FGF‐23 and cognitive performance in hemodialysis patients

Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF‐23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF‐23 being found within the brain, there are no prior studies assessing whether FGF‐23 levels are associated with cognitive performance. We measured FGF‐23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross‐sectional association between patient characteristics and FGF‐23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF‐23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF‐23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF‐23 levels. Higher FGF‐23 was independently associated with a lower memory score (per doubling of FGF‐23, β = ?0.08 SD [95% confidence interval, CI: ?0.16, ?0.01]) and highest quartile vs. lowest quartile (β = ?0.42 SD [?0.82, ?0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (β = ?0.03 SD [?0.10, 0.04]); however, there was a trend in the quartile analysis (β = ?0.28 SD [?0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF‐23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF‐23 levels in hemodialysis patients may contribute to cognitive impairment.     

Plasma fibroblast growth factor-23 levels are independently associated with carotid artery atherosclerosis in maintenance hemodialysis patients

Fibroblast growth factor-23 (FGF-23) has been suggested to play a role in vascular calcification in chronic kidney disease. Common carotid artery intima-media thickness (CIMT) assessment and common carotid artery (CCA) plaque identification using ultrasound are well-recognized tools for identification and monitoring of atherosclerosis. The aim of this study was to test that elevated FGF-23 levels might be associated with carotid artery atherosclerosis in maintenance hemodialysis (HD) patients. In this cross-sectional study, plasma FGF-23 concentrations were measured using a C-terminal human enzyme-linked immunosorbent assay kit. Carotid artery intima-media thickness was measured and CCA plaques were identified by B-Mode Doppler ultrasound. One hundred twenty-eight maintenance HD patients (65 women and 63 men, mean age: 55.5 ± 13 years, mean HD vintage: 52 ± 10 months, all patients are on HD thrice a week) were involved. The mean CIMT were higher with increasing tertiles of plasma FGF-23 levels (0.66 ± 0.14 vs. 0.75 ± 0.05 vs. 0.86 ± 0.20 mm, P<0.0001). Log plasma FGF-23 were higher in patients with plaques in CCA than patients free of plaques (3.0 ± 0.17 vs. 2.7 ± 0.23, P<0.0001). Significant correlation was recorded between log plasma FGF-23 and CIMT (r=0,497, P=0.0001). In multiple regression analysis, a high log FGF-23 concentration was a significant independent risk factor of an increased CIMT. Further studies are needed to clarify whether an increased plasma FGF-23 level is a marker or a potential mechanism for atherosclerosis in patients with end-stage renal disease.     

Associations with home hemodialysis modality failure and mortality

Background: Limited data exist on risk factors for home hemodialysis (HH) failure and mortality. We sought to determine whether age, helper status, or ethnicity was associated with home dialysis failure or mortality. Methods: We conducted a retrospective cohort study of all prevalent and incident patients from a regional dialysis unit who initiated HH training from December 2000 to September 2002. Baseline demographics, program entry and exit dates, and mortality were ascertained. Characteristics of those more likely to remain in the program were assessed using logistic regression; survival was determined using Cox proportional hazards models. Results: Of the 1117 patients enrolled for dialysis, 116 patients were trained in the HH program (6.8%). Of those, 45.7% remained in the program, 10.3% received a transplant, 10.3% returned to in‐center dialysis, 1.7% were lost to follow‐up, and 31.7% expired. Compared to patients who returned to center or received a transplant, patients who remained on HH were more likely to be older, to have been on dialysis longer, and to have diabetes as their primary renal disease. Ethnicity, sex, or type of helper did not affect home program status. Among those who remained in the HH program, those with hypertension or other renal diseases had better survival than those with diabetes, as did those who had related helpers compared to those with unrelated helpers. Conclusions: Older and younger ages, but not ethnicity, helper status, or sex, were associated with home dialysis failure. Diabetes remained an independent risk factor for increased mortality. HH remains a viable option for many patients.     

Association between afebrile status and in‐hospital mortality among adult chronic hemodialysis patients with bacteremia

Aim: We aimed to compare the in‐hospital mortality between febrile and afebrile chronic hemodialysis (HD) patients with bacteremia and analyze the blood culture positive rate according to the C‐reactive protein (CRP) level. Methods: We collected data from 2006 to 2014. One hundred ninety bacteremic events were assigned to the “febrile group” (n = 162) and “afebrile group” (n = 28) based on the presence of fever. Fever was defined as a tympanic temperature >37.5°C or axillary temperature >37.0°C. Results: In‐hospital mortality (41.4% vs. 6.1%) was higher; and the interval between admission and blood culture was longer (3 vs. 1 h) in the afebrile group than in the febrile group. The mean reason for blood culture in the afebrile group was a high CRP level. Conclusions: An afebrile status in HD patients with bacteremia is associated with higher in‐hospital mortality. Blood culture and empirical antibiotic administration, irrespective of the fever status, should be considered in HD patients with a CRP ≥ 5 mg/dL.     

Neither oxidized nor anti-oxidized low-density lipoprotein level is associated with atherosclerosis or mortality in hemodialysis patients

It is anticipated that oxidized low‐density lipoprotein (oxLDL) and anti‐oxLDL are associated with atherosclerosis and mortality. However, data on this issue are controversial and limited. We aimed to investigate the effect of these two markers on the extent and progression of atherosclerosis and mortality in a group of hemodialysis patients. In this prospective observational study with a follow‐up of 36 months, 124 hemodialysis patients were studied. Ninety‐five patients underwent carotid intima media thickness (CA‐IMT) measurement by B‐Mode ultrasonography both at baseline and at the end of the study. oxLDL and anti‐oxLDL were measured by enzyme‐linked immunosorbent assay. The extent and progression of CA‐IMT, along with overall and cardiovascular mortality, were assessed. The mean age at baseline was 54.0 ± 14.8 years, 57.3% male and 20% diabetic. The mean oxLDL and anti‐oxLDL levels were 8.11 ± 3.16 mU/L and 1.30 ± 0.31, respectively. Baseline mean CA‐IMT was 0.82 ± 0.20 mm. Fifteen patients died during a follow‐up period of 28.5 ± 6.6 months, 11 from cardiovascular causes. Only oxLDL, not anti‐oxLDL, was correlated with the extent of atherosclerosis at baseline. However, both had no role in the progression of atherosclerosis. Also, in unadjusted and adjusted models, both parameters were not associated with overall or cardiovascular mortality. Neither oxLDL nor anti‐oxLDL level is associated with the progression of atherosclerosis or mortality in hemodialysis patients.     

Inverse association between docosahexaenoic acid and mortality in patients on hemodialysis during over 10 years

We have previously conducted a cohort study to investigate n‐3 polyunsaturated fatty acids (PUFAs) in red blood cells (RBCs) and risk of all‐cause mortality in hemodialysis (HD) patients over 5 years and found that n‐3 PUFAs, especially docosahexaenoic acid (DHA), might be an independent predictor of all‐cause mortality. In the present study, we extended the study for another 5 years to determine whether DHA levels in RBCs still predict the mortality of HD patients during a 10‐year study period. The study cohort consisted of 176 patients (64.1 ± 12.0 [mean ± standard deviation] years of age, 96 men and 80 women) under HD treatment. The fatty acid composition of patients' RBCs was analyzed by gas chromatography. During the study period of 10 years, 97 deaths occurred. After adjustment for 10 confounding factors, the hazard ratio of all‐cause mortality of the HD patients in the highest DHA tertile (>8.1%) was 0.52 (95% confidence interval 0.30–0.91) compared with those in the lowest DHA tertile (<7.2%). However, other n‐3 PUFAs such as eicosapentaenoic acid and docosapentaenoic acid (n‐3) did not reveal any significant correlations. The level of DHA in RBCs could be an independent predictor of all‐cause mortality in HD patients even during a long period of follow‐up.     

Comparison of survival between short-daily hemodialysis and conventional hemodialysis using the standardized mortality ratio

More frequent hemodialysis (5 or more times weekly, both short during the day and long overnight) has been shown to improve patient well-being, reduce symptoms during and between treatments, and have beneficial effects on clinical outcomes. Because of the relatively small patient sample sizes, there are little or no data on mortality from any single study at this time. This study compares survival in 117 U.S. patients treated by short-daily hemodialysis in 2003 and 2004, with patients reported in the 2003 data from the United States Renal Data System (USRDS). Expected mortality was calculated from the USRDS and compared with observed actual mortality. The standardized mortality ratio (SMR) was used to adjust for differences in patient age, sex, race, and cause of renal failure. The SMR for the short-daily hemodialysis patients was 0.39, statistically significantly better (p < 0.005) than data from the overall U.S. population of hemodialysis patients and indicating that daily hemodialysis patients had a 61% better survival. Patients treated by short-daily hemodialysis have a better survival rate than comparable populations treated by conventional hemodialysis.     

The effect of frequent hemodialysis on matrix metalloproteinases,their tissue inhibitors,and FGF23: Implications for blood pressure and left ventricular mass modification in the Frequent Hemodialysis Network trials

Background: Frequent hemodialysis modifies serum phosphorus, blood pressure, and left ventricular mass (LVM). We ascertained whether frequent hemodialysis is associated with specific changes in biomarker profile among patients enrolled in the frequent hemodialysis network (FHN) trials. Methods: This was a post hoc analysis of biomarkers among patients enrolled to the FHN trials. In particular, we hypothesized that frequent hemodialysis is associated with changes in a specific set of biomarkers which are linked with changes in blood pressure or LVM. Results: Among 332 randomized patients, 243 had biomarker data available. Of these, 124 patients were assigned to 3‐times‐a‐week hemodialysis (94 [Daily Trial] and 30 [Nocturnal Trial]) and 119 patients were assigned to 6‐times‐a‐week hemodialysis (87 [Daily Trial] and 32 [Nocturnal Trial]). Frequent hemodialysis lowered phosphate, blood pressures, LVM, log fibroblast growth factor (FGF)23, and tissue inhibitors of metalloproteinase (TIMP)—2 levels. The fall in phosphate was associated with changes in FGF23 (r = 0.48, P < 0.001) [Daily Trial] and (r = 0.55, P < 0.001) [Nocturnal Trial]) and tended to be associated with changes in systolic blood pressure (r = 0.18, P = 0.057) [Daily Trial] and (r = 0.31, P = 0.04) [Nocturnal Trial]. Within the Daily Trial, changes in MMP2 (r = 0.20, P = 0.034) were associated with changes in LVM. In the Nocturnal Trial, changes in TIMP‐1 (r = 0.37, P = 0.029) and MMP 9 (r = ?0.38, P = 0.01) were associated with LVM changes. MMP2 changes were associated with changes in systolic blood pressure. Conclusions: Reduction of serum phosphate by frequent hemodialysis may modulate FGF23 levels and systolic blood pressure. Markers of matrix turnover are associated with LVM changes. Frequent hemodialysis may affect pathological mediators of chronic kidney disease‐mineral bone‐metabolism disorder.     

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.     

Catheter‐related bacteremia and mortality in frequent nocturnal home hemodialysis

Frequent nightly home hemodialysis (NHHD) has emerged as an attractive alternative to thrice weekly in‐center hemodialysis, albeit with preponderant long‐term hemodialysis catheter used. Sixty‐three NHHD patients from University of Virginia Lynchburg Dialysis Facility were matched 1:2 with 121 conventional hemodialysis patients admitted to Fresenius Medical Care North America facilities from January 1, 2007 to December 31, 2010. Matching considered age (± 5 years), gender, race, dialysis vintage, and diabetes. The primary end‐point was the combined incidence of bacteremia/sepsis, for up to 20 months or upon changing to a fistula/graft (with catheter removal), transferring to peritoneal dialysis (PD), or at the time of kidney transplant or death. No significant differences were observed in rate of fistula/graft conversion, transfer to PD, transplant, or death between NHHD and in‐center hemodialysis (IHD) groups. For the first catheter used, the rate of catheter‐related sepsis was not significantly different between the NHHD (1.77 per 100 patient months) and IHD (2.03 per 100 patient months; P = 0.21). Combining all catheters, the rate of bacteremia/sepsis per 100 patient months in the NHHD group was 1.51 and in the IHD group was 2.01 (P = 0.35). Median catheter lifespan for the first catheter was 5.6 (1.7～19.0) for NHHD and 4.6 (2.7～7.8) for the IHD group (P = 0.64), and for all catheters used was 5.2 (Q1～Q3 = 1.5～15.2) months in NHHD group, and 4.1 (2.0～6.8) months in IHD group (P = 0.20). The rate of bacteremia and death is not different for up to 20 months in catheter users who dialyze via frequent NHHD vs. thrice weekly IHD.     

Relationship between Geriatric Nutritional Risk Index and total lymphocyte count and mortality of hemodialysis patients

We examined the relationships between Geriatric Nutritional Risk Index (GNRI), total lymphocyte count (TLC), and mortality in hemodialysis (HD) patients. We examined GNRI and TLC in 120 maintenance HD patients and followed these patients for 120 months. Predictors of all‐cause death were examined using life table analysis and the Cox proportional hazards model. TLC marginally correlated with GNRI (r = 0.176; p = 0.090) and significantly with phosphorus levels (r = 0.206; p = 0.026). Life table analysis revealed that subjects with a GNRI < 90 (n = 19) had lower survival rates than did those with a GNRI ≥ 90 (n = 101; Wilcoxon's test, p = 0.048), but subjects with a TLC < 1500/mm³ (n = 76) had similar survival rates compared with subjects with a TLC ≥ 1500/mm³ (n = 44; Wilcoxon's test, p = 0.500). Multivariate Cox proportional hazards analyses demonstrated that GNRI is a significant predictor of mortality (hazard ratio 9.315, 95% confidence interval 1.161–74.753, p = 0.036), after adjusting for age, sex, presence of type 2 diabetes mellitus, Kt/V, normalized protein catabolic rate, hematocrit, phosphorus, systolic blood pressure and TLC. Our findings suggest the TLC may be used as a simple nutritional tool, but may not be a predictor of mortality in HD patients. These findings require confirmation by further studies.     

Serum sulfatide abnormality is associated with increased oxidative stress in hemodialysis patients

Sulfatides are major glycosphingolipids of lipoproteins that influence atherosclerosis and blood coagulation. Our previous cross‐sectional study of hemodialysis patients showed that serum sulfatide levels decreased markedly with increasing duration of hemodialysis treatment, which may contribute to the development of cardiovascular disease. However, this past study could not demonstrate the time‐dependent change in serum sulfatide levels in each patient, and the underlying mechanism is unknown. To confirm the time‐dependent aggravation of serum sulfatide abnormality, 95 stable hemodialysis outpatients were followed up for 3 years. To show the underlying mechanisms, we statistically analyzed correlations between serum sulfatide levels and clinical factors, including an oxidative stress marker, malondialdehyde. Serum sulfatides were quantified by mass spectrometry after conversion to lysosulfatides. Malondialdehyde was measured using a colorimetric assay. The results showed a time‐dependent decrease in serum sulfatide levels associated with increased malondialdehyde levels, although the absolute level of serum malondialdehyde does not determine the baseline level of serum sulfatides. Multiple linear regression analysis showed a significant correlation only between the time‐dependent change in serum sulfatide levels and the time‐dependent change in serum malondialdehyde levels. This study demonstrated, for the first time, a time‐dependent aggravation of serum sulfatide abnormality in hemodialysis patients, as well as the potential relationship between serum sulfatide abnormality and increasing oxidative stress. These findings suggest that oxidative stress might be an aggravating factor in serum sulfatide abnormality. As continuation of hemodialysis treatment hardly improves abnormal serum sulfatide levels or increased oxidative stress, development of novel therapeutic strategies may be important.     

Epicardial fat thickness is associated with impaired coronary flow reserve in hemodialysis patients

Cardiovascular disease (CVD) is the main cause of mortality in hemodialysis (HD) patients. Epicardial fat tissue (EFT) is a new risk factor in CVD. The aim of this study was to evaluate the association between EFT and coronary artery flow reserve (CFR), which is an early indicator of endothelial dysfunction in coronary vessels of HD patients. We performed a cross‐sectional study including 71 chronic HD patients and 65 age‐ and sex‐matched healthy controls. Epicardial fat tissue was significantly higher in HD patients when compared to healthy controls (6.53 ± 1.01 mm vs. 5.79 ± 1.06 mm, respectively, P < 0.001). On transthoracic Doppler echocardiography, CFR values were significantly lower in HD patients when compared to healthy controls (1.73 ± 0.11 vs. 2.32 ± 0.28, P < 0.001). Correlation analysis showed CFR values to be inversely correlated with EFT (r = ?0.287, P < 0.05). Multiple linear regression analysis was used to define independent determinants of EFT in HD patients. Artery flow reserve, age, body mass index and total cholesterol levels were independently correlated with EFT thickness. This study demonstrated that EFT was significantly higher among HD patients compared to healthy controls. In addition, this study was the first to demonstrate an inverse correlation between EFT and CFR in this patient population.     

Statin use is associated with lower inflammation and erythropoietin responsiveness index in hemodialysis patients

Patients with end-stage renal disease are prone to inflammation and inflammation is related to erythropoietin-stimulating agent hyporesponsiveness and mortality in this population. Statins have been demonstrated to reduce cardiovascular mortality in selected populations of end-stage renal disease patients. These drugs have pleiotrophic effects such as anti-inflammation. In this retrospective analysis, we determined whether the use of statins improves inflammation and inflammation-related anemia in a cohort of hemodialysis patients. Data were analyzed from Fresenius Medical Care Dialysis Clinics in Turkey between 2005 and 2007. Seventy prevalent hemodialysis patients who were on statins at the start of the study and have been on statins during follow-up (statin users) and 1293 patients who were not on statin at the start of the study and had never been prescribed any lipid-modifying drugs during follow-up (statin nonusers) were included in the study. High-sensitive C-reactive protein levels were significantly decreased in statin users (1.50±1.49 vs. 1.33±1.11 mg/L, P=0.05) compared with nonusers (1.93±3.22 vs. 2.05±2.77 mg/L). Hemoglobin levels and the rate of erythropoietin-stimulating agent users were similar. However, the prescribed erythropoietin-stimulating agent dose (31.6±27.5 vs. 47.3±45.2 U/kg/week, P<0.05) and the erythropoietin response index (2.90±2.73 vs. 4.51±4.48 U/kg/week/Hb, P=0.001) were lower in statin users compared with statin nonusers. On stepwise multiple regression analysis, gender, high-sensitive C-reactive protein, duration of hemodialysis, serum ferritin, and statin use were independent determinants of the erythropoietin responsiveness index. Our results suggest that statin treatment leads to lower inflammation and improves hematopoiesis in hemodialysis patients.     

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.