Catabolic Rate Research Articles

The Physiological and Molecular Mechanism of Abscisic Acid in Regulation of Fleshy Fruit Ripening.

The ripening of fleshy fruits is coupled with the degradation of both chlorophyll and cell walls, as well as changes in the metabolism of phenylpropanoids, flavonoids, starch/sucrose, and carotenoids. These processes are controlled by phytohormones and other factors, including abscisic acid (ABA), ethylene, auxin, polyamines, sugar, and reactive oxygen species. The ripening of climacteric fruits is controlled by ethylene and non-climacteric fruit ripening is regulated mainly by ABA. Also, ABA and ethylene may interact in both types of fruit ripening. ABA concentrations in fleshy fruits are regulated in response to developmental and environmental cues and are controlled by the relative rates of ABA biosynthesis and catabolism, the former mainly via 9-cis-epoxycarotenoid dioxygenases (NCEDs) and β-glucosidases and the latter via ABA 8'-hydroxylases (CYP707As) and β-glycosyltransferases. In strawberry fruit ripening, ABA is perceived via at least two receptors, Pyrabactin resistance (PYR)/PYR-like (PYL) and putative abscisic acid receptor (ABAR), which are linked separately to the conserved signaling pathway ABA-FaPYR1-FaABIl-FaSnRK2 and the novel signaling pathway ABA-FaABAR-FaRIPK1-FaABI4. Downstream signaling components include important transcription factors, such as AREB (ABA responsive element binding protein)/ABF (ABRE binding factors ABA responsive factor), ethylene response factor (ERF), and V-myb Myeloblastosis viral oncogene homolog (MYB), as well as ripening-related genes. Finally, a comprehensive model of ABA linked to ethylene, sugar, polyamines, auxin and reactive oxygen species in the regulation of strawberry fruit ripening is proposed. Next, new integrated mechanisms, including two ABA signaling pathways, ABA and ethylene signaling pathways, and ABA/ethylene to other phytohormones are interesting and important research topics in ripening, especially in non-climacteric fruits.

Longitudinal Causal Effects of Normalized Protein Catabolic Rate on All-Cause Mortality in Patients With End-Stage Renal Disease: Adjusting for Time-Varying Confounders Using the G-Estimation Method.

In this study, we aimed to estimate the causal effect of normalized protein catabolic rate (nPCR) on mortality among end-stage renal disease (ESRD) patients in the presence of time-varying confounding affected by prior exposure using g-estimation. Information about 553 ESRD patients was retrospectively collected over an 8-year period (2011-2019) from hemodialysis facilities in Kerman, Iran. nPCR was dichotomized as <1.2 g/kg/day versus ≥1.2 g/kg/day. Then a standard time-varying accelerated failure time (AFT) Weibull model was built, and results were compared with those generated by g-estimation. After appropriate adjustment for time-varying confounders, weighted g-estimation yielded 78% shorter survival time (95% confidence interval (95% CI): -81, -73) among patients with a continuous nPCR <1.2 g/kg/day than among those who had nPCR ≥1.2 g/kg/day during follow-up, though it was 18% (95% CI: -57, 54) in the Weibull model. Moreover, hazard ratio estimates of 4.56 (95% CI: 3.69, 5.37) and 1.20 (95% CI: 0.66, 2.17) were obtained via weighted g-estimation and the Weibull model, respectively. G-estimation indicated that inadequate dietary protein intake characterized by nPCR increases all-cause mortality among ESRD patients, but the Weibull model provided an effect estimate that was substantially biased toward the null.

Evolution of body composition and wasting indicators by time of day of haemodialysis.

It has been a long-standing clinical concern that haemodialysis (HD) patients on afternoon shifts (ASs) are more prone to protein-energy wasting (PEW) than those on morning shifts (MSs), as their dialysis scheme and post-dialysis symptoms may interfere with meal intake. We evaluated the effect of time of day of HD on the evolution of body composition changes and PEW surrogates. We conducted a retrospective study among 9.963 incident HD patients treated in NephroCare centres (2011-16); data were routinely collected in the European Clinical Database. The course of multi-frequency bioimpedance determined lean and fat tissue indices (LTI and FTI) between patients in MSs/ASs over 2 years were compared with linear mixed models. Secondary PEW indicators were body mass index, albumin, creatinine index and normalized protein catabolic rate. Models included fixed (age, sex, vascular access and diabetes mellitus) and random effects (country and patient). Mean baseline LTI and FTI were comparable between MSs (LTI: 12.5 ± 2.9 kg/m2 and FTI: 13.7 ± 6.0 kg/m2) and ASs (LTI: 12.4 ± 2.9 kg/m2 and FTI: 13.2 ± 6.1 kg/m2). During follow-up, LTI decreased and FTI increased similarly, with a mean absolute change (baseline to 24 months) of -0.3 kg/m2 for LTI and +1.0 kg/m2 for FTI. The course of these malnutrition indicators did not differ between dialysis shifts (P for interaction ≥0.10). We also did not observe differences between groups for secondary PEW indicators. This study suggests that a dialysis shift in the morning or in the afternoon does not impact the long-term nutritional status of HD patients. Regardless of time of day of HD, patients progressively lose muscle mass and increase body fat.

Dynapaenia and sarcopaenia in chronic haemodialysis patients: do muscle weakness and atrophy similarly influence poor outcome?

Sarcopaenia, defined as a decline in both muscle mass and function, has been recognized as a major determinant of poor outcome in haemodialysis (HD) patients. It is generally assumed that sarcopaenia is driven by muscle atrophy related to protein-energy wasting. However, dynapaenia, defined as weakness without atrophy, has been characterized by a different disease phenotype from sarcopaenia. The aim of this study was to compare the characteristics and prognosis of sarcopaenic and dynapaenic patients among a prospective cohort of chronic HD (CHD) patients. Two hundred and thirty-two CHD patients were enrolled from January to July 2016 and then followed prospectively until December 2018. At inclusion, weakness and atrophy were, respectively, evaluated by maximal voluntary force (MVF) and creatinine index (CI). Sarcopaenia was defined as the association of weakness and atrophy (MVF and CI below the median) while dynapaenia was defined as weakness not related to atrophy (MVF below the median, and CI above the median). From a total of 187 prevalent CHD patients [65% of men, age 65.3 (49.7-82.0) years], 44 died during the follow-up period of 23.7 (12.4-34.9) months. Sarcopaenia and dynapaenia were observed in 33.7 and 16% of the patients, respectively. Compared with patients with sarcopaenia, patients with dynapaenia were younger and with a lower Charlson score. In contrast, mortality rate was similar in both groups (38 and 27%, respectively). After adjustment for age, sex, lean tissue index, serum albumin, high-sensitivity C-reactive protein (hs-CRP), haemoglobin (Hb), normalized protein catabolic rate (nPCR), dialysis vintage and Charlson score, only patients with dynapaenia were at increased risk of death [hazard ratio (HR) = 2.99, confidence interval 1.18-7.61; P = 0.02]. Screening for muscle functionality is highly warranted to identify patients with muscle functional impairment without muscle atrophy. In contrast to sarcopaenia, dynapaenia should appear as a phenotype induced by uraemic milieu, characterized by young patients with low Charlson score and poor prognosis outcome independently of serum albumin, hs-CRP, Hb, nPCR and dialysis vintage.

COVID-19–Associated Acute Kidney Injury and Quantified Protein Catabolic Rate: A Likely Effect of Cytokine Storm on Muscle Protein Breakdown

Rationale & ObjectivesPreviously we reported a cohort of patients with coronavirus disease 2019 (COVID-19)–associated acute kidney injury (AKI) with striking biochemical evidence of tissue breakdown in the absence of apparent rhabdomyolysis. We sought to quantify the extent of tissue catabolism in similar patients.Study DesignDuring acute peritoneal dialysis (PD) in patients with COVID-19–associated AKI, we measured urea Kt/V adequacy and calculated the daily urea nitrogen generation rate while quantifying daily protein intake.Setting & PopulationWe did calculations in 8 patients with COVID-9–associated AKI undergoing acute PD at Mount Sinai Hospital in New York City. As a comparator, we obtained urea kinetic parameters from our database of ambulatory patients receiving maintenance PD.Exposure or Predictors8 patients with COVID-19–associated AKI undergoing acute PD.OutcomesUrea nitrogen generation rate in relation to daily protein intake.Analytical ApproachUrea nitrogen generation rate from urea kinetics was related to measured daily dietary protein intake in these patients and we compared it with this relationship in ambulatory maintenance PD patients for whom both parameters were calculated from urea kinetics.ResultsUrea nitrogen generation rate in patients with AKI was 10.2 ± 5 g/d, which is more than 2-fold higher than for stable outpatients receiving maintenance PD (4.7 ± 3 g/d) despite similar dietary protein intake (74.8 ± 11 vs 67.2 ± 29 g/d, respectively). This strongly suggests endogenous protein breakdown, probably from muscle. Urea nitrogen generation rate in these patients with AKI corresponds to 315 g/d of ongoing muscle breakdown and cumulative 2.5 kg of muscle breakdown during the early course of AKI.LimitationsSmall number of participants and assumptions in comparing urea nitrogen generation rate with protein intake.ConclusionsIn highly catabolic patients, an endogenous source of urea generation such as muscle protein breakdown seems to be the most likely explainable cause for our findings. This is the first study that we are aware of to quantify the degree of endogenous protein breakdown induced by COVID-19–related cytokine storm.

The modulating effect of dietary protein intake on mortality in long-term hemodialysis patients: A nationwide population-based study.

A high prevalence of protein-energy wasting and malnutrition among uremic patients is associated with an increase in morbidity and mortality. We aimed to investigate the modulating effect of daily dietary protein intake (DPI) evaluated by normalised protein catabolic rate (nPCR) on mortality in long-term haemodialysis (HD) patient from a nationwide population-based study. By Taiwan Renal Registry Data System between 2005 and 2012, we divided the long-term HD patients into average nPCR<1.2 and nPCR≥1.2 groups according to the current guideline. The relation of nPCR with three-year all-cause and cardiovascular (CV) mortality were evaluated. The cox regression method for predicted mortality by nPCR was used. Among 88330 HD patients, 58122 (65.8%) patients were in average nPCR<1.2 group and 30208 (34.2%) in average nPCR≥1.2 group. Both all-cause and cardiovascular (CV) mortality risks were increased in nPCR<1.2 group after adjusting for demographics and laboratories cofactors in our multivariate cox regression model. Patients with nPCR<1.2 and albumin≥3.7 had a higher adjusted hazard ratio (aHR) for all-cause and CV mortality (1.16 [95% confidence interval (CI): 1.07-1.25, P<.001]; 1.15 [95% CI: 1.02-1.31, P=.03], respectively), compared with the reference group with nPCR≥1.2 and albumin≥3.7. Interestingly, there was no difference in mortality risk between low DPI subgroup (nPCR<1.2 and Alb<3.7) and the reference group (nPCR≥1.2 and Alb<3.7). Further stratification analysis revealed that low DPI subgroup (nPCR<1.2, Alb≥3.7 and TC≥150) had an increased risk of both all-cause and CV mortality (aHR 1.14 [95% CI: 1.04-1.25, P=.005]; aHR 1.17 [95% CI: 1.02-1.35, P=.026], respectively). Low DPI (as presented by nPCR) independently correlated with all-cause and CV mortality among HD patients. Mortality risks were higher in low DPI patients even with normoalbuminaemia and non-hypocholesterolaemia. Further investigations on the importance of increasing DPI in HD patients is warranted.

Ontogeny of hepatic methionine catabolic enzyme activities (Transmethylation and Transsulphuration) and associated physiological amino acids in E10-21 chick embryos and D1-49 broilers.

Developmental changes in hepatic methionine adenosyltransferase, cystathionine β-synthase, cystathionase, and glycine N-methyltransferase were determined in broiler chick embryos and hatched chicks by using radiometric and spectrometric methods. Hepatic free methionine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, cystathionine, and cysteine levels were also investigated. Results showed an increase in hepatic MAT activity from E10 to E21 during embryogenesis, suggesting greater transmethylation rates throughout the rapid embryonic growth and development period. A strong positive correlation between embryo BW and MAT activity also supports this idea. The MAT specific activity continued to increase after hatching, but there was a negative correlation between chick BW and MAT activities from D1 to D49. This may indicate different MAT isozymes exist for chick embryo hepatic tissue compared to hepatic tissue of hatched chick and growing broilers. The developmental pattern of MAT isozymes could be critical for methionine metabolism to cope with the demand imposed on the embryo, chicks, and growing broilers. Additionally, the specific activity of hepatic CBS in chick embryos was determined to be lower compared to that observed in older broilers (35 and 49days). Since liver CBS specific activity is at the lowest point from D1-7 in young chicks, the ability to convert adequate homocysteine to cysteine through transsulphuration may be limiting for cysteine synthesis at this time. Steady-state hepatic homocysteine levels in chick embryos and chicks may be a function of the rates of homocysteine formation, remethylation, and catabolism via the transsulphuration pathway. The present study indicates young chicks from D1 to D7 may have a limited ability for adequate transsulphuration; therefore, dietary cystine may be needed for optimum performance.

Total Cellular ATP Production Changes With Primary Substrate in MCF7 Breast Cancer Cells.

Cancer growth is predicted to require substantial rates of substrate catabolism and ATP turnover to drive unrestricted biosynthesis and cell growth. While substrate limitation can dramatically alter cell behavior, the effects of substrate limitation on total cellular ATP production rate is poorly understood. Here, we show that MCF7 breast cancer cells, given different combinations of the common cell culture substrates glucose, glutamine, and pyruvate, display ATP production rates 1.6-fold higher than when cells are limited to each individual substrate. This increase occurred mainly through faster oxidative ATP production, with little to no increase in glycolytic ATP production. In comparison, non-transformed C2C12 myoblast cells show no change in ATP production rate when substrates are limited. In MCF7 cells, glutamine allows unexpected access to oxidative capacity that pyruvate, also a strictly oxidized substrate, does not. Pyruvate, when added with other exogenous substrates, increases substrate-driven oxidative ATP production, by increasing both ATP supply and demand. Overall, we find that MCF7 cells are highly flexible with respect to maintaining total cellular ATP production under different substrate-limited conditions, over an acute (within minutes) timeframe that is unlikely to result from more protracted (hours or more) transcription-driven changes to metabolic enzyme expression. The near-identical ATP production rates maintained by MCF7 and C2C12 cells given single substrates reveal a potential difficulty in using substrate limitation to selectively starve cancer cells of ATP. In contrast, the higher ATP production rate conferred by mixed substrates in MCF7 cells remains a potentially exploitable difference.

An Analytic Model of Tissue Self-Healing and Its Network Implementation: Application to Fibrosis and Aging.

Here we present a model capable of self-healing and explore its ability to resolve pathological alterations in biological tissue. We derive a simple analytic model consisting of an agent representing a cell that exhibits anabolic or catabolic activity, and which interacts with its tissue substrate according to tissue stiffness. When perturbed, this system returns toward a stable fixed point, a process corresponding to self-healing. We implemented this agent-substrate mechanism numerically on a hexagonal elastic network representing biological tissue. Agents, representing fibroblasts, were placed on the network and allowed to migrate around while they remodeled the network elements according to their activity which was determined by the stiffnesses of network elements that each agent encountered during its random walk. Initial injury to the network was simulated by increasing the stiffness of a single central network element above baseline. This system also exhibits a fixed point represented by the uniform baseline state. During the approach to the fixed point, interactions between the agents and the network create a transient spatially extended halo of stiffer network elements around the site of initial injury, which aids in overall injury repair. Non-equilibrium constraints generated by persistent injury prohibit the network to return to baseline and results in progressive stiffening, mimicking the development of fibrosis. Additionally, reducing anabolic or catabolic rates delay self-healing, reminiscent of aging. Our model thus embodies what may be the simplest set of attributes required of a spatiotemporal self-healing system, and so may help understand altered self-healing in chronic fibrotic diseases and aging.

The lacking equation that estimates the protein catabolic rate in patients on once-weekly haemodialysis.

The normalized protein catabolic rate (PCRn) is one of the key indices derived from the urea kinetic model (UKM) in haemodialysis (HD) patients. Ideally, it should be assessed using the double pool UKM (KDOQI clinical practice guidelines, AIKD, 2015), as the web-based software Solute-Solver (SS) does (Daugirdas et al., AJKD, 2009). Simple formulae exist to compute PCRn for patients on thrice- or twice-weekly HD schedule, but not for patients on once-weekly HD schedule (1HD/wk). Aim of the present technical note was to introduce the lacking equation that estimates PCRn in the 1HD/wk regimen. Data of a single HD session associated to monthly UKM studies were retrieved from the electronic database of our dialysis unit for 80 historical patients on 1HD/wk regimen. The UKM parameters, as calculated with SS, were used in a subgroup of 40 randomly selected patients (group 1) to build-up a multiple regression model of PCRn. The latter was used to predict PCRn (PCRnPred) values in the cohort of the remaining 40 patients (group 2). The Bland-Altman plot was used to analyse the agreement between PCRnPred and the paired "observed" (PCRnObs) values, as measured with SS. The following equation was established by means of the multiple regression analysis: PCRn =-0.46 + 0.01 × C0 + 0.09 × eKt/V + 3.94 × Kru/V, where C0 is pre-dialysis blood urea nitrogen concentration, eKt/V is the equilibrated Kt/V, Kru is the residual renal urea clearance and V is the post-dialysis urea distribution volume. The PCRnPred values were 0.99 ± 0.24g/kg/day; the PCRnObs values were 0.96 ± 0.23g/kg/day (mean difference 0.03 ± 0.05g/kg/day). Their difference at the Bland-Altman analysis ranged from -0.08 to + 0.13g/kg/day. Finally, a nomogram was drawn: it can be used to estimate not only PCRn from Kru/V and C0, but also C0 as a function of Kru/V and PCRn. The equation here introduced allows a simple and accurate estimate of PCRn in patients on once-weekly HD regimen. The availability of the nomogram relating C0 to PCRn and Kru/V could be a further step to make safer and safer the once-weekly HD regimen. The following equation was established by means of the multiple regression analysis [Formula: see text] where PCRn is the normalized protein catabolic rate (PCRn), C0 is pre-dialysis blood urea nitrogen concentration (BUN), eKt/V is the equilibrated Kt/V, Kru is the residual renal urea clearance and V is the post-dialysis urea distribution volume. A nomogram relating pre-dialysis BUN to PCRn and Kru/V could be drawn: it can be used to estimate not only PCRn from Kru/V and pre-dialysis BUN, but also pre-dialysis BUN as a function of Kru/V and PCRn.

Examining the relationship between nutrition, quality of life, and depression in hemodialysis patients.

Lifestyle changes associated with end-stage renal disease may be a factor in depression and quality of life (QOL) for patients receiving hemodialysis. This cross-sectional study examined the relationship between nutritional status, QOL, and depression in 124 hemodialysis patients. Nutritional markers included serum albumin, normalized protein catabolic rate (nPCR), body mass index (BMI), body fat percentage, and daily protein intake. Physical and Mental dimension scores of the Kidney Disease QOL-Short Form (KDQOL-SF), and the Center for Epidemiological Studies of Depression (CESD) survey were used to measure QOL and depression, respectively. Data were analyzed using regression analyses. Measures of effect size were used for interpretation. Nutritional status indicators explained a moderate amount of the variability of the Physical dimension of QOL (crude R2 = .14, covariate-adjusted ΔR2 = .06) but had weak explanatory ability for the Mental dimension of QOL (crude R2 = .05, covariate-adjusted ΔR2 = .02) and CESD (crude R2 = .02, covariate-adjusted ΔR2 = .005). Additional findings suggested the presence of non-linear relationships between protein intake and both the Physical and Mental QOL dimension scores. Longer dialysis vintage was also correlated with lower psychosocial patient outcomes. While nutritional status is an important element in predicting hemodialysis patient outcomes, its relationship to depression and QOL, in this sample, demonstrated only moderate explanatory ability. However, dialysis vintage and level of education had a significant relationship with depression and QOL. These findings suggest that patients with longer dialysis vintage and limited health literacy require unique plans of care. Future studies aimed at understanding the interrelationships between non-modifiable patient characteristics and psychosocial outcomes are imperative.

Effects of nutrition on pregnant and lactating sows

It has been suggested that the long-term reproduction of the sow is best served by minimizing weight and fat loss in lactation. Such a strategy would require only a minimal restoration of weight in the following pregnancy, which would be beneficial, since the greater feed intake and weight gain in pregnancy, the greater the weight loss in lactation. Feeding ad libitum should be practised during lactation while gestation feed intake must be held low. A relationship between feed intake and embryo survival has been demonstrated in several studies, but the data are sometimes difficult to interpret. High energy feeding during the premating period and during early pregnancy, however, are often associated with increased embryo mortality. A short-term starvation in lactation decreased prolactin to post-weaning concentrations, and insulin and glucose to very low concentrations. Prolactin increased very rapidly after refeeding indicating that a neural mechanism might be involved. The increasing levels of cholecystokinin after refeeding and the neural reflex triggered might be related to this increase in prolactin. No changes in LH release were observed during the periods of starvation or refeeding. The catabolic rate during the first week of lactation is higher in sows with higher backfat thickness than in late gestation. As lactation progresses a more balanced metabolism is achieved regardless of backfat thickness before parturition. High-weight-loss primiparous sows need a longer recovery period from their negative energy balance during lactation than do low-weight-loss primiparous sows or multiparous sows. Several investigations have demonstrated that sows losing excessive amounts of body weight have extended weaning to oestrous intervals and an increase in anoestrus. Sows with low body-weight loss during lactation have higher plasma insulin and lower cortisol around weaning than do sows with high body-weight loss. What remains undefined is the degree of weight or condition loss below which an extension in the remating interval will occur and the level of dietary energy intake required to prevent this extension.

Variations in isotope incorporation rates and trophic discrimination factors of carbon and nitrogen stable isotopes in scales from three European sea bass (Dicentrarchus labrax) populations

Carbon (δ13C) and nitrogen (δ15N) stable isotope analyses are used in marine ecology to study trophic relationships and migrations of species since they reflect dietary sources consumed which may vary geographically. However, better estimations of isotope incorporation rates and trophic discrimination factors (TDF) under controlled conditions are required. Moreover, variability of isotope incorporation rates and TDF among and within populations has been poorly described, especially in fish scales, whereas the use of non-lethal method is becoming a standard. This study aimed to experimentally assess whether carbon and nitrogen isotope incorporation rates (λC and λN, respectively) and TDF of scales vary in the European sea bass (Dicentrarchus labrax) among (1) Atlantic, West Mediterranean and East Mediterranean populations, (2) sexes and (3) individuals. Fish were reared under controlled conditions and switched from a diet 1 to a diet 2 with different δ13C and δ15N values. Scales were sampled repeatedly on 16 fish within the three populations, from the day of diet change (day 0) to the end of the experiment (day 217). Isotope incorporation rates of scales and TDF were determined using a time-dependent model. Isotopic carbon and nitrogen half-lives (t50C and t50N) were similar among the three populations but males had significantly lower t50C and t50N than females (29 ± 2 and 35 ± 2 days vs. 53 ± 7 and 80 ± 11 days, respectively). Females had higher growth rates but lower catabolic rates than males. Variability of λC and λN was large within sexes: t50C ranged from 17 to 159 days and t50N ranged from 18 to 342 days among individuals. Thus, variability between sexes and among individuals must be considered to avoid misinterpretation in field-based studies. For the 48 fish, TDF were 4.91 ± 0.03 and 2.46 ± 0.06‰ for carbon and nitrogen, respectively, and similar between sexes and among populations. Besides, TDF varied among individuals from 2.95 to 5.59‰ and from 0.93 to 3.55‰ for carbon and nitrogen, respectively. Empirical mixing models were run to estimate how different TDF influenced estimation of the contributions of food sources to diet of their consumer. The output differed considerably when using TDF from fish literature or those estimated herein, which confirms that a tissue-specific TDF must be used to avoid misinterpretation in field-based studies. Individual variation in TDF did not, however, influence estimation of the contributions of food sources, confirming that scales are a valid tissue for non-lethal sampling.

Influence of Dialysis Modality on the Treatment of Anemia in Patients with End-Stage Kidney Disease

Abstract Anemia is a common complication among the patients with end-stage kidney disease. Management of anemia is influenced by several factors: iron deficiency, subtherapeutic dosage of erythropoietin, microinflammation, vitamin D deficiency, increased iPTH levels and inadequate hemodialysis. The aim of the study was to examine impact of dialysis modality on blood hemoglobin level as well as status of iron, status of vitamin D, hemodialysis adequacy and erythropoietin dose. The study included 120 patients which were divided into two groups: the group of patients treated with hemodiafiltration and the group of patients treated with standard hemo-dialysis. For statistical analysis Kolmogorov-Smirnov test, Student’s t-test and Mann-Whitney U-test were used. Blood hemoglobin level and parameters of hemodialysis adequacy (Kt/V index, spKt/V index, URR index), hematocrit ad protein catabolic rate (nPCR) were statisticaly significant lower in patients treated with regular hemodialysis compared to patients treated with regular hemodiafiltration. Serum ferritin level, C-reactive protein level and average monthly dose of intravenous iron were higher in the patients treated with regular hemodialysis compared to patients treated with hemodiafiltration. Patients treated with hemodiafiltration have lower grade of microinflammation, better iron status and better control of anemia compared to the patients treated with regular hemodialysis. Dialysis modality is an important factor that influences management of anemia in the patients with end-stage kidney disease.

Association between modified simple protein-energy wasting (PEW) score and all-cause mortality in patients receiving maintenance hemodialysis

BackgroundProtein-energy wasting (PEW) is a frequently observed complication that leads to increased mortality in hemodialysis patients. However, a multifaceted assessment of PEW by combined objective nutritional parameters has not yet been established.MethodsIn total, 144 Japanese patients receiving maintenance hemodialysis at a hemodialysis center were retrospectively followed for 7 years. The primary outcome was all-cause death. The main exposure was a modified simple PEW score (0, 1, 2, 3, or 4), calculated from four parameters: serum albumin and creatinine levels, normalized protein catabolic rate, and body mass index. These parameters are included in the subcategories of PEW as defined by the International Society of Renal Nutrition and Management. The cutoff values of the modified simple PEW score components were based on the receiver operating characteristics curves determined by univariate logistic regression analyses. Risk estimates for all-cause mortality were calculated by the Cox proportional hazards model adjusted for potential confounding factors.ResultsDuring the median 5.7-years follow-up period, 37 patients died of any cause. When patients were divided into three subgroups (G1–G3) based on the modified simple PEW score, a multivariable-adjusted analysis showed that the risks of all-cause death in groups G2 and G3 were significantly higher than in the lowest score group (G1), with hazard risk (95% confidence interval) 3.10 (1.16–8.26) (P = 0.024) and 5.68 (1.85–17.45) (P = 0.002), respectively.ConclusionsThe modified simple PEW score is a useful composite indicator of nutritional status that stratifies the risk of all-cause mortality in patients undergoing maintenance hemodialysis.

Growth-associated catabolic potential of Acetoanaerobium sticklandii DSM 519 on gelatin and amino acids.

Acetoanaerobium sticklandii DSM 519 is a hyperammonia-producing anaerobe that catabolizes proteins and amino acids into organic solvents and volatile acids via the Stickland reactions. However, the specific growth rate and metabolic capability of this organism on proteins and amino acids are not yet known. Therefore, the present study was intended to evaluate its specific growth rate and metabolic potential on gelatin and amino acids in the experimental media. We carried out metabolic assay experiments to calculate its ability to utilize pure gelatin, single amino acids, and amino acid pairs at different growth phases. The results of this study show that complete assimilation of gelatin was achieved by its log-phase culture. The subsequent fermentation of amino acids was much faster than gelatin hydrolysis. The rate of gelatin degradation was associated with the growth and catabolic rates of this organism. Many amino acids were not assimilated completely for its growth and energy conservation. A log-phase culture of this organism preferably utilized l-cysteine, l-arginine, and l-serine, and released more fraction of ammonia. As shown by our analysis, the catabolic rates of these amino acids were determined by the rates of respective enzymes involved in amino acid catabolic pathways and feedback repression of ammonia. The growth kinetic data indicated that at the initial growth stage, a metabolic shift in its solventogenesis and acidogenesis phases was associated with catabolism of certain amino acids. Thus, the results of this study provide a new insight to exploit its log-phase culture as a starter for the production of biofuel components from gelatin processing industries.

Range of plasma brain natriuretic peptide (BNP) levels in hemodialysis patients at a high risk of 1-year mortality and their relationship with the nutritional status: a retrospective cohort study in one institute

BackgroundBrain natriuretic peptide (BNP) levels are used as a marker of heart failure, which is the leading cause of morbidity and mortality in dialysis patients. BNP levels increase as renal function declines. The range of BNP levels associated with satisfactory longevity in dialysis patients currently remains unknown.MethodsIn total, 660 patients receiving maintenance hemodialysis were enrolled. BNP levels were measured at the end of the year and in a follow-up to assess 1-year mortality between 2008 and 2012. Patients were divided into six groups according to BNP levels: < 50 (reference), 50 to < 100, 100 to < 300, 300 to < 500, 500 to < 1000, and ≥ 1000 pg/mL. One-year mortality at each BNP level was analyzed using Cox’s proportional hazards model after adjustments for confounding factors.ResultsDuring the follow-up period, 78 (11.8%) deaths were recorded. After adjustments for confounding factors, such as gender, age, hemodialysis vintage, and primary disease, the risk of 1-year mortality was significantly high with BNP levels of 500 to < 1000 (hazard ratio [HR] 3.010; 95% confidence interval [CI] 1.065–10.729; P = 0.037) and more than 1000 pg/mL (HR 5.291; 95%CI 2.014–18.170; P = 0.0003). After adjustments for Kt/V, the risk of 1-year mortality was also significantly high with BNP levels of 500 to < 1000 (HR 3.045; 95%CI 1.065–10.929; P = 0.037) and more than 1000 pg/mL (HR 5.221; 95%CI 1.943–18.165; P = 0.0006). Following further adjustments for nutritional factors, such as albumin levels, total cholesterol levels, the normalized protein catabolic rate (nPCR), body mass index (BMI), and percent creatinine generation rate (%CGR), BNP levels of 500–1000 (HR 1.990; 95%CI 0.639–7.570; P = 0.244), and more than 1000 pg/mL (HR 2.100; 95%CI 0.663–8.105; P = 0.213) were no longer risk factors.ConclusionIn dialysis patients, a BNP level ≥ 500 pg/mL is a risk factor for 1-year mortality. The risk associated with high BNP levels is reduced by nutritional factors, which suggests a relationship between high BNP levels and the nutritional status. In conclusion, efforts are needed to maintain BNP levels at lower than 500 pg/mL and improve the nutritional status.

AAV-Mediated ApoC2 Gene Therapy: Reversal of Severe Hypertriglyceridemia and Rescue of Neonatal Death in ApoC2-Deficient Hamsters

Apolipoprotein C2 (ApoC2) is a key activator of lipoprotein lipase for plasma triglyceride metabolism. ApoC2-deficient patients present with severe hypertriglyceridemia and recurrent acute pancreatitis, for whom the only effective treatment is the infusion of normal plasma containing ApoC2. However, since ApoC2 has a fast catabolic rate, a repeated infusion is required, which limits its clinical use. To explore a safe and efficient approach for ApoC2 deficiency, we herein established an adeno-associated virus expressing human ApoC2 (AAV-hApoC2) to evaluate the efficacy and safety of gene therapy in ApoC2-deficient hypertriglyceridemic hamsters. Administration of AAV-hApoC2 via jugular or orbital vein in adult and neonatal ApoC2-deficient hamsters, respectively, could prevent the neonatal death and effectively improve severe hypertriglyceridemia of ApoC2-deficient hamsters without side effects in a long-term manner. Our novel findings in the present study demonstrate that AAV-hApoC2-mediated gene therapy will be a promising therapeutic approach for clinical patients with severe hypertriglyceridemia caused by ApoC2 deficiency.

Blood clearance kinetics and organ delivery of medium-chain triglyceride and fish oil-containing lipid emulsions: Comparing different animal species

Medium-chain triglycerides (TG) (MCT) and fish oil (FO) TG are incorporated as the core TG component into intravenous (IV) lipid emulsions for infusion in parenteral nutrition. Bolus injections of IV emulsions, on the other hand, have emerged as a novel therapeutic approach to treat various acute disorders. However, intravascular metabolism and organ delivery of acute IV injection of emulsions containing both MCT and FO are not fully defined, nor have they been characterized across common experimental animal models. We characterized and compared blood clearance kinetics and organ distribution of bolus injections of MCT/FO emulsions among different animal species. We also examined whether sex differences or feeding status can affect catabolic properties of MCT/FO lipid emulsions. Blood clearance rates of lipid emulsions with specific TG composition were compared in rats IV injected with [3H]cholesteryl hexadecyl ether labeled pure n-6 long-chain (LCT) and n-3 FO TG lipid emulsions, or emulsions containing MCT and FO at different ratios (wt/wt), which include 8:2 (80% MCT: 20% FO), 5:4:1 (50% MCT: 40% LCT: 10% FO) and SMOF (30% LCT: 30% MCT: 25% olive oil: 10% FO). Dose-response effects (0.016mg-1.6mgTG/g body weight) of the MCT/FO 8:2 emulsions on blood clearance properties and organ delivery were determined in both mice and rats. Blood clearance kinetics and organ uptake of MCT/FO 8:2 emulsions were compared between male and female rats and between fed and fasted rats. Changes in plasma lipid profiles after acute injections of MCT/FO 8:2 lipid emulsion at different doses (0.043, 0.133, and 0.4mgTG/g body weight) were characterized in non-human primates (Cynomolgus monkeys). MCT/FO 8:2 emulsion was cleared faster in rats when compared with other emulsions with different TG contents. Mice had faster blood clearance and higher fractional catabolic rates (FCR) when compared with the rats injected with MCT/FO 8:2 emulsions regardless of the injected doses. Mice and rats had similar plasma TG and free fatty acid (FFA) levels after low- or high-dose injections of the MCT/FO emulsion. Tissue distribution of the MCT/FO 8:2 lipid emulsion are comparable between mice and rats, where liver had the highest uptake per recovered dose among all organs (>60%). Feeding status and sex differences did not alter the blood clearance rate of the MCT/FO 8:2 emulsion in rats. In a nonhuman primate model, dose-response increases in plasma TG and FFA were observed after IV injection of MCT/FO 8:2 emulsions within the 1st 10min. A lipid emulsion containing both MCT and FO TG is cleared rapidly in blood and readily available for organ uptake in rodent and primate animal models. Characterization of the blood clearance properties of the MCT/FO 8:2 emulsion administered in various animal models may provide further insight into the safety and efficacy profiles for future therapeutic use of bolus injections of MCT/FO emulsions in humans.

Association of normalized protein catabolic rate (nPCR) with the risk of bone fracture in patients undergoing maintenance hemodialysis: The Q-Cohort Study

Normalized protein catabolic rate (nPCR) is used as a surrogate for daily dietary protein intake and nutritional status in patients receiving maintenance hemodialysis. It remains uncertain whether the nPCR level is associated with the incidence of bone fracture. A total of 2869 hemodialysis patients registered in the Q-Cohort Study, a multicenter, prospective, observational study, were followed up for 4 years. The primary outcome was bone fracture at any site. The main exposure was the nPCR level at baseline. Patients were assigned to four groups based on their baseline nPCR levels (G1: <0.85, G2: 0.85≤, <0.95, G3: 0.95≤, <1.05 [reference], G4: ≥1.05g/kg/day). We examined the relationship between the nPCR levels and the risk for bone fracture using Cox proportional hazards models. During the follow-up period, 136 patients experienced bone fracture at any site. In the multivariable analyses, the risk for bone fracture was significantly higher in the lowest (G1) and highest (G4) nPCR groups than the reference (G3) group (hazard ratio [95% confidence intervals]: G1, 1.93 [1.04-3.58]; G2, 1.27 [0.67-2.40]; G3 1.00 (reference); G4, 2.21 [1.25-3.92]). The association remained almost unchanged, even when patients were divided into sex-specific nPCR quartiles, when analysis was limited to patients with a dialysis vintage ≥2 years, assumed to have lost residual kidney function, or when a competing risk model was applied. Our results suggest that both lower and higher nPCR levels are associated with an increased risk for bone fracture in hemodialysis patients.