Determinants of circulating soluble transferrin receptor level in chronic haemodialysis patients
Der-Cherng Tarng and
Tung-Po Huang
Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Abstract
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Background. The aim of this study was to identify the factors determining the circulating soluble transferrin receptor (sTfR) concentrations in haemodialysis (HD) patients on maintenance recombinant human erythropoietin (rHuEpo) treatment.
Methods. In a prospective cross-sectional study, 91 chronic HD patients and 18 anaemic controls with normal renal function were recruited. For each subject, blood samples were measured for complete blood count, reticulocyte count, percentage of hypochromic red cells (% HRC), serum ferritin, serum iron, transferrin saturation (TS), serum erythropoietin (sEpo), C-reactive protein (CRP), and sTfR. HD patients received constant rHuEpo doses and basal sEpo was measured
86 h after the last injection. The age, gender, dialysis vintage, and the above-mentioned parameters were used as independent variables and logarithmic sTfR (log10sTfR) as a dependent variable in the forward stepwise multiple regression model.
Results. HD patients were similar to controls regarding haematocrit, serum ferritin, TS, and % HRC, but had significantly lower sTfR, sEpo, and reticulocyte index. Univariate analyses showed that the sTfR level strongly correlated with sEpo (r=0.60, P<0.001) and % HRC (r=0.60, P<0.001), and significantly with serum ferritin (r=-0.29, P<0.01), TS (r=-0.27, P<0.05), and dose of rHuEpo administered (r=0.27, P<0.05) in HD patients. sTfR also had a positive correlation with haematocrit (r=0.26, P<0.05), red blood cell (RBC) count (r=0.23, P<0.05), and reticulocyte count (r=0.24, P<0.05), but not with CRP (r=0.16, P>0.05). Multivariate regression analysis disclosed that sEpo, HRC, and serum ferritin were the independent predictors of sTfR level. Overall, the model explained 58.8% of the variability in sTfR (R2=0.588, P<0.001).
Conclusions. Circulating sTfR is a good index of marrow erythropoietic activity in HD patients during rHuEpo treatment. Its level is also independently up-regulated by functional iron deficiency in the process of enhanced erythropoiesis. Our study showed that sTfR levels quantitatively reflect the integrated effects of iron availability, iron reserves, and erythropoietic stimulation.
Keywords: haemodialysis; recombinant human erythropoietin; soluble transferrin receptor
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Introduction
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Anaemia is a common problem in patients with end-stage renal disease (ESRD) and is present in a vast majority of patients requiring maintenance dialysis therapy. Fortunately, renal anaemia has been shown to be effectively alleviated or reversed by recombinant human erythropoietin (rHuEpo) which speeds up erythropoiesis by as much as several folds [1]. To double the erythropoietic activity would require 2-fold iron demand. In such a state, iron turnover will be a function of iron stores and the erythropoietic activity of bone marrow. Therefore, the assessment of iron requirements and an adequate iron supply are a prerequisite to an optimal response to rHuEpo. A number of laboratory tests are employed to determine the iron status in patients receiving rHuEpo therapy; however, a valid method for the diagnosis of iron deficiency is still debatable [2]. Iron availability may not keep pace with iron demand for the rHuEpo-enhanced erythropoiesis, a situation known as functional iron deficiency. Current indices for assessing this issue include the transferrin saturation (TS), percentage of hypochromic red cells (% HRC), erythrocyte zinc protoporphyrin, and erythrocyte ferritin [2,3]. Nonetheless, it is still a challenge to judge iron-deficient erythropoiesis in individuals with normal or even increased iron stores.
Soluble transferrin receptor (sTfR) is derived primarily from erythroid progenitor cells in the bone marrow, and the increased erythropoiesis will elevate the circulating receptor levels [4]. In another aspect, circulating receptor levels rise in the iron-depleted status due to the post-transcriptional induction of TfR expression in the erythroid precursor cells [5]. Accordingly, sTfR has emerged as a reliable index for overall erythropoiesis or tissue iron deficiency. Measurement of sTfR is useful for the quantitative assessment of erythropoiesis in haemodialysis (HD) patients treated with rHuEpo [6]. Investigators further proposed the baseline sTfR as a predictor for a haemoglobin response when initiating rHuEpo therapy in patients receiving chronic HD [7]. It has been known that sTfR is a surrogate marker for detecting iron deficiency in healthy adults [8], term infants [9], and anaemic patients of rheumatoid arthritis [10]. However, data on the specificity of sTfR for detection of iron-deficient erythropoiesis were insufficient, even inconclusive and controversial in ESRD patients receiving rHuEpo therapy [7,11]. The rHuEpo-enhanced erythropoiesis, which itself raises serum receptor levels, may be a major confounding factor in evaluating the relationship between sTfR and iron deficiency. Therefore, it deserved reappraisal on the factors determining circulating TfR levels in chronic HD patients receiving rHuEpo therapy. We employed the iron metabolism parameters (e.g. serum ferritin and iron, TS and HRC) and erythropoiesis-stimulating factors (e.g. serum (s)Epo and dose of rHuEpo administered) in assessing the interrelations among the iron storage, iron availability, erythropoietic stimulation, and sTfR in the forward stepwise multiple regression model.
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Subjects and methods
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Patients
In a cross-sectional study, a cohort of 91 HD patients (50 men and 41 women, mean age of 57±13 years) were recruited from a pool of 142 ESRD patients undergoing maintenance HD at two dialysis centres of the affiliated hospital of National Yang-Ming University. Inclusion criteria were age over 20 years, duration of prior dialysis of more than 6 months, time on rHuEpo therapy over 6 months, and rHuEpo doses and haematocrit values stable for 3 months prior to enrolment. Patients were excluded if the following events occurred in the preceding 8 weeks: bleeding, haemolysis, acute liver diseases, infections, blood transfusions, oral or i.v. iron or ascorbic acid supplementation, and treatment with angiotensin-converting enzyme inhibitors. All patients were dialysed for 44.5 h thrice weekly, using a single-use dialyser with 1.5-m2 effective surface area of cellulose diacetate membrane, blood flow of 250350 ml/min, and dialysate flow of 500 ml/min. rHuEpo (Eprex, Cilag, Switzerland) was administered subcutaneously once or twice a week to maintain the stable haematocrit values in all patients. Eighteen adults (10 men and eight women, mean age of 56±13 years) served as controls with anaemia defined by haematocrit of <36% for men and <33% for women but normal renal function defined by creatinine clearance of >100 ml/min. Control subjects with reduced haematocrit caused by hypoplastic or dyserythropoietic anaemia (n=9) or haemolysis (n=9) made up the group with simple anaemia. They had not received red cell transfusions or iron supplements in the preceding 8 weeks.
Laboratory measurements
Blood samples were drawn from fasting controls or before the first dialysis session of the week in HD patients after an overnight fast (
86 h after the last dose of rHuEpo). Each sample was run in duplicate for all assays. Haemoglobin, haematocrit, red blood cell (RBC) count, and % HRC (red cell haemoglobin concentration <28 g/dl) were measured using the Technicon H*2 instrument (Bayer Diagnostics, Tarrytown, NY, USA). Reticulocyte was measured by an automated flow cytometry and a reticulocyte index was calculated using the formula: observed reticulocyte count (%)x(patient's haematocrit/45%). Serum iron was determined by an autoanalyser (Hitachi 73660, Naka, Japan) using a colorimetric method, total iron-binding capacity (TIBC) by a two-step saturation analysis using the TIBC Microtest (Daiichi, Tokyo, Japan), and serum ferritin by a radioimmunoassay (GammaDab®; DiaSorin, Stillwater, MN, USA). The percentage of TS was calculated by dividing serum iron concentration by TIBCx100. Serum C-reactive protein (CRP) was measured by an immunoturbidimetric assay using a rate nephrelometry (Beckman, Galway, Ireland). sEpo assay was performed by radioimmunoassay using a commercially available kit (Incstar, Stillwater, MN, USA). Serum sTfR concentrations were measured by an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, USA) according to the procedure recommended by the manufacturer. The central 95th percentile of the reference distribution of this sTfR assay is 7402390 mg/l in 225 healthy persons described by the manufacturer. The minimum detectable level was <42.3 mg/l (0.5 nmol/l). Intra-assay coefficient of variance (CV) of the assay for sTfR ranged from 6 to 9% and inter-assay CV ranged from 8 to 12%.
Statistical analysis
Statistical analysis was performed using the computer software Statistical Package of Social Science (SPSS 8.0, 1997; SPSS Inc., Chicago, IL, USA). Data are expressed as mean values±SD. Serum ferritin, sTfR, sEpo, and CRP values were reported as median with interquartile range, because the data were non-normally distributed and positively skewed. For comparison of two groups, Student's t-test was used for normally distributed variables and MannWhitney rank sum test for variables with non-normal distribution. Data of more than two groups were analysed using one-way ANOVA or KruskallWallis' test followed by multiple comparison for significance of difference. Pearson's
2 test was used for frequency measures. Univariate correlations were performed using Spearman rank test, because the distributions of serum ferritin, sTfR, sEpo, and CRP levels were log normal. A t-test was used to compare the slopes of the correlations between sTfR and % HRC or between sTfR and sEpo in HD patients stratified by less than 25, 2575 and greater than 75 percentiles of serum ferritin. To identify the independent predictors of sTfR level, we used a stepwise multiple regression analysis with log sTfR as the dependent variable. Independent variables included age, gender, dialysis vintage, serum ferritin, serum iron, TS, HRC, sEpo, CRP, dose of rHuEpo administered, haematocrit, RBC count, and reticulocyte count. Because multicollinearity among iron parameters would tend to reduce the efficiency of regression if they were simultaneously entered in the regression, sTfR was related to alternative sets of eleven variables in which only one the iron parameters (serum iron, TS, or HRC) was entered. Only the equations in which all coefficients differed from zero at the 5% level were retained.
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Results
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The average dialysis vintage was 52±51 months and mean maintenance dose of rHuEpo was 78±38 U/kg/week in 91 HD patients. The diagnoses of ESRD included glomerulonephritis (23%), interstitial nephritis (9%), hypertension (10%), diabetes (29%), lupus nephritis (9%), and shrunken kidney of unknown aetiology (20%). In comparison with anaemic controls, the two groups were similar with respect to age, sex distribution, as well as the mean values of haematocrit, haemoglobin, serum ferritin, serum iron, TS, and % HRC (Table 1
). Anaemia of HD patients was characterized by the defective production of Epo. Median values of sEpo and sTfR, and mean reticulocyte index were significantly lower in HD patients as compared with those in anaemic controls (Table 1
).
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Table 1. Erythropoietic and iron metabolism parameters in anaemic controls and HD patients, successively stratified by lower and upper quartiles of serum ferritin, HCR of 10% and TS of 20%
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Iron status and sTfR level
HD patients were successively stratified by less than 25, 2575, and greater than 75 percentiles of serum ferritin; by <10 and
10% of HRC; as well as by <20 and
20% of TS, respectively (Table 1
). Median serum ferritin values in less than 25, 2575, and greater than 75 percentiles were 48, 236, and 833 mg/l. The sTfR level in patients of lower quartile was significantly higher than those of upper quartile or 2575 percentiles. sEpo, haematocrit, reticulocyte index, and % HRC values were not significantly different among the three subgroups, except TS was lower in patients of lower quartile than those of upper quartile. sTfR value was significantly higher for patients of HRC >10% than for those of HRC
10%. In contrast, the sTfR level showed no significant difference between the two subgroups of patients of TS, <20 and
20%. There were also no differences in the values of haematocrit, reticulocyte index, serum ferritin, and % HRC between the two subgroups. Only the sEpo level was higher for patients of TS <20% than for those of TS
20%.
Inflammation and sTfR level
Serum CRP concentrations were significantly increased in HD patients as compared with anaemic controls (Table 1
). HD patients with higher serum ferritin (upper quartile) and higher % HRC (>10%) had increased CRP levels; however, circulating sTfR had no correlation with serum CRP (Table 2
). No significant difference was observed in circulating sTfR concentrations between HD patients with the CRP level either <10 or
10 mg/l (median sTfR values: 1330 vs 1480 mg/l, P>0.05).
Factors determining the sTfR level
Univariate analyses (Table 2
) showed that the sTfR level strongly correlated with % HRC (Figure 1A
, P<0.001) and sEpo (Figure 1E
, P<0.001), and significantly correlated with serum ferritin (P=0.005), TS (P=0.010), and rHuEpo dose (P=0.021) in HD patients. The positive correlations either with % HRC (Figure 1B
D
) or with sEpo (Figure 1F
H
) still existed in the three subgroups of less than 25, 2575, and greater than 75 percentiles of serum ferritin. Over the whole range of % HRC and sEpo examined, the slope of the relationship was significantly greater for patients of lower quartile than for patients of upper quartile of serum ferritin (Figure 1B
vs D or F vs H, P<0.05). Stepwise multiple regression analysis disclosed that sEpo, HRC, and serum ferritin were the three independent predictors of sTfR in HD patients. The most significant equation was: logsTfR=3.062+0.125xlogsEpo+0.004x%HRC-0.042xlogferritin (r=0.767, P<0.001). Stratifying the patients on the basis of serum ferritin of less than 25, 2575, and greater than 75 percentiles did not alter the significance of % HRC and sEpo in predicting sTfR. Figure 2
is a plot of the sTfR level predicted by the model against the actual sTfR level observed and the residuals are normally distributed in the model. Overall, sEpo, % HRC, and serum ferritin explained 58.8% of the variability in sTfR level of the HD patients (r=0.77, P<0.001). The relationship between sTfR and erythropoietic parameters further disclosed that the sTfR level correlated positively with haematocrit, RBC count, and reticulocyte count (Table 2
).

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Fig. 1. Correlations of sTfR with percentage of HCR and sEpo in HD patients. Total patients () were stratified into patients with serum ferritin of less than 25 percentile ( ), of 2575 percentile ( ), and of greater than 75 percentile ( ). Correlation coefficients were (A) r=0.60, P<0.001; (B) r=0.77, P<0.001; (C) r=0.49, P<0.005; (D) r=0.41, P<0.05; (E) r=0.60, P<0.001; (F) r=0.81, P<0.001; (G) r=0.37, P<0.05; and (H) r=0.65, P<0.005, respectively.
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Fig. 2. Predicted vs observed sTfR levels. Circulating sTfR levels are expressed as log sTfR. The predictor variables included in the model were sEpo, % HRC, and serum ferritin. Predicted log sTfR=3.062+0.125xlogsEpo+0.004x% HRC-0.042xlogferritin (r=0.767, P<0.001). Overall, the model explained 58.8% of the variability of the log10 of sTfR.
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Discussion
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Hughes et al. [12] proposed that sEpo returns to the baseline value 72 h after s.c. administration of rHuEpo (100 U/kg). In the study of Kampf et al. [13], there was no statistical difference between the pharmacokinetic variables after an initial s.c. rHuEpo dose and after long-term multiple s.c. doses. No accumulation of Epo in serum was found with two to three doses per week after a treatment period of 6 weeks. Besarab et al. [14] found that in patients with s.c. administration of rHuEpo, 40 U/kg twice weekly, sEpo almost completely returned to the baseline level 34 days after the last dose of rHuEpo. Based on the pharmacokinetic findings, sEpo values in the blood obtained
86 h after the last dose of rHuEpo should reflect the baseline or endogenous sEpo levels under our experimental conditions. Epo stimulates red cell production by inducing proliferation and differentiation of committed erythroid progenitor cells, as well as inhibiting their apoptosis in the bone marrow. Erythropoiesis thus depends on the proliferative capacity of erythroid progenitors and the stimulation by Epo. In the presence of a normal marrow stem cell reserve, erythropoiesis will theoretically increase in proportion to the degree of anaemia. However, it does not necessarily mean that this increase is sufficient to fully compensate for the anaemia. In particular, erythropoiesis can be inappropriately low for the degree of anaemia because of inadequate Epo production in ESRD patients. The depressed erythropoiesis, due to insufficient Epo stimulation in our HD patients, is supported by the significantly lower sEpo levels as compared with the anaemic controls (Table 1
) and the positive correlations between sTfR and endogenous sEpo (Figure 1E
H
).
Circulating sTfR is derived primarily from erythroid precursor cells, and its levels provide a reliable measure of total erythropoiesis. We demonstrated that sTfR not only positively correlates with rHuEpo dose but also with haematocrit, RBC, and reticulocyte counts in HD patients. Parts of our results are in line with the finding that increased erythropoiesis resulting from rHuEpo treatment will affect the serum receptor levels in ESRD patients [6]. From a clinical point of view, the baseline sTfR has been reported to be useful for predicting a haemoglobin response when initiating rHuEpo therapy in HD patients [7]. Ahluwalia et al. [7] further proposed that combined with automated reticulocyte counting, circulating sTfR is valuable for predicting a haemoglobin response when increasing the dose of rHuEpo.
Maintenance of cellular iron homeostasis is largely exerted post-transcriptionally by the interaction of RNA stemloop structures, termed iron-responsive elements (IREs), with specific cytoplasmic proteins, known as iron-regulatory protein (IRP). Conversion of IRP to its IRE-binding form occurs during cellular iron deprivation and during oxidative stress [5]. Under these conditions, IRPs bind with high affinity to IREs present within the 3'-untranslated region of TfR mRNA, thus stabilizing TfR mRNA via protection from digestion by an as yet undefined RNase. This results in enhancing TfR expression and cellular iron uptake. Using serial measurements in subjects with varying baseline iron reserves, Skikne et al. [8] have indicated that the circulating sTfR level closely reflects iron deficiency. An in vitro study showed that rHuEpo can up-regulate TfR expression on erythroid precursor cells through an IRP activation [15]. The regulation of IRP by rHuEpo is mediated indirectly through alteration of the availability of iron from the so-called regulatory iron pool that is thought to be responsible for IRP activity. Increased haeme formation after rHuEpo administration and thus a reduction of iron in the regulatory pool will cause a conformational change of IRP and an enhancement of its IRE-binding affinity, and consequently strengthen TfR expression. Intriguingly, circulating sTfR exhibited a strong association with serum ferritin (iron reserves), as well as % HRC and TS (iron availability) in our HD patients on maintenance rHuEpo. Our data are in agreement with the report of Tonbul et al. [11] who proposed sTfR as a reliable marker of iron deficiency during rHuEpo therapy. However, Ahluwalia et al. [7] failed to discriminate between the effects of rHuEpo and iron deficiency, making it difficult to assess the usefulness of sTfR as a marker of iron deficiency. In the absence of multivariate analysis to account for the confounding factors, such discrepancy may to some extent be misleading. In adjusting for the erythropoiesis-stimulating factors (e.g. sEpo and rHuEpo dose) and inflammatory index (e.g. CRP) in the stepwise multivariate regression model, % HRC and serum ferritin are still validated to be two independent determinants of sTfR levels in the present study.
A variety of methods are available for assessing body iron stores. The golden standard remains the assessment of the cytological grading of liver or bone marrow iron. Serum ferritin measurement is known as a non-invasive procedure and is of value as an indirect indicator of total body iron stores in healthy individuals and in HD patients. However, ferritin levels are affected by inflammation. CRP, serum amyloid-A and circulating cytokines are increased in ESRD patients [16]. Because of the acute-phase reactivity of ferritin, investigators proposed that many dialysis patients without stainable iron in their bone marrow have normal serum ferritin levels. The threshold serum ferritin level below which iron depletion or iron-deficient erythropoiesis is predictably present in a HD patient is probably higher than that seen in individuals with normal renal function. However, precisely where that threshold lies remains a subject of some debate [2]. Our findings suggest, however, that the relationship between serum ferritin and adequacy of iron for erythropoiesis is not continuous. Rather, the relationship between available iron and erythropoiesis differs between groups of patients according to the quartile of serum ferritin (Figure 1B
vs D
).
To assess iron-deficient erythropoiesis is a hard task in HD patients during rHuEpo treatment, especially in those with normal or even increased iron stores. TS is one of the markers for iron availability, and its value of <20% is suggestive of functional iron deficiency [17,18]. However, TS has wide fluctuations due to a diurnal variation in serum iron and transferrin affected by the nutritional status. This may lead to a lack of sensitivity and specificity for TS to assess the iron utilization during rHuEpo treatment and under diagnosis of iron deficiency in most HD patients when current guidelines are used [2,3]. Interest has been generated in the use of erythrocyte index, % HRC, made available by the flow cytometric haematological analyser Technicon H. This assay provides direct insight into bone marrow iron supply and utilization by measuring the haemoglobin concentration in an individual red cell. Pioneering studies have indicated that HRC >10% is the most accurate marker for iron-deficient erythropoiesis, and that HRC can be employed to predict response to i.v. iron in dialysis patients on rHuEpo therapy [3]. However, % HRC can be affected by inflammation [19] and its cut-off value for functional iron deficiency varies from 3.7 to 10% in different series [3,19]. Reasons of different study populations, a bias in simple size, presence or absence of inflammation, and different criteria for the diagnosis of iron deficiency may possibly account for the variance in HRC threshold values. For HRC being a time-averaged measurement of the degree of haemoglobinization in red cells, NKF-DOQI Clinical Practice Guidelines and European Best Practice Guidelines for the management of anaemia of chronic renal failure recommended that HRC is a surrogate guide to monitor the iron status in dialysis patients receiving rHuEpo treatment [17,18]. So far, fewer studies have compared sTfR with this erythrocyte index. Bovy et al. [19] stated that sTfR correlated well with % HRC. Parts of our data corroborate with their findings.
The limitation of our study is that in a cross-sectional study design, we cannot afford the diagnostic threshold of sTfR for detecting iron-deficient erythropoiesis. However, we focus on the factors determining the circulating sTfR level in HD patients on maintenance rHuEpo. Based on our findings and the previously published data, we conclude that rHuEpo not only promotes erythropoiesis but also affects cellular iron metabolism. The present study demonstrates that sTfR levels quantitatively reflect the integrated effects of iron availability (% HRC), iron reserves (serum ferritin), and erythropoietic stimulation (sEpo). In addition, subclinical inflammation is frequently encountered in HD patients [16]. Our study disclosed that inflammation could result in an elevation of serum ferritin and % HRC, which might bring their values for patients with true iron deficiency into the normal or even high ranges. Thus, identifying between functional iron deficiency and an inflammatory iron block is an important clinical issue. Potentially, sTfR in these special cases can distinguish between both forms because elevated sTfR levels are characteristic for iron deficiency regardless of whether there is an inflammation. Accordingly, we infer that circulating sTfR levels may be useful in monitoring iron status for HD patients if the doses of rHuEpo are maintained constantly in those patients, who are likely to be in steady-state erythropoietic stimulation. Some studies have indicated that the ratio of sTfR to ferritin using logarithmic transformation (TfRferritin index) is superior to sTfR alone for identification of patients with iron deficiency [20]. sTfR adjusted for serum ferritin values might be a feasible marker for detecting functional iron deficiency in dialysis patients. However, we need a prospective, longitudinal study of a large sample size to verify this thesis by comparing the different parameters of iron status and using the more appropriate diagnostic criteria of iron deficiency.
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Acknowledgments
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Part of this work was presented at the American Society of Nephrology 32nd Annual Meeting and Scientific Exposition, 1999. This study was supported by grants nos VTY 88-P1-07 and VGH 90-256 from the Research Program of National Yang-Ming University School of Medicine and Taipei Veterans General Hospital, Taiwan.
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Notes
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Correspondence and offprint requests to: Der-Cherng Tarng, MD, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. Email: dctarng{at}vghtpe.gov.tw 
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Received for publication: 16. 7.01
Accepted in revised form: 7. 1.02