Research brief
Megestrol Acetate in a Moderate Dose for the Treatment of Malnutrition-Inflammation Complex in Maintenance Dialysis Patients

https://doi.org/10.1016/j.jrn.2004.10.006Get rights and content

Background

Malnutrition-inflammation complex syndrome and anorexia, common conditions in maintenance dialysis patients, are strongly associated with higher mortality and hospitalization and lower quality of life (QoL) in this population. Megestrol acetate, 800 mg/day, has been shown to increase appetite and food intake and to mitigate inflammation in cachectic AIDS and cancer patients, leading to weight gain, but it is also associated with side effects at this dose.

Methods

We evaluated the efficacy of the oral solution of megestrol acetate in half of its conventional dose in improving the nutritional state and inflammation in 10 hypoalbuminemic dialysis patients (albumin <3.7 g/dL). Six women and 4 men, ages 60.2 years, took 400 mg of megestrol acetate solution daily for 16 weeks. Anthropometry, dual energy x-ray absorptiometry, 24-hour diet recalls, and biochemical measurements of nutrition and inflammation, including serum C-reactive protein and leptin, were performed.

Results

At the end of the 16 weeks of intervention, weight and body mass index increased by 9%, body fat proportion by 31%, and triceps skinfold by 40% (P < .01). Serum albumin increased from 3.0 to 3.3 g/dL and continued to increase significantly to 3.6 g/dL after 3 months postintervention (P = .03). Serum leptin increased from 5.2 to 10.7 ng/mL (P = .09). Daily protein and energy intake increased progressively up to 27% to 42% by the end of the trial (P ≤ .01). In 8 patients without acute infection, serum C-reactive protein declined from 1.24 to 0.78 mg/L (P = .06). QoL and appetite were reported to be improved. No major side effects were observed, and all 10 patients completed the 16 weeks of daily intake of megestrol acetate without interruption.

Conclusions

Megestrol acetate oral solution in half of its conventional dose is safe and improves the nutritional state, inflammation, and anorexia in maintenance dialysis patients. Larger-scale placebo-controlled randomized studies are needed to confirm the beneficial effects of 400 mg/day of megestrol acetate in 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

References (43)

  • V. Eubanks et al.

    Effects of megestrol acetate on weight gain, body composition, and pulmonary function in patients with cystic fibrosis

    J Pediatr

    (2002)
  • N.R. Neyra et al.

    Serum transferrin and serum prealbumin are early predictors of serum albumin in chronic hemodialysis patients

    J Rena Nutr

    (2000)
  • B.R. Don et al.

    Leptin is a negative acute phase protein in chronic hemodialysis patients

    Kidney Int

    (2001)
  • K. Kalantar-Zadeh et al.

    Outcome measures and reverse epidemiology in dialysis patients

    J Renal Nutr

    (2004)
  • K. Caglar et al.

    Therapeutic effects of oral nutritional supplementation during hemodialysis

    Kidney Int

    (2002)
  • United States Renal Data System

    (2002)
  • K. Kalantar-Zadeh et al.

    Association among SF36 quality of life measures and nutrition, hospitalization, and mortality in hemodialysis

    J Am Soc Nephrol

    (2001)
  • G.A. Kaysen et al.

    Characteristics and effects of inflammation in end-stage renal disease

    Semin Dial

    (2003)
  • M. Mann et al.

    Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature

    Arch Intern Med

    (1997)
  • P. Strang

    The effect of megestrol acetate on anorexia, weight loss and cachexia in cancer and AIDS patients (review)

    Anticancer Res

    (1997)
  • E. Karcic et al.

    Treating malnutrition with megestrol acetateLiterature review and review of our experience

    J Nutr Health Aging

    (2002)
  • Cited by (79)

    • Nutritional management of maintenance hemodialysis patients

      2021, Nutritional Management of Renal Disease, Fourth Edition
    • Anorexia and appetite stimulants in chronic kidney disease

      2021, Nutritional Management of Renal Disease, Fourth Edition
    View all citing articles on Scopus

    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.

    View full text