Megestrol Acetate Improves Weight Gain in Pediatric Patients With Chronic Kidney Disease

RESEARCH BRIEF

Megestrol Acetate Improves Weight Gain in Pediatric Patients With Chronic Kidney Disease David J. Hobbs, MBSc,* Timothy E. Bunchman, MD,* David P. Weismantel, MD, MS,‡ Morgan R. Cole, PharmD,† Karen B. Ferguson, RD, CNSD,* Tracy R. Gast, RD,* and Gina-Marie Barletta, MD* Objective: Megestrol acetate (MA) has been used to treat weight loss in pediatric patients with malignancies, cystic fibrosis and HIV/AIDS. We herein report our experience with MA in pediatric patients with chronic kidney disease (CKD). Design: We conducted a retrospective cohort study. Charts were evaluated for clinical, treatment, and laboratory data at six time points: approximately 6 months prior to initiation of MA, at initiation and cessation of MA, and at 2-, 4-, and 8-month follow-up. Anthropometric measurements were corrected for age and sex by conversion to z scores. Setting: Division of Pediatric Nephrology, Helen DeVos Children’s Hospital, Grand Rapids, MI. Patients: Pediatric patients (n 5 25) with CKD and poor weight gain. Intervention: Patients were administered MA at initial and tapered doses of 14.4 6 8.1 mg/kg/d and 10.1 6 6.5 mg/kg/d, respectively, for 5.4 6 6.3 months. Results: The study population (n 5 25) was 60% male, 16% African American, 72% white, and 12% Hispanic with a mean 6 SD age of 8.9 6 5.4 years. Prior to MA therapy, patients demonstrated a decrease in BMI and poor weight gain. The treatment phase was associated with significant increases in BMI (P , .0001) and weight (P , .0001), which were well sustained at 8-month follow-up (P , 0.01 and P , 0.001, respectively). Patients demonstrated continued increases in height. A single patient exhibited physical adverse side effects (cushingoid features) associated with MA; otherwise, MA was well tolerated. Conclusions: MA appears to effectively improve weight gain in pediatric CKD patients with minimal adverse side effects and may therefore serve as a safe, short-term, nutritional strategy. Ó 2010 by the National Kidney Foundation, Inc. All rights reserved.

A

N IMPORTANT goal in the management of pediatric patients with chronic kidney dis-

*Pediatric Nephrology, Dialysis and Transplantation, Helen DeVos Children’s Hospital and Michigan State University College of Human Medicine, Grand Rapids, MI. †Department of Pharmacy, Helen DeVos Children’s Hospital, Grand Rapids, MI. ‡Department of Family Medicine, Michigan State University College of Human Medicine, East Lansing, MI. D.J.H. is supported by an American Society of Nephrology Student Scholar Grant. This study was presented at the 2009 American Society of Pediatric Nephrology meeting, Baltimore, MD. Address reprint requests to Gina-Marie Barletta, MD, Pediatric Nephrology, Dialysis and Transplantation, Helen DeVos Children’s Hospital, 221 Michigan Street NE, Suite 406, Grand Rapids, MI 49503. E-mail: [email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.01.010

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ease (CKD) is optimization of a child’s capacity for normal growth and development. Malnutrition and growth failure are common complications associated with CKD and often result in significant morbidity and mortality. Recent data suggest that inflammation is an underlying cause of growth failure and malnutrition in children with CKD.1,2 The management of pediatric growth failure and malnutrition typically consists of nutritional counseling and caloric supplementation using either oral nutritional supplements or gastrostomy tube (G-tube) feedings. However, minimal data exist in the pediatric CKD population regarding the use of novel, more preventative, and alternative therapeutic strategies such as the administration of appetite stimulants.3 Megestrol acetate (MA) is a synthetic, orally active derivative of progesterone with appetite-

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stimulating properties. The precise mechanism of action is uncertain; however, it has been hypothesized to induce appetite via stimulation of the hypothalamus and inhibition of proinflammatory mediators, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-a.4 MA interacts with the hypothalamic-pituitary-adrenal axis,5,6 which may account for a number of reported side effects, including adrenal and gonadal insufficiency, hypertension, hyperglycemia, and fluid retention.5–14 The usefulness of MA as a treatment for weight loss and/or growth failure has been demonstrated in pediatric patients with underlying malignancies, cystic fibrosis, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) with resultant improved growth.15–18 We herein report our experience with MA in pediatric patients with CKD.

Materials and Methods Study Design A retrospective cohort study was performed to evaluate all pediatric patients with CKD treated for poor weight gain with MA since the inception of the pediatric nephrology program at Helen DeVos Children’s Hospital in September 2003. Patients receiving concomitant growth hormone or patients with systemic lupus erythematosus (SLE) on prednisone (due to corticosteroid exposure and/or altered steroid production) were excluded from the study.19 The study was approved by the Spectrum Health Institutional Review Board. Data Collection Patient charts were reviewed for anthropometric measurements at six consecutive time points: approximately 6 months prior to initiation of therapy with MA (mean, 5.9 6 3.3 months), at the time of initiation (baseline) and cessation of MA therapy (mean duration of therapy, 5.4 6 6.3 months), and at 2-month (mean, 2.3 6 0.4 months), 4month (mean, 4.3 6 0.9 months), and 8-month (mean, 7.7 6 1.5 months) follow-up (postcessation of MA therapy). Other clinical and laboratory parameters (including blood pressure [BP], serum creatinine, BUN, potassium, albumin, and glucose levels) were evaluated before and after treatment with MA. Body mass index (BMI, calculated as weight/height2) and height and weight measurements were adjusted according to age and gender

using z scores. Estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) was calculated using the Schwartz formula.20 A proportionality constant (k) of 0.55 was used to calculate eGFR in nonadolescents and adolescent females, and a k of 0.70 was used in adolescent boys.

Statistical Analysis Statistical analyses were performed using SAS version 9.1 (SAS Institute , Cary, NC). Wilcoxon signed rank test was implemented to determine significant differences between parameters at baseline and at the end of therapy. To determine the effect of MA therapy on changes in BMI and height and weight z scores, a repeated-measures ANOVA with Tukey correction for multiple comparisons was used while controlling for patient age, stage of CKD, and G-tube feedings. All ANOVA comparisons were made to baseline. A value of P , .05 was considered statistically significant. Continuous data were expressed as mean 6 SD or median (range), as specific to data, and categorical data were expressed as number (percentage).

Results Thirty pediatric patients with underlying CKD and poor weight gain who were treated with MA were identified. A total of 5 patients were excluded from the study: 2 of 5 received growth hormone and 3 of 5 received prednisone for treatment of SLE. Demographic data of the study population (n 5 25) are outlined in Table 1. The study population was comprised of 72% white, 16% African American, and 12% Hispanic patients. Mean age was 8.9 6 5.4 years (range, 1.7–19.7 years)— 36% were 5 years or younger, 28% were 5 to 10 years old, and 36% were older than 10 years. The population was 60% male. Patients were classified according to baseline stage of CKD: 32% were Stage I CKD (mean 6 SD eGFR, 113 6 15 mL/min/1.73 m2), 8% were Stage II (81 6 1 mL/min/1.73 m2), 36% were Stage III (47 6 12 mL/min/1.73 m2), 8% were Stage IV (16 6 2 mL/min/1.73 m2), and 16% were Stage V (9 6 2 mL/min/1.73 m2; 3 of 4 required hemodialysis and 1 of 4 required peritoneal dialysis). Underlying etiology of CKD included renal dysplasia (n 5 12), posterior urethral valves (n 5 8), prune belly syndrome with dysplasia (n 5 1), antiglomerular basement membrane disease (n 5 1), cortical necrosis (n 5 1), trauma (n 5 1), and

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Table 1. Demographics and Clinical Characteristics of Study Population Parameter Study population (n) Gender (M/F) Age (y), mean (SD) Range Ethnicity/race, n (%) African American White Hispanic Cause of chronic kidney disease, n (%) Renal dysplasia Posterior urethral valves Prune belly syndrome with dysplasia Anti-glomerular basement membrane disease Cortical necrosis Trauma Ischemic injury Stage of chronic kidney disease, n (%) Stage I Stage II Stage III Stage IV Stage V Hypertension, n (%) Gastrostomy tube feedings, n (%)

25 15/10 8.9 (5.4) 1.7-19.7 4 (16) 18 (72) 3 (12) 12 (48) 8 (32) 1 (4) 1 (4) 1 (4) 1 (4) 1 (4) 8 (32) 2 (8) 9 (36) 2 (8) 4 (16) 12 (48) 7 (28)

ischemic injury (n 5 1). Twenty-eight percent (n 5 7) received nutrition via G-tube feedings, which was controlled for in our statistical analysis. Patients received MA at initial and tapered doses of 14.4 6 8.1 mg/kg/d and 10.1 6 6.5 mg/kg/d, respectively, for 5.4 6 6.3 months. The tapered dose was implemented after a demonstrated improvement of weight gain and/or subjective improvement of appetite—assessed during routine follow-up. Patient growth was assessed over approximately 8 months. Changes in weight z scores are described in Figure 1A. Prior to MA therapy, weight z score did not change (–1.4 6 1.4 to –1.4 6 1.1, P 5 .99). After treatment with MA, weight z score significantly increased to –0.6 6 1.2 (P , .0001). This improvement in baseline weight z score was well sustained during follow-up at 2 months (–0.5 6 1.1, P , .0001), 4 months (–0.7 6 1.2, P ,.0001), and 8 months (–0.7 6 1.3, P ,.0001). Changes in BMI z scores are described in Figure 1B. Prior to MA therapy, BMI z score decreased from 0.1 6 1.1 to –0.2 6 1.0 (baseline, P 5 .59). After MA therapy, BMI z score significantly increased to 0.8 6 1.3 (P ,.0001). This improvement over baseline BMI z score was well

sustained during follow-up at 2 months (0.7 6 1.4, P , .001), 4 months (0.5 6 1.6, P , .001), and 8 months (0.4 6 1.5, P , .01). Changes in height z scores are described in Figure 1C. Prior to MA therapy, height z score increased from –2.1 6 1.4 to –1.9 6 1.3 (baseline, P 5 .94). During the treatment phase, height z score increased to –1.8 6 1.2 (P 5 .99). Height z scores continued to improve through 8-month follow-up (–1.7 6 1.4, P 5 .49). There was no significant change in diastolic (baseline versus end of therapy, P 5.33) or systolic (P 5.27) BP or serum creatinine (P 5.21), BUN (P 5 .26), serum potassium (P 5 .27), albumin (P 5 .83), or glucose levels (P 5 .27; Table 2). One of eight patients with G-tube feedings was able to discontinue such feedings after receiving MA therapy. One patient experienced cosmetic side effects associated with MA (cushingoid appearance) after 2 months of MA treatment, which reverted after MA therapy was discontinued. An additional patient with SLE who was excluded from the study analysis due to concomitant treatment with high-dose prednisone (see Methods) developed elevated BP readings after 10 months of MA therapy—the dose of MA remained unchanged, and as the dose of prednisone was reduced, the patient’s BP normalized. No patients displayed findings compatible with adrenal or gonadal insufficiency.

Discussion Malnutrition leading to growth failure has been associated with increased morbidity and mortality in pediatric patients with CKD.2,21,22 Little consensus data exist to guide the management of malnutrition and growth failure in this patient population.3 We retrospectively reviewed our experience with MA in pediatric patients with CKD and poor weight gain. MA appears to effectively stimulate appetite and improve short-term weight gain in pediatric CKD patients with minimal adverse side effects and may therefore serve as a safe, short-term, nutritional strategy. Prior to MA therapy, our study population demonstrated non–statistically significant decreases in BMI and weight z scores (Figure 1A, B). As seen in routine exams, patients were not gaining enough weight for proper growth. The clinical indication for initiation of MA in this patient population was inadequate nutrition for

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Figure 1. Longitudinal z scores of (A) weight, (B) BMI, and (C) height. Statistical analysis by ANOVA with Tukey correction for multiple comparisons while controlling for patient age, gender, stage of CKD, and G-tube feedings. Data expressed as mean. The y-axis error bars display 61 SD. Dotted line indicates the mean treatment phase of MA, which was 5.4 6 6.3 months. All comparisons were made to baseline (Start-MA). StartMA, start of megestrol acetate therapy; End-MA, discontinuation of megestrol acetate therapy; *P , .01, **P , .001, ***P , .0001.

optimal growth. Based on the clinical picture of each patient (adequate nutrition, stable labs), the patient was weaned from therapy and, shortly thereafter, therapy was discontinued. Patients discontinued therapy when improved nutrition MA therapy appeared to significantly increase weight and BMI over baseline, which persisted after 2-, 4-, and 8-months postcessation of MA therapy (Figure 1A, B). Indeed, follow-up BMI and

weight measurements remained significantly improved (compared to baseline) at 8-month follow-up (Figure 1A, B). The statistical analyses used a Tukey correction for multiple comparisons and adjusted for potential confounding variables such as patient age, G-tube feedings, and stage of CKD. Taken together, these data indicate that treatment with MA appears to effectively improve weight gain in pediatric patients with CKD.

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Table 2. Comparison of Parameters at Baseline (Start) and End of Megestrol Acetate Therapy Parameter Blood pressure (mm Hg) Systolic Diastolic Serum creatinine (mg/dL) Blood urea nitrogen (mg/dL) Potassium (mmol/L) Albumin (g/dL) Glucose (mg/dL)

Baseline

End

P Value

107 (93–144) 65 (44–94) 1.3 (0.4–9.1) 20 (8–105) 4.4 (3.5–5.7) 3.9 (2.8–4.8) 91 (70–183)

111 (94–132) 70 (48–85) 1.4 (0.3–10.1) 18 (6–86) 4.2 (2.9–6.0) 3.9 (2.7–4.7) 87 (55–135)

.27 .33 .21 .26 .27 .83 .27

Data expressed as median (range); Baseline, start of MA therapy; End, cessation of MA therapy. Statistical analysis by Wilcoxon signed rank.

Precise dosing regimens and guidelines for MA therapy in pediatric patients with CKD have yet to be established. Clarick et al.18 retrospectively investigated the use of MA in pediatric patients with HIV and concluded that patients receiving greater than 7 mg/kg/day tend to have better weight gain than did patients receiving lower doses. However, this group further commented that, because no data exist regarding adverse effects in children, dosages that exceed 8 mg/kg should be avoided. Eubanks et al.17 conducted a small randomized clinical trial to evaluate the use of MA in pediatric patients with cystic fibrosis. Patients were treated with MA at an initial dose of 10 mg/kg/d, then dosing was titrated 2.5 mg/ kg/d based on weight loss/gain and/or adverse effects. The mean dosage of MA at the end of the study was 7.5 mg/kg/d. Azcona et al.15 initiated therapy with MA in pediatric patients with solid tumors at 10 mg/kg/d. Dosages were subsequently adjusted according to individual response to therapy after approximately 10 days of treatment. The median or mean duration of therapy for these studies ranged from 3 to 7 months.15,17,18 In our retrospective cohort study, mean initial and tapered doses were 14 mg/kg/d and 10 mg/kg/d, respectively, which were administered over a period of 5 to 6 months. Although our MA dosage appears slightly higher than that in most of these studies, our patients tolerated treatment with MA without experiencing significant adverse effects. MA has been noted to induce a number of adverse side effects, particularly adrenal insufficiency, gonadal failure, hypertension, hyperglycemia, and fluid retention.5–14 In this study, BPs, glucose levels and remained stable (Table 2); however, we observed an adverse reaction in a single study patient (cushingoid features), which reverted

with discontinuation of MA therapy. We also report that a patient (excluded from study analysis) receiving MA and high-dose prednisone experienced elevated BP that reverted with reduction in prednisone dose. No patients demonstrated fluid retention as evidenced by an absence of change in BP and/or weight. Further serum studies including the hormonal milieu engendered by pubertal staging would be required, however, to rule out serious adverse side effects or asymptomatic adrenal and gonadal suppression related to treatment with MA23,24; however, we observed no physical manifestations compatible with such findings. Our findings suggest that, with proper dosing adjustment and management, MA therapy can be safely administered to pediatric patients with CKD. Although our study is representative of a small, heterogeneous, single-center retrospective experience, it demonstrates the potential usefulness of MA to effectively stimulate appetite and improve growth in pediatric CKD patients with minimal adverse side effects. Future research should utilize a multicenter, randomized clinical trial model to better establish the dosage and treatment effect of MA in this population including dietary intake and endocrinological studies. Prospective studies are necessary to investigate overall long-term effects of MA in this pediatric population with underlying CKD.

Conclusions MA appears to effectively improve short-term weight gain in pediatric CKD patients with minimal adverse side effects. MA therapy may therefore serve as a safe, short-term, nutritional strategy in this difficult-to-treat pediatric population.

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placebo in patients with neoplastic cachexia. Am J Clin Oncol 21(4):347-351, 1998 14. Von Roenn JH, Armstrong D, Kotler DP, et al: Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med 121(6):393-399, 1994 15. Azcona C, Castro L, Crespo E, et al: Megestrol acetate therapy for anorexia and weight loss in children with malignant solid tumors. Aliment Pharmacol Ther 10:577-586, 1996 16. Marchand V, Baker SS, Stark TJ, et al: Randomized, doubleblind, placebo-controlled pilot trial of megestrol acetate in malnourished children with cystic fibrosis. J Pediatr Gastroenterol Nutr 31(3):264-269, 2002 17. Eubanks V, Koppersmith N, Wooldridge N, et al: Effects of megestrol acetate on weight gain, body composition, and pulmonary function in patients with cystic fibrosis. J Pediatr 140(4): 439-444, 2002 18. Clarick RH, Hanekom WA, Yogev R, et al: Megestrol acetate treatment of growth failure in children infected with human immunodeficiency virus. Pediatrics 99(3):354-357, 1997 19. Jara LJ, Navarro C, Medina G, Vera-Lastra O, et al: Immune-neuroendocrine interactions and autoimmune diseases. Clin Dev Immunol 13(2-4):109-123, 2006 20. Schwartz GJ, Haycock GB, Edelmann CM, et al: A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58(2):259-263, 1976 21. Sylvestre LC, Fonseca KP, Stinghen AE, et al: The malnutrition and inflammation axis in pediatric patients with chronic kidney disease. Pediatr Nephrol 22:864-873, 2007 22. Wong CS, Hingorani S, Gillen DL, et al: Hypoalbuminemia and risk of death in pediatric patients with end-stage renal disease. Kidney Int 61:630-637, 2002 23. Bodenner DL, Medhi M, Evans WJ, et al: Effects of megestrol acetate on pituitary function and end-organ hormone secretion: a post hoc analysis of serum samples from a 12-week study in healthy older men. Am J Geriatr Pharmacother 3(3):160-167, 2005 24. Romeo RD, Bellani R, Karatsoreos IN, et al: Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity. Endocrinology 147(4):1664-1674, 2006