plasma PTX3 levels correlated negatively with body mass index, hemoglobin, pre-albumin, total cholesterol, triglyceride, and low-density lipoprotein. These data support the main conclusions: PTX3 levels are markedly elevated in HD patients; HD procedure itself induces PTX3 elevation; plasma PTX3 is associated with CVD in maintenance HD patients.     

Effects of Double Filtration Plasmapheresis on Nocturnal Respiratory Function in Myasthenic Patients

Assessment of respiratory function using combined oximetry‐cutaneous capnography has never been evaluated in patients with myasthenia gravis (MG). We investigated the effects of double filtration plasmapheresis (DFPP) on respiratory status in 18 MG patients. Results of combined oximetry and transcutaneous capnography, MG scores, and acetylcholine receptor antibody titers before and after DFPP treatment were compared. The respiratory monitoring was performed at three time periods (morning, afternoon, and sleep). Mean MG score was markedly lower after DFPP treatment (5.7) than before treatment (7.9). Before DFPP, the minimum pulse oximetric saturation (SpO₂) level obtained during the night session was significantly lower (P = 0.0513 and P = 0.0199) than the levels obtained during the two daytime sessions. A similar phenomenon was noted for maximum transcutaneous carbon dioxide tension (PtcCO₂). After DFPP treatment, the maximum and mean PtcCO₂ levels were significantly higher (P = 0.0056) in the morning than in the afternoon. Of all the respiratory function parameters measured, only minimum SpO₂ levels obtained during morning sessions before DFP treatment differed significantly from those obtained after DFPP treatment (P = 0.0322). Overall, however, minimum SpO₂ levels as well as mean and maximum PtcCO₂ levels improved significantly during sleep after DFPP. In conclusion, we found that respiratory function abnormalities were common in myasthenic patients without clinical respiratory symptoms. DFPP treatment resulted in minimal improvement of respiratory parameters.     

Skin Autofluorescence,a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products,Decreases During the Summer in Dialysis Patients

Tissue advanced glycation end products (AGEs) are a measure of cumulative metabolic and oxidative stress and cytokine‐driven inflammatory reactions. AGEs are thought to contribute to the cardiovascular complications of hemodialysis (HD) patients. Skin autofluorescence (SAF) is related to the tissue accumulation of AGEs and rises with age. SAF is one of the strongest prognostic markers of mortality in these patients. The content of AGEs is high in barbecue food. Due to the location in northern Sweden, there is a short intense barbecue season between June and August. The aim of this study was to investigate if seasonal variations in SAF exist in HD patients, especially during the barbecue season. SAF was measured noninvasively with an AGE Reader in 34 HD‐patients (15 of those with diabetes mellitus, DM). Each time the median of three measures were used. Skin‐AF was measured before and after each one HD at the end of February and May in 31 patients (22 men/9 women); the end of May and August in 28 (20 m/8 w); the end of August and March in 25 (19 m/6 w). Paired statistical analyses were performed during all four periods (n = 23, 17 m/6 w); as was HbA1c of those with DM. There was at a median 5.6% increase in skin‐AF during the winter period (February–May, P = 0.004) and a 10.6% decrease in the skin‐AF during the summer (May–August, P < 0.001). HbA1c in the DM rose during the summer (P = 0.013). In conclusion, skin‐AF decreased significantly during the summer. Future studies should look for favorable factors that prevent skin‐AF and subsequently cardiovascular diseases.     

The methylguanidine-to-creatinine ratio, serum NOx concentrations, and vascular disease in nondiabetic hemodialysis patients

Background. Hemodialysis (HD) patients are in a highly oxidative state, which may contribute to accelerated atherosclerosis. Methylguanidine (MG) and lipid peroxides may be used as markers of the oxidative status in HD patients. A recent study demonstrated the non-enzymatic generation of nitric oxide (NO) via a reaction between hydrogen peroxide and arginine. We determined the relationships between serum concentrations of the oxidation products of NO (NOx) and oxidative status markers, and the relationships between these markers and the prevalence of atherosclerotic disease in HD patients. Methods. We measured serum concentrations of MG, creatinine (Cr), NOx, and thiobarbituric acid reactive substances (TBARS), and determined the presence of apparent vascular disease in 324 nondiabetic HD patients. Results. The MG concentration, but not the NOx concentration, was correlated with the Cr concentration (r = 0.64; P < 0.001). Based on simple linear regression analysis, the NOx concentration (r = 0.13; P < 0.05) correlated with the MG/Cr ratio, but did not correlate with the TBARS concentration. Multiple linear regression analysis revealed that the serum NOx concentration (r = 0.13; P < 0.01) and the duration of dialysis (r = 0.13; P = 0.05) correlated with the MG/Cr ratio. There were no significant differences in the concentrations of NOx, TBARS, or the MG/Cr ratio between HD patients with and without vascular disease. Multivariate logistic regression analysis showed that only age and hypertension were independent risk factors for prevalent vascular disease. Conclusions. These results suggest that non-enzymatic synthesis of NO via oxidative stress may occur in HD patients. However, the serum markers of oxidation status at any one single moment may not correlate with the prevalence of apparent vascular disease in HD patients. Received: July 21, 1999 / Accepted: April 10, 2000     

Impact of rHuEPO therapy initiation on soluble adhesion molecule levels in haemodialysis patients

Background: Increased levels of soluble adhesion molecules have been reported in haemodialysis (HD) patients. Recent studies have shown that recombinant human erythropoietin (rHuEPO) elicits proliferation and migration of endothelial cells and modifies endothelial function. The present study was design to explore the effects of rHuEPO on serum levels of soluble adhesion molecules in HD patients. Methods: Soluble serum levels of E‐selectin (sE‐selectin), intracellular adhesion molecule‐1 (sICAM‐1) and vascular cell adhesion molecule‐1 (sVCAM‐1) were measured by ELISA in 29 rHuEPO naïve HD patients (20 males, 9 females) and 10 control subjects at baseline and second month. The HD patients with a haemoglobin level lower than 10.0 mg/dL (n = 19) were administered rHuEPO therapy and other HD patients (n = 10) were followed as a placebo group. Results: Serum levels of soluble adhesion molecules were significantly higher in HD patients compared with the control group. A significant rise from the baseline in sE‐selectin levels (77 ± 70 vs 100 ± 86 ng/mL, P < 0.05) was observed 2 months after rHuEPO initiation, while sICAM‐1 and sVCAM‐1 levels decreased (271 ± 261 vs 197 ± 89 and 1043 ± 243 vs 990 ± 236 ng/mL, respectively, P < 0.05). Conclusions: The present data indicate that rHuEPO could have an important action on serum levels of soluble adhesion molecules in HD patients. rHuEPO might modify the expression of adhesion molecules from endothelial cells either. However, the exact mechanism responsible for the serum elevation of these molecules in HD patients is yet to be fully elucidated.     

Is hepatitis C virus infection a risk factor for panel‐reactive antibody positivity?

Abstract Patients with high levels of panel‐reactive antibody (PRA) represent an increasingly large group in the waiting lists for cadaveric renal transplantation. Hepatitis C virus (HCV) infection has been found to be associated with a high prevalence of positivity of autoimmune serological tests. We planned this study to evaluate the effect of HCV positivity on the PRA levels in our hemodialysis (HD) patients. We included 38 HCV‐infected (group I: 20 male, 18 female patients, mean duration of HD 73.6 ± 50.6 months) and 43 hepatitis marker‐negative (group II: 23 male, 20 female patients, mean duration of HD 22.2 ± 22.4 months) HD patients. The PRA positivity ratio and number of transfusions were not significantly higher in group I than in group II (PRA ABC; 28.9%, % 19.4, P > 0.05, PRA DR; 21.8 %, 20.9, P > 0.05, respectively, and blood transfusions 7.0 ± 5.7, 6.6 ± 5.2, respectively, P = 0.06). HD duration correlated significantly with PRA positivity in our patients (PRA‐positive patients: 56.1 ± 57.9 months, PRA‐negative patients: 43.3 ± 41.9 months, P = 0.021). In conclusion, HD duration was found to be the main factor affecting PRA sensitivity independently of HCV positivity and blood transfusion.     

The Effects of Angiotensin Converting Enzyme Inhibitors on Potassium Homeostasis in Dialysis Patients With and Without Residual Renal Function

Hyperkalemia is exacerbated by angiotensin converting enzyme inhibitors (ACE‐I). Distal potassium (K⁺) secretion is negligible in anuric patients. ACE‐I therapy may reduce renal, peritoneal, and colonic K⁺ losses. We examined the effect of ACE‐I therapy on serum, urinary, and dialysate K⁺ in a cross‐section of peritoneal and hemodialysis patients. Serum, 24‐h urine K⁺, and peritoneal dialysate excretion K⁺ levels were measured and the results were compared in the various dialysis and treatment groups. Eighty‐one hemodialysis (HD) and 32 peritoneal dialysis (PD) patients were included. Serum K⁺ in HD patients with no residual renal function (RRF) was higher in those receiving ACE‐I therapy (P = 0.02). Serum K⁺ levels in HD patients receiving ACE‐I treatments with RRF was similar to that in oligoanuric HD patients not receiving an ACE‐I. Urinary K⁺ excretion was significantly reduced in those on ACE‐I therapy versus those not on an ACE‐I (P < 0.05). Mean serum K⁺ was lower in PD versus HD patients (P < 0.05). PD patients with no RRF on ACE‐I therapy had higher serum K⁺ concentrations (P = 0.002) and dialysate K⁺ excretion was lower (P = 0.05), in comparison with PD patients not on an ACE‐I. PD patients with RRF on ACE‐I therapy had higher serum K⁺ concentrations compared with those not on ACE‐I therapy (P = 0.03). Both urinary and dialysate K⁺ excretion were reduced (P = 0.001 and P = 0.002, respectively). ACE‐I therapy increases serum K⁺ concentration in dialysis patients. PD patients have relatively lower serum K⁺ levels compared with HD patients. In PD patients, ACE‐I therapy reduces dialysate K⁺. These changes may result from reduced peritoneal movement of K⁺.     

Differential effects of advanced glycation end-products on renal tubular cell inflammation

Aim: The authors recently showed that advanced glycation end‐products (AGE) in the form of glycated albumin (GA) upregulated renal tubular expression of interleukin (IL)‐8 and soluble intercellular adhesion molecule‐1 (sICAM‐1), but not other important cytokines known to mediate diabetic nephropathy. This implies that other molecules such as the carbonyl intermediates of AGE or other modified protein lysine‐albumin may participate in diabetic tubular injury. Methods: Human proximal tubular epithelial cells (PTEC) were growth‐arrested and exposed to methylglyoxal (MG), MG‐bovine serum albumin (BSA)‐AGE, carboxymethyllysine (CML)‐BSA, AGE‐BSA or BSA with or without prior addition of rosiglitazone that was previously shown to attenuate the pro‐inflammatory effect of GA alone. Results: MG‐BSA‐AGE and AGE‐BSA upregulated tubular expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)‐β, and vascular endothelial growth factor (VEGF), whereas CML‐BSA stimulated expression of IL‐6, CCL‐2, CTGF, TGF‐β and VEGF. These AGE compounds also activated nuclear factor (NF)‐κB and their effects were attenuated by pre‐incubation with anti‐RAGE antibody. MG and BSA did not affect the expression of any of these molecules. Rosiglitazone did not affect the in vitro biological effects of MG, MG‐BSA‐AGE, AGE‐BSA or CML‐BSA on PTEC. Conclusion: AGE exhibit differential inflammatory and fibrotic effects on PTEC via RAGE activation and NF‐κB signal transduction. Rosiglitazone had no effect on these responses. Further investigations on compounds that nullify the downstream effects of these AGE are warranted.     

Plasma levels of advanced glycation end products during haemodialysis, haemodiafiltration and haemofiltration: potential importance of dialysate quality.

BACKGROUND: Advanced glycation end products (AGEs) accumulate in patients with end-stage renal disease (ESRD). The aim of this study was to investigate the potential influence of different modalities of renal replacement therapies on plasma AGE levels. METHODS: The removal of AGEs by high-flux haemodialysis (HD) using standard and ultrapure dialysis fluid (SDF and UDF), by haemodiafiltration (HDF) and by haemofiltration (HF) was studied by fluorescence spectroscopy and by a carboxymethyllysine (CML)-specific ELISA. In addition, molecular weight distribution of fluorescent AGE products in serum of several patients was analysed by gel filtration. RESULTS: The highest AGE-typical fluorescence was found in the serum of patients on HD using SDF (114,667+/-18,967 arbitrary units (AU)), followed by patients on HDF (86,912+/-24,411 AU, P<0.005), by patients on HD using UDF (74,953+/-21,152 AU, P<0.0001) and by patients on HF (74 039+/-17 027 AU, P<0.0001). Similar results were found for serum CML levels with the highest values in HD patients on SDF (1609+/-504 ng/ml), followed by patients on HF (1354+/-614 ng/ml, P<0.001), then by HD patients on UDF (1310+/-403 ng/ml, P<0.001) and by patients on HDF (1132+/-338 ng/ml, P<0.001). The removal rate of AGEs, as evaluated by the determination of the pre-/post-dialysis AGE differences, was comparable across all groups. CONCLUSION: These findings suggest that factors other than removal are responsible for the lower pre-dialysis AGE levels found in patients on convective dialysis as well as on HD with UDF. A role of water quality is assumed. This is corroborated by the finding that the high molecular weight AGE-fraction is preferentially lowered in comparison with patients on HD with SDF, as analysed by gel filtration chromatography. These findings could be best explained by a less severe oxidative stress (i.e. resulting in decreased AGE generation) with HF and HDF, as well as with ultrapure HD.