FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients

Fibroblast growth factor 23 (FGF-23) is elevated in patients with end-stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF-23 (including cardiac troponin T [cTNT]) and determined its association with mortality over 3.5 years of follow-up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF-23 was 1259 (491, 2885) RU/mL. Independent predictors (estimate standard error) of log-transformed FGF-23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF-23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study.     

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.     

Effect of serum FGF‐23, MGP and fetuin‐A on calcium‐phosphate metabolism in maintenance hemodialysis patients

This study was aimed to explore the role of serum fibroblast growth factor (FGF)‐23, matrix Gla protein (MGP) and fetuin‐A in the calcium‐phosphate metabolism and their predicting value in coronary artery calcification in maintenance hemodialysis (MHD) patients. This study included 64 patients who receive hemodialysis in our hospital. The serum FGF‐23, MGP and fetuin‐A were analyzed by enzyme‐linked immunosorbent assay (ELlSA). Coronary artery calcification score (CACS) was evaluated by coronary artery computed tomography scan. The 64 patients (30 males, 34 females, 60.6 ± 11.3 years of age) received an average dialysis vintage of 6.88 ± 2.94 years. We divided the CACS into three levels, and 13 (20.31%), 16 (25%), and 35 (54.69%) exhibited a CACS of 0–100, 100–400, and >400, respectively. Dialysis vintage, serum FGF‐23, fetuin‐A, phosphorus and high‐density lipoprotein‐C levels were identified as independent variables of CACS by stepwise multiple regression analysis. The area under receiver operating characteristic curve indicated that serum FGF‐23 and fetuin‐A were useful for identifying CAC in MHD patients. The cut‐off value corresponding to the highest Youden's index was serum FGF‐23 ≥ 256 pg/mL and fetuin‐A ≤ 85 μg/mL, which was defined as the optimal predictors of CAC. Different combinations of serum FGF‐23 and fetuin‐A in parallel or in series effectively boosted the identification of CAC. The incidence of CAC is high in MHD patients. Serum FGF‐23 and fetuin‐A levels are closely correlated with CAC.     

Clearance of FGF‐23 during continuous renal replacement therapy

FGF‐23 is a 32 kDa protein that is a key regulator of phosphorus and vitamin D metabolism. Emerging evidence also demonstrates that FGF‐23 increases within 24 hours of acute kidney injury (AKI) and may be associated with adverse clinical outcomes. We conducted this study to evaluate FGF23 clearance during continuous veno‐venous hemofiltration (CVVH) in critically ill patients with AKI. We demonstrate that plasma clearance of FGF‐23 during CVVH is ～11 mL/min and the mean sieving coefficient is 0.27 ± 0.1. Future studies will need to clarify FGF‐23's role in adverse outcomes among AKI patients, and whether therapies aimed at reducing FGF‐23 levels may be beneficial.     

Infective spondylodiscitis in patients on high‐flux hemodialysis and on‐line hemodiafiltration

Infective spondylodiscitis (ISD) is a rare but potentially devastating condition in hemodialysis (HD) patients. Reports are limited especially in patients receiving high‐flux HD and hemodiafiltration (HDF). In a retrospective analysis, 13 patients on our maintenance high‐flux HD/HDF program were identified as having has infective spondylodiscitis over a 10‐year period (1997–2006), an incidence of approximately 1 episode every 215 patient‐years. The incidence was around 3 times higher in patients dialyzing with tunnelled central venous catheters (TCVC) than in those with arteriovenous fistulae. Affected patients were elderly (mean age 70 years) and had multiple comorbidities. Access problems, particularly TCVC infection, were common in the months preceding it's onset. Tunnelled central venous catheter removal during these episodes did not necessarily prevent it. Diagnosis was based on a history of back pain, raised C‐reactive protein, positive blood cultures, and characteristic magnetic resonance findings. Many patients were apyrexial and had normal white cell counts. In our patients on high‐flux HD/hemodiafiltration, its incidence appears comparable to that in conventional HD settings. No patients had infection with waterborne organisms. Blood cultures were positive in 77%. Gram‐positive organisms predominated, particularly Staphylococcus aureus. The major route of infection was hematogenous, with the most likely source the venous access. All received antibiotics for 6 to 12 weeks or until death. Only 2 patients underwent surgical drainage. Mortality was high (46%) and predicted by the development of complications, and by pre‐existing cardiovascular comorbidity. Prevention, using strategies to reduce the prevalence of bacteremia, including limiting the use of TCVC, should be an overriding aim.     

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.     

Anti‐inflammatory effects of linagliptin in hemodialysis patients with diabetes

Inflammation and glycemic control are important prognosis‐related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti‐inflammatory effects of monotherapy with linagliptin—a dipeptidase‐4 inhibitor—in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin‐6 (IL‐6), high‐sensitivity C‐reactive protein, GA, blood glucose, and active glucagon‐like peptide‐1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low‐density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL‐6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL‐6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon‐like peptide‐1 levels increased 2.5‐fold during the treatment. Over the 6‐month treatment period, body weight and levels of high‐sensitivity C‐reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti‐inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.     

Clinical and psychosocial factors predicting health‐related quality of life in hemodialysis patients

Many patients with end‐stage renal disease have significant impairment in health‐related quality of life (HRQoL). Most previous studies have focused on clinical factors; however, quality of life can also be affected by psychosocial factors. The aim of this study was to identify the possible predictors of HRQoL among clinical and psychosocial factors in hemodialysis (HD) patients. The study included 101 patients who were undergoing HD. Psychosocial factors were evaluated using the Hospital Anxiety and Depression Scale, Multidimensional Scale of Perceived Social Support, Montreal Cognitive Assessment, and Pittsburgh Sleep Quality Index. We also assessed laboratory and clinical factors, including albumin, Kt/V as a marker of dialysis adequacy, normalized protein catabolic rate, and duration of HD. The Euro Quality of Life Questionnaire 5‐Dimensional Classification (EQ‐5D) was used to evaluate HRQoL. The mean EQ‐5D index score was 0.704 ± 0.199. The following variables showed a significant association with the EQ‐5D index: age (P < 0.001), depression (P < 0.001), anxiety (P < 0.001), support from friends (P < 0.001), cognitive function (P < 0.001), duration of HD (P = 0.034), triglyceride (P = 0.031), total iron‐binding capacity (P = 0.036), and phosphorus (P = 0.037). Multiple regression analysis showed that age (95% confidence interval [CI] ?0.008 to ?0.002), anxiety (95% CI ?0.025 to ?0.009), and support from friends (95% CI 0.004 to 0.018) were independent predictors of impaired HRQoL. This study explored determinants of impaired HRQoL in HD patients. We found that impaired HRQoL was independently associated with age, anxiety, and support from friends. We should consider psychosocial as well as clinical factors when evaluating ways to improve HRQoL in HD patients.     

Perihospitalization patterns of hemoglobin levels and erythropoiesis‐stimulating agent doses in US hemodialysis patients, 1998–2009

Anemia management in hemodialysis patients is of primary importance for clinicians and dialysis providers. Through a retrospective claims analysis, we studied prevalent US hemodialysis patients 1998–2009, and examined patterns of hemoglobin levels and erythropoiesis‐stimulating agent (ESA, epoetin [EPO], and darbepoetin [DPO] ) doses surrounding hospitalization events. Medicare outpatient claims were used to determine monthly ESA doses and associated hemoglobin levels. ESA dose trajectories were defined with repeated measures models incorporating an autoregressive covariance matrix that compared subsequent measurements with the index month of hospitalization, with variance component covariance matrices chosen for pair‐wise comparisons. Regarding prehospitalization hemoglobin levels, a biphasic pattern occurred in both the EPO (1998–2009, n = 161,242) and DPO (2004–2009, n = 4391) populations; levels rose from 1998 to 2004, fell thereafter in the EPO population, and fell after 2006 or 2007 in the DPO population. In the EPO population, the proportions of patients with hemoglobin less than 10 g/dL were 30.1% in 1998, 14.5% in 2004, and 28.3% in 2009; corresponding values for the DPO population were 21.0% in 2004 and 31.6% in 2009. While some degree of year‐to‐year variability occurred, EPO dose trends were less pronounced, with an apparent peak in 2004 followed by a modest decline; trends were similar for DPO. Trends in EPO dose trajectories did not completely parallel those for hemoglobin level; while EPO doses increased yearly up to 2004, doses stabilized, but did not materially decrease after 2004. No definite annual trends for DPO dose trajectories were apparent.     

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.     

Association between antiinflammatory cytokine,IL‐10, and sleep quality in patients on maintenance hemodialysis

Elevated proinflammatory cytokines have been attributed to poor sleep quality in patients receiving hemodialysis. This is the first investigation about the relationship between sleep quality and circulating levels of antiinflammatory markers in these patients. A total of 72 patients who were receiving maintenance hemodialysis were enrolled in this cross‐sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to measure sleep quality. Patients were divided into two groups: good sleepers (PSQI score < 5) and poor sleepers (PSQI score ≥ 5). Assessments were made for serum biochemical parameters (albumin, parathyroid hormone), inflammatory (interleukin [IL]‐6, tumor necrosis factor‐alpha [TNF‐α], and high‐sensitivity c‐reactive protein [hs‐CRP] ) and antiinflammatory (IL‐10) markers. Fifty‐four patients (75%) were classified as poor sleepers. Poor sleepers showed significantly lower levels of serum IL‐10 and higher serum triglyceride and parathyroid hormone concentrations. These patients were more likely to have more comorbidities. The global PSQI score was significantly correlated with serum IL‐10 (p = 0.03) and triglyceride levels (p = 0.01). Multivariate logistic regression analysis showed a direct correlation between PSQI and having comorbidities (p = 0.011, odds ratio [OR] = 3.918; confidence interval 95% [CI] = 2.742–19.031), between PSQI and serum triglyceride (p = 0.027, OR = 1.027 [95% CI = 1.007–1.048] ), and an inverse correlation between PSQI and serum IL‐10 level (p = 0.021, OR = 0.424 [95% CI = 0.195–0.922]). Reduced circulating levels of the antiinflammatory cytokine IL‐10 were significantly associated with poor sleep quality in hemodialysis patients. Factors including serum IL‐10 and triglyceride concentrations and having comorbidities may predict patients prone to poor sleep quality.     

Association of bioimpedance spectroscopy‐based volume estimation with postdialysis hypotension in patients receiving hemodialysis

Clinical examination to determine the dry weight of patients on hemodialysis (HD) has been problematic, with studies showing discordance between physician assessment and objective measures of volume status.We studied the association between predialysis bioimpedance spectroscopy (BIS)‐based estimates of fluid overload and postdialysis hypotension in 635 patients in the United States Renal Data System ACTIVE/ADIPOSE (A Cohort study To Investigate the Value of Exercise/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD) study receiving HD in 2009–2011. We recorded predialysis and postdialysis weight and blood pressures over 3 consecutive HD sessions and performed BIS before a single session. Using a previously reported method of estimating normohydration weight, we estimated postdialysis fluid overload (FO_post) in liters. We used logistic regression with extracellular water/total body water (ECW/TBW) or estimated FO_post as the primary predictor and 1 or more postdialysis systolic blood pressures less than 110 mmHg as the dependent variable. Models were adjusted for age, sex, race, ultrafiltration rate per kilogram of body weight, end‐stage renal disease vintage, diabetes mellitus, heart failure, and albumin. Higher ECW/TBW was associated with lower odds of postdialysis hypotension (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15–0.84 per 0.1, P = 0.02). Every liter of FO_post was associated with lower adjusted odds of postdialysis hypotension (OR 0.86, 95% CI 0.79–0.95, P = 0.003). Prospective studies are needed to determine whether this application of BIS could improve current clinical efforts to minimize episodes of postdialysis hypotension without leading to volume overload.