Research briefMegestrol Acetate in a Moderate Dose for the Treatment of Malnutrition-Inflammation Complex in Maintenance Dialysis Patients
Section snippets
Subject Recruitment and Study Design
A prospective, open-label study design was used. The study was conducted at the General Clinical Research Center (GCRC) of Northwestern Memorial Hospital in Chicago, IL. The study protocol was approved by the Institutional Review Board of Northwestern University. Because of the off-label use of megestrol acetate in this patient population, an Investigational New Drug number was obtained from the US Food and Drug Administration.
Between July 2000 and July 2001, MHD and chronic peritoneal dialysis
Anthropometric Measurements
Patients’ heights and weights were measured to the nearest 0.5 cm and 0.1 kg, respectively. The BMI was calculated using the following equation: weight (kg) ÷ height squared (m2). For comparison, weight measurements and BMI calculations for the 6 months before entering the study and 6 months after the termination of the study were evaluated using postdialysis weights obtained from the RCG. Other anthropometric measurements performed included midarm circumference, midarm muscle circumference,
Body Composition Analysis
Dual-energy x-ray absorptiometry (DEXA) scan was performed to measure total body fat and fat free mass at both the beginning and the end of the study. DEXA scans were performed in the Nuclear Medicine Department of Northwestern Memorial Hospital. In addition, body composition using bioelectrical impedance analysis via Bioelectrical Body Composition Analyzer Quantum II (RJL Systems Inc, Detroit, MI) was performed every 4 weeks postdialysis to assess volume status.
Biochemical Analysis
A complete blood count and chemistry panel as well as total cholesterol, C-reactive protein (CRP), leptin, and megestrol acetate levels were measured. An HIV serology test (if not available in the past 12 months before the study) was performed at baseline. Serum albumin was measured using bromocresol green. Serum CRP was measured with rate nephelometry using a Beckman Array automated nephelometer (Beckman Instruments, Fullerton, CA). Serum leptin was measured using ELISA DSL (Diagnostics
Nutritional Intake and Sense of Well Being
One 24-hour diet recall was obtained during the monthly visit, and used food models. The software program Nutritionist 4 (version 4.0, 1995, First Data Bank, San Bruno, CA) was used for nutrient analysis. A modified version of the Kidney Disease and Quality of Life, version 1.2 (1995, RAND, Santa Monica, CA) questionnaire was used to evaluate patients’ overall sense of well being. The core component of the Kidney Disease and Quality of Life is a SF36 QoL questionnaire that has been previously
Dialysis Adequacy and Protein Catabolic Rate
Adequacy of dialysis was monitored according to the RCG’s protocol using the urea kinetic modeling developed by Daugirdas.27 The simplified equation using 2 blood urea nitrogen methods was used to calculate normalized protein nitrogen appearance.28 These measurements were performed monthly.
Statistical Analysis
Values before and after treatment were compared using a dependant t-test and a nonparametric test of significance for paired samples based on the degree of normalcy of the distributions. A P value <.05 was considered statistically significant, and a P value between .05 and .10 borderline significant given the small sample size. Descriptive and comparative analyses are conducted using Stata 7.0 (College Station, TX). Values are presented as mean ± standard error of the mean.
Results
Twenty-six MHD and 2 CPD patients of the total 190 MHD and 38 CPD were found to be qualified for the study. Fourteen MHD and 2 CPD patients agreed to participate and were enrolled in the study. Nine MHD and 1 CPD patients (6 female, 4 male) completed the study. Of the 6 MHD patients who did not complete the study, 2 patients transferred to other dialysis centers, 3 were noncompliant with the monthly visit to the GCRC in spite of many reminders, and 1 patient died at an outside hospital
Body Weight and BMI
Changes in body weight and BMI are shown in Figures 1A and 1B, respectively. There was a mean weight loss of 0.5 ± 1.1 kg (not statistically significant) during the 6 months before the initiation of megestrol acetate. With megestrol acetate therapy, the mean body weight increased to 55.9 ± 3.7 kg from the baseline weight of 51.3 ± 3.4 kg(P = .0005) (Fig 1A) and the BMI increased from 19.5 ± 0.7 to 21.3 ± 0.9 (P = .0005) (Fig 1B). Eight of the 10 patients gained weight within the first 4 weeks
Body Composition and Anthropometry
As shown in Table 2, the actual magnitude of FFM measured by DEXA scan increased by 1.4 % from 42.1 ± 3.4 to 42.7 ± 3.6 kg (not statistically significant) by the end of the megestrol acetate therapy period. The percentage of FFM, however, decreased to 76.0 ± 2.2 from 81.7 ± 2.0 (P = .001) with a significant increase in the percentage of body fat (18.3 ± 2.0 to 24 ± 2.2 %, P = .001) and fat weight (9.1 ± 0.9 to 13.2 ± 1.3 kg, P = .002). Mean total body water as measured by bioelectrical
Biochemical Markers
Table 3 shows the changes in laboratory measurements. An increase in serum albumin concentration over the intervention period from 3.0 ± 0.2 g/dL to 3.3 ± 0.2 g/dL was observed (Fig 2A), although this was not statistically significant. However, serum albumin continued to increase even after 3 months after the completion of the intervention to 3.6 ± 0.1 g/dL (P = .03). Figure 2B shows the changes in serum CRP over time. Serum CRP was not analyzed in 2 patients because they had abrupt increases
Food Intake
A substantial increase in the daily energy and protein intake was observed in all patients (Table 4). By the end of the treatment period, the mean energy and protein intake was up by 27% and 42%, respectively, from baseline. As shown in Figure 3, there was a statistically significant increase in the nPNA (0.87 to 1.10 g/kg/day, P < .001) after 16 weeks of megestrol acetate therapy; 6 months after discontinuing the megestrol acetate treatment, the nPNA level decreased to 0.93 g/kg/day.
Perception of Well Being and QoL
All patients reported improvement in their appetite and in sense of well being and QoL score. The improvement in sense of well being, however, did not reach statistical significance (data not shown here).
Safety
Of the 16 patients initially enrolled, 3 patients were noncompliant with follow-up appointments and measurements could not be performed on them; 1 patient died of causes unrelated to the megestrol acetate use as described above, and 2 patients were transferred to other dialysis facilities for personal reasons. None of the remaining 10 dialysis patients left the study because of any side effects or adverse reactions. A total of 3 adverse occurrences were reported during the 16 weeks of the
Discussion
In this study, we found that administering the oral suspension of megestrol acetate in half of its conventional dose (400 mg/day instead of 800 mg/day) in 10 hypoalbuminemic dialysis patients for 16 weeks improved several markers of nutritional state and inflammation in these subjects, and no significant side effect was observed. The most impressive results were the significant increase in body weight and BMI by 9% and the increase in body fat by 31%, which persisted up to 3 months after the
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Supported in part by a grant (M. R.) from Bristol Myers Squibb, the former manufacturer of megestrol acetate (Megace) oral solution. This is an investigator-initiated project supported in part by grant M01 RR-00048 from the National Center for Research Resources, National Institutes of Health and Bristol Myers Squibb. Dr. Kalantar-Zadeh was supported by grant DK61162 from the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health.