Response
to Growth Hormone-Releasing Hormone on Hemodialysis German Ramirez,
in Adult Renal Failure
Barry B. Bercu, Polly A. Bittle, Connie W. Ayers, and Arunabha
Patients
Ganguly
Exogenous synthetic growth hormone-releasing hormone (GHRH [hpGRF-40]), 1 pg/kg body weight, was administered intravenously (IV) to eight men with chronic renal failure on chronic hemodialysis and to seven men matched for age (control group). Basal and stimulated growth hormone (GH) concentrations following GHRH (hpGRF-40) in renal failure patients were significantly higher than in controls. Basal prolactin and somatomedin C/insulin-like growth factor-l (SmC/IGF-1) concentrations were significantly higher in the renal failure patients compared with controls. Following GHRH there was no further increase in serum concentration of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin. SmC/IGF-1, or cortisol. GH appears to be the only pituitary hormone where there is an exaggerated response to its specific releasina hormone in adults with renal failure. @ 1990 by W.6: Saunders Company.
M
hypophyseal abnormaliANY HYPOTHALAMIC ties occur in patients with renal failure or on chronic hemodialysis. These include blunted thyroid-stimulating hormone (TSH) secretion following exogenous thyrotropinreleasing hormone (TRH),‘-4 hyperprolactinemia,5.6 elevated basal levels of luteinizing hormone (LH),7-9 and poor gonadotropin secretory response to gonadotropin-releasing hormone (GnRH)’ in uremic male patients. In females, uremia causes amenorrhea associated with hypothalamic anovulation.” The hypothalamic-pituitary adrenocortical axis is also abnormal; corticotropin is not released in response to insulininduced hypoglycemia” and there is a blunted response following exogenous corticotropin-releasing hormone (CRH).” The secretory pattern of growth hormone (GH) is also abnormal in renal failure patients. Hypoglycemia fails to release GH13 and hyperglycemia produces a paradoxical increase in GH as was reported by Saaman et alI4 and confirmed by usI TRH stimulates GH releaseI and prolonged secretion occurs after L-dopa.13 Finally, growth hormone-releasing hormone (GHRH) produces an exaggerated release of pituitary GH in uremic childrenI This latter finding is unique, because GH is the only pituitary hormone where there is an exaggerated secretion following administration of the specific stimulatory hypothalamic hormone. In the present study, GHRH was administered to adult male patients on chronic hemodialysis to assess pituitary GH secretion and regulation.
From the Divisions of Nephrology and Endocrinology, Department of Internal Medicine, James A. Haley Veterans’ Hospital, and the Division of Pediatric Endocrinology, Department of Pediatrics, of the University of South Florida, Tampa, FL: and the All Children’s Hospital, St Petersburg, FL. Supported in part by the Eleanor Naylor Dana Charitable Trust (B.B.B.), the Alberta Carapella Kidney Fund at the University of South Florida (G.R.), and Genentech. Inc. Presented in part at the Annual Meeting of the Endocrine Society, Seattle, WA, 1989. Address reprint requests to German Ramirez. MD. James A. Haley VA Hospital, Nephrology Section 11 IF, 13000 Bruce B. Downs Blvd. Tampa, FL 33612. @ 1990 by W.B. Saunders Company. 0026-0495/90/3907-0017$03.00/0
764
MATERIAL AND METHODS Eight men with chronic renal failure (mean age, 50.5 years; range, 26 to 70 years), and seven age-matched control men (mean age, 48.1 years; range, 27 to 68 years) were studied. The patients who participated in this study were maintained on chronic hemodialysis at the James A. Haley VA Hospital in Tampa, FL. The patients were established dialysis patients with a mean duration on dialysis of 13 months, range 3 to 86 months. All patients received the following medications: aluminum hydroxide and multivitamins (complex B plus C). None of the patients were restricted in terms of protein intake and all were dialyzed three times weekly, 4 hours per dialysis. By using specific laboratory criteria for dietary evaluation. none of the patients were considered to be undernourished.‘6 None of the study patients were diabetic or treated with antihypertensive medications. The study was approved by the Institutional Review Board of the University of South Florida and the Research and Development Committee of the James A. Haley VA Hospital. For dialysis patients, the study was performed on a day between dialysis treatment days. All patients and normal volunteers were asked to take nothing by mouth after midnight prior to the scheduled test the next morning. After informed consent was obtained, the weight and vital signs were recorded. Then, an intravenous (IV) solution of normal saline, through a no. 20 gauge catheter in an antecubital vein, was infused at a slow rate to keep the vein open (KVO) during the initial 3-hour test period. All volunteers and patients remained in the supine position throughout the test. GHRH (hpGRF-40) was diluted and administered by slow IV push over 60 seconds at a dose of 1 pg/kg body weight. This hormone was kindly provided by Dr Michael Thorner of the University of Virginia, Charlottesville, VA, and Drs Wylie Vale and Jean Rivier of the Salk Institute, La Jolla, CA. The time interval for blood sampling is shown in Fig 1. The following hormones were measured: GH, LH, follicle-stimulating hormone (FSH), TSH, prolactin, cortisol, and somatomedin C/insulin-like growth factor-l (SmC/ IGF-1). Blood samples were centrifuged immediately and the serum stored at -20°C until assayed. All specimens for individual hormones were measured in one assay. GH, FSH, and LH were measured using commercially available radioimmunoassay kits (Diagnostic Products, Los Angeles, CA), prolactin (Baxter Travenol Diagnostics, Cambridge, MA), TSH (Amersham, Arlington Heights, IL), cortisol (Diagnostic Products), and plasma SmC/IGF-1 (Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity (S) and intraassay coefficient of variation (CV) for the different radioimmunoassays were as follows: GH, S = 0.6 Kg/L, CV c( 5%: FSH, S = 2 IU/L, CV < 2%; LH, S = 3 IU/L, CV < 2%; prolactin, S = 2.5 rg/L, CV < 2%; TSH, S = 0.1 mu/L. CV < 5%; cortisol, S = 5.52
Metabolism, Vol 39, No 7 (July), 1990: oo 764-768
GHRH
BESPONSE
IN ADULT
HEMODIALYSIS
765
PATIENTS
0’
-60’
-30’
60’
5’
-15’
10’
15’
30’
120’
180’
t
t
24
Hr
45’ I
Y
YU
v
t
P roKcti n
IV NS Kvo
initiated
CV 6.3%; SmC/IGF-1,
Statistical
analysis was performed
v
SmC/IGF- 1
WefaHcttn cozse’
Fig 1. Schedule of blood sampling for different hormones (time in minutes) before and after GHRH (hpGRF-40). NS, normal saline; KVO. keep vein open.
nmol/L,
t
FSH TSH SmWIGF-
Pr%ti n Cortisol
1
FLfHH TSH SmC/IGF-
Inject (IV) hoGRF l-40
1
1 ug/kg and the GH levels were significantly higher (P < .05) in renal failure versus control group at times 10, 60, 120, and 180 minutes post-GHRH injection. Peak values were reached between 15 and 30 minutes in the renal failure patients, and in the controls between 10 and 30 minutes. The secretory area under the curve was significantly higher in the dialysis patients compared with the controls (P < .Ol) (Fig 2). The disappearance time from blood for GH was calculated from the peak GH concentration and the values obtained after the administration of the GHRH in renal failure patients and controls (Fig 3). Half-time disappearance in renal failure patients was 76.3 of:3.8 minutes compared with 57.2 f 5.8 minutes in controls (P < .05).
S = 0.1 U/mL, CV = 5%. using Student’s t test and ANOVA where appropriate. The secretory area under the curve was determined between 0 and 120 minutes by the trapezoidal rule. All results are expressed as mean + SEM. RESULTS
Growth Hormone The results for GH, before and after exogenous GHRH, are shown in Fig 2. Basal serum values were significantly higher (P < .OS) in the renal failure patients compared with the control group (mean at each time of -30, - 15, and 0 minutes). GHRH caused a prompt increase in both groups,
50
_
Patients
_c_
Control
80
TIME IN MN
110
Fig 2. GH levels after GHRH in chronic dialysis patients compared with controls. lP < .05 statistical difference between patients and controls at each time point. Area under curve P -c .Ol, dialysis group v controls.
RAMIREZ ET AL
766
SmC/lGF-I The concentration of SmC/IGF-I was. in general. significantly higher in the dialysis patients (1.10 + 0.20 mU/mL) compared with the control group (0.68 k 0.19 mU/mL) (P < .05 at 1, 3, and 24 hours), but still within the published normal range (0.34 to 1.90 U/mL, Nichols Institute Diagnostics). In both groups there was no increase following GHRH administration. Prolactin and TSH Prolactin and shown in Fig 4. higher (P < .05) showed a change
TSH concentrations following GHRH are Prolactin concentrations were significantly in the dialysis population, but neither group after GHRH administration.
Gonadotropins and Cortisol The concentrations of LH, FSH. and cortisol were similar in both groups before and after exogenous GHRH (data not shown). DISCUSSION
In the present study, basal GH and prolactin concentrations were significantly higher in chronic dialysis patients compared with controls. This is similar to previous reports of patients with renal failure.6~‘7-‘0 In these patients a prolonged disappearance time for GH has been reported.‘* A possible explanation for the GH increment in renal failure patients could be due to the lack of GH excretion or catabolism by the kidney. In the rat, GH is extensively filtered in the glomerulus and subsequently reabsorbed and catabolized within tubular epithelial cells.2’ Although increasing amounts of GH are found in the urine of patients with chronic renal failure and proteinuria,” this finding does not necessarily
20 k
1
y=
16.3357
u = 5.6041
R = l .OO
0
PATIENTS
R = 0.95
n
CONTROLS
[ 10 (-0.0038x)]
[lo
(-0,0053x)]
imply increased synthesis and/or release of GH. In our study, it appears that the clearance rate of GH is decreased in renal failure patients and this could explain, in part, the high basal GH levels. The greater response of GH following GHRH suggests increased release perhaps due to greater stores of GH as well as delayed clearance. However, an exaggerated release of GH in adults with renal failure occurs only after GHRH, L-dopa, and hyperglycemia. but not following hypoglycemia.‘3 These observations suggest abnormal differential neuroendocrine regulation of GH secretion, possibly due to alterations in hypothalamic neurotransmitters and their effect on the hypothalamic hormones, GHRH and/or somatostatin. Some investigators23 have found decreased pituitary GH in uremic and diet-restricted rats, and concluded that the GH disturbances in the uremic state were caused by malnutrition. However, Allegra et alZ4 could not corroborate these GH abnormalities in malnourished humans. Plasma SmC/IGF-1 concentrations were elevated in renal failure patients and there was no further increase following GHRH in dialysis patients or in controls. SmC/IGF- 1 levels have been both low” and high” in patients with chronic renal failure when measured by specific radioimmunoassay. However, some investigators2’ have suggested that high somatomedin values may be an artifact caused by increased binding of somatomedin by uremic serum. Powell et a12’extracted the plasma of patients with renal failure and suggested that a compound eluding with acid-ethanol in the carrier protein fraction of the uremic serum interfered with the radioimmunoassay producing falsely low values of SmC/IGF-1. The significance of these findings is difficult to understand because the physiologic role of GH in the adult patient is still unclear. Moreover, the role GH plays in the pathophysiology
2
10
MIN
TIME
IN MIN
Fig 3. Linear representstion of GH serum levels Y time from the peak GH level achieved after the administration of GHRH in chronic dialysis patients and controls. Half-life for dialysis patients was 76 minutes v 57 minutes for controls.
GHRH RESPONSE IN ADULT HEMODIALYSIS PATIENTS
PATIENTS CONTROLS
-
3.0 -
767
REFERENCES
:2.5 -
2.0 -
1 .s -
1.0
:20
!
1
1
I
I
I
0
60
120
180
-
*
o0
15
30
TltlE
*
PATIENTS CONTROLS
45
60
,
T
120
180
IN MIN
Fig 4. TSH and prolactin concentrations in chronic dialysis patients compared with normal controls after GHRH. lP < .05 between patients and controls at each point time.
of uremic patients is also unknown. Of all the hypophyseal hormones. GH is unique, because there is a qualitative and quantitative exaggerated increase following administration of the specific hypothalamic stimulatory hormone. Basal TSH, FSH. LH, and cortisol were normal in our study. However, several investigators have found elevated basal levels of gonadotropins in male patients with chronic renal failure.‘.” In our study, as previously reported in adults,” basal LH and FSH levels were slightly elevated in uremic patients but not statistically different and neither of these hormones increased after GHRH. ACKNOWLEDGMENT
The authors would like to thank Pat Schobert, BS, MT, Richard Adams, BS, MT, and the Nuclear Medicine Department at the James A. Haley VA Hospital for their assistance in the laboratory analysis of the blood specimens. We would like to especially thank Barbara. Clark and the Voluntary Services Department of the James A. Haley VA Hospital for their generosity in helping complete this project.
1. Ramirez G, O’Neill WM, Jubiz W, et al: Thyroid dysfunction in uremia: Evidence for thyroid and hypophyseal abnormalities. Ann Intern Med 84612-616, 1916 2. Waldhausl W, Schmidt P, Frischauf H. et al: Effect of thyrotropin releasing hormone (TRH) on hTSH and hGH in patients with chronic renal failure. Proc Eur Dial Transplant Assoc Eur Ren Assoc 8:161-166, 1971 3. Gonzalez-Barcena D. Kastin AJ, Schalch DS. et al: Response to thyrotropin releasing hormone in patients with renal failure and after infusion in normal man. J Clin Endocrinol Metab 36: I 17-l 20, 1973 4. Lim VS. Fang VS. Katz Al, et al: Thyroid dysfunction in chronic renal failure: A study of the pituitary thyroid axis and peripheral turnover kinetics of thyroxin and triiodothyronine. J Clin Invest 60:522-534, 1977 5. Peces R, Horcajada C, Lopez Novoa JM. et al: Hyperprolactinemia in chronic renal failure: Impaired responsiveness to stimulation and suppression. Nephron 28: 1 I - 16. I98 1 6. Ramirez G, O’Neill WM, Bloomer HA, et al: Abnormalities in the regulation of prolactin in patients with chronic renal failure. J Clin Endocrinol Metab 45:685-667, 1977 7. Holdsworth S. Atkin RC, DeKretser DM: The pituitary testicular axis in men with chronic renal failure. N Engl J Med 296:1245-1249. 1977 8. Phadke AG. MacKinnon KJ, Dossetor JB: Male fertility in uremia: Restoration by human allografts. Can Med Assoc J IO2:607608.1970 9. Lim VS, Fang VS: Gonadal dysfunction in uremic men: A study of the hypothalamic-pituitary testicular axis before and after renal transplantation. Am J Med 58:655-662, 1975 10. Lim VS, Henriquez C. Sivertsen G, et al: Ovarian function in chronic renal failure: Evidence suggesting hypothalamic anovulation. Ann Intern Med 93:21-27, 1980 11. Ramirez G, Gomez-Sanchez C, Meikle WA, et al: Evaluation of the hypothalamic hypophyseal adrenal axis in patients receiving longterm hemodialysis. Arch Intern Med 142: 1448- 1452, I982 12. Luger A, Lang I, Kovarik J, et al: Abnormalities in the hypothalamic-pituitary-adrenocortical axis in patients with chronic renal failure. Am J Kidney Dis 9:51-54. 1987 13. Ramirez G, O’Neill WM. Bloomer HA, et al: Abnormalities in the regulation of growth hormone in chronic renal failure. Arch Intern Med 138:267-27 1, 1978 14. Saaman N. Cumming WS, Craig JW, et al: Serum growth hormone and insulin levels in severe renal disease. Diabetes 15:546, 1966 15. Bessarione D, Perfumo F, Giusti M. et al: Growth hormone response to growth hormone-releasing hormone in normal and uraemic chiidren. Comparison with hypoglyceamia following insulin administration. Acta Endocrinol 114:5-l 1. 1987 16. Blumenkrantz MJ, Kopple JD, Gutman RA, et al: Methods for assessing nutritional status of patients with renal failure. Am J ClinNutr 33:1567-1585, 1980 17. Ramirez G. Butcher DE, Newton JL, et al: Bromocriptine and the hypothalamic hypophyseal function in patients with chronic renal failure on chronic hemodialysis. Am J Kidney Dis h:l l-l 18. 1985 18. Samaan NA, Freeman RM: Growth hormone levels in severe renal failure. Metabolism 19:102-l 13, 1970 19. Wright AD, Lowy C, Fraser TR. et al: Serum growth hormone and glucose intolerance in renal failure. Lancet 2:798-80 I. 1968 20. Cameron DP, Burger HG, Catt KJ. et al: Metabolic clear-
768
RAMIREZ ET AL
ante of human growth hormone in patients with hepatic and renal failure, and in the isolated perfused pig liver. Metabolism 21:895904.1972 21. Johnson and catabolism 1977
V, Maak T: Renal extraction, filtration, absorption of growth hormone. Am J Physiol 233:F185-196,
22. Hattori N, Kato Y, Murakami Y, et al: Urinary growth hormone levels measured by ultrasensitive enzyme immunoassay in patients with renal insufficiency. J Clin Endocrinol Metab 66:727732.1988 23. Lacour B, Roullet JB, Bluet-Pajot MT, et al: Plasma pituitary content of growth hormone, luteinizing hormone prolactin in uremic rats. Nephron 44:235-239, 1986 24. Allegra
V, Amendolagine
F, Mengozzi
and and
G, et al: Growth
hormone secretion abnormalities in uremic patients: Which is the role of impaired glucose hypothalamic sensitivity? Nephron 48:7677,1988 25. Goldberg AC, Trivedi B, Delmez JA, et al: Uremia reduces insulin-like growth factor I, increases insulin-like growth factor II and modifies their serum protein binding. J Clin Endocrinol Metab 55:1040-1045, 1982 26. Enberg G, Hall K: Immunoreactive IGF-2 in serum of healthy subjects and patients with growth hormone disturbances and uremia. Acta Endocrinol 107: 164- 170, 1984 27. Powell DR, Rosenfeld RG, Baker BK, et al: Serum somatomedin levels in adults with chronic renal failure: The importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab 63:1186-1192, 1986
to Growth Hormone-Releasing Hormone on Hemodialysis German Ramirez,
in Adult Renal Failure
Barry B. Bercu, Polly A. Bittle, Connie W. Ayers, and Arunabha
Patients
Ganguly
Exogenous synthetic growth hormone-releasing hormone (GHRH [hpGRF-40]), 1 pg/kg body weight, was administered intravenously (IV) to eight men with chronic renal failure on chronic hemodialysis and to seven men matched for age (control group). Basal and stimulated growth hormone (GH) concentrations following GHRH (hpGRF-40) in renal failure patients were significantly higher than in controls. Basal prolactin and somatomedin C/insulin-like growth factor-l (SmC/IGF-1) concentrations were significantly higher in the renal failure patients compared with controls. Following GHRH there was no further increase in serum concentration of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin. SmC/IGF-1, or cortisol. GH appears to be the only pituitary hormone where there is an exaggerated response to its specific releasina hormone in adults with renal failure. @ 1990 by W.6: Saunders Company.
M
hypophyseal abnormaliANY HYPOTHALAMIC ties occur in patients with renal failure or on chronic hemodialysis. These include blunted thyroid-stimulating hormone (TSH) secretion following exogenous thyrotropinreleasing hormone (TRH),‘-4 hyperprolactinemia,5.6 elevated basal levels of luteinizing hormone (LH),7-9 and poor gonadotropin secretory response to gonadotropin-releasing hormone (GnRH)’ in uremic male patients. In females, uremia causes amenorrhea associated with hypothalamic anovulation.” The hypothalamic-pituitary adrenocortical axis is also abnormal; corticotropin is not released in response to insulininduced hypoglycemia” and there is a blunted response following exogenous corticotropin-releasing hormone (CRH).” The secretory pattern of growth hormone (GH) is also abnormal in renal failure patients. Hypoglycemia fails to release GH13 and hyperglycemia produces a paradoxical increase in GH as was reported by Saaman et alI4 and confirmed by usI TRH stimulates GH releaseI and prolonged secretion occurs after L-dopa.13 Finally, growth hormone-releasing hormone (GHRH) produces an exaggerated release of pituitary GH in uremic childrenI This latter finding is unique, because GH is the only pituitary hormone where there is an exaggerated secretion following administration of the specific stimulatory hypothalamic hormone. In the present study, GHRH was administered to adult male patients on chronic hemodialysis to assess pituitary GH secretion and regulation.
From the Divisions of Nephrology and Endocrinology, Department of Internal Medicine, James A. Haley Veterans’ Hospital, and the Division of Pediatric Endocrinology, Department of Pediatrics, of the University of South Florida, Tampa, FL: and the All Children’s Hospital, St Petersburg, FL. Supported in part by the Eleanor Naylor Dana Charitable Trust (B.B.B.), the Alberta Carapella Kidney Fund at the University of South Florida (G.R.), and Genentech. Inc. Presented in part at the Annual Meeting of the Endocrine Society, Seattle, WA, 1989. Address reprint requests to German Ramirez. MD. James A. Haley VA Hospital, Nephrology Section 11 IF, 13000 Bruce B. Downs Blvd. Tampa, FL 33612. @ 1990 by W.B. Saunders Company. 0026-0495/90/3907-0017$03.00/0
764
MATERIAL AND METHODS Eight men with chronic renal failure (mean age, 50.5 years; range, 26 to 70 years), and seven age-matched control men (mean age, 48.1 years; range, 27 to 68 years) were studied. The patients who participated in this study were maintained on chronic hemodialysis at the James A. Haley VA Hospital in Tampa, FL. The patients were established dialysis patients with a mean duration on dialysis of 13 months, range 3 to 86 months. All patients received the following medications: aluminum hydroxide and multivitamins (complex B plus C). None of the patients were restricted in terms of protein intake and all were dialyzed three times weekly, 4 hours per dialysis. By using specific laboratory criteria for dietary evaluation. none of the patients were considered to be undernourished.‘6 None of the study patients were diabetic or treated with antihypertensive medications. The study was approved by the Institutional Review Board of the University of South Florida and the Research and Development Committee of the James A. Haley VA Hospital. For dialysis patients, the study was performed on a day between dialysis treatment days. All patients and normal volunteers were asked to take nothing by mouth after midnight prior to the scheduled test the next morning. After informed consent was obtained, the weight and vital signs were recorded. Then, an intravenous (IV) solution of normal saline, through a no. 20 gauge catheter in an antecubital vein, was infused at a slow rate to keep the vein open (KVO) during the initial 3-hour test period. All volunteers and patients remained in the supine position throughout the test. GHRH (hpGRF-40) was diluted and administered by slow IV push over 60 seconds at a dose of 1 pg/kg body weight. This hormone was kindly provided by Dr Michael Thorner of the University of Virginia, Charlottesville, VA, and Drs Wylie Vale and Jean Rivier of the Salk Institute, La Jolla, CA. The time interval for blood sampling is shown in Fig 1. The following hormones were measured: GH, LH, follicle-stimulating hormone (FSH), TSH, prolactin, cortisol, and somatomedin C/insulin-like growth factor-l (SmC/ IGF-1). Blood samples were centrifuged immediately and the serum stored at -20°C until assayed. All specimens for individual hormones were measured in one assay. GH, FSH, and LH were measured using commercially available radioimmunoassay kits (Diagnostic Products, Los Angeles, CA), prolactin (Baxter Travenol Diagnostics, Cambridge, MA), TSH (Amersham, Arlington Heights, IL), cortisol (Diagnostic Products), and plasma SmC/IGF-1 (Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity (S) and intraassay coefficient of variation (CV) for the different radioimmunoassays were as follows: GH, S = 0.6 Kg/L, CV c( 5%: FSH, S = 2 IU/L, CV < 2%; LH, S = 3 IU/L, CV < 2%; prolactin, S = 2.5 rg/L, CV < 2%; TSH, S = 0.1 mu/L. CV < 5%; cortisol, S = 5.52
Metabolism, Vol 39, No 7 (July), 1990: oo 764-768
GHRH
BESPONSE
IN ADULT
HEMODIALYSIS
765
PATIENTS
0’
-60’
-30’
60’
5’
-15’
10’
15’
30’
120’
180’
t
t
24
Hr
45’ I
Y
YU
v
t
P roKcti n
IV NS Kvo
initiated
CV 6.3%; SmC/IGF-1,
Statistical
analysis was performed
v
SmC/IGF- 1
WefaHcttn cozse’
Fig 1. Schedule of blood sampling for different hormones (time in minutes) before and after GHRH (hpGRF-40). NS, normal saline; KVO. keep vein open.
nmol/L,
t
FSH TSH SmWIGF-
Pr%ti n Cortisol
1
FLfHH TSH SmC/IGF-
Inject (IV) hoGRF l-40
1
1 ug/kg and the GH levels were significantly higher (P < .05) in renal failure versus control group at times 10, 60, 120, and 180 minutes post-GHRH injection. Peak values were reached between 15 and 30 minutes in the renal failure patients, and in the controls between 10 and 30 minutes. The secretory area under the curve was significantly higher in the dialysis patients compared with the controls (P < .Ol) (Fig 2). The disappearance time from blood for GH was calculated from the peak GH concentration and the values obtained after the administration of the GHRH in renal failure patients and controls (Fig 3). Half-time disappearance in renal failure patients was 76.3 of:3.8 minutes compared with 57.2 f 5.8 minutes in controls (P < .05).
S = 0.1 U/mL, CV = 5%. using Student’s t test and ANOVA where appropriate. The secretory area under the curve was determined between 0 and 120 minutes by the trapezoidal rule. All results are expressed as mean + SEM. RESULTS
Growth Hormone The results for GH, before and after exogenous GHRH, are shown in Fig 2. Basal serum values were significantly higher (P < .OS) in the renal failure patients compared with the control group (mean at each time of -30, - 15, and 0 minutes). GHRH caused a prompt increase in both groups,
50
_
Patients
_c_
Control
80
TIME IN MN
110
Fig 2. GH levels after GHRH in chronic dialysis patients compared with controls. lP < .05 statistical difference between patients and controls at each time point. Area under curve P -c .Ol, dialysis group v controls.
RAMIREZ ET AL
766
SmC/lGF-I The concentration of SmC/IGF-I was. in general. significantly higher in the dialysis patients (1.10 + 0.20 mU/mL) compared with the control group (0.68 k 0.19 mU/mL) (P < .05 at 1, 3, and 24 hours), but still within the published normal range (0.34 to 1.90 U/mL, Nichols Institute Diagnostics). In both groups there was no increase following GHRH administration. Prolactin and TSH Prolactin and shown in Fig 4. higher (P < .05) showed a change
TSH concentrations following GHRH are Prolactin concentrations were significantly in the dialysis population, but neither group after GHRH administration.
Gonadotropins and Cortisol The concentrations of LH, FSH. and cortisol were similar in both groups before and after exogenous GHRH (data not shown). DISCUSSION
In the present study, basal GH and prolactin concentrations were significantly higher in chronic dialysis patients compared with controls. This is similar to previous reports of patients with renal failure.6~‘7-‘0 In these patients a prolonged disappearance time for GH has been reported.‘* A possible explanation for the GH increment in renal failure patients could be due to the lack of GH excretion or catabolism by the kidney. In the rat, GH is extensively filtered in the glomerulus and subsequently reabsorbed and catabolized within tubular epithelial cells.2’ Although increasing amounts of GH are found in the urine of patients with chronic renal failure and proteinuria,” this finding does not necessarily
20 k
1
y=
16.3357
u = 5.6041
R = l .OO
0
PATIENTS
R = 0.95
n
CONTROLS
[ 10 (-0.0038x)]
[lo
(-0,0053x)]
imply increased synthesis and/or release of GH. In our study, it appears that the clearance rate of GH is decreased in renal failure patients and this could explain, in part, the high basal GH levels. The greater response of GH following GHRH suggests increased release perhaps due to greater stores of GH as well as delayed clearance. However, an exaggerated release of GH in adults with renal failure occurs only after GHRH, L-dopa, and hyperglycemia. but not following hypoglycemia.‘3 These observations suggest abnormal differential neuroendocrine regulation of GH secretion, possibly due to alterations in hypothalamic neurotransmitters and their effect on the hypothalamic hormones, GHRH and/or somatostatin. Some investigators23 have found decreased pituitary GH in uremic and diet-restricted rats, and concluded that the GH disturbances in the uremic state were caused by malnutrition. However, Allegra et alZ4 could not corroborate these GH abnormalities in malnourished humans. Plasma SmC/IGF-1 concentrations were elevated in renal failure patients and there was no further increase following GHRH in dialysis patients or in controls. SmC/IGF- 1 levels have been both low” and high” in patients with chronic renal failure when measured by specific radioimmunoassay. However, some investigators2’ have suggested that high somatomedin values may be an artifact caused by increased binding of somatomedin by uremic serum. Powell et a12’extracted the plasma of patients with renal failure and suggested that a compound eluding with acid-ethanol in the carrier protein fraction of the uremic serum interfered with the radioimmunoassay producing falsely low values of SmC/IGF-1. The significance of these findings is difficult to understand because the physiologic role of GH in the adult patient is still unclear. Moreover, the role GH plays in the pathophysiology
2
10
MIN
TIME
IN MIN
Fig 3. Linear representstion of GH serum levels Y time from the peak GH level achieved after the administration of GHRH in chronic dialysis patients and controls. Half-life for dialysis patients was 76 minutes v 57 minutes for controls.
GHRH RESPONSE IN ADULT HEMODIALYSIS PATIENTS
PATIENTS CONTROLS
-
3.0 -
767
REFERENCES
:2.5 -
2.0 -
1 .s -
1.0
:20
!
1
1
I
I
I
0
60
120
180
-
*
o0
15
30
TltlE
*
PATIENTS CONTROLS
45
60
,
T
120
180
IN MIN
Fig 4. TSH and prolactin concentrations in chronic dialysis patients compared with normal controls after GHRH. lP < .05 between patients and controls at each point time.
of uremic patients is also unknown. Of all the hypophyseal hormones. GH is unique, because there is a qualitative and quantitative exaggerated increase following administration of the specific hypothalamic stimulatory hormone. Basal TSH, FSH. LH, and cortisol were normal in our study. However, several investigators have found elevated basal levels of gonadotropins in male patients with chronic renal failure.‘.” In our study, as previously reported in adults,” basal LH and FSH levels were slightly elevated in uremic patients but not statistically different and neither of these hormones increased after GHRH. ACKNOWLEDGMENT
The authors would like to thank Pat Schobert, BS, MT, Richard Adams, BS, MT, and the Nuclear Medicine Department at the James A. Haley VA Hospital for their assistance in the laboratory analysis of the blood specimens. We would like to especially thank Barbara. Clark and the Voluntary Services Department of the James A. Haley VA Hospital for their generosity in helping complete this project.
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