Clinical Science (1970)38, 191-196.
IRON ABSORPTION I N CHRONIC RENAL DISEASE
J. W. E S C H B A C H , J. D. C O O K A N D C. A. F I N C H
Department of Medicine, University of Washington School of Medicine, Seattle
(Received 12 June 1969)
SUMMARY
1. Absorption of inorganic iron was studied in thirty-four patients with chronic
renal failure by a double isotope technique.
2. Eight patients with normal iron balance had a mean absorption of 3-5%, ten
patients with iron overload had a mean absorption of 3.6%, and sixteen patients with
iron depletion had a mean absorption of 58%. Thus, alterations in absorption
appeared to be related to disturbances in iron balance.
3. The rate of erythropoiesis had no evident effect on iron absorption nor did the
degree of anaemia.
4. The presence of renal disease and the degree of azotaemia likewise did not
appear to affect absorption.
Iron absorption in man is primarily dependent on the iron requirement of the individual as
reflected by the size of his iron stores (Pirzio-Biroli & Finch, 1960). The level of erythropoiesis
also affects absorption (Bothwell, Pirzio-Biroli & Finch, 1958), and it has been suggested that
anaemia per se may increase absorption (Mendel, 1961). Patients with renal disease have widely
varying iron stores and have the unique situation of severe anaemia without the usual increase
in erythropoietin. The effects of these factors on iron absorption in patients with renal failure
have therefore been examined.
MATERIALS AND METHODS
Thirty-four observations were made in thirty-two patients with chronic renal disease. Four
patients had polycystic kidney disease, one had congenital obstructive renal disease, three had
chronic pyelonephritis, and the remaining patients had chronic glomerulonephritis. Patient
T.D. was anephric. All had severe renal failure with an endogenous creatinine clearance of
less than 5 ml/min, but their azotaemia was stabilized by thrice-weekly haemodialysis in the
Correspondence:Dr C. A. Finch, University of Washington School of Medicine AA512,Division of Hematology, Seattle, Washington 98105, U.S.A.
191
192
J. W. Eschbach, J. D. Cook and C. A . Finch
home (Kiil dialyser) or by dietary management prior to initiation of haemodialysis (J.Ca.,
W.S.,, C.McC., L.N.). All were free of systemic infection and had adequate folic acid and
vitamin B and C intake. The patients were divided into three groups according to the probable
extent of their iron stores.
Sixteen patients were iron deficient, ten showed iron overload, and eight appeared to be in
normal iron balance. The criteria for iron deficiency were a total iron binding capacity greater
than 300 pg/100 ml, a transferrin saturation of 18% or less, and in seven patients absent bone
marrow iron stores. Increased iron stores were considered to be present when the transferrin
saturation was greater than 50% and when marrow iron and non-erythroid iron turnover were
increased (Eschbach et al., 1967). Patients with a total iron binding capacity below 350 pg/100
ml and with transferrin saturations between 18 and 50% were considered to have normal iron
balance.
Haematological studies included serum iron and iron binding capacity (Morgan & Carter,
1960), bone marrow aspirations for evaluation of reticuloendothelial haemosiderin (Rath &
Finch, 1948), and reticulocyte counts. In the latter, 5000 red cells were counted and the reticulocyte percentage was corrected for the degree of anaemia to provide an index of erythropoiesis
(Simon, Giblett & Finch, 1966). Plasma erythropoietin assays were performed in hypoxic
protein-starved mice as described by Adamson et al. (1966). An assay was considered significant if 59Feutilization was greater than 1%.
Iron absorption was determined by a double isotope technique (Saylor & Finch, 1953).
Five mg of elemental iron as iron sulphate, 30 mg ascorbic acid and 50 pCi of 55Fe were
dissolved in distilled water immediately prior to its administration. After an overnight fast,
the subject ingested the solution and took nothing for a further 2 hr 8-16 pCi of 59Fe were
given intravenously the same morning. Iron absorption was expressed as the percentage of 55Fe
ingested that appeared in the circulating red cell after 10-14 days, corrected for the percentage
red cell utilization of the simultaneously administered 59Fe. Ferrokinetic studies were derived
from the above injected dose of "Fe as previously reported for patients with chronic renal
failure (Eschbach et al., 1967). If transfusions were required, the above studies were not
performed for at least 5 days after transfusion.
R E S UL T S
Seven subjects (eight studies) with chronic renal disease were considered to be in normal iron
balance (Table 1). Their transferrin saturation averaged 30% with a range of 2241%. Nonerythroid iron turnover averaged 0.22 mg/100 ml whole blood per day (normal 0.16 mg).
Erythropoiesis as measured by the erythroid iron turnover (EIT) averaged 0.45 mg/100 ml
whole blood per day (normal 0.60 mg: Hosain, Marsaglia & Finch, 1967). The mean absorption of radioiron was 3.5% with a range of 1.0-7.4%.
The ten patients with chronic renal disease and increased iron stores (Table 1) had a mean
transferrin saturation of 82% (range 5 1-9 1%), increased non-erythroid iron turnover (average
0.52 mg), and increased marrow haemosiderin in all four patients in whom specimens were
obtained. Erythropoiesis was also below normal as indicated by an average EIT of 0.42 mg/100
ml whole blood per day. The mean iron absorption in this group was 3.6% with a range of
1* 14.9%.
The third group of sixteen patients with iron deficiency (Table 1) had an average transferrin
Averages
M
M
F
M
M
M
F
M
M
M
W.K.
M
ALVCZages
V.F.
R.He.
J.S.
L.B.
R.L.
R.B.
I.W.
D.Du.
6/66
5/67
6/67
8/67
8/67
8/67
9/67
12/67
12/67
2/68
3/68
3/68
4/68
7/68
9/68
9/68
7/67
9/67
10167
1/68
1/68
3/68
6/68
8/68
7/60
10166
X:I
:: 12/67
Averages
Iron defiaencv
C.S.
M
M
R.V.
E.M.
M
J.G.
M
H.K.
M
D.Da.
M
L.M.
F
EM.
J.R.
M.H.
R.H.
10.8
7.2
14.8
13.4
12.4
11.8
11.9
12.0
14.6
12.1
11.8
14.4
9.0
13.1
14.6
14.9
11.3
10.9
8.4
26.8
13.9
13.0
5.9
19.7
11.3
9.I
9.5
12.0
13.0
9.2
10.7
16.2
11.4
12.0
18.3
11.2
7.8
=
0
absent. 4 f
=
0.2
0
0
0
0
0
0
0.5
3.0
0
0
0
0
0
0
0
0
2.2
0.8
91
62
67
60
135
56
82
57
76
36
35
41
50
31
59
50
49
60
53
64
39
53
49
49
36
47
197
184
108
261
206
133
128
154
185
177
206
excessive.
1.2
3.7
0
3.0
4.0
2.0
0.8
4.0
2.5
2.0
0.5
0
0
0
0
0
2.0
be/'%'d)
Plasma
365
348
339
357
364
368
360
378
341
349
570
31 I
414
339
491
475
386
292
223
223
196
299
197
232
226
224
21 1
241
273
213
217
216
329
260
277
222
250
r/).
18
I5
11
12
13
14
10
8
12
13
12
14
9
16
14
10
10
92
60
65
52
94
71
9i
82
51
82
RP
-.
33
29
31
28
41
22
30
26
30
binding Tramferrin
capacity saturation
(pe/lW ml)
Total iron
100
21
26
31
5.4
73
..
62
71
70
84
72
78
89
22
87
39
58
4.6
6.9
4.4
5.2
4.5
._
1.2
2.2
3.6
1.1
2.9
3.2
3.5
1.o
1.7
2.3
6.0
7.4
1.2
4.8
3.7
0.90
...
0.84
1.10
0.64
0.36
0.87
1.17
0.91
0.79
0.61
1.33
1.07
0.74
0.70
0.77
0.77
0.77
0'99
0.44
0.80
0.72
1.83
0.77
1.03
1.15
1.20
0.49
0.94
0.65
0.80
0.57
0.93
0.57
0.87
0.46
0.43
0.59
PITt
100 ml whole blood-1 day-1.
-
0
0
-
0
0
0
1+
-
ZF~
Intestinal
Marrow abso tion
iron*
of
(%)
$ RCU = red cell utilization of s9Fe at 1&14 days
f % S*Fe utilization in hypoxic, protein starved micc,omcanof five animals.
t PIT = plasha iron turnover; EIT = erythroid iron turnover; mg
0
27
31
23
22
19
17
23
23
31
27
21
20
25
22
24
23
24
14
29
23
22
17
17
20.9
18
26
22
21
29
16
20
21
24
16
29
33
23
Sex Dateof Crcatinine Haematocrit Transfusions/
study (mg/100ml)
(%)
month
Normal iron balance
L.N.
M
10166
7/67
D.T.
M
_,__
W.S.1
8/67
F
WSr
Pt
76
92
85
100
74
97
_.
83
100
79
86
73
81
98
72
119
80
87
23
12
62
49
46
40
46
46
48
66
44
75
88
66
79
62
56
85
41
69
RCUt
0.73
0.88
0.56
0.65
0.65
0.77
0.57
n47
- _.
0.30
0.87
0.93
0.79
0.57
0.49
1.31
0.77
0.76
0.23
0.05
0.50
0.35
0.84
0.31
0.47
0.53
0.58
0.32
0.42
0.32
0.73
0.33
0.45
0.58
0.33
0.52
0.30
0.45
EITt
5.00
0.35
0.31
2.32
0.60
3.52
0.40
1.41
5.42
1.56
-
-
3.32
0.75
0.59
...
0.20
0.07
0.73
0.50
0.73
0.27
0.19
1.50
0.52
2.19
001
0.02
0.33
0.45
1.60
1.7
.
.3_
0.22
0.40
0.03
-
0.27
0.27
0.27
0.27
0.13
0.87
047
0.06
0.06
0.72
0.02
0.72
0.72
0..3
1.
.
0.27
0.27
0.27
0.4I
0.39
0.13
0.0%
0.72
0.04
0.02
0.04
0.02
0.27
0.47
0.87
o.47
- ..
0.27
0.27
Plasma
Saline
crythro- controls§
poietinf
TABLE
1 . Biochemical, haematological and radioactive iron measurements in thirty-four patients with chronic renal failure
%
I--
s-
194
J. W. Eschbach, J. D. Cook and C. A. Finch
saturation of 12% (range 8-1 8%) and decreased non-erythroid iron turnover (average 0.12
mg). All seven of the marrow specimens obtained were devoid of stainable iron. The mean EIT
was 0-73 mg/100 ml whole blood per day. The average iron absorption was 58%, and in all but
one absorption was greater than 21%. There was no obvious explanation for the low absorption of 5 4 % in patient H.K. (Table 1).
Average values (pre-dialysis) of plasma phosphate (7.6 mg/100 ml), creatinine (12.4 mg/100
ml) and blood urea nitrogen (78 mg/100 ml) were similar in all three groups of patients. Corrected reticulocyte counts averaged 1.5% in all three groups.
DISCUSSION
It has long been recognized that iron absorption is dependent on the needs of the individual
for iron (Pirzio-Biroli & Finch, 1960; Bothwell et al., 1958; Cook, Layrisse & Finch, 1969).
Thus, for a 5 mg dose of reduced iron, normal males absorbed an average of 6%, and subjects
with iron deficiency absorbed an average of 44% (Kuhn et al., 1968).
70
-0
0
2oI
10
*:
,
20
* ,
2
:
,
'.
40
60
,.*
80
,
I00
Transferrin saturation
FIG.1 . Iron absorption in thirty-four patients with chronic renal failure. Iron deficiency: transferrin
saturation of 18% or less; iron overload: > 50% transferrin saturation.
In the present study iron needs of patients with chronic renal disease were defined on the
basis of transferrin saturation. Transferrin saturation is known to be depressed in iron deficiency (Bainton & Finch, 1964), while in chronic renal disease increased transferrin saturation
has been shown to be related to increased reticuloendothelial iron stores (Eschbach el al.,
1967). This latter relationship was confirmed in this study in which non-erythroid iron turnover
was abnormally high in all patients with transferrin saturations greater than 50%. The relationship between transferrin saturation and iron absorption in these subjects is shown in Fig. 1.
Absorption was increased in all but one patient when transferrin saturation fell below 18%
whereas absorption was normal or depressed in the other two patient groups.
Anaemia has been considered a stimulus for iron absorption (Mendel, 1961). However,
Iron absorption in chronic renal disease
195
absorption was not enhanced in the iron overload and normal iron balance groups despite the
presence of anaemia in all patients.
There was a significant correlation between erythropoiesis and absorption (r = 0.572,
P < 0.05). Although this seems consistent with the relationship between erythropoiesis and iron
absorption proposed by other investigators (Bothwell et al., 1958), close scrutiny of the data
suggests that this relationship is an indirect one, mediated by changes in iron stores. Actually
erythropoiesis in the iron depleted group was comparable to that in the normal subject, so that
the increased absorption cannot be attributed to increased erythropoiesis. The normal level of
erythropoiesis did mean that subjects required no transfusions and usually led to iron depletion
from blood loss associated with dialysis. Those patients with depressed erythropoiesis, on the
other hand, developed iron overload from transfusion. Thus, the level of erythropoiesis does
affect iron balance and thereby iron absorption. The lack of direct relationship between
erythropoiesis and absorption is illustrated by observations on individual patients. For
example, L.M. had a subnormal erythropoiesis when she was iron deficient, yet absorption was
enhanced. Conversely, E.M., when iron replete, had a relatively active erythropoiesis yet
absorption was low.
Erythropoietin was assayed to determine if its presence might be a common factor between
increased absorption and the relatively increased erythropoiesis. Erythropoietin levels were
measured in thirty-two patients, and eleven of these showed detectable erythropoietin activity.
Absorption in the seven patients with iron deficiency who showed measurable erythropoietin
was similar (average absorption 62%) to the seven with no demonstrable erythropoietin (average absorption 65%) so that no evidence was found to support this thesis.
These studies, especially as they relate to iron deficient patients, indicate that absorption
of inorganic iron in chronic renal disease is normal. Absorption showed changes according to
the iron status of the individual patient. The effectiveness of absorption is also shown by the
satisfactory response of iron deficient patients with renal failure when given medicinal oral
iron (Comty, McDade & Kaye, 1968).
Although the mechanism of absorption of inorganic iron may be unimpaired in chronic renal
disease, alterations in iron balance produced by therapy exceed normal compensatory mechanisms. Obligatory iron overload occurs when iron administered as transfused red cells exceeds
the 1-2 mg per day which the body can excrete (Bothwell & Finch, 1962). On the other hand,
iron depletion occurs when the amount of blood lost in the haemodialyser (a minimum of 5
ml of red cells containing 5 mg of iron remains in the Kiil haemodialyser after use), from blood
sampling and menstruation exceeds the 2-3 mg of iron per day which may be absorbed from
diet. Thus, iron balance in these patients is largely predictable from the magnitude of blood
loss on the one hand and frequency of transfusion on the other.
ACKNOWLEDGMENTS
We are indebted to Mrs Mary Eng and Mrs Kari Hollung for technical assistance, and to Dr
J. W. Adamson and Dr R. D. Woodson for the erythropoietin assays. This investigation was
supported by U.S. Public Health Service Research grant No. 5-R01-HE-06242, NIH Training
grant No. TI-AM-5130 and NIH Research grant No. AM-06741. A portion of this work was
conducted through the Clinical Research facility of the University of Washington supported by
NIH grant No. FR-37.
196
J. W . Eschbach, J. D. Cook and C.A . Finch
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