Anemia and Iron Deficiencies among Long - Term Renal Transplant Recipients

J Am Soc Nephrol 13: 794–797, 2002
Anemia and Iron Deficiencies among Long-Term Renal
Transplant Recipients
MATTHIAS LORENZ, JOSEF KLETZMAYR, AGNES PERSCHL,
ALEXANDER FURRER, WALTER H. HO
¨ RL, and GERE SUNDER-PLASSMANN
Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Vienna, Austria.
Abstract. Iron deficiency anemia after renal transplantation has
(TSAT), polycystic kidney disease, and age were observed.
not been systematically investigated. The prevalence of anemia
Negative associations with erythropoietin therapy, use of aza-
and the indicators of iron deficiency among 438 renal trans-
thioprine, serum ferritin levels, and body mass index were
plant recipients were examined. Anemia was present in 39.7%
observed. The risk for anemia was closely related to the highest
of the patients. The prevalence of iron deficiencies, as indi-
quartile of HRBC percentages (odds ratio, 2.35; 95% confi-
cated by a percentage of hypochromic red blood cells (HRBC)
dence interval, 1.48 to 3.75; P ? 0.00029), whereas ferritin
of ?2.5%, was 20.1%. The majority of severely anemic pa-
levels and TSAT conferred no risk for anemia. Therefore,
tients exhibited HRBC values in the upper quartile. Positive
assessment of the HRBC proportion is superior to decreased
associations of hemoglobin levels with creatinine clearance,
ferritin and decreased TSAT measurements for the diagnosis of
serum transferrin levels, male gender, transferrin saturation
iron deficiencies among renal transplant recipients.
Anemia among long-term renal transplant recipients (RTR) is
of the whole patient population. To avoid multicollinearity, anemia
not well documented (1). Even fewer data on iron status and
was related to five sets of variables, in which one of five iron markers
iron deficiencies among these patients are available. In this
was entered. In these models, the most important predictors of hemo-
study, we examined the prevalence of anemia and iron defi-
globin levels (derived from the stepwise regression analyses) were
also considered, i.e., creatinine clearance values below or above the
ciency anemia among long-term RTR in stable condition.
median, azathioprine use (yes/no term), and polycystic kidney disease
(yes/no term).
Materials and Methods
All patients who visited the kidney transplant outpatient service at
Results
the University Hospital of Vienna during a period of 4 wk were
The characteristics of all 438 RTR are indicated in Table 1. The
included in a cross-sectional study. The patients exhibited stable graft
proportions of patients with iron status markers within or outside
function. Blood chemistry values were determined by using standard
the reference range are presented in Table 2. The prevalence of
methods. Transferrin saturation (TSAT) was calculated as iron level/
serum transferrin level ? 70.9. Whole blood counts and percentages
anemia among RTR was 39.7%. Iron deficiency was indicated by
of hypochromic red blood cells (HRBC) were analyzed with a Tech-
a proportion of HRBC of ?2.5% for 88 patients (20.1%). The
nicon H*2 hematology analyzer (Bayer Diagnostics, Tarrytown, NY).
association of all variables with hemoglobin levels is presented in
Creatinine clearance values were calculated with the equation de-
Table 3. Increased serum ferritin levels were associated with
scribed by Cockcroft and Gault (2).
decreased hemoglobin concentrations. Serum transferrin levels
Independent associations with hemoglobin levels were examined in
were elevated in parallel with hemoglobin levels. The risks for
multiple stepwise regression analyses. The distribution of skewed data
anemia conferred by five markers of iron metabolism are pre-
was normalized by natural logarithmic transformation. Logistic re-
sented in Figure 1. Among anemic or severely anemic patients,
gression models were constructed to examine the risks (odds ratios
HRBC elevations were more frequent than hypoferritinemia or
and 95% confidence intervals) for anemia (i.e., hemoglobin levels of
decreased TSAT values. The majority of patients with hemoglo-
?12 g/dl for women and ?13 g/dl for men) associated with markers
bin levels of ?11 g/dl presented with HRBC values in the highest
of iron metabolism in the highest (HRBC) or lowest (serum ferritin
quartile (Table 4).
levels, TSAT, serum iron levels, and serum transferrin levels) quartile
Discussion
Received June 27, 2001. Accepted October 30, 2001.
Our study suggests that we do not attach enough importance
Correspondence to Dr. Matthias Lorenz, Division of Nephrology and Dialysis,
to the diagnosis and management of anemia among RTR in
Department of Medicine III, University of Vienna, Wa¨hringer Gu¨rtel 18-20,
stable condition. This is obviously attributable to the preva-
A-1090 Wien, Austria. Phone: 43-1-40480-422; Fax: 43-1-40400-4392,
lence of unrecognized iron deficiencies, which is related to the
E-mail: Matthias.Lorenz@nephro.imed3.akh-wien.ac.at
poor information obtained from ferritin or TSAT measure-
1046-6673/1303-0794
ments. Only 10.1% of severely anemic patients presented with
Journal of the American Society of Nephrology
Copyright © 2002 by the American Society of Nephrology
serum ferritin levels of ?12 ?g/L, and TSAT values of ?15%

---

J Am Soc Nephrol 13: 794–797, 2002
Anemia among RTR
795
Table 1. Patient characteristicsa
Table 3. Independent associations with hemoglobin levels
among 438 kidney graft recipients (by multiple
Mean (95% CI) or
Count (Frequency)
stepwise regression analyses)a
?
P
Age (yr)
51.6 (50.4 to 52.9)
Transplanted since (yr)
4.86 (4.51 to 5.20)
Creatinine clearance
0.349
?0.000001
Serum creatinine level (mg/
1.80 (1.72 to 1.87)
Erythropoietin therapy
?0.199
0.000003
dl)
Serum transferrin level
0.237
0.000684
Creatinine clearance (ml/min)
52.8 (51.0 to 54.6)
Female gender
?0.139
0.000863
Hemoglobin level (g/dl)
13.0 (12.8 to 13.2)
TSAT (ln)
0.294
0.023151
HRBC (%)
2.52 (1.98 to 3.06)
Azathioprine therapy
?0.090
0.027514
Serum ferritin level (?g/L)
197 (161 to 232)
Polycystic kidney disease
0.090
0.022034
Serum iron level (?g/dl)
82.5 (79.4 to 85.5)
Serum ferritin level (ln)
?0.104
0.038727
Serum transferrin level (mg/
267 (262 to 272)
Age
0.100
0.024022
dl)
Body mass index
?0.086
0.042400
TSAT (%)
23.1 (22.0 to 24.2)
a
Body mass index (kg/m2)
25.5 (25.1 to 25.9)
r2 ? 0.2917, P ? 0.00001; selection cut off, F ? 1. The
C-reactive protein level (mg/
0.30 (0.19 to 0.42)
variables follow the order in which they were entered into the
equation (each immunosuppressant was coded as a dummy
dl)
variable; HRBC proportions, C-reactive protein levels, iron
Current erythropoietin therapy
29 (6.6%)
supplementation, and serum iron levels were not significant).
Current oral iron therapy
28 (6.4%)
a HRBC, hypochromic red blood cells; TSAT, transferrin
saturation; CI, confidence interval.
a significant proportion of RTR. Factors related to the preva-
lence of iron deficiencies may include occult blood losses,
blood sampling, and adherence to a low-meat dietary regimen.
were observed for 29%. These results underestimate by far the
Ferritin levels may vary and may be elevated independently
number of patients with functional iron deficiencies, because
of iron stores in conditions such as inflammatory or infectious
HRBC values of ?2.5% were detected for 46.4% and values in
diseases, malignancies, or iron overload (3,4). In contrast to the
the upper quartile were detected for 52.2% of our severely
negative association of serum ferritin levels with hemoglobin
anemic patients, reaching 64.1% among female patients. These
concentrations, C-reactive protein levels demonstrated no as-
findings strongly suggest that iron deficiencies, as diagnosed
sociation with hemoglobin concentrations in our study. This
by serum ferritin or TSAT measurements, remain undetected in
finding may be attributable to immunosuppressive therapy,
Table 2. Indices of iron status within or out of the reference rangea
All Patients
Women
Men
Hemoglobin (g/dl) (1,9)
?11
69 (15.8%)
39 (22.0%)
30 (11.5%)
?12/13
174 (39.7%)
75 (42.4%)
99 (37.9%)
12/13 to 17/18
257 (58.7%)
98 (55.4%)
159 (60.9%)
?17/18
7 (1.6%)
4 (2.3%)
3 (1.1%)
HRBC (%) (6)
?2.5
350 (79.9%)
128 (72.3%)
222 (85.1%)
2.5 to 10
64 (14.6%)
35 (19.8%)
29 (11.1%)
?10
24 (5.5%)
14 (7.9%)
10 (3.8%)
Serum ferritin level (?g/L) (10,11)
?12
33 (7.5%)
22 (12.4%)
11 (4.2%)
12 to 400
363 (82.9%)
137 (77.4%)
226 (86.6%)
?400
44 (9.6%)
18 (11.1%)
24 (9.2%)
TSAT (%) (10,12)
?15
89 (20.3%)
51 (28.8%)
38 (14.6%)
15 to 45
334 (76.3%)
120 (67.8%)
214 (82%)
?45
15 (3.4%)
6 (3.4%)
9 (3.4%)
a The reference ranges are indicated according to the literature.

---

796
Journal of the American Society of Nephrology
J Am Soc Nephrol 13: 794–797, 2002
substantially increased the risk for anemia, whereas decreased
serum ferritin levels and decreased TSAT conferred no risk
(Figure 1). Therefore, our findings support a concept in which
continuous decreases in HRBC levels, even to ?2%, may
indicate gradual improvement of the iron supply (6,7).
A potential limitation of our study may be the lack of
analysis of angiotensin I-converting enzyme (ACE) inhibi-
tion. The effect of ACE inhibition on hemoglobin levels is
a matter of debate. However, the largest study reported to
date clearly demonstrated that ACE inhibitor therapy did not
decrease hemoglobin levels among RTR with normal hemo-
globin levels (8). Another point of concern may be the lack
of bone marrow examinations as the standard iron supply
test. However, invasive studies are not reasonable for a large
patient population.
Figure 1. Markers of iron status and risk of anemia among 438 renal
In summary, we demonstrate that (1) anemia and iron
transplant recipients (the worst versus the other three quartiles, by
deficiencies are under-recognized among RTR in stable
logistic regression analysis). Hypochromic red blood cells (RBC):
condition, (2) the proportion of HRBC is the most important
odds ratio (OR), 2.35; 95% confidence interval (CI), 1.48 to 3.75; P
indicator of iron deficiencies among RTR, and (3) measure-
? 0.00029; serum transferrin level: odds ratio, 1.96; 95% confidence
ments of serum ferritin levels and TSAT are not always
interval, 1.23 to 3.11; P ? 0.004395; serum iron level: odds ratio,
sufficient for the diagnosis of iron deficiencies among RTR.
1.56; 95% confidence interval, 0.97 to 2.49; P ? 0.063608; serum
References.
ferritin level: odds ratio, 0.73; 95% confidence interval, 0.46 to 1.18;
P ? 0.19989; transferrin saturation (TSAT): odds ratio, 1.02; 95%
confidence interval, 0.63 to 1.63; P ? 0.942653.
References
1. Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch
GM, Gaston RS, Roth D, Scandling JD, Singer GG: Recommen-
dations for the outpatient surveillance of renal transplant recip-
which was demonstrated to suppress C-reactive protein pro-
ients: American Society of Transplantation. J Am Soc Nephrol
duction (5). There was also a weak negative independent
11[Suppl 15]: S1–S86, 2000
association of C-reactive protein with HRBC in our study
2. Cockcroft DW, Gault MH: Prediction of creatinine clearance
population (data not shown), indicating that increases in HRBC
from serum creatinine. Nephron 16: 31– 41, 1976
values were not related to inflammation anemia.
3. Kaltwasser JP, Gottschalk R: Erythropoietin and iron. Kidney Int
In this study, a proportion of HRBC in the highest quartile
55[Suppl 69]: S49 –S56, 1999
Table 4. Prevalence of iron deficiencies among anemic (hemoglobin levels of ?12 g/dl for women or ?13 g/dl for men)
and severely anemic (hemoglobin levels of ?11 g/dl) RTR, according to standard cut-off levels or worst quartiles
of laboratory parameters of iron statusa
No. of Patients
Anemic Patients
Severely Anemic Patients
All Patients
Women
Men
All Patients
Women
Men
(n ? 174)
(n ? 75)
(n ? 99)
(n ? 69)
(n ? 39)
(n ? 30)
HRBC (%)
?10
13 (7.5%)
8 (10.7%)
5 (5.1%)
11 (15.9%)
6 (15.4%)
5 (16.7%)
?2.5
49 (28.2%)
28 (37.3%)
21 (21.2%)
32 (46.4%)
22 (56.4%)
10 (33.3%)
?2b
57 (32.8%)
33 (44.0%)
24 (24.2%)
36 (52.2%)
25 (64.1%)
11 (36.7%)
Serum ferritin level (?g/L)
?12
11 (6.3%)
9 (12.0%)
2 (2.0%)
7 (10.1%)
5 (12.8%)
2 (6.7%)
?32.2b
38 (21.8%)
24 (32.0%)
14 (14.1%)
16 (23.2%)
10 (25.6%)
6 (20.0%)
TSAT (%)
?15
37 (21.3%)
24 (32.0%)
13 (13.1%)
18 (26.1%)
12 (30.8%)
6 (20.0%)
?16.6b
42 (24.1%)
26 (34.7%)
16 (16.2%)
20 (29.0%)
14 (35.9%)
6 (20.0%)
a RTR, renal transplant recipients.
b Cut-off level according to highest (HRBC) and lowest (serum ferritin level and TSAT) quartile.

---

J Am Soc Nephrol 13: 794–797, 2002
Anemia among RTR
797
4. Miles AMV, Markell MS, Daskalakis P, Sumrani NB, Hong J,
8. Stigant CE, Cohen J, Vivera M, Zaltzman JS: ACE inhibitors and
Sommer BG, Friedman EA: Anemia following renal transplan-
angiotensin II antagonists in renal transplantation: An analysis of
tation: Erythropoietin response and iron deficiency. Clin Trans-
safety and efficacy. Am J Kidney Dis 35: 58 – 63, 2000
plant 11: 313–315, 1997
9. National Kidney Foundation–Kidney Disease Outcomes Quality
5. Van Lente F, Castellani W, Abbott LB: Changes in concentra-
Initiative (NKF-K/DOQI) Work Group: NKF-K/DOQI clinical
tions of C-reactive protein in serum after kidney or heart trans-
practice guidelines for anemia of chronic kidney disease: Update
plantation. Clin Chem 32: 633– 636, 1986
2000. Am J Kidney Dis 37[suppl 1]: S182–S238, 2001
6. Macdougall IC, Cavill I, Hulme B, Bain B, McGregor E, McKay
10. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL:
P, Sanders E, Coles GA, Williams JD: Detection of functional
Prevalence of iron deficiency in the United States. JAMA 277:
973–976, 1997
iron deficiency during erythropoietin treatment: A new approach.
11. Jordan CD, Flood JG, Laposata M, Lewandrowski KB: Case
Br Med J 304: 225–226, 1992
records of the Massachusetts General Hospital: Weekly clinico-
7. Braun J, Lindner K, Schreiber M, Heidler RA, Ho¨rl WH: Per-
pathological exercises: Normal reference laboratory values.
centage of hypochromic red blood cells as predictor of erythro-
N Engl J Med 327: 718 –724, 1992
poietic and iron response after i.v. iron supplementation in main-
12. Sham RL, Raubertas RF, Braggins C, Cappuccio J, Gallagher M,
tenance haemodialysis patients. Nephrol Dial Transplant 12:
Phatak
PD:
Asymptomatic
hemochromatosis
subjects:
1173–1181, 1997
Genotypic and phenotypic profiles. Blood 96: 3707–3711, 2000
Access to UpToDate on-line is available for additional clinical information
at http://www.jasn.org/

---