Departments of Gastrointestinal Surgery and Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
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ABSTRACT |
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The renal handling of carboxyamidated gastrins,
NH2-terminal progastrin fragments,
and glycine-extended gastrins was examined in healthy volunteers. The
respective urinary clearances after a meal amounted to 0.09 ± 0.02%, 0.17 ± 0.04% (P < 0.05), and 0.04 ± 0.01% (P < 0.01) of the glomerular filtration rate. During intravenous
infusion of carboxyamidated gastrin-17, progastrin fragment-(135),
and glycine-extended gastrin-17, the respective urinary clearances
amounted to 0.08 ± 0.02, 0.46 ± 0.08, and 0.02 ± 0.01%,
respectively, of the glomerular filtration rate. The metabolic
clearance rate of the three peptides was 24.4 ± 1.3, 6.0 ± 0.4, and 8.6 ± 0.7 ml · kg
1 · min
1.
A maximum rate for tubular transport or degradation of the peptides could not be determined, nor was a renal plasma threshold recorded. Plasma concentrations and urinary excretion rates correlated for gastrin-17 and progastrin fragment-(1
35)
(r = 0.94 and 0.97, P < 0.001), whereas the excretion of
glycine-extended gastrin diminished with increasing plasma
concentrations. We conclude that renal excretion of progastrin products
is negligible compared with renal metabolism and that renal handling of
the peptides depends on their molecular structure. Hence, the kidneys
exhibited a higher excretion of
NH2-terminal progastrin fragments
than of carboxyamidated and especially glycine-extended gastrins.
gastrointestinal peptides; metabolism; urinary excretion
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INTRODUCTION |
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THE KIDNEYS ARE active in the metabolism of gastrin. Canine and porcine renal extraction of carboxyamidated gastrin-17 varies from 9 to 40%, but <0.4% of the filtered gastrin-17 is present in the urine (4, 5, 22, 23, 31). This implies either complete absorption of filtered gastrin-17 in the renal tubules or excretion of nondetectable degradation fragments in the urine. In humans, the kidneys also seem to be important regulators of plasma gastrin levels as inferred from the elevated concentrations of gastrin in patients with renal failure (19, 32). Like in other mammals, the concentration of gastrin peptides in human urine is usually low; however, analysis of postprandial urine has revealed significant differences between the excretion of COOH- and NH2-terminal fragments of gastrin (11, 12). Until now, urinary excretion of gastrin in humans has only been investigated in postprandial urine or in urine from patients with hypergastrinemia (8, 11, 12, 27). Intravenous administration of gastrin enables a more detailed information about renal handling of different gastrin peptides.
To find out whether urinary excretion of gastrin is related to either
the molecular form or to bioactivity of the peptides, we studied
endogenous gastrins in postprandial urine from normal subjects as well
as urinary excretion of gastrin during intravenous administration of
three different products of progastrin. The first product was
carboxyamidated gastrin-17 (gastrin-17), which is the bioactive main
product. The second was glycine-extended gastrin-17 (gastrin-17-Gly),
which is the immediate precursor of gastrin-17 (15). Glycine-extended
gastrins are cosecreted in small amounts along with carboxyamidated
gastrin and are not bioactive with regard to acid secretion (13, 21),
although it has been suggested that glycine-extended gastrins may
stimulate cellular growth (28). The third product was the
NH2-terminal fragment-(135) of
progastrin [progastrin-(1
35)], which circulates in plasma
with other NH2-terminal fragments
of progastrin (26). So far, no biological function has been connected
with these fragments (Fig. 1).
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MATERIALS AND METHODS |
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Peptides
Human carboxyamidated nonsulfated gastrin-17 was purchased from Sigma (St. Louis, MO). Glycine-extended human nonsulfated gastrin-17 and human progastrin-(1After sterile filtration, the peptides were diluted in isotonic saline
containing 1 g/l human serum albumin. The syringes were weighed before
and after the infusions, and the remaining peptide from the infusion
lines was stored at 20°C until radioimmunoassay.
Subjects
The studies were carried out in healthy subjects without a history of medical or surgical illness. Informed consent was obtained, and the studies were approved by the Ethics Committee for Medical Research in Copenhagen in accordance with the Helsinki II declaration.Experiments
Recovery of gastrin in urine.
Recovery was measured by adding gastrin-17, gastrin-17-Gly, and
progastrin-(135) separately to urine and assay buffer in different
concentrations. Degradation with time was investigated by incubating
the peptides in urine for 1, 2, 4, 8, and 24 h. After incubation, all
samples were immediately frozen in liquid nitrogen and stored at
20°C until analysis.
Renal excretion of endogenous gastrin. Renal excretion of postprandial gastrin was studied in seven subjects (23-33 yr, body surface 1.81 ± 0.05 m2). After an overnight fast, each subject ingested a meal consisting of two boiled eggs, two slices of bread with cheese, 250 ml yogurt, and 250 ml milk. Voided urine was collected 10 times at 30-min intervals starting with a basal period of 60 min before the meal. Venous blood samples were drawn from the cubital vein at the end of each urine sampling. Diuresis was maintained with isotonic saline infused in the other arm. Glomerular filtration rate (GFR) was determined by a single intravenous injection of 4 MBq of 51Cr-EDTA (Amersham, Buckinghamshire, UK) 1 h before the meal. The activity of the tracer in plasma was measured in venous blood samples drawn at regular intervals until the end of the study.
A more detailed investigation of the renal handling of gastrin peptides was made by stepwise infusion of three products of progastrin: gastrin-17, progastrin-(1Renal excretion of gastrin-17.
Renal excretion of gastrin-17 was studied in eight subjects (22-33
yr, body surface 1.82 ± 0.05 m2). The peptide was infused at
three consecutive dose rates (60, 120, and 240 pmol · kg1 · h
1),
each lasting 90 min. Urine was collected for intervals of 30 min during
the whole study, and venous blood was drawn at the end of each sampling
period. Diuresis was maintained with isotonic saline infused
intravenously in the opposite arm, and GFR was measured by a single
injection of 51Cr-EDTA.
Renal excretion of progastrin-(135) and gastrin-17-Gly.
Renal excretion of progastrin-(1
35) and gastrin-17-Gly was studied in
eight subjects (23-28 yr, body surface 1.87 ± 0.09 m2). Each peptide was infused
simultaneously at three consecutive dose rates, each lasting 90 min
[progastrin-(1
35): 15, 30, and 60 pmol · kg
1 · h
1;
gastrin-17-Gly, 30, 60, and 120 pmol · kg
1 · h
1].
Urine and blood samples were drawn as stated above. GFR was measured by
a single injection of 51Cr-EDTA.
Laboratory Analyses
Radioimmunoassay. Three sequence-specific antisera were used to measure the peptides in plasma and urine. Gastrin-17 was measured using antiserum 2604, which was raised against the 2-17 fragment of human gastrin-17 and is specific for the bioactive COOH terminus. The antiserum binds gastrin-71, -52, -34, and -17 with equimolar potency, and its reactivity with cholecystokinin peptides is <0.5% (30). Synthetic human gastrin-17 was used as a standard, and monoiodinated 125I-gastrin-17 was used as tracer (29).
Gastrin-17-Gly was measured using antiserum 7270. This antiserum was raised against the 5-17 fragment of gastrin-17-Gly. Gastrin-17-Gly was used as standard and monoiodinated 125I-gastrin-17-Gly as tracer (14). Antiserum 7270 does not recognize amidated gastrins, cholecystokinins, or glycine-extended cholecystokinins. Progastrin-(1Urine analysis.
After measurement of urine volume, samples were collected in
ice-chilled tubes and stored at 20°C until analysis. The
urine was concentrated, and the peptides were extracted using
octadecylsilicyl silica columns (Sep-Pak
C18 cartridges, Waters Associates,
Milford, MA) (8). The cartridges were prewashed with 10 ml of 75%
alcohol in 0.01 M HCl followed by 10 ml distilled water. Volumes of
urine up to 20 ml were filtered through the cartridges with a flow rate of 10 ml/min. After being washed with 10 ml distilled water, the peptides were eluted by 40 ml of 75% alcohol in 0.01 M HCl. The eluate
was dried under airflow and reconstituted in assay buffer. The
concentration of the progastrin products in urine was measured by radioimmunoassay.
Chromatography.
Plasma and urine samples of 1 ml were applied to Sephadex G-50
superfine columns (10 × 1,000 mm, Pharmacia, Uppsala, Sweden) and
eluted with 0.125 M
NH4HCO3
(pH 8.2) at room temperature with a flow rate of 3 ml/h. Void volume
and total volume were determined by elution of
125I-albumin and
22NaCl. The columns were
calibrated with gastrin-17, gastrin-17-Gly, and progastrin-(135).
Fractions of 1 ml were collected and measured using antisera 2604, 7270, and 88235.
Calculations
The MCR of gastrin was calculated by dividing dose rate by the plateau increment in plasma gastrin. Urinary clearance of gastrin (Clu) was calculated by the standard formula
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The GFR was determined by single injection of 51Cr-EDTA and venous blood sampling without urine collection (3). The estimated value computed by single-injection technique represents the average GFR of the interval from time 0 until the end of blood sampling. The activity of the tracer in plasma and the solution injected was measured in a well-scintillation counter, and the counts per milliliter plasma sample were plotted on semilogarithmic paper. After injection of the tracer, the curve falls rapidly until equilibrium with the extracellular fluid has been achieved; thereafter, the curve decreases at a constant linear rate. GFR is equivalent to the total body clearance (Clb) of the tracer calculated as injected dose divided by the area under the curve (AUC) of radioactivity in plasma
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RESULTS |
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Recovery
The recoveries of gastrin-17, gastrin-17-Gly, and progastrin-(1
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Renal Excretion of Endogenous Gastrin
The basal concentrations of carboxyamidated gastrins, NH2-terminal progastrin fragments, and glycine-extended gastrin in plasma were 10 ± 2, 12 ± 2, and 6 ± 1 pM, respectively. During the meal, carboxyamidated gastrins and NH2-terminal progastrin fragments in plasma reached peak concentrations of 25 ± 4 and 16 ± 4 pM (P < 0.01), respectively, whereas the concentration of glycine-extended gastrin remained almost constant (Fig. 3). The average GFR was 98.1 ± 1.7 ml · min
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Renal Excretion of Gastrin-17
Gastrin-17 was infused at three consecutive dose rates of 58 ± 5, 115 ± 11, and 223 ± 12 pmol · kg
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Gel chromatography of plasma revealed a major peak in the elution
position of gastrin-17 (Fig. 6). The
concentration of gastrin-17 in urine was too low for gel
chromatographic analysis.
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Renal Excretion of Progastrin-(135) and Gastrin-17-Gly
Urinary excretion rate of progastrin-(135) increased concomitantly
with the concentration of the peptide in plasma (Fig. 7). The correlation between excretion rate
and plasma concentration was significant
(r = 0.97, P < 0.001; Fig.
8). A
Tm value was not reached within
the present dose rates. The average MCR of progastrin-(1
35) at steady
state was 6.0 ± 0.4 ml · min
1 · kg
1,
and the average urinary clearance was 0.430 ± 0.057 ml · min
1 · 1.73 m
2, equivalent to 0.46 ± 0.08% of GFR (Table 2). This value was significantly higher than
Clu/GFR (%) for gastrin-17
(P < 0.01).
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Unlike gastrin-17 and progastrin-(135), there was no rise in urinary
excretion of gastrin-17-Gly with increasing dose rates of the peptide,
although the plasma concentrations reached high levels during infusion.
After the start of the two first dose rates, a minor rise in the
urinary excretion rate of gastrin-17-Gly was followed by a gradual fall
(P < 0.05; Fig.
9). The average MCR at steady state was 8.6 ± 0.7 ml · kg
1 · min
1,
and the average urinary clearance was 0.016 ± 0.005 ml · min
1 · 1.73 m
2, equivalent to 0.02 ± 0.01% of GFR (Table 2) and significantly lower than
Clu/GFR (%) for gastrin-17 and
progastrin-(1
35) (P < 0.01). The
plasma concentration of carboxyamidated gastrins remained constant
during infusion of progastrin-(1
35) and gastrin-17-Gly, whereas
urinary excretion apart from an initial fall oscillated during the
study. Urinary excretions of gastrin-17-Gly and carboxyamidated gastrins were not correlated.
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Gel chromatography of plasma revealed major peaks in the elution
positions of progastrin-(135) and gastrin-17-Gly (Fig. 6). The
concentrations of the peptides in urine were too low for gel chromatography.
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DISCUSSION |
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The present results showed that urinary excretion of intact progastrin
products contributes only little to the metabolic clearance rate of
postprandially released and infused gastrin in humans. The low
concentration in urine was not due to analytical bias, since urine did
not influence immunoreactivity and measurement of the peptides. The
excretion of carboxyamidated gastrins and NH2-terminal
progastrin fragments increased postprandially as well as during
infusion of gastrin-17 and progastrin-(135). However, the ratio of
urinary clearance to GFR of carboxyamidated gastrins and
NH2-terminal progastrin fragments
differed significantly, with the
NH2-terminal progastrin fragments
being twice that of carboxyamidated gastrins during meal stimulation
and nearly six times higher for progastrin-(1
35) than for gastrin-17.
Urinary clearance of glycine-extended gastrins was significantly lower than the clearances of carboxyamidated gastrins and of
NH2-terminal progastrin fragments,
and urinary excretion decreased both postprandially and during infusion
of gastrin-17-Gly. Conversion of gastrin-17-Gly to the amidated form in
the nephron was unlikely, since the urinary excretion of amidated
gastrin was independent of the plasma concentration of gastrin-17-Gly.
Although the urinary excretion of intact peptides only constituted a
small fraction of the filtered amount, the results indicate that
urinary clearance of progastrin-derived peptides depends on their
molecular structure.
The MCR values of gastrin-17, gastrin-17-Gly, and progastrin-(135)
were as previously recorded in humans. Because neither renal plasma
flow nor arterial plasma concentration of gastrin was measured, renal
metabolism of gastrin can only roughly be estimated. With the
assumption of a renal plasma flow of 12 ml · kg
1 · min
1
and a fractional extraction of 0.4, total renal clearance of gastrin,
which includes metabolism and excretion, would be ~5 ml · kg
1 · min
1
or ~20% of the total body clearance. Plasma concentrations used in
pharmacokinetic calculations have to represent the concentration at the
metabolic inlet. Because the clearance of gastrointestinal peptides
also occurs in nonsplanchnic tissues such as extremities (23, 24,
30), the calculated MCR will be overrated if venous plasma from an arm
vein rather than arterial plasma is used. The same problem complies
with calculation of urinary clearance. Therefore, the estimated values
of MCR and urinary clearance of gastrin may be somewhat higher than
under ideal experimental conditions. Studies in pigs have revealed an
identical extraction ratio of gastrin-17 and gastrin-17-Gly in the
limbs (23). If extraction of gastrin also occurs in the human
extremities, it is anticipated that the bias in calculating MCR and
urinary clearance will be of the same magnitude for the two peptides.
Renal clearance of peptides is accomplished by glomerular filtration with subsequent absorption and degradation in the proximal tubules of the nephron (3, 6, 9, 16). Several membrane-bound peptidases have been isolated from the kidneys (10, 34). Thus filtered progastrin products would be either reabsorbed and metabolized in the tubules or degraded intraluminally by peptidases in the brush border of the tubular cells and then absorbed or excreted as degraded fragments in urine. Investigations of radiolabeled gastrin-17 suggest that at least part of the peptide is absorbed into tubular cells (18). Uptake of gastrin may be initiated by binding to nonspecific membrane sites at the brush border of the tubular cells or to specific receptors. Gastrin/cholecystokinin B receptor expression has been demonstrated in renal tissue (35). However, we have not been able to show receptor binding for either carboxyamidated or glycine-extended gastrin in renal tissue (unpublished data). Consequently, it is still unclear whether absorption of progastrin products is facilitated by specific receptors.
An earlier study found
NH2-terminal octa-, nona-, and
decapeptide fragments of gastrin-34 in postprandial human urine in
concentrations several hundred times that of carboxyamidated gastrin
(11). It was suggested that
NH2-terminal gastrin fragments
were less well absorbed in the tubules than COOH-terminal fragments. In addition, it has been assumed that fragments without biological activity extracted by the kidneys were mainly excreted in urine rather
than reabsorbed and metabolized in analogy with the inactive C-peptide
of proinsulin (25). Our results confirm that
NH2-terminal progastrin fragments
including progastrin-(135) are excreted in urine in larger amounts
than carboxyamidated gastrins, although the difference was less
pronounced than reported for small
NH2-terminal fragments of
gastrin-34. The difference in urinary clearance was hardly related to
bioactivity regarding acid secretion, since the inactive gastrin-17-Gly
displayed the lowest urinary clearance of the three peptides.
Urinary clearance has no meaning as an indicator of renal elimination
for substances metabolized by the kidney. However, a comparison of
urinary clearance with GFR provides a measure of the fraction excreted
relative to the amount filtered. Urinary clearance of gastrin-17,
gastrin-17-Gly, and progastrin-(135) comprised 0.08, 0.02, and
0.50%, respectively, of GFR, which indicates either a high degree of
tubular absorption or urinary excretion of degradation fragments that
are not measured by the assays used in this study. The glomerular
membrane functions both as a size-selective and as a charge-selective
barrier. Negatively charged macromolecules are restricted to a greater
extent than neutral or positively charged molecules of the same size
because of negative charges in the glomerular membrane (6, 7). For
proteins with a molecular mass less than 15 kDa, the charges of the
glomerular membrane have no appreciable effect on the glomerular
filtration, whereas the forces of diffusion increase with decreasing
molecular size. This has been shown with the anionic polypeptide
aprotinin (33) and is a result of the Gibbs-Donnan equilibrium between
plasma and the almost protein-free ultrafiltrate of Bowman's space,
which tends to restrict the filtration of cations but to enhance
filtration of anions over the glomerular membrane. The filtered load of
a substance equals GFR multiplied by the plasma concentration and the
fraction of the filtered substance in relation to glomerular plasma
(GFR × P × f). For small charged molecules, the filtration fraction f depends on binding to plasma proteins as well as the Donnan
ratio, rz, which is determined by
the net anion concentration from plasma proteins and the salt
concentration (22, 33). Under physiological conditions, this ratio is
~1.05. Because the small peptides gastrin-17 (2.1 kDa),
gastrin-17-Gly (2.2 kDa), and progastrin-(1
35) (3.9 kDa) carry a net
negative charge (z =
6,
7, and
1, respectively) and because they are not bound to
plasma proteins, the filtration fraction is equivalent to
the Donnan ratio. This is equivalent to 1.05 for progastrin-(1
35) and
can be estimated for gastrin-17 and gastrin-17-Gly to be 1.34 and 1.41, respectively. The calculations suggest that the filtration rate of
gastrin-17 and gastrin-17-Gly should exceed that of progastrin-(1
35)
with 28 and 34%, respectively, provided an identical GFR and plasma
concentration in the glomerular capillaries. Thus differences in
urinary clearance result from both glomerular as well as tubular
handling of the peptides. In spite of a high filtration fraction,
gastrin-17-Gly had the lowest urinary clearance of the three peptides.
This might be explained in part by the different COOH- and
NH2-terminal derivatization of the
peptides that may influence their handling in the renal tubules.
Gastrin-17 and gastrin-17-Gly are both protected against degradation
from aminopeptidases by the
NH2-terminal pyroglutamyl residue.
Gastrin-17 is also protected against degradation by carboxypeptidases due to the amidation of its COOH-terminal carboxyl group. This makes
gastrin-17-Gly more susceptible to COOH-terminal degradation into
fragments excreted either in urine or absorbed in the renal tubules,
fragments which we at present are unable to measure.
Contrary to earlier observations, we found no evidence of a renal
plasma threshold for progastrin products (27). However, a spillage was
constantly present, which correlated linearly with the concentration of
gastrin-17 and progastrin-(135) in plasma. Absorption and degradation
of peptides in the nephron are assumed to be controlled by saturable
processes. Consequently, below-saturation absorption increases
continuously with the filtered load, and after saturation, the
excretion parallels the rate of filtration of the substance (16). In
spite of supraphysiological plasma concentrations of the three
peptides, a Tm level for tubular
transport or degradation was not achieved.
We conclude that the urinary clearance of progastrin-derived peptides varies with their molecular structure under the influence of the glomerular filtration and the handling of the peptides in the renal tubules. Moreover, our results show that the capacity of tubular transport and metabolism is high and far from being saturated under normal physiological conditions. Bioactivity seemed to be without influence on the renal handling of the peptides.
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ACKNOWLEDGEMENTS |
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The expert technical assistance of Inge Mortensen, Winna Stavnstrup, and Lone Olsen is gratefully acknowledged.
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FOOTNOTES |
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This study was supported by grants from the Danish Hospital Foundation for Medical Research, Region of Copenhagen, the Faroe Islands, and Greenland, and the Danish Foundation for the Advancement of Medical Science.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. Palnaes Hansen, Dept. of Gastrointestinal Surgery C, Rigshospitalet, DK-2100 Copenhagen, Denmark.
Received 16 July 1998; accepted in final form 8 December 1998.
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