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1.  Treg/Th17 imbalance is associated with cardiovascular complications in uremic patients undergoing maintenance hemodialysis 
Biomedical Reports  2013;1(3):413-419.
Investigations of Treg/Th17 imbalance associated with cardiovascular complications in hemodialysis are limited. The aim of this study was to examine the association between Treg/Th17 balance and cardiovascular comorbidity in maintenance hemodialysis (MHD). Uremic patients included in the present study were divided into three groups: the WHD group comprising 30 patients with no cardiovascular complications or maintenance hemodialysis (MHD), the MHD1 group comprising 36 patients presenting with cardiovascular complications during MHD, and the MHD2 group comprising 30 patients with a lack of cardiovascular complications during MHD. The control group comprised 20 healthy volunteers. Th17 and Treg cells were measured by fluorescence-activated cell scanning (FACS). IL-6 and IL-10 levels were determined by enzyme-linked immunosorbent assay (ELISA). Monocyte surface expression of the costimulatory molecules CD80 and CD86 was assessed by FACS after the monocytes were cocultured with Th17 or Treg cells in the presence or absence of IL-17. Results revealed that the percentage of Th17 of total CD4(+) cells was significantly higher in the MHD1 (36.27±9.62% in) and WHD (35.98±8.85%) groups compared with the MHD2 (19.64±5.97%) and healthy (1.12±1.52%) groups. Elevated IL-6 levels were obtained in Th17 cells for the MHD1 and WHD groups, whereas a marked decrease was evident when IL-17 was blocked. However, no significant differences or cardiovascular complications were detected in the expression of CD80 and CD86 in the MHD group, whereas the expression of the uremic subgroups was statistically higher compared with the healthy controls. To the best of our knowledge, this is the first study to demonstrate that the Treg/Th17 imbalance may be associated with the pathogenesis of cardiovascular complications in uremic patients undergoing hemodialysis through the B7-independent upregulation of IL-6 induced by IL-17.
doi:10.3892/br.2013.63
PMCID: PMC3917002  PMID: 24648960
cardiovascular; Th17 cell; regulatory T cell; inflammatory cytokine; costimulatory molecule
2.  Glycemic Control and Cardiovascular Mortality in Hemodialysis Patients With Diabetes 
Diabetes  2012;61(3):708-715.
Previous observational studies using differing methodologies have yielded inconsistent results regarding the association between glycemic control and outcomes in diabetic patients receiving maintenance hemodialysis (MHD). We examined mortality predictability of A1C and random serum glucose over time in a contemporary cohort of 54,757 diabetic MHD patients (age 63 ± 13 years, 51% men, 30% African Americans, 19% Hispanics). Adjusted all-cause death hazard ratio (HR) for baseline A1C increments of 8.0–8.9, 9.0–9.9, and ≥10%, compared with 7.0–7.9% (reference), was 1.06 (95% CI 1.01–1.12), 1.05 (0.99–1.12), and 1.19 (1.12–1.28), respectively, and for time-averaged A1C was 1.11 (1.05–1.16), 1.36 (1.27–1.45), and 1.59 (1.46–1.72). A symmetric increase in mortality also occurred with time-averaged A1C levels in the low range (6.0–6.9%, HR 1.05 [95% CI 1.01–1.08]; 5.0–5.9%, 1.08 [1.04–1.11], and ≤5%, 1.35 [1.29–1.42]) compared with 7.0–7.9% in fully adjusted models. Adjusted all-cause death HR for time-averaged blood glucose 175–199, 200–249, 250–299, and ≥300 mg/dL, compared with 150–175 mg/dL (reference), was 1.03 (95% CI 0.99–1.07), 1.14 (1.10–1.19), 1.30 (1.23–1.37), and 1.66 (1.56–1.76), respectively. Hence, poor glycemic control (A1C ≥8% or serum glucose ≥200 mg/dL) appears to be associated with high all-cause and cardiovascular death in MHD patients. Very low glycemic levels are also associated with high mortality risk.
doi:10.2337/db11-1015
PMCID: PMC3282812  PMID: 22315308
3.  Serum catalytic Iron: A novel biomarker for coronary artery disease in patients on maintenance hemodialysis 
Indian Journal of Nephrology  2013;23(5):332-337.
Cardiovascular disease is the leading cause of morbidity and mortality in maintenance hemodialysis (MHD) patients. We evaluated the role of serum catalytic iron (SCI) as a biomarker for coronary artery disease (CAD) in patients on MHD. SCI was measured in 59 stable MHD patients. All patients underwent coronary angiography. Significant CAD was defined as a > 70% narrowing in at least one epicardial coronary artery. Levels of SCI were compared with a group of healthy controls. Significant CAD was detected in 22 (37.3%) patients, with one vessel disease in 14 (63.63%) and multi-vessel disease in eight (36.36%) patients. The MHD patients had elevated levels of SCI (4.70 ± 1.79 μmol/L) compared with normal health survey participants (0.11 ± 0.01 μmol/L) (P < 0.0001). MHD patients who had no CAD had SCI levels of 1.36 ± 0.34 μmol/L compared with those having significant CAD (8.92 ± 4.12 μmol/L) (P < 0.0001). Patients on MHD and diabetes had stronger correlation between SCI and prevalence of CAD compared with non-diabetics. Patients having one vessel disease had SCI of 8.85 ± 4.67 μmol/L versus multi-vessel disease with SCI of 9.05 ± 8.34 μmol/L, P = 0.48. In multivariate analysis, SCI and diabetes mellitus were independently associated with significant CAD. We confirm the high prevalence of significant CAD in MHD patients. Elevated SCI levels are associated with presence of significant coronary disease in such patients. The association of SCI is higher in diabetic versus the non-diabetic subgroup. This is an important potentially modifiable biomarker of CAD in MHD patients.
doi:10.4103/0971-4065.116293
PMCID: PMC3764705  PMID: 24049267
Coronary artery disease; maintenance hemodialysis; oxidative stress; serum catalytic iron
4.  Cross-over study of influence of oral vitamin C supplementation on inflammatory status in maintenance hemodialysis patients 
BMC Nephrology  2013;14:252.
Background
Both vitamin C deficiency and inflammation are prevalent in maintenance hemodialysis (MHD) patients. In this study, we aimed to elucidate the effect of oral vitamin C supplementation on inflammatory status in MHD patients with low vitamin C level and high hypersensitive C-reactive protein (hs-CRP) level.
Methods
A total of 128 patients were recruited in our present study. Patients were divided into two groups. In group 1 (n = 67), patients were orally administered with 200 mg/day vitamin C in the first 3 months, and then the vitamin C supplementation was withdrawn in the next 3 months. In group 2 (n = 61), patients were not given vitamin C in the first 3 months, and then they were orally administered with 200 mg/day in the next 3 months. Levels of hs-CRP, prealbumin, albumin and hemoglobin as well as the EPO resistance index (ERI) were determined at the baseline and every 3 months throughout the study. Plasma vitamin C level was determined by high-performance liquid chromatography with UV detection.
Results
Among the 128 patients, 28 of them dropped out of the study before completion. Consequently, a total of 100 patients (group 1: n = 48; group 2: n = 52) were included in the final analysis. At the baseline, the plasma vitamin C level of all patients was less than 4 μg/mL. However, this proportion was decreased to 20% after the vitamin C supplementation for 3 months. Compared with patients without the vitamin C supplementation, a decreased level of hs-CRP and an increased level of prealbumin were induced by the vitamin C supplementation for 3 months in both groups. However, levels of these biomarkers returned to their original state after the supplementation was withdrawn. Same beneficial effects on plasma albumin, hemoglobin and ERI response to vitamin C supplementation were observed in the two groups without statistical significance.
Conclusions
The inflammatory status in MHD patients with plasma vitamin C deficiency and high levels of inflammatory markers could be partially improved by long-term oral administration of small doses of vitamin C.
Trial registration
The clinical trial number: NCT01356433.
doi:10.1186/1471-2369-14-252
PMCID: PMC3840610  PMID: 24228847
Hemodialysis; Inflammation; Vitamin C
5.  PHOSPHATE BINDER USE AND MORTALITY AMONG HEMODIALYSIS PATIENTS IN THE DOPPS: EVALUATION OF POSSIBLE CONFOUNDING BY NUTRITIONAL STATUS 
Background
Poor nutritional status and both hyperphosphatemia and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (MHD) patients. We assessed associations of PB prescription with survival and indicators of nutritional status among (MHD) patients.
Study Design
Prospective cohort study (DOPPS) 1996 to 2008.
Setting and Participants
23,898 MHD patients at 923 facilities in 12 countries.
Predictors
Patient-level PB prescription; and case-mix-adjusted facility percentage PB prescription using an instrumental-variable analysis.
Outcome
All-cause mortality.
Results
Overall, 88% of patients were prescribed PBs. The distributions of age, comorbidities and other characteristics showed small differences between facilities with higher and lower percentage PB prescription. Patient-level PB prescription was strongly associated at baseline with indicators of better nutrition, i.e., higher serum creatinine, albumin, normalized protein-catabolic rate, BMI and absence of cachectic appearance. Overall, patients prescribed PBs displayed 25% lower mortality (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.68–0.83) when adjusted for serum phosphorus and other covariates; further adjustment for nutritional indicators attenuated this association (HR = 0.88, 95% CI = 0.80–0.97). This inverse association, however, was observed only for patients with serum phosphorus ≥3.5mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage PB prescription (range: 23–100%) was positively associated with better nutritional status and inversely associated with mortality (HR for 10% more PB = 0.93, 95% CI = 0.89–0.96). Further adjustment for nutritional indicators reduced this association to HR = 0.95 (95% CI = 0.92–0.99).
Limitations
Results were based on PB prescription; PB and nutritional data were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding.
Conclusions
Longer survival and better nutritional status were observed for MHD patients prescribed PBs and in facilities with greater percentage PB prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research.
doi:10.1053/j.ajkd.2011.12.025
PMCID: PMC3901075  PMID: 22385781
6.  Effects of Sevelamer and Calcium-Based Phosphate Binders on Lipid and Inflammatory Markers in Hemodialysis Patients 
American Journal of Nephrology  2007;28(2):275-279.
Introduction
Cardiovascular disease accounts for almost half of all deaths in individuals with chronic kidney disease stage 5 despite advances in both dialysis treatment and cardiology. A combination of lipid-lowering and anti-inflammatory effects along with avoidance of hypercalcemia should be taken into account when choosing phosphorus binders for maintenance hemodialysis (MHD) patients.
Methods
We examined the association of sevelamer versus calcium-based phosphorus binders with lipid profile, inflammatory markers including C-reactive protein (CRP), and mineral metabolism in MHD patients who participated in the Nutritional and Inflammatory Evaluation of Dialysis Patients (NIED) study from October 2001 to July 2005.
Results
Of the 787 MHD patients in the NIED study, 697 were on either sevelamer, a calcium-based binder, or both and eligible for this study. We compared the groups based on taking sevelamer monotherapy (n = 283) or calcium binder monotherapy (n = 266) for serum phosphate control. There were no differences between the groups on dialysis vintage. There were significant differences in age, serum calcium and phosphorus levels, as well as intact parathyroid hormone levels. Using a logistic regression models, the sevelamer group had a higher odds of serum CRP <10 mg/l [odds ratio (OR): 1.06, 95% CI: 1.02–1.11] and LDL cholesterol <70 mg/dl (OR: 1.33, 95% CI: 1.19–1.47) when compared to the calcium binder group independent of age, vintage, body mass index, statin use or other variables.
Conclusion
The improvements in multiple surrogate markers of inflammation and lipids in the NIED study make sevelamer a promising therapy for treatment in MHD patients with high risk of cardiovascular disease and mortality.
doi:10.1159/000111061
PMCID: PMC2785908  PMID: 17992011
End-stage renal disease; Cardiac computed tomography; Coronary calcium; Phosphate binders
7.  Anxiety, locus of control, and coping strategies among end-stage renal disease patients undergoing maintenance hemodialysis 
Indian Journal of Nephrology  2011;21(3):177-181.
End-stage kidney disease (ESKD) patients on maintenance hemodialysis (MHD) have a lot of anxiety. Anxiety and coping are associated with the locus of control; the present investigation aimed to study the state and trait anxiety, locus of control, and active and passive coping among patients on MHD. Thirty MHD patients and 30 controls were administered State–Trait Anxiety Inventory, Rotter's Locus of Control Scale, and Coping Responses Inventory. There were significantly higher scores on state and trait anxiety, respectively (67.53 ± 10.89 vs. 59.40 ± 6.97, P < 0.01, and 62.97 ± 8.45 vs. 58.07 ± 7.06, P < 0.05), and locus of control (11.27 ± 3.55 vs. 9.04 ± 1.86, P < 0.01) in patients as compared to controls. On coping responses, patients and controls differed on positive reappraisal (54.33 ± 4.67 vs. 51.17 ± 3.12, P < 0.01), seeking guidance and support (58.07 ± 5.51 vs. 53.27 ± 4.22, P < 0.01), problem solving (51.03 ± 4.70 vs. 47.57 ± 4.73, P < 0.01), cognitive avoidance (60.27 ± 6.76 vs. 56.80 ± 4.08, P < 0.05), acceptance or resignation (61.67 ± 6.30 vs. 58.83 ± 4.23, P < 0.01), emotional discharge (68.07 ± 6.78 vs. 64.30 ± 4.50, P < 0.05), approach coping (205.57 ± 10.55 vs. 189.70 ± 11.37, P < 0.01), and avoidance coping (255.30 ± 16.45 vs. 241.10 ± 10.50, P < 0.01). A higher prevalence of anxiety trait could be the cause of anxiety in MHD patients besides the medical problems. The locus of control among patients though a mixed one was significantly more toward externalism. Thus, there is a need to identify this group well in advance and prepared not only medically but also psychologically for MHD.
doi:10.4103/0971-4065.83729
PMCID: PMC3161435  PMID: 21886977
Coping responses; end-stage kidney disease; hemodialysis; locus of control; psyhchonephrology; state anxiety; trait anxiety
8.  Correlation between the microinflammatory state and left ventricular structural and functional changes in maintenance haemodialysis patients 
The aim of this study was to examine the correlation between the microinflammatory state and structural and functional changes of the left ventricle in maintenance haemodialysis patients (MHD). In total, 48 MHD patients and 30 healthy volunteers participated in this study. The microinflammatory state was detected from high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels determined by ELISA. The structure and function of the left ventricle was measured according to ultrasound cardiogram examination. The serum levels of hs-CRP, IL-6 and TNF-α in the MHD patients were higher compared with those in the controls (P<0.05). Furthermore, the measurements of the left atrial diameter (LAD), left venticular diameter (LVD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT) and the left ventricular mass index (LVMI) increased significantly and the left ventricular function (LVEF) was reduced. Correlation analysis demonstrated that the concentrations of hs-CRP, TNF-α and IL-6 correlated with the LVMI (P<0.05), but only hs-CRP correlated with the loss of function of the heart in the haemodialysis patients (P<0.05). The microinflammatory state may be closely associated with the structural and functional impairment of the heart in MHD patients.
doi:10.3892/etm.2013.1131
PMCID: PMC3786853  PMID: 24137221
haemodialysis; microinflammatory; left ventricle; structural and functional changes
9.  Blood volume-monitored regulation of ultrafiltration in fluid-overloaded hemodialysis patients: study protocol for a randomized controlled trial 
Trials  2012;13:79.
Background
Data generated with the body composition monitor (BCM, Fresenius) show, based on bioimpedance technology, that chronic fluid overload in hemodialysis patients is associated with poor survival. However, removing excess fluid by lowering dry weight can be accompanied by intradialytic and postdialytic complications. Here, we aim at testing the hypothesis that, in comparison to conventional hemodialysis, blood volume-monitored regulation of ultrafiltration and dialysate conductivity (UCR) and/or regulation of ultrafiltration and temperature (UTR) will decrease complications when ultrafiltration volumes are systematically increased in fluid-overloaded hemodialysis patients.
Methods/design
BCM measurements yield results on fluid overload (in liters), relative to extracellular water (ECW). In this prospective, multicenter, triple-arm, parallel-group, crossover, randomized, controlled clinical trial, we use BCM measurements, routinely introduced in our three maintenance hemodialysis centers shortly prior to the start of the study, to recruit sixty hemodialysis patients with fluid overload (defined as ≥15% ECW). Patients are randomized 1:1:1 into UCR, UTR and conventional hemodialysis groups. BCM-determined, ‘final’ dry weight is set to normohydration weight −7% of ECW postdialysis, and reached by reducing the previous dry weight, in steps of 0.1 kg per 10 kg body weight, during 12 hemodialysis sessions (one study phase). In case of intradialytic complications, dry weight reduction is decreased, according to a prespecified algorithm. A comparison of intra- and post-dialytic complications among study groups constitutes the primary endpoint. In addition, we will assess relative weight reduction, changes in residual renal function, quality of life measures, and predialysis levels of various laboratory parameters including C-reactive protein, troponin T, and N-terminal pro-B-type natriuretic peptide, before and after the first study phase (secondary outcome parameters).
Discussion
Patients are not requested to revert to their initial degree of fluid overload after each study phase. Therefore, the crossover design of the present study merely serves the purpose of secondary endpoint evaluation, for example to determine patient choice of treatment modality. Previous studies on blood volume monitoring have yielded inconsistent results. Since we include only patients with BCM-determined fluid overload, we expect a benefit for all study participants, due to strict fluid management, which decreases the mortality risk of hemodialysis patients.
Trial registration
ClinicalTrials.gov, NCT01416753
doi:10.1186/1745-6215-13-79
PMCID: PMC3493292  PMID: 22682149
Dialysis; Ultrafiltration; Renal dialysis; Fluid shifts; Blood volume; Multicenter study; Randomized controlled trials.
10.  Mineral and bone disorders and survival in hemodialysis patients with and without polycystic kidney disease 
Nephrology Dialysis Transplantation  2011;27(7):2899-2907.
Background
Maintenance hemodialysis (MHD) patients with polycystic kidney disease (PKD) have better survival than non-PKD patients. Mineral and bone disorders (MBD) are associated with accelerated atherosclerosis and cardiovascular death in MHD patients. It is unknown whether the different MBD mortality association between MHD populations with and without PKD can explain the survival differential.
Methods
Survival models were examined to assess the association between different laboratory markers of MBD [such as serum phosphorous, parathyroid hormone (PTH), calcium and alkaline phosphatase] and mortality in a 6-year cohort of 60 089 non-PKD and 1501 PKD MHD patients.
Results
PKD and non-PKD patients were 57 ± 13 and 62 ± 15 years old and included 46 and 45% women and 14 and 32% Blacks, respectively. Whereas PKD individuals with PTH 150 to <300 pg/mL (reference) had the lowest risk for mortality, the death risk was higher in patients with PTH <150 [hazard ratio (HR): 2.16 (95% confidence interval 1.53–3.06)], 300 to <600 [HR: 1.30 (0.97–1.74)] and ≥600 pg/mL [HR: 1.46 (1.02–2.08)], respectively. Similar patterns were found in non-PKD patients. Fully adjusted death HRs of time-averaged serum phosphorous increments <3.5, 5.5 to <7.5 and ≥7.5 mg/dL (reference: 3.5 to <5.5 mg/dL) for PKD patients were 2.82 (1.50–5.29), 1.40 (1.12–1.75) and 2.25 (1.57–3.22). The associations of alkaline phosphatase and calcium with mortality were similar in PKD and non-PKD patients.
Conclusion
Bone–mineral disorder markers exhibit similar mortality trends between PKD and non-PKD MHD patients, although some differences are observed in particular in low PTH and phosphorus ranges.
doi:10.1093/ndt/gfr747
PMCID: PMC3398062  PMID: 22207323
hemodialysis; mineral and bone disorders; mortality; parathyroid hormone; polycystic kidney disease
11.  Diagnosed Prevalence and Health Care Expenditures of Mental Health Disorders Among Dual Eligible Older People 
The Gerontologist  2012;53(2):334-344.
Purpose: Little is known about mental health disorders (MHDs) and their associated health care expenditures for the dual eligible elders across long-term care (LTC) settings. We estimated the 12-month diagnosed prevalence of MHDs among dual eligible older adults in LTC and non-LTC settings and calculated the average incremental effect of MHDs on medical care, LTC, and prescription drug expenditures across LTC settings. Methods: Participants were fee-for-service dual eligible elderly beneficiaries from 7 states. We obtained their 2005 Medicare and Medicaid claims data and LTC program participation data from federal and state governments. We grouped beneficiaries into non-LTC, community LTC, and institutional LTC groups and identified enrollees with any of 5 MHDs (anxiety, bipolar, major depression, mild depression, and schizophrenia) using the International Classification of Diseases Ninth Revision codes associated with Medicare and Medicaid claims. We obtained medical care, LTC, and prescription drug expenditures from related claims. Results: Thirteen percent of all dual eligible elderly beneficiaries had at least 1 MHD diagnosis in 2005. Beneficiaries in non-LTC group had the lowest 12-month prevalence rates but highest percentage increase in health care expenditures associated with MHDs. Institutional LTC residents had the highest prevalence rates but lowest percentage increase in expenditures. LTC expenditures were less affected by MHDs than medical and prescription drug expenditures. Implications: MHDs are prevalent among dual eligible older persons and are costly to the health care system. Policy makers need to focus on better MHD diagnosis among community-living elders and better understanding in treatment of MHDs in LTC settings.
doi:10.1093/geront/gns163
PMCID: PMC3888217  PMID: 23275518
12.  Acetate free citrate-containing dialysate increase intact-PTH and BAP levels in the patients with low intact-PTH 
BMC Nephrology  2013;14:18.
Background
Recently, acetate-free citrate containing dialysate (A(−)D) was developed. We have already reported about the significant effect of A(−)D on metabolic acidosis, anemia, and malnutrition in maintenance hemodialysis (MHD) patients. In this study, we compared the effect of A(−)D and acetate containing dialysate (A(+)D) on serum calcium and intact-parathyroid hormone (int-PTH) levels.
Method
Single session study: Seventeen patients were treated with A(+)D in one session and also treated with A(−)D in another session. Serum levels of pH, HCO3-, total (t)-calcium, ionized (i)-calcium, and int-PTH were evaluated at the beginning and the end of each session. Cross over study: A total of 29 patients with MHD were treated with A(+)D for 4 months, switched to A(−)D for next 4 months, and returned to A(+)D for the final 4 months.
Results
In single session study, serum i-calcium and t-calcium levels significantly increased, and int-PTH levels decreased after HD with A(+)D, whereas HD with A(−)D did not affect iCa and int-PTH. In cross over study, if all patients were analyzed, there was no significant difference in serum int-PTH or bone alkaline phosphatase (BAP) levels during each study period. In contrast, in the patients with low int-PTH (<60 pg/mL), serum levels of int-PTH and BAP were significantly increased during the A(−)D, without significant changes in serum t-calcium or i-calcium levels.
Conclusion
A(−)D containing citrate could affect calcium and PTH levels, and, in 4 month period of crossover study, increased int-PTH levels pararelled with increasing BAP levels, exclusively in MHD patients with low int-PTH levels.
doi:10.1186/1471-2369-14-18
PMCID: PMC3583681  PMID: 23327614
Acetate free citrate-containing dialysate; Low intact-parathyroid hormone; Bone alkaline phosphatase; Total calcium; Ionized calcium
13.  Effects of three blood purification methods on serum fibroblast growth factor-23 clearance in patients with hyperphosphatemia undergoing maintenance hemodialysis 
The aim of the present study was to investigate the effects of three blood purification methods on fibroblast growth factor-23 (FGF-23) clearance in patients with hyperphosphatemia undergoing maintenance hemodialysis (MHD). In addition, the correlation between serum FGF-23 and phosphorus (Pi) levels and the clinical implications were identified. Sixty-five MHD patients with hyperphosphatemia were randomly divided into three groups: Hemodialysis, HD (n=23); hemodiafiltration, HDF (n=21); and hemodialysis+hemoperfusion, HD+HP (n=21) groups. Serum Pi, FGF-23, blood urea nitrogen, serum creatinine and associated bio-marker levels were measured prior to and following treatment. The expression level of serum FGF-23 was observed to be positively correlated with Pi (r=0.45, P<0.01). The three blood purification methods that were adopted for the present study exhibited significant and effective clearance of serum Pi (P<0.05). The post-treatment serum FGF-23 levels were significantly decreased in the HDF and HD+HP groups (P<0.05). Therefore, HDF may be an effective method for clearing serum FGF-23 in MHD patients exhibiting hyperphosphatemia.
doi:10.3892/etm.2014.1543
PMCID: PMC3964936  PMID: 24669256
hyperphosphatemia; fibroblast growth factor-23; hemodialysis; hemodiafiltration; hemoperfusion
14.  Design and Development of a Dialysis Food Frequency Questionnaire 
OBJECTIVES
Periodic assessment of dietary intake across a given dialysis population may help improve clinical outcomes related to such nutrients as dietary protein, phosphorus, or potassium. Whereas dietary recalls and food records are used to assess dietary intake at individual level and over shorter time periods, food frequency questionnaires (FFQ) are employed to rank subjects of a given population according to their nutrient intake over longer time periods.
DESIGN
To modify and refine the conventional Block’s FFQ in order to develop a dialysis patients specific FFQ.
SETTING
Eight DaVita outpatient dialysis clinics in Los Angeles area, which participated in the “Nutrition and Inflammation in Dialysis Patients” (NIED) Study.
PATIENTS
154 maintenance hemodialysis (MHD) patients
MAIN OUTCOME MEASURE
Dietary intake of participating MHD patients using a 3-day food record, supplemented by a person-to-person dietary interview, to capture food intake over the last hemodialysis treatment day of the week and the 2 subsequent non-dialysis days.
RESULTS
Analyses of the food records identified the key contributors to the daily nutrient intake in the 154 participating MHD patients. A “Dialysis-FFQ” was developed to include approximately 100 food items representing 90% of the patients’ total food intake of the NIED Study population. Distinctions were made in several food items based on key nutritional issues in dialysis patients such as protein, phosphorus and potassium.
CONCLUSIONS
We have developed a “Dialysis FFQ” to compare and rank dialysis patients according to their diverse nutrient intake. Whereas, the Dialysis-FFQ may be a valuable tool to compare dialysis patients and to identify those who ingest higher or lower amounts of a given nutrient, studies are needed to examine the utility of the Dialysis-FFQ for nutritional assessment of dialysis patients.
doi:10.1053/j.jrn.2010.05.013
PMCID: PMC3047592  PMID: 20833073
Dietary assessment; chronic kidney disease (CKD); dialysis; dietary recalls; food records; dialysis food frequency questionnaire (FFQ); nutritional epidemiology
15.  Optimal Nutrition in Hemodialysis Patients 
Protein energy wasting (PEW) is highly prevalent in patients undergoing maintenance hemodialysis (MHD) patients. Importantly, there is a robust association between the extent of PEW and the risk of hospitalization and death in these patients, regardless of the nutritional marker used. The multiple etiologies of PEW in advanced kidney disease are still being elucidated. Apart from the multiple mechanisms that might lead to PEW, it appears that the common pathway for all the derangements is related to exaggerated protein degradation along with decreased protein synthesis. The hemodialysis procedure per se is an important contributor to this process. Metabolic and hormonal derangements such as acidosis, inflammation and resistance to anabolic properties of insulin resistance and growth hormone are all implicated for the development of PEW in MHD patients. Appropriate management of MHD patients at risk for PEW requires a comprehensive combination of strategies to diminish protein and energy depletion, and to institute therapies that will avoid further losses. The mainstay of nutritional treatment in MHD patients is provision of an adequate amount of protein and energy, using oral supplementation as needed. Intradialytic parenteral nutrition should be attempted in patients who cannot use the gastrointestinal tract efficiently. Other anabolic strategies such as exercise, anabolic hormones, anti-inflammatory therapies and appetite stimulants can be considered as complementary therapies in suitable patients.
doi:10.1053/j.ackd.2012.12.002
PMCID: PMC3582995  PMID: 23439378
16.  Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial 
Background
Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration.
Methods
Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups.
Results
Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018).
Conclusions
In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.
Electronic supplementary material
The online version of this article (doi:10.1007/s13539-013-0115-9) contains supplementary material.
doi:10.1007/s13539-013-0115-9
PMCID: PMC3830006  PMID: 24052226
Albumin; Hypoalbuminemia; Inflammation; Protein intake; Hemodialysis; Oral nutrition supplements; Anti-oxidant ingredients; Anti-inflammatory ingredients
17.  A Study of the Immunoloregulation of Double Filtration Plasmapheresis in Maintenance Hemodialysis Patients with Chronic Hepatitis C 
PLoS ONE  2013;8(12):e82524.
Although a large number of drugs have been used to treat chronic hepatitis C (CHC), there still remains a great challenge to treat maintenance hemodialysis (MHD) patients with chronic hepatitis C. To clarify the immunnoloregulation of double filtration plasmapheresis (DFPP) in MHD patients with CHC, DFPP was performed in 20 MHD patients with CHC (HCV-antibody positive, serum HCV RNA >500 IU/ml more than 6 months and HCV genotype 1b). The clinical data was collected and peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry at the time of hour 0, hour 3, day 3, day 7 and day 28 after the DFPP, respectively. Serum HCV particles could be removed partially by the DFPP. The titer of serum HCV RNA could remain in a lower level even 28 days after the treatment. Compared to MHD patients without HCV infection, the frequencies of innate immune cells were similar in MHD patients with CHC, while Th1/Th2 was elevated and the frequencies of regulatory T (Treg) cells were higher in those MHD patients with CHC. The frequencies of monocytes and natural killer (NK) cells remained after the DFPP in MHD patients with CHC. There were no significant changes of Th1, Th2 and Th1/Th2 in PBMC after DFPP. DFPP could reduce the frequencies of Th17 cells and Treg cells in PBMC from 7 days after DFPP in MHD patients with CHC. DFPP could partially remove the serum HCV particles mechanically. The titer of HCV RNA could remain in a lower level at least for 28 days probably due to the redistribution of the immunocytes in circulation.
doi:10.1371/journal.pone.0082524
PMCID: PMC3864956  PMID: 24358197
18.  Dual factor pulse pressure: body mass index and outcome in type 2 diabetic subjects on maintenance hemodialysis. A longitudinal study 2003–2006 
Vascular Health and Risk Management  2008;4(6):1401-1406.
Background:
Inverse associations between risk factors and mortality have been reported in epidemiological studies of patients on maintenance hemodialysis (MHD).
Objective:
The aim of this prospective study was to estimate the effect of the dual variable pulse pressure (PP) – body mass index (BMI) on cardiovascular (CV) events and death in type 2 diabetic (T2D) subjects on MHD in a Caribbean population.
Methods:
Eighty Afro-Caribbean T2D patients on MHD were studied prospectively from 2003 to 2006. Proportional-hazard modeling was used.
Results:
Of all, 23.8% had a high PP (PP ≥ 75th percentile), 76.3% had BMI < 30 Kg/m2, 21.3% had the dual factor high PP – absence of obesity. During the study period, 23 patients died and 13 CV events occurred. In the presence of the dual variable and after adjustment for age, gender, duration of MHD, and pre-existing CV complications, the adjusted hazard ratio (HR) (95% CI) of CV events and death were respectively 2.7 (0.8–8.3); P = 0.09 and 2.4 (1.1–5.9); P = 0.04.
Conclusions:
The dual factor, high PP – absence of obesity, is a prognosis factor of outcome. In type 2 diabetics on MHD, a specific management strategy should be proposed in nonobese subjects with wide pulse pressure in order to decrease or prevent the incidence of fatal and nonfatal events.
PMCID: PMC2663455  PMID: 19337552
dual factor; pulse pressure; body mass index; type 2 diabetes; outcome
19.  Genetic polymorphism of ACE and the angiotensin II type1 receptor genes in children with chronic kidney disease 
Aim and Methods
We investigated the association between polymorphisms of the angiotensin converting enzyme-1 (ACE-1) and angiotensin II type one receptor (AT1RA1166C) genes and the causation of renal disease in 76 advanced chronic kidney disease (CKD) pediatric patients undergoing maintenance hemodialysis (MHD) or conservative treatment (CT). Serum ACE activity and creatine kinase-MB fraction (CK-MB) were measured in all groups. Left ventricular mass index (LVMI) was calculated according to echocardiographic measurements. Seventy healthy controls were also genotyped.
Results
The differences of D allele and DI genotype of ACE were found significant between MHD group and the controls (p = 0.0001). ACE-activity and LVMI were higher in MHD, while CK-MB was higher in CT patients than in all other groups. The combined genotype DD v/s ID+II comparison validated that DD genotype was a high risk genotype for hypertension .~89% of the DD CKD patients were found hypertensive in comparison to ~ 61% of patients of non DD genotype(p = 0.02). The MHD group showed an increased frequency of the C allele and CC genotype of the AT1RA1166C polymorphism (P = 0.0001). On multiple linear regression analysis, C-allele was independently associated with hypertension (P = 0.04).
Conclusion
ACE DD and AT1R A/C genotypes implicated possible roles in the hypertensive state and in renal damage among children with ESRD. This result might be useful in planning therapeutic strategies for individual patients.
doi:10.1186/1476-9255-8-20
PMCID: PMC3167745  PMID: 21859496
angiotensin-converting enzyme; angiotensin II type one receptor; DNA polymorphisms; end-stage renal disease, Children
20.  Association of Relatively Low Serum Parathyroid Hormone with Malnutrition-Inflammation Complex and Survival in Maintenance Hemodialysis Patients 
Background
Low serum parathyroid hormone (PTH) has been implicated as a primary biochemical marker of adynamic bone disease in individuals with chronic kidney disease (CKD) who undergo maintenance hemodialysis (MHD) treatment. We hypothesized that the malnutrition-inflammation complex is associated with low PTH levels in these patients and confounds the PTH-survival association.
Methods
We examined 748 stable MHD outpatients in Southern California and followed them for up to 5 years (10/2001-12/2006).
Results
In 748 MHD patients, serum PTH <150 pg/ml was more prevalent among non-Blacks and diabetics. There was no association between serum PTH and coronary artery calcification score, bone mineral density or dietary protein or calorie intake. Low serum PTH was associated with markers of protein-energy wasting and inflammation, and this association confounded the relationship between serum PTH and alkaline phosphatase. Although 5-year crude mortality rates were similar across PTH increments, after adjustment for the case-mix and surrogates of malnutrition and inflammation, a moderately low serum PTH in 100 to 150 pg/ml range was associated with the greatest survival compared to other serum PTH levels, i.e., a death hazard ratio of 0.52 (95% confidence interval: 0.29-0.92, p<0.001) compared to PTH of 300 to 600 pg/ml (reference).
Conclusions
Low serum PTH may be another facet of the malnutrition-inflammation complex in CKD, and after controlling for this confounder, a moderately low PTH in 100 to 150 pg/ml range appears associated with the greatest survival. Limitations of observational studies should be considered.
doi:10.1053/j.jrn.2009.10.006
PMCID: PMC3175364  PMID: 20199875
Parathyroid hormone (PTH); adynamic bone disease; malnutrition-inflammation complex; alkaline phosphatase; paricalcitol; cytokines
21.  Association between high molecular weight apolipoprotein isoforms and lipoprotein levels in advanced chronic kidney disease and the effect of hemodialysis 
Indian Journal of Nephrology  2013;23(1):18-23.
To explore the association between high molecular weight apo(a) isoforms and lipoprotein(a) [Lp(a)] in chronic kidney disease (CKD) and the effect of maintenance hemodialysis (MHD), plasma Lp(a) and apo(a) isoforms were determined in age and sex-matched CKD stage 4 and stage 5 patients (repeated after 4 weeks of MHD) and healthy controls (n = 18). Median Lp(a) increased with severity of CKD. Upon HMW apo(a) isoform stratification, Lp(a) in S2 isoform group was 37.6 mg/dl in CKD stage 4 and 64.0 mg/dl in stage 5 (P < 0.024 and P < 0.001 vs. controls), whereas in S3 + S4 group there was no significant increase. Following MHD, Lp(a) also decreased significantly only in the S2 group. Increase in Lp(a) in CKD patients with HMW apo(a) isoforms is mainly restricted to S2 isoform group, furthermore, decrease in Lp(a) levels in response to MHD is also seen in this group only.
doi:10.4103/0971-4065.107189
PMCID: PMC3621233  PMID: 23580800
Apo(a) isoforms; chronic kidney disease; lipoprotein(a); maintenance hemodialysis
22.  rHuEPO Hyporesponsiveness and Related High Dosages Are Associated with Hyperviscosity in Maintenance Hemodialysis Patients 
The Scientific World Journal  2013;2013:792698.
Objective. Increased viscosity may increase the risk of thrombosis or thromboembolic events. Recombinant human erythropoietin (rHuEPO) is the key stone treatment in anemic ESRD patients with the thrombotic limiting side effect. We evaluated the influence of clinical and laboratory findings on plasma viscosity in MHD patients in the present study. Method. After applying exclusion criteria 84 eligible MHD patients were included (30 female, age: 54.7 ± 13.7 years). Results. Patients with high viscosity had longer MHD history, calcium × phosphorus product, and higher rHuEPO requirement (356.4 versus 204.2 U/kg/week, P: 0.006). rHuEPO hyporesponsiveness was also more common in hyperviscosity group. According to HD duration, no rHuEPO group had the longest and the low rHuEPO dosage group had the shortest duration. Despite similar Hb levels, 68% of patients in high rHuEPO dosage group; and 38.7% of patients in low rHuEPO dosage group had higher plasma viscosity (P: 0.001). Patients with hyperviscosity had higher rHuEPO/Hb levels (P: 0.021). Binary logistic regression analyses revealed that rHuEPO hyporesponsiveness was the major determinant of hyperviscosity. Conclusion. We suggest that the hyperviscous state of the hemodialysis patients may arise from the inflammatory situation of long term HD, the calcium-phosphorus mineral abnormalities, rHuEPO hyporesponsiveness, and related high dosage requirements.
doi:10.1155/2013/792698
PMCID: PMC3806397  PMID: 24198729
23.  Erythrocyte glutathione transferase: a new biomarker for hemodialysis adequacy, overcoming the Kt/Vurea dogma? 
Cell Death & Disease  2012;3(8):e377-.
Kt/Vurea ratio is commonly used to assess the delivered dose of dialysis in maintenance hemodialysis (MHD) patients. This parameter only reflects the efficacy of dialytic treatments in removing small toxins, but not middle and protein-bound toxins. Erythrocyte glutathione transferase (e-GST), an enzyme devoted to cell depuration against a lot of large and small toxins, is overexpressed in uremic patients. Aim of the present study is to verify whether e-GST may represent a novel biomarker to assess the adequacy of different dialytic techniques complementary to Kt/Vurea parameter. Furthermore, it will be investigated whether e-GST could reflect the ‘average' adequacy of multiple dialytic sessions and not of a single one treatment as it occurs for Kt/Vurea. One hundred and three MHD patients and 82 healthy subjects were tested. Fourty four patients were treated with standard bicarbonate hemodialysis (HD) and 59 patients were on online hemodiafiltration (HDF). In all MHD patients e-GST activity was 60% higher than in healthy controls. In HDF, e-GST activity was lower than in HD subgroup (8.2±0.4 versus 10.0±0.4 U/gHb, respectively). Single-pool Kt/Vurea and total weekly Kt/Vurea were higher in HDF than in HD, but no correlation was found between e-GST activity and Kt/Vurea data. e-GST, whose level is stable during the erythrocyte life-span, provides information on the long-term depurative efficacy of dialysis treatments.
doi:10.1038/cddis.2012.112
PMCID: PMC3434653  PMID: 22914325
chronic kidney disease; erythrocyte glutathione S-transferase; hemodialysis adequacy; Kt/Vurea; oxidative stress; uremic toxins
24.  Low levels of vitamin C in dialysis patients is associated with decreased prealbumin and increased C-reactive protein 
BMC Nephrology  2011;12:18.
Background
Subclinical inflammation is a common phenomenon in patients on either continuous ambulatory peritoneal dialysis (CAPD) or maintenance hemodialysis (MHD). We hypothesized that vitamin C had anti-inflammation effect because of its electron offering ability. The current study was designed to test the relationship of plasma vitamin C level and some inflammatory markers.
Methods
In this cross-sectional study, 284 dialysis patients were recruited, including 117 MHD and 167 CAPD patients. The demographics were recorded. Plasma vitamin C was measured by high-performance liquid chromatography. And we also measured body mass index (BMI, calculated as weight/height2), Kt/V, serum albumin, serum prealbumin, high-sensitivity C-reactive protein (hsCRP), ferritin, hemoglobin. The relationships between vitamin C and albumin, pre-albumin and hsCRP levels were tested by Spearman correlation analysis and multiple regression analysis.
Patients were classified into three subgroups by vitamin C level according to previous recommendation [1,2] in MHD and CAPD patients respectively: group A: < 2 ug/ml (< 11.4 umol/l, deficiency), group B: 2-4 ug/ml (11.4-22.8 umol/l, insufficiency) and group C: > 4 ug/ml (> 22.8 umol/l, normal and above).
Results
Patients showed a widely distribution of plasma vitamin C levels in the total 284 dialysis patients. Vitamin C deficiency (< 2 ug/ml) was present in 95(33.45%) and insufficiency (2-4 ug/ml) in 88(30.99%). 73(25.70%) patients had plasma vitamin C levels within normal range (4-14 ug/ml) and 28(9.86%) at higher than normal levels (> 14 ug/ml). The similar proportion of different vitamin C levels was found in both MHD and CAPD groups.
Plasma vitamin C level was inversely associated with hsCRP concentration (Spearman r = -0.201, P = 0.001) and positively associated with prealbumin (Spearman r = 0.268, P < 0.001), albumin levels (Spearman r = 0.161, P = 0.007). In multiple linear regression analysis, plasma vitamin C level was inversely associated with log10hsCRP (P = 0.048) and positively with prealbumin levels (P = 0.002) adjusted for gender, age, diabetes, modality of dialysis and some other confounding effects.
Conclusions
The investigation indicates that vitamin C deficiency is common in both MHD patients and CAPD patients. Plasma vitamin C level is positively associated with serum prealbumin level and negatively associated with hsCRP level in both groups. Vitamin C deficiency may play an important role in the increased inflammatory status in dialysis patients. Further studies are needed to determine whether inflammatory status in dialysis patients can be improved by using vitamin C supplements.
doi:10.1186/1471-2369-12-18
PMCID: PMC3112084  PMID: 21548917
25.  Total and Individual Coronary Artery Calcium Scores as Independent Predictors of Mortality in Hemodialysis Patients 
American Journal of Nephrology  2010;31(5):419-425.
Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001–9/2007) survival of 166 MHD patients, aged 53 ± 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1–100, 101–400, and 400+. The 101–400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1–48.1, p = 0.02) and 13.3 (95% CI: 1.3–65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1–21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2–9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1–14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.
doi:10.1159/000294405
PMCID: PMC2883846  PMID: 20389057
Chronic kidney disease; Coronary artery calcium; Dialysis; Inflammation; Phosphorus binder; Sevelamer; Death risk

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