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Plasma Α2 Macroglobulin Is Increased in Nephrotic Patients As a Result Of

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Plasma Α2 Macroglobulin Is Increased in Nephrotic Patients As a Result Of View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 54 (1998), pp. 530–535 a Plasma 2 macroglobulin is increased in nephrotic patients as a result of increased synthesis alone MONIQUE G.M. DE SAIN-VAN DER VELDEN,TON J. RABELINK,DIRK-JAN REIJNGOUD, MIREILLE M. GADELLAA,HIERONYMUS A.M. VOORBIJ,FRANS STELLAARD, and GEORGE A. KAYSEN Departments of Nephrology and Hypertension, and Clinical Chemistry, University Hospital Utrecht, Utrecht, Laboratory of Nutrition and Metabolism, and Laboratory of Metabolic Disorders, University Hospital Groningen, Groningen, The Netherlands; Department of Medicine, Division of Nephrology, University of California Davis, Davis, and Department of Veterans Affairs, Northern California System of Clinics, Pleasant Hill, California, USA a a a Plasma 2 macroglobulin is increased in nephrotic patients as a Plasma 2 macroglobulin ( 2M), which accounts for 3 to result of increased synthesis alone. 5% of the total proteins, is mainly synthesized in the liver Background. a a 2 Macroglobulin ( 2M), a protease inhibitor, is [1], while small amounts of this protein are synthesized by often increased in plasma of patients with the nephrotic syn- a drome. Although it has been speculated that synthesis is in- microglia as well [2]. 2M is a proteinase inhibitor [3], and creased, no direct measurements have been performed. binds numerous growth factors, cytokines and hormones a 5 Methods. 2M synthesis in both normal subjects (N 4) and [4]. The concentration in plasma is normally about 2 g/liter nephrotic patients (N 5 7) were measured using endogenous and usually remains quite constant throughout life, al- 13 labeling with C valine in order to establish the mechanism of though levels gradually decline until adult age [5]. While increased plasma level in the nephrotic syndrome and the rela- a inherited deficiency has been reported [6, 7], a total tionship between 2M synthesis rate and plasma concentration a over a wide range of plasma concentration values. A primed (15 absence of 2M may not be compatible with life. a mmol/kg)/continuous (15 mmol/kg/hr) infusion was administered Increased levels of 2M are well described in patients for six hours. Blood samples were collected at different intervals with the nephrotic syndrome regardless of the primary a and at each time point 2M was isolated from EDTA plasma disease [8–10], and may contribute to complications in the using immunoprecipitation and SDS-polyacrylamide gel electro- a nephrotic syndrome like increased plasma viscosity [11] and phoresis (PAGE). Care was taken to ensure that the 2M used for combustion had not been subjected to proteolysis. The rate of decreased availability of zinc [12, 13]. On the other hand, 13 a appearance of C valine derived from the isolated a M was 2M may act as a thrombin inhibitor [10, 14]. While an 2 a measured by gas chromatography combustion isotope ratio mass increase in synthesis of 2M in nephrotic rats has been spectrometry. previously established [15], the mechanism for the increase a Results. Plasma 2M was significantly elevated in nephrotic of a M plasma concentration in the nephrotic humans subjects (3.13 6 0.33 g/liter) versus controls (1.64 6 0.15 g/liter; 2 5 a remains to be elucidated. One study reported that a change P 0.012). The 2M fractional synthesis rate [(FSR), which is equal to fractional catabolic rate (FCR) in steady state] was the in plasma volume is responsible for the increased plasma a same in the two groups: 2.70 6 0.18%/day for the nephrotic levels of 2M in the nephrotic syndrome [16]. Since several 6 a patients versus controls 2.74 0.21%/day. However, the 2M other studies reported normal plasma volumes in the absolute synthesis rate (ASR) was significantly (P 5 0.012) a nephrotic syndrome [17, 18], accumulation of 2Min increased in the patients (3.69 6 0.33 mg/kg/day) versus controls 6 a plasma of the nephrotic syndrome must be a consequence (2.06 0.35 mg/kg/day). Plasma 2M concentration correlated directly to its ASR (r2 5 0.821; P 5 0.0001; N 5 11). of altered metabolism rather than a consequence of plasma Conclusions. Increased plasma a M concentration in nephrotic volume contraction. 2 a patients is therefore a result of increased synthesis alone. Once acted upon by a protease, 2M changes conforma- a tion and is cleared rapidly by the 2M receptor [19]. a Recently, it has been shown that the 2M receptor is a identical to the low density lipoprotein receptor mediated Key words: stable isotopes, 2 macroglobulin, nephrotic syndrome, gas chromatography combustion isotope ratio mass spectrometry, FCR, anal- protein (LRP) [20]. We have previously established that buminemia, protein, valine tRNA pool. increased very-low density lipoprotein (VLDL) is a conse- quence of decreased clearance in nephrotic patients [21]. Received for publication January 20, 1998 a and in revised form March 3, 1998 Numerous studies implied that LRP/ 2M receptor plays a Accepted for publication March 4, 1998 role in the metabolism of apo E containing lipoproteins like © 1998 by the International Society of Nephrology VLDL [22, 23]. If the decreased clearance of VLDL is a 530 a de Sain-van der Velden et al: Synthesis of 2MinNS 531 consequence of alteration in the LRP, this could also result agents and the electrophoretic apparatus (mini protean II) a in a reduced uptake of 2M. On the other hand, there could were from Bio-Rad (Hercules, CA, USA). be an increase in synthesis due to the increased hepatic response. The aim of the present study was to measure the Chemical measurements synthesis rate of a M in patients with the nephrotic syn- 2 Urea, creatinine, total protein and albumin were mea- drome and compare them with measurements in a control sured with standard laboratory methods on an Ektachem group using an endogenous labeling with [13C] valine. 950 (Johnson & Johnson, Clinical Diagnostics, NY, USA). METHODS Proteinuria and albuminuria were measured with standard laboratory methods on a Hitachi-911 (Boehringer, Mann- Subjects and protocol heim, Germany). The colloid osmotic pressure (COP) was Seven patients (six with a membranous glomerulonephri- measured using a 4400 colloid osmometer (Wescor Inc., a tis and one minimal change disease) were recruited from Logan, UT, USA). 2M was measured using a routine the clinic of nephrology and hypertension at the University nephelometric assay (Behringwerke AG, Marburg, Germa- Hospital Utrecht. Five were male. The mean age was 49 6 ny). three years. They received no medication except diuretics. Four healthy control subjects were also studied. Two were Isolation and purification of a macroglobulin from male and the mean age of the control group was 30 6 1 2 plasma year. The patients and volunteers agreed to participate after informed consent in accordance with the Helsinki a 2Macroglobulin was isolated from EDTA plasma by Declaration of Human Rights. The study was approved by immunoprecipitation and purified by sodium dodecyl sul- our Institutional Ethical Committee for Studies in Humans. fate-polyacrylamide gel electrophoresis according to a One day before the infusion study, the subjects collected method of Jahoor et al [24]. Briefly, varying amounts of 24-hour urine samples that were analyzed for protein and EDTA-plasma were incubated with 200 ml of antibody (6 albumin. mg/ml). This mixture was pipetted into a small tube and the The infusion protocol has been described in detail pre- volume was made up to 1.0 ml with a solution of 0.15 M viously [17] with some minor modifications. Briefly, a NaCl containing 0.5 mM thimerosal (BDH, Limited, Poole, primed (15 mmol/kg)/continuous (15 mmol/kg/hr) infusion 13 England, UK). This solution was vortexed and incubated of C valine was administered for six hours. Blood samples for one hour at 25°C and then for 48 hours at 4°C. After were drawn through a second intravenous catheter in the incubation, the tubes were centrifuged (5000 3 g, 20 min, contralateral arm into EDTA (10 cc) containing tubes at a room temperature) to precipitate the 2M antibody com- baseline and at t 5 4, 4.5, 5, 5.5 and 6 hours. Samples were a plex. After removing the supernatant, the 2M antibody kept on ice (maximum 1 hr) until plasma was separated by precipitates were washed three times with 1.0 ml of 0.15 M centrifugation (20 min, 3000 rpm, 4°C). The plasma was NaCl and dissolved in 35 ml of sample buffer (0.187 M Tris, 2 immediately stored at 80°C. Experiments were done in 0.104 M sodium dodecyl sulfate, 3.26 M glycerol, 0.85 M the fasted state and subjects were only allowed to drink mercaptoethanol, pH 6.8) containing 0.03% (wt/vol) bro- water during the tracer infusions. mophenol blue. The b-mercaptoethanol was added to the Twenty-two patients (including the seven who were sample buffer just prior to use. The mixture was heated for subjected to the infusion protocol) with the nephrotic five minutes at 100°C and then cooled. After centrifugation syndrome were screened for 24 hour proteinuria, plasma (5 min, 850 3 g), samples were loaded on a 4.5% SDS a albumin and plasma 2M concentration. Four were female polyacrylamide gel. Controls on each gel included a wide 6 and the mean age was 45 9 years (range 24 to 63 years). range protein standard (Novex, San Diego, CA, USA), an Histologically proven diagnoses were: membranous glo- a M standard and a reduced a M antibody. The gels were 5 5 2 2 merulopathy (N 11), minimal change disease (N 6), electrophoresed embedded in an ice bath in 25 mM Tris, 5 mesangial proliferative (N 1), membranoproliferative 192 mM glycine buffer (pH 8.3) containing 3.5 mM SDS at 5 5 glomerulonephritis (N 1), and focal sclerosis (N 3).
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