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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1109
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 2 795-799
Copyright © 2005 by The Endocrine Society

Renal Contribution to Increased Clearance of Exogenous Growth Hormone in Obese Hypertensive Patients

Madelon M. Buijs, Peter W. de Leeuw, Alphons J. H. M. Houben, Abraham A. Kroon, Marijke Frölich, Hanno Pijl and A. Edo Meinders

Departments of General Internal Medicine (M.M.B., H.P., A.E.M.) and Clinical Chemistry (M.F.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Internal Medicine, Maastricht University Hospital (P.W.d.L., A.J.H.M.H., A.A.K.), 6202 AZ Maastricht, The Netherlands

Address all correspondence and requests for reprints to: Dr. P. W. de Leeuw, Department of Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: p.deleeuw{at}intmed.unimaas.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To evaluate the possible role of the kidney in the enhanced metabolic clearance rate (MCR) of GH in obesity, we studied the kinetics of GH and renal fractional extraction of GH (RFEGH) in 12 male hypertensive patients over a wide range of body weights (71.7–129 kg) while undergoing contrast angiography on suspicion of renal artery stenosis. A continuous infusion of recombinant human GH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. After 2 h of GH infusion, when plasma GH had reached a steady state at concentrations that were still in the physiological range, blood was sampled from the left and right renal arteries and veins for determination of GH levels. Subsequently, the GH infusion was stopped, and GH kinetics were investigated with noncompartmental analysis. In none of the patients was hemodynamically significant renal artery stenosis present. Whole body MCR of GH averaged 375 ± 142 ml/min. Average GH levels were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001). RFEGH was 8.6 ± 6.8%. The MCRs of both GH and RFEGH correlated significantly with body weight, body fat mass, and endogenous creatinine clearance. Renal uptake of GH per 100 g kidney tissue correlated inversely with MCR. These results suggest that RFEGH rises with increasing adiposity, but per unit of renal mass, the capacity of the kidney to remove GH from the circulation falls at high MCR values.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
BOTH LOWER AND upper body obese individuals have significantly reduced plasma GH concentrations (1, 2). In lower body obesity, hyposomatotropism, in particular, is caused by an increased metabolic clearance rate (MCR) of GH, whereas in upper body obesity, both decreased secretion and a higher MCR are responsible for the reduced GH levels (1, 3, 4). Plasma GH is primarily degraded by kidneys, liver, and peripheral tissues. The MCR of GH ranges from 200–600 ml/min, with an inverse relationship between plasma GH level and MCR (5, 6). The estimated plasma half-life (t1/2) of total GH is about 19 min (6, 7). It is unclear which factors contribute to the increased MCR and shortened t1/2 of GH that is observed in obesity.

In the kidneys, GH is thought to be cleared by way of glomerular filtration, followed by tubular absorption and peritubular degradation. Less than 1% of filtered GH is excreted in urine. These assumptions are based on observations made in animal experiments, where levels of peritubular uptake and tubular secretion of GH were low, and only degradation products of GH returned to the circulation (8, 9). Data obtained from healthy human subjects and patients with chronic renal failure support the idea that the kidneys have an important role in human GH clearance as well (10, 11). Chronic renal failure is associated with elevated plasma GH concentrations, prolonged t1/2 of total and free GH, and lower MCR. In a previous study it was estimated that renal clearance accounted for 25%, 46%, and 53% of the total metabolic clearance at plasma GH concentrations of 5, 25, and 45 µg/liter (0.23, 1.15, and 2.07 nmol/liter), respectively (12).

To unravel whether the kidneys contribute to the increased MCR of obese individuals, we measured whole body GH kinetics and renal fractional extraction of GH in hypertensive patients with a wide range of body weights, who were undergoing contrast angiography on suspicion of renal artery stenosis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Twelve male patients, in whom renovascular hypertension was suspected, participated in the study. The diagnosis of hypertension was made when office systolic blood pressure was 160 mm Hg or greater and/or diastolic blood pressure was 95 mm Hg or greater on at least three different occasions. Except for high blood pressure and adiposity, no other abnormalities, such as edema, were apparent on physical examination. When on the basis of clinical, biochemical, or ultrasound data a renovascular disease was suspected, patients underwent digital subtraction angiography with renal arterial and venous blood sampling. The use of antihypertensive agents had been discontinued 3 wk or more before angiography. None of the patients used diuretics or other drugs that could have modified the measurements. Patients were not diabetic, they did not use insulin, and all had hemoglobin A1c below 6.7%. For reasons of standardization, patients were asked to adhere to a sodium-restricted diet (55 mEq sodium/d) during the last week before study (13). Dietary compliance was checked by measuring sodium and creatinine excretion in 24-h urine, collected the day before angiography. Patients had to refrain from tobacco or alcohol consumption the day before the experiment. The study protocol was approved by the medical ethics committee of Maastricht University Hospital. Written informed consent was obtained from all participants.

Experimental procedures

The study comprised one occasion on which all investigations took place in the morning after overnight fasting from 2200 h the preceding day. After voiding, the patients stayed recumbent for the duration of the experiment. Body composition was measured using bioelectrical impedance analysis (Bodystat, Douglas, UK). One cannula was inserted into an antecubital vein for venous blood sampling. A second cannula was placed into the contralateral arm, and this cannula was used for various infusions. Renal arterial and venous cannulation were performed under fluoroscopic control via the femoral route.

At 0800 h (0 min), a continuous infusion of somatostatin (Ferring Pharmaceuticals Ltd. BV, Hoofddorp, The Netherlands) was started at a rate of 250 µg/h for 240 min, using a calibrated Terumo precision pump. Forty-five minutes later, a second infusion of recombinant human GH (rhGH; 4.5 mU/kg·h; Pharmacia Corp., Peapack, NJ) was begun using another calibrated Terumo precision pump. This rhGH infusion was maintained for 145 min. At 240 min, i.e. after completion of all studies, contrast angiography was performed.

Before somatostatin infusion (–10 min), basal blood samples for plasma GH and creatinine concentrations were obtained from a peripheral vein. The plasma GH level was additionally determined in peripheral blood at 30, 60, 90, 120, 150, 160, 170, 175, 180, and 191 min, then every 5 min until 240 min. Creatinine concentrations were also determined after 180 min of somatostatin infusion. At 170 min, while the rhGH infusion was still running, blood samples were obtained simultaneously from the arterial and left renal veins. Subsequently, renal blood flow was measured in the left kidney by means of the 133Xe washout technique. The same procedure was repeated in the right kidney at 180 min. Thereafter, the infusion of rhGH was discontinued (at 190 min). The renal samples were used to determine plasma GH and creatinine concentrations and oxygen saturation. The latter was used to check whether the venous catheter had been properly positioned in the renal vein (14). At 205, 215, and 230 min, additional blood samples from the arterial and right renal veins were obtained to determine GH. At the same time, blood flow was measured again in the right kidney (because this requires the arterial catheter to be positioned in the renal artery, we refrained from obtaining measurements bilaterally). Blood pressure was measured intraarterially during the procedures.

Assays

Blood for plasma GH concentrations was collected on heparin; creatinine concentrations were determined in serum. Heparin samples were kept on ice, and all samples were centrifuged within 30 min of sampling (2000 x g at 4 C, during 10 min). Plasma and serum samples were stored at –80 C and transported on dry ice before assay.

Plasma GH was measured by time-resolved fluoroimmunoassay (Delfia, Wallac, Turku, Finland) specific for 22-kDa GH, which was used as the standard (Genotropin, Pharmacia Corp.), as calibrated against the WHO First International Reference Preparation, 80/505 (to convert micrograms per liter to milliunits per liter, multiply by 2.6). The limit of detection was 0.03 mU/liter. The intraassay coefficient of variation varied from 1.6–8.4%, and the interassay coefficient of variation ranged from 2.0–9.9%. Serum creatinine was determined using a fully automated Hitachi 747 (Hitachi, Tokyo, Japan) system.

Calculations

Body mass index (BMI) was calculated as body weight (kilograms)/height (meters)2. Body surface area (BSA) was calculated as {surd}((weight (kg) x length (cm))/3600). Endogenous creatinine clearance (ECC), as a measure of the glomerular filtration rate (GFR), was calculated from peripheral venous creatinine concentrations using the formula of Cockcroft and Gault (15)

Whole body GH kinetics were investigated with noncompartmental methods using WinNonlin V1.1 (Scientific Consulting, Apex, NC). The noncompartmental method was chosen because it requires fewer assumptions (4). Moreover, because the volume of distribution could be considered completely saturated at the time of GH withdrawal, a monocompartment elimination model seems reasonable (12).

Renal blood flow was determined by means of the 133Xe washout technique as described previously (13, 16). Flow data were analyzed for right and left kidneys separately and expressed as milliliter per minute (100 g)–1. Renal plasma flow (RPF) was calculated with the formula RPF = renal blood flow x (1 – Ht), where Ht is the arterial hematocrit. Renal GH uptake (RUGH) by each kidney was computed as renal plasma flow x (arterial GH concentration – renal venous GH concentration) and expressed as milliunits per minute (100 g)–1. Total RU was taken as the sum of uptake by right and left kidneys. Because kidneys normally do not produce GH, the total renal fractional extraction of GH (RFEGH) can be derived from the formula (total arterial delivery – total venous efflux) x (total arterial delivery)–1x 100%. Total arterial GH delivery to the kidneys amounts to: arterial GH x (RPFL + RPFR), where RPFL and RPFR represent renal plasma flow through the left and right kidneys, respectively. Similarly, total venous efflux of GH can be calculated as: (VL x RPFL) + (VR x RPFR), where VL and VR represent the concentrations of GH in the left and right renal veins, respectively. The single kidney fractional extraction of GH was derived from the formula: ((A – V)/A) x 100%, where A and V represent the GH concentrations in the renal artery and vein, respectively. Single kidney and total renal fractional extractions of creatinine were determined in the same way.

Statistical analysis

Anthropometric descriptives were correlated with clearance parameters by use of Pearson’s correlation coefficients. All data are expressed as the mean ± SD. P < 0.05 was considered statistically significant. Statistical calculations and data management were performed using SPSS for Windows V10.0.7 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the patients who were enrolled in the study are shown in Table 1Go. In none of these patients were angiographic signs of hemodynamically significant renal artery stenosis present. Intraarterial blood pressure ranged from 149–241 mm Hg systolic and from 88 to 127 mm Hg diastolic. ECC averaged 95 ± 19 (range, 71–131) ml/min·1.73 m2. A significant positive correlation existed between ECC and body fat mass (r = 0.83; P < 0.001). Peripheral venous creatinine concentrations were not influenced by somatostatin infusion [–10 min, 1.13 ± 0.28 mg/dl (100 ± 25 µmol/liter); 180 min, 1.10 ± 0.27 mg/dl (97 ± 24 µmol/liter)]. Renal arterial creatinine concentrations averaged 1.08 ± 0.26 mg/dl (96 ± 23 µmol/liter). In the left and right renal veins, mean creatinine concentrations were 0.90 ± 0.23 mg/dl (80 ± 20 µmol/liter) and 0.87 ± 0.20 mg/dl (77 ± 18 µmol/liter), respectively. Total renal fractional extraction of creatinine averaged 18 ± 6%. Renal plasma flow in the left and right kidneys averaged 118 ± 34 and 127 ± 34 ml/min (100 g)–1, respectively. Flows in both kidneys tended to decrease with increasing body mass.


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  		TABLE 1. Patient characteristics

 
Figure 1Go shows the plasma GH concentration profile in a representative subject. Somatostatin infusion adequately suppressed endogenous GH secretion in all patients. After 30 min of somatostatin, plasma GH levels had dropped from 0.99 ± 1.30 to 0.38 ± 0.41 mU/liter. Steady state plasma levels of GH were generally reached after 80–120 min of rhGH infusion, although in two individuals the profiles were somewhat irregular. Table 2Go summarizes the kinetic data obtained by noncompartmental analysis. Significant positive correlations existed between the MCR of GH and body weight (r = 0.69; P = 0.014), body fat mass (r = 0.65; P = 0.021), BSA (r = 0.65; P = 0.021), and ECC (r = 0.66; P = 0.018), but not with lean body mass. Inverse relationships of borderline statistical significance were observed between GH elimination t1/2 and body weight, BMI, and body fat mass.



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  		FIG. 1. Plasma GH concentrations after iv infusion of 4.5 mU/kg·h 22-kDa recombinant human GH in a representative patient (from 45–190 min). Somatostatin was concomitantly infused from 0–240 min.

 

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  		TABLE 2. GH kinetics estimated by noncompartmental analysis

 
GH concentrations in the left and right renal arteries and veins at the completion of the rhGH infusion are depicted in Fig. 2Go. Because GH levels still increased from 160–180 min, plasma concentrations were somewhat higher in the right renal artery and vein (sampled at 180 min) than in the left renal artery and vein (sampled at 170 min). Average GH concentrations were significantly higher in arterial plasma than in simultaneously sampled renal venous plasma (P < 0.001), consistent with renal extraction of GH. However, in the right kidney of two patients we found higher GH levels in venous than arterial blood (Fig. 2Go). Nevertheless, average RFEGH did not differ between the two kidneys (8.7 ± 6.6% in the left kidney and 8.7 ± 9.2% in the right kidney). This was also true when the two patients with no measurable extraction of GH by the right kidney were left out of the analysis. Total RFEGH was 8.6 ± 6.8%.



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  		FIG. 2. Correlation between arterial and renal venous levels of GH for the left and right kidneys separately. Solid line, Regression line; dotted line, line of identity.

 
Total RFEGH correlated significantly with body weight (r = 0.71; P = 0.014), BMI (r = 0.81; P = 0.002), body fat mass (r = 0.82; P = 0.002), and ECC (r = 0.87; P = 0.001), but not with lean body mass or blood pressure. When the two kidneys of patients with demonstrable extraction of GH were considered separately, significant inverse relationships were observed between plasma flow through the kidney and ipsilateral fractional extraction of GH (Fig. 3Go). This relationship was more prominent in the left than in the right kidney, because the two patients in whom renal venous levels of GH were higher than the corresponding arterial ones were omitted in this analysis. Finally, we examined the relationship between total RUGH and total body GH clearance (Fig. 4Go). An inverse correlation was observed (r = –0.68; P = 0.030), indicating that a higher MCR of GH is associated with lesser renal uptake of this hormone per unit tissue mass. A similar relationship was observed when total renal clearance of GH was substituted for RUGH.



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  		FIG. 3. Relationship between the fractional extraction of GH and ipsilateral renal plasma flow for the left and right kidneys separately. Solid line, Regression line; dotted line, 95% confidence intervals for regression line.

 


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  		FIG. 4. Relationship between renal uptake of GH and total GH clearance. Solid line, Regression line; dotted line, 95% confidence intervals for regression line.

 
RFEGH of the right kidney was not influenced by the arterial GH concentration (P > 0.05), because RFEGH averaged 8 ± 10%, 16 ± 10%, 3 ± 16%, and 8 ± 16% at decay GH concentrations of 26.15 ± 7.18, 11.96 ± 5.07r, 7.11 ± 3.27, and 3.72 ± 1.75 mU/liter, respectively.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study shows that over a wide range of body weight and fat mass the kidney contributes to the removal of GH from the circulation. Whereas previous observations in humans have indicated only that GH accumulates when renal function is reduced, the present data provide more direct evidence for extraction of GH by the kidneys. Although we found renal venous concentrations of GH to be higher than the corresponding arterial ones in two patients, the concentration gradient over the kidney in these subjects was extremely small. Presumably, in these two patients there was no or very little extraction in their right kidney at the time of measurement.

Given its molecular mass (~21 kDa), GH should be able to pass the glomerular barrier freely. However, one would expect the extraction of GH to be close to that of creatinine if glomerular filtration of the peptide would be complete and GH would circulate entirely in its free form. In fact, we found that total RFEGH averaged 8.6% in our subjects, which was only about half the extraction of creatinine. Because tubular reabsorption of small peptide hormones normally does not occur (17, 18), these data point toward incomplete filtration of GH. In this respect, our results would be compatible with a glomerular sieving coefficient for free GH of about 0.4–0.5, which is close to that described in rats (8). Alternatively, binding of GH to GH-binding proteins could account for our observation. Studies in rats also suggest that glomerular filtration with subsequent peritubular breakdown forms the main route of GH removal by the kidneys (8, 9). A characteristic common of most small peptide hormones is that their renal uptake is not saturable, leading to a stable extraction fraction over a wide range of arterial concentrations (8, 12, 17, 18). Our data for GH appear to be no exception to that rule, because extraction remained relatively stable after the infusion had been discontinued.

As expected (3, 4, 6, 19), we found the MCR of exogenously infused GH to be clearly correlated with various anthropometric variables, such as body weight, body fat mass, and BSA, and the same was true for RFEGH. Excess body weight is associated with increases in both renal plasma flow and GFR (20, 21). Although changes in renal perfusion hardly influence the clearance of compounds with a low extraction ratio (22), concomitant increments in transcapillary hydrostatic pressure will (23). Such a situation ensues when the renal vasodilatory effect of obesity is greater at the level of the preglomerular vessels than at the postglomerular ones and can be recognized by a higher filtration fraction, which has indeed been found in obese individuals (21, 23). Both the renin-angiotensin system and the actions of insulin have been considered candidates in the obesity-related renal hemodynamic changes, but the exact mechanism remains to be elucidated (24).

The relationship between ECC and whole body GH clearance found in this study confirms earlier observations in healthy humans (12) and, in concert with many other data showing that GFR is increased in obese subjects, also suggests that the renal uptake of GH is augmented in obese individuals. In this respect, it may seem surprising that we found a higher RFEGH to be associated with lower, rather than higher, renal plasma flow. However, the xenon washout technique that we applied actually measures flow per unit of tissue mass (24). Accordingly, lower flow rates in this instance can be due to either increased renal mass, which does occur with greater body size (25), or renal vascular abnormalities secondary to obesity-associated hypertension. It may be, therefore, that in younger obese patients afferent vasodilation prevails (24), whereas in a middle-aged hypertensive population such as ours, efferent vasoconstriction and loss of vasodilatory capacity dominate the hemodynamic pattern. Finally, if renal mass increases in conjunction with obesity, this does not entail the development of new, functionally active nephrons, but, rather, of fatty and interstitial tissue. When this is not matched by a concurrent rise in flow (as our data suggest), this may lead to the situation in which total renal perfusion and glomerular filtration are enhanced while perfusion per unit mass of tissue lags behind. Under those conditions, an elevated RFEGH could coincide with reduced xenon flow rates.

Using indirect methods, Haffner and co-workers (12) estimated that the kidney accounts for 25% and 4% of total MCR of GH in healthy subjects and patients with chronic renal failure, respectively, at plasma GH concentrations similar to those used in the present study. Interestingly, we found an inverse relationship between RUGH (again, per 100 g tissue) and total body clearance of GH. This means that even if glomerular filtration of GH increases with increasing obesity, the capacity of the kidney per 100 g functional tissue to remove the peptide progressively falls. Although speculative, this may also be related to renovascular abnormalities and loss of functional tissue just as in renal insufficiency. In this respect, it is worth noting that some patients had rather low GFR values, which may be a reflection of hypertensive kidney damage (nephrosclerosis). Therefore, we cannot exclude the possibility that impaired extraction efficiency is due to such hypertension-related intrarenal changes, rather than to obesity-related phenomena.

In this study we used a somatostatin infusion to suppress endogenous GH secretion. Unmodified creatinine clearance values have been observed during infusion of somatostatin (26), and in our study the plasma creatinine concentration did not change during the study period. Although prolonged GH infusion stimulates the production of IGF-I, which, in turn, enhances GFR (27), it is not likely that the short-term infusion used in this study induced changes in GFR. However, it is not known whether somatostatin or GH can affect RFEGH and renal clearance of GH.

In summary, the MCR of GH enhances with increasing adiposity. We found in hypertensive patients that approximately 9% of arterially delivered GH at physiological plasma concentrations is removed from the circulation by the kidneys, and that this fraction gets higher when body mass increases. Therefore, we suggest that the kidneys contribute to the increased MCR of GH observed in obesity. However, with increasing MCR, the capacity of the kidney per unit tissue mass to remove GH from the circulation diminishes.


   Acknowledgments
 
We thank Pharmacia Corp. (Peapack, NJ) for its generous gift of rhGH, and Ferring Pharmaceuticals Ltd. BV (Hoofddorp, The Netherlands) for its gift of somatostatin for this study.


   Footnotes
 
First Published Online November 30, 2004

Abbreviations: BMI, Body mass index; BSA, body surface area; ECC, endogenous creatinine clearance; GFR, glomerular filtration rate; MCR, metabolic clearance rate; RFEGH, renal fractional extraction of GH; rhGH, recombinant human GH; RUGH, renal GH uptake; t1/2, half-life.

Received June 14, 2004.

Accepted November 17, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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