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,
*
Department of Vascular Medicine and Metabolism, University Medical Center
Utrecht, Utrecht, The Netherlands
Department of Clinical Chemistry, University Medical Center Utrecht,
Utrecht, The Netherlands
Department of Metabolic Diseases, University Medical Center Utrecht,
Utrecht, The Netherlands
Department of Medicine, Division of Nephrology, University of
California-Davis, Davis, and Department of Veterans Affairs Northern
California System of Clinics, Mather, California
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Department of Nutrition and Metabolism, University Hospital Groningen,
Groningen, The Netherlands.
Correspondence to Dr. Monique G. M. de Sain-van der Velden, University Medical Center Utrecht, Department of Metabolic Diseases, H.P. KC-02.069.1, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands. Phone: 31-30-2504294; Fax: 31-30-2504295; E-mail: M.G.deSain{at}lab.azu.nl
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Abstract |
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Introduction |
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Hypotransferrinemia in the nephrotic syndrome may induce low plasma iron concentrations that eventually result in microcytic anemia (15, 16), although the urinary loss of erythropoietin may also be significant as a cause of anemia in this patient population (17, 18). The pathophysiologic mechanism responsible for the decreased plasma transferrin concentration in the nephrotic syndrome is poorly understood. Transferrin synthesis may be modulated as a component of the acute-phase cascade (19) or as a consequence of iron deficiency (6). Furthermore, malnutrition causes downregulation of hepatic transferrin gene expression, resulting in decreased synthesis (20, 21). Inflammation, iron deficiency, and malnutrition are often found in the nephrotic syndrome (22). Jensen et al. (23), using 125I-labeling studies, measured transferrin kinetics in eight patients with the nephrotic syndrome. Both synthesis rate (extrapolated from this indirect measurement of transferrin turnover) and transferrin fractional catabolic rate were increased. This was confirmed by Kaysen et al. (22), who studied transferrin kinetics in rats with Heymann nephritis. However, these radioactive kinetic studies may not represent the physiologic situation, as the studied protein is isolated, labeled, and reinjected. Labeling of the protein may alter its conformation; thus, kinetic studies that use stable isotopes for the direct evaluation of endogenously synthesized protein have an advantage over studies that use exogenous tracers.
The present study was undertaken to determine directly whether transferrin synthesis was increased in the nephrotic syndrome using endogenous labeling with 13C-valine. We further aimed to determine potential mechanisms that lead to the hypotransferrinemia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Control studies were done in six healthy subjects (four males, two females) who were on a similar diet as the nephrotic syndrome patients. One d before the infusion protocol the subjects collected a 24 h urine sample that was analyzed for urea, creatinine, protein, transferrin, iron and albumin. All patients and volunteers agreed to participate after signing an informed consent form, in accordance with the Helsinki Declaration of Human Rights. The Institutional Ethical Committee for studies in humans approved this study.
Materials
L-[1-13C]-valine (isotope mole fraction > 0.99; Mass Trace,
Woburn, MA) was dissolved in sterile 0.9% saline and sterilized through a
0.22-µm filter. Cyanogen bromide (CNBr)-Sepharose 4B was from Pharmacia
(Uppsala, Sweden). Human antitransferrin antibody was from Dade Behring
(Marburg, Germany). O-phenylenediamine (OPDA) was from Sigma (St. Louis, MO).
N-methyl-N-(tertiair-butyldimethylsilyl)trifluoroacetamide (MTBSTFA) and
pyridine were from Pierce (Rockford, IL). All other chemicals were obtained
from Riedel de Haën (Seelze, Germany).
Infusion Protocol
The subjects came to the research unit in the morning after a 12-h fast.
Two intravenous cannulas were placed for blood sampling and infusion of the
labeled valine. No food was given during the tracer infusion, and the subjects
were allowed only to drink water.
At baseline (t = 0), a priming dose of 15 µmol/kg L-[1-13C]-valine was administered intravenously in 2 min, followed by a continuous infusion of 15 µmol/kg per h L-[1-13C]-valine during 6 h. Blood samples were taken in heparin-containing and ethylenediamine-tetraacetate-containing tubes from the contralateral arm at t = 0, 15, 30, 60, 120, 180, 240, 270, 300, 330, and 360 min. Samples were kept on ice until plasma was separated by centrifugation (20 min, 2000 x g, 4°C).
Preinfusion Measurements
Preinfusion plasma and urinary concentrations of transferrin were measured
using a routine nephelometric assay (Dade Behring). Urinary iron was measured
using the Keberle method
(24).
Plasma albumin, total protein, and iron were measured with standard laboratory methods on a Vitros 950 (Johnson & Johnson, Clinical Diagnostics, Rochester, NY). Soluble transferrin receptor was measured using an Immunometric assay (Orion Diagnostica, Espoo, Finland). C-reactive protein (CRP) was measured using an enzymelinked immunosorbent assay (Detectionlimit 0.2 µg/ml; Hemagen Diagnostics, Waltham, MA). Urinary urea, urinary creatinine, protein-uria, and albuminuria were measured with standard laboratory methods on a Hitachi 911 (Boehringer, Mannheim, Germany). The colloid osmotic pressure (COP) was measured using a 4400 colloid osmometer (Wescor Inc., Logan, UT).
Isolation and Purification of Transferrin from Plasma
From each sampling point, transferrin was purified by affinity
chromatography according to van Eijk et al.
(25) with some slight
modifications. One ml of human antitransferrin antibody was coupled to 7 ml of
CNBr-activated Sepharose 4B. Sepharose 4B activation was prepared according to
the instructions manual. In short, 2 g of CNBr-activated Sepharose 4B was
suspended in 15 ml of 1 mM ice-cold HCl. After centrifugation (10 min, 1750
x g, 4°C), which was repeated each wash step, the gel was
washed four times with 1 mM HCl and subsequently washed twice with 0.1 M
Borate buffer (pH 8.5) containing 0.5 M NaCl (coupling buffer). After the
supernatant was removed, 1 ml of human antitransferrin antibody was diluted 15
times in coupling buffer and added to the activated gel before an overnight
incubation. The remaining active groups were blocked with 0.2 M glycine (pH
8.0) for 1 h at room temperature, followed by a washout procedure. The
uncoupled human antitransferrin was washed out three times alternately with a
high-pH buffer (0.1 M Borate buffer [pH 8.5] containing 1.0 M NaCl) and a
low-pH buffer (0.1 M acetate buffer [pH 4.0] containing 1.0 M NaCl). Finally,
the high- and low-wash buffers were washed out twice with 0.1 M Borate buffer
(pH 8.5) containing 0.5 M NaCl. The gel was stored for a maximum of 4 wk at
4°C.
Ethylenediaminetetraacetate plasma containing approximately 400 µg of transferrin was diluted twice with 0.2 M Na2HPO4 containing 1.0 M NaCl. The diluted plasma sample was applied to a column containing 2 ml of gel suspension. Unbound substances were washed away with 30 ml of 0.1 M phosphate-citrate buffer (pH 8.5) containing 0.5 M NaCl. The sample was eluted in 7 ml of phosphate-citrate buffer (pH 2.8) containing 0.5 M NaCl and dried under N2 at 45°C, followed by hydrolysis in 6 M HCl at 110°C for 24 h (26). The released amino acids were purified by cation exchange chromatography (AG-50W-X8; Bio-Rad Laboratories, Hercules, CA) and dried under N2 at 50°C. Derivatization was done according to the method of Husek (27).
Isolation and Purification of Albumin
Albumin was isolated according to the method of Korner and Debro
(28). In short, 0.5 ml of
heparin plasma was deproteinized with 0.5 ml 20% trichloric acid. After
centrifugation (10 min, 1750 x g, room temperature), the pellet
was dissolved in 3 ml of ethanol, after which an aliquot of the supernatant
was used to monitor protein purity and identification using a 4 to 15%
gradient sodium dodecyl sulfatephastgel. To remove free amino acids, a second
aliquot of the ethanolic protein solution, containing 500 µg of protein,
was evaporated under N2 at 45°C. The dried residue was
redissolved in 1 ml of 0.3 M NaOH at 37°C for 30 min and cooled to room
temperature. After a 5-min ice-incubation step, albumin was reprecipitated
with 1 ml of 2 M HClO4 at 4°C and, subsequently, twice with 1
ml of 0.2 M HClO4 at 4°C before hydrolysis, cation exchange,
and derivatization as described above.
Conversion of Valine into 
-Keto-Isovaleric Acid
A standard curve (between 0 and 20% enrichment), prepared by enzymatic
conversion of L-[1-13C]-valine into -keto-isovaleric acid
(-KIV), was used. To each standard (100 µg), 500 µl of
Tris-buffer (1.0 M [pH 7.7]) and 50 µl of L-amino acid oxidase (6 mg/ml in
Tris buffer, freshly prepared) were added. The standards were incubated for 90
min at 37°C. After incubation, 450 µl of H2O was added and
the standards were derivatized with 1 ml of OPDA (20 mg/ml in 4 M HCl, freshly
prepared) for 1 h at 90°C, cooled to room temperature in the dark, and
extracted twice with 2 ml of ethylacetate. The ethylacetate phase was
dehydrated with Na2SO4, transferred to new tubes, and
dried under N2 at 40°C. Next, 100 µl of CHCl3 was
added and dried under N2 at 40°C. Finally, the samples were
derivatized with 50 µl of MTBSTFA:pyridine (3:1) for 15 min at room
temperature.
Isolation of -KIV from Plasma
-KIV was isolated from plasma according to the method of
Rocchicciolo et al.
(29) with some slight
modifications. In short, 4 ml of absolute ethanol was added to 500 µl of
plasma. After centrifugation (20 min, 1750 x g, 4°C), the
supernatant was removed and dried under N2 at 50°C. One ml of
H2O was added, and the samples were derivatized with 1 ml of OPDA
for 1 h at 90°C, cooled to room temperature, extracted twice with
ethylacetate, and dried. Next, 100 µl of CHCl3 was added and the
samples were dried again followed by derivatization with MTBSTFA:pyridine
(3:1) as described above.
Measurement of Stable Isotope Enrichment
The O-t-butyldimethylsilyl-quinoxalinol derivatives of KIV were prepared,
based on the procedure of Rocchicciolo et al.
(29). Positive chemical
ionization was used to measure the ions at m/z 245/246 for plasma
[1-13C]-KIV enrichment using electron impact. KIV enrichment was
measured by gas chromatography mass spectrometry (GC-MS) on a Hewlett-Packard
HP 5890 type II gas chromatograph (Palo Alto, CA) interfaced to an HP 5989B
mass spectrometer. The gas chromatograph was equipped with a coating CP Sil
19CB capillary column (Chrompack, Bergen op Zoom, The Netherlands). The
injection (2 µl) was performed in the split mode (1:20). The flow rate of
the carrier gas (helium) was 1 ml/min. The injector temperature was 240°C,
and the oven temperature was programmed starting at 210°C for 1 min, then
increased from 210°C to 280°C at 25°C/min and held at 280°C
for 3 min. The KIV eluted at 2.6 min. Samples were measured in the selected
ion monitoring (SIM) mode. The source and the quadrupole temperature were
250°C and 150°C, respectively.
Amino acids isolated from hydrolysates of transferrin and albumin (m/z 44/45) were analyzed as their N(O,S)-methoxycarbonyl methyl ester derivative by gas chromatography combustion isotope ratio mass spectrometry (GC/C/IRMS) on a Varian 3400 gas chromatograph, equipped with a CuO combustion oven and interfaced to a DELTA S isotope ratio mass spectrometer (Finningan-MAT, Bremen, Germany) as described by Reijngoud et al. (30). The GC/MS measurements were performed in duplicate, whereas the GC/C/IRMS measurements were performed only once.
Model and Calculations
Transferrin and albumin fractional synthesis rate (FSR; expressed as %/d)
were calculated using a linear regression model. The following standard
equation was used:
 | (1) |
PEt6 — PEt3 is the increase in enrichment of transferrin-bound [1-13C]-valine over the time period 3 to 6 h (t6 — t3) of the infusion, and Epl is the steady-state plasma tracer/tracee ratio (%) of KIV. In this calculation, the plateau enrichment of KIV in plasma is assumed to represent the enrichment of the intrahepatic valine pool from which transferrin is synthesized.
To determine kinetics of several proteins, a mono-exponential can also be
used, as described below:
 | (2) |
A(t) is the tracer/tracee ratio (%) of valine at time t (in hours), Ap is the steady-state plasma tracer/tracee ratio (%) of KIV, d is the delay time, and k represents the FSR of the protein. Calculations were done using GraphPad Prism 2.0 software (San Diego, CA).
Comparison of both equations used for calculating protein kinetics, showed an unreliable equation for transferrin kinetics (y = 0.67x + 4.17) in contrast to albumin kinetics (y = 1.03x + 17.3). The lack of a mono-exponential model for studying transferrin kinetics is probably due to the enormous delay (±3 h) or to a too low enrichment of L-[1-13C]-valine in transferrin in the first 3 h of the study protocol. Therefore, we used equation 1 to determine kinetics of both proteins.
The absolute synthesis rate (ASR), which is the amount of protein synthesized per day, was calculated as the product of the FSR and the plasma pool (plasma volume x plasma concentration). Plasma volume was determined using Evans blue as described previously (31). To adjust for different body weights, these quantities are expressed per kilogram of body weight.
Statistical Analyses
Data are expressed as mean ± SEM. The significance of differences
was assessed by t test. If normality test or equal variance test
failed, a Mann-Whitney rank sum test was performed. Correlations were
performed by linear regression analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Proteinuria, albuminuria, transferrinuria, and urinary iron loss in nephrotic patients are shown in Table 3. Mean proteinuria in the nephrotic patients is 12.0 ± 2.3 g/d (range, 6.1 to 23.2 g/d). The loss of albumin and transferrin is significantly different between nephrotic patients and control subjects (albumin, 110.7 ± 16.4 mg/kg per d, P < 0.001; transferrin, 9.7 ± 1.6 mg/kg per d, P < 0.001). Urinary iron concentration is significantly higher in the patient group (4 ± 1 versus 1 ± 0 µmol/L, P < 0.001). A strong correlation is observed between the loss of albumin and transferrin in urine both expressed in g/d (r2 = 0.901, P = 0.001; Figure 1) and both expressed in g/L (r2 = 0.809, P = 0.006). Furthermore, strong correlations are found between proteinuria and transferrinuria (r2 = 0.887, P = 0.002) and between transferrinuria and urinary iron (r2 = 0.761, P = 0.01) in nephrotic patients. Creatinine clearance (86 ± 7 versus 125 ± 8 ml/min per m2, P < 0.001) is significantly decreased in the nephrotic patients. No significant difference is found for urinary urea in both groups (289 ± 37 versus 364 ± 40 mmol/d; Table 3).
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Isolation of Transferrin from Plasma
Figure 2 shows the elution
pattern of the isolated transferrin. The purity of eluted transferrin peak is
checked by a 7.5% homogeneous sodium dodecyl sulfate phastgel (Pharmacia,
Uppsala, Sweden) (Figure 3).
Different fractions in the elution peak (lanes 3 to 6) show one band at
approximately 80 kD and run at the same size as commercially available
transferrin (lane 7). In addition, no contamination with albumin is found in
lanes 3 to 6. The transferrin fractions
(21,22,23,24)
were pooled, hydrolyzed, and derivatized as described in the Materials and
Methods section.
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Synthesis Rate of Transferrin in Nephrotic Patients and in Control
Subjects
Transferrin kinetics in nephrotic patients and control subjects are shown
in Table 4. The ASR of
transferrin in the patient group tends to be higher compared with control
subjects (10.0 ± 1.1 versus 7.4 ± 0.7 mg/kg per d;
Figure 4), although statistical
significance is not reached (P = 0.07). FSR of transferrin is,
however, significantly higher in the patients compared with control subjects
(17.3 ± 1.4 versus 7.4 ± 0.6%/d, P <
0.0001). The wide variation in both groups, however, is striking. Two patients
(5 and 7) have lower ASR values (7.1 and 6.2 mg/kg per d, respectively)
compared with the mean value in the control group. Both patients also have the
lowest FSR (12.7 and 14.6%/d), although these FSR values are twice as high as
those in control subjects. The same two patients also have the lowest
creatinine clearance (67 and 62 ml/min per m2). Furthermore,
patient 7 has the highest CRP value and patient 5 has the third highest CRP
value. With the exclusion of these two patients from the group (n =
5), the difference in ASR between the nephrotic patients and control subjects
was highly significant (P = 0.007).
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Synthesis Rate of Albumin in Nephrotic Patients and in Control
Subjects
Albumin kinetics in nephrotic patients and control subjects are shown in
Table 4. The ASR of albumin in
the patient group is significantly higher compared with control subjects
(240.3 ± 26.3 versus 105.3 ± 12.2 mg/kg per d,
P = 0.0012). Furthermore, FSR of albumin is also significantly higher
in the patients compared with control subjects (25.7 ± 1.8
versus 7.2 ± 1.0%/d, P < 0.0001).
Correlations
Considering the data in control subjects and patients together, several
parameters are tested. Transferrin synthesis rates do not correlate with
plasma transferrin (r2 = 0.183, n = 13), plasma albumin
(r2 = 0.241, n = 13), or COP (r2 = 0.243,
n = 13). Within the patient group (n = 7), the transferrin
synthesis rate did not significantly correlate with plasma iron (r2
= 0.116), plasma CRP (r2 = 0.136), transferrinuria (r2 =
0.047), urinary iron (r2 = 0.001), and proteinuria (r2 =
0.074). Exclusion of patients 5 and 7 also reveals no significant correlation
between ASR of transferrin and CRP (r2 = 0.128, n = 5).
Furthermore, in the patient group (n = 7), no correlation was found
between albumin synthesis rate and CRP (r2 = 0.005). There was a
positive correlation between the synthesis rate for transferrin and albumin in
the patient group (r2 = 0.648, P = 0.03, n = 7)
and in the whole group (r2 = 0.631, P = 0.0012, n
= 13).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, using stable isotopes, we showed that transferrin synthesis in nephrotic patients tended to be increased. Transferrin synthesis was increased 1.3-fold compared with control subjects, although statistical significance was not reached (10.0 ± 1.1 versus 7.4 ± 0.7 mg/kg per d, P = 0.07). The failure to reach statistical significance may be due to the wide variation in transferrin synthesis rate in both groups (Figure 4) and the low number of participants in both groups. In the present study, patients and control subjects were not matched for age. Although there is no strong effect of age on plasma transferrin concentration (12,13), no data are available on its effect of age on transferrin synthesis directly. The wide variation in transferrin synthesis rate within our control subjects (range, 5.0 to 9.0 mg/kg per d) was also reported by others (22,23,33,34,35). Two patients (5 and 7) had lower ASR values of transferrin (7.1 and 6.2 mg/kg per d) compared with the mean value in the control group and also had two of the lowest three albumin synthesis rates (169.7 and 187.6 mg/kg per d). The same two patients also had two of the highest three CRP values. Furthermore, both patients also had the lowest creatinine index (an index for muscle mass; 0.79 and 0.88, respectively). The reduction in muscle mass indicates that both patients are not well nourished. Because inflammation and malnutrition affect transferrin synthesis (20,36), this might suggest that the failure of these two patients to increase transferrin synthesis to a greater extent might have been a reflection of an underlying inflammatory event or that malnutrition prevents this response. Exclusion of both patients from the group (n = 5) revealed a significant difference in transferrin synthesis rate between the nephrotic patients and control subjects (P = 0.007). The increase in transferrin synthesis rate in five of seven nephrotic patients is not sufficient to compensate the low plasma transferrin concentrations as shown in this study (1.48 ± 0.08 versus 2.57 ± 0.11 g/L, P < 0.0001). In general, this seems to be what is observed with regard to other liver-derived proteins that are lost into the urine in the nephrotic syndrome. Although albumin synthesis rate is increased, it clearly does not increase plasma albumin levels to normal (31).
For therapeutic reasons, the mechanisms of hypotransferrinemia and the insufficient compensation by synthesis are of relevance. Transferrin is regulated by several control mechanisms. Iron depletion, proteinuria, inflammation, and malnutrition reduce plasma transferrin concentrations. The stimulus for increased transferrin synthesis in the nephrotic syndrome and its regulation are not known.
Our data suggest that iron depletion is not a main stimulus for transferrin synthesis in the nephrotic patients, as no significant correlation was found between plasma iron concentration and transferrin synthesis rate in nephrotic patients (r2 = 0.116, n = 7). This is in accordance with the animal studies of Kaysen et al. (22), who described that both transferrin mRNA and transferrin gene transcription were increased in Heymann nephritis and Nagase analbuminemic rats (NAR) and were unaffected by the administration of iron. This suggests that in the nephrotic syndrome, a process other than iron depletion stimulates transferrin synthesis.
There was also no correlation between proteinuria and transferrin synthesis (r2 = 0.074, n = 7) or transferrinuria and transferrin synthesis (r2 = 0.047, n = 7). This suggests that loss of transferrin in urine is not directly responsible for increased transferrin synthesis in our nephrotic patients, which is in agreement with studies in Heymann nephritis and in NAR (22).
Alternatively, inflammation could play a role in transferrin metabolism, because transferrin synthesis is suppressed as a component of the acute-phase cascade (36). Because no significant relationship has been found between transferrin synthesis and CRP (r2 = 0.136) or between albumin synthesis and CRP (r2 = 0.005), it is unlikely that inflammation suppresses increased transferrin synthesis for the group as a whole, but it is possible that inflammation and/or malnutrition did significantly suppress the otherwise inadequate synthesis response in the two patients in whom there was overlap with the control group.
Finally, malnutrition could affect transferrin synthesis in nephrotic patients. We recently showed that both nephrotic patients and control subjects exhibited an identical relationship between valine oxidation and urea appearance (37), suggesting that this relationship is unaffected by external loss of protein. This implies that nephrotic patients are able to invoke a normal dietary adaptive response to a low-protein diet, e.g., reducing valine oxidation, and patients therefore are not at an increased risk for malnutrition (38). Moreover, malnutrition is associated with a low transferrin synthesis (20), whereas transferrin synthesis in the present study is increased for the nephrotic group as a whole.
We further tested the hypothesis that transferrin synthesis was related to albumin synthesis, because it was suggested that a group of hepatic proteins are upregulated coordinately in the nephrotic syndrome (1,39). Previously, we described a proportionate increase of albumin and fibrinogen synthesis (31), and we tested whether this is also true for albumin and transferrin. A correlation was found between the synthesis rates of both proteins (r2 = 0.648, P = 0.03, n = 7), suggesting that regulation of synthesis of both proteins is interrelated. Other groups (22,23) also observed a strong correlation for transferrin synthesis and albumin synthesis.
In hereditary analbuminemic rats (NAR), transferrin mass was increased entirely as a consequence of increased synthesis (22), suggesting that a low COP could be a stimulus for increased synthesis. In our group, no significant correlation was found between transferrin synthesis rate and COP (r2 = 0.243, n = 13), in contrast to albumin synthesis rate and COP (31).
The therapeutic approach to maximizing plasma transferrin concentrations in nephrotic patients should be aimed primarily at reducing urinary protein excretion rather than at treatment with anti-inflammatory agents, iron supplementation, or a high-protein diet. In addition, urinary loss of iron should not be ignored. In the present study, urinary iron correlated with urinary transferrin levels (r2 = 0.761, P = 0.01), which is in accordance with the study by Howard et al. (32). At a pH of approximately 6, iron dissociates from transferrin, and depending on the state in which iron exists, it catalyzes the Haber-Weiss reaction with the formation of hydroxyl radicals (40,41). These radicals are toxic to virtually all biologic membranes and could play a role in the pathogenesis of the tubulointerstitial disease present in the nephrotic syndrome. Thus replacement of iron lost into the urine may not be risk free and should not be undertaken without clear evidence of iron deficiency.
In conclusion, transferrin synthesis is increased in the nephrotic syndrome, although less so than albumin, and this response does not compensate the low plasma transferrin concentrations. Transferrin synthesis correlates with albumin synthesis, indicating that several proteins synthesized in the liver are upregulated simultaneously in the nephrotic syndrome.
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Acknowledgments |
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