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Keywords:

  • Maintenance dialysis;
  • Ultrapure dialysis fluid;
  • Uremic dyslipidemia

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Dyslipidemia, a prominent feature of end-stage renal disease, is considered a risk factor for premature atherosclerosis in hemodialysis (HD) patients. Dyslipidemia is related to loss of kidney function as well as use of low-flux cellulosic dialyzer membranes, but the effects of dialysate purity are unknown. Forty-eight incident HD patients started high-flux polysulfone maintenance HD, either with conventional (potentially contaminated) or with on-line produced ultrapure dialysate. The quality of the dialysis fluid (CFU/mL, endotoxin concentration), markers of inflammation (C-reactive protein, Il-6), and parameters of the lipid profile and oxidative stress (oxidized low-density lipoprotein) were measured before initiation of HD, and after 6, 12 and 24 months on HD. Compared to baseline, treatment with conventional (mildly contaminated) dialysate significantly increased the uremic low-grade systemic inflammatory response syndrome (SIRS), augmented uremic dyslipidemia (triglycerides by +21%, and high-density lipoprotein (HDL) cholesterol by −10%) and enhanced oxidative stress. In contrast, the use of ultrapure dialysate significantly decreased uremia-associated SIRS, dyslipidemia (triglycerides −7% and HDL cholesterol +11%) and oxidative stress. Ultrapure dialysis fluid improves potential parameters of cardiovascular risk by decreasing inflammatory reactions, improving uremic dyslipidemia and lowering oxidative stress.

Atherosclerotic vascular disease is the main cause of increased mortality in end-stage renal disease (ESRD; chronic kidney disease, stage 5) and undergoing maintenance hemodialysis, and it appears to be caused by a synergism of traditional and non-traditional risk factors. Coronary events are the best single predictor of mortality in patients with ESRD and account for almost 50% of deaths (1). Based on the data of the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study, the vast majority of incident dialysis patients have at least one traditional risk factor for cardiovascular disease: these include advanced age, diabetes, hypertension, and uremic dyslipidemia (2). Many new dialysis patients also have non-traditional risk factors unique to the loss of renal function and/or utilization of procedures aimed to replace excretory renal function. Uremia and renal replacement therapy with bio-incompatible components of the extracorporeal circuit may result in marked oxidative stress, the production of complement and cytokines, increased adherence molecules in endothelial cells, and other pro-inflammatory mediators. These factors may provide the proper environment for the development of accelerated atherosclerosis (3).

Dialysis fluid produced by state-of-the-art water preparation and distribution is contaminated with Gram-negative bacteria and cytokine-inducing substances derived from these microorganisms. Depending on the type of dialysis membrane (cellulosic or synthetic; low- or high-flux), cytokine inducing substances may penetrate intact dialyzer membranes, induce cytokine production in the patient's blood and contribute to low-grade systemic inflammation noticeable in ESRD patients. By contrast, the use of ultrapure dialysis fluid (defined as <0.1 bacteria/mL, or endotoxin content <0.03 IE/mL) may be associated with lower systemic inflammation (4,5). Uremic dyslipidemia is a common feature of ESRD patients (6,7) and may often coexist with inflammation (8). Whether or not ultrapure dialysis fluid has an impact on uremic dyslipidemia has not been evaluated. We conducted a prospective randomized study to analyze the effects of the microbiological purity of dialysis fluid on plasma lipids, and markers of inflammation and oxidative stress.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Patients with ESRD starting maintenance hemodialysis as their choice of renal replacement therapy were eligible for participation in the study. Inclusion criteria were: (i) a creatinine clearance <15 mL/min; (ii) no previous renal replacement therapy; (iii) a life expectancy of at least two years (no major comorbid conditions such as severe heart failure, severe chronic obstructive lung disease, liver cirrhosis, or malignancy); and (iv) dyslipidemia compatible with uremic dyslipidemia. Exclusion criteria were: (i) chronic infection; (ii) chronic inflammatory disorders; (iii) primary or secondary hyperlipidemia (other than uremic); (iv) drugs affecting lipid levels; and (v) unwillingness to participate in the study.

Definition of uremic dyslipidemia

Uremic patients with dyslipidemia characteristically have hypertriglyceridemia, increased concentrations of triglyceride-rich lipoprotein remnants, and reduced high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually within normal limits or slightly reduced in these individuals.

Study design

Forty-eight clinic outpatients (25 males, 23 females) with uremic dyslipidemia gave informed, written consent. This prospective randomized, open-labeled study was conducted according to the principles of the Declaration of Helsinki and was approved by the ethical committee.

Patients were randomly assigned either to a subgroup treated with commercial dialysate or to a subgroup treated with online produced ultrapure dialysis fluid by an additional step of ultrafiltration using high-flux polysulfone filters (Diasafe; Fresenius, Bad Homburg, Germany). Hemodialysis sessions were performed with the same microbiological quality of dialysis fluid throughout the study period of 24 months. There were no other differences in hemodialysis treatments among the two study arms. Regular hemodialysis was performed with volumetrically controlled ultrafiltration (MTS 4008 H; Fresenius). Bicarbonate was used as buffer. All patients received single-use biocompatible synthetic high-flux membranes (APS 650, polysulfone; Asahi, Tokyo, Japan). Blood flow rates were chosen between 250 to 350 mL/min, and ultrafiltration rates were set according to individual needs. Dialysate flow rate was fixed at 500 mL/min for all treatments. Heparinization of the individual patient did not differ throughout the study period. Hemodialysis was prescribed and monitored using a single pool urea kinetic model to ensure a delivered dialysis dose of at least 1.2 per dialysis for thrice weekly sessions.

Study parameters

Demographic characteristics

The age of the patient, gender, and cause of ESRD were recorded at the initiation of hemodialysis therapy. Post-dialytic weight (dry weight) was judged by clinical acumen, chest x-ray and sonographic assessment of the diameter of the inferior vena cava. The number of iron-repleted patients receiving erythropoietin (epoietin alpha; Ortho Biotech/Janssen-Cilag, Neuss, Germany) was recorded and the dose of erythropoietin expressed as IU per kg body weight per session was calculated. Target hemoglobin levels were 11 g/dL. All patients with erythropoietin substitution received intravenous iron (Ferrlecit, sodium ferric gluconate complex in sucrose; Sanofi-Aventis Deutschland, Frankfurt, Germany); none of the patients took oral iron preparations. Iron repletion was assessed by ferritin levels (target >300 µg/L) and transferrin saturation (TSAT) (target >30%).

Microbiological quality of dialysis fluid

The European Renal Association–European Dialysis and Transplant Association (ERA–EDTA) European Best Practice Guidelines for Hemodialysis (9) set the maximum allowable level for bacteria and endotoxin concentrations at 100 CFU/mL and 0.25 EU/ mL, respectively. These levels are recommendations rather than requirements. Bacterial growth and endotoxin concentrations of dialysis fluid samples were tested each month so that each machine was tested at least twice per year. Conventional dialysis fluid used in this study showed a wide range of bacterial growth (0–100 CFU/mL, 155 samples). Bacterial growth was absent in 30% of the probes of conventional dialysis fluid; 1–10 CFU/mL were detected in 15%, 10–50 CFU/mL in 45%, and 50–100 CFU/mL in 10%. Endotoxin concentrations were not measurable in 65% of the probes (N = 80), and ranged from 0.05 to 0.25 EU/mL in 30% of the probes; in 5% of the probes endotoxin concentrations were above 0.25 EU/mL. The standards for ultrapure dialysis fluid were <0.1 CFU/mL and <0.03 EU/mL, respectively. None of the probes from ultrapure dialysate (80 samples) showed bacterial growth or had measurable endotoxin concentrations. Thus, the purity of the dialysis fluids used met the standards of the ERA-EDTA.

Laboratory measurements

Study parameters

Blood samples were drawn after at least 12 h fasting at the mid-week dialysis session prior to the start of the dialysis pump and heparinization. Serum total cholesterol and triglyceride concentrations were estimated using enzymatic methods (CHOD-PAP and GPO-PAP, respectively; Roche Diagnostics, Mannheim, Germany). HDL cholesterol was determined after precipitation with phosphotungstic acid / magnesium chloride. LDL cholesterol was measured directly with a commercially available direct LDL-C assay (LDL-C Plus assay; Roche Diagnostics).

Serum interleukin (IL)-6 concentrations were measured by immunoassay (IL-6-Quantikine; R & D Systems, Abingdon, UK), the upper limit of normal for human serum IL-6 concentrations was 12.5 pg/mL. Serum C-reactive protein (CRP) levels were determined by particle-enhanced immunoturbidimetry (COBAS Integra 700; Roche, Mannheim, Germany), the upper limit of normal for serum CRP was 0.5 mg/dL for healthy adults. Oxidized LDL (oxLDL) was measured by enzyme-linked immunosorbent assay (Mercodia, Uppsala, Sweden)

Urea, hemoglobin (Hb), and albumin were measured with standard methods. Kt/V was calculated by the urea values derived before and immediately after hemodialysis. To avoid assay drifts all samples were analyzed simultaneously at each time mark.

Statistical analysis

Data are expressed as mean ± SD, or as a percentage. Comparisons between the two study groups at baseline were done by an unpaired t-test or by Fisher's exact test. According to normal or non-normal distribution of data, either the parametric t-test or non-parametric Wilcoxon's signed rank test was used. If applicable, an analysis of variance was used. Multivariable logistic regression analysis was conducted to investigate independent determinants of uremic dyslipidemia. Differences were considered to be statistically significant if the P values were <0.05. All analyses were performed using the SPSS program package (SPSS, Chicago, IL, USA)

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Forty out of forty-eight patients completed the 24 month study period. Three patients underwent kidney transplantation, 2 patients from the ultrapure and 1 patient from the conventional group. Three patients died (2 patients on ultrapure dialysis fluid, 1 patient receiving conventional dialysis fluid) and 2 patients were transferred to other dialysis centers (1 patient from each treatment group). Per protocol analysis was carried out in 40 patients. The characteristics of these patients are given in Table 1. There were no statistically significant differences in age, gender, cause of ESRD, postdialytic dry weight, number of patients receiving erythropoietin intravenously, or delivered dose of dialysis per session.

Table 1. Patient characteristics at baseline
 Conventional dialysateUltrapure dialysate
  1. Mean ± SD. There were no significant differences between the conventional and ultrapure groups. ESRD, end-stage renal disease; GN, glomerulonephritis; iPTH, intact parathyroid hormone.

N2119
Age (years)66 ± 1063 ± 14
Gender (male/female)13/812/7
Cause of ESRD  
 Chronic GN108
 Polycystic Kidney Disease76
 Nephroangiosclerosis33
 Unknown12
Dry body weight (kg)82 ± 1279 ± 14
Body mass index (kg/m2)27 ± 326 ± 3
Use of erythropoietin19/2118/19
iPTH (pg/mL)132 ± 24148 ± 36

Microbiological purity and inflammation

The two study groups did not differ significantly in the degree of systemic inflammation at baseline. Compared to untreated uremia, commencement of hemodialysis utilizing conventional dialysis fluid significantly increased the low-grade systemic inflammatory response syndrome, although >95% of the tested probes met the current standards for dialysis fluid. A significant and sustained increase in both CRP and IL-6 concentrations was found as evidence for increased inflammation by use of conventional dialysis fluid. In contrast, use of ultrapure dialysis fluid slightly but significantly reduced uremia-associated inflammation, as evidenced by a significant reduction in CRP and IL-6 concentrations (Table 2).

Table 2. Effects of different microbiological qualities of dialysis fluid on parameters of inflammation and oxidative stress
 Dialysis fluidBaseline6 months12 months24 months
  • *

    P < 0.05 vs. baseline value. CHD, conventional dialysis fluid; CRP, C-reactive protein; IL-6, interleukin-6; OxLDL, oxidized low-density lipoprotein; UPD, ultrapure dialysis fluid.

CRP (mg/dL)CHD0.9 ± 0.41.6 ± 0.6*1.7 ± 0.5*1.8 ± 0.4*
UPD0.8 ± 0.40.6 ± 0.3*0.6 ± 0.30.5 ± 0.2*
IL-6 (pg/mL)CHD9.8 ± 4.413.1 ± 4.9*14.8 ± 6.0*12.7 ± 5.4*
UPD9.2 ± 5.58.4 ± 4.9*8.0 ± 3.7*8.3 ± 3.3*
OxLDL (U/L)CHD44.5 ± 10.249.2 ± 9.8*52.1 ± 6.9*51.3 ± 9.4*
UPD43.2 ± 9.740.8 ± 9.2*39.9 ± 8.4*39.3 ± 9.2*

Microbiological quality of dialysis fluid, dyslipidemia and oxidative stress

Both treatment groups had comparable lipid values at the baseline (Table 3). Use of conventional dialysis fluid was associated with aggravation of uremic dyslipidemia. There was a further raise in serum triglycerides and decrease in HDL-cholesterol throughout the study period. Increased inflammation did not affect total cholesterol or LDL cholesterol concentrations. In contrast, use of ultrapure dialysis fluid improved uremic dyslipidemia by the slight but significant reductions of triglycerides and increases in HDL cholesterol concentrations. The comparison of mean triglyceride levels or HDL cholesterol levels among the two treatment groups at the end of the study revealed a difference of 27% or 24%, respectively. Compared to untreated uremia, the use of conventional dialysis fluid aggravated and the use of ultrapure dialysis fluid reduced oxidative stress, as shown by increases or decreases of oxLDL cholesterol (Table 2).

Table 3. Effects of different microbiological qualities of dialysis fluid on blood lipids
 Dialysis fluidBaseline6 months12 months24 months
  • *

    P < 0.05 vs. baseline value. CHD, conventional dialysis fluid; HDL, high-density lipoprotein; LDL, low-density lipoprotein; UPD, ultrapure dialysis fluid.

Triglycerides (mg/dL)CHD234 ± 70288 ± 58*282 ± 72*279 ± 64*
UPD221 ± 64201 ± 52*210 ± 60*205 ± 62*
Cholesterol (mg/dL)CHD219 ± 32225 ± 22208 ± 24230 ± 38
UPD200 ± 33190 ± 30195 ± 28192 ± 26
HDL cholesterol (mg/dL)CHD36 ± 433 ± 3*32 ± 4*32 ± 5*
UPD37 ± 541 ± 4*40 ± 3*42 ± 2*
LDL cholesterol (mg/dL)CHD134 ± 21136 ± 26127 ± 20136 ± 18
UPD142 ± 24138 ± 21140 ± 20144 ± 16

Association between dyslipidemia and inflammation

Multivariate linear regression models showed that the changes in serum triglycerides or HDL cholesterol concentrations were independently correlated with corresponding changes in both CRP and IL-6 levels (P < 0.01). Changes in lipid parameters were not associated with age, gender or parathyroid hormone levels.

Microbiological purity of dialysis fluid and markers of anemia or nutrition

Compared to the uremic state before initiation of hemodialysis, the use of conventional dialysis fluid was associated with hyporesponsiveness to exogenous erythropoietin administration in iron-repleted patients, and with a slight deterioration of the nutritional status, as assessed by lower serum albumin concentrations and body weight compared to baseline values. Use of ultrapure dialysis fluid was associated with a minor but significant improvement of nutritional status (Table 4).

Table 4. Effects of different microbiological qualities of dialysate on hematological parameters and markers of nutritional status
 Dialysis fluidBaseline6 months12 months24 months
  • *

    P < 0.05 vs. baseline value. CHD, conventional dialysis fluid; TSAT, transferrin saturation; UPD, ultrapure dialysis fluid.

Hemoglobin (g/dL)CHD10.8 ± 0.511.2 ± 0.511.2 ± 0.610.7 ± 0.7
UPD10.9 ± 0.610.8 ± 0.711.1 ± 0.810.9 ± 0.8
Epo-dose (IU/week/kg)CHD72 ± 2286 ± 26*88 ± 22*84 ± 24*
UPD74 ± 3068 ± 24*70 ± 28*66 ± 30*
Ferritin (µg/L)CHD482 ± 92500 ± 76520 ± 96504 ± 86
UPD510 ± 62482 ± 94468 ± 102520 ± 72
TSAT (%)CHD31 ± 333 ± 434 ± 936 ± 4
UPD34 ± 432 ± 533 ± 334 ± 8
S-albumin (g/dL)CHD3.8 ± 0.33.6 ± 0.2*3.5 ± 0.2*3.5 ± 0.03*
UPD3.7 ± 0.43.9 ± 0.3*4.0 ± 0.3*3.9 ± 0.3*
Body weight (kg)CHD82 ± 1281 ± 1480 ± 16*80 ± 12*
UPD79 ± 1481 ± 16*82 ± 12*81 ± 11*

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Compared with the general population, maintenance hemodialysis patients suffer from accelerated atherosclerosis, which is, at least in part, resistant to conventional pharmacotherapy (10). This resistance to standard therapy of dyslipidemia is most likely related to the frequent coexistence of traditional and non-traditional risk factors in this population, which act synergistically to promote atherosclerosis. The data of our study demonstrate that inflammation, oxidative stress and dyslipidemia are biologically linked, and that ultrapure dialysis fluid is associated with an improved cardiovascular risk factor profile.

Mild chronic inflammation is a common feature of ESRD. It has been well recognized that 30–50% of hemodialysis patients have biochemical evidence of an activated inflammatory response. The clinical significance of elevated CRP or IL-6 levels as strong predictors of adverse clinical outcomes in patients receiving hemodialysis has been well documented (11). There is no debate that bacterial products found in conventional dialysis fluid can pass through intact dialyzer membranes and that endotoxin or other bacterial fragments are potent stimuli for inflammation associated with bio-incompatible dialysis procedures. Switching from conventional dialysis fluid to ultrapure dialysis fluid has been shown repeatedly to be associated with a decrease in the circulating concentrations of biomarkers of inflammation (4,5). The present investigation differs from previous studies in that the study population was comprised of incident and not prevalent dialysis patients. Commencement of hemodialysis utilizing conventional dialysis fluid was associated in our patients with a sustained increase in the markers of inflammation, although bacterial contamination was low (median, 32 CFU/mL) and 95% of the tested dialysis fluid probes were in accordance with current standards for endotoxin concentrations. By contrast, beginning ultrapure high-flux hemodialysis slightly but significantly improved uremic inflammation.

Uremic dyslipidemia may be present in at least 25% of hemodialysis patients (6,7). The multiple pathophysiological mechanisms that are responsible for the development of uremic dyslipidemia remain to be defined (12). The mechanisms underlying the decreased catabolism of triglyceride-rich lipoproteins may involve both the down-regulation of the expression of several key genes along with the direct inhibitory effects of uremic toxins or cytokines on the lipolytic enzymes (plasma lipoprotein lipase and hepatic lipase). Regarding the reduction of HDL-levels, two main mechanisms have been proposed: a diminished activity of lecithin-cholesterol acyltransferase (LCAT)—the enzyme responsible for the esterification of free cholesterol in HDL-particles—as well as an increased activity of cholesteryl ester transfer protein (CETP) that facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins, thus reducing the serum cholesterol concentration of HDL. Uremia-induced insulin resistance may be a further contributing mechanism (12). Comparison of two microbiological qualities of dialysis fluid in our uremic patients revealed the strong impact of endotoxin and other cytokine-inducing bacterial fragments on dyslipidemia. While conventional dialysis fluid aggravated uremic dyslipidemia, the use of ultrapure dialysis fluid improved the lipid profile.

Compared to conventional high-flux hemodialysis, the effects on triglyceride levels achieved with ultrapure high-flux hemodialysis were in the range of 26–32%. This order of magnitude may be higher than the levels achieved with triglyceride-lowering pharmacotherapy. An effect of confounding factors such as the hemodialysis components (buffer, biocompatibility and flux of dialyzer membrane), medications (neither lipid lowering drugs nor sevelamer were used), diet, seasonal variations (two-year study period), change in parathyroid hormone levels, or heparin dosage could be excluded, because these factors were not different in the two treatment arms and were left unchanged throughout the study period. Moreover, our findings are in line with observations reported by Izuhara et al. (13). The switch from conventional dialysate to ultrapure dialysate reduced the mean triglyceride concentrations in their patients from 150 mg/dL to 124 mg/dL. In contrast, confirmatory as well contradictory effects of ultrapure low-flux dialysis or online hemodiafiltration on blood lipids have been noted by Vaslaki et al., who used conventional low-flux cuprophane membrane hemodialysis (14).

Dyslipidemia and inflammation often coexist, not only in infection (15) or inflammatory disorders (16), but also in healthy subjects (17). The pathophysiological mechanisms responsible for the development or aggravation of dyslipidemia by inflammation/infection, particularly in uremia, have not been fully explained. Studies in humans and experimental animals demonstrated that infection/inflammation induced by endotoxins or several cytokines, including IL-6, may induce multiple alterations in lipid and lipoprotein metabolism. Infection/inflammation may increase serum triglyceride levels secondary to decreased lipoprotein lipase activity.

Marked alterations in proteins important in HDL metabolism, including LCAT and CETP, could lead to decreased reverse cholesterol transport and increased delivery to immune cells, thereby lowering HDL plasma levels (18). In contrast, ultrapure high-flux dialysis, while not adding to inflammation, may improve lipid profile, at least in part, by the removal of inhibitors of lipoprotein lipase such as remnant particles (19).

Oxidative stress, as indirectly evidenced by the accumulation of lipid, protein or carbohydrate oxidation markers, results from increased superoxide and hydrogen peroxide production by activated granulocytes and monocytes (20–22). Cytokines are potent activators for nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that is responsible for the overproduction of reactive oxygen species (ROS). Uremia per se causes spontaneous leukocyte activation resulting in increased ROS generation. Bioincompatible components, such as cellulosic membranes, may cause a further rise in the production of ROS (22).

The present investigation demonstrates that cytokine-inducing substances derived from the bacterial contamination of conventional dialysis fluid are a major source of enhanced oxidative stress in maintenance dialysis patients. Our data are in agreement with observations that the switch from conventional dialysis fluid to ultrapure dialysis fluid results in lower concentrations of biomarkers of carbonyl stress, oxLDL cholesteral or advanced glycation end products (13,23–25).

CONCLUSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES

Hemodialysis patients are at risk of injury from microbiological contaminants in the dialysate, even when the ERA–EDTA standards for bacteria and endotoxin levels are used. There is a need for more rigid worldwide standards, particularly for maximum allowable endotoxin levels. Until new standards for dialysis fluid purity are proposed, online produced ultrapure dialysis fluid represents a real alternative for all patients receiving hemodialysis. Ultrapure dialysis fluid can improve the atherogenic risk profile of these patients by reducing inflammation, oxidative stress and dyslipidemia. It remains to be shown in long term clinical studies what contribution ultrapure dialysis fluid will provide for the prevention of the progression of arteriosclerosis.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. REFERENCES
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