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Effect of urea cream on sorafenib-associated hand-foot skin reaction in patients with hepatocellular carcinoma: A multicenter, randomised, double-blind controlled study.
Lee, YS, Jung, YK, Kim, JH, Cho, SB, Kim, DY, Kim, MY, Kim, HJ, Seo, YS, Yoon, KT, Hong, YM, et al
European journal of cancer (Oxford, England : 1990). 2020;:19-27
Abstract
BACKGROUND Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment in patients with hepatocellular carcinoma (HCC). In the present study, we aimed to investigate the role of urea cream in the prevention of HFSR or amelioration of HFSR severity. PATIENTS AND METHODS Patients with HCC were treated with either placebo cream or urea cream for 12 weeks concomitantly with sorafenib treatment. HFSR development, the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire score, and adverse events were assessed at 2, 4, 8 and 12 weeks. RESULTS Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analysed. The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance. In the incidence by time point, the incidence of severe HFSR of grade II or higher was significantly lower in the urea cream group than in the placebo control group at 2 weeks (13.8% versus 23.9%, P = 0.042). The urea cream group showed a significantly better HF-QoL questionnaire score than the placebo control group (11.8 versus 19.7, P = 0.014) at 12 weeks. CONCLUSIONS Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream may be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib. TRIAL REGISTRATION ClinicalTrials.gov (NCT03212625).
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Urea reduction ratio may be a simpler approach for measurement of adequacy of intermittent hemodialysis in acute kidney injury.
Liang, KV, Zhang, JH, Palevsky, PM
BMC nephrology. 2019;(1):82
Abstract
BACKGROUND Assessment of adequacy of intermittent hemodialysis (IHD) is conventionally based upon urea kinetic models for calculation of single pool Kt/Vurea (Kt/V), with 1.2 accepted as minimum adequate clearance for thrice weekly IHD. In the Acute Renal Failure Trial Network (ATN) Study, adequacy of IHD in patients with acute kidney injury (AKI) was assessed using Kt/V. However, equations for Kt/V require volume of distribution of urea, which is highly variable in AKI. Therefore, simpler methods are needed to assess adequacy of IHD in AKI. We assessed correlation of urea reduction ratio (URR) with Kt/V and determined URR thresholds corresponding to Kt/V values to determine if URR could be a simpler means to assess the delivered dose of IHD. METHODS Using patients who received IHD for 2.5-6 h and with pre-dialysis BUN ≥20 mg/dL, we plotted URR against Kt/V. We determined URR thresholds (0.60 to 0.75) corresponding to Kt/V ≥ 1.2, 1.3, and 1.4. We generated receiver operating characteristic (ROC) curves for increasing URR values for each level of Kt/V to identify the corresponding thresholds of URR. RESULTS There was strong correlation between URR and Kt/V. ROC curves comparing URR with Kt/V ≥ 1.2, 1.3, and 1.4 had area under the curves (AUC) of 0.99. Sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.2 were 0.769 (95% CI: 0.745 to 0.793) and 0.999 (95% CI: 0.997 to 1.000), respectively and the sensitivity and specificity of URR ≥0.67 for corresponding values of Kt/V ≥ 1.4 were 0.998 (95% CI: 0.995 to 1.000) and 0.791 (95% CI: 0.771 to 0.811), respectively. CONCLUSIONS Targeting a URR ≥0.67 provides a simplified means of assessing adequacy of IHD in patients with AKI. Use of URR will enhance ability to assess delivery of small solute clearance and improve adherence with clinical practice guidelines in AKI.
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Does the Blood Pump Flow Rate have an Impact on the Dialysis Dose During Low Dialysate Flow Rate Hemodialysis?
Leclerc, M, Bechade, C, Henri, P, Zagdoun, E, Cardineau, E, Lobbedez, T, Ficheux, M
Blood purification. 2018;(4):279-285
Abstract
We conducted a prospective study to assess the impact of the blood pump flow rate (BFR) on the dialysis dose with a low dialysate flow rate. Seventeen patients were observed for 3 short hemodialysis sessions in which only the BFR was altered (300,350 and 450 mL/min). Kt/V urea increased from 0.54 ± 0.10 to 0.58 ± 0.08 and 0.61 ± 0.09 for BFR of 300, 400 and 450 mL/min. For the same BFR variations, the reduction ratio (RR) of β2microglobulin increased from 0.40 ± 0.07 to 0.45 ± 0.06 and 0.48 ± 0.06 and the RR phosphorus increased from 0.46 ± 0.1 to 0.48 ± 0.08 and 0.49 ± 0.07. In bivariate analysis accounting for repeated observations, an increasing BFR resulted in an increase in spKt/V (0.048 per 100 mL/min increment in BPR [p < 0.05, 95% CI (0.03-0.06)]) and an increase in the RR β2m (5% per 100 mL/min increment in BPR [p < 0.05, 95% CI (0.03-0.07)]). An increasing BFR with low dialysate improves the removal of urea and β2m but with a potentially limited clinical impact.
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Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance.
Matone, A, Scott-Boyer, MP, Carayol, J, Fazelzadeh, P, Lefebvre, G, Valsesia, A, Charon, C, Vervoort, J, Astrup, A, Saris, WH, et al
PloS one. 2016;(3):e0150495
Abstract
BACKGROUND AND SCOPE Weight loss success is dependent on the ability to refrain from regaining the lost weight in time. This feature was shown to be largely variable among individuals, and these differences, with their underlying molecular processes, are diverse and not completely elucidated. Altered plasma metabolites concentration could partly explain weight loss maintenance mechanisms. In the present work, a systems biology approach has been applied to investigate the potential mechanisms involved in weight loss maintenance within the Diogenes weight-loss intervention study. METHODS AND RESULTS A genome wide association study identified SNPs associated with plasma glycine levels within the CPS1 (Carbamoyl-Phosphate Synthase 1) gene (rs10206976, p-value = 4.709e-11 and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tissue showed that CPS1 expression levels were associated with successful weight maintenance and with several SNPs within CPS1 (cis-eQTL). In order to contextualize these results, a gene-metabolite interaction network of CPS1 and glycine has been built and analyzed, showing functional enrichment in genes involved in lipid metabolism and one carbon pool by folate pathways. CONCLUSIONS CPS1 is the rate-limiting enzyme for the urea cycle, catalyzing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria. Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle. Furthermore, glycine could be linked to metabolic health and insulin sensitivity through the betaine osmolyte. These considerations, and the results from the present study, highlight a possible role of CPS1 and related pathways in weight loss maintenance, suggesting that it might be partly genetically determined in humans.
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Stimulated sweating as a therapy to reduce interdialytic weight gain and improve potassium balance in chronic hemodialysis patients: a pilot study.
Pruijm, M, El-Housseini, Y, Mahfoudh, H, Jarraya, F, Hachicha, J, Teta, D, Burnier, M
Hemodialysis international. International Symposium on Home Hemodialysis. 2013;(2):240-8
Abstract
Controlling the extracellular volume in hemodialysis patients is a difficult task. The aim of this study was to evaluate the capacity of different methods of stimulated sweating to reduce mean interdialytic weight gain (IWG), to improve blood pressure regulation, and potassium/urea balance. Two center, crossover pilot study. In Lausanne, hemodialysis patients took four hot-water baths a week, 30 minutes each, on nondialysis days during 1 month. In Sfax, patients visited the local Hammam Center four times a week. Hemodynamic parameters were recorded, and weekly laboratory analysis was performed. Results were compared with a preceding 1-month control period. In Lausanne, five patients (all men, median age 55 years) participated. Bathing temperature was (mean ± standard deviation) 41.2 ± 3°C and sweating-induced weight loss 600 ± 500 g. Mean IWG (control vs. intervention period) decreased from 2.3 ± 0.9 to 1.8 ± 1 kg (P = 0.004), Systolic blood pressure from 139 ± 21 to 136 ± 22 mmHg (P = 0.4), and diastolic blood pressure form 79 ± 12 to 75 ± 13 mmHg (P = 0.08); antihypertensive therapy could be reduced from 2.8 ± 0.4 to 1.9 ± 0.5 antihypertensive drugs per patient (P = 0.01). In Sfax (n = 9, median age 46 years), weight loss per Hammam session was 420 ± 100 g. No differences were found in IWG or BP, but predialysis serum potassium level decreased from 5.9 ± 0.8 to 5.5 ± 0.9 mmol/L (P = 0.04) and urea from 26.9 ± 6 to 23.1 ± 6 mmol/L (P = 0.02). Hot-water baths appear to be a safe way to reduce IWG in selected hemodialysis patients. Hammam visits reduce serum potassium and urea levels, but not IWG. More data in larger patient groups are necessary before definite conclusion can be drawn.
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Survival after treatment with phenylacetate and benzoate for urea-cycle disorders.
Enns, GM, Berry, SA, Berry, GT, Rhead, WJ, Brusilow, SW, Hamosh, A
The New England journal of medicine. 2007;(22):2282-92
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Abstract
BACKGROUND The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects. METHODS We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia. RESULTS Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes. CONCLUSIONS Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.
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Nutritional therapy improves growth and protein status of children with a urea cycle enzyme defect.
Acosta, PB, Yannicelli, S, Ryan, AS, Arnold, G, Marriage, BJ, Plewinska, M, Bernstein, L, Fox, J, Lewis, V, Miller, M, et al
Molecular genetics and metabolism. 2005;(4):448-55
Abstract
BACKGROUND Poor growth has been described in patients with urea cycle enzyme defects treated with protein-restricted diets, while protein status is seldom reported. OBJECTIVE To assess the effects of nutritional therapy with a medical food on growth and protein status of patients with a urea cycle enzyme defect. METHODS A 6-mo multicenter outpatient study was conducted with infants and toddlers managed by nutrition therapy with Cyclinex-1 Amino Acid-Modified Medical Food with Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome variables were anthropometrics and plasma amino acids (selected), albumin, and transthyretin concentrations. RESULTS Seventeen patients completed the study. Mean (+/-SE) baseline age was 11.30+/-3.20 months (median 4.40 months; range 0.22-38.84 months). Length and weight z-scores increased significantly during the 6-month study. Head circumference increased, but not significantly. Three patients were stunted and two were wasted (-2.0 z-score) at baseline while at study end, only one patient was both stunted and wasted. The majority of patients increased in length, head circumference, and weight z-scores during study. Mean (+/-SE) plasma albumin concentration increased from 34+/-2g/L at baseline to 38+/-1g/L at study end. Plasma transthyretin increased from a mean (+/-SE) of 177+/-13 mg/L at baseline to 231+/-15 mg/L at study end. No correlation was found between plasma NH(3) concentrations and medical food intake. Plasma NH(3) concentration was positively correlated with the percentage of Food and Agriculture Organization/World Health Organization/United Nations recommended protein ingested. CONCLUSIONS Intakes of adequate protein and energy for age result in anabolism and linear growth without increasing plasma NH(3) concentrations. Medical food intakes did not correlate with plasma NH(3) concentrations.
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Is decreased treatment time in hemodialysis patients harmful if solute clearance is maintained?
Hartley, GH, Goodship, TH, Hoenich, NA, Hawkins, T, Fawcett, PR, McHugh, Ml, Tapson, JS
The International journal of artificial organs. 2002;(9):844-51
Abstract
An association between decreased duration of hemodialysis and increased morbidity and mortality in patients has been suggested. Whether this is due only to decreased solute clearance is unclear. In this prospective randomised study the effect of reducing treatment time whilst maintaining constant solute clearance was examined in fourteen patients. The study lasted for a period of 36 weeks (3x12 week study periods) and used a crossover design. The patients dialysis prescription (KW) was not changed on entering the study and was maintained during short (150 minutes) and long dialysis (240 minutes) by varying blood flow, dialysate flow and dialyzer surface area. The delivered KW was kinetically assessed. Fractional urea clearance was also measured during each treatment period by measurement of urea concentration in spent dialysate and total body water using 3H2O. At the end of each treatment period a full biochemical and hematological profile, nutritional intake and status, 24 h ambulatory blood pressure, nerve conduction studies, and quality of life questionnaire were performed. Within patients the delivered single pool KW was uniform throughout the 3 treatment periods and fractional urea clearance did not vary. However, Kt/W assessed using equilibrated models (Daugardis and Smye) was significantly lower in the short dialysis period. No differences between short and long dialysis sessions were noted in any of the measured variables. Thus, over a 36 week period there is no evidence to suggest that hemodialysis patients are adversely affected by decreased duration of treatment provided that solute clearance is maintained.
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Estimating phosphate removal in haemodialysis: an additional tool to quantify dialysis dose.
Gutzwiller, JP, Schneditz, D, Huber, AR, Schindler, C, Gutzwiller, F, Zehnder, CE
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002;(6):1037-44
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Abstract
BACKGROUND Half of the dialysis population suffers from hyperphosphataemia, which is now recognized as a major factor of haemodialysis (HD) morbidity and mortality. Current control is focussed on reducing dietary phosphate intake and diminishing absorption using phosphate binders, whereas control and quantification of phosphate removal by HD is undervalued. The aim of this prospective study was to develop a simple, bedside formula to estimate dialytic phosphate removal in stable HD patients. METHODS This was a prospective, randomized trial. Phosphate and urea elimination were assessed in a representative group of patients at two dialysis centres using randomly different dialysers (1.3-2.4 m(2)). Quantification was performed by partial dialysate collection, concentration measurements in blood and effluent dialysate spot samples, and Kt/V(urea) during standard high-flux HD. Multiple linear regression analyses were used in 77% of all data sets to generate an equation to predict phosphate removal. The formula was validated in the remaining 23% of data sets, in the same group of patients using a large capillary filter, and in diabetic patients treated with a small dialyser at different blood flows (200, 250, and 300 ml/min). RESULTS A formula allowing quantification of phosphate removal within one HD session was developed in 18 of 74 patients during 41 treatments (137 out of 177 data sets) and was determined as: M(PO4pred)=0.1t -17+50c(ds60)+11c(b60), where t is treatment time in min, c(ds60) and c(b60) are phosphate concentrations in dialysate and plasma measured 60 min into HD in mmol/l, and M(PO4pred) is estimated phosphate removed in mmol. The precision was remarkable (r(2)=0.92-0.94). The comparison of phosphate and Kt/V(urea) showed a significant association (r(2)=0.28), albeit with remarkable scatter. CONCLUSIONS We present the first approach to quantify phosphate removal during high-flux HD by a bedside formula. Only 28% of the variation in phosphate removal was explained by Kt/V(urea). It appears that other factors not adequately accounted for by Kt/V(urea) affect phosphate removal. Therefore, we propose an individual control and quantification of phosphate removal in HD.