Acta med. scand. Vol. 199, pp. 113-1 19, 1976

Iron Absorption in Patients with Chronic Uremia Undergoing Regular Hemodialysis Nils Milman and Lars Larsen From Medicul Department P , Divisions of' Neplirology und Gastroenterology. Rigshospitalet,Copenhagen Denmark ~

ABSTRACT. Gastrointestinal iron absorption has been measured by whole body counting in 17 patients with chronic uremia undergoing regular hemodialysis. Absorption was expressed as whole body retention 14 days after oral administration of 10 pCi "Fe together with a carrier dose of 10 mg Fez+. The percentage incorporation in the total erythrocyte mass of administered W e (erythrocyte incorporation) and absorbed "Fe (red cell utilization) was estimated as well. Geometric mean iron absorption was 14.3k2.0 (S.D.) % and significantly higher than the value obtained in a normal control group QKO.03). Geometric mean erythrocyte incorporation was 11.61t2.3 (S.D.) % and arithmetic mean red cell utilization was 84.4f6.0 (S.E.M.) %. Neither of these parameters differed from corresponding values in the control group @>0.1 andp>0.2, respectively). The correlation between iron absorption and erythrocyte incorporation was highly significant (r=O.!M, p < 0.001). Patients on regular hernodialysis are subjected to considerable iron loss which should be treated by iron supplementation; oral iron administration is recommended in view of the adequate gastrointestinal absorption.

The uremic condition is almost invariably accompanied by a more or less pronounced anemia which in the predialytic stage is usually of slight degree, neither restricting physical activities nor requiring blood transfusions (3 I ) . During regular dialysis treatment (RDT) the anemia is accentuated and becomes a prominent therapeutic problem, influencing the well-being and working capacity of the patients. Primarily the anemia emerges from a deficient erythropoiesis due to insufficient production of renal erythropoietic stimulating factor ( 2 , 12, 15). 8-75298 I

Other reasons are a reduced red blood cell life span (2, 5, 15) and a considerable blood loss in connection with dialyses and blood sampling (3, 5 , 20). Marrow depression by uremic toxins should also be taken into account as dialytic therapy improves the rate of erythropoiesis (2, 14, 24). Erythropoietic stimulating factor is not available for clinical use and regular blood transfusions, which used to be regarded as inevitable in RDT ( I I ) , have now been abandoned as a routine treatment of the anemia as a consequence of their clear disadvantages (7, 14, 22, 30). The therapeutic measures have been aimed instead at blood-saving procedures and at providing optimal conditions for erythropoiesis by securing adequate supplies of factors necessary in Hb formation, including iron. The appreciable iron loss in RDT makes great demands on gastrointestinal absorptive capacity. Previous investigations on this subject have yielded contradictory results (3, 5 , 7 , 13, 26) and the present study was undertaken to reexamine gastrointestinal iron absorption in patients undergoing RDT and assess whether oral iron therapy alone is sufficient to maintain the iron balance or whether parenteral iron supplementation is indicated.

PATIENT MATERIAL Seventeen patients ( I 2 males, 5 females) participated in the study. Further data are given i n Table 1. All had a 24-hour endogenous creatinine clearance of S O . I ml/min and had been on dialytic treatment during 1 4 9 months (mean 23). Dialysis was performed for 8 to 10 hours twice weekly using the Gambro-Lundia& artificial kidney. All patients were taking a protein-, sodium-, and potassiumrestricted diet containing an average of 0.9 g protein/kg b.wt./day together with vitamin supplements, except foActa med. scand. 199

114 N. Milman and L . Larsen

Table I . Clinical, renal and hematological datu on 17 patients on regular hernodialysis, investigated f o r iron absorption

Pat. no.

Sex

Age (y.)

I

6

23

2 3

6 6 6 6 6

52 28 32 26 55 32 54 36 39 54 42

4 5 6 7 8 9 10 I1 12

6

6 6 6 6 6

13 14 15 16

0 0

38 38 36 35

17

0

50

An thmetic mean S.D. Normal

P 0

Diagnosis Hereditary nephropathy (A1port) Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Nephrosclerosis Chronic glomerulonephritis Chronic glomerulonephritis Chronic glomerulonephritis Polycystic kidneys Chronic pyelonephritis Bilateral nephrectomy (nephrosclerosis) Chronic glomerulonephritis Chronic glomerulonephritis Primary hyperoxaluria Bilateral nephrectomy (acute glomerulonephritis) Bilateral nephrectomy (polycystic kidneys)

39

Serum creatinine (mmol/l)

Erythrocyte folate (nmol/l)

28

592

0.90 1.70 1.60 1.60 1.39 1.72 I.18 I .65 1.34 1.26 1.54

29 32 27 37 34 35 32 30 23 44

599 65 I 703 903 51 I 629 303 477 444 348 688

1.41 I .67 1.22 0.95

30 33 36 27

950 340 548 5 10

I97 807 665 326

375 47 I 346 274

1.24

29

385

425

3 I9

1.39

31

564

449

34 1

6

183

~0.13

late, which was given to only one patient (no. 3). Aluminium aminoacetate was administered in order to correct hyperphosphatemia. None of the patients had been subjected to gastrointestinal surgery or had clinical signs of malassimilation or infection; four females were menstruating. All patients had negative Coombs’ test and normal serum bilirubin. In 13 patients achlorhydria was excluded by the pentagastrin test. Blood sampling was restricted to a minimum, biochemical monitoring being made once or twice monthly. Blood transfusions were avoided as a routine, but two nephrectomized patients (nos. 16 and 17) required regular transfusions, which were withheld 2 weeks before and during the investigation. Most patients received peroral iron therapy as ferrous fumarate, 200 mg (66 mg elemental Fe’+), together with ascorbic acid, 250 mg, thrice daily; this treatment was discontinued at least 2 weeks before and during the iron absorption test.

METHODS Iron absorption was measured by whole body counting-using the whole body monitor-by the method described in a previous paper (25). All non-vital medicine, including aluminium aminoacetate, was withheld for 4 days before the study and blood sampling was avoided in Actn med. scnnd. 199

Serum B12 (pmol/l)

1.21

0.26

10

Serum urea (mmol/l)

18

~ 7 . 5

140-600

206

Erythrocyte glucose-6phosphate dehydrogenase (Uimean erythrocyte)

480 (2 300) 340 415 492 737 723 I95 567 610

2 30 247-665

318 253 507 3 29 403 335 212 550 344 I98 365 320

92 205-320

the investigation period. Measurements of the whole body 59Feactivity were performed at 4 hours and 14 days after the oral administration of 10 pCi 59Fetogether with 9 . 9 mg Fez+ (as sulphate) as carrier to the fasting subject and corrected for background and radioactive decay before calculation of the percentage absorption of iron. Erythrocyte volume was estimated according to the method described by Jarnum (23) and at the last counting procedure blood samples were drawn in order to assess the ”Fe activity. From these measurements were calculated the erythrocyte iron incorporation (EIC), i.e. the percentage of administered “Fe recovered in the total erythrocyte mass, and red cell utilization, i.e. the percentage of absorbed 5uFerecovered in the erythrocytes. Hb values were calculated as the averages of pre- and postdialytic measurements within two months before the study and serum creatinine and serum urea were taken as the averages of predialytic values in the same period. Hematological parameters. including Hb. mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), hematocrit, serum iron. plasma transferrin. plasma total iron-binding capacity (TIBC). erythrocyte glucose-6-phosphate dehydrogenase, erythrocyte folate and serum vitamin B,,, were estimated by procedures described earlier (25. 3 1 ) and reticulocyte counts were corrected for anemia (35). Bone marrow specimens were obtained by iliac crest

Iron absorption in chronic uremia

Table 11. Hemntologicul tkuta, iron nhsorption h ernodiu1.vsis

Pat. no.

Geometric mean S.D. Normal range 7.0-10.5

~rythrocytrincvrporcrtion in 17 patients on regular

Transferrin saturation (7%)

(fl)

Plasma Serum transPlasma iron ferrin TlBC (+rnol/l) (+mol/l) (pmolfl)

15 21 27 12 3

20.4 20.5 21.8 19.3 19.0 18.8 20.0 19.5 21.0 20.3 20.0 21.8 20.1 22.0 21.5 21.7 20.0

89 89 I02 I02 91 102 87 98 95 90 108 90 98 91 82 101 97

9.3 IS. I 16.5 33.4 35.6 9.8 17.3 9.6 21.8 8.8 15.5 17.3 16.9 14. I 12.3 36.4 14.3

26.8 25.6 32.7 23.4 21.7 27.6 22.2 29.8 23.5 22.3 26.8 20.3 28.8 34.4 39.9 21.0 20.3

53.6 51.2 65.4 46.8 43.4 55.2 44.4 59.6 47.0 44.6 53.6 40.6 57.6 68.8 79.8 42.0 40.6

17.4 29.5 25.2 71.4 82.0 17.8 39.0 16.1 46.4 19.7 28.9 42.6 29.3 20.5 15.4 86.7 35.2

15 8

20.5 I .o

95 7

17.9 8.9

26.3 5.5

52.6 11.0

36.7 22.8

Hb (mmol/l) (1/1000) (mmol/l)

I 6.1 2 4.5 3 2.6 4 3.2 5 2.1 6 3.4 7 4.6 8 3.0 9 4.5 10 4.4 II 3.3 12 3.1 13 3.7 14 2.9 15 5.4 16 4.2 17 2.7 Arithmetic mean 3.8 S.D. 1.1

'I

Corrected reticulocyte count MCHC

rind

16 6 12 9 18 21 9 I8 31 18 25 1

(12

18.6-22.3

MCV

81-109

I I5

10.7-34.0 24.2-47.7 48.4-95.4

Marrow 59Fe iron absorption EIC ( M + )(%) (%') 2+ I+ 2+ I+ 2+ I+ 2+ 2+ I+ 240 I+ 0 0 I+

-

3+

16.3 8.7 20.6 9.6 5.3 46.4 7.0 18.4 25.4 15.4 18.9 5.0 9.4 21.2 54.4 5.9 20.6

7.7 18.3 5.1 5.7 35.0 5.5 18.3 22.9 10.0 20.6 3.6 12.5 19.5 64.6 2.6 9.4

18. I 13.8

16. I 15. I

14.3 2.0

11.6 2.3

11.0

1.9-38.3" 1.6-37.0"

Larsen & Milman (25).

puncture, stained for iron with Prussian blue, whereafter the iron content was graded according to Rath and Finch (33). The Institute of Pathology, Rigshospitalet, provided with help and advice in the technical preparation and assessment of the marrow aspirates and liver biopsies. In 3 patients the stainable liver iron content was assessed as well. The controi group consisted of 27 healthy subjects. Details concerning this group have been reported in a previous publication (25). Logarithmic transformation of the values for iron absorption and EIC was performed and employed in the calculation of the geometric mean according to Cook et al. (9). In the statistical analysis, regression lines were calculated according to the method of least squares and the Mann-Whitney rank sum test was used to evaluate significant differences between patients on RDT and controls.

RESULTS Clinical, hematological and biochemical data, together with values for iron absorption and EIC, are shown in Tables I and 11.

Iron absorption m d erythrocyte incorporution of 59Fe In the patients, iron absorption ranged from 5.3 to 54.496, with an arithmetic mean of 18.1213.8 (S.D.)%(Fig. I ) and a geometric mean of 14.3k2.0 (S.D.)%. EIC ranged from 2.6 to 64.6%, with a geometric mean of I1.6k2.3 (S.D.)%. Red cell utilization of absorbed "YFe averaged 84.4k6.0 (S.E.M.) % (arithmetic mean); 15 patients had values above 60%, while the two patients who received regular transfusions had values around 45 %. The control group had an arithmetic mean iron absorption of 11.5? 10.4 (S.D.)% and a geometric mean absorption of 8.5+2. I (S.D.)%. Geometric mean EIC was 7.722.2 (S.D.) %, while arithmetic mean red cell utilization was 92.9k4.0 (S.E.M.)% (25). Iron absorption was higher in the patients compared to the controls (pO. I and p>0.2, respectively). Acra med. scand. 199

116 N . Milrnan und L. Larsen

. .

60-

50 -

I

-6

. .

0

1 0

0

w

.. . .

r =-0.54 p < 0.05

.

% a

0 0

'

a

b.

3

*

b -

20

40

60

1W

80

Transferrin saturation, per cent Patients in dialysis

Fig. 3 . Relation between transferrin saturation and iron

Control subjects

Fig. 1 . Absorption of 58Fein patients undergoing regular

absorption in dialysis patients.

hemodialysis and in controls.

and the corrected reticulocyte count (r=0.59, p < The correlation between iron absorption and EIC was highly significant in patients (r=0.94, p