Effects of percutaneous transluminal angioplasty and associated factors in access hand oxygenation in patients undergoing hemodialysis.

In hemodialysis (HD) patients with arteriovenous fistula (AVF), changes in systemic or peripheral tissue circulation occur non-physiologically via the presence of AVF; however, associations between blood flow and tissue oxygenation in the brain and access hand are uncertain. In this study, 85 HD patients with AVF were included and evaluated for changes in flow volume (FV) and regional oxygen saturation (rSO2) in the brain and hands with AVF before and after percutaneous transluminal angioplasty (PTA). Furthermore, we evaluated the factors that determine access hand rSO2 without stenosis after PTA. Brachial arterial FV increased after PTA (p < 0.001), and carotid FV decreased (p = 0.008). Access hand rSO2 significantly decreased after PTA (p < 0.001), but cerebral rSO2 did not significantly change (p = 0.317). In multivariable linear regression analysis of factors associated with access hand rSO2, serum creatinine (standardized coefficient: 0.296) and hemoglobin (standardized coefficient: 0.249) were extracted as independent factors for access hand rSO2. In conclusion, a decrease in access hand oxygenation and maintenance of cerebral oxygenation were observed throughout PTA. To maintain access hand oxygenation, it is important to adequately manage Hb level and maintain muscle mass, in addition to having an AVF with appropriate blood flow.

Intercorrelated variability in blood and hemodynamic biomarkers reveals physiological network in hemodialysis patients.

Increased intra-individual variability of a variety of biomarkers is generally associated with poor health and reflects physiological dysregulation. Correlations among these biomarker variabilities should then represent interactions among heterogeneous biomarker regulatory systems. Herein, in an attempt to elucidate the network structure of physiological systems, we probed the inter-variability correlations of 22 biomarkers. Time series data on 19 blood-based and 3 hemodynamic biomarkers were collected over a one-year period for 334 hemodialysis patients, and their variabilities were evaluated by coefficients of variation. The network diagram exhibited six clusters in the physiological systems, corresponding to the regulatory domains for metabolism, inflammation, circulation, liver, salt, and protein. These domains were captured as latent factors in exploratory and confirmatory factor analyses (CFA). The 6-factor CFA model indicates that dysregulation in each of the domains manifests itself as increased variability in a specific set of biomarkers. Comparison of a diabetic and non-diabetic group within the cohort by multi-group CFA revealed that the diabetic cohort showed reduced capacities in the metabolism and salt domains and higher variabilities of the biomarkers belonging to these domains. The variability-based network analysis visualizes the concept of homeostasis and could be a valuable tool for exploring both healthy and pathological conditions.

Synchrony of biomarker variability indicates a critical transition: Application to mortality prediction in hemodialysis.

Critical transition theory suggests that complex systems should experience increased temporal variability just before abrupt state changes. We tested this hypothesis in 763 patients on long-term hemodialysis, using 11 biomarkers collected every two weeks and all-cause mortality as a proxy for critical transitions. We find that variability-measured by coefficients of variation (CVs)-increases before death for all 11 clinical biomarkers, and is strikingly synchronized across all biomarkers: the first axis of a principal component analysis on all CVs explains 49% of the variance. This axis then generates powerful predictions of mortality (HR95 = 9.7, p < 0.0001, where HR95 is a scale-invariant metric of hazard ratio; AUC up to 0.82) and starts to increase markedly ∼3 months prior to death. Our results provide an early warning sign of physiological collapse and, more broadly, a quantification of joint system dynamics that opens questions of how system modularity may break down before critical transitions.

Prediction of Mortality in Hemodialysis Patients Using Moving Multivariate Distance.

There is an increasingly widespread use of biomarkers in network physiology to evaluate an organism's physiological state. A recent study showed that albumin variability increases before death in chronic hemodialysis patients. We hypothesized that a multivariate statistical approach would better allow us to capture signals of impending physiological collapse/death. We proposed a Moving Multivariate Distance (MMD), based on the Mahalanobis distance, to quantify the variability of the multivariate biomarker profile as a whole from one visit to the next. Biomarker profiles from a visit were used as the reference to calculate MMD at the subsequent visit. We selected 16 biomarkers (of which 11 are measured every 2 weeks) from blood samples of 763 chronic kidney disease patients hemodialyzed at the CHUS hospital in Quebec, who visited the hospital regularly (∼every 2 weeks) to perform routine blood tests. MMD tended to increase markedly preceding death, indicating an increasing intraindividual multivariate variability presaging a critical transition. In survival analysis, the hazard ratio between the 97.5th percentile and the 2.5th percentile of MMD reached as high as 21.1 [95% CI: 14.3, 31.2], showing that higher variability indicates substantially higher mortality risk. Multivariate approaches to early warning signs of critical transitions hold substantial clinical promise to identify early signs of critical transitions, such as risk of death in hemodialysis patients; future work should also explore whether the MMD approach works in other complex systems (i.e., ecosystems, economies), and should compare it to other multivariate approaches to quantify system variability.

Estimation of homeostatic dysregulation and frailty using biomarker variability: a principal component analysis of hemodialysis patients.

Increased intraindividual variability in several biological parameters is associated with aspects of frailty and may reflect impaired physiological regulation. As frailty involves a cumulative decline in multiple physiological systems, we aimed to estimate the overall regulatory capacity by applying a principal component analysis to such variability. The variability of 20 blood-based parameters was evaluated as the log-transformed coefficient of variation (LCV) for one year's worth of data from 580 hemodialysis patients. All the LCVs were positively correlated with each other and shared common characteristics. In a principal component analysis of 19 LCVs, the first principal component (PC1) explained 27.7% of the total variance, and the PC1 score exhibited consistent correlations with diverse negative health indicators, including diabetes, hypoalbuminemia, hyponatremia, and relative hypocreatininemia. The relationship between the PC1 score and frailty was subsequently examined in a subset of the subjects. The PC1 score was associated with the prevalence of frailty and was an independent predictor for frailty (odds ratio per SD: 2.31, P = 0.01) using a multivariate logistic regression model, which showed good discrimination (c-statistic: 0.85). Therefore, the PC1 score represents principal information shared by biomarker variabilities and is a reasonable measure of homeostatic dysregulation and frailty.

Aging and death-associated changes in serum albumin variability over the course of chronic hemodialysis treatment.

BACKGROUND: Several epidemiological studies have demonstrated associations between variability in a number of biological parameters and adverse outcomes. As the variability may reflect impaired homeostatic regulation, we assessed albumin variability over time in chronic hemodialysis (HD) patients. METHODS: Data from 1346 subjects who received chronic HD treatment from May 2001 to February 2015 were analyzed according to three phases of HD treatment: post-HD initiation, during maintenance HD treatment, and before death. The serum albumin values were grouped according to the time interval from HD initiation or death, and the yearly trends for both the albumin levels and the intra-individual albumin variability (quantified by the residual coefficient of variation: Alb-rCV) were examined. The HD initiation and death-associated changes were also analyzed using generalized additive mixed models. Furthermore, the long-term trend throughout the maintenance treatment period was evaluated separately using linear regression models. RESULTS: Albumin levels and variability showed distinctive changes during each of the 3 periods. After HD initiation, albumin variability decreased and reached a nadir within a year. During the subsequent maintenance treatment period (interquartile range = 5.2-11.0 years), the log Alb-rCV showed a significant upward trend (mean slope: 0.011 ± 0.035 /year), and its overall mean was -1.49 ± 0.08 (equivalent to an Alb-rCV of 3.22%). During the 1-2 years before death, this upward trend clearly accelerated, and the mean log Alb-rCV in the last year of life was -1.36 ± 0.17. The albumin levels and variability were negatively correlated with each other and exhibited exactly opposite movements throughout the course of chronic HD treatment. Different from the albumin levels, albumin variability was not dependent on chronological age but was independently associated with an individual's aging and death process. CONCLUSION: The observed upward trend in albumin variability seems to be consistent with a presumed aging-related decline in homeostatic capacity.

Variability of laboratory parameters is associated with frailty markers and predicts non-cardiac mortality in hemodialysis patients.

BACKGROUND: The levels of many laboratory parameters are associated with the outcomes of dialysis patients, but the significance of their variability has not been well studied. METHODS: A total of 384 patients receiving stable hemodialysis treatment during 2002 were followed up for mortality until the end of 2013. The within-patient coefficients of variation (CV) were calculated for 13 laboratory parameters from 1 year of data. We defined variability as CV and analyzed the survival of the patients according to the baseline CV values of each parameter by proportional hazard modeling. RESULTS: During the 11-year observation period, 125 patients died. Higher CV levels for eight parameters, namely, blood urea nitrogen (BUN), sodium, hemoglobin, creatinine, total protein, albumin, potassium and phosphate, were significantly associated with all-cause mortality. The adjusted hazard ratios for a high BUN-CV (>15 %) and a high Na-CV (>1.3 %) against a lower CV were 1.92 (95 % CI 1.31-2.81) and 1.95 (1.36-2.80), respectively. The increased mortality risk associated with each variability was attributed to excess non-cardiac deaths. The CV values of most parameters were correlated with each other and often exhibited negative associations with age, diabetes, and mobility as well as the levels of hemoglobin, albumin, creatinine, Na, the protein catabolic rate, and the creatinine generation rate. Therefore, a high variability was generally associated with frailty-related adverse prognostic factors. CONCLUSIONS: The variability of several blood parameters had a significant impact on all-cause and non-cardiac mortality. The levels of the variabilities were most likely related to poor physical conditions of the patients.

Prerenal uremia induced by severe diarrhea due to colon adenoma: a case of McKittrick-Wheelock syndrome in an elderly patient.

McKittrick-Wheelock syndrome can be successfully treated by emergent dialysis, prescription of bicarbonate, and endoscopic submucosal dissection, which allow elderly people suffering from this syndrome to maintain their activities of daily living. In patients with this syndrome, a large colonic villous adenoma secretes excessive amounts of mucus and causes severe electrolyte depletion and dehydration. An 81-year-old man who had been suffering from chronic renal failure (creatinine 256.4 µmol/L), hypertension, and arrhythmia presented with frequent mucous diarrhea for a month. He was hospitalized for appetite loss, vomiting, general fatigue, and acute renal failure. His blood tests and blood gas analysis revealed urea nitrogen 58.9 mmol/L, creatinine 954.7 µmol/L, pH 7.13, and a base excess of -20.1 mmol/L. Although his symptoms were improved by the emergent dialysis and rehydration, he suffered a relapse only 4 days after he was discharged. At the second admission, a near-circumferential tumor was found in the rectum by the colonoscopy, which was pathologically confirmed as a villous adenoma. Considering his age and complications, endoscopic submucosal dissection was selected, and internal use of sodium bicarbonate was prescribed. Diarrhea and appetite loss were improved by these treatments, and the creatinine level was also improved to 168.0 µmol/L.

(Pro)renin receptor-mediated activation of mitogen-activated protein kinases in human vascular smooth muscle cells.

Blockade of (pro)renin receptor has benefits in diabetic angiotensin II type-1a-receptor-deficient mice, suggesting the importance of (pro)renin receptor-mediated intracellular signals. To determine the mechanism whereby the human (pro)renin receptor activates mitogen-activated protein kinases in human vascular smooth muscle cells (hVSMC), we treated the cells with recombinant human prorenin. Prorenin enhanced hVSMC proliferation and activated extracellular-signal-related protein kinase (ERK) in a dose- and time-dependent manner but did not influence activation of p38 or c-Jun NH(2)-terminal kinase. The activated ERK level was reduced to the control level by the tyrosine kinase inhibitor genistein, and the MEK inhibitor U0126 markedly reduced the activated ERK level to the control level, whereas the level of activated ERK was unaffected by the angiotensin-converting enzyme inhibitor imidaprilat or the angiotensin II receptor blocker candesartan. A human (pro)renin receptor was present in hVSMCs, and its knockdown with small interfering RNA (siRNA) significantly inhibited the prorenin-induced ERK activation. These results suggest that prorenin stimulates ERK phosphorylation in hVSMCs through the receptor-mediated activation of tyrosine kinase and subsequently MEK, independently of the generation of angiotensin II or the activation of its receptor. The (pro)renin receptor-mediated ERK signal transduction is thus a possible new therapeutic target for preventing vascular complications.

Left-right asymmetry in the alimentary canal of the Drosophila embryo.

In many animal groups, left-right (LR) asymmetry within the body is observed. The left and right sides of the body are generally defined with reference to the anterior-posterior (AP) and dorsal-ventral (DV) axes. In this study, we investigated whether LR asymmetry is solely dependent on the AP and DV polarities in Drosophila embryos. We focused on the proventriculus, a posterior part of the foregut, and the hindgut because LR asymmetry in these body parts is highly stable in normal embryos. In embryos with a fully reversed AP polarity, LR asymmetry in both the proventriculus and the hindgut was re-oriented in relation to the reversed AP polarity. This demonstrates that inversion of AP polarity does not affect LR asymmetry of these tissues, and implies that LR asymmetry is specified in relation to the AP and DV polarities. Our findings were not consistent with the alternative hypothesis that LR asymmetry is predetermined by maternal signals that localize asymmetrically along the LR axis in the oocyte and/or early embryo.

Oxidative stress induced by iron released from transferrin in low pH peritoneal dialysis solution.

BACKGROUND: Transferrin binds extracellular iron and protects tissues from iron-induced oxidative stress. The binding of iron and transferrin is pH dependent and conventional peritoneal dialysis (PD) solutions have unphysiologically low pH values. Herein, we investigated whether conventional PD solution releases iron from transferrin and if the released iron causes oxidative stress. METHODS: Effects of PD solutions on iron binding to transferrin were examined with purified human transferrin and transferrin in dialysates drained from PD patients. Oxidative stress induced by iron released from transferrin was evaluated in terms of the formation of thiobarbituric acid reactive substance (TBARS) and protein carbonylation in the human red blood cell (RBC) membrane. The iron deposition in peritoneal tissue from PD patients was evaluated by Perls' staining with diaminobenzidine intensification. RESULTS: Low pH PD solution released iron from transferrin. This iron release occurred within 1 min. Iron release was not observed in neutralized PD solution. Iron released from transferrin in low pH PD solution increased TBARS formation and protein carbonylation in the human RBC membrane. Iron deposition, which is prominent in the fibrotic area facing the peritoneal cavity, was observed in the peritoneum of PD patients. CONCLUSIONS: Iron released from transferrin in low pH PD solution can produce oxidative stress in the peritoneum of a PD patient. Neutralizing PD solution can avoid this problem. Iron deposition in the peritoneum may participate in the pathogenesis of peritoneal fibrosis in PD patients.

Calcification and osteopontin localization in the peritoneum of patients on long-term continuous ambulatory peritoneal dialysis therapy.

BACKGROUND: Peritoneal calcification is an uncommon complication of continuous ambulatory peritoneal dialysis (CAPD), which is mainly observed in patients on long-term therapy. Although some asymptomatic patients must have microscopic calcification in their peritoneum, little information on this topic has been published. Recent studies have revealed active participation of adhesive/chemotactic protein osteopontin (OPN) in dystrophic calcification. METHODS: Peritoneal tissue was obtained by biopsy or at autopsy from 18 CAPD patients (median duration, 122 months), 5 control haemodialysis (HD) patients, and 3 pre-CAPD patients. The distribution of calcium deposits and OPN protein was determined by von Kossa staining and immunohistochemistry, respectively. Smooth muscle cells and macrophages were identified with anti-alpha smooth muscle actin (alpha-SMA) and anti-CD68 antibodies. RESULTS: Calcium deposits with various configurations were observed in specimens from 12 of the 18 CAPD patients. They included massive calcification facing the peritoneal cavity, scattered granular or crystalloid deposits in the submesothelial stroma, and oval-shaped deposits formed within hyalinized vasa. Most were present in highly sclerosed areas and accompanied by extracellular OPN precipitation. Cytoplasmic OPN was detected in infiltrating leukocytes, granulation tissue cells, fibroblast-like cells and mast cells. Computerized tomography examination also detected peritoneal calcification in seven of the CAPD patients. No calcium deposits or OPN staining was detected in control specimens. CONCLUSIONS: The results of our study suggest that microscopic peritoneal calcification is frequent in patients on CAPD for more than 10 years. Myofibroblast infiltration, OPN expression, calcium deposition, and associated OPN precipitation seem to be components of the peritoneal changes in such patients.