Gender,low Kt/V,and mortality in Japanese hemodialysis patients: Opportunities for improvement through modifiable practices

Guidelines have recommended single pool Kt/V > 1.2 as the minimum dose for chronic hemodialysis (HD) patients on thrice weekly HD. The Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown that “low Kt/V” (<1.2) is more prevalent in Japan than many other countries, though survival is longer in Japan. We examined trends in low Kt/V, dialysis practices associated with low Kt/V, and associations between Kt/V and mortality overall and by gender in Japanese dialysis patients. We analyzed 5784 HD patients from Japan DOPPS (1999–2011), restricted to patients dialyzing for >1 year and receiving thrice weekly dialysis. Logistic regression models estimated the relationships of patient characteristics with Kt/V. Logistic models also were used to estimate the proportion of low Kt/V cases attributable to various treatment practices. Multivariable Cox regression was used to estimate the associations of low Kt/V, blood flow rate (BFR), and treatment time (TT), with all‐cause mortality. From 1999 to 2009, the prevalence of low Kt/V declined in men (37–27%) and women (15–10%). BFR <200 mL/min, TT <240 minutes, and dialyzate flow rate (DFR) < 500 mL/min were common (35, 13, and 19% of patients, respectively) and strongly associated with low Kt/V. Fifteen percent of low Kt/V cases were attributable to BFR <200 and 13% to TT <240, compared to only 3% for DFR <500. Lower Kt/V was associated with elevated mortality, more so among women (hazard ratio [HR] = 1.13 per 0.1 lower Kt/V, 95% CI: 1.07–1.20) than among men (HR = 1.06 per 0.1 lower Kt/V, 95% CI: 1.00–1.12). The relatively large proportion of low Kt/V cases in Japanese facilities may potentially be reduced 30% by increasing BFR to 200 mL/min and TT to 4 hours thrice weekly in HD patients. Associations of low Kt/V with elevated mortality suggest that modification of these practices may further improve survival for Japanese HD patients.     

Enhanced expression of hemoglobin scavenger receptor and heme oxygenase‐1 is associated with aortic valve stenosis in patients undergoing hemodialysis

A high prevalence and a rapid progression of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD) has been reported. In these circumstances, intraleaflet hemorrhage of aortic valve may be related to the development of AS in HD patients. We immunohistochemically examined the relationship among intraleaflet hemorrhage, neovascularization, hemoglobin scavenger receptor (CD163), and heme oxygenase‐1 (HO‐1) using surgically resected aortic valve specimens from AS patients undergoing HD. The study population consisted of 26 HD patients and 25 non‐HD patients with severe AS who had undergone aortic valve replacement. Frozen aortic valve samples surgically obtained from AS patients were stained immunohistochemically with antibodies against smooth muscle cells, macrophages, glycophorin‐A (a protein specific to erythrocyte membranes), CD31, CD163, and HO‐1. Morphometric analysis demonstrated that the CD163‐positive macrophage score, the number of CD31‐positive microvessels, and the percentage of glycophorin‐A and HO‐1‐positive area were significantly higher in HD patients than in non‐HD patients (CD163‐positive macrophage score, P < 0.0001; CD31‐positive microvessels, P < 0.0001; glycophorin‐A, P < 0.0001; HO‐1, P < 0.0001). Double immunostaining for CD163 or HO‐1 and macrophages revealed that the majority of CD163‐ or HO‐1‐positive cells were macrophages. Furthermore, CD163‐positive macrophage score was positively correlated with glycophorin‐A, HO‐1‐positive area, and the number of CD31‐positive microvessels (glycophorin‐A, R = 0.66, P < 0.0001; HO‐1, R = 0.50, P < 0.0005; microvessels, R = 0.38, P < 0.01). These findings suggest a positive association among intraleaflet hemorrhage, neovascularization, and enhanced expression of CD163 and HO‐1 as a response to intraleaflet hemorrhage in stenotic aortic valves in AS patients undergoing HD.     

Association of mineral metabolism factors with all-cause and cardiovascular mortality in hemodialysis patients: the Japan dialysis outcomes and practice patterns study

Abnormalities in mineral metabolism have been linked to mortality in hemodialysis (HD) patients. We postulated that these abnormalities would have a particularly large deleterious impact on deaths due to cardiovascular causes in Japan. This study describes the recent status of abnormal mineral metabolism, significant predictors, and potential consequences in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Phases 1 and 2, in Japan. Major predictor variables were patient demographics, comorbidities, and laboratory markers of mineral metabolism such as albumin-adjusted serum calcium (calciumAlb), phosphorus, and intact PTH (iPTH). In a cross section of 3973 Japanese HD patients in DOPPS I and II, a large faction had laboratory values outside of the recommended Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline range for serum concentrations of phosphorus (51% of patients above upper target range), calciumAlb (43.7% above), calcium-phosphorus (Ca x P) product (41.1% above), and iPTH (18.6% above). All-cause mortality was significantly and independently associated with calciumAlb (relative risk [RR]=1.22 per 1 mg/dL, p=0.0005) and iPTH (RR=1.04 per 100 pg/mL, p=0.04). Cardiovascular mortality was significantly associated with calciumAlb (RR=1.28, p=0.02), phosphorus (RR=1.13 per 1 mg/dL, p=0.008), Ca x P product (RR=1.07 per 2 mg(2)/dL(2), p=0.002), and PTH (RR=1.08, p=0.0001). This study expands our understanding of the relationship between altered mineral metabolism and mortality outcomes, showing slightly stronger associations with cardiovascular causes than observed for all-cause mortality. These findings have important therapeutic implications for Japanese HD patients.     

Sertraline can reduce uremic pruritus in hemodialysis patient: A double blind randomized clinical trial from Southern Iran

Introduction: Uremic pruritus is an undesirable complication of end stage renal disease (ESRD). In spite of introduction of many treatments for this complication, it has no certain cure. The aim of this study was to assess sertraline effect on uremic pruritus. Methods: In the present clinical trial study, we randomly divided our patients into two groups; trial group that received sertraline and control group that consumed placebo. We measured the severity of pruritus by two scoring systems (visual analogue scale and DUO) at the beginning and during the study with a‐2‐week interval. Data were analyzed by SPSS 18.0 and a P value < 0.050 considered as significant. Findings: The mean age of our patients was 44.1 ± 16.1 years. Pruritus intensity significantly decreased in both groups (P < 0.001) and both scoring systems. Although the amount of decrease in trial group was significantly more than control group (P < 0.001). We found a direct relation between blood urea nitrogen and phosphorus and the degree of itching in VAS system (P < 0.009). There was a reverse significant relation between itching and calcium in both scoring systems (P < 0.012). Also pruritus intensity was directly correlated with C‐reactive protein in both scoring systems (P < 0.05). Discussion: Depends on present study and previous ones, inflammation appears to play a significant role in uremic itching. Sertraline is an effective drug in reducing this complaint possibly due to its effect on reducing inflammatory cytokines. In addition there is no need to adjust sertraline dosage in patients with ESRD. Sertraline might be a treatment for patients with ESRD who do not respond to other routine drugs.     

Heparin‐grafted dialysis membrane allows minimal systemic anticoagulation in regular hemodialysis patients: A prospective proof‐of‐concept study

This prospective, multicenter, proof‐of‐concept study aimed to evaluate the possibility to reduce the ordinary heparin dose and the systemic anti‐Xa activity during hemodialysis (HD) sessions using a new heparin‐grafted HD membrane. In 45 stable HD patients, the use of a heparin‐grafted membrane with the ordinary heparin dose was followed by a stepwise weekly reduction of dose. Reduction was stopped when early signs of clotting (venous pressure, quality of rinse‐back) occurred during two out of three weekly HD sessions. Heparin dose was decreased for 67% of patients resulting in the lowering of these patients' anti‐Xa activity by 50%. Dose reductions were achieved with both types of heparin (low‐molecular‐weight heparin: 64 ± 14 to 35 ± 12 IU/kg, P < 0.0001; unfractionated heparin: 82 ± 18 to 46 ± 13 IU/kg, P < 0.0001) resulting in a decrease of anti‐Xa activity at dialysis session end (low‐molecular‐weight heparin: 0.51 ± 0.25 to 0.25 ± 0.11 IU/mL, P < 0.0001; unfractionated heparin: 0.28 ± 0.23 to 0.13 ± 0.07 IU/mL, P < 0.0001). Failure to further decrease heparin dose was related to signs of clotting in blood lines (57% of sessions), in dialyzer (9%), or both (34%). Significant reduction of heparin dose and anti‐Xa activity at the end of HD sessions was possible in stable HD patients using heparin‐grafted membrane. HD patients who require low anti‐Xa activity at the end of HD sessions might benefit from a heparin‐grafted membrane to reduce bleeding risk and other heparin adverse events.     

Vascular imaging for hemodialysis vascular access planning

Introduction: Central venous catheters (CVC) increase risks associated with hemodialysis (HD), but may be necessary until an arteriovenous fistula (AVF) or graft (AVG) is achieved. The impact of vascular imaging on achievement of working AVF and AVG has not been firmly established. Methods: Retrospective cohort of patients initiating HD with CVC in 2010–2011, classified by exposure to venography or Doppler vein mapping, and followed through December 31, 2012. Standard and time‐dependent Cox models were used to determine hazard ratios (HRs) of death, working AVF, and any AVF or AVG. Logistic regression was used to assess the association of preoperative imaging with successful AVF or AVG among 18,883 individuals who had surgery. Models were adjusted for clinical and demographic factors. Findings: Among 33,918 patients followed for a median of 404 days, 39.1% had imaging and 55.7% had surgery. Working AVF or AVG were achieved in 40.6%; 46.2% died. Compared to nonimaged patients, imaged patients were more likely to achieve working AVF (HR = 1.45 [95% confidence interval [CI] 1.36, 1.55], P < 0.001]), any AVF or AVG (HR = 1.63 [1.58, 1.69], P > 0.001), and less likely to die (HR = 0.88 [0.83‐0.94], P < 0.001). Among patients who had surgery, the odds ratio for any successful AVF or AVG was 1.09 (1.02–1.16, P = 0.008). Discussion: Fewer than half of patients who initiated HD with a CVC had vascular imaging. Imaged patients were more likely to have vascular surgery and had increased achievement of working AV fistulas and grafts. Outcomes of surgery were similar in patients who did and did not have imaging.     

A high blood level in the venous chamber and a wet‐stored dialyzer help to reduce exposure for microemboli during hemodialysis

During hemodialysis (HD), microemboli develop in the blood circuit of the apparatus. These microemboli can pass through the venous chamber and enter into the patient's circulation. The aim of this study was to investigate whether it is possible to reduce the risk for exposure of microemboli by altering of the treatment mode. Twenty patients on chronic HD were randomized to a prospective cross‐over study of three modes of HD: (a) a dry‐stored dialyzer (F8HPS, Fresenius, steam sterilized) with a low blood level in the venous chamber (DL), (b) the same dialyzer as above, but with a high level in the venous chamber (DH), and (c) a wet‐stored dialyzer (Rexeed, Asahi Kasei Medical, gamma sterilized) with a high blood level (WH). Microemboli measurements were obtained in a continuous fashion during 180 minutes of HD for all settings. A greater number of microemboli were detected during dialysis with the setting DL vs. WH (odds ratio [OR] 4.07, 95% confidence interval [CI] 4.03–4.11, P < 0.0001) and DH vs. WH (OR 1.18, 95% CI 1.17–1.19, P < 0.0001) and less for DH vs. DL (OR 0.290, 95% CI 0.288–0.293, P < 0.0001). These data indicate that emboli exposure was least when using WH, greater with DH, and most with DL. This study shows that using a high blood level in the venous chamber and wet‐stored dialyzers may reduce the number of microemboli.     

Effects of enoxaparin on myeloperoxidase release during hemodialysis

Myeloperoxidase (MPO) is a proteolytic and prooxidant enzyme largely assembled with the vascular wall, and a heparin‐binding protein. We studied if low‐molecular‐weight heparin enoxaparin administered for hemodialysis (HD) anticoagulation causes systemic MPO activation. Plasma MPO levels were measured in patients undergoing maintenance HD with an intravenous bolus of enoxaparin. Patients were retested during HD employing dialyzers with heparin‐grafted polyacrylonitrile membrane and no systemic enoxaparin administration. During enoxaparin‐anticoagulated HD plasma MPO levels strikingly increased in all patients (8.6‐fold at 10 minutes and 3.3‐fold at 120 minutes, both P < 0.0001). The increments were directly associated with the enoxaparin dosage and strongly inversely with the predialysis levels of the enzyme. The increase in plasma MPO during systemic heparin‐free HD was significantly less pronounced. Enoxaparin administered for HD anticoagulation induces a marked and dose‐dependent increase in plasma MPO as a plausibly favorable result of the liberation of the enzyme from the vascular wall.     

Pruritus in hemodialysis patients: The problem remains

Pruritus is still one of the most common and disturbing symptoms of end-stage renal disease. The objective of this study is to analyze the prevalence of pruritus in hemodialysis patients and the possible factors implicated in its genesis. In a cross-sectional study, 101 patients on hemodialysis at our center were screened for pruritus. The relationship of various factors with pruritus was evaluated. Of the 101 patients included, 31(30.7%) had pruritus at the time of examination. Patients with pruritus were significantly older than those without pruritus (P=0.0027). Pruritus tended to be more prevalent in patients undergoing dialysis 3 times a week than in those undergoing daily dialysis, but the difference did not reach statistical significance (P=0.0854). Lower transferrin saturation levels were found in patients with pruritus than in those without pruritus (P=0.0144). C-reactive protein levels were significantly higher in patients with pruritus than in those without pruritus (P=0.0013). There was no significant difference between the groups in the levels of the other inflammatory biomarkers measured. However, there was a tendency toward a correlation between the levels of α-1-glycoprotein and the intensity of pruritus (P=0.0834). Our results suggest a possible relationship of the inflammatory response upregulation to pruritus. Additionally, there was a positive relationship between pruritus and iron deficiency, possibly associated with inflammatory elevation of hepcidin. A better understanding of the factors implicated in the genesis of pruritus related to end-stage renal disease is crucial in the development of more effective treatments for this symptom.     

Positive association between plasma levels of oxidized low‐density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end‐stage renal disease

End‐stage renal disease (ESRD) patients undergoing hemodialysis (HD) have a high prevalence of cardiovascular events. Low‐density lipoprotein (LDL) in dialysis patients has been shown to be susceptible to in vitro peroxidation; therefore, oxidized‐LDL (ox‐LDL) could be generated in these patients. Moreover, myeloperoxidase (MPO) released from activated neutrophils may play a role in the induction of LDL oxidation. The purpose of this study was to investigate the relationship between plasma ox‐LDL levels, plasma MPO levels, and serum high‐sensitivity C‐reactive protein (hs‐CRP) levels during initial HD in patients with diabetic ESRD. Patients (n = 28) had serial venous blood samples drawn before and after HD at the initial, second, and third sessions. Plasma ox‐LDL levels were measured using a specific monoclonal antibody (DLH3), and plasma MPO levels were measured using an enzyme‐linked immunosorbent assay kit. Plasma ox‐LDL levels and MPO levels after a single HD session increased significantly (ox‐LDL, P < 0.005; MPO, P < 0.0001) compared with levels before that HD session. However, the increase was transient since the levels returned to pre‐HD session levels. Additionally, plasma MPO levels showed a positive correlation with plasma ox‐LDL levels during HD (R = 0.62, P = 0.0029). No significant change was observed in serum hs‐CRP levels before and after each HD session. This study demonstrates that plasma MPO levels are directly associated with plasma ox‐LDL levels in diabetic ESRD patients during initial HD. These findings suggest a pivotal role for MPO and ox‐LDL in the progression and acceleration of atherosclerosis in patients undergoing HD.     

Plasma myeloperoxidase,NT‐proBNP,and troponin‐I in patients on CAPD compared with those on regular hemodialysis

Myeloperoxidase (MPO) is a hemoprotein that is released during inflammation and may lead to irreversible protein and lipid modification, increasing levels of oxidized low density lipoprotein, and promoting athrogenesis. Recently, it has been considered as a risk factor for cardiovascular diseases. Similarly, the measurement of carotid intima‐media thickness gives an indication about the degree of atherosclerosis and prediction of clinical cardiovascular events. Elevated white blood cells counts may indicate a state of acute inflammation and follow its progression. Dialysis patients are at a high risk of developing cardiovascular disease compared with healthy subjects. The role of N‐terminal pro‐brain natriuretic peptide and increased cardiac troponin in identification and prognostication of cardiovascular diseases in end‐stage renal disease patients has been investigated. The current study aimed to evaluate plasma MPO and its possible relationship with carotid intima‐media thickness, troponin I, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), and insulin resistance as measured by homeostatic model assessment (HOMA index) in a cohort of Saudi patients who are undergoing hemodialysis (HD) vs. continuous ambulatory peritoneal dialysis for end‐stage renal disease. Plasma MPO was significantly higher in patients on continuous ambulatory peritoneal dialysis (CAPD) than in those on HD and in normal subjects (P<0.001). Conversely, NT‐proBNP plasma levels were significantly higher in patients on HD (both predialysis and postdialysis) than in those on CAPD (P<0.01) and than normal subjects. Similarly, plasma troponin‐I levels were significantly higher in patients on HD compared with those of CAPD and than normal subjects (P<0.001). Plasma troponin‐I and NT‐proBNP levels were positively correlated in the 3 groups namely those on CAPD, Pre‐HD, and post‐HD (r: 0.464 and P=0.047; r: 0.330 and P=0.013; and r: 0.452 and P=0.024), respectively. There was no correlation between the MPO level and carotid intima‐media thickness (P>0.05). However, plasma MPO level correlated positively with the white blood cell count in patients on CAPD and in those on HD (P<0.05). Our findings suggest an increased oxidative stress in CAPD patients compared with HD patients, while the reported difference in plasma NT‐proBNP and troponin‐I may be related to the rapid decline of residual renal function in HD and type of membrane used in the HD dialysis procedure itself.     

Monocyte/lymphocyte ratio as a better predictor of cardiovascular and all‐cause mortality in hemodialysis patients: A prospective cohort study

Introduction: Patients with chronic kidney disease, especially those with end‐stage renal disease, have an increased risk of death. Previous studies have suggested neutrophil/lymphocyte ratio (NLR) was related to worse outcome in patients undergoing hemodialysis (HD). However, monocyte/lymphocyte ratio (MLR) has not been evaluated in HD patients. In this study, we prospectively studied the predictive value of MLR for all‐cause and cardiovascular mortality in HD patients and compared it with NLR. Methods: Patients who had been on a HD treatment for at least 6 months were enrolled. MLR was calculated by dividing the monocyte count by the lymphocyte count. Survival outcomes were estimated using the Kaplan‐Meier method and compared by the log‐rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of MLR and other clinical factors on all‐cause and cardiovascular mortality. Results: Mortality rates for the lowest, middle, and highest MLR tertile group were 3.65, 7.02, and 11.15, respectively per 100 patient‐years. The Kaplan‐Meier analysis revealed that survival rates were significantly different among three MLR groups (P < 0.001). In multivariate Cox regression analyses, MLR was independently associated with all‐cause mortality (HR 4.842; 95% CI, 2.091–11.214; P < 0.001) and cardiovascular mortality (HR 6.985, 95% CI 1.943–25.115, P = 0.003) as continuous variables. NLR was not an independent predictor of all‐cause nor cardiovascular mortality after adjusted with MLR. Conclusions: The main finding of the study suggest that higher MLR was a strong and independent predictor of all‐cause and cardiovascular mortality and overwhelmed NLR among HD patients.     

The effect of small dose of topiroxostat on serum uric acid in patients receiving hemodialysis

Introduction : Topiroxostat, a recently developed xanthine oxidase inhibitor, is expected to have fewer adverse effects than allopurinol because it has different mechanism of action from alloprinol. However, its dosage, usage and safety have not been established in patients with impaired renal function or those undergoing dialysis at the development since no studies was conducted in these patients. Methods : Cross over clinical trial using 3 months of allopurinol and topiroxostat on 27 maintain Japanese HD patients were carried out. The effects on oxidative stress status of both drugs were also evaluated by measuring oxidation reduction potential. Findings : Twenty‐five of twenty‐seven patients completed study. The mean serum uric acid levels in the topiroxostat‐treated arm was significantly lower than it in the allopurinol‐treated arm time‐dependently (P < 0.0001). Corrected oxidative stress ratio defined as biological antioxidant potential/diacron reactive oxygen metabolites was significantly increased in topiroxostat‐arm (*P = 0.0035), but not in allopurinol‐arm (P = 0.1429). No significant difference was seen in diacron reactive oxygen metabolites, biological antioxidant potential, static oxidation‐reduction potential, and capacity oxidation‐reduction potential between pre and post treatment of both drugs. Discussion : It is suggested that a low dose of topiroxostat decreased serum uric acid sufficiently to maintain it below 7.0 mg/dL in patients receiving hemodialysis.     

Statins are associated with a reduced risk of bone fracture in hemodialysis (HD) patients

The Dialysis Outcomes and Practice Patterns Study reported a statistically non-significant protective effect of HMG-co reductase inhibitors (statins) on bone fracture risk in hemodialysis (HD) patients. We sought to determine whether statin exposure was associated with reduced risk of bone fracture in our HD population. This was a retrospective cohort study of 174 prevalent HD patients. Fracture data are abstracted from the medical record. Subjects were considered to be on a statin if they were exposed at any time since the date of dialysis initiation. The subjects were 174 HD patients (68.4% male) with a median age of 69.1 and age range from 25.2 to 96.3 years. The median age at initiation of HD was 62.5, ranging from 15.2 to 90.5 years. The mean (SD) dialysis vintage was 7.3 (4.5) years. Seventy-seven subjects (44.3%) had statin exposure. There were a total of 54 first bone fractures. There was a positive correlation between bone fracture and dialysis vintage (p=0.023) and a negative association between bone fracture and statin exposure (p=0.044). Those with statin exposure had a higher prevalence of CAD (p=0.030) compared with those not exposed. Logistic regression analysis (stepwise, alpha=0.05) was performed with dependent variable bone fracture and independent variables age at HD initiation (forced), dialysis vintage, gender (forced), prednisone use (forced), and statin exposure. The significant predictors of bone fracture (R2=0.14, p=0.004) were age at HD initiation (p=0.016), dialysis vintage (p=0.007), and absence of statin exposure (p=0.019). Statin exposure appears to be associated with a reduced frequency of bone fracture in HD patients. Future studies evaluating the potential anabolic effect of statins on bone are required.