Mortality In CKD Patients Research Articles

Prognostic value of left ventricular global longitudinal strain in chronic kidney disease patients: a systematic review and meta-analysis.

The objective of this meta-analysis was to evaluate whether left ventricular global longitudinal strain (GLS) is a potential marker of predicting adverse outcomes in CKD patients. CKD is a growing health burden currently affecting 10-15% of adults worldwide, and disproportionally increasing propensity to develop cardiovascular diseases and events. Although obtained from several relatively small studies, the evidence supporting the prognostic value of GLS in patients with CKD is still building. We conducted a Medline literature research using electronic databases (PubMed, Ovid, Embase and Web of Science) to identify relevant studies reporting the association between GLS and the primary outcomes, including all-cause mortality, major cardiac events (MCE), and cardiovascular mortality in CKD patients. Sensitivity analysis and subgroup analysis were performed to find the origin of heterogeneity. A total of 11 observational studies with 2167 patients with CKD were enrolled. In patients with CKD, GLS was associated with all-cause mortality (HR: 1.09, 95% CI 1.06-1.12) with no heterogeneity among the studies (I2 = 46.5%, P = 0.06). In addition, GLS was associated with MCE and cardiovascular mortality with no heterogeneity (HR 1.16, 95% CI 1.11-1.22; HR 1.18, 95% CI 1.12-1.24, respectively). Overall, GLS was also associated with combined adverse events in CKD patients (HR 1.09, 95% CI 1.07-1.12) with moderate heterogeneity (I2 = 51.2%, P = 0.025). Our meta-analysis demonstrates that GLS is associated with all-cause mortality, MCE, cardiovascular mortality, and combined adverse events in CKD patients.

P0892PROFILE OF FIBROBLAST GROWTH FACTOR 23 IN CHRONIC KIDNEY DISEASE IN INDIAN POPULATION

Abstract Background Chronic kidney disease (CKD) is a complex disease. Recent discovery that fibroblast growth factor 23 (FGF23) play a major role in development of CKD related bone mineral disorder (BMD) indicated a paradigm shift in our understanding of CKD–BMD. Recent research indicates that higher levels of FGF23 are associated with rapid progression of CKD and higher mortality in CKD patients. It is found that FGF23 level in blood is elevated significantly early in the course of CKD, even before a rise in parathyroid hormone (PTH) level which could contribute directly to tissue injury in heart, blood vessels and kidneys, apart from just being a marker of adverse outcome, and this needs further research. The dietary habits, especially phosphate intake is likely to be different in Indian CKD population compared to western CKD population. Aims and objectives Method This is an observational study on 75 consecutive patients visiting Apollo hospital nephrology OPD in Chennai, India from June 2015 to Nov 2015. FGF23 level were determined simultaneously with serum creatinine, albumin, Vitamin D level, serum calcium, phosphate and serum PTH level done on enrolment. Serum samples when not immediately processed, were stored at -20oC. Results The age of the patient population varied from 19 to 80 years, mean 53.33 yrs with a SD of 15.49. 57(76%) were males and 18(24%) females. In our study, 46.7%patients belonged to CKD stage 4 while CKD stage 3 and 5 had 25.3% and 28% among the study population respectively. The mean FGF23 level in study population was 154.82pg/ml (Normal range 11-48.6 pg/ml). Though the FGF23 values in stage 5 CKD were higher than those in stage 3 and 4 CKD, the difference was not statistically significant (p=0.74). In our study, 63 patients (84%) had high FGF23 level and 56(74.7%) patients were already on phosphate binding drugs and PTH suppressing drugs like vit D or cinacalcet for at least 2 months. 48(85.7%) patients of those on medications and 15 (79%) of those not on medications had high FGF23 level (P value -0.48, Yates P value-0.739). In our study, PTH had an inverse correlation with eGFR and the association was statistically significant (P value 0.001). Serum Phosphorus level had an inverse correlation with eGFR and the association was statistically significant (P value 0.0001). Correlation of FGF23 values with eGFR was negative which was expected as the FGF23 levels increased with decreasing eGFR, but the association was not statistically significant. Similar results were obtained when FGF23 values were studied for association with serum calcium levels where the P value was 0.359 which was not statistically significant. Similarly, vit D levels had a negative association with P value of 0.077 and PTH levels had a positive association with P value of 0.987 (No statistical significance). Similarly, FGF23 levels and phosphate levels had a positive association without statistical significance(p= 0.224). Conclusion In conclusion, our data indicate that the rise of serum FGF23 levels in progressive Indian CKD patients is a common finding in CKD stage 3 and beyond.

P1070ONLINE HIGH-VOLUME HEMODIAFILTRATION REDUCES PRE-DIALYSIS LEVELS OF INDOXYL SULFATE COMPARED TO HIGH-FLUX HEMODIALYSIS: RESULTS FROM HDFIT MULTICENTRIC RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims Online High-Volume Hemodiafiltration (OL-HDF) combines convective and diffusive clearances and is associated with better outcomes compared to standard hemodialysis (HD). Although HDF has been shown to improve the clearance and pre-dialysis concentration of middle size uremic toxins, little is known about its effect on concentration of protein-bound uremic toxins (PBUT), particularly in comparison to high-flux HD. Here, we investigated whether high-volume post-dilution OL-HDF impacts pre-dialysis plasma levels of PBUT indoxyl sulfate (IxS), p-cresyl sulfate (pCS) and indole 3-acetic acid (IAA) compared to high-flux HD over time, since accumulation of these PBUT has been associated with increased overall mortality of CKD patients. Method This is post hoc analysis of the multicentric randomized controlled trial (RCT) studying the impact of post-dilution high-volume OL-HDF versus high-flux HD on measured physical activity (HDFit - clinicalTrials.gov: NCT02787161), which included clinically stable HD patients with a vintage >3 to <24 months. Total plasma levels of IxS, pCS and IAA were determined by high performance liquid chromatography (HPLC) with fluorescence detection at baseline, 3 and 6 months. The difference between HDF and HD in respect to changes in the PBUT concentrations during the follow up, analyzed using linear mixed effect models, was compared. Results are presented as mean differences between groups in the change from baseline along with 95% confidence intervals (CI). Results 193 patients (mean age 53 years old, 70% males and 60% white – no differences between groups) were analyzed. There were no differences between HD and OL-HDF groups regarding clinical and biochemical characteristics at the baseline. In the OL-HDF group, 99% of patients achieved a convective volume higher than 22 L and both groups had similar dialysis session duration and blood flows throughout the follow up. The mean differences (95% CI) in concentrations over time for PBUTs among HDF and HD groups are shown in Figure 1. HDF group presented a significantly lower trajectory of IxS levels and a lower trajectory of pCS levels than HD group. Trajectories of IAA levels were not different between groups. Conclusion OL-HDF reduced the pre-dialysis concentration of IxS and pCS through 6 months-period compared to high-flux HD.

High alkaline phosphatase and low intact parathyroid hormone associate with worse clinical outcome in peritoneal dialysis patients.

Alkaline phosphatase (ALP) is used as a biomarker to monitor the chronic kidney disease-mineral bone disorder (CKD-MBD) and high levels of parathyroid hormone (PTH) that were reported to be related to increased mortality in CKD patients. Therefore, we conducted this longitudinal cohort study to evaluate the relations between ALP and intact PTH (iPTH) and the associations with all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients. In 1276 incident PD patients (median age 50 years, 56% males), baseline serum ALP, iPTH, and metabolic biomarkers potentially linked to CKD-MBD were analyzed in relation to mortality during follow-up period of up to 60 months. All-cause and cardiovascular mortality risk of ALP and iPTH were analyzed with competing-risks regression models with transplantation as competing risk adjusting for all covariates. After adjustments for confounders by logistic regression model, older age, higher change level to levels of iPTH, S-albumin, calcium, alanine transaminase (ALT), and lower level of phosphorus were associated with higher ALP level (>79 U/L), and female gender, non-diabetes mellitus, younger age, lower calcium, higher ALT, total bilirubin, phosphorus, and ALP were associated with higher iPTH level (>300 pg/mL). During 60 months (median 44 months) of follow-up, the all-cause mortality rate was 16%, and 91 (46%) of the 199 deaths were caused by cardiovascular disease. In competing-risks regression analysis, "high ALP + low iPTH" was independently associated with all-cause and cardiovascular mortality after adjustment for age, gender, presence of diabetes, and cardiovascular disease, the calendar year of recruitment and vitamin D therapy in PD patients. The subhazard ratio (sHR) of group "high ALP + low iPTH" was 1.96 times and 3.35 times higher than sHR of group "low ALP + high iPTH" for all-cause mortality and cardiovascular mortality, respectively. The combination of high ALP and low iPTH was independently associated with increased all-cause and cardiovascular mortality in PD patients, suggesting that ALP and iPTH have the potential to predict clinical outcomes and might be useful risk assessment tools in PD patients. Further studies exploring the observed association between combination of ALP with iPTH and mortality are warranted.

Long-term outcomes of dialysis in patients with chronic kidney disease and new-onset atrial fibrillation: A population-based cohort study.

BackgroundChronic kidney disease (CKD) is associated with substantial cardiovascular morbidity. Atrial fibrillation (AF) is a prevalent arrhythmia that increases the risk of both stroke and cardiovascular mortality. Information about the mortality risk among patients with advanced CKD and new-onset AF (NAF) in the presence and absence of dialysis is important. However, the association between advanced CKD and NAF in patients with and without dialysis is unclear.ObjectiveTo investigate long-term outcomes of the association between advanced CKD and NAF in patients with and without dialysis.MethodsWe conducted a nested case-control study based on the National Health Insurance Program in Taiwan. Each participant aged 20 years and older who had CKD with dialysis from 2000 to 2013 was assigned to the dialysis group, whereas sex-, age-, CKD duration-, and index date-matched participants without dialysis were randomly selected and assigned to the non-dialysis group. We used the Cox regression model to estimate the hazard ratio (HR) with the 95% confidence interval (CI) for mortality in CKD patients with combined dialysis and NAF. Patients with neither NAF nor dialysis served as the reference group.ResultsWe identified 3,673 dialysis cases and 7,346 Non-dialysis matched controls for enrolment in the study. The crude mortality rates were 3.3 (95% CI: 3.1–3.5), 10.98 (95% CI: 9.3–13.0), 9.2 (95% CI: 8.7–10.0), and 18.0 (95% CI: 15.4–21.2) in the [Non-dialysis, non-NAF], [Non-dialysis, NAF], [Dialysis, non-NAF], and [Dialysis, NAF] groups, respectively. After adjustment for age, gender, and co-morbidities, the aHRs were 2.0 (95% CI: 1.7–2.3), 2.7 (95% CI: 2.5–2.9), and 3.5 (95% CI: 2.9–4.1) in the [Non-Dialysis, NAF], [Dialysis, non-NAF], and [Dialysis, NAF] groups compared with the [Non-Dialysis, non-NAF] group, respectively. The Kaplan-Meier survival curves showed the highest mortality risk in the [Dialysis, NAF] group among the study groups. Patients with concurrent peritoneal dialysis and AF had the highest mortality risk: aHR = 4.3 (95% CI: 2.3–8.0). However, there was a relatively lower effect of NAF on mortality in patients on dialysis than in patients who were not.ConclusionsPatients with advanced CKD and NAF had a significantly increased risk of mortality. Dialysis is not risky for patients with concurrent CKD and NAF. Dialysis offers a sufficient survival benefit to be considered as a standard treatment, as indicated by the superior physical status of patients on dialysis.

Parathyroid Hormone Measurement in Chronic Kidney Disease: From Basics to Clinical Implications.

Accurate measurement of parathyroid hormone (PTH) is crucial for therapeutic decision-making in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD). The second-generation PTH assays, often referred to as “intact PTH” assays, are the current standard and most available assays in clinical practice. However, intact PTH assays measure both full-length biologically active PTH and heterogeneous PTH fragments in the circulation, providing the equivocal value of PTH measurement in patients with CKD-MBD. Due to the variability of PTH assays, preanalytical sample errors, and the phenomenon of end-organ PTH hyporesponsiveness, current CKD-MBD guidelines recommend a wide range for serum PTH targets (2–9 the upper normal limit of the intact PTH assay) in dialysis patients to diminish the risk of developing adynamic bone disease. Nevertheless, a sizeable proportion of CKD patients still experience renal osteodystrophy despite having serum PTH levels within the recommended range. The primary cause of this inconsistency is the analytical interference of various PTH fragments and oxidized PTH forms that considerably accumulate in CKD patients. Therefore, a new mass spectrometry-based assay, which is capable of specifically measuring the whole spectra of PTH fragments, can potentially improve diagnostic accuracy for renal osteodystrophy. However, the effects of different PTH fragments on bone metabolism, vascular calcification, and mortality in CKD patients warrant further research.

Serum C-Reactive Protein in chronic kidney disease patients undergoing hemodialysis and correlation with dialytic age

Mortality in CKD patients undergoing hemodialysis considerably high. Previous study showed that mortality in patients undergoing hemodialysis was strongly correlated with chronic inflammation. The current study examined whether the serum c-reative protein concentration (hsCRP) changed from pre- to post-dialysis. In addition, the current study also investigated the correlation between dialysis age and hsCRP in chronic kidney disease patients undergoing hemodialysis. The study was a case-series study of 30 patients with hemodialysis. The patients were devided into three group based on dialysis age. Hemodialysis had been undergone for 4 hours, using hemoflow F8HPS, polysulfone synthetic dialysis membrane, and bicarbonate dialysis fluid. The primary outcome was serum concentration of high-sensitivity C-reactive protein (hsCRP), which was assessed in the pre-and-post dialysis, measured using chemiluminescent method. Dialysis does increased the hsCRP post-dialysis. It resulted in significant (p<0.05) increment of serum hsCRP concentration, pre-dialysis 1.04±0.90 mg/L compared to post-dialysis mean value 1.84±2.01 mg/dL. There was no significant difference among serum hsCRP concentration mean value among group of dialysis age. The correlations between various measurement of serum hsCRP concentration and dialysis age were statistically insignificant.

Asymptomatic hyperuricemia and cardiovascular mortality in patients with chronic kidney disease who progress to hemodialysis.

Hyperuricemia has been associated with higher mortality in the general population, but less is known about CKD patients. The aim of our study was to determine the impact of elevated serum uric acid on cardiovascular mortality of CKD patients who later progress to hemodialysis. In this retrospective study, 120 CKD patients (entire population of patients with ESKD on January 1st, 2012) were observed from their first visit at the Nephrology outpatient clinic, while transitioning to hemodialysis, and until their death or January 1, 2016. After non-cardiovascular death exclusion, 83 CKD patients (33 female, 50 male) were left for further analysis. The average time of observation was 8.8 ± 4.2years. Serum uric acid was measured regularly (every 3months). No patients were treated for hyperuricemia. Mean uric acid of 420µmol/L was set as a cut-off between normouricemic and hyperuricemic patients as per the laboratory's reference values. Survival rates were analyzed using Kaplan-Meier survival curves. Three Cox regression models were used to assess the influence of uric acid on survival. Mean uric acid was 379.8 ± 71.6µmol/L (range 220-574). Sixty-three (75.9%) patients were normouricemic and 20 (24.1%) were hyperuricemic. Cholesterol was the only variable to show statistically significant difference (p = 0.004) between the groups. Bivariate analysis revealed an association between death and age, hyperuricemia, arterial hypertension, and history of cardiovascular disease. Kaplan-Meier survival analysis showed higher risk of cardiovascular death for hyperuricemic patients (log rank test; p < 0.0005). In Cox regression models, hyperuricemia remained a predictor of cardiovascular mortality (SE = 0.500, Exp(B) = 14.120, 95% CI 5.297-37.640) in our patients next to age and arterial hypertension. The results indicate an association between hyperuricemia and cardiovascular mortality inCKD patients who transition to hemodialysis.

Neutrophil-to-lymphocyte ratio and incident end-stage renal disease in Chinese patients with chronic kidney disease: results from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE)

BackgroundChronic kidney disease (CKD) leads to end-stage renal failure and cardiovascular events. An attribute to these progressions is abnormalities in inflammation, which can be evaluated using the neutrophil-to-lymphocyte ratio (NLR). We aimed to investigate the association of NLR with the progression of end stage of renal disease (ESRD), cardiovascular disease (CVD) and all-cause mortality in Chinese patients with stages 1–4 CKD.MethodsPatients with stages 1–4 CKD (18–74 years of age) were recruited at 39 centers in 28 cities across 22 provinces in China since 2011. A total of 938 patients with complete NLR and other relevant clinical variables were included in the current analysis. Cox regression analysis was used to estimate the association between NLR and the outcomes including ESRD, CVD events or all-cause mortality.ResultsBaseline NLR was related to age, hypertension, serum triglycerides, total serum cholesterol, CVD history, urine albumin to creatinine ratio (ACR), chronic kidney disease-mineral and bone disorder (CKD-MBD), hyperlipidemia rate, diabetes, and estimated glomerular filtration rate (eGFR). The study duration was 4.55 years (IQR 3.52–5.28). Cox regression analysis revealed an association of NLR and the risk of ESRD only in patients with stage 4 CKD. We did not observe any significant associations between abnormal NLR and the risk of either CVD or all-cause mortality in CKD patients in general and CKD patients grouped according to the disease stages in particular.ConclusionOur results suggest that NLR is associated with the risk of ESRD in Chinese patients with stage 4 CKD. NLR can be used in risk assessment for ESRD among patients with advanced CKD; this application is appealing considering NLR being a routine test.Trial registration ClinicalTrials.gov Identifier NCT03041987. Registered January 1, 2012. (retrospectively registered) (https://www.clinicaltrials.gov/ct2/show/NCT03041987?term=Chinese+Cohort+Study+of+Chronic+Kidney+Disease+%28C-STRIDE%29&rank=1)

Elevated Circulating Osteoprotegerin Levels in the Plasma of Hemodialyzed Patients With Severe Artery Calcification.

We studied the correlations between circulating osteoprotegerin (OPG) level and radial artery calcification (RAC) assessed histologically and carotid artery intima-media thickness (CCA-IMT). Moreover, we studied the relationship between OPG levels and all-cause and cardiovascular (CV) mortality during a 5-year observation period. The study comprised 59 CKD patients (36 hemodialyzed (HD), 23 predialysis). The biochemical parameters included: creatinine, calcium, phosphate, intact parathormone, C-reactive protein, interleukin-6, tumor necrosis factor receptor II (TNFRII), transforming growth factor-β, hepatocyte growth factor, fibroblast growth factor 23, osteonectin (ON), osteopontin, osteoprotegerin, and osteocalcin. CCA-IMT and the presence of atherosclerotic plaques was assessed by ultrasound. Fragments of radial artery obtained during creation of HD access were prepared for microscopy and stained for calcifications with alizarin red. RAC was detected in 34 patients (58%). In multiple regression adjusted for dialysis status, TNFRII, ON and Framingham risk score (FRS) were identified as the independent predictors of OPG. Serum OPG above the median value of 7.55 pmol/L significantly predicted the presence of RAC in simple logistic regression (OR 5.33; 95%CI 1.39-20.4; P = 0.012) and in multiple logistic regression adjusted for FRS, dialysis status and CCA-IMT values (OR 6.56; 95%CI 1.06-40.6; P = 0.036). OPG levels above the median were associated with higher CCA-IMT values (1.02 ± 0.10 vs. 0.86 ± 0.13; P < 0.001) and predicted the presence of atherosclerotic plaques in carotid artery (OR 14.4; 95%CI 2.84-72.9; P < 0.001), independently of FRS, dialysis status and RAC. In this study, elevated serum OPG levels correlated with higher CCA-IMT, the presence of atherosclerotic plaques and the severity of the RAC independently of each other. During follow-up, 25 patients (42%) died, including 21 due to CV causes. In multiple Cox regression, OPG above the median predicted overall survival independently of dialysis status, Framingham risk score, CCA-IMT above the median value, and the presence of atherosclerotic plaques in CCA, but not independently of RAC. We postulate that circulating OPG may play a dual role as a marker for both medial arterial calcification and atherosclerosis, hence it seems to be a valuable tool for assessing CV risk in patients with CKD. OPG might be an early indicator of all-cause mortality in CKD patients with advanced medial arterial calcification.

2297 The direct effect of trimethylamine N-oxide (TMAO) on cardiac muscle contractile mechanics

OBJECTIVES/SPECIFIC AIMS: The objective of this study was to determine if trimethylamine N-oxide (TMAO) alone could acutely alter cardiac contractile function on a beat-to-beat basis. METHODS/STUDY POPULATION: CD1 adult mouse hearts were extracted, attached to a force transducer, oxygenated, and paced within an organ bath. Changes in contractility were measured after pipetting or reverse perfusing TMAO through the aorta via a modified Langendorff apparatus to facilitate TMAO delivery into the myocardium. To determine if our findings translated to the human heart, we performed contractility experiments using human right atrial appendage biopsy tissue retrieved during cardiopulmonary bypass procedures. To investigate whether TMAO alters contractile rate, in a separate series of experiments, the atria and sinoatrial node of isolated hearts were kept intact to allow for spontaneous beating without artificial pacing and were treated with TMAO or vehicle. In addition, intracellular calcium measurements were performed on spontaneously beating embryonic rat cardiomyocytes after TMAO or vehicle treatment. RESULTS/ANTICIPATED RESULTS: We found acute exposure to TMAO, diluted into the organ bath, increased average contraction amplitude 20% and 41% at 300 µM and 3000 µM, respectively (p&lt;0.05, n=6). Langendorff reverse perfusion of mouse hearts ex vivo with 300 µM TMAO generated an even greater response than nonperfusion peripheral exposure and increased isometric force 32% (p&lt;0.05, n=3). Consistent with what we observed in mouse hearts, incubation of human atrial muscle tissue with TMAO at 3000 µM increased isometric tension 31% compared with vehicle (p&lt;0.05, n=4). TMAO treatment (3000 µM) also increased average beating frequency of ex vivo mouse hearts by 27% compared with vehicle (p&lt;0.05, n=3) and increased the spontaneous beating frequency of primary rat cardiomyocytes by 13% compared with vehicle treatment (p&lt;0.05, n=4). DISCUSSION/SIGNIFICANCE OF IMPACT: TMAO, at pathological concentrations, directly increases the force and rate of cardiac contractility. Initially, these inotropic and chronotropic effects may be adaptive during CKD; however, chronic increases in isometric tension and beating frequency can promote cardiac remodeling and heart failure. Further translational studies are needed to understand the intricate relationship between the microbiome, kidneys, and heart and to examine if TMAO represents a therapeutic target for reducing cardiovascular mortality in CKD patients.

Fibroblast Growth Factor-23: A Novel Biomarker for Cardiovascular Disease in Chronic Kidney Disease Patients.

Fibroblast Growth Factor (FGF)-23 increase is considered one of the earliest biochemical abnormalities in chronic kidney disease-mineral bone disorder (CKD-MBD). Furthermore, accumulating data have provided evidence of a link between increased FGF-23 levels and cardiovascular morbidity and mortality in CKD patients as well as in several other populations including cardiology patients and general population. The cellular and molecular mechanisms underlying the deleterious effect of FGF-23 on the cardiovascular system are not yet completely defined and are the focus of intense research. However, animal and human studies have demonstrated important actions of FGF-23 in the heart and vessels through which could promote the development of cardiovascular complications in uremia. Moreover, significant interactions have been reported between FGF-23 and other well recognized cardiovascular risk factors such as renin-angiotensin system and inflammation which could account, at least in part, for the observed associations between FGF-23 and adverse clinical outcomes. Further studies are needed to clarify the mechanisms responsible for the pleiotropic actions of FGF-23 and moreover to identify whether it is a modifiable risk factor and a potential target of therapeutic interventions which could probably help to reduce the unacceptably high cardiovascular morbidity and mortality of CKD patients.

Transcriptomic profiling of tight junctions dysfunction in endothelial cells and epithelial cells in renal failure

BackgroundChronic kidney disease (CKD) has been recently identified as a significant risk factor for vascular diseases such as cerebral small‐vessel diseases (CSVD), and up to 50% of deaths in patients with end‐stage renal failure are due to cardiovascular disease (CVD). There is a 10 to 30‐fold higher cardiovascular mortality in CKD patients than in the age‐matched general population, despite adjustment for classical cardiovascular risk factors. Tight junctions (TJ) are specialized membrane domains that play multiple functions in kidney epithelial cells, including the maintenance of cellular polarity and work as a primary regulatory barrier particularly in cerebral microvasculatures and kideny. Studies indicate emerging links between TJ dysfunction and the development of kidney disease and following CVD and CSVD. The goal of this study was to elucidate the transcription profiling related to TJ dysfunction and its role in preventing renal failure through the regulation of TJs.MethodsTo profile the exhaustive signatures in TJ dysfunction human endothelium and epithelium, we performed whole transcriptome analysis to explore novel genes in primary human aortic endothelial cells (HAECs), human brain microvascular endothelial cells (HBMECs) and immortalized human kidney proximal tubule epithelial cells (HK‐2) using our CKD models, in vitro. In addition, we analyzed human arteries from CVD and CKD patients. Total RNA was extracted using the Nucleospin RNA isolation kit (Clontech). cDNA was synthesized and fragmented using SMART‐seq2 and Nextera XT (Illumina), respectively to generate libraries for sequencing on Hi‐seq 2000 (Illumina). The abundancies of each gene, (FPKM, fragment per kilo‐base exon per million mapped reads), were estimated using RNA‐seq by Expectation Maximization (RSEM). Log 2 transformed FPKM were normalized by quantile normalization, which were then subjected to differential expression analysis to calculate significant fold change (Gene‐E, Broad Institute). Gene selections were performed by the combinations of fold‐changes on log 2 ratio, and p value &lt; 0.05. Data were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www.genome.jp/kegg/) and The Database for Annotation, Visualization and Integrated Discovery v6.7 (DAVID, http://david.abcc.ncifcrf.gov/).ResultsPathway analysis among the differentially expressed genes in comparing normal samples to CKD groups revealed that these genes are mainly involved in cytoskeleton formation, cell metabolic, proliferation, and apoptosis processes. Among these TJ dysfunction related genes, heat shock protein 70 families (HSPA1, HSPB7), SYT, SNAP25, and aryl hydrocarbon receptor nuclear translocator (ARNT) in HIF‐1signaling pathways were identified. In addition, MT‐RNR1 and cannabinoid receptor 1 were also detected that are involved in ATP production in the mitochondria and as co‐chaperone for HSP70.ConclusionWe have identified a group of genes differentially expressed in healthy and CKD endothelial cells and epithelial cells. Our data contribute to our understanding of the direct effects in the presence of TJ dysfunction at endothelial cells and epithelial cells. This gene set may have pathophysiological significance and may serve to inform rational development of therapeutic strategies to prevent CVD adverse effects in CKD patients.

Coronary artery calcium density for the prediction of mortality in CKD patients: One size does not fit all

Coronary artery calcium density for the prediction of mortality in CKD patients: One size does not fit all

Transcriptomic profiling in cardiovascular disease with renal failure in human

BackgroundChronic kidney disease (CKD) is a major health issue globally; it affects 50 million people worldwide and over 26 million Adults in the United States. Studies indicate that up to 50% of deaths in patients with ens‐stage renal failure are due to cardiovascular disease (CVD) and there is a 10 to 30‐fold higher cardiovascular mortality in CKD patients than in the age‐matched general population, despite adjustment for classical cardiovascular risk factors. To profile the exhaustive signatures in calcifited human endotelials, we performed whole transcriptome analysis to explore novel genes in primary human aortic endothelial cells (HAECs) and human brain microvascular endothelial cells (HBMECs).MethodsHAECs and HBECs were treated with calcification medium, and total RNA was extracted using the Nucleospin RNA isolation kit (Clontech). cDNA was synthesized and fragmented using SMART‐seq2 and Nextera XT (Illumina), respectively to generate libraries for sequencing on Hi‐seq 2000 (Illumina). Five million single‐ended raw reads from each sample were mapped to the human reference genome consortium GRCh38 by Burrows‐Wheeler Aligner (BWA); the abundancies of each gene, (FPKM, fragment per kilo‐base exon per million mapped reads), were estimated using RNA‐seq by Expectation Maximization (RSEM). Log 2 transformed FPKM were normalized by quantile normalization, which were then subjected to differential expression analysis to calculate significant fold change (Gene‐E, Broad Institute). Gene selections were performed by the combinations of fold‐changes on log 2 ratio, and p value &lt; 0.05. Data were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www.genome.jp/kegg/) and The Database for Annotation, Visualization and Integrated Discovery v6.7 (DAVID, http://david.abcc.ncifcrf.gov/).ResultsPathway analysis among the top 500 up‐regulated genes in comparing untreated HAECs and HBMECs to those treated with calcification medium revealed that these genes are mainly involved in cell metabolic, proliferation, and apoptosis processes. Among these genes, they were found to play roles in cell cycle regulation, apoptosis, oxidative stress, and stress resistance such as heat shock protein 70 families (HSPA1, HSPA5, and HSP40), NF‐kappa‐B inhibitor alpha, and aryl hydrocarbon receptor nuclear translocator (ARNT) in HIF‐1, NF‐kappa B and c‐AMP signaling pathways. In addition, MT‐RNR1 and cannabinoid receptor 1 are also detected that involved in amount of ATP produced in mitochondria and co‐chaperone of HSP70.ConclusionWe have identified a group of genes differentially expressed in healthy and calcified endothelial cells. Our data contribute to our understanding of the direct effects in the presence of hyperphosphatemia and hypocalcemia at endothelial cells. This gene set may have pathophysiological significance and may serve to inform rational development of therapeutic strategies to prevent CVD adverse effects in CKD patients.

Vascular Calcification - Pathological Mechanism and Clinical Application - . Vascular calcification in chronic kidney disease-mineral and bone disorder (CKD-MBD)

Chronic kidney disease-mineral and bone disorder (CKD-MBD), is sequential pathophysiology that starts in the very early stages of CKD. Three major aspects of CKD-MBD are laboratory abnormalities, bone abnormalities and vascular calcification. In dialysis patients, the prevalence of death due to cardiovascular disease accounts for more than 40% of all-cause mortality. Therefore, arteriosclerosis with vascular calcification may be an important pathophysiological mechanism in the development of cardiovascular disease. Vascular calcification is known to be an important risk factor influencing mortality in CKD patients. A number of studies have suggested a close association between serum FGF23 concentration and the risks of mortality, cardiovascular disease vascular calcification as well as CKD progression. Renal insufficiency leads to decline in klotho level and impaired phosphate excretion. However serum phosphate levels are maintained in the normal range by up regulation of FGF23 and PTH in early CKD stage. Early treatment intervention is necessary to improve the prognosis of the CKD patient.

Multidisciplinary Predialysis Education Reduced the Inpatient and Total Medical Costs of the First 6 Months of Dialysis in Incident Hemodialysis Patients

BackgroundThe multidisciplinary pre-dialysis education (MPE) retards renal progression, reduce incidence of dialysis and mortality of CKD patients. However, the financial benefit of this intervention on patients starting hemodialysis has not yet been evaluated in prospective and randomized trial.MethodsWe studied the medical expenditure and utilization incurred in the first 6 months of dialysis initiation in 425 incident hemodialysis patients who were randomized into MPE and non-MPE groups before reaching end-stage renal disease. The content of the MPE was standardized in accordance with the National Kidney Foundation Dialysis Outcomes Quality Initiative guidelines.ResultsThe mean age of study patients was 63.8±13.2 years, and 221 (49.7%) of them were men. The mean serum creatinine level and estimated glomerular filtration rate was 6.1±4.0 mg/dL and 7.6±2.9 mL⋅min−1⋅1.73 m−2, respectively, at dialysis initiation. MPE patients tended to have lower total medical cost in the first 6 months after hemodialysis initiation (9147.6±0.1 USD/patient vs. 11190.6±0.1 USD/patient, p = 0.003), fewer in numbers [0 (1) vs. 1 (2), p<0.001] and length of hospitalization [0 (15) vs. 8 (27) days, p<0.001], and also lower inpatient cost [0 (2617.4) vs. 1559,4 (5019.6) USD/patient, p<0.001] than non-MPE patients, principally owing to reduced cardiovascular hospitalization and vascular access–related surgeries. The decreased inpatient and total medical cost associated with MPE were independent of patients' demographic characteristics, concomitant disease, baseline biochemistry and use of double-lumen catheter at initiation of hemodialysis.ConclusionsParticipation of multidisciplinary education in pre-dialysis period was independently associated with reduction in the inpatient and total medical expenditures of the first 6 months post-dialysis owing to decreased inpatient service utilization secondary to cardiovascular causes and vascular access–related surgeries.Trial RegistrationClinicalTrials.gov NCT00644046

Preface

The 58th Annual Meeting of the Japanese Society for Dialysis Therapy (JSDT) was held in Fukuoka from 20 to 23 June 2013, at the commercial and industrial centre of Kyushu Island (hosted by President, Hideki Hirakata MD, PhD, Fukuoka Red Cross Hospital). Over 3600 papers were presented in this meeting. Among them, CKD-MBD, which plays a critical role in the pathogenesis of cardiovascular disease among the dialysis population, was a current and noteworthy topic. At this annual JSDT meeting, many papers on phosphate (P) management were presented. It has been reported that excessive P load, along with decline in kidney function constitutes the bedrock of CKD-MBD. Therefore, P management is an issue of burning concern in clinical practice. In Japan, calcium (Ca) carbonate and three non-Ca-based phosphate binders, lanthanum carbonate (LC), sevelamer hydrochloride (SH), and bixalomer, are clinically available as P binders. Although Ca carbonate is cheap and well-tolerable, it has an increased risk for Ca overload, which might lead to vascular calcification and higher cardiovascular morbidity and mortality in CKD patients. Recently, a meta-analysis on 11 randomized controlled trials (4622 patients) that compared outcomes between CKD patients with Ca-based P binders and those with non-Ca-based binders demonstrates that all-cause mortality was significantly lower in patients with non-Ca-based P binders than those with Ca-based P binders (risk ratio 0.78, 95%CI 0.61–0.98) 1. The LC chewable tablet has been clinically available since 2004. In a randomized crossover study in hemodialysis patients, LC and SH improved serum P control to a similar extent without Ca overload 2. In treatment-related adverse events, constipation was significantly lower during LC treatment as compared with SH treatment. However, the chewable tablet formulation of LC could not exert its clinical effect without sufficient mastication. Recently, the granule formation of LC, which is likely to be more effective in reducing serum P concentrations even in patients with masticatory dysfunction, has become clinically available. This issue of the Therapeutic Apheresis and Dialysis Supplements contains six papers concerning recent progress in P management by LC treatment, which were presented in the 58th JSDT meeting. We are convinced that these papers will provide useful suggestions for P management in clinical settings. Conflict of interest: No potential conflict of interests.

Serum Osteoprotegerin level and the extent of cardiovascular calcification in haemodialysis patients

Background Cardiovascular disease is the leading cause of death in chronic kidney disease and hemodialysis population. The mechanisms of vascular damage in this population are not fully explained by traditional cardiovascular risk factor. Osteoprotegerin (OPG) has been shown as an independent predictor of mortality in CKD patients and proposed as a potential biomarker for vascular calcification. Methods A total of 80 subjects (60 hemodialysis patients and 20-age and sex matched healthy control) were studied. Vascular and valvular calcification was measured using plain X-ray and transthoracic echocardiography. Circulating OPG was measured in addition to standard clinical biochemical analysis. Results Osteoprotegerin level showed significant difference between hemodialysis (5.4 ± 2.8 pmol/l) and controls (0.96 ± 0.41 pmol/l) P p = 0.003 and overall valvular calcification with p value Conclusion There is strong positive relationship between osteoprotegerin and both vascular and valvular calcification in hemodialysis patients. This positive correlation may open the gate for routine estimation of this agent as a surrogate marker of cardiovascular calcification in hemodialysis patients.

Effect of Hemoglobin Target on Progression of Chronic Kidney Disease

Background: The introduction of erythropoietinn stimulating agent (ESA) in clinical practice has completely altered the management of patients with chronic kidney disease. However, the successful correction of anemia has not always resulted in improvement of mortality in CKD patients. One of the main reasons for failure of preservation of renal function is excessive elevation of hemoglobin (Hb) levels for CKD patients. This indicates the need for maintaining appropriate target levels of Hb to preclude the progression of CKD. The aim of this study was to compare the effects of two Hb levels on progression of CKD patients in a 2 year period. Subjects: A total of 167 patients with chronic kidney disease (2mg