sTfR & sTfR/logF INDEX IN ACKD
Soluble Serum Transferrin Receptor and Transferrin Receptor-Ferritin Index in Anemia of Chronic Kidney Disease Sandra Margetic, MS; Elizabeta Topic, PhD; Andrea Tesija-Kuna, MS; Ines Vukasovic, MS The authors are with the Clinical Institute of Chemistry, Sestre Milosrdnice University Hospital, Zagreb, Croatia.
Objective. The aim of this study was to assess the value of the soluble serum transferrin receptor (sTfR) and the transferrin receptor-ferritin index (sTfR/logF) as new markers of iron status in patients with anemia of chronic kidney disease (ACKD) both treated and not treated with recombinant human erythropoietin (rHuEPO) therapy. Materials and Methods. The study included 53 patients and 61 controls. The concentration of sTfR was determined by an immunoturbidimetric assay. Values for the sTfR/logF index were calculated as the ratio of sTfR to logarithm ferritin level. Results. The results showed iron-depleted patients had significantly higher median sTfR and sTfR/logF values (sTfR: 1.75 and 1.40 mg/L; sTfR/logF: 0.99 and 0.77) relative to those of iron-repleted patients (sTfR: 1.07 and 0.73 mg/L; sTfR/logF: 0.39 and 0.26) in ACKD patients—both those treated and those not treated with rHuEPO. Receiver operating characteristic analysis showed a higher diagnostic accuracy of the sTfR/logF index (area under curve [AUC] ¼ 0.970) versus sTfR concentration (AUC ¼ 0.890) in the assessment of the iron status of ACKD patients. The tested parameters showed no significant differences according to C-reactive protein concentration (p ¼ 0.108 and 0.147), in contrast to serum ferritin concentration (p ¼ 0.045). Conclusions: The study results showed the tested parameters to be reliable in the assessment of the iron status of patients with ACKD, with a higher discriminating power of the sTfR/logF index versus the sTfR. It is expected that combined measurements of ferritin and sTfR concentrations with sTfR/logF index calculation could improve diagnostic reliability for accurate evaluation of the iron status of patients with ACKD, particularly those with concomitant inflammatory or infective conditions.
A
nemia is a common complication of chronic kidney disease. It has multiple causes, but the main pathological process is hypoproliferative erythropoiesis resulting from insufficient erythropoietin (EPO) production by the kidneys, whereas iron deficiency is the most common cause of resistance to recombinant human erythropoietin (rHuEPO) therapy.1 Accurate assessment of the iron status of patients with anemia of chronic kidney disease (ACKD) is necessary to identify patients who have true iron deficiency as well as those with functional iron deficiency, which is a major factor limiting the efficacy of rHuEPO therapy.2–4
Because of the insufficient sensitivity and specificity of conventional hematologic and biochemical parameters in assessing the iron status of patients with ACKD, many attempts have been made to evaluate new diagnostic parameters of the iron status of patients with ACKD.5–7 The National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF/ DOQI) guidelines recommend serum ferritin concentration and percentage of transferrin saturation (Tfsat) as the preferred indirect measurements of iron status in patients with chronic kidney disease.8 Recently, soluble serum transferrin receptor (sTfR) was introduced as a promising new diagnostic tool of iron status.
Human transferrin receptor (TfR) is a transmembrane dimeric glycoprotein expressed on the surfaces of nearly all types of cells, in particular, rapidly proliferating cells and cells with special iron requirements, such as erythropoietic cells of bone marrow. Thus, the number of TfRs on a cell is tightly regulated by both the cell’s iron status and proliferative status. The physiological function of TfR is uptake of erythroid iron by receptor-mediated endocytosis.9 Clinical interest in TfR intensified with the identification of the soluble form of TfR in human serum and its relation to erythropoiesis and body iron status. Soluble transferrin receptor is a proteolytic product of the intact TfR and circulates in the blood
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DIALYSIS & TRANSPLANTATION 1
sTfR & sTfR/LOGF INDEX IN CKD ANEMIA as a monomeric fragment of the extracellular domain. Because TfR is predominantly expressed by erythroid progenitor cells, the main sources of sTfR are erythropoietic cells of the bone marrow including circulating reticulocytes. Serum concentration of sTfR is correlated directly with erythropoietic activity and inversely with the amount of iron available for erythropoiesis, providing a quantitative measure of functional iron status.10–12 More recently, a number of studies examined the clinical utility of sTfR in different types of anemia. The studies confirmed the clinical significance of sTfR in the diagnosis of iron deficiency anemia as well as in the differential diagnosis of iron deficiency anemia and anemia of chronic disease.13 –15 Some studies indicated more diagnostic efficacy of the transferrin receptor-ferritin index (sTfR/ logF) than of sTfR alone, as a parameter that combines into a ratio serum ferritin that reflects the storage iron compartment and sTfR as an indicator of functional iron compartment.15–17 Several studies of patients with ACKD also suggested the clinical efficiency of sTfR in evaluating the iron status of these patients.18 –19 The present study was performed to assess the value of sTfR and sTfR/ logF as new markers of iron status in patients with ACKD, both in those treated and in those not treated with rHuEPO. Materials and Methods Patients A total of 53 patients with ACKD were included in the study, and 61 apparently healthy volunteers served as the control group (CG). All patients had been under treatment at the Department of Nephrology and Dialysis, Sestre Milosrdnice University Hospital, Zagreb, Croatia. Healthy volunteers were recruited from the Centar Health Center in Zagreb, Croatia. Baseline demographic characteristics of both the control
Table I. Demographic characteristics of the study patients. Age (yr) Patient Group
Male
Female
n (%)
n (%)
Range
Median
controls (n ¼ 61)
25 (41%)
36 (59%)
18–63
41.5
ACKD patients (n ¼ 53)
30 (57%)
23 (4%3)
22–71
59.0
and patient groups are presented in Table I. The patient group included 21 patients with ACKD treated with rHuEPO therapy (2,000–4,000 IU/ week). All patients on rHuEPO therapy received intravenous iron supplements (800 mg/month). Patients not on rHuEPO therapy (n ¼ 32) received no iron supplement. All patients were on maintenance hemodialysis (median duration of dialysis ¼ 5.9 years; range, 2–12 years). A patient with a hemoglobin concentration below 130 g/L if male or 120 g/L if female was defined has having anemia, which was a criterion for exclusion from the study. None of the patients in the study had a history of hematologic disorders such as myelodysplastic or myeloproliferative syndrome, megaloblastic or hemolytic anemia, or of malignant disease that may have influenced the parameters evaluated. Informed consent for the investigation was obtained from all participants. The protocol of the study was approved by the Hospital Ethics Committee. Analytical Methods Blood samples were drawn before the first dialysis session of the week after an overnight fast. For patients receiving iron supplements, the time free from iron therapy before blood sampling was 3–6 days. Conventional hematologic parameters and biochemical markers of iron status were determined in all patients and control subjects. Blood samples were obtained using ethylenediamine taetraacetic acid as an anticoagulant for
2 DIALYSIS & TRANSPLANTATION AUGUST 2006
routine hematologic parameters. Serum samples were used for determination of biochemical markers of iron status and sTfR, EPO, and Creactive protein (CRP) concentrations. Complete blood count and reticulocyte count (Rtc) were determined on an automated blood counter (CellDyn3200CS; Abbott Diagnostics, Abbott Park, IL). Biochemical analyses were performed on an Olympus AU2700 autoanalyzer (Olympus Diagnostica GmbH, Lismeehan, O’Callaghan’s Mills, County Clare, Ireland). Serum ferritin was measured using a commercially available automated particle-enhanced immunoturbidimetric assay. Serum iron was measured using an automated photometric color test with 2,4,6tri(2-pyridyl)-5-triazine as a reagent. Unsaturated iron-binding capacity (UIBC) was measured using a photometric color test (nitroso-PSAP method). Total iron-binding capacity (TIBC) was calculated as the sum of the UIBC and the serum iron concentration. The proportion of Tfsat was calculated as the ratio of iron to TIBC level. Serum CRP was measured by an immunoturbidimetric assay using commercial antihuman CRP antibodies. Endogenous EPO concentration was determined in ACKD patients without rHuEPO therapy (n ¼ 32) by an enzyme-linked immunosorbent assay (ELISA, Quantikine IVD, R&D Systems Inc., Minneapolis, MN). The concentration of sTfR was determined by a commercially available particle-enhanced immunoturbidimetric assay (IdeA sTfR IT, Orion Corporation Orion Diagnostica,
sTfR & sTfR/LOGF INDEX IN CKD ANEMIA Espoo, Finland). The test is based on the detection of the immunoreaction between sTfR and sTfR-specific antibodies in a liquid phase. The amount of immunoprecipitate is proportional to the sTfR concentration in the sample. The reference range stated by the manufacturer is 0.9–2.3 mg/L, with a borderline value of 1.9 mg/L for irondeficient erythropoiesis. The sTfR/ logF index was calculated as the ratio of sTfR to the logarithm ferritin level. Statistical Analysis The control and patient populations are described by basic statistical parameters: mean, range (minimum and maximum), standard deviation (SD), and median. All sets of data
were tested for normality (Kolmogorov-Smirnov test). Data showing a normal distribution are described by mean SD, data not showing normal distribution is described as median and range. Differences between groups were tested using the parametric Student’s t-test when data were normally distributed and the nonparametric Mann-Whitney rank sum test when the data were not. A difference was considered statistically significant at p < 0.050. Receiver operating characteristic (ROC) analysis was performed for both sTfR and sTfR/logF. ROC curves were plotted, and AUC was calculated to assess the discriminating power of the sTfR and sTfR/logF
parameters in the evaluation of the iron status of patients with ACKD. To measure the strength of association between pairs of variables, we used the Spearman’s rank-order correlation test. The test results are expressed by the correlation coefficient (r) and level of significance (p). Results The results of the statistical analysis of the sTfR, sTfR/logF index, and conventional hematologic and biochemical parameters of the control group (A), the total ACKD group (B), and ACKD patient subgroups of those treated (B1) and not treated with rHuEPO therapy (B2) are shown in Table II. For the control group,
Table II. Values of sTfR, sTfR/logF index, and conventional hematologic and biochemical parameters in the control group and in patients with ACKD.
Controls
All Patients with ACKD
Patients with ACKD Treated with rHuEPO
Patients with ACKD Not Treated with rHuEPO
p value*
Parameter
(n ¼ 61)
(n ¼ 53)
(n ¼ 21)
(n ¼ 32)
sTfR (mg/L)
1.09 0.30
1.07 (0.27–3.31)
1.50 (0.54–3.31)
0.97 (0.27–3.24)
0.018
0.67 0.25
0.407 (0.09–2.13)
0.597 (0.88–1.89)
0.375 (0.09–2.13)
0.043
97.3 17.05
102.3 16.97
94.3 13.65
0.186
4.68 0.37
3.18 0.56
3.40 0.69
3.04 0.43
0.067
m 0.44 0.04
28.2 5.22
0.29 0.06
0.27 0.04
0.088
sTfR/logF index Hgb{ (g/L)
m 149 14.0 f 138 8.6
RBC (1012/L) {
Hct (L/L)
f 0.41 0.02 MCV (fL)
88.7 4.0
88.8 4.47
87.8 4.7
89.4 4.3
0.202
RDW (%)
11.5 (10.4–14.1)
13.7 1.56
13.8 1.6
13.6 1.5
0.569
43.2 (22–79.9)
26.8 (10.4–79.5)
32.6 (16.1–79.5)
27.5 (10.4–75.6)
0.173
357.7 (15.8–778.0)
339.3 (27.6–743.8)
395.2 (15.8–778.0)
0.144
9
Rtc (10 /L) ferritin{ (mg/L)
m 78.2 (30.5–314) f 38.6 (21.3–187)
iron (mmol/L)
18.1 4.9
11.2 (4.6–35.2)
10.6 (5.1–22.9)
11.8 (4.6–35.2)
0.497
Tfsat (%)
33.1 9.8
28.7 (7.7–56.9)
26.7 (11.1–56.0)
29.9 (7.7–56.9)
0.480
TIBC (mmol/L)
53.8 7.6
40.8 7.8
38.8 6.7
42.0 8.5
0.149
UIBC (mmol/L)
36.9 7.8
26.8 10.6
27.0 7.5
26.6 12.4
0.876
*Levels of significance between ACKD patients treated with rHuEPO and those not treated with rHuEPO. { Ferritin and hemoglobin concentrations and hematocrit were significantly different between male and female subjects only in the control group (CG). The remaining parameters tested were not statistically significantly different according to sex in either the control subjects or the patients with ACKD. f ¼ female, Hgb ¼ hemoglobin, m ¼ male, MCV ¼ mean corpuscular volume, RBC ¼ red blood cells, RDW ¼ red blood cell distribution width, Rtc ¼ reticulocytes, TIBC ¼ total iron binding, UIBC ¼ unsaturated iron binding capacity.
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DIALYSIS & TRANSPLANTATION 3
sTfR & sTfR/LOGF INDEX IN CKD ANEMIA
Figure 1. Patients with ACKD treated (n ¼ 21) and those not treated (n ¼ 32) with rHuEPO therapy according to iron status (as defined by the NKF-K/DOQI guidelines): iron-repleted groups (ferritin > 100 lg/L and Tfsat > 20%) and iron depleted groups (ferritin < 100 lg/L and/or Tfsat < 20%).
mean SD sTfR and sTfR/logF index values were 1.09 0.30 mg/L and 0.67 0.25, respectively, with measured ranges of 0.87–1.64 and 0.37– 1.47, respectively. The differences in the sTfR and sTfR/logF between patients treated and not treated with rHuEPO were statistically significant (p ¼ 0.018 for sTfR and p ¼ 0.043 for sTfR/logF index). The sTfR and sTfR/logF index were significantly higher in patients receiving rHuEPO therapy (median sTfR: 1.50 mg/L, median sTfR/logF: 0.597) than in those who did not receive rHuEPO therapy (median sTfR: 0.97 mg/L, median sTfR/logF: 0.375). In contrast, no statistically significant differences were found in all tested conventional hematologic and biochemical parameters between patients treated and patients not treated with rHuEPO (p > 0.05). Both ACKD patient groups, those treated and not treated with rHuEPO, were divided into iron repleted groups (ferritin > 100mg/L and Tfsat > 20%) and iron depleted groups (ferritin < 100 mg/L and/or Tfsat < 20%) according to the NKF-K/DOQI guidelines. A total of 36 (67.9%) patients (14 on rHuEPO therapy and 22 without rHuEPO therapy) had adequate iron stores according to the K/DOQI guidelines. The remaining 17 (32.1%) patients (7 on rHuEPO ther-
apy and 10 without rHuEPO) had inadequate Tfsat and/or ferritin levels (Figure 1). Statistically significant differences in sTfR and sTfR/logF values between those who were iron repleted and those who were iron depleted according to the K/DOQI guidelines were found among both patients on rHuEPO therapy and patients not receiving rHuEPO therapy (p ¼ 0.044 and p < 0.001 for sTfR; p ¼ 0.015 and p < 0.001 for sTfR/logF index), with the medians of both parameters significantly higher in the irondepleted patients (sTfR of 1.75 mg/L and sTfR/logF of 0.99 in ACKD patients with rHuEPO therapy, sTfR of 1.40 mg/L and sTfR/logF of 0.77 in ACKD patients without rHuEPO therapy) than in iron-repleted patients (sTfR of 1.07 mg/L and sTfR/logF of 0.39 in ACKD patients with rHuEPO, sTfR of 0.73 mg/L and sTfR/logF of 0.26 in ACKD patients without rHuEPO). In addition, significant differences in UIBC between the iron-repleted and iron-depleted groups were recorded for both patients with and without rHuEPO therapy (p < 0.001) and in iron concentration for patients without rHuEPO therapy (p ¼ 0.016). No significant differences were found for the remaining parameters tested (Hgb, Hct, Rtc, TIBC) between patients who were iron depleted
4 DIALYSIS & TRANSPLANTATION AUGUST 2006
and iron repleted (p > 0.05) according to K/DOQI guidelines (Table III). ROC analysis showed the discriminating power of the sTfR and sTfR/ logF index in the assessment of iron status estimated on the basis of ferritin and Tfsat values. For sTfR concentration, an AUC of 0.890 was obtained with the best combination of diagnostic sensitivity (81.8%) and specificity (90.5%) at a cutoff of 1.51 mg/L. The sTfR/logF index showed higher discriminating power in evaluating the iron status of ACKD patients (AUC ¼ 0.970), with the best combination of diagnostic sensitivity (90.9%) and specificity (97.6%) at a cutoff of 0.969 (Figure 2). In patients with ACKD, no significant differences in sTfR, sTfR/logF, Tfsat, and iron concentrations (p > 0.05) were found between patients whose CRP concentrations were normal ( < 9 mg/L) and those whose CRP concentrations were elevated ( > 9 mg/L). However, serum ferritin concentrations were significantly higher in patients with elevated CRP concentration than in those with normal CRP (p ¼ 0.045; Table IV). Endogenous EPO concentration of ACKD patients who had not received
Figure 2. Receiver operating characteristic (ROC) analysis of sTfR and sTfR/logF parameters in the evaluation of iron status in the patients with ACKD (n ¼ 53). Se ¼ diagnostic sensitivity, Sp ¼ diagnostic specificity.
sTfR & sTfR/LOGF INDEX IN CKD ANEMIA
Table III. Characteristics of ACKD patients treated with rHuEPO and those not treated with rHuEPO, according to iron-repleted and iron-depleted status (as defined by K/DOQI guidelines). ACKD Patients with rHuEPO
ACKD Patients without rHuEPO
(n ¼ 21)
Parameter sTfR (mg/L)
(n ¼ 32)
Iron-Repleted Group
Iron-Depleted Group
Iron-Repleted Group
Iron-Depleted Group
(n ¼ 14)
(n ¼ 7)
(n ¼ 22)
(n ¼ 10)
1.75 (0.60–3.31)
0.73 (0.27–1.46)
1.07 (0.54–2.18) p ¼ .044
sTfR/logF index
0.39 (0.19–0.92)
0.99 (0.23–1.89)
0.26(0.09–0.61)
p ¼ .015 Hgb (g/L)
99.7 15.7
98.2 19.8
95.7 13.8
93.3 13.8 p ¼ 0.618
29.5 5.1
28.7 4.8
29.0 5.0
27.2 5.3
p ¼ 0.610 Rtc (109/L)
32.1 (16.5–69.5)
p ¼ 0.244 36.2 (16.1–79.5)
28.1 (17.2–70.0)
p ¼ 0.314 TIBC (mmol/L)
37.7 7.8
43.6 7.2
43.8 9.0
47.2 8.3 p ¼ 0.340
20.3 8.4
39.5 9.7
23.2 4.5
34.1 7.1
p < 0.001 iron (mmol/L)
12.2 (5.1–21.0)
33.0 (16.7–77.9) p ¼ 0.241
p ¼ 0.078 UIBC (mmol/L)
0.77 (0.11–2.13) p < 0.001
p ¼ .949 Hct (%)
1.40(0.75–3.24) p < 0.001
p < 0.001 9.1 (6.0–21.9)
14.2 (5.0–35.2)
p ¼ 0.075
7.6 (4.6–14.3) p ¼ 0.016
p-values in bold indicate statistically significant differences (p < 0.05).
rHuEPO therapy (n ¼ 32) was determined. To measure the strength of association between sTfR and EPO concentrations as well as between sTfR/logF value and EPO concentration, we used Spearman’s correlation test. Our results showed statistically significant positive correlations of sTfR and sTfR/logF values with EPO concentration (r ¼ 0.668 and 0.690, p < 0.001). In the subgroup of ACKD patients not treated with rHuEPO (n ¼ 32), there were 5 patients with associated polycystic kidney disease. These patients had higher median sTfR and EPO concentrations (16.2 IU/L for EPO and 1.51 mg/L for sTfR) than the other patients (n ¼ 27) untreated with rHuEPO (10.7 IU/L for EPO and 1.06 mg/L for sTfR;).
Discussion The aim of this study was to assess the value of sTfR and sTfR/logF as new markers of the iron status of
ACKD patients both treated and not treated with rHuEPO. The sTfR and sTfR/logF values of the control subjects were mostly
Table IV. Characteristics of patients with ACKD (n ¼ 53) according to serum C-reactive protein concentrations. CRP < 9 mg/L
CRP > 9 mg/L (n ¼ 17)
p-value
sTfR (mg/L)
1.13 (0.32–3.31)
1.06 (0.27–1.58)
0.108
sTfR/logF index
0.54 (0.11–2.13)
0.49 (0.09–0.69)
0.147
Tfsat (%)
25.6 (11.1–51.1)
30.3 (18.1–56.9)
0.343
Parameter
iron (mmol/L) ferritin (mmol/L)
(n ¼ 36)
11.7 (4.6–42.9)
9.5 (5.3–31.4)
0.657
315.7 (15.8–553)
485.1 (72.8–778.1)
0.045
p-value in boldface denotes a statistically significant difference (p < 0.05).
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DIALYSIS & TRANSPLANTATION 5
sTfR & sTfR/LOGF INDEX IN CKD ANEMIA consistent with those reported by other studies investigating sTfR concentrations in healthy adult subjects.20,21 In a previous study we showed that the sTfR and sTfR/logF values of healthy subjects were not influenced by sex and age.15 In ACKD patients, sTfR and sTfR/ logF values were statistically significantly different between patients treated with rHuEPO and those not treated with rHuEPO (p ¼ 0.018 for sTfR and p ¼ 0.043 for sTfR/logF index), with values significantly higher in patients receiving rHuEPO therapy. No significant differences in any of the conventional hematologic and biochemical parameters (p > 0.05) were found in patients according to rHuEPO treatment status. These results suggest that, in addition to iron deficiency, EPO is an important stimulus of TfR synthesis and expression. According to the NKF-K/DOQI guidelines, the recommended markers of iron deficiency in ACKD patients are serum ferritin concentration below 100 mg/L and/or percentage of Tfsat below 20%. In our study, 36 of 53 (67.9%) patients (14 on rHuEPO therapy and 22 without rHuEPO therapy) had adequate iron stores according to K/DOQI guidelines. The other 17 (32.1%) patients (7 on rHuEPO therapy and 10 without rHuEPO therapy) had inadequate Tfsat and/or ferritin levels. The results showed that among both patients treated with rHuEPO therapy and those not treated rHuEPO therapy, there were significantly different sTfR and sTfR/logF values between iron-repleted patients and iron-depleted patients ( p ¼ 0.044 and p < 0.001 for sTfR; p ¼ 0.015 and p < 0.001 for sTfR/logF), with both parameters significantly higher in iron-depleted patients. In contrast, only 2 of the remaining parameters tested showed significant differences according to iron status: UIBC in both the rHuEPO-
treated and -untreated groups (p < 0.001) and iron concentration in patients not treated with rHuEPO (p ¼ 0.016). The results obtained in our study are consistent with those of Fusaro et al. and Tonbul et al., who also showed that ACKD patients with iron deficiency had significantly higher sTfR concentrations in relation to healthy subjects and to ACKD patients without iron deficiency.22,23 ROC analysis showed acceptable discriminating power of sTfR (AUC ¼ 0.890) and excellent discriminating power of the sTfR/logF index (AUC ¼ 0.970) in the assessment of the iron status of patients with ACKD. These results are consistent with earlier reports indicating improved diagnostic efficacy of the sTfR/logF index as compared with sTfR alone in the assessment of iron status.15 –17 The best combination of diagnostic sensitivity (81.8%) and specificity (90.5%) was obtained at a cutoff of 1.51 mg/L for sTfR, which is in accordance with the results of Fusaro et al.22 In our patient population the best combination of sensitivity (90.9%) and specificity (97.6%) for the sTfR/logF index was obtained at a cutoff of 0.969. One of the main difficulties in performing a laboratory assessment of the iron status of anemic patients is the unreliability of conventional markers of iron status of patients with concurrently present acute or chronic inflammatory states, in which serum ferritin, iron, and transferrin concentrations are all known to show acute phase responses to inflammation, so iron and transferrin may fall and ferritin rise irrespective of the reticuloendothelial iron stores.24 –26 In contrast, sTfR does not appear to behave as an acute phase reactant and does not correlate with inflammatory parameters such as CRP.21,25,27 The results obtained in our study largely support the existing concepts. The measured values of the sTfR and sTfR/logF index showed no
6 DIALYSIS & TRANSPLANTATION AUGUST 2006
significant differences according to CRP concentration in ACKD patients, suggesting the tested parameters were not influenced by either acute or chronic inflammatory conditions. Tfsat percentage and iron concentration showed no significant differences either (p ¼ 0.343 and p ¼ 0.657). However, ferritin concentration was significantly higher in patients with elevated CRP concentration than in those with normal CRP (p ¼ 0.045). Consistent with other studies,28,29 our results showed statistically significant positive correlations of sTfR and sTfR/logF values with endogenous EPO concentration in ACKD patients not receiving rHuEPO (r ¼ 0.668 and r ¼ 0.690, p < 0.001). The positive correlation between sTfR and EPO indicates that reduced EPO concentration is associated with decreased sTfR concentration. Among the ACKD patients not treated with rHuEPO (n ¼ 32), 5 patients had concomitant polycystic kidney disease. These patients had higher median sTfR and EPO concentrations (1.51 mg/L for sTfR and 16.2 IU/L for EPO) than in the rest of the ACKD patients without rHuEPO therapy (1.06 mg/L for sTfR and 10.7 IU/L for EPO). Although statistical evaluation of the sTfR and EPO values was not possible because of the small number of patients with polycystic kidney disease, these results are consistent with what is reported in the literature.29 Patients with polycystic kidney disease are considered to have overproduction of EPO because of ischemia and hypoxia produced by compression from the adjacent cysts. Overproduction of EPO in these patients often results in their having rHuEPO therapy introduced later than for those patients without polycystic kidney disease. The measured sTfR and EPO values in these ACKD patients also point to EPO as a factor of TfR synthesis and expression.
sTfR & sTfR/LOGF INDEX IN CKD ANEMIA Conclusion Tthe sTfR and sTfR/logF values found in this study suggest these parameters are reliable in the assessment of the iron status of patients with ACKD. The results showed that the sTfR/logF index has notably higher discriminating power than sTfR alone. There is still no single hematologic or biochemical parameter that is both specific and sensitive enough to reliably evaluate the iron status of ACKD patients. As the conventional laboratory parameters of iron status are often influenced by acute phase responses, it is expected that the sTfR and the sTfR/logF index could improve diagnostic reliability of accurately evaluating iron status, particularly in ACKD patients with concomitant inflammatory or infective conditions. Accordingly, we believe that the combined measurement of serum ferritin, sTfR, and the sTfR/logF index may be an effective approach to monitoring the iron status of patients with ACKD.
5.
6.
7.
8.
9. 10.
11.
12.
Acknowledgements We thank Dr. Branka Kunovic for assistance in specimen collection and Antonija Redovnikovic´ for her help in editing the manuscript. The study was supported in part by Project 134019 of the Croatian Ministry of Science and Technology.
13.
14.
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AUGUST 2006
DIALYSIS & TRANSPLANTATION 7
