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Medium cut-off (MCO) dialyzers help remove larger middle molecules associated with symptoms related to the accumulation of uremic retention solutes. We investigated the effect of an MCO dialyzer on the improvement of quality of life (QOL) in maintenance hemodialysis (HD) patients. Forty-nine HD patients with high-flux dialysis were randomly assigned to either an MCO (Theranova 400, Baxter) or a high-flux (FX CorDiax 80 or 60, Fresenius Medical Care) dialyzer and completed the study. QOL was assessed at baseline and after 12 weeks of treatment using the Kidney Disease Quality of Life Short Form-36, and pruritus was assessed using a questionnaire and visual analog scale. The reduction ratios of middle molecules were also evaluated. Laboratory markers, including serum albumin, did not differ between the two groups after 12 weeks. Removals of kappa and lambda free light chains were greater for MCO dialyzer than high-flux dialyzer. The MCO group had higher scores than the high-flux group in the domains of physical functioning and physical role (75.2 ± 20.8 vs. 59.8 ± 30.1, P  = 0.042; 61.5 ± 37.6 vs. 39.0 ± 39.6, P  = 0.047, respectively), and the MCO group had lower mean scores for morning pruritus distribution and the frequency of scratching during sleep (1.29 ± 0.46 vs. 1.64 ± 0.64, P  = 0.034; 0.25 ± 0.53 vs. 1.00 ± 1.47, P  = 0.023, respectively). MCO dialyzers may improve patient-reported outcomes, particularly the physical components of QOL and uremic pruritus, in patients with high-flux dialyzers.

Exogenous and endogenous advanced glycation end products (AGEs) contribute to the pathogenesis and progression of renal disease. This is a one-month controlled dietary counseling trial that restricts nutritional AGEs in patients with end-stage renal disease (ESRD) undergoing haemodialysis (n = 22 participants in the intervention and n = 20 participants in the control group). Haematological, biochemical markers, the soluble form of the receptor for AGEs (sRAGE), and carboxymethyl lysine (CML) were measured at baseline and at follow-up. Mononuclear cells were isolated and the protein expression of RAGE and the inflammatory marker COX-2 was measured using Western immunoblotting. The intervention group presented a lower increase in CML compared to the control group (12.39% median change in the intervention vs. 69.34% in the control group, p = 0.013), while RAGE (% mean change −56.54 in the intervention vs. 46.51 in the control group, p < 0.001) and COX-2 (% mean change −37.76 in the intervention vs. 0.27 in the control group, p < 0.001) were reduced compared to the control group. sRAGE was reduced in both groups. In addition, HbA1c (at two months), total cholesterol, and triglycerides were reduced in the intervention versus the control group. The adoption of healthy cooking methods deserves further research as a possible way of modulating inflammatory markers in patients with CKD.

Hyperphosphatemia and calcium load were associated with vascular calcification. The role of calcium-containing phosphate binders (CCPBs) use as important determinants of death and cardiovascular events in predialysis hyperphosphatemic chronic kidney disease (CKD) patients remain unclear due to the absence of evidence for reduced mortality with CCPB use compared with placebo. We aimed to investigate the effect of using CCPBs or nonuse in all-cause mortality rates and cardiovascular events in CKD stage 5 patients between 2000 and 2005 in the Taiwanese National Health Insurance Research Database. Patients with known coronary heart disease and those who had undergone dialysis or renal transplantation were excluded. The CCPB users were matched with nonusers by the propensity score model. Multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) of all-cause mortality and cardiovascular events. During a mean follow-up of 4.58 years, 879 CCPB users were matched with 3516 nonusers. CCPB use was an independent risk factor for cardiovascular events [adjusted hazard ratio (HR) 1.583, 95% confidence interval (CI) 1.393-1.799]. The increased cardiovascular risk was dose-dependent and consistent across all subgroup analyses. Compared with no use, CCPB use was associated with no significant all-cause mortality risk (1.74 vs. 1.75 events per 100 person-years, adjusted HR 0.964, 95% CI 0.692-1.310). CCPB use in CKD stage 5 patients was associated with a significantly increased cardiovascular event risk compared with the nonusers, whereas the all-cause mortality risk was similar between the two groups. Whether these relationships are causal require further randomized controlled trials.

Background. Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. Methods. Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V9.2. Results. 22 subjects (79%) completed the study. Observed trends were as follows (none reaching statistical significance): decline in WBC count (-0.51×109/L, P=0.057) and reductions in levels of C-reactive protein (-8.61 mg/L, P=0.071) and total indoxyl glucuronide (-0.11 mg%, P=0.058). No statistically significant changes were observed in other uremic toxin levels or measures of QOL. Conclusions. Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power—further studies are warranted.

Both the amount of dialysis and the size of the molecules removed may influence morbidity and mortality among patients receiving long-term hemodialysis. The multicenter Hemodialysis Study randomly assigned 1846 patients, according to a two-by-two factorial design, either to the standard dialysis dose currently recommended in the United States or to a high dialysis dose, with either a high-flux or a low-flux dialyzer. Neither mortality from any cause nor morbidity differed between the groups during a mean follow-up of 2.84 years. There was no major benefit from increasing the dialysis dose or from switching to high-flux membranes. Two treatment-related factors implicated in the substantial mortality and morbidity among patients undergoing maintenance hemodialysis 1 are the dose of dialysis delivered and the size of molecules removed. An index of the dialysis dose is the fractional clearance of urea (molecular mass, 60 D) which is commonly expressed as the intradialytic urea-reduction ratio 2 or as Kt/V, where K represents the rate of urea clearance by the dialyzer in milliliters per minute, t the duration in minutes of the treatment session, and V the volume of distribution of urea in the patient in milliliters. 3 Current guidelines in the United States target a . . .

Purpose The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728. Methods A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration ( C max ), area under the concentration–time curve (AUC) from time of dose to 72 h (AUC 72 ), AUC extrapolated to infinity (AUC ∞ ), AUC to last measurable concentration (AUC last ), half-life ( t ½ h), volume of distribution ( V z ), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD. Results Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC 72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC ∞ and AUC last ) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t 1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI. Conclusions Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

Background Infrequent dialysis, namely once-a-week session combined with very low-protein, low-phosphorus diet supplemented with ketoacids was reported as a useful treatment schedule for ESRD patients with markedly reduced residual renal function but preserved urine output. This study reports our findings from the application of a weekly dialysis schedule plus less severe protein restriction (standard low-protein low-phosphorus diet) in stage 5 CKD patients with consistent dietary discipline. Methods This is a multicenter, prospective controlled study, including 68 incident CKD patients followed in a pre-dialysis clinic with Glomerular Filtration Rate 5 to 10 ml/min/1.73/ m 2 who became unstable on the only medical treatment. They were offered to begin a Combined Diet Dialysis Program (CDDP) or a standard thrice-a-week hemodialysis (THD): 38 patients joined the CDDP, whereas 30 patients chose THD. Patients were studied at baseline, 6 and 12 months; hospitalization and survival rate were followed-up for 24 months. Results Volume output and residual renal function were maintained in the CDDP Group while those features dropped quickly in THD Group. Throughout the study, CDDP patients had a lower erythropoietin resistance index, lower β2 microglobulin levels and lower need for cinacalcet of phosphate binders than THD, and stable parameters of nutritional status. At 24 month follow-up, 39.4% of patients were still on CDDP; survival rates were 94.7% and 86.8% for CDDP and THD patients, respectively, but hospitalization rate was much higher in THD than in CDDP patients. The cost per patient per year resulted significantly lower in CDDP than in THD Group. Conclusions This study shows that a CDDP served to protect the residual renal function, to maintain urine volume output and to preserve a good nutritional status. CDDP also blunted the rapid β2 microglobulin increase and resulted in better control of anemia and calcium-phosphate abnormalities. CDDP was also associated with a lower hospitalization rate and reduced need of erythropoietin, as well as of drugs used for treatment of calcium-phosphate abnormalities, thus leading to a significant cost-saving. We concluded that in selected ESRD patients with preserved urine output attitude to protein restriction, CDDP may be a beneficial choice for an incremental hemodialysis program.

Diacerein seems to improve metabolic control and reduce inflammatory marker levels in individuals with type 2 diabetes mellitus (Type 2 DM), but for participants with chronic kidney disease (CKD) its effect is unknown. This study aimed to evaluate the effect of diacerein vs. placebo on urinary albumin/creatinine ratio (ACR), glomerular filtration rate (GFR), and inflammatory cytokines in type 2 DM participants with CKD. Blood pressure (BP) and metabolic control were secondary outcomes. This randomized, placebo-controlled, parallel trial of adjuvant treatment of type 2 DM with diacerein enrolled seventy-two participants with CKD, aged 30-80 years, with glycated hemoglobin levels from 53-97 mmol/mol (7.0-11.0%), receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic agents. Participants randomized to diacerein or placebo were followed-up up to 90 days. Both groups had a marked reduction in ACR, but there was no effect on glomerular filtration rate. While the diacerein group had reduced TNF-α levels at the 75th percentile with a borderline significance (P = 0.05), there were no changes in the IL levels at the 75th percentile. Diacerein prevented the increase in blood glucose to the level observed in the placebo group (P = 0.04), improving metabolic control by 74%, reducing 24-hour diastolic BP, nighttime systolic and diastolic BP compared to the placebo group. In conclusion, among patients with type 2 DM and CKD, diacerein does not have an effect on ACR or GFR, but slows metabolic control deterioration and is associated with lower nighttime systolic and diastolic blood pressure. Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clinicos; ReBeC) U1111-1156-0255.

Background and Objective Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for anti-hyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. Methods Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™). Results Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC ∞ ) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC ∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CL CR ) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC ∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC ∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. Conclusions One-half the usual dose of saxagliptin 5mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CL CR 30–50 mL/min) or severe (CL CR <30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.

Purpose The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m 2 . This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m 2 in normal renal function and ESRD patients. Methods Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m 2 (cycle 1 day 1–2), escalated to 27 mg/m 2 on cycle 1 day 8; if tolerated, 56 mg/m 2 starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively. Results 26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients. Conclusion There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure–response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.