Publications by authors named "Salim Mujais"

35 Publications

Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi.

Antimicrob Agents Chemother 2017 12 22;61(12). Epub 2017 Nov 22.

Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship ( > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.
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http://dx.doi.org/10.1128/AAC.01034-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700339PMC
December 2017

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics.

Eur J Clin Pharmacol 2017 Jun 7;73(6):669-678. Epub 2017 Mar 7.

Global Clinical Pharmacology and Exploratory Development Science, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA.

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 ), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC), AUC extrapolated to infinity (AUC), AUC to last measurable concentration (AUC), half-life (t h), volume of distribution (V ), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD.

Results: Isavuconazole C 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 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC and AUC) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t (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 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 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.
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http://dx.doi.org/10.1007/s00228-017-2213-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423998PMC
June 2017

Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment.

Antimicrob Agents Chemother 2016 05 22;60(5):3025-31. Epub 2016 Apr 22.

Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.

Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment.
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http://dx.doi.org/10.1128/AAC.02942-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862513PMC
May 2016

Comparison of the safety, tolerability, and pharmacokinetics of fidaxomicin in healthy Japanese and caucasian subjects.

Clin Drug Investig 2015 Jun;35(6):375-84

Astellas Pharma Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan,

Background And Objectives: Fidaxomicin treatment of Clostridium difficile infection is known to produce minimal systemic exposure, as the antibacterial (antibiotic) remains primarily in the gut. In this randomized, double-blind, placebo-controlled study, the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of fidaxomicin were evaluated in healthy Japanese and Caucasian subjects.

Methods: Thirty-six healthy subjects were randomly assigned in a 3:1 ratio to receive either fidaxomicin or placebo. Cohort 1 (100 mg) and Cohort 2 (200 mg) comprised 12 Japanese subjects each and Cohort 3 (200 mg) comprised 12 Caucasian subjects. Subjects received a single dose of the study drug on Day 1 and received multiple doses for 10 days after a wash-out period.

Results: After multiple 200 mg dosing of fidaxomicin, both mean maximum plasma concentrations (C max) in Japanese (8.7 ± 5.3 ng/mL) and Caucasian (7.0 ± 3.7 ng/mL) subjects and the area under the concentration-time curve (AUC) were higher in Japanese subjects (58.5 ± 36.7 ng·h/mL) than in Caucasian subjects (37.6 ± 15.7 ng·h/mL), although variation in both groups was large. The mean fecal concentrations of fidaxomicin in Japanese and Caucasian subjects were 2669 and 2181 μg/g, respectively. The possibly study drug-related adverse events were diarrhea (n = 1), feeling hot (n = 1), and hypersomnia (n = 2), which were mild in severity.

Conclusions: In both Japanese and Caucasian subjects, fidaxomicin demonstrated similarly minimal systemic absorption, and was mainly excreted in feces. Fidaxomicin was safe and well-tolerated in all subjects.
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http://dx.doi.org/10.1007/s40261-015-0291-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449367PMC
June 2015

Glucoregulatory hormones and choice of osmotic agent in peritoneal dialysis.

Perit Dial Int 2010 Nov-Dec;30(6):626-32. Epub 2010 Apr 26.

Astellas Pharma Global Development, Deerfield, Illinois, USA.

Objective: The present study was performed to explore the range of effects of amino acid-based peritoneal dialysis (PD) solutions on glucoregulatory hormones in comparison with an osmotically equivalent glucose-based solution. ♢

Methods: 13 adult nondiabetic patients on PD underwent 2 peritoneal dwells of 2 hours' duration with either 1.5% dextrose solution or 1.1% amino acid solution. Serial sampling for glucoregulatory hormones was done throughout the duration of the dwell. ♢

Results: Instillation of the 1.5% dextrose solution resulted in a modest change in plasma glucose, paralleled by a small increase in plasma insulin levels and plasma insulin-like growth factor (IGF-1). Plasma glucagon was not changed and plasma growth hormone level declined. Instillation of the 1.1% amino acid solution resulted in an increase in plasma glucose, plasma insulin, plasma glucagon, and plasma IGF-1. Plasma growth hormone level declined. Both solutions led to an increase in plasma norepinephrine but no changes were observed in epinephrine or dopamine. ♢

Conclusions: Our observations suggest that the mere replacement of glucose by amino acids in PD solutions does not necessarily imply "glucose sparing" from the perspective of induction of a glucoregulatory hormonal response because of the aminogenic stimulation of secretion of multiple hormones.
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http://dx.doi.org/10.3747/pdi.2009.00107DOI Listing
December 2011

Metabolic effects of incremental doses of intraperitoneal amino acids on automated peritoneal dialysis.

Perit Dial Int 2010 Mar-Apr;30(2):201-7. Epub 2010 Feb 11.

Division of Nephrology, Department of Medicine, The University of Ottawa, Ottawa, Ontario, Canada.

Background: The use of amino acid (AA) dialysate to ameliorate protein-energy malnutrition has been limited by adverse metabolic effects.

Objective: We undertook this study to examine the acute metabolic effects of escalating doses of AAs delivered with lactate/bicarbonate dialysate on automated peritoneal dialysis (APD).

Patients And Methods: 12 APD patients were treated with conventional lactate-buffered dialysate (week 1), followed by lactate/bicarbonate-buffered dialysate (week 2), then 2 - 2.5 L 1.1% AA solution were added (week 3), and then an additional 2 - 2.5 L 1.1% AA were added (week 4). The primary outcomes were change in serum bicarbonate and pH, change in protein catabolic rate (PCR), and change in normalized ultrafiltration (milliliters/gram of carbohydrate infused).

Results: Serum bicarbonate rose from week 1 to week 2 (28.9 +/- 3.2 vs 26.9 +/- 4.1 mmol/L, p = 0.03). Addition of one bag of AAs led to a decline in plasma bicarbonate (26.9 +/- 2.1 vs 28.9 +/- 3.2 mmol/L, p < 0.01), which was further magnified by the addition of the second bag of AAs (23.8 +/- 2.7 vs 26.9 +/- 2.1 mmol/L, p < 0.01). Serum bicarbonate fell significantly by week 4 compared to week 1 (23.8 +/- 2.7 vs 26.9 +/- 3.2 mmol/L, p < 0.01) although there was no significant change in venous pH or PCR when week 4 was compared to week 1. Normalized ultrafiltration was stable for the first 3 weeks but rose significantly in week 4 compared to week 1 (5.32 +/- 2.30 vs 4.14 +/- 1.58 mL/g, p = 0.03).

Conclusions: Higher doses of AAs mixed with newer bicarbonate/lactate dialysate on APD result in a small decrease in serum bicarbonate but improved normalized ultrafiltration. This merits further study as both a nutritional supplement and a glucose-sparing strategy.
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http://dx.doi.org/10.3747/pdi.2009.00040DOI Listing
July 2011

Health-related quality of life in CKD Patients: correlates and evolution over time.

Clin J Am Soc Nephrol 2009 Aug 30;4(8):1293-301. Epub 2009 Jul 30.

Astellas Pharma Global Development, Three Parkway North, Deerfield, IL 60015, USA.

Background And Objectives: Very few large-scale studies have investigated the determinants of health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients not on dialysis or the evolution of HRQOL over time.

Design And Setting: A prospective evaluation was undertaken of HRQOL in a cohort of 1186 CKD patients cared for in nephrology clinics in North America. Baseline and follow-up HRQOL were evaluated using the validated Kidney Disease Quality Of Life instrument.

Results: Baseline measures of HRQOL were reduced in CKD patients in proportion to the severity grade of CKD. Physical functioning score declined progressively with more advanced stages of CKD and so did the score for role-physical. Female gender and the presence of diabetes and a history of cardiovascular co-morbidities were also associated with reduced HRQOL (physical composite score: male: 41.0 +/- 10.2; female: 37.7 +/- 10.8; P < 0.0001; diabetic: 37.3 +/- 10.6; nondiabetic: 41.6 +/- 10.2; P < 0.0001; history of congestive heart failure, yes: 35.4 +/- 9.7; no: 40.3 +/- 10.6; P < 0.0001; history of myocardial infarction, yes: 36.1 +/- 10.0; no: 40.2 +/- 10.6; P < 0.0001). Anemia and beta blocker usage were also associated with lower HRQOL scores. HRQOL measures declined over time in this population. The main correlates of change over time were age, albumin level and co-existent co-morbidities.

Conclusions: These observations highlight the profound impact CKD has on HRQOL and suggest potential areas that can be targeted for therapeutic intervention.
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http://dx.doi.org/10.2215/CJN.05541008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723973PMC
August 2009

Health-related quality of life and hemoglobin levels in chronic kidney disease patients.

Clin J Am Soc Nephrol 2009 Jan 5;4(1):33-8. Epub 2008 Nov 5.

Hospital of St Raphael, Yale University, New Haven, CT 06511, USA.

Background: The relationship between quality of life (QofL) and anemia has been the subject of recent debates; it has been suggested that the QofL changes associated with the treatment of anemia of chronic kidney disease (CKD) or ESRD patients should not be used in making decisions to treat anemia in CKD patients.

Design, Setting, Participants, & Measurements: This study examines the relationship between Kidney Disease Quality of Life (KDQofL) questionnaire domains and hemoglobin (Hgb) levels in 1200 patients with stage 3, 4, and 5 CKD followed in seven centers. QofL measures were compared in a stepwise fashion for hemoglobin levels of <11, 11 to <12, 12 to <13, and > or =13. ANOVA was used to examine the relationship between QofL scores and Hgb level, age, CKD stage, and albumin level; a history of diabetes, congestive heart failure, or myocardial infarction; use of erythropoetic-stimulating agents (ESA); and the interaction of hemoglobin level and ESA.

Results: The results demonstrate that with increasing Hgb levels there is a statistically significant increase in all four physical domains, the energy/vitality domain, and the physical composite score of the SF-36, and the general health score on the kidney disease component of the questionnaire. The most dramatic improvements in these various domains occurred between the <11 and the 11 to 12 group.

Conclusions: Higher Hgb levels are associated with improved QofL domains of the KDQofL questionnaire. These findings have implications for the care of CKD patients in terms of the initiation of and the Hgb target of ESA therapy.
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http://dx.doi.org/10.2215/CJN.00630208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2615698PMC
January 2009

A prospective evaluation of renal replacement therapy modality eligibility.

Nephrol Dial Transplant 2009 Feb 28;24(2):555-61. Epub 2008 Aug 28.

Humber River Regional Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: Patient eligibility for renal replacement therapy (RRT) modalities is frequently debated, but little prospective data are available from large patient cohorts.

Methods: We prospectively evaluated medical and psychosocial eligibility for the three RRT modalities in patients with chronic kidney disease (CKD) stages III-V who were enrolled in an ongoing prospective cohort study conducted at seven North American nephrology practices.

Results: Ninety-eight percent of patients were considered medically eligible for haemodialysis (HD), 87% of patients were assessed as medically eligible for peritoneal dialysis (PD) and 54% of patients were judged medically eligible for transplant. Age was the leading cause of non-eligibility for both PD and transplant. Anatomical concerns (adhesions, hernias) were the second most frequent concern for PD eligibility followed by weight. Weight was also a concern for transplant eligibility. The proportion of patients medically eligible for RRT did not vary by CKD stage. There was, however, significant inter-centre variation in the proportion of patients medically eligible for PD and transplant. Ninety-five percent of patients were considered psychosocially eligible for HD, 83% of patients were assessed as psychosocially eligible for PD and 71% of patients were judged psychosocially eligible for transplant. The percentage of patients who were assessed as having neither medical nor psychosocial contraindications for RRT was 95% for HD, 78% for PD and 53% for transplant.

Conclusions: Most CKD patients are considered by their medical care providers to be suitable for PD. Enhanced patient education, promotion of home dialysis for suitable patients and empowerment of patient choice are expected to augment growth of home dialysis modalities.
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http://dx.doi.org/10.1093/ndt/gfn484DOI Listing
February 2009

Perceived knowledge among patients cared for by nephrologists about chronic kidney disease and end-stage renal disease therapies.

Kidney Int 2008 Nov 30;74(9):1178-84. Epub 2008 Jul 30.

Hospital of St. Raphael, Yale University, New Haven, Connecticut 06511, USA.

The need to educate patients in order to enable them to participate in making appropriate choices for all therapeutic options in end stage renal disease would seem obvious yet there are many barriers to providing such information. We measured 'perceived knowledge' of the therapeutic options for end stage renal disease in a cohort of patients with chronic kidney disease in established treatment programs. A self administered questionnaire was given to 676 patients with stage 3-5 chronic kidney disease as part of the CRIOS study designed to identify trends in practice patterns and outcomes over a 4 year period. The median patient age was 66, about three-fourths were Caucasian and almost half were diabetic. When patients were asked to rate their level of knowledge, about one-third reported limited or no understanding of their chronic kidney disease and no awareness regarding their treatment options. A significant and substantial number of patients indicated they had no familiarity with transplant, hemodialysis, and continuous ambulatory or automated peritoneal dialysis. Perceived knowledge improved with the progression of kidney disease and frequency of nephrology visits; however, only about half of patients with 4 or more nephrology appointments in the prior year reported knowing of hemodialysis, continuous ambulatory peritoneal dialysis or transplant. Age, gender and disease had no impact on levels of patient knowledge, but African-Americans reported having significantly less understanding than Asians or Caucasians. These findings suggest that the lack of perception concerning the treatment options chronic kidney and end stage renal disease reflects, in part, problems with the education of patients by nephrologists and not a lack of referral of these patients to nephrologists for care. The discrepancy of perceived knowledge between African-Americans and other races needs special attention.
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http://dx.doi.org/10.1038/ki.2008.376DOI Listing
November 2008

Predictive value of brain natriuretic peptides in patients on peritoneal dialysis: results from the ADEMEX trial.

Clin J Am Soc Nephrol 2008 Mar 16;3(2):407-15. Epub 2008 Jan 16.

Mexican Nephrology Collaborative Study Group, Unidad de Investigacioñ Médica en Enfermedades Nefrolìicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Background And Objectives: Natriuretic peptides have been suggested to be of value in risk stratification in dialysis patients. Data in patients on peritoneal dialysis remain limited.

Design, Setting, Participants, & Measurements: Patients of the ADEMEX trial (ADEquacy of peritoneal dialysis in MEXico) were randomized to a control group [standard 4 x 2L continuous ambulatory peritoneal dialysis (CAPD); n = 484] and an intervention group (CAPD with a target creatinine clearance > or =60 L/wk/1.73 m(2); n = 481). Natriuretic peptides were measured at baseline and correlated with other parameters as well as evaluated for effects on patient outcomes.

Results: Control group and intervention group were comparable at baseline with respect to all measured parameters. Baseline values of natriuretic peptides were elevated and correlated significantly with levels of residual renal function but not with body size or diabetes. Baseline values of N-terminal fragment of B-type natriuretic peptide (NT-proBNP) but not proANP(1-30), proANP(31-67), or proANP(1-98) were independently highly predictive of overall survival and cardiovascular mortality. Volume removal was also significantly correlated with patient survival.

Conclusions: NT-proBNP have a significant predictive value for survival of CAPD patients and may be of value in guiding risk stratification and potentially targeted therapeutic interventions.
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http://dx.doi.org/10.2215/CJN.03820907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2390944PMC
March 2008

Comparison between bicarbonate/lactate and standard lactate dialysis solution in peritoneal transport and ultrafiltration: a prospective, crossover single-dwell study.

Perit Dial Int 2008 Jan-Feb;28(1):35-43

Peritoneal Dialysis Program, University Health Network, and University of Toronto, Toronto, Ontario, Canada.

Objective: It has been proposed that biocompatible bicarbonate/lactate based (Bic/Lac), physiologic-pH peritoneal dialysis (PD) solutions will be beneficial in long-term PD. However, we do not yet have detailed knowledge concerning the comparative physiology of buffer transport for these new solutions and their impact on underlying peritoneal transport of solutes and ultrafiltration (UF). The purpose of this study was to investigate the profile of buffer handling and peritoneal membrane transport characteristics during a single dwell of the new Bic/Lac-based versus standard lactate-based (Lac) PD solution.

Methods: In this prospective crossover study, we compared a 25 mmol/L bicarbonate/15 mmol/L lactate buffered, physiologic pH, low glucose degradation product (GDP) solution (Physioneal; Baxter Healthcare, McGaw Park, Illinois, USA) with a standard lactate buffered, acidic pH, conventional solution (Dianeal; Baxter). 18 patients underwent two peritoneal equilibration tests (PETs) with 2.5% Dianeal and 2.5% Physioneal separated by 1 week. Buffer transport, mass transfer area coefficients (MTACs), solute transport, and UF were determined for the two PETs. All bags were weighed by a nurse before instillation and after drainage to assess the net UF in each dwell.

Results: 18 patients that met the inclusion criteria were enrolled in this study. Whereas intraperitoneal pH remained constant at 7.52 +/- 0.11 throughout the dwell with the Bic/Lac solution, pH was still in the acidic range with the Lac solution after 1 hour (7.29 +/- 0.13, p < 0.001); this difference disappeared after the second hour of dwell. The MTACs for creatinine (10.68 +/- 3.66 vs 10.73 +/- 2.96 mL/minute/1.73 m(2), p > 0.05) and urea (27.94 +/- 10.50 vs 27.62 +/- 6.95 mL/min/1.73 m(2), p > 0.05), for Bic/Lac versus Lac respectively, did not differ between these two solutions; transport of glucose and other solutes was also similar. However, after a 4-hour dwell with Bic/Lac solution, net UF was significantly lower than that observed with Lac solution (274.2 +/- 223.3 mL vs 366.1 +/- 217.3 mL, p = 0.026).

Conclusions: Compared to standard Lac-based solution, Bic/Lac based, pH neutral, low-GDP solution avoids intraperitoneal acidity. Peritoneal mass transport kinetics are similar for small solutes. Net UF is significantly lower with Bic/Lac solution; the mechanism for this is unclear.
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June 2008

Improving cycler prescriptions in peritoneal dialysis through informatic profiling.

Adv Chronic Kidney Dis 2007 Jul;14(3):263-8

Renal Division, Baxter Healthcare Corporation, McGaw Park, IL, USA.

Cycler-based dialysis is the most common form of peritoneal dialysis in the United States of America, accounting for more than two thirds of patients on the modality. The advent of modern cyclers has enhanced the accessibility of therapy-delivery data. Cyclers have transformed peritoneal dialysis from an unobserved home therapy into an observable home therapy on many levels. We will discuss 3 of these levels herein. The ability to profile prescription behavior at a population level with attention to fill volume, number of cycles used per night, and total time on the cycler will be analyzed. Insights into the dynamics of flow during cycler therapy and the concept of transition point will then be explored. Finally, we will review the impact on patient care of making the delivery of the dialysis prescription easily observable to the medical team. It is our contention that these 3 levels of profiling offer practical lessons to enhance delivery of care for patients on cycler-based peritoneal dialysis.
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http://dx.doi.org/10.1053/j.ackd.2007.04.001DOI Listing
July 2007

Why is the evidence favoring hemodialysis over peritoneal dialysis misleading?

Semin Dial 2007 May-Jun;20(3):200-2

Division of Nephrology, Department of Medicine, Wake Forest University Medical Center, Winston-Salem, North Carolina 27157-1053, USA.

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http://dx.doi.org/10.1111/j.1525-139X.2007.00274.xDOI Listing
July 2007

ADEMEX: the evidence and the nephrosopher.

Perit Dial Int 2007 May-Jun;27(3):234-7

Baxter Healthcare Corporation, 1620 Waukegan Road, McGaw Park, IL 60085, USA.

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August 2007

Impact of initial dialysis modality and modality switches on Medicare expenditures of end-stage renal disease patients.

Kidney Int 2005 Jul;68(1):319-29

Departement of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.

Background: The number of end-stage renal disease (ESRD) enrollees and Medicare expenditures have increased dramatically. Pathways and associated Medicare expenditures in ESRD treatment need to be examined to potentially improve the efficiency of care.

Methods: This study examines the impact of initial dialysis modality choice and subsequent modality switches on Medicare expenditure in a 3-year period. The Dialysis Morbidity and Mortality Study Wave 2 data by the United States Renal Data System (USRDS) is used along with the USRDS Core CD and USRDS claims data.

Results: A total of 3423 incident dialysis patients (approximately equal number of peritoneal dialysis and hemodialysis) were included in the analysis. Unadjusted average annual Medicare expenditure (in 2004 dollars) for peritoneal dialysis as first modality was 53,277 dollars(95% CI 50,626 dollars-55,927 dollars), and 72,189 dollars (95% CI 67,513 dollars-76,865 dollars) for hemodialysis. Compared to "hemodialysis, no switch" subgroup, "peritoneal dialysis, no switch" had a significantly lower annual expenditure (44,111 dollars vs. 72,185 dollars) (P < 0.001). "Peritoneal dialysis, with at least one switch" and "hemodialysis, with at least one switch" had a lower or similar annual expenditure of 66,639 dollars and 72,335 dollars, respectively. After adjusting for patient characteristics, annual Medicare expenditure was still significantly lower for patients with peritoneal dialysis as the initial modality (56,807 dollars vs. 68,253 dollars) (P < 0.001). Similarly, compared to "hemdialysis, no switch" subgroup, "peritoneal dialysis, no switch" and "peritoneal dialysis, with at least one switch" had a significantly lower total expenditure. Further analysis showed that time-to-first switch also independently impacted total expenditure.

Conclusion: Initial modality choice (peritoneal dialysis or hemodialysis) and subsequent modality switches had significant implications for Medicare expenditure on ESRD treatments.
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http://dx.doi.org/10.1111/j.1523-1755.2005.00413.xDOI Listing
July 2005

Health-related quality of life predicts outcomes but is not affected by peritoneal clearance: The ADEMEX trial.

Kidney Int 2005 Mar;67(3):1093-104

Unidad de Investigacion Médica en Enfermedades Nefrolgicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Background: We hypothesized that increasing small solute clearance in peritoneal dialysis (PD) would lead to improvements in patient health-related quality of life (HRQOL).

Methods: Patients were randomized to a control group [standard 4 x 2 L continuous ambulatory peritoneal dialysis (CAPD)] and an intervention group (CAPD with a target creatinine clearance >/=60 L/week/1.73 m(2)). The Kidney Disease Quality of Life Short Form was obtained at baseline and at 6, 12, and 24 months. Physical (PCS), mental (MCS), and kidney disease component summary (KDCS) scores were computed.

Results: The two groups were comparable at baseline with respect to HRQOL. Baseline variables highly predictive of better QOL included absence of diabetes, younger age, higher starting GFR, and serum albumin. Baseline values of QOL were highly predictive of survival and hospitalizations. An unadjusted comparison revealed that patients in the intervention group had significantly higher PCS and KDCS scores at six months. However, there were no significant differences between the intervention and control patients at 12 or 24 months. When similar analyses were carried out adjusting for different patterns of patient dropout, there were no significant differences between the two groups at any time point in terms of PCS, MCS, and KDCS scores.

Conclusion: We found no evidence of a long-term benefit in HRQOL of CAPD patients by increasing peritoneal small-solute clearances when HRQOL parameters were adjusted for patient dropout. Measures of HRQOL have a significant predictive value for patient survival and hospitalizations.
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http://dx.doi.org/10.1111/j.1523-1755.2005.00175.xDOI Listing
March 2005

Superiority of icodextrin compared with 4.25% dextrose for peritoneal ultrafiltration.

J Am Soc Nephrol 2005 Feb 29;16(2):546-54. Epub 2004 Dec 29.

Yale University School of Medicine, New Haven, CT, USA.

Several clinical observations suggest the superiority of icodextrin compared with 4.25% dextrose in optimizing peritoneal ultrafiltration (UF), but no rigorous controlled evaluation has hitherto been performed. For comparing icodextrin and 4.25% dextrose during the long dwell of automated peritoneal dialysis, a multicenter, randomized, double-blind trial was conducted in 92 patients (control, 45; icodextrin, 47) with 4-h dialysate to plasma ratio creatinine >0.70 and D/D(0) glucose <0.34. Long-dwell net UF and the UF efficiency ratio (net UF volume per gram of dialysate carbohydrate absorbed) were determined at baseline, week 1, and week 2. The control and treatment groups were comparable at baseline (all patients using 4.25% dextrose for the long dwell) with regard to mean (+/-SEM) net UF (201.7 +/- 103.1 versus 141.6 +/- 75.4 ml, respectively; P = 0.637) and the percentage of patients with negative net UF (control, 37.8%; treatment, 42.6%; P = 0.641). During the study period, net UF was unchanged from baseline in the control group but increased significantly (P < 0.001) in the icodextrin group from 141.6 +/- 75.4 to 505.8 +/- 46.8 ml at week 1 and 540.2 +/- 46.8 ml at week 2. In the icodextrin group, the incidence of negative net UF was significantly lower (P < 0.0001) than in the control group. Findings were similar for UF efficiency ratio. Rash was reported significantly more often in the icodextrin group. This study showed that in high-average and high transporters, icodextrin is superior to 4.25% dextrose for long-dwell fluid and solute removal.
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http://dx.doi.org/10.1681/ASN.2004090793DOI Listing
February 2005

Impact of fill volume on peritoneal clearances and cytokine appearance in peritoneal dialysis.

Perit Dial Int 2004 Mar-Apr;24(2):156-62

Unidad de Investigación Médica en Enfermedades Nefrológicas, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, Col. Doctores, DF, México.

Background: Current adequacy guidelines for peritoneal dialysis encourage the use of large fill volumes for the attainment of small solute clearance targets. These guidelines have influenced clinical practice in a significant way, and adoption of higher fill volumes has become common in North America. Several studies, however, have challenged the relevance of increasing small solute clearance; this practice may result in untoward consequences in patients.

Objective: The present study was designed to explore the relationship between dialysate volume and the clearance of different sized molecules, fluid dynamics, and appearance of peritoneal cytokines.

Methods: Thirteen adult prevalent patients on continuous ambulatory peritoneal dialysis were studied. Three different dialysate volumes (2.0, 2.5, and 3.0 L) were infused on consecutive days in a random order. Several measurements of peritoneal fluid dynamics (intraperitoneal pressure, net ultrafiltration, fluid absorption), solute clearances (urea, creatinine, beta2-microglobulin, albumin, IgG, and transferrin), and appearance of interleukin-6 and tumor necrosis factor alpha (TNFalpha) were assessed.

Results: Increase in dialysate fill volume (from 2 to 2.5 to 3 L) was examined in relationship to body surface area (BSA). The dialysate volume/BSA (DV/BSA) ratio increased from 1262 to 1566 to 1871 mL/m2 on 2.0, 2.5, and 3.0 L dialysate volumes, respectively. In parallel, diastolic blood pressure increased from 82.7 +/- 8.8 to 87.0 +/- 9.5 to 92 +/- 8.3 mmHg (p < 0.05). Net ultrafiltration rate also increased, from 0.46 +/- 0.48 to 0.72 +/- 0.42 to 0.97 +/- 0.49 mL/minute (p < 0.01), despite a concomitant increase in fluid absorption, from 1.05 +/- 0.34 to 1.21 +/- 0.40 to 1.56 +/- 0.22 mL/min (p < 0.01). Urea peritoneal clearance increased from 8.27 +/- 0.68 to 9.92 +/- 1.6 to 12.98 +/- 4.03 mL/min (p < 0.01); creatinine peritoneal clearance increased from 6.69 +/- 1.01 to 7.64 +/- 1.12 to 8.69 +/- 1.76 mL/min (p < 0.01). Clearance of the other measured molecules did not change. Appearance of interleukin-6 increased 17% and 43% (p < 0.01), and TNFalpha appearance increased 14% and 50% (p < 0.01) when dialysate volumes of 2.5 and 3.0 L were used, compared with 2.0 L.

Conclusions: These results show that, with higher values of DV/BSA ratio, small solute peritoneal clearance is increased, but clearances of large molecules remain unchanged. With the use of higher volumes, fluid absorption rate and the appearance of proinflammatory cytokines in the dialysate are increased.
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August 2004

Buffer transport in peritoneal dialysis.

Kidney Int Suppl 2003 Dec(88):S37-42

Division of Renal Medicine, Department of Clinical Sciences, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.

Buffer transport in peritoneal dialysis. The success of peritoneal dialysis as a robust modality of renal replacement therapy has invited a quest for ameliorations in its underlying technology aimed at enhancing patient satisfaction and preserving the central instrument of the therapy, namely the peritoneal membrane. The health and longevity of the membrane have motivated and continue to drive a series of iterative innovations in the composition, methods of production, and delivery of dialysis solutions. It is the purpose of this article to review aspects of these innovations pertaining to buffer composition in dialysis solutions and the peritoneal mechanisms of buffer transport.
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http://dx.doi.org/10.1046/j.1523-1755.2003.08804.xDOI Listing
December 2003

Acid-base profile in patients on PD.

Authors:
Salim Mujais

Kidney Int Suppl 2003 Dec(88):S26-36

Renal Division, Baxter Healthcare Corporation, McGaw Park, Illinois, USA.

Acid-base profile in patients on PD. Secular trends in dialysis dose in peritoneal dialysis (PD) and modes of dialysis delivery [automated PD (APD) versus continuous ambulatory PD (CAPD)] require a reexamination of acid-base status in patients treated with these renal replacement modalities. We explored steady-state acid-base profile and its determinants in 175 patients on CAPD and 77 patients on APD. The majority (62% to 70%) of patients had serum bicarbonate levels in the normal range, and a minority (17% to 27%) had values just above 28 mEq/L. Only a small percentage (10% to 12%) of patients in either the CAPD or the APD groups had a serum HCO3 less than 22 mEq/L, an indication of the successful correction of acidosis in most patients. The anion gap was elevated (> 16 mEq/L) in the majority of patients on CAPD and APD and bore an inverse relationship to serum HCO3 and a direct relationship to serum albumin and serum phosphate. In CAPD patients, but not APD patients, a significant inverse relationship was observed between the anion gap and peritoneal permeability as assessed by four-hour D/P(creatinine). The correction of acidosis in PD appears to be predominantly achieved by the continuous supplementation of alkali via dialysis, with residual renal function not differentiating the degree of correction. Steady-state serum bicarbonate in patients on CAPD appeared to be responsive to the underlying peritoneal membrane permeability characteristics of the patient that govern alkali loss and gain, but the higher dialysate volumes in APD appear to override this effect. Higher albumin, blood urea nitrogen (BUN), and phosphate in patients with lower HCO3 suggest a discrepancy between daily acid load and dialysis dose.
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http://dx.doi.org/10.1046/j.1523-1755.2003.08803.xDOI Listing
December 2003

Patient and technique survival on peritoneal dialysis in the United States: evaluation in large incident cohorts.

Kidney Int Suppl 2003 Dec(88):S3-12

Renal Division, Baxter Healthcare Corporation, McGaw Park, IL, USA.

Patient and technique survival on peritoneal dialysis in the United States: Evaluation in large incident cohorts. Secular trends in dialysis require a frequent re-examination of outcomes in patients on renal replacement modalities. We examined three large cohorts of patients initiating peritoneal dialysis (PD) in 1999, 2000, and 2001 (total of > 30,000 patients) to ascertain trends in patient outcomes, technique success, and predictors of both parameters of interest. Trends toward improved patient survival, higher technique success, and increasing use of cycler-based therapy, with more recent calendar years were noted. Age and diabetes were clear predictors of patient survival, but did not appear to influence technique success. Technique success was higher in patients on automated PD (APD) than in patients on continuous ambulatory PD (CAPD), but this difference was mostly concentrated in the first year on therapy. Patients starting PD after a failed allograft had excellent survival. We conclude that the current state of PD in the United States is characterized by improving patient outcomes, higher technique success, and a predominance of use of cycler-based therapy. Several opportunities for improving technique success amenable to practice interventions have been identified. The high success of PD in patients with failed allograft suggests that it is beneficial to utilize this modality more frequently in this patient group than current practice.
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http://dx.doi.org/10.1046/j.1523-1755.2003.08801.xDOI Listing
December 2003

Implications of the ADEMEX trial.

Contrib Nephrol 2003 (140):131-41

Renal Division, Baxter Healthcare Corporation, McGaw Park, Ill., USA.

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http://dx.doi.org/10.1159/000071433DOI Listing
January 2004

The uremic syndrome: therapeutic-evaluative discordance.

Kidney Int Suppl 2003 May(84):S2-5

Renal Division, Baxter Healthcare Corporation, McGaw Park, IL 60085-9815, USA.

Significant discordances are observed between the therapeutic needs of patients with end-stage renal disease and the current emphasis in renal science and technologies. These discordances manifest in the observation that renal replacement therapies fail to attenuate the impact of the patient status at the time of initiation of renal replacement on mortality and morbidity; in the failure to apply a rigorous approach for fluid management, despite its technical simplicity; in the inadequacy of dialysis in the correction of deficient excretion of some solutes (phosphate and potassium), and in the greater impact of hormonal replacement on outcome than that observed by dialytic techniques. We suggest that these discordances find their root in the limited spectrum of uremic solute removal that is currently available with various dialytic techniques, and we suggest that a re-examination of the therapeutic targets in dialytic therapy may be needed in order to supercede the therapeutic plateau at which the therapy is currently fixed.
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http://dx.doi.org/10.1046/j.1523-1755.63.s84.29.xDOI Listing
May 2003

Future of icodextrin as an osmotic agent in peritoneal dialysis.

Kidney Int Suppl 2002 Oct(81):S80-7

Division of Baxter Novum and Renal Medicine, Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1046/j.1523-1755.62.s81.11.xDOI Listing
October 2002

Metabolic and laboratory effects of icodextrin.

Kidney Int Suppl 2002 Oct(81):S62-71

Manchester Royal Infirmary, Manchester, England, United Kingdom.

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http://dx.doi.org/10.1046/j.1523-1755.62.s81.9.xDOI Listing
October 2002

Use of icodextrin in high transport ultrafiltration failure.

Kidney Int Suppl 2002 Oct(81):S53-61

Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1046/j.1523-1755.62.s81.8.xDOI Listing
October 2002

Review of clinical trial experience with icodextrin.

Kidney Int Suppl 2002 Oct(81):S46-52

Renal Division, Baxter Healthcare Corporation, McGaw Park, Illinois 60085-9815, USA.

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http://dx.doi.org/10.1046/j.1523-1755.62.s81.7.xDOI Listing
October 2002
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