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Recombinant human growth hormone therapy in malnourished dialysis patients: A randomized controlled study
Recombinant Human Growth Hormone Therapy in Malnourished Dialysis Patients: A Randomized Controlled Study Pedro Iglesias, MD, Juan J. Dı´ez, MD, Marı´a J. Ferna´ndez-Reyes, MD, Abelardo Aguilera, MD, Sebastia´n Burgue´s, MD, Jorge Martı´nez-Ara, MD, Jose L. Miguel, MD, Antonio Go´mez-Pan, MD, and Rafael Selgas, MD ● Recombinant human growth hormone (rhGH; Saizen, Serono, Spain) has been recently used as an anabolic agent in several catabolic states, including malnourished chronic dialysis patients. However, up-to-date, comparative studies with control groups of dialysis patients have not been reported. The aim of the present study was to assess the effects of rhGH on nutritional status in a group of malnourished adult chronic dialysis patients undergoing both continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). The patients were randomly assigned to the control group (nine patients; 6 women, 3 men; mean age, 58.3 ⴞ 5.6 years; seven undergoing CAPD, two undergoing HD) or the rhGH group (eight patients; three women, five men; mean age, 63.9 ⴞ 3.1 years; four undergoing CAPD, four undergoing HD). Both groups were similar at baseline. All patients were given dietary prescriptions (35 kcal/kg/d and 1 g protein/kg ideal body weight/d) during 4 weeks. In the rhGH group, rhGH was administered at 0.2 IU/kg/d subcutaneously (SC) during this period. Anthropometric and analytic parameters were assessed before (0 weeks) therapy and at 2 and 4 weeks after starting therapy. The rhGH group showed an increase of 1.238 kg in body weight from 64.3 ⴞ 4.3 (mean ⴞ standard error of the mean [SEM]) to 65.6 ⴞ 4.9 kg (P F 0.05). Serum insulin-like growth factor type 1 (IGF-1) concentrations increased from 216.6 ⴞ 42.5 to 581.2 ⴞ 171.5 ng/mL (4 weeks; P F 0.01) and transferrin levels increased from 271.2 ⴞ 16.3 to 314.5 ⴞ 21.2 mg/dL (4 weeks; P F 0.05). A significant reduction in blood urea nitrogen (BUN) level was observed (62.1 ⴞ 1.8 v 46.8 ⴞ 3.8 mg/dL; 4 weeks; P F 0.05). Mean daily protein intake, determined by individual dietary survey, at 0 and 4 weeks, remained constant in both groups. In conclusion, weight gain and IGF-1 and transferrin level increases and BUN level decreases, despite the constant oral intake, suggest that short-term rhGH administration is associated with an anabolic reaction in malnourished dialysis patients. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Growth hormone; malnutrition; anabolism; chronic renal failure; dialysis.
P
ATIENTS WITH end-stage renal disease (ESRD) undergoing dialysis often show different grades of protein calorie malnutrition. It represents one of the main clinical problems of these patients. The prevalence of malnutrition in dialysis patients has been reported to range from 12% to 51%.1-3 In fact, in different studies, several signs of malnutrition have been observed in 10% to 70% of hemodialysis (HD) patients and 18% to 51% of continuous ambulatory peritoneal dialysis (CAPD) patients.4 It is generally accepted that there is a relationship between the extent of protein calorie malnutrition and increased morbidity and mortality in dialysis patients.1,3,5-7 The cause of this poor nutritional status is multifactorial. Among the main factors contributing to malnutrition are anorexia and reduction of nutrient intake, metabolic and horFrom the Departments of Endocrinology and Nephrology, Hospital La Paz; and Laboratorios Serono, Madrid, Spain. Received October 22, 1997; accepted in revised form April 14, 1998. Address reprint requests to Pedro Iglesias, MD, C/ Marı´a Sevilla Diago, 9, 3° dcha, 28022 Madrid, Spain.
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3203-0014$3.00/0 454
monal derangements, catabolic intercurrent illnesses, presence of uremic toxins and loss of nutrients, and catabolic effects associated with dialysis. A number of reports have suggested that the treatment of malnutrition in these patients could reduce the risk for morbidity and mortality.2,3,8,9 For this reason, different preventive and therapeutic measures have been used to treat malnutrition in patients with ESRD. These include anabolic hormones, such as growth hormone (GH), and its major mediator, insulin-like growth factor type 1 (IGF-1). In this setting, recombinant human GH (rhGH) has been recently used as an anabolic agent in several catabolic states.10-12 Preliminary studies in dialysis patients have suggested that rhGH administration reduces urea generation and improves the efficacy of dietary protein utilization, diminishing body protein catabolism. However, so far, controlled, randomized studies of dialysis patients have not been reported. Therefore, we set out to perform a controlled, randomized study evaluating the effects of short-term rhGH administration on nutritional status in a group of malnourished dialysis patients.
American Journal of Kidney Diseases, Vol 32, No 3 (September), 1998: pp 454-463
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
PATIENTS AND METHODS
Patients Seventeen malnourished patients with chronic renal failure (nine women, eight men; age, 60.9 ⫾ 3.2 [mean ⫾ standard error of the mean (SEM)] years; range, 30 to 78 years) undergoing dialysis (11 CAPD, 6 HD) were studied. The patients had the following primary renal diseases: hypertensive nephrosclerosis (five patients), chronic glomerulonephritis (four patients), polycystic kidney disease (two patients), chronic pyelonephritis (one patient), interstitial nephropathy (one patient), lupus nephropathy (one patient), and unknown primary renal disease (three patients). Inclusion criteria were dialysis therapy during at least 6 months, age greater than 18 years, and protein calorie malnutrition with at least one of the following: weight loss of greater than 10% in the last 6 months or greater than 5% in the last month, reduction of greater than 20% of midarm muscle circumference (MAMC) and/or ideal body weight according to sex and age, serum albumin level less than 4.0 g/dL, protein catabolic rate (PCR) less than 0.9 g/kg/d, and lymphocyte count less than 1,000/µL. Exclusion criteria were diseases that might contraindicate the use of rhGH (such as diabetes mellitus and/or carcinoma within the previous 5 years), corticosteroid therapy in the previous 6 months, uncontrolled hypertension (diastolic blood pressure ⬎ 95 mm Hg), severe secondary hyperparathyroidism (intact parathyroid hormone ⬎ 600 pg/mL), congestive heart failure, dose of erythropoietin not stabilized in the previous 2 months, low dose of dialysis (weekly urea Kt/V ⬍ 3 for HD and ⬍ 1.7 for CAPD), and infectious or surgical stress. All patients received written and oral information and gave written consent before study entry. The study was conducted in accordance with the Declaration of Helsinki II and was approved by the Local Ethical Committee of the Hospital La Paz and by the Clinical Research Board of the Spanish Ministry of Health.
Study Design The study was a pilot, randomized, controlled group study that lasted 12 weeks. Patients were randomly assigned to control or rhGH groups by means of a table of random numbers generated by computer. In the control group (nine patients; six women, three men; mean age, 58.3 ⫾ 5.6 years; seven CAPD, two HD; time on dialysis, 49.9 ⫾ 18.5 months), six patients were hypertensive and seven were receiving recombinant human erythropoietin (rhEPO) therapy (weekly mean dose, 102.8 ⫾ 15.9 U/kg subcutaneously [SC]). The rhGH group consisted of eight patients (three women, five men; mean age, 63.9 ⫾ 3.1 years; four CAPD, four HD; time on dialysis, 73.9 ⫾ 21.4 months). Four of them were hypertensive and seven were receiving rhEPO therapy (weekly dose, 109.5 ⫾ 21.8 U/kg SC). During the study, there were no changes in rhEPO doses, and two patients of each group were treated with iron intravenously. Baseline clinical and analytic characteristics of the two groups of patients are listed in Table 1. There were no significant differences between groups in age, sex, cause of renal disease, type of dialysis, duration of dialysis, presence of hypertension, rhEPO therapy, weekly dose of rhEPO, and
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Table 1. Clinical and Analytic Data of the Studied Patients rhGH Group
Control Group
Clinical data No. of patients 8 9 Age (yr) 63.9 ⫾ 3.1 58.3 ⫾ 5.6 Sex (M/F) 5/3 3/6 Hypertension (yes/no) 4/4 6/3 Relative body weight (%) 99.6 ⫾ 7.5 107.0 ⫾ 7.1 EPO (yes/no) 7/1 7/2 EPO dosage (U/kg/ week) 109.5 ⫾ 21.8 102.8 ⫾ 15.9 Loss of weight 1 0 Reduction ⬎20% weight/MAMC 3 1 PCR ⬍ 0.9 g/kg/d 6 5 Albumin ⬍ 4.0 g/dL 6 9 Prealbumin ⬍ 29 mg/dL 1 1 Lymphocyte count ⬍1,000 (⫻103/µL) 4 2 Dialysis parameters Type of dialysis (HD/CAPD) 4/4 2/7 Time on dialysis (mon) 73.9 ⫾ 21.4 49.9 ⫾ 18.5 PCR (g/kg/d) 0.839 ⫾ 0.040 0.954 ⫾ 0.070 Weekly urea Kt/V CAPD 1.80 ⫾ 0.19 2.11 ⫾ 0.10 HD 3.60 ⫾ 0.36 4.14 ⫾ 0.54 Analytic data Hematocrit (%) 33.6 ⫾ 1.2 29.9 ⫾ 2.0 Hemoglobin (g/dL) 10.9 ⫾ 0.4 9.6 ⫾ 0.6 Lymphocyte (⫻µL) 1,245.6 ⫾ 165.5 1,269.6 ⫾ 164.5 Sodium (mmol/L) 140.3 ⫾ 0.7 137.8 ⫾ 0.9 Potassium (mmol/L) 4.7 ⫾ 0.3 4.6 ⫾ 0.3 Glucose (mg/dL) 85.4 ⫾ 3.8 96.0 ⫾ 5.5 Cholesterol (mg/dL) 204.4 ⫾ 15.1 184.9 ⫾ 14.7 Triglyceride (mg/dL) 152.6 ⫾ 26.3 126.2 ⫾ 15.3 Total protein (g/dL) 6.9 ⫾ 0.2 6.4 ⫾ 0.1 Albumin (g/dL) 3.8 ⫾ 0.2 3.5 ⫾ 0.1 RbP (mg/dL) 16.2 ⫾ 2.2 17.9 ⫾ 3.3 Prealbumin (mg/dL) 44.2 ⫾ 3.4 37.0 ⫾ 5.1 Transferrin (mg/dL) 271.2 ⫾ 16.3 237.7 ⫾ 6.3 GH (ng/mL) 5.0 ⫾ 1.1 5.1 ⫾ 2.2 IGF-1 (ng/mL) 216.6 ⫾ 42.5 231.4 ⫾ 43.6 TSH (µU/ml) 2.1 ⫾ 1.2 1.5 ⫾ 0.3 FT4 (ng/dL) 1.4 ⫾ 0.1 1.3 ⫾ 0.1 Hemoglobin A1c (%) 5.5 ⫾ 0.2 5.8 ⫾ 0.2 NOTE. Data expressed as the number of patients or the mean ⫾ SEM. Abbreviations: EPO, erythropoietin therapy; HD, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis; PCR, protein catabolic rate; RbP, retinol binding protein; GH, growth hormone; IGF 1, insulin-like growth factor type 1; TSH, thyrotropin; FT4, free thyroxine.
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inclusion criteria (Table 1). The study design consisted of three consecutive periods (Fig 1): the inclusion period (phase I), therapy period (phase II), and follow-up period (phase III). In phase I, inclusion criteria were verified in every patient and written informed consent was obtained. Thereafter, anthropometric and analytic parameters were determined 4 weeks before phase II (–4 weeks) to confirm the baseline clinical situation of the patients. During phase II, all patients received dietary treatment (35 kcal/kg/d and 1 g protein/kg ideal body weight/d) for 4 weeks. In the rhGH group, rhGH was administered at 0.2 IU/kg/d SC at 8:00 AM in patients undergoing CAPD and, in patients undergoing HD, rhGH was administered immediately after the dialysis session. Patients were followed up during the 4 weeks (phase III) after discontinuation of therapy period. During the three phases, patients were seen for eight visits; two of them in phase I (–4 and –1 weeks), five in phase II (0, 1, 2, 3, and 4 weeks), and one in phase III.
Anthropometric Parameters Anthropometric parameters were assessed in every patient at –4, 0, 1, 2, 3, 4, and 8 weeks, and always by the same investigator, using the recommendations of Frisancho.13 Anthropometric measurements were made at 8:00 AM in patients undergoing CAPD and immediately after the dialysis session in patients undergoing HD. Dry weight (Wt) and height (H) were registered and body mass index (BMI [kg/m2] ⫽ Wt [kg]/H[m]2) was then obtained. Other anthropometric indices evaluated included triceps skin-fold (TSF), midarm circumference (MAC), and midarm muscle circumference (MAMC [cm] ⫽ MAC [cm] – 3.14 ⫻ TSF [cm]). TSF was determined using a caliper (Holtain LTD., Crosswell, Crymych, Dyfed SA41 3UF. UK) and hand grip strength was evaluated with a conventional manual dynamometer. Blood pressure at baseline and after treatment was also registered.
Laboratory Parameters and Hormone Assay Blood samples were drawn at –4, 0, 2, 4, and 8 weeks for determination of complete blood cell count; serum electro-
IGLESIAS ET AL
lyte, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, cholesterol, triglyceride, total protein, albumin, transferrin, prealbumin, retinol-binding protein (RbP), glucose, glycosylated hemoglobin (HbA1c), GH, IGF-1, free thyroxine (FT4), and thyrotropin (TSH) levels. Serum insulin and C-peptide concentrations were also assessed at 0 and 4 weeks. Blood samples were centrifuged immediately and the serum stored at –20°C until assayed. Blood cell count was measured in a Coulter counter (Technicon H3RTX, Bayer, Germany), and the serum chemistry determinations were performed using an automated multichannel analyzer. HbA1c was measured by high-performance liquid chromatography (Variant; Biorad, Hercules, CA). The intra-assay and interassay coefficients of variation were 1.91% and 3.70%, respectively. Normal range was 4.5% to 6.5%. Human serum GH and TSH concentrations were determined by using an automated immunoenzymatic assay (AIA 1200; Tosoh Corporation, Tokyo, Japan). Maximal intra- and interassay coefficients of variation of GH assay were 5.4% and 3.3%, respectively. The sensitivity of the GH assay was 0.1 ng/mL. Normal was less than 5 ng/mL. For TSH assay, the sensitivity was 0.06 µU/mL and maximum intra- and interassay coefficients of variation were 3.3% and 3.4%, respectively. Normal range for TSH was 0.6 to 5.0 mU/mL. Serum IGF-1 concentrations were measured by specific radioimmumoassay after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra- and interassay coefficients of variation were 2.9% and 11.4%, respectively. The sensitivity of the assay was 12.9 ng/mL. The normal range was 83 to 450 ng/mL for patients younger than 40 years of age and 54 to 389 ng/mL for patients aged 40 years or older. FT4 was measured by commercially available immunoenzymatic assay kits (AIA-PACK FT4, Tosoh Corp, Tokyo, Japan) that use the automated system AIA-1200. Maximal intra- and interassay coefficients of variation were 9.6% and 7.7%, respectively. The sensitivity of FT4 assay was 0.1 ng/dL. Normal range was 0.91 to 2.18 ng/dL. Serum insulin concentrations were analyzed with a commercial radioimmunoassay (Sorin; Biomedica, Saluggia, Italy). The intra- and interassay coefficients of variation were 6.6% and 6.2%, respectively. The sensitivity of insulin assay was 3 mIU/mL. The normal range in our laboratory was 5 to 25 mIU/mL. Serum C-peptide concentrations were determined by radioimmunoassay (Medgenix; Diagnostics, Fleurus, Belgium). Maximal intra- and interassay coefficients of variation were 7.6% and 8.8%, respectively. The sensitivity of the assay was 0.1 ng/mL and the normal range was 0.5 to 3.0 ng/mL.
Dietary Regimen Mean daily dietary intake was determined from individual 24-hour food records during a 3-day period before the beginning of phases II and III. Daily calorie, carbohydrate, lipid, and protein intake was calculated for each patient using a commercially available computer software (Wander; Sandoz Nutricio´n, 1990, Barcelona, Spain).
Urea Kinetic Analysis Fig 1. Study design. In rhGH group, rhGH was administered at 0.2 IU/kg/d SC during 4 weeks.
Urea kinetic parameters (urea Kt/V and PCR) were calculated according to previously described methods.14
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
Statistical Methods Results are expressed as mean ⫾ SEM. Clinical and analytic data at different time points of the study for the same patients were compared by using repeated-measures analysis of variance. For comparison between rhGH and control groups, the Mann-Whitney U test was used. The chi-square test was used to study the relationship between qualitative variables. Bilateral contrast was used for all comparisons. The differences were considered significant for P less than 0.05.
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23.9 ⫾ 1.0 cm at 4 weeks (P ⬍ 0.05; Table 2). No significant differences were observed between groups in TSF, MAC, and hand-grip strength during the study. Finally, blood pressure remained unchanged after rhGH treatment (systolic, 134.0 ⫾ 8.9 v 128.7 ⫾ 5.9 mm Hg; diastolic, 77.7 ⫾ 3.0 v 77.5 ⫾ 2.7 mm Hg; 0 weeks v 4 weeks). Laboratory Parameters
RESULTS
Anthropometric Measurements At the beginning of the study (–4 weeks), there were no significant differences in body weight between the rhGH (64.7 ⫾ 4.4 kg) and control groups (70.4 ⫾ 6.2 kg). The same was observed at 0 weeks (64.3 ⫾ 4.3 v 70.3 ⫾ 6.3 kg; rhGH v control; not significant [NS]). The rhGH group showed a mean increase of 1.238 kg in body weight from 64.3 ⫾ 4.3 to 65.6 ⫾ 4.9 kg (4 weeks; P ⬍ 0.05; Table 2). No changes in body weight were observed in the control group. The results of the BMI were similar to those obtained for body weight in both groups at the end of phase II. The evaluation of MAMC showed a significant increase in both the rhGH group, from 22.7 ⫾ 1.0 to 23.7 ⫾ 0.9 cm at 4 weeks (P ⬍ 0.05) and the control group, from 22.8 ⫾ 0.9 to
The comparative analysis between both groups at 0 weeks of values for hematocrit, hemoglobin, lymphocyte, serum electrolytes, BUN, creatinine, calcium, phosphorus, cholesterol, triglycerides, total protein, albumin, transferrin, prealbumin, RbP, glucose, and HbA1c did not show any significant difference (Tables 1 and 3). The hemoglobin and hematocrit values did not change with respect to baseline in either group. However, in the rhGH group, both hemoglobin (11.2 ⫾ 0.4 v 9.9 ⫾ 0.4 g/dL; P ⬍ 0.05) and hematocrit (35.1% ⫾ 0.9% v 29.5% ⫾ 1.4%; P ⬍ 0.05) values increased significantly with respect to the control group at 4 weeks. The lymphocyte count was not affected by rhGH therapy. Serum concentrations of creatinine, uric acid, and electrolytes (sodium, potassium, and chlo-
Table 2. Anthropometric Measurements Throughout the Study Weeks
Weight (kg) rhGH Control BMI (kg/m2) rhGH Control TSF (mm) rhGH Control MAC (cm) rhGH Control MAMC (cm) rhGH Control
⫺4
0
1
2
3
4
8
64.7 ⫾ 4.4 70.4 ⫾ 6.2
64.3 ⫾ 4.3 70.3 ⫾ 6.3
64.7 ⫾ 4.4 70.4 ⫾ 6.3
64.9 ⫾ 4.5 69.8 ⫾ 6.1
65.2 ⫾ 4.7 70.0 ⫾ 6.0
65.6 ⫾ 4.9* 70.3 ⫾ 6.2
65.2 ⫾ 5.5* 69.8 ⫾ 6.1
26.5 ⫾ 2.1 28.1 ⫾ 2.0
26.4 ⫾ 2.1 28.0 ⫾ 2.0
26.5 ⫾ 2.1 28.0 ⫾ 2.0
26.6 ⫾ 2.1 27.8 ⫾ 1.9
26.7 ⫾ 2.1 27.9 ⫾ 1.9
26.9 ⫾ 2.3* 28.0 ⫾ 1.9
27.3 ⫾ 2.5 27.8 ⫾ 1.9
18.6 ⫾ 3.3 20.3 ⫾ 3.2
17.2 ⫾ 3.0 20.0 ⫾ 3.2
15.4 ⫾ 3.2 18.7 ⫾ 3.3
15.8 ⫾ 3.7 18.9 ⫾ 3.2
15.6 ⫾ 3.9 18.6 ⫾ 3.2
15.3 ⫾ 4.0 18.4 ⫾ 3.0*
16.2 ⫾ 4.1 19.0 ⫾ 3.4
28.5 ⫾ 1.6 29.4 ⫾ 2.0
28.1 ⫾ 1.9 29.1 ⫾ 1.8
28.1 ⫾ 1.8 28.9 ⫾ 1.7
28.2 ⫾ 2.1 29.4 ⫾ 1.8
28.6 ⫾ 2.0 29.4 ⫾ 1.9
28.5 ⫾ 2.1 29.6 ⫾ 1.9
29.0 ⫾ 2.1 29.6 ⫾ 1.9
22.6 ⫾ 0.8 23.0 ⫾ 1.1
22.7 ⫾ 1.0 22.8 ⫾ 0.9
23.2 ⫾ 0.9 23.0 ⫾ 0.8
23.1 ⫾ 1.0 23.4 ⫾ 0.9
23.5 ⫾ 0.9 23.5 ⫾ 1.1*
23.7 ⫾ 0.9* 23.9 ⫾ 1.0*
24.0 ⫾ 0.9 23.6 ⫾ 1.0*
NOTE. Values expressed as mean ⫾ SEM. Abbreviations: BMI, body mass index; TSF, triceps skinfold; MAC, mid-arm circumference; MAMC, midarm muscle circumference. *P ⬍ 0.05 v 0 weeks.
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IGLESIAS ET AL Table 3. Effects of rhGH on Different Biochemical Parameters During the Study Weeks
Glucose (mg/dL) rhGH Control Creatinine (mg/dL) rhGH Control BUN (mg/dL) rhGH Control Calcium (mg/dL) rhGH Control Phosphorus (mg/dL) rhGH Control Total protein (g/dL) rhGH Control Albumin (g/dL) rhGH Control RbP (mg/dL) rhGH Control Transferrin (mg/dL) rhGH Control Prealbumin (mg/dL) rhGH Control
⫺4
0
85.8 ⫾ 3.5 94.7 ⫾ 4.3
85.4 ⫾ 3.8 96.0 ⫾ 5.5
104.2 ⫾ 4.7* 85.4 ⫾ 4.1†
103.9 ⫾ 5.0* 88.3 ⫾ 4.3‡
96.3 ⫾ 8.0 95.1 ⫾ 8.0
8.8 ⫾ 0.8 9.7 ⫾ 0.8
9.3 ⫾ 0.4 9.6 ⫾ 0.8
9.4 ⫾ 0.5 9.6 ⫾ 0.9
9.3 ⫾ 0.5 9.9 ⫾ 0.9
9.4 ⫾ 0.8 10.4 ⫾ 0.8
58.5 ⫾ 6.3 63.5 ⫾ 6.9
62.1 ⫾ 1.8 65.7 ⫾ 8.4
51.6 ⫾ 3.7§ 62.8 ⫾ 7.3
46.8 ⫾ 3.8§ 67.8 ⫾ 7.4‡
64.8 ⫾ 5.1 67.1 ⫾ 7.0
9.4 ⫾ 0.3 9.5 ⫾ 0.1§
9.6 ⫾ 0.4 9.2 ⫾ 0.2
10.0 ⫾ 0.3 9.3 ⫾ 0.2
10.4 ⫾ 0.4* 9.6 ⫾ 0.1\
9.3 ⫾ 0.4 9.4 ⫾ 0.2§
6.0 ⫾ 0.8 5.9 ⫾ 0.8
6.5 ⫾ 0.4 5.3 ⫾ 0.7
6.6 ⫾ 0.4 5.7 ⫾ 0.7
6.2 ⫾ 0.4 6.8 ⫾ 0.2
6.3 ⫾ 0.6 5.9 ⫾ 0.7
6.9 ⫾ 0.2 6.5 ⫾ 0.2
6.9 ⫾ 0.2 6.4 ⫾ 0.1
6.6 ⫾ 0.2 6.4 ⫾ 0.2
7.0 ⫾ 0.1 6.8 ⫾ 0.2*
6.9 ⫾ 0.2 6.6 ⫾ 0.2
3.8 ⫾ 0.2 3.6 ⫾ 0.1
3.8 ⫾ 0.2 3.5 ⫾ 0.1
3.6 ⫾ 0.2 3.5 ⫾ 0.1
3.8 ⫾ 0.2 3.7 ⫾ 0.1*
3.7 ⫾ 0.1 3.6 ⫾ 0.1
16.9 ⫾ 3.0 17.1 ⫾ 2.9
16.2 ⫾ 2.2 17.9 ⫾ 3.3
12.8 ⫾ 1.0 12.1 ⫾ 1.3
11.3 ⫾ 1.3§ 11.8 ⫾ 1.1
11.0 ⫾ 1.3§ 13.2 ⫾ 1.2
256.5 ⫾ 16.3 238.0 ⫾ 18.6
271.2 ⫾ 16.3 237.7 ⫾ 16.3
290.1 ⫾ 18.4 233.8 ⫾ 14.3‡
314.5 ⫾ 21.2§ 245.7 ⫾ 17.0‡
291.7 ⫾ 18.0 233.6 ⫾ 17.1‡
49.0 ⫾ 10.0 39.8 ⫾ 7.4
44.2 ⫾ 3.4 37.0 ⫾ 5.1
42.2 ⫾ 4.4 36.1 ⫾ 5.1
42.3 ⫾ 3.8 37.2 ⫾ 4.5
42.5 ⫾ 5.6 34.2 ⫾ 4.8
2
4
8
NOTE. Values expressed as mean ⫾ SEM. *P ⬍ 0.01 (v 0 weeks). †P ⬍ 0.01 (rhGH v control). ‡P ⬍ 0.05 (rhGH v control). §P ⬍ 0.05 (v 0 weeks). \P ⬍ 0.001 (v 0 weeks).
ride) did not show any change throughout the study in either group. Serum phosphorus concentrations remained stable during the protocol, whereas serum calcium concentrations increased in both rhGH (9.6 ⫾ 0.4 v 10.4 ⫾ 0.4 mg/dL; 0 weeks v 4 weeks; P ⬍ 0.01) and control group (9.2 ⫾ 0.2 v 9.6 ⫾ 0.1 mg/dL; 0 weeks v 4 weeks; P ⬍ 0.001). The use of rhGH did not produce any significant modification in serum concentrations of albumin, total protein, and prealbumin. Baseline serum RbP levels (16.2 ⫾ 2.2 mg/dL) decreased during phases II (11.3 ⫾ 1.3 mg/dL; P ⬍ 0.05) and III (11.0 ⫾ 1.3 mg/dL; P ⬍ 0.05) after rhGH
therapy. Moreover, the rhGH group showed a significant increase in serum transferrin concentrations during the treatment period (271.2 ⫾ 16.3 v 314.5 ⫾ 21.2 mg/dL; 0 weeks v 4 weeks; P ⬍ 0.05), and these were significantly greater than those obtained in the control group at 2 weeks (290.1 ⫾ 18.4 v 233.8 ⫾ 14.3 mg/dL; P ⬍ 0.05), 4 weeks (314.5 ⫾ 21.2 v 245.7 ⫾ 17.0 mg/dL; P ⬍ 0.05), and 8 weeks (291.7 ⫾ 18.0 v 233.6 ⫾ 17.1 mg/dL; P ⬍ 0.05; Table 3 and Fig 2B). There was a significant increase in the control group in levels of total protein (6.4 ⫾ 0.1 v 6.8 ⫾ 0.2 g/dL, 0 weeks v 4 weeks; P ⬍ 0.01) and albumin (3.5 ⫾ 0.1 v 3.7 ⫾ 0.1 g/dL; 0
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
459
26.3 v 192.4 ⫾ 35.3 mg/dL; 0 weeks v 4 weeks; NS). This increase, however, was statistically significant with respect to the control group at 2 weeks (183.2 ⫾ 27.0 v 122.9 ⫾ 12.0 mg/dL; rhGH v control; P ⬍ 0.05) and 4 weeks (192.4 ⫾ 35.3 v 129.7 ⫾ 16.3 mg/dL; rhGH v control; P ⬍ 0.05). These changes returned to baseline at the end of phase III. Fasting glucose levels increased significantly with rhGH administration (104.2 ⫾ 4.7 and 103.9 ⫾ 5.0 v 85.4 ⫾ 3.8 mg/dL; 2 and 4 weeks v 0 weeks; P ⬍ 0.01) and returned to pretreatment levels at the end of the follow-up period (96.3 ⫾ 8.0 mg/dL). HbA1c values were unchanged during the study. Hormonal Results
Fig 2. Evolution of serum (A) IGF-1, (B) transferrin, and (C) BUN concentrations during the study period in both groups of patients (mean ⴞ SEM). Solid circles represent the rhGH group, whereas open circles represent the control group. *P F 0.05 v 0 weeks. **P F 0.01 v 0 weeks. aP F 0.05, rhGH v control.
weeks v 4 weeks; P ⬍ 0.01) at the end of phase II, with no modifications in serum RbP, prealbumin, and transferrin concentrations. rhGH therapy did not modify serum cholesterol levels, although a small increase of serum triglyceride concentrations was noted (152.6 ⫾
Baseline GH levels remained constant in both groups. Serum IGF-1 concentrations increased significantly from 216.6 ⫾ 42.5 ng/mL (0 weeks) to 518.7 ⫾ 112.1 ng/mL (2 weeks; P ⬍ 0.05) and 581.2 ⫾ 171.5 ng/mL (4 weeks; P ⬍ 0.01) after rhGH administration, and a statistically significant increase of IGF-1 concentrations was also observed in the control group at the end of the treatment phase (231.4 ⫾ 43.6 v 258.7 ⫾ 50.3 ng/mL; 0 weeks v 4 weeks; P ⬍ 0.05; Fig 2A and Table 4). However, the magnitude of the difference was much larger in the rhGH group. Serum insulin levels showed a tendency to increase with rhGH therapy, although this increment was not statistically significant. The value of serum insulin at 4 weeks was greater than the normal range only in the rhGH group. Serum C peptide levels increased in the rhGH group from 28.8 ⫾ 8.1 to 34.7 ⫾ 5.2 ng/mL. This increment was statistically significant with respect to the control group (34.7 ⫾ 5.2 v 12.7 ⫾ 2.2 ng/mL; rhGH v control; P ⬍ 0.01). Finally, rhGH therapy did not produce any significant modification in thyroid function during the treatment period (Table 4). Nutrient Intake and Urea Kinetic Responses The daily intake of calories (30.1 ⫾ 3.7 v 27.4 ⫾ 2.9 kcal/kg/d; 0 v 4 weeks) and proteins (1.31 ⫾ 0.15 v 1.19 ⫾ 0.09 g/kg/d; 0 v 4 weeks) was unchanged with rhGH therapy. rhGH treatment was associated with a significant and reversible reduction in serum BUN concentrations from 62.1 ⫾ 1.8 mg/dL at 0 weeks to 51.6 ⫾ 3.7 mg/dL (P ⬍ 0.05) at 2 weeks, and to 46.8 ⫾ 3.8
460
IGLESIAS ET AL Table 4. Hormone Results During the Study Weeks
Insulin (µU/mL) rhGH Control C-peptide (ng/mL) rhGH Control GH (ng/mL) rhGH Control IGF-1 (ng/mL) rhGH Control TSH (µU/mL) rhGH Control FT4 (ng/dL) rhGH Control
⫺4
0
2
— —
16.9 ⫾ 3.0 18.9 ⫾ 2.0
— —
36.6 ⫾ 9.4 19.0 ⫾ 3.0
— —
— —
28.8 ⫾ 8.1 16.8 ⫾ 1.6
— —
34.7 ⫾ 5.2 12.7 ⫾ 2.2*
— —
8.5 ⫾ 3.3 4.9 ⫾ 2.0
5.0 ⫾ 1.1 5.1 ⫾ 2.2
5.2 ⫾ 2.1 4.1 ⫾ 1.3
3.5 ⫾ 0.8 2.6 ⫾ 1.2
5.4 ⫾ 1.2 2.7 ⫾ 0.6
226.0 ⫾ 46.7 234.9 ⫾ 38.6
216.6 ⫾ 42.5 231.4 ⫾ 43.6
518.7 ⫾ 112.1† 240.2 ⫾ 36.8§
581.2 ⫾ 171.5‡ 258.7 ⫾ 50.3†
251.5 ⫾ 59.4 244.3 ⫾ 43.0
2.2 ⫾ 1.1 2.4 ⫾ 0.4
2.1 ⫾ 1.2 1.5 ⫾ 0.3
1.6 ⫾ 0.8 2.2 ⫾ 0.6
2.3 ⫾ 1.3 2.9 ⫾ 0.7
1.1 ⫾ 0.5 2.6 ⫾ 0.8
1.4 ⫾ 0.1 1.5 ⫾ 0.2†
1.4 ⫾ 0.1 1.3 ⫾ 0.1
1.6 ⫾ 0.2 1.3 ⫾ 0.1
1.6 ⫾ 0.2 1.2 ⫾ 0.1
1.0 ⫾ 0.2 1.3 ⫾ 0.1
4
8
NOTE. Values expressed as mean ⫾ SEM. *P ⬍ 0.01 (rhGH v control). †P ⬍ 0.05 (v 0 weeks). ‡P ⬍ 0.01 (v 0 weeks). §P ⬍ 0.05 (rhGH v control).
mg/dL (P ⬍ 0.05) at 4 weeks. At this point, BUN concentrations in the rhGH group were significantly less than those obtained in the control group (67.8 ⫾ 7.4 mg/dL; P ⬍ 0.05; Fig 2C). No significant modification in PCR and KtV was observed during phases II and III. Side Effects rhGH therapy was in general well tolerated and no clinically deleterious side effects were observed, except for transitory local pain at the site of injection (one patient), headache (one patient), sporadic nausea and vomiting (three patients), pruritus (four patients), hypotension (two patients), hand paresthesias (two patients), and nocturnal anxiety (one patient). In the control group, the side effects registered were hypotension (one patient), transient chest pain (one patient), and arthralgia (two patients). DISCUSSION
Our results show that short-term rhGH treatment in a small group of malnourished dialysis patients is accompanied by a significant increase in body weight, a reduction in serum BUN con-
centrations, and a significant increase in transferrin and serum IGF-1 concentrations. However, no changes in other nutritional indices, such as albumin and prealbumin levels, lymphocyte count, and PCR were associated with rhGH therapy. This indicates that the use of pharmacological doses of rhGH might improve several nutritional parameters in these patients. Calorie protein malnutrition is frequent in uremic patients, and this poor nutritional status is associated with increased morbidity and mortality.3 Moreover, it is now well established that dialysis therapy is an important catabolic process. It is known that the GH–IGF-1 axis is impaired in uremia. Uremic patients show elevated serum GH concentrations and abnormal responses to different stimuli, and it has been postulated that resistance to this hormone is a common feature, not only in ESRD patients, but also in malnourished non-ESRD patients.15,16 Because of the known effects of GH on protein metabolism, several studies have investigated whether rhGH therapy would be useful as a treatment for dialysis patients. Thus, the effects of rhGH have been analyzed in stable HD,17,18
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
malnourished HD15,19-22 stable CAPD,23 and malnourished CAPD patients.19,24 Also evaluated has been the anabolic effect of this hormone associated with intradialytic parenteral nutrition in malnourished HD patients.25 These reports showed that the use of pharmacological doses of rhGH in dialysis patients was accompanied by anabolic effects, such as a decrease in predialysis BUN concentrations, reduction in PCR, and improvement in serum albumin, transferrin, and IGF-1 concentrations.17,18,23,25 To the best of our knowledge, this is the first randomized, controlled trial in which the effects of rhGH therapy in malnourished dialysis patients have been evaluated. Different anthropometric parameters, such as body weight, BMI, skin-fold thickness, MAMC, and muscle strength have been used in ESRD patients to evaluate nutritional state.3 GH has remarkable effects on body composition. In fact, its administration reduces fat mass and increases muscle mass.26 To date, several published reports of uremic children undergoing rhGH treatment have shown an improvement in various nutritional parameters, such as increment of MAMC and reduction of TSF.27,28 However, these findings have not been observed by other investigators in adult ESRD patients. In 1991, Sanaka and Sugino19 reported an increase in body weight in two severely malnourished dialysis patients, and an improvement in MAMC in one of them. A recent study of patients undergoing CAPD performed by Kang et al24 in 1994 showed a significant increase in lean body mass, total body muscle, muscle strength, and subjective exercise capacity with rhGH therapy. More recently, Ahlme´n et a1,18 in 1996, in a preliminary report, observed a significant increase in lean body mass in a group of 20 elderly patients undergoing chronic dialysis treated with rhGH for 6 months. In 1997, Garibotto et al22 showed that rhGH administration in malnourished HD patients was followed by an increase in muscle protein synthesis, with no effect on muscle protein degradation. In the present study, rhGH therapy showed a slight, but significant, increment in body weight. However, MAMC increased, not only in the rhGH group, but also in the control group. TSF thickness did not modify in any group of patients. Other known physiological effects of GH in patients with normal renal function are fluid
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and sodium retention,29,30 which is sometimes associated with peripheral edema, weight gain, and, more rarely, an increase in blood pressure. In our patients, we could not show that the increase in body weight was exclusively caused by an increment in lean body mass. Unfortunately, we did not register the residual renal function at baseline. However, no patient developed edema, no significant changes in blood pressure values after rhGH treatment were found, and no significant changes in serum electrolyte or creatinine levels were observed. Finally, it was not necessary to modify the antihypertensive drugs in the four hypertensive patients in rhGH group to control blood pressure. This suggests that the increment in body weight in rhGH patients might be related to the anabolic effect of GH. Finally, rhGH therapy was not accompanied by a statistically significant improvement in muscle strength. Perhaps the duration of therapy was too short to improve body composition and modify muscle function. Results of the studies on the effects of rhGH therapy on red blood cell counts in dialysis patients have not been uniform. Some investigators have observed an improvement in hematocrit values,19,21 whereas other studies have failed to show similar responses.17,23,25 In the present report, both hematocrit and hemoglobin values did not change in relation to baseline after rhGH treatment, although the hematocrit and hemoglobin values were significantly greater than those observed in the control group. It has been recently reported that IGF-1 has functional analogies with erythropoietin. In fact, IGF-1 has the capacity to stimulate human erythroid colony formation in vitro.31,32 However, to date, the role of rhGH therapy on erythropoiesis in adult dialysis patients is unclear. As in the majority of previous reports, we did not find any modification in lymphocyte count with rhGH administration. The effect of rhGH on serum protein concentration is not well defined at present. Some investigators have noted an increase in serum albumin concentrations after rhGH therapy,18,19, 21,25 although this effect has not been observed by others.23 In 1996, Ikizler et al33 found a shift in plasma amino acid profile after rhGH therapy in patients undergoing CAPD, suggesting an anabolic process. In our study, both serum total
462
protein, albumin, and prealbumin concentrations were not modified. RbP showed a small, but statistically significant, decrease during rhGH therapy and the follow-up period, and serum transferrin concentrations increased only in the rhGH group. This effect has also been observed with the administration of rhGH associated with intradialytic parenteral nutrition in malnourished HD patients.25 In our study, both serum total protein and albumin concentrations increased in the control group at the end of the therapy period; however, this increment was not statistically different from the rhGH group. Therapy with rhGH was not associated with changes in basal serum concentrations of GH. This was also observed by Kopple et al34 in 1990 in a group of adult malnourished HD patients treated with rhGH. These investigators found an increment of serum GH concentrations of 19fold to 20-fold within 0.5 hours of the first dose of rhGH, but morning fasting preinjection values were usually normal or near normal. This would indicate that rhGH does not accumulate in adult dialysis patients. The half-life of endogenous GH is 10 to 20 minutes and the half-life of rhGH is 5 hours when it is administered SC. In our patients, serum samples for GH were drawn just before rhGH injection, and it probably explains the absence of an increment of serum GH concentrations. Moreover, it is probable that both rhGH and the increment of serum IGF-1 contribute to stimulating the endogenous secretion of hypothalamic somatostatin, decreasing the endogenous secretion of GH from anterior pituitary. Our results confirmed the findings of previous studies on rhGH treatment in dialysis patients with regard to modifications in serum IGF-1 and BUN concentrations. In this setting, the increment in IGF-1 and reduction in BUN concentrations have been uniformly described. We did not find any relationship between the changes in IGF-1 levels and variations in BUN or transferrin levels. Perhaps these modifications could be related to changes in circulating free IGF-1, but not total IGF-1 concentrations, because it has been recently described by others.22 As previously reported, rhGH did not modify nutrient intake. Finally, PCR showed a small, but not significant, decrement in the rhGH group. This suggests a diminished PCR as a result of an anabolizing state induced by rhGH. A reduction
IGLESIAS ET AL
in BUN level associated with stable intake suggests nitrogen retention with an improvement of the efficacy of dietary protein utilization. In general, rhGH therapy in adult dialysis patients has been well tolerated.18,19,23 To date, no clinically deleterious side effects have been reported, although the periods of rhGH administration have been short. Only minor side effects, such as facial edema and pruritus, have been reported.24 In our study, rhGH tolerance was acceptable, although minor side effects were more frequently observed than in other studies. The possible explanation for this observation could be related to the higher dose of rhGH used in this study. Treatment with rhGH was accompanied by a significant increase in glucose levels with a slight increase in insulin levels and no modifications in HbA1c. The effect on carbohydrate metabolism must be considered, especially in patients with diabetes. It seems that thyroid function is not affected after pharmacological doses of rhGH in adult dialysis patients. Finally, a small, but not clinically important, increase in triglyceride levels was observed, and cholesterol levels were not modified by rhGH. In conclusion, our data support the concept that rhGH has anabolic effects in malnourished dialysis patients because of the following: the increase in body weight; the increment in IGF-1, the major mediator of GH action with potent anabolic actions; the increase in transferrin concentrations; and the reduction in BUN levels associated with stable daily dietary intake. It seems that most rhGH side effects are dose dependent and more pronounced in patients receiving pharmacological doses of rhGH. Longterm, randomized, controlled, double-blind clinical trials in larger groups of patients are needed to determine the potential clinical use of rhGH in malnourished dialysis patients. ACKNOWLEDGMENT The authors thank Victoria Martı´nez, Olga Celadilla, Marı´a Jose´ Castro, and Sonia Sa´nchez for their cooperation in the study, and Laboratories Serono SA for providing rhGH.
REFERENCES 1. Kaminski MV Jr, Lowrie EG, Rosenblatt SG, Haase T: Malnutrition is lethal, diagnosable, and treatable in ESRD patients. Transplant Proc 23:1810-1815, 1991
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
2. Blagg CR: Importance of nutrition in dialysis patients. Am J Kidney Dis 17:458-461, 1991 3. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 50:343-357, 1996 4. Bergstro¨m J, Lindholm B: Nutrition and adequacy of dialysis: How do hemodialysis and CAPD compare? Kidney Int 43:39-50, 1993 (suppl 40) 5. Acchiardo SR, Moore LW, Latour PA: Malnutrition as the main factor in morbidity and mortality of hemodialysis patients. Kidney Int 24:199-203, 1983 (suppl 16) 6. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 7. Hakim RM, Levin N: Malnutrition in hemodialysis patients. Am J Kidney Dis 21:125-137, 1993 8. Ikizler TA, Wingard RL, Hakim RM: Interventions to treat malnutrition in dialysis patients: The role of the dose of dialysis, intradialytic parenteral nutrition, and growth hormone. Am J Kidney Dis 26:256-265, 1995 9. Dı´ez JJ, Iglesias P: Hormona de crecimiento: Una nueva perspectiva terapeu´tica en la malnutricio´n asociada a la uremia. Nefrologı´a 15:539-549, 1995 10. Douglas RG, Humberstone DA, Haystead A, Shaw JHF: Metabolic effects of recombinant human growth hormone: Isotopic studies in the postabsorptive state and during total parenteral nutrition. Br J Surg 77:758-790, 1990 11. Mjaaland M, Unnenberg K, Hotvedt R, Revhaug A: Nitrogen retention caused by growth hormone in patients undergoing gastrointestinal surgery with epidural analgesia and parenteral nutrition. Eur J Surg 157:21-27, 1991 12. Mulligan K, Grunfeld C, Hellerstein MK, Neese RA, Schambelan M: Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 77:956-962, 1993 13. Frisancho AR: New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 34:2540-2545, 1981 14. Selgas R, Bajo MA, Fernandez-Reyes MJ, Bosque E, Lopez-Revuelta K, Jimenez C, Borrego F, de Alvaro F: An analysis of adequacy of dialysis in a selected population on CAPD for over 3 years: The influence of urea and creatinine kinetics. Nephrol Dial Transplant 8:1244-1253, 1993 15. Kopple JD: The rationale for the use of growth hormone or insulin-like growth factor-I in adult patients with renal failure. Miner Electrolyte Metab 18:269-275, 1992 16. Blake PG: Growth hormone and malnutrition in dialysis patients. Perit Dial Int 15:210-216, 1995 17. Ziegler TR, Lazarus JM, Young LS, Hakim R, Wilmore DW: Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis. J Am Soc Nephrol 2:1130-1135, 1991 18. Ahlme´n J, Johannsson G, Johansson A, Bengtsson BA: Growth hormone (GH) treatment of elderly patients on chronic dialysis. J Am Soc Nephrol 7:1436, 1996 (abstr) 19. Sanaka T, Sugino N: Improvement of malnutrition indices in adult patients with end-stage renal disease by recombinant human growth hormone. Nippon Jinzo Gakkai Shi 33:1153-1159, 1991
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20. Kopple JD, Brunori G, Leiserowitz M, Mattimore C, Hirschberg R: Growth hormone treatment for patients with renal failure. Jpn J Nephrol 33:468-475, 1991 21. Sinobe M, Sanaka T, Higuchi C, Hizuka N, Niehi H, Sugino N: The improvement of catabolic state in hemodialysis patients by recombinant human growth hormone (rhGH). J Am Soc Nephrol 4:431, 1993 (abstr) 22. Garibotto G, Barreca A, Russo R, Sofia A, Araghi P, Cesarone A, Malaspina M, Fiorini F, Minuto F, Tizianello A: Effects of recombinant human growth hormone (GH) on muscle protein turnover in malnourished hemodialysis patients. J Clin Invest 99:97-105, 1997 23. Ikizler AT, Wingard RL, Breyer JA, Schulman G, Parker RA, Hakim RM. Short-term effects of recombinant human growth hormone in CAPD patients. Kidney Int 46:1178-1183, 1994 24. Kang DH, Lee SW, Kang SW, Kim HS, Choi KH, Lee HY, Han DS: Recombinant human growth hormone (rhGH) improves nutritional status of undernourished adult CAPD patients. J Am Soc Nephrol 5:494, 1994 (abstr) 25. Schulman G, Wingard RL, Hutchison RL, Lawrence P, Hakim RM: The effects of recombinant human growth hormone and intradialytic parenteral nutrition in malnourished hemodialysis patients. Am J Kidney Dis 21:527-534, 1993 26. Jørgensen JOL, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS: Beneficial effects of growth hormone treatment in GHdeficient adults. Lancet 1:1221-1225, 1989 27. Koch VH, Lippe BM, Nelson PA, Boechat MI, Sherman BM, Fine RM: Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure. J Pediatr 115:365-371, 1989 28. Tonshoff B, Mehls O, Heinrich U, Blum W, Ranke MB: Improvement of uremic growth failure by recombinant human growth hormone. Kidney Int 36:201-204, 1989 29. Salomon F, Cuneo RC, Hesp R, So¨nken PH: The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797-1803, 1989 30. Hoffman DM, Crampton L, Sernia C, Nguyen TV: Short-term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab 81:1123-1128, 1996 31. Claustres M, Chatelain P, Sultan C: Insulin-like growth factor-I stimulates human erythroid colony formation in vitro. J Clin Endocrinol Metab 65:78-82, 1987 32. Merchav S, Tatarsky I, Hochberg Z: Enhancement of erythropoiesis in vitro by human growth hormone is mediated by insulin-like growth factor-I. Br J Haematol 70:267271, 1988 33. Ikizler TA, Wingard RL, Flakoll PJ, Schulman G, Parker RA, Hakim RM: Effects of recombinant human growth hormone on plasma and dialysate amino acid profiles in CAPD patients. Kidney Int 50:229-234, 1996 34. Kopple JD, Leiserowitz M, Brunori G, Mattimore C: Treatment of malnourished maintenance hemodialysis (MHD) patients with recombinant human growth hormone. J Am Soc Nephrol 1:364, 1990 (abstr)
P
ATIENTS WITH end-stage renal disease (ESRD) undergoing dialysis often show different grades of protein calorie malnutrition. It represents one of the main clinical problems of these patients. The prevalence of malnutrition in dialysis patients has been reported to range from 12% to 51%.1-3 In fact, in different studies, several signs of malnutrition have been observed in 10% to 70% of hemodialysis (HD) patients and 18% to 51% of continuous ambulatory peritoneal dialysis (CAPD) patients.4 It is generally accepted that there is a relationship between the extent of protein calorie malnutrition and increased morbidity and mortality in dialysis patients.1,3,5-7 The cause of this poor nutritional status is multifactorial. Among the main factors contributing to malnutrition are anorexia and reduction of nutrient intake, metabolic and horFrom the Departments of Endocrinology and Nephrology, Hospital La Paz; and Laboratorios Serono, Madrid, Spain. Received October 22, 1997; accepted in revised form April 14, 1998. Address reprint requests to Pedro Iglesias, MD, C/ Marı´a Sevilla Diago, 9, 3° dcha, 28022 Madrid, Spain.
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3203-0014$3.00/0 454
monal derangements, catabolic intercurrent illnesses, presence of uremic toxins and loss of nutrients, and catabolic effects associated with dialysis. A number of reports have suggested that the treatment of malnutrition in these patients could reduce the risk for morbidity and mortality.2,3,8,9 For this reason, different preventive and therapeutic measures have been used to treat malnutrition in patients with ESRD. These include anabolic hormones, such as growth hormone (GH), and its major mediator, insulin-like growth factor type 1 (IGF-1). In this setting, recombinant human GH (rhGH) has been recently used as an anabolic agent in several catabolic states.10-12 Preliminary studies in dialysis patients have suggested that rhGH administration reduces urea generation and improves the efficacy of dietary protein utilization, diminishing body protein catabolism. However, so far, controlled, randomized studies of dialysis patients have not been reported. Therefore, we set out to perform a controlled, randomized study evaluating the effects of short-term rhGH administration on nutritional status in a group of malnourished dialysis patients.
American Journal of Kidney Diseases, Vol 32, No 3 (September), 1998: pp 454-463
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
PATIENTS AND METHODS
Patients Seventeen malnourished patients with chronic renal failure (nine women, eight men; age, 60.9 ⫾ 3.2 [mean ⫾ standard error of the mean (SEM)] years; range, 30 to 78 years) undergoing dialysis (11 CAPD, 6 HD) were studied. The patients had the following primary renal diseases: hypertensive nephrosclerosis (five patients), chronic glomerulonephritis (four patients), polycystic kidney disease (two patients), chronic pyelonephritis (one patient), interstitial nephropathy (one patient), lupus nephropathy (one patient), and unknown primary renal disease (three patients). Inclusion criteria were dialysis therapy during at least 6 months, age greater than 18 years, and protein calorie malnutrition with at least one of the following: weight loss of greater than 10% in the last 6 months or greater than 5% in the last month, reduction of greater than 20% of midarm muscle circumference (MAMC) and/or ideal body weight according to sex and age, serum albumin level less than 4.0 g/dL, protein catabolic rate (PCR) less than 0.9 g/kg/d, and lymphocyte count less than 1,000/µL. Exclusion criteria were diseases that might contraindicate the use of rhGH (such as diabetes mellitus and/or carcinoma within the previous 5 years), corticosteroid therapy in the previous 6 months, uncontrolled hypertension (diastolic blood pressure ⬎ 95 mm Hg), severe secondary hyperparathyroidism (intact parathyroid hormone ⬎ 600 pg/mL), congestive heart failure, dose of erythropoietin not stabilized in the previous 2 months, low dose of dialysis (weekly urea Kt/V ⬍ 3 for HD and ⬍ 1.7 for CAPD), and infectious or surgical stress. All patients received written and oral information and gave written consent before study entry. The study was conducted in accordance with the Declaration of Helsinki II and was approved by the Local Ethical Committee of the Hospital La Paz and by the Clinical Research Board of the Spanish Ministry of Health.
Study Design The study was a pilot, randomized, controlled group study that lasted 12 weeks. Patients were randomly assigned to control or rhGH groups by means of a table of random numbers generated by computer. In the control group (nine patients; six women, three men; mean age, 58.3 ⫾ 5.6 years; seven CAPD, two HD; time on dialysis, 49.9 ⫾ 18.5 months), six patients were hypertensive and seven were receiving recombinant human erythropoietin (rhEPO) therapy (weekly mean dose, 102.8 ⫾ 15.9 U/kg subcutaneously [SC]). The rhGH group consisted of eight patients (three women, five men; mean age, 63.9 ⫾ 3.1 years; four CAPD, four HD; time on dialysis, 73.9 ⫾ 21.4 months). Four of them were hypertensive and seven were receiving rhEPO therapy (weekly dose, 109.5 ⫾ 21.8 U/kg SC). During the study, there were no changes in rhEPO doses, and two patients of each group were treated with iron intravenously. Baseline clinical and analytic characteristics of the two groups of patients are listed in Table 1. There were no significant differences between groups in age, sex, cause of renal disease, type of dialysis, duration of dialysis, presence of hypertension, rhEPO therapy, weekly dose of rhEPO, and
455
Table 1. Clinical and Analytic Data of the Studied Patients rhGH Group
Control Group
Clinical data No. of patients 8 9 Age (yr) 63.9 ⫾ 3.1 58.3 ⫾ 5.6 Sex (M/F) 5/3 3/6 Hypertension (yes/no) 4/4 6/3 Relative body weight (%) 99.6 ⫾ 7.5 107.0 ⫾ 7.1 EPO (yes/no) 7/1 7/2 EPO dosage (U/kg/ week) 109.5 ⫾ 21.8 102.8 ⫾ 15.9 Loss of weight 1 0 Reduction ⬎20% weight/MAMC 3 1 PCR ⬍ 0.9 g/kg/d 6 5 Albumin ⬍ 4.0 g/dL 6 9 Prealbumin ⬍ 29 mg/dL 1 1 Lymphocyte count ⬍1,000 (⫻103/µL) 4 2 Dialysis parameters Type of dialysis (HD/CAPD) 4/4 2/7 Time on dialysis (mon) 73.9 ⫾ 21.4 49.9 ⫾ 18.5 PCR (g/kg/d) 0.839 ⫾ 0.040 0.954 ⫾ 0.070 Weekly urea Kt/V CAPD 1.80 ⫾ 0.19 2.11 ⫾ 0.10 HD 3.60 ⫾ 0.36 4.14 ⫾ 0.54 Analytic data Hematocrit (%) 33.6 ⫾ 1.2 29.9 ⫾ 2.0 Hemoglobin (g/dL) 10.9 ⫾ 0.4 9.6 ⫾ 0.6 Lymphocyte (⫻µL) 1,245.6 ⫾ 165.5 1,269.6 ⫾ 164.5 Sodium (mmol/L) 140.3 ⫾ 0.7 137.8 ⫾ 0.9 Potassium (mmol/L) 4.7 ⫾ 0.3 4.6 ⫾ 0.3 Glucose (mg/dL) 85.4 ⫾ 3.8 96.0 ⫾ 5.5 Cholesterol (mg/dL) 204.4 ⫾ 15.1 184.9 ⫾ 14.7 Triglyceride (mg/dL) 152.6 ⫾ 26.3 126.2 ⫾ 15.3 Total protein (g/dL) 6.9 ⫾ 0.2 6.4 ⫾ 0.1 Albumin (g/dL) 3.8 ⫾ 0.2 3.5 ⫾ 0.1 RbP (mg/dL) 16.2 ⫾ 2.2 17.9 ⫾ 3.3 Prealbumin (mg/dL) 44.2 ⫾ 3.4 37.0 ⫾ 5.1 Transferrin (mg/dL) 271.2 ⫾ 16.3 237.7 ⫾ 6.3 GH (ng/mL) 5.0 ⫾ 1.1 5.1 ⫾ 2.2 IGF-1 (ng/mL) 216.6 ⫾ 42.5 231.4 ⫾ 43.6 TSH (µU/ml) 2.1 ⫾ 1.2 1.5 ⫾ 0.3 FT4 (ng/dL) 1.4 ⫾ 0.1 1.3 ⫾ 0.1 Hemoglobin A1c (%) 5.5 ⫾ 0.2 5.8 ⫾ 0.2 NOTE. Data expressed as the number of patients or the mean ⫾ SEM. Abbreviations: EPO, erythropoietin therapy; HD, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis; PCR, protein catabolic rate; RbP, retinol binding protein; GH, growth hormone; IGF 1, insulin-like growth factor type 1; TSH, thyrotropin; FT4, free thyroxine.
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inclusion criteria (Table 1). The study design consisted of three consecutive periods (Fig 1): the inclusion period (phase I), therapy period (phase II), and follow-up period (phase III). In phase I, inclusion criteria were verified in every patient and written informed consent was obtained. Thereafter, anthropometric and analytic parameters were determined 4 weeks before phase II (–4 weeks) to confirm the baseline clinical situation of the patients. During phase II, all patients received dietary treatment (35 kcal/kg/d and 1 g protein/kg ideal body weight/d) for 4 weeks. In the rhGH group, rhGH was administered at 0.2 IU/kg/d SC at 8:00 AM in patients undergoing CAPD and, in patients undergoing HD, rhGH was administered immediately after the dialysis session. Patients were followed up during the 4 weeks (phase III) after discontinuation of therapy period. During the three phases, patients were seen for eight visits; two of them in phase I (–4 and –1 weeks), five in phase II (0, 1, 2, 3, and 4 weeks), and one in phase III.
Anthropometric Parameters Anthropometric parameters were assessed in every patient at –4, 0, 1, 2, 3, 4, and 8 weeks, and always by the same investigator, using the recommendations of Frisancho.13 Anthropometric measurements were made at 8:00 AM in patients undergoing CAPD and immediately after the dialysis session in patients undergoing HD. Dry weight (Wt) and height (H) were registered and body mass index (BMI [kg/m2] ⫽ Wt [kg]/H[m]2) was then obtained. Other anthropometric indices evaluated included triceps skin-fold (TSF), midarm circumference (MAC), and midarm muscle circumference (MAMC [cm] ⫽ MAC [cm] – 3.14 ⫻ TSF [cm]). TSF was determined using a caliper (Holtain LTD., Crosswell, Crymych, Dyfed SA41 3UF. UK) and hand grip strength was evaluated with a conventional manual dynamometer. Blood pressure at baseline and after treatment was also registered.
Laboratory Parameters and Hormone Assay Blood samples were drawn at –4, 0, 2, 4, and 8 weeks for determination of complete blood cell count; serum electro-
IGLESIAS ET AL
lyte, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, cholesterol, triglyceride, total protein, albumin, transferrin, prealbumin, retinol-binding protein (RbP), glucose, glycosylated hemoglobin (HbA1c), GH, IGF-1, free thyroxine (FT4), and thyrotropin (TSH) levels. Serum insulin and C-peptide concentrations were also assessed at 0 and 4 weeks. Blood samples were centrifuged immediately and the serum stored at –20°C until assayed. Blood cell count was measured in a Coulter counter (Technicon H3RTX, Bayer, Germany), and the serum chemistry determinations were performed using an automated multichannel analyzer. HbA1c was measured by high-performance liquid chromatography (Variant; Biorad, Hercules, CA). The intra-assay and interassay coefficients of variation were 1.91% and 3.70%, respectively. Normal range was 4.5% to 6.5%. Human serum GH and TSH concentrations were determined by using an automated immunoenzymatic assay (AIA 1200; Tosoh Corporation, Tokyo, Japan). Maximal intra- and interassay coefficients of variation of GH assay were 5.4% and 3.3%, respectively. The sensitivity of the GH assay was 0.1 ng/mL. Normal was less than 5 ng/mL. For TSH assay, the sensitivity was 0.06 µU/mL and maximum intra- and interassay coefficients of variation were 3.3% and 3.4%, respectively. Normal range for TSH was 0.6 to 5.0 mU/mL. Serum IGF-1 concentrations were measured by specific radioimmumoassay after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra- and interassay coefficients of variation were 2.9% and 11.4%, respectively. The sensitivity of the assay was 12.9 ng/mL. The normal range was 83 to 450 ng/mL for patients younger than 40 years of age and 54 to 389 ng/mL for patients aged 40 years or older. FT4 was measured by commercially available immunoenzymatic assay kits (AIA-PACK FT4, Tosoh Corp, Tokyo, Japan) that use the automated system AIA-1200. Maximal intra- and interassay coefficients of variation were 9.6% and 7.7%, respectively. The sensitivity of FT4 assay was 0.1 ng/dL. Normal range was 0.91 to 2.18 ng/dL. Serum insulin concentrations were analyzed with a commercial radioimmunoassay (Sorin; Biomedica, Saluggia, Italy). The intra- and interassay coefficients of variation were 6.6% and 6.2%, respectively. The sensitivity of insulin assay was 3 mIU/mL. The normal range in our laboratory was 5 to 25 mIU/mL. Serum C-peptide concentrations were determined by radioimmunoassay (Medgenix; Diagnostics, Fleurus, Belgium). Maximal intra- and interassay coefficients of variation were 7.6% and 8.8%, respectively. The sensitivity of the assay was 0.1 ng/mL and the normal range was 0.5 to 3.0 ng/mL.
Dietary Regimen Mean daily dietary intake was determined from individual 24-hour food records during a 3-day period before the beginning of phases II and III. Daily calorie, carbohydrate, lipid, and protein intake was calculated for each patient using a commercially available computer software (Wander; Sandoz Nutricio´n, 1990, Barcelona, Spain).
Urea Kinetic Analysis Fig 1. Study design. In rhGH group, rhGH was administered at 0.2 IU/kg/d SC during 4 weeks.
Urea kinetic parameters (urea Kt/V and PCR) were calculated according to previously described methods.14
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
Statistical Methods Results are expressed as mean ⫾ SEM. Clinical and analytic data at different time points of the study for the same patients were compared by using repeated-measures analysis of variance. For comparison between rhGH and control groups, the Mann-Whitney U test was used. The chi-square test was used to study the relationship between qualitative variables. Bilateral contrast was used for all comparisons. The differences were considered significant for P less than 0.05.
457
23.9 ⫾ 1.0 cm at 4 weeks (P ⬍ 0.05; Table 2). No significant differences were observed between groups in TSF, MAC, and hand-grip strength during the study. Finally, blood pressure remained unchanged after rhGH treatment (systolic, 134.0 ⫾ 8.9 v 128.7 ⫾ 5.9 mm Hg; diastolic, 77.7 ⫾ 3.0 v 77.5 ⫾ 2.7 mm Hg; 0 weeks v 4 weeks). Laboratory Parameters
RESULTS
Anthropometric Measurements At the beginning of the study (–4 weeks), there were no significant differences in body weight between the rhGH (64.7 ⫾ 4.4 kg) and control groups (70.4 ⫾ 6.2 kg). The same was observed at 0 weeks (64.3 ⫾ 4.3 v 70.3 ⫾ 6.3 kg; rhGH v control; not significant [NS]). The rhGH group showed a mean increase of 1.238 kg in body weight from 64.3 ⫾ 4.3 to 65.6 ⫾ 4.9 kg (4 weeks; P ⬍ 0.05; Table 2). No changes in body weight were observed in the control group. The results of the BMI were similar to those obtained for body weight in both groups at the end of phase II. The evaluation of MAMC showed a significant increase in both the rhGH group, from 22.7 ⫾ 1.0 to 23.7 ⫾ 0.9 cm at 4 weeks (P ⬍ 0.05) and the control group, from 22.8 ⫾ 0.9 to
The comparative analysis between both groups at 0 weeks of values for hematocrit, hemoglobin, lymphocyte, serum electrolytes, BUN, creatinine, calcium, phosphorus, cholesterol, triglycerides, total protein, albumin, transferrin, prealbumin, RbP, glucose, and HbA1c did not show any significant difference (Tables 1 and 3). The hemoglobin and hematocrit values did not change with respect to baseline in either group. However, in the rhGH group, both hemoglobin (11.2 ⫾ 0.4 v 9.9 ⫾ 0.4 g/dL; P ⬍ 0.05) and hematocrit (35.1% ⫾ 0.9% v 29.5% ⫾ 1.4%; P ⬍ 0.05) values increased significantly with respect to the control group at 4 weeks. The lymphocyte count was not affected by rhGH therapy. Serum concentrations of creatinine, uric acid, and electrolytes (sodium, potassium, and chlo-
Table 2. Anthropometric Measurements Throughout the Study Weeks
Weight (kg) rhGH Control BMI (kg/m2) rhGH Control TSF (mm) rhGH Control MAC (cm) rhGH Control MAMC (cm) rhGH Control
⫺4
0
1
2
3
4
8
64.7 ⫾ 4.4 70.4 ⫾ 6.2
64.3 ⫾ 4.3 70.3 ⫾ 6.3
64.7 ⫾ 4.4 70.4 ⫾ 6.3
64.9 ⫾ 4.5 69.8 ⫾ 6.1
65.2 ⫾ 4.7 70.0 ⫾ 6.0
65.6 ⫾ 4.9* 70.3 ⫾ 6.2
65.2 ⫾ 5.5* 69.8 ⫾ 6.1
26.5 ⫾ 2.1 28.1 ⫾ 2.0
26.4 ⫾ 2.1 28.0 ⫾ 2.0
26.5 ⫾ 2.1 28.0 ⫾ 2.0
26.6 ⫾ 2.1 27.8 ⫾ 1.9
26.7 ⫾ 2.1 27.9 ⫾ 1.9
26.9 ⫾ 2.3* 28.0 ⫾ 1.9
27.3 ⫾ 2.5 27.8 ⫾ 1.9
18.6 ⫾ 3.3 20.3 ⫾ 3.2
17.2 ⫾ 3.0 20.0 ⫾ 3.2
15.4 ⫾ 3.2 18.7 ⫾ 3.3
15.8 ⫾ 3.7 18.9 ⫾ 3.2
15.6 ⫾ 3.9 18.6 ⫾ 3.2
15.3 ⫾ 4.0 18.4 ⫾ 3.0*
16.2 ⫾ 4.1 19.0 ⫾ 3.4
28.5 ⫾ 1.6 29.4 ⫾ 2.0
28.1 ⫾ 1.9 29.1 ⫾ 1.8
28.1 ⫾ 1.8 28.9 ⫾ 1.7
28.2 ⫾ 2.1 29.4 ⫾ 1.8
28.6 ⫾ 2.0 29.4 ⫾ 1.9
28.5 ⫾ 2.1 29.6 ⫾ 1.9
29.0 ⫾ 2.1 29.6 ⫾ 1.9
22.6 ⫾ 0.8 23.0 ⫾ 1.1
22.7 ⫾ 1.0 22.8 ⫾ 0.9
23.2 ⫾ 0.9 23.0 ⫾ 0.8
23.1 ⫾ 1.0 23.4 ⫾ 0.9
23.5 ⫾ 0.9 23.5 ⫾ 1.1*
23.7 ⫾ 0.9* 23.9 ⫾ 1.0*
24.0 ⫾ 0.9 23.6 ⫾ 1.0*
NOTE. Values expressed as mean ⫾ SEM. Abbreviations: BMI, body mass index; TSF, triceps skinfold; MAC, mid-arm circumference; MAMC, midarm muscle circumference. *P ⬍ 0.05 v 0 weeks.
458
IGLESIAS ET AL Table 3. Effects of rhGH on Different Biochemical Parameters During the Study Weeks
Glucose (mg/dL) rhGH Control Creatinine (mg/dL) rhGH Control BUN (mg/dL) rhGH Control Calcium (mg/dL) rhGH Control Phosphorus (mg/dL) rhGH Control Total protein (g/dL) rhGH Control Albumin (g/dL) rhGH Control RbP (mg/dL) rhGH Control Transferrin (mg/dL) rhGH Control Prealbumin (mg/dL) rhGH Control
⫺4
0
85.8 ⫾ 3.5 94.7 ⫾ 4.3
85.4 ⫾ 3.8 96.0 ⫾ 5.5
104.2 ⫾ 4.7* 85.4 ⫾ 4.1†
103.9 ⫾ 5.0* 88.3 ⫾ 4.3‡
96.3 ⫾ 8.0 95.1 ⫾ 8.0
8.8 ⫾ 0.8 9.7 ⫾ 0.8
9.3 ⫾ 0.4 9.6 ⫾ 0.8
9.4 ⫾ 0.5 9.6 ⫾ 0.9
9.3 ⫾ 0.5 9.9 ⫾ 0.9
9.4 ⫾ 0.8 10.4 ⫾ 0.8
58.5 ⫾ 6.3 63.5 ⫾ 6.9
62.1 ⫾ 1.8 65.7 ⫾ 8.4
51.6 ⫾ 3.7§ 62.8 ⫾ 7.3
46.8 ⫾ 3.8§ 67.8 ⫾ 7.4‡
64.8 ⫾ 5.1 67.1 ⫾ 7.0
9.4 ⫾ 0.3 9.5 ⫾ 0.1§
9.6 ⫾ 0.4 9.2 ⫾ 0.2
10.0 ⫾ 0.3 9.3 ⫾ 0.2
10.4 ⫾ 0.4* 9.6 ⫾ 0.1\
9.3 ⫾ 0.4 9.4 ⫾ 0.2§
6.0 ⫾ 0.8 5.9 ⫾ 0.8
6.5 ⫾ 0.4 5.3 ⫾ 0.7
6.6 ⫾ 0.4 5.7 ⫾ 0.7
6.2 ⫾ 0.4 6.8 ⫾ 0.2
6.3 ⫾ 0.6 5.9 ⫾ 0.7
6.9 ⫾ 0.2 6.5 ⫾ 0.2
6.9 ⫾ 0.2 6.4 ⫾ 0.1
6.6 ⫾ 0.2 6.4 ⫾ 0.2
7.0 ⫾ 0.1 6.8 ⫾ 0.2*
6.9 ⫾ 0.2 6.6 ⫾ 0.2
3.8 ⫾ 0.2 3.6 ⫾ 0.1
3.8 ⫾ 0.2 3.5 ⫾ 0.1
3.6 ⫾ 0.2 3.5 ⫾ 0.1
3.8 ⫾ 0.2 3.7 ⫾ 0.1*
3.7 ⫾ 0.1 3.6 ⫾ 0.1
16.9 ⫾ 3.0 17.1 ⫾ 2.9
16.2 ⫾ 2.2 17.9 ⫾ 3.3
12.8 ⫾ 1.0 12.1 ⫾ 1.3
11.3 ⫾ 1.3§ 11.8 ⫾ 1.1
11.0 ⫾ 1.3§ 13.2 ⫾ 1.2
256.5 ⫾ 16.3 238.0 ⫾ 18.6
271.2 ⫾ 16.3 237.7 ⫾ 16.3
290.1 ⫾ 18.4 233.8 ⫾ 14.3‡
314.5 ⫾ 21.2§ 245.7 ⫾ 17.0‡
291.7 ⫾ 18.0 233.6 ⫾ 17.1‡
49.0 ⫾ 10.0 39.8 ⫾ 7.4
44.2 ⫾ 3.4 37.0 ⫾ 5.1
42.2 ⫾ 4.4 36.1 ⫾ 5.1
42.3 ⫾ 3.8 37.2 ⫾ 4.5
42.5 ⫾ 5.6 34.2 ⫾ 4.8
2
4
8
NOTE. Values expressed as mean ⫾ SEM. *P ⬍ 0.01 (v 0 weeks). †P ⬍ 0.01 (rhGH v control). ‡P ⬍ 0.05 (rhGH v control). §P ⬍ 0.05 (v 0 weeks). \P ⬍ 0.001 (v 0 weeks).
ride) did not show any change throughout the study in either group. Serum phosphorus concentrations remained stable during the protocol, whereas serum calcium concentrations increased in both rhGH (9.6 ⫾ 0.4 v 10.4 ⫾ 0.4 mg/dL; 0 weeks v 4 weeks; P ⬍ 0.01) and control group (9.2 ⫾ 0.2 v 9.6 ⫾ 0.1 mg/dL; 0 weeks v 4 weeks; P ⬍ 0.001). The use of rhGH did not produce any significant modification in serum concentrations of albumin, total protein, and prealbumin. Baseline serum RbP levels (16.2 ⫾ 2.2 mg/dL) decreased during phases II (11.3 ⫾ 1.3 mg/dL; P ⬍ 0.05) and III (11.0 ⫾ 1.3 mg/dL; P ⬍ 0.05) after rhGH
therapy. Moreover, the rhGH group showed a significant increase in serum transferrin concentrations during the treatment period (271.2 ⫾ 16.3 v 314.5 ⫾ 21.2 mg/dL; 0 weeks v 4 weeks; P ⬍ 0.05), and these were significantly greater than those obtained in the control group at 2 weeks (290.1 ⫾ 18.4 v 233.8 ⫾ 14.3 mg/dL; P ⬍ 0.05), 4 weeks (314.5 ⫾ 21.2 v 245.7 ⫾ 17.0 mg/dL; P ⬍ 0.05), and 8 weeks (291.7 ⫾ 18.0 v 233.6 ⫾ 17.1 mg/dL; P ⬍ 0.05; Table 3 and Fig 2B). There was a significant increase in the control group in levels of total protein (6.4 ⫾ 0.1 v 6.8 ⫾ 0.2 g/dL, 0 weeks v 4 weeks; P ⬍ 0.01) and albumin (3.5 ⫾ 0.1 v 3.7 ⫾ 0.1 g/dL; 0
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
459
26.3 v 192.4 ⫾ 35.3 mg/dL; 0 weeks v 4 weeks; NS). This increase, however, was statistically significant with respect to the control group at 2 weeks (183.2 ⫾ 27.0 v 122.9 ⫾ 12.0 mg/dL; rhGH v control; P ⬍ 0.05) and 4 weeks (192.4 ⫾ 35.3 v 129.7 ⫾ 16.3 mg/dL; rhGH v control; P ⬍ 0.05). These changes returned to baseline at the end of phase III. Fasting glucose levels increased significantly with rhGH administration (104.2 ⫾ 4.7 and 103.9 ⫾ 5.0 v 85.4 ⫾ 3.8 mg/dL; 2 and 4 weeks v 0 weeks; P ⬍ 0.01) and returned to pretreatment levels at the end of the follow-up period (96.3 ⫾ 8.0 mg/dL). HbA1c values were unchanged during the study. Hormonal Results
Fig 2. Evolution of serum (A) IGF-1, (B) transferrin, and (C) BUN concentrations during the study period in both groups of patients (mean ⴞ SEM). Solid circles represent the rhGH group, whereas open circles represent the control group. *P F 0.05 v 0 weeks. **P F 0.01 v 0 weeks. aP F 0.05, rhGH v control.
weeks v 4 weeks; P ⬍ 0.01) at the end of phase II, with no modifications in serum RbP, prealbumin, and transferrin concentrations. rhGH therapy did not modify serum cholesterol levels, although a small increase of serum triglyceride concentrations was noted (152.6 ⫾
Baseline GH levels remained constant in both groups. Serum IGF-1 concentrations increased significantly from 216.6 ⫾ 42.5 ng/mL (0 weeks) to 518.7 ⫾ 112.1 ng/mL (2 weeks; P ⬍ 0.05) and 581.2 ⫾ 171.5 ng/mL (4 weeks; P ⬍ 0.01) after rhGH administration, and a statistically significant increase of IGF-1 concentrations was also observed in the control group at the end of the treatment phase (231.4 ⫾ 43.6 v 258.7 ⫾ 50.3 ng/mL; 0 weeks v 4 weeks; P ⬍ 0.05; Fig 2A and Table 4). However, the magnitude of the difference was much larger in the rhGH group. Serum insulin levels showed a tendency to increase with rhGH therapy, although this increment was not statistically significant. The value of serum insulin at 4 weeks was greater than the normal range only in the rhGH group. Serum C peptide levels increased in the rhGH group from 28.8 ⫾ 8.1 to 34.7 ⫾ 5.2 ng/mL. This increment was statistically significant with respect to the control group (34.7 ⫾ 5.2 v 12.7 ⫾ 2.2 ng/mL; rhGH v control; P ⬍ 0.01). Finally, rhGH therapy did not produce any significant modification in thyroid function during the treatment period (Table 4). Nutrient Intake and Urea Kinetic Responses The daily intake of calories (30.1 ⫾ 3.7 v 27.4 ⫾ 2.9 kcal/kg/d; 0 v 4 weeks) and proteins (1.31 ⫾ 0.15 v 1.19 ⫾ 0.09 g/kg/d; 0 v 4 weeks) was unchanged with rhGH therapy. rhGH treatment was associated with a significant and reversible reduction in serum BUN concentrations from 62.1 ⫾ 1.8 mg/dL at 0 weeks to 51.6 ⫾ 3.7 mg/dL (P ⬍ 0.05) at 2 weeks, and to 46.8 ⫾ 3.8
460
IGLESIAS ET AL Table 4. Hormone Results During the Study Weeks
Insulin (µU/mL) rhGH Control C-peptide (ng/mL) rhGH Control GH (ng/mL) rhGH Control IGF-1 (ng/mL) rhGH Control TSH (µU/mL) rhGH Control FT4 (ng/dL) rhGH Control
⫺4
0
2
— —
16.9 ⫾ 3.0 18.9 ⫾ 2.0
— —
36.6 ⫾ 9.4 19.0 ⫾ 3.0
— —
— —
28.8 ⫾ 8.1 16.8 ⫾ 1.6
— —
34.7 ⫾ 5.2 12.7 ⫾ 2.2*
— —
8.5 ⫾ 3.3 4.9 ⫾ 2.0
5.0 ⫾ 1.1 5.1 ⫾ 2.2
5.2 ⫾ 2.1 4.1 ⫾ 1.3
3.5 ⫾ 0.8 2.6 ⫾ 1.2
5.4 ⫾ 1.2 2.7 ⫾ 0.6
226.0 ⫾ 46.7 234.9 ⫾ 38.6
216.6 ⫾ 42.5 231.4 ⫾ 43.6
518.7 ⫾ 112.1† 240.2 ⫾ 36.8§
581.2 ⫾ 171.5‡ 258.7 ⫾ 50.3†
251.5 ⫾ 59.4 244.3 ⫾ 43.0
2.2 ⫾ 1.1 2.4 ⫾ 0.4
2.1 ⫾ 1.2 1.5 ⫾ 0.3
1.6 ⫾ 0.8 2.2 ⫾ 0.6
2.3 ⫾ 1.3 2.9 ⫾ 0.7
1.1 ⫾ 0.5 2.6 ⫾ 0.8
1.4 ⫾ 0.1 1.5 ⫾ 0.2†
1.4 ⫾ 0.1 1.3 ⫾ 0.1
1.6 ⫾ 0.2 1.3 ⫾ 0.1
1.6 ⫾ 0.2 1.2 ⫾ 0.1
1.0 ⫾ 0.2 1.3 ⫾ 0.1
4
8
NOTE. Values expressed as mean ⫾ SEM. *P ⬍ 0.01 (rhGH v control). †P ⬍ 0.05 (v 0 weeks). ‡P ⬍ 0.01 (v 0 weeks). §P ⬍ 0.05 (rhGH v control).
mg/dL (P ⬍ 0.05) at 4 weeks. At this point, BUN concentrations in the rhGH group were significantly less than those obtained in the control group (67.8 ⫾ 7.4 mg/dL; P ⬍ 0.05; Fig 2C). No significant modification in PCR and KtV was observed during phases II and III. Side Effects rhGH therapy was in general well tolerated and no clinically deleterious side effects were observed, except for transitory local pain at the site of injection (one patient), headache (one patient), sporadic nausea and vomiting (three patients), pruritus (four patients), hypotension (two patients), hand paresthesias (two patients), and nocturnal anxiety (one patient). In the control group, the side effects registered were hypotension (one patient), transient chest pain (one patient), and arthralgia (two patients). DISCUSSION
Our results show that short-term rhGH treatment in a small group of malnourished dialysis patients is accompanied by a significant increase in body weight, a reduction in serum BUN con-
centrations, and a significant increase in transferrin and serum IGF-1 concentrations. However, no changes in other nutritional indices, such as albumin and prealbumin levels, lymphocyte count, and PCR were associated with rhGH therapy. This indicates that the use of pharmacological doses of rhGH might improve several nutritional parameters in these patients. Calorie protein malnutrition is frequent in uremic patients, and this poor nutritional status is associated with increased morbidity and mortality.3 Moreover, it is now well established that dialysis therapy is an important catabolic process. It is known that the GH–IGF-1 axis is impaired in uremia. Uremic patients show elevated serum GH concentrations and abnormal responses to different stimuli, and it has been postulated that resistance to this hormone is a common feature, not only in ESRD patients, but also in malnourished non-ESRD patients.15,16 Because of the known effects of GH on protein metabolism, several studies have investigated whether rhGH therapy would be useful as a treatment for dialysis patients. Thus, the effects of rhGH have been analyzed in stable HD,17,18
GROWTH HORMONE THERAPY IN DIALYSIS PATIENTS
malnourished HD15,19-22 stable CAPD,23 and malnourished CAPD patients.19,24 Also evaluated has been the anabolic effect of this hormone associated with intradialytic parenteral nutrition in malnourished HD patients.25 These reports showed that the use of pharmacological doses of rhGH in dialysis patients was accompanied by anabolic effects, such as a decrease in predialysis BUN concentrations, reduction in PCR, and improvement in serum albumin, transferrin, and IGF-1 concentrations.17,18,23,25 To the best of our knowledge, this is the first randomized, controlled trial in which the effects of rhGH therapy in malnourished dialysis patients have been evaluated. Different anthropometric parameters, such as body weight, BMI, skin-fold thickness, MAMC, and muscle strength have been used in ESRD patients to evaluate nutritional state.3 GH has remarkable effects on body composition. In fact, its administration reduces fat mass and increases muscle mass.26 To date, several published reports of uremic children undergoing rhGH treatment have shown an improvement in various nutritional parameters, such as increment of MAMC and reduction of TSF.27,28 However, these findings have not been observed by other investigators in adult ESRD patients. In 1991, Sanaka and Sugino19 reported an increase in body weight in two severely malnourished dialysis patients, and an improvement in MAMC in one of them. A recent study of patients undergoing CAPD performed by Kang et al24 in 1994 showed a significant increase in lean body mass, total body muscle, muscle strength, and subjective exercise capacity with rhGH therapy. More recently, Ahlme´n et a1,18 in 1996, in a preliminary report, observed a significant increase in lean body mass in a group of 20 elderly patients undergoing chronic dialysis treated with rhGH for 6 months. In 1997, Garibotto et al22 showed that rhGH administration in malnourished HD patients was followed by an increase in muscle protein synthesis, with no effect on muscle protein degradation. In the present study, rhGH therapy showed a slight, but significant, increment in body weight. However, MAMC increased, not only in the rhGH group, but also in the control group. TSF thickness did not modify in any group of patients. Other known physiological effects of GH in patients with normal renal function are fluid
461
and sodium retention,29,30 which is sometimes associated with peripheral edema, weight gain, and, more rarely, an increase in blood pressure. In our patients, we could not show that the increase in body weight was exclusively caused by an increment in lean body mass. Unfortunately, we did not register the residual renal function at baseline. However, no patient developed edema, no significant changes in blood pressure values after rhGH treatment were found, and no significant changes in serum electrolyte or creatinine levels were observed. Finally, it was not necessary to modify the antihypertensive drugs in the four hypertensive patients in rhGH group to control blood pressure. This suggests that the increment in body weight in rhGH patients might be related to the anabolic effect of GH. Finally, rhGH therapy was not accompanied by a statistically significant improvement in muscle strength. Perhaps the duration of therapy was too short to improve body composition and modify muscle function. Results of the studies on the effects of rhGH therapy on red blood cell counts in dialysis patients have not been uniform. Some investigators have observed an improvement in hematocrit values,19,21 whereas other studies have failed to show similar responses.17,23,25 In the present report, both hematocrit and hemoglobin values did not change in relation to baseline after rhGH treatment, although the hematocrit and hemoglobin values were significantly greater than those observed in the control group. It has been recently reported that IGF-1 has functional analogies with erythropoietin. In fact, IGF-1 has the capacity to stimulate human erythroid colony formation in vitro.31,32 However, to date, the role of rhGH therapy on erythropoiesis in adult dialysis patients is unclear. As in the majority of previous reports, we did not find any modification in lymphocyte count with rhGH administration. The effect of rhGH on serum protein concentration is not well defined at present. Some investigators have noted an increase in serum albumin concentrations after rhGH therapy,18,19, 21,25 although this effect has not been observed by others.23 In 1996, Ikizler et al33 found a shift in plasma amino acid profile after rhGH therapy in patients undergoing CAPD, suggesting an anabolic process. In our study, both serum total
462
protein, albumin, and prealbumin concentrations were not modified. RbP showed a small, but statistically significant, decrease during rhGH therapy and the follow-up period, and serum transferrin concentrations increased only in the rhGH group. This effect has also been observed with the administration of rhGH associated with intradialytic parenteral nutrition in malnourished HD patients.25 In our study, both serum total protein and albumin concentrations increased in the control group at the end of the therapy period; however, this increment was not statistically different from the rhGH group. Therapy with rhGH was not associated with changes in basal serum concentrations of GH. This was also observed by Kopple et al34 in 1990 in a group of adult malnourished HD patients treated with rhGH. These investigators found an increment of serum GH concentrations of 19fold to 20-fold within 0.5 hours of the first dose of rhGH, but morning fasting preinjection values were usually normal or near normal. This would indicate that rhGH does not accumulate in adult dialysis patients. The half-life of endogenous GH is 10 to 20 minutes and the half-life of rhGH is 5 hours when it is administered SC. In our patients, serum samples for GH were drawn just before rhGH injection, and it probably explains the absence of an increment of serum GH concentrations. Moreover, it is probable that both rhGH and the increment of serum IGF-1 contribute to stimulating the endogenous secretion of hypothalamic somatostatin, decreasing the endogenous secretion of GH from anterior pituitary. Our results confirmed the findings of previous studies on rhGH treatment in dialysis patients with regard to modifications in serum IGF-1 and BUN concentrations. In this setting, the increment in IGF-1 and reduction in BUN concentrations have been uniformly described. We did not find any relationship between the changes in IGF-1 levels and variations in BUN or transferrin levels. Perhaps these modifications could be related to changes in circulating free IGF-1, but not total IGF-1 concentrations, because it has been recently described by others.22 As previously reported, rhGH did not modify nutrient intake. Finally, PCR showed a small, but not significant, decrement in the rhGH group. This suggests a diminished PCR as a result of an anabolizing state induced by rhGH. A reduction
IGLESIAS ET AL
in BUN level associated with stable intake suggests nitrogen retention with an improvement of the efficacy of dietary protein utilization. In general, rhGH therapy in adult dialysis patients has been well tolerated.18,19,23 To date, no clinically deleterious side effects have been reported, although the periods of rhGH administration have been short. Only minor side effects, such as facial edema and pruritus, have been reported.24 In our study, rhGH tolerance was acceptable, although minor side effects were more frequently observed than in other studies. The possible explanation for this observation could be related to the higher dose of rhGH used in this study. Treatment with rhGH was accompanied by a significant increase in glucose levels with a slight increase in insulin levels and no modifications in HbA1c. The effect on carbohydrate metabolism must be considered, especially in patients with diabetes. It seems that thyroid function is not affected after pharmacological doses of rhGH in adult dialysis patients. Finally, a small, but not clinically important, increase in triglyceride levels was observed, and cholesterol levels were not modified by rhGH. In conclusion, our data support the concept that rhGH has anabolic effects in malnourished dialysis patients because of the following: the increase in body weight; the increment in IGF-1, the major mediator of GH action with potent anabolic actions; the increase in transferrin concentrations; and the reduction in BUN levels associated with stable daily dietary intake. It seems that most rhGH side effects are dose dependent and more pronounced in patients receiving pharmacological doses of rhGH. Longterm, randomized, controlled, double-blind clinical trials in larger groups of patients are needed to determine the potential clinical use of rhGH in malnourished dialysis patients. ACKNOWLEDGMENT The authors thank Victoria Martı´nez, Olga Celadilla, Marı´a Jose´ Castro, and Sonia Sa´nchez for their cooperation in the study, and Laboratories Serono SA for providing rhGH.
REFERENCES 1. Kaminski MV Jr, Lowrie EG, Rosenblatt SG, Haase T: Malnutrition is lethal, diagnosable, and treatable in ESRD patients. Transplant Proc 23:1810-1815, 1991
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2. Blagg CR: Importance of nutrition in dialysis patients. Am J Kidney Dis 17:458-461, 1991 3. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 50:343-357, 1996 4. Bergstro¨m J, Lindholm B: Nutrition and adequacy of dialysis: How do hemodialysis and CAPD compare? Kidney Int 43:39-50, 1993 (suppl 40) 5. Acchiardo SR, Moore LW, Latour PA: Malnutrition as the main factor in morbidity and mortality of hemodialysis patients. Kidney Int 24:199-203, 1983 (suppl 16) 6. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 7. Hakim RM, Levin N: Malnutrition in hemodialysis patients. Am J Kidney Dis 21:125-137, 1993 8. Ikizler TA, Wingard RL, Hakim RM: Interventions to treat malnutrition in dialysis patients: The role of the dose of dialysis, intradialytic parenteral nutrition, and growth hormone. Am J Kidney Dis 26:256-265, 1995 9. Dı´ez JJ, Iglesias P: Hormona de crecimiento: Una nueva perspectiva terapeu´tica en la malnutricio´n asociada a la uremia. Nefrologı´a 15:539-549, 1995 10. Douglas RG, Humberstone DA, Haystead A, Shaw JHF: Metabolic effects of recombinant human growth hormone: Isotopic studies in the postabsorptive state and during total parenteral nutrition. Br J Surg 77:758-790, 1990 11. Mjaaland M, Unnenberg K, Hotvedt R, Revhaug A: Nitrogen retention caused by growth hormone in patients undergoing gastrointestinal surgery with epidural analgesia and parenteral nutrition. Eur J Surg 157:21-27, 1991 12. Mulligan K, Grunfeld C, Hellerstein MK, Neese RA, Schambelan M: Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 77:956-962, 1993 13. Frisancho AR: New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 34:2540-2545, 1981 14. Selgas R, Bajo MA, Fernandez-Reyes MJ, Bosque E, Lopez-Revuelta K, Jimenez C, Borrego F, de Alvaro F: An analysis of adequacy of dialysis in a selected population on CAPD for over 3 years: The influence of urea and creatinine kinetics. Nephrol Dial Transplant 8:1244-1253, 1993 15. Kopple JD: The rationale for the use of growth hormone or insulin-like growth factor-I in adult patients with renal failure. Miner Electrolyte Metab 18:269-275, 1992 16. Blake PG: Growth hormone and malnutrition in dialysis patients. Perit Dial Int 15:210-216, 1995 17. Ziegler TR, Lazarus JM, Young LS, Hakim R, Wilmore DW: Effects of recombinant human growth hormone in adults receiving maintenance hemodialysis. J Am Soc Nephrol 2:1130-1135, 1991 18. Ahlme´n J, Johannsson G, Johansson A, Bengtsson BA: Growth hormone (GH) treatment of elderly patients on chronic dialysis. J Am Soc Nephrol 7:1436, 1996 (abstr) 19. Sanaka T, Sugino N: Improvement of malnutrition indices in adult patients with end-stage renal disease by recombinant human growth hormone. Nippon Jinzo Gakkai Shi 33:1153-1159, 1991
463
20. Kopple JD, Brunori G, Leiserowitz M, Mattimore C, Hirschberg R: Growth hormone treatment for patients with renal failure. Jpn J Nephrol 33:468-475, 1991 21. Sinobe M, Sanaka T, Higuchi C, Hizuka N, Niehi H, Sugino N: The improvement of catabolic state in hemodialysis patients by recombinant human growth hormone (rhGH). J Am Soc Nephrol 4:431, 1993 (abstr) 22. Garibotto G, Barreca A, Russo R, Sofia A, Araghi P, Cesarone A, Malaspina M, Fiorini F, Minuto F, Tizianello A: Effects of recombinant human growth hormone (GH) on muscle protein turnover in malnourished hemodialysis patients. J Clin Invest 99:97-105, 1997 23. Ikizler AT, Wingard RL, Breyer JA, Schulman G, Parker RA, Hakim RM. Short-term effects of recombinant human growth hormone in CAPD patients. Kidney Int 46:1178-1183, 1994 24. Kang DH, Lee SW, Kang SW, Kim HS, Choi KH, Lee HY, Han DS: Recombinant human growth hormone (rhGH) improves nutritional status of undernourished adult CAPD patients. J Am Soc Nephrol 5:494, 1994 (abstr) 25. Schulman G, Wingard RL, Hutchison RL, Lawrence P, Hakim RM: The effects of recombinant human growth hormone and intradialytic parenteral nutrition in malnourished hemodialysis patients. Am J Kidney Dis 21:527-534, 1993 26. Jørgensen JOL, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS: Beneficial effects of growth hormone treatment in GHdeficient adults. Lancet 1:1221-1225, 1989 27. Koch VH, Lippe BM, Nelson PA, Boechat MI, Sherman BM, Fine RM: Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure. J Pediatr 115:365-371, 1989 28. Tonshoff B, Mehls O, Heinrich U, Blum W, Ranke MB: Improvement of uremic growth failure by recombinant human growth hormone. Kidney Int 36:201-204, 1989 29. Salomon F, Cuneo RC, Hesp R, So¨nken PH: The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797-1803, 1989 30. Hoffman DM, Crampton L, Sernia C, Nguyen TV: Short-term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab 81:1123-1128, 1996 31. Claustres M, Chatelain P, Sultan C: Insulin-like growth factor-I stimulates human erythroid colony formation in vitro. J Clin Endocrinol Metab 65:78-82, 1987 32. Merchav S, Tatarsky I, Hochberg Z: Enhancement of erythropoiesis in vitro by human growth hormone is mediated by insulin-like growth factor-I. Br J Haematol 70:267271, 1988 33. Ikizler TA, Wingard RL, Flakoll PJ, Schulman G, Parker RA, Hakim RM: Effects of recombinant human growth hormone on plasma and dialysate amino acid profiles in CAPD patients. Kidney Int 50:229-234, 1996 34. Kopple JD, Leiserowitz M, Brunori G, Mattimore C: Treatment of malnourished maintenance hemodialysis (MHD) patients with recombinant human growth hormone. J Am Soc Nephrol 1:364, 1990 (abstr)