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GH Increases Extracellular Volume by Stimulating Sodium Reabsorption in the Distal Nephron and Preventing Pressure Natriuresis

Research Center for Endocrinology and Metabolism (G.J.), Department of Clinical Neurophysiology (Y.B.S.), Department of Clinical Nutrition (L.E.), Department of Clinical Chemistry (P.-A.L.) and Department of Nephrology (H.H.), Sahlgrenska University Hospital, Göteborg SE-413 45, Sweden

Address all correspondence and requests for reprints to: Gudmundur Johannsson, M.D., Ph.D., Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: . gudmundur.johannsson{at}medic.gu.se

Abstract

Although sodium retention and volume expansion occur during GH administration, blood pressure is decreased or unchanged. The aim was to study the effect of short- and long-term GH replacement in adults on sodium balance, renal hemodynamics, and blood pressure. Ten adults with severe GH deficiency were included into a 7-d, randomized, placebo-controlled, cross-over trial followed by 12 months of open GH replacement. All measurements were performed under metabolic ward conditions. Extracellular water (ECW) was determined using multifrequency bioelectrical impedance analysis. Renal plasma flow and glomerular filtration rate were assessed using renal paraminohippurate and Cr⁵¹ EDTA clearances, respectively. Renal tubular sodium reabsorption was assessed using lithium clearance. Plasma renin activity (PRA), plasma concentrations of angiotensin II, aldosterone, atrial natriuretic peptides and brain natriuretic peptides (BNP) and 24-h urinary norepinephrine excretion were measured. Seven days of GH treatment decreased urinary sodium excretion. Lithium clearance as a marker of proximal renal tubular sodium reabsorption was unaffected by GH treatment. ECW was increased after both short- and long-term treatment. This increase was inversely correlated to the decrease in diastolic blood pressure (r = -0.70, P = 0.02) between baseline and 12 months. Short-term treatment increased PRA and decreased BNP. The increase in PRA correlated with an increase in 24-h urinary norepinephrine excretion (r = 0.77, P < 0.01). Glomerular filtration rate and renal plasma flow did not change during treatment. The sodium- and water-retaining effect of GH takes place in the distal nephron. The sustained increase in ECW in response to GH is associated with an unchanged or decreased blood pressure. This together with unchanged or decreased atrial natriuretic peptides and BNP may prevent pressure-induced escape of sodium.

THE SODIUM- AND water-retaining effect of GH has been known for decades (1). Although the exact mechanism underlying the antinatriuretic action of GH is not fully elucidated, several direct and indirect mechanisms have been suggested. GH increases serum and tissue levels of IGF-I, and both GH and IGF-I receptors are expressed in renal tubules (2), making direct sodium- and water-retaining effects of GH and IGF-I possible and plausible (3).

Indirect mechanisms for the sodium-sparing effect of GH have also been proposed to be mediated by an interaction with the renin-angiotensin-aldosterone system (RAAS) in some (4, 5, 6, 7) but not all studies (8). Moreover, short-term GH and IGF-I administration, respectively, has been reported to suppress plasma atrial natriuretic peptide (ANP) and to impair the ANP response to a saline load, which might contribute to sodium retention (9, 10). This is not, however, a consistent finding in all studies (8, 11).

GH may also increase glomerular filtration rate (GFR) and renal plasma flow (RPF) (12, 13) by directly influencing the local IGF-I and nitric oxide (NO) production in the kidney (14, 15) or more indirect by increasing the extracellular water (ECW) and plasma volume. GH may therefore affect both renal hemodynamics and renal tubular function.

Despite the volume expansion induced by GH administration, blood pressure is reported to be either unchanged (16, 17, 18, 19, 20, 21) or decreased (22, 23) in response to GH treatment. A probable explanation is the decrease in peripheral resistance (22), observed following GH replacement therapy, which in turn may, at least in part, be explained by increased endothelial NO formation (21).

Thus, GH and IGF-I affect volume and pressure regulation in a complex manner. The aim of this trial was to study the effect of GH replacement on sodium and fluid retention by exploring the short- and long-term effect of GH treatment on ECW, sodium balance, renal hemodynamics, and blood pressure in adults with severe GH deficiency.

Materials and Methods

Patients

Ten adults (nine males and one female) with adult-onset hypopituitarism were recruited consecutively among patients being considered for GH replacement therapy. The median age was 53 yr (range 48–69 yr), and their body mass index at entry was 27.3 kg/m² (range 18.9–30.2). The hypopituitarism was a result of nonfunction pituitary adenoma or its treatment in seven patients, and in three patients it was because of treated Cushing’s disease, empty sella syndrome, and idiopathic hypopituitarism. Three of the 10 patients had panhypopituitarism and two had isolated GH deficiency. A GH peak of less than 3 µg/liter during insulin-induced hypoglycemia was used to confirm the GH deficiency. Subjects with renal disease, hypertension, diabetes mellitus, previous stroke, or polyneuropathy were not eligible for the study.

Study protocol

The study was designed as a two-phase trial. The initial phase of the study was a 7-d randomized, double-blind, placebo-controlled, cross-over trial with a 4-wk washout period in between followed by 12 months of open GH treatment. Randomization was performed at the clinical trial section at the Sahlgrenska University Hospital Pharmacy. The dose of GH during the double-blind period was 9.5 µg/kg per day, and the dose of GH during the open phase was individualized to normalize the serum IGF-I level (24). Three months before the 12-month visit, the daily dose of GH was kept stable. Other hormonal replacement therapy for hypopituitarism, such as glucocorticoids, L-thyroxine, and gonadal steroids, was kept stable for at least 3 months before entering the trial. Other medication was not allowed.

Five patients were randomly allocated to receive GH in the first period and placebo in the second period, and five patients were randomized to receive treatment in the reverse order. Before and at the end of each treatment period in the placebo-controlled phase and after the 12-month open treatment period, the patients spent 3 d in a metabolic ward unit. Collection of urine was initiated in the morning of d 1 and ended in the morning of d 3, and the results presented are the mean of two 24-h sampling periods. On the second day, multifrequency bioelectrical impedance analysis (MF-BIA) and an oral glucose tolerance test using an oral glucose load of 75 g were performed. On the third day, after an overnight fast and before leaving bed, blood samples were collected and blood pressure measured in both the supine and after 30 min in the upright position. On the third morning, measurements of renal paraminohippurate (PAH), renal Cr⁵¹ EDTA (Cr-EDTA), and lithium clearances were performed.

Body weight was measured daily in the morning to the nearest 0.1 kg. Body height was measured barefoot to the nearest 0.01 m. Body mass index was calculated as the weight in kilograms divided by the height in meters squared. Systolic and diastolic blood pressure was measured to the nearest 5 mmHg using the sphygmomanometric cuff method.

Metabolic ward regimen

Three days before each metabolic ward period, the patients were given sodium chloride capsules to keep the sodium intake constant. The metabolic ward dietitian made a food history interview to customize the metabolic ward menu for each patient. During the 3 d at the metabolic ward, the patients were given a strictly controlled menu with the same food items. Only the food on the menu was allowed, and the patients were encouraged to eat all food that was served. All food was prepared under metabolic ward kitchen conditions and weighed to nearest 0.1 g on a scale (Sigma, St. Louis, MO). The same batches of food were used for all metabolic ward periods for each patient, and food was kept deep frozen until day of consumption. Intake of sodium was regulated to median 150 mmol/d (range 149.75–150), intake of potassium was regulated to median 69 mmol/d (range 67–76), and median protein content was 88 g (range 75–108 g) during the metabolic ward period.

ECW

ECW was determined using MF-BIA (25). In short, reactance and resistance were determined by using a Xitron 4000B Bio-Impedance spectrum analyzer (Xitron Technologies, San Diego, CA). The equipment was calibrated daily. Resistance and reactance were measured at 50 frequencies from 5kHz to 500kHz. Data were analyzed using a computer program supplied by the manufacturer (BIS 4000 system utility version 1.00D) in which a semicircular function is fitted to the data in a Cole-Cole plot. The resistances at frequency zero and infinity are predicted and correspond to extracellular resistance and total body water resistance, respectively (25). These predictions combined with body weight, height, and resistivity of extracellular and intracellular water are then used to calculate the ECW, intracellular and total body water volume based on equations in the supplied computer program. MF-BIA has been found to be a valid method for indirect measurement of ECW in both healthy adults and adults with GH deficiency (26, 27).

Renal hemodynamics

RPF and GFR were assessed using PAH and Cr-EDTA clearances, respectively. The technique of continuous infusion and urine collection was used. The patient initially received a priming dose of Cr-EDTA (0.6x body surface area = megabecquerel) and PAH (0.04x body weight/ml 20% solution). The bolus doses were followed by an iv infusion of both at a rate of 0.83 ml/min to produce a plasma concentration of 500 counts/min per milliliter and 50–100 µmol/liter of Cr-EDTA and PAH, respectively. The subjects were initially hydrated with tap water (10 ml/kg body weight) to ensure diuresis. When urine flow was established, the priming doses of Cr-EDTA and PAH was administered. The equilibration period started when the subject had voided (approximately 45 min). The patients were supine throughout the study but were allowed to stand up to void for each urine collection. This procedure resulted in a complete bladder emptying according to ultrasound examination. Thereafter four 60-min periods followed in which the subjects emptied the bladder at the end of each period. Between the periods they drank the same volume of water as that of urine passed in the preceding period. The mean of four measurements was used for the renal hemodynamic assessment. Plasma and urine were assayed for PAH and Cr-EDTA. Clearance values were expressed per 1.73 m² body surface area.

Renal tubular sodium reabsorption

At 2100 h the day before assessment, 600 mg (16.2 mmol) of lithium (Li) carbonate was administered orally. Blood and urinary samples were collected at 1000 h the next day and then every clearance period for analysis of serum Na and Li. The mean serum value for each clearance period was used in the calculation of renal clearance (milliliter per minute). On the basis of the assumption that Li is absorbed solely in the proximal tubules and to the same extent as Na and water, Li clearance (CLi) equals the output of isotonic fluid from the proximal tubule (28). Plasma and urinary concentrations of Li were measured by atomic absorption and Na concentrations by flame photometry. Fractional Li excretion was calculated as CLi/GFR.

Other assays

ANP and brain natriuretic peptide (BNP) were measured from plasma that was instantly chilled and centrifuged at 4 C after collection and thereafter stored at -70 C until they were assayed. ANP and BNP were measured using a solid-phase immunoradiometric assay (SHIONOGI & Co. Ltd., Osaka, Japan) with a within-run coefficient of variation of 6.3% (mean 18.9 ng/liter) and 2.5% (mean 22.1 ng/liter) and detection limits of 2.5 ng/liter and 2.0 ng/liter, respectively.

RIA was used for determination of plasma renin activity (PRA; Renin-RIA bead, Abbot Diagnostics Division, South Pasadena CA) and plasma aldosterone (DiaSorin, Inc., Saluggia, Italy). Plasma angiotensin II concentration was assayed according to the methods of Kappelgaard et al. (29) and Morton and Webb (30). PRA and angiotensin II had within-run coefficient of variation of 8.8% and 5.1%, respectively.

The serum concentration of IGF-I was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum insulin was determined using a RIA (Phadebas, Pharmacia, Uppsala, Sweden), and blood glucose was measured by the glucose-6-phosphate dehydrogenase method (Kebo Lab, Stockholm, Sweden). Urinary norepinephrine (NE) and metoxycatecholamines were measured using HPLC.

Ethics

After oral and written information, informed consent was obtained from all the patients. The Ethics Committee at the University of Göteborg approved the study.

Statistical analysis

All analyses made in the blinded phase of the trial were performed before the treatment code was broken. All descriptive statistical results are presented as the median and the 25th and 75th percentiles. The Wilcoxon’s matched pairs signed rank sum test was used to compare the effects of GH treatment with the effects of placebo and baseline values with values obtained after 12 months of open GH replacement therapy. A carry-over effect was sought for by comparing baseline values of the GH period with baseline values in the placebo period in the five subjects who were first randomized to GH treatment. Correlations were sought by calculating the Spearman rank coefficient. Significance was obtained if the probability value was 0.05 or less.

Results

All subjects completed the blinded cross-over phase and the 12-month open GH treatment without any noticeable side effects. No carry-over effect was detected in the five subjects who were randomized to GH during the first treatment period. The median daily dose of GH was 0.83 mg (range 0.50–1.00) during the placebo-controlled period and 0.33 mg/day (range 0.27–0.83) after 12 months of GH treatment.

Serum concentration of IGF-I increased in response to both short-term treatment and 12 months of treatment of open GH replacement (Table 1). The area under the curve for blood glucose and plasma insulin during the 2-h oral glucose tolerance test were both increased after the short-term GH treatment (P < 0.01 for each, respectively) but returned to baseline values following the 12-month GH replacement therapy (data not shown). Median body weight increased (P < 0.05) following the short-term GH period [0.7 (0.0–1.0) kg], compared with placebo [0.1 (-0.8–0.7) kg], but it was unchanged after the long-term treatment.

During the short-term GH treatment, the ECW increased and the 24-h urinary sodium excretion decreased, compared with placebo (Table 1). Twelve months of GH replacement therapy maintained the increased ECW, and the 24-h urinary sodium excretion did not differ significantly from the baseline levels. The changes in ECW and diastolic blood pressure were inversely related following 12 months of GH treatment (Fig. 1) and a similar pattern was seen during the 7 d of treatment in the controlled part of the trial (r = -0.4, P = 0.3).

View larger version (11K): [in this window] [in a new window]   Figure 1. The inverse correlation between changes in extracellular fluid volume (ECW) and diastolic blood pressure between baseline and 12 months of GH treatment in 10 hypopituitary adults. The Spearman rank coefficient was calculated.

The supine diastolic blood pressure decreased from a median value of 88 (range 80–90) mm Hg at baseline to 78 (range 70–80) mm Hg at 12 months of open treatment (P = 0.02). During the short-term treatment, there was no significant change in diastolic blood pressure [85 (range 80–100) to 75 (range 70–90) mm Hg], compared with placebo treatment [83 (range 70–90) to 80 (range 70–80) mm Hg). The 24-h urinary excretion of NE increased in response to short-term GH treatment, compared with placebo (Table 1). This increase was not sustained after 12 months of treatment. The 24-h urinary excretion of aldosterone was not affected by the short- or long-term GH treatment (data not shown).

The supine values of PRA increased in response to short-term GH treatment, compared with placebo but not with baseline values after 12 months of treatment (Table 2). The supine plasma concentrations of angiotensin II and aldosterone were not affected by the treatment (Table 2). In standing position, PRA and plasma concentration of angiotensin II increased following 7 d of GH treatment, compared with placebo, whereas plasma aldosterone concentration did not change. The stimulated increment in PRA and angiotensin II elicited by moving from supine to standing position was more marked during GH treatment than during placebo (P < 0.05).

View larger version (13K): [in this window] [in a new window]   Figure 2. The positive correlation found between changes in PRA and 24-h urinary NE excretion between baseline and 12 months of GH replacement in 10 hypopituitary adults. The Spearman rank coefficient was calculated.

ANP and BNP (Table 1)

Plasma ANP concentration tended to be reduced in response to GH treatment, compared with placebo (P = 0.06) (Fig. 3A). A similar tendency was seen at 12 months, compared with baseline (P = 0.07). Plasma BNP concentration decreased in response to GH, compared with placebo treatment (Fig. 3B), and tended to be reduced at 12 months, compared with baseline (P = 0.09). No correlations were found between changes in ANP or BNP and in ECW or any other measurement in this trial.

View larger version (8K): [in this window] [in a new window]   Figure 3. The median and 25th to 75th percentile change in ANP (A) and BNP (B) in response to 7 d of GH and placebo in a randomized cross-over trial with a 4-wk washout period in 10 hypopituitary adults. *, P < 0.05, compared with placebo.

GFR, RPF, CLi, and fractional Li excretion were all unaffected by both short- and long-term GH treatment. The filtration fraction increased in response to short-term GH treatment, compared with placebo, but this effect was not sustained after 12 months of treatment (Table 3).

The major finding in this study is that the sodium-retaining effect of GH seems to occur in the distal nephron. With unchanged or even decreased blood pressure levels together with decreased or unchanged plasma concentrations of natriuretic peptides, pressure or escape natriuresis does not occur, allowing for increased ECW both during short- and long-term GH replacement.

Decreased urinary sodium excretion in the presence of unchanged CLi indicates that the increased renal tubular sodium reabsorption in response to GH treatment took place mainly in the distal nephron. In contrast to previous trials (22, 31, 32), renal hemodynamics did not change in response to GH treatment in this trial. Several factors may explain this difference. Previous trials have used pharmacological doses for a short time, whereas we have used more appropriate replacement doses with less marked increment and lower final serum levels of IGF-I. The standardized sodium and protein intake during the period of measurements in this trial is unique and may also help to explain the contrasting finding in this study, compared with previous ones. Of importance in this study, however, is the marked effect of GH/IGF-I on renal tubular sodium reabsorption despite the lack of effects on renal hemodynamics.

The enhanced tubular sodium reabsorption and the increased ECW did not offset pressure natriuresis, which would be anticipated for elimination of the sodium load (33, 34). Diastolic blood pressure was reduced during the GH treatment, an effect most likely explained by increased NO formation and reduced peripheral vascular resistance (21, 22). The inverse relationship found between the decrease in diastolic blood pressure and the increase in ECW between baseline and 12 months of GH treatment favor blood pressure reduction as a potential mechanism in preventing the pressure natriuresis reported with other sodium-retaining agents (34). Moreover, the escape from the sodium-retaining action of mineralocorticoids is coincident with increased concentration of plasma ANP suggesting that natriuretic peptides play a role in this phenomenon (35). The trend for reduced plasma ANP and BNP concentrations may therefore be of importance in preventing sodium and water escape during GH replacement. Increase ratio between total body nitrogen and body cell mass has been observed (36), suggesting extracellular proteins to increase during GH administration. This may also contribute to the sustained increase in ECW during more prolonged GH treatment and in patients with acromegaly (1).

Several factors may contribute to the increased renal tubular sodium reabsorption in response to GH. Our trial together with a previous one (8), also using a more appropriate dose of GH for replacement in adults, does favor that stimulation of RAAS may be of some importance for the sodium-retaining effect of GH. The mechanism does not seem to be a stimulation of the adrenal cortex (37) because plasma aldosterone levels did not change in response to GH. The primary effect may be increased PRA, which in turn will increase serum angiotensin II levels and thereby increase directly the sodium retaining effect in the renal tubules. The main shortcoming of this explanation is that the sodium-retaining effects of angiotensin II takes place mainly in the proximal tubule (38), but our result form the lithium clearance suggests that this takes place in the distal nephron. More recent lines of evidence suggest, however, that angiotensin II directly increases sodium reabsorption in the more distal part of the nephron (39).

Although contrasting effects in terms of angiotensin II and aldosterone occur in previous studies, a consistent finding is the increased PRA in response to GH administration (6, 7, 8, 11, 40). In genetically GH-deficient Lewis rats as well as in man, GH administration increases plasma angiotensinogen concentration (5, 8), indicating that PRA is increased secondary to increased renin substrate. GH treatment restores the attenuated renin secretion response to hypotension in hypophysectomized rats (4), and in this study it results in a more marked rise in PRA and angiotensin II in response to an orthostatic test. Renin release is amplified by renal sympathetic activity and circulating catecholamines (41). Our relationship between the increase in 24-h urinary NE excretion and the increase in PRA may therefore indicate that short-term GH treatment increases renal sympathetic activity, which in turn may be responsible for the increase in PRA. Although urinary NE excretion is not a specific measure of renal sympathetic nervous function (42, 43), the increase in urinary NE seen following the short-term GH treatment may indicate an acute selective increase in renal sympathetic activity because sympathetic outflow to other vascular beds remains unaffected by short-term GH treatment (Sverrisdóttir, Y. B., personal communication).

The decrease in insulin sensitivity and increase in insulin levels during the short-term GH treatment may also have contributed to the increased urinary excretion of NE (44). However, all the above-mentioned effects are lost during long-term GH replacement suggesting that the more prolonged effects of GH/IGF-I are mediated through direct actions on the distal nephron and not through the interaction with renal sympathetic activity and RAAS. This is supported by unchanged or even reduced activity of the RAAS in acromegaly patients (45, 46).

In contrast to most previous trials that have studied the relationship between GH/IGF-I and natriuretic peptides, we have used a solid-phase immunoradiometric assay to measure mature ANP and BNP (47). Both peptides affect blood pressure, renal hemodynamics, renal tubular function, and sodium and water homeostasis (48). Competitive blockage of ANP and BNP results in increased blood pressure, increased plasma concentrations of PRA, aldosterone, and catecholamines (49). It is therefore plausible that the reduction seen in plasma ANP and BNP in response to short-term GH treatment is a primary event that may explain both the increase in PRA and urinary NE excretion. The small reduction observed in plasma ANP and BNP concentration is not likely to solely explain the sodium-retaining effects in response to GH treatment. This may be supported by the lack of any association between changes in these peptides and changes in ECW and urinary sodium excretion.

This study, performed under metabolic ward conditions, suggests that the sodium- and water-retaining effect of GH takes place mainly in the distal nephron by a direct action of GH/IGF-I because other plausible indirect mechanisms are only modestly or transiently affected. Of major importance for the sustained increase in ECW in response to GH is the unchanged or decreased blood pressure, which prevents pressure-induced natriuresis. We may hypothesize that GH/IGF-I reduces natriuresis and increases ECW and, by its parallel action on blood pressure and plasma natriuretic peptides, prevents escape natriuresis.

Acknowledgments

We are indebted to dietitian Birgitta K. Lundgren of the Metabolic Ward for excellent contribution to this study and the personnel at the Endocrine Ward, the Research Center for Endocrinology and Metabolism, and the Research Laboratory of Nephrology at Sahlgrenska University Hospital for skillful technical support. Pharmacia kindly provided the GH and placebo preparations during the blinded phase of the trial.

Footnotes

This work was supported by grants from the Swedish Medical Research Council (Project no. 11621, 12170, and 13192), Swedish Society for Medical Research, and Swedish Heart and Lung Foundation.

Abbreviations: ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide; CLi, lithium clearance; Cr-EDTA, Cr⁵¹ EDTA; ECW, extracellular water; GFR, glomerular filtration rate; Li, lithium; MF-BIA, multifrequency bioelectrical impedance analysis; NE, norepinephrine; NO, nitric oxide; PAH, paraminohippurate; PRA, plasma renin activity; RAAS, renin-angiotensin-aldosterone system; RPF, renal plasma flow.

Received July 27, 2001.

Accepted January 3, 2002.

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