INTRODUCTION

 

Corresponding Author: Imuetinyan R Edeki, Department of Internal medicine, University of Benin Teaching Hospital, PMB 1111, Edo State, Nigeria. teeidubor@yahoo.com

Anaemia is a frequent complication of CKD, with iron deficiency being the commonest cause of anaemia.1,2Iron supplementation whether oral or parenteral, is essential in treatment of anaemia in CKD.3

 

Intravenous iron therapy is used when rapid haemoglobin response is required and this may delay the need for commencement of erythropoiesis stimulating agents (ESA).4 Iron therapy when used alone may be effective in treatment of anaemia in pre-dialysis CKD patients.5Parenteral iron is reported to be more effective than oral iron supplementation in CKD patients due to better systemic absorption and improved bioavailability.5Oral iron therapy is associated with some gastrointestinal side effects,6 reduced intestinal absorption due to gut oedema,7 increased degradation by gastric juices and limited bioavailability due to hepatic first-pass effect.5

In pre-dialysis patients with CKD, the choice of route of iron administration is based on severity of iron deficiency, availability of venous access, response to prior oral iron therapy, cost, patient compliance and side effects of prior oral or intravenous iron therapy.5 However, oral therapy is not recommended for use in patients with CKD on dialysis.5

Parenteral iron therapy may rarely be associated with anaphylactic reactions, increased risk of infection, iron deposition in tissues and renal tubular toxicity when given in excess.8 Rarely, adverse reactions to intravenous iron administration may include difficulty in breathing, hypotension, hypertension, pruritus, nausea and vomiting, chest pain, fever and dizziness.9

The rationale for the use of iron therapy in CKD are to ensure adequate iron stores for erythropoiesis, to prevent iron deficiency as well as to correct iron deficiency anaemia. Various guidelines have stated the need for routine iron therapy in patients with CKD patients.5,10,11 Several studies have also shown the effectiveness of parenteral iron supplementation over oral administration in CKD with varying limitations.10,11,12 These limitations include paucity of knowledge on the long-term clinical benefits of iron therapy (aside the direct effect on haemoglobin) and long-term adverse effects of iron therapy when given in excess of what is required- ventricular arrhythmias, heart failure and worsening carotid atherosclerosis.13,14

Although knowledge of iron studies will better guide physicians on appropriate dose and frequency of iron therapy, routine iron studies are rarely carried out in Nigerian CKD patients prior to parenteral iron therapy. This is probably because the tests are expensive and are not readily available in most Nigerian hospitals.

There are varying reports on the effectiveness of the standard dosing regimen of parenteral iron therapy used in patients with CKD as calculated iron doses are rarely used locally, thus the purpose of this study.

 

METHODOLOGY

This was a single-centre cross-sectional study conducted at the Nephrology clinic at the University of Benin Teaching hospital, southern Nigeria from March 2021 to January 2022. Ninety-five pre-dialysis CKD patients were consecutively recruited for the study. Twenty-three (24.2%) patients were found to have iron deficiency anaemia and were subsequently studied. Inclusion criteria were iron deficient anaemic CKD patients aged 18years and above who gave informed consent. Pregnant CKD patients as well as those with haemoglobinopathies, human immunodeficiency virus, known malignancies, chronic infections, recent blood transfusion in the preceding 4 weeks and those on ESA were excluded. A researcher administered questionnaire was used to obtain socio-demographic and clinical information from each participant.

Pre-intervention tests included-full blood count (FBC) including red cell indices, serum ferritin, transferrin saturation (TSAT), folate, vitamin B12, erythropoietin (EPO) and C-reactive protein, while post-intervention tests (FBC, serum ferritin and TSAT) were repeated 2 weeks after last dose of parenteral iron.

Iron deficiency anaemia was defined as iron deficiency with PCV less than 30%or Hb concentration<10g/dl.5,15

Iron deficiency was defined as TSAT <20%.5Participants with iron deficiency anaemia were given iron sucrose 200mg as an intravenous infusion (given in 200 millilitres of normal saline over 20 – 30 minutes, after a negative test dose) weekly for 5 weeks (a total dose of 1g), following which a repeat of investigations was done 2 weeks after. Resuscitation drugs were available prior to commencement of parenteral iron therapy and a trained medical personnel present to observe participants.

Adequate response to intravenous iron sucrose therapy was defined as increase in haemoglobin concentration by at least 1g/dl (or PCV rise of 3%) from baseline level at end of study.16

Inadequate response to iron therapy was defined as increase in PCV > 1% but < 3% post iron therapy while no response to iron therapy was defined as increment in PCV < 1% post iron therapy.

Data were analysed using IBM SPSS version 20, with normally distributed data expressed as means and standard deviation. Categorical data were expressed as frequency and proportion while chi- square and Fisher’s exact test were used in determining significant association between categorical variables. Paired t test was used to compare mean values of two related groups for unskewed data, while one way analysis of variance was used to determine statistically significant differences between the means of at least 3 independent groups. P value < 0.05 was set as level of significance.

 

RESULTS

The 23 pre-dialysis CKD patients in this study had a mean age of 58.1±14.9years, comprising of 9(39.1%) males and 14(60.9%) females. Majority were aged 50 years and above with secondary level of education. There was 1(4.3%) participant in CKD stage 2, 6(26.1%) in stage 3, 10(43.5%) in CKD stage 4 and 6(26.1%) in CKD stage 5. Diabetes mellitus (47.8%) was the most common cause of CKD followed by hypertension (39.2%) and chronic glomerulonephritis (8.7%). Table 1

The mean PCV pre-parenteral iron therapy and post-parenteral iron therapy in iron-deficient patients with CKD was 28.4 ± 4.7% and 30.4 ± 3.7% respectively (p<0.001). The mean PCV change following parenteral iron therapy was 2.0± 1.8%. There was also significant increase in mean haemoglobin concentration (9.5 ± 1.6 vs. 10.3 ± 1.4 g/dl) and red blood cell count (3.6 ± 0.8 vs. 3.8 ± 0.6 x 106 cells/mm3) following parenteral iron therapy (p<0.001). Mean MCV (82.0 ± 8.4 vs. 85.1± 4.9 fL; p =0.003) andMCH (27.1 ± 2.8vs. 28.4 ± 2.2 pg; p= 0.006) were also increased following iron therapy.

Ferritin levels increased significantly from 120.4± 46.9 to 211.2 ± 36.7 µg/L post therapy (p = 0.001). Similarly, TSAT levels increased significantly (20.5 ± 6.0 to 27.9 ± 16.9%) following parenteral iron therapy. (p- 0.011) Table 2

Three (13%) of iron - deficient subjects with CKD had optimal response to iron therapy. Sixteen (69.6%) had inadequate response while 4 (17.4%) had no response to iron therapy. Table 2

Mean baseline PCV and EPO in those with adequate response to iron therapy was lower than those who had inadequate and no response but this did not reach statistical significance (p = 0.143). A comparison of baseline PCV of those with adequate, inadequate and no response in a post-hoc analysis using Fisher’s least significance difference test, showed that those that had adequate response had significantly lower haematocrit (p = 0.13). Table 4

Age, gender, CKD stage, folate, vitamin B12 and EPO levels did not significantly affect response to parenteral iron therapy. Table 3 and 4

 

DISCUSSION

This study assessed the effectiveness of parenteral iron therapy in pre-dialysis iron deficient anaemic patients with chronic kidney disease. Although the mean PCV, Hb concentration, red blood cell count serum feritin and TSA significantly improved in iron deficient anaemic patients with CKD following parenteral iron therapy, PCV response was generally inadequate.

There was a significant mean PCV increase of 2.0± 1.8%. This is similar to a mean PCV increase of 2.42± 1.98% following intravenous iron therapy reported by Arogundade et al.17This could be explained by the fact that similar total doses of parenteral iron was used in both studies.

Similarly, there was no statistically significant difference in total white blood cell and platelet count. These findings are in consonance to findings by Fish bane et al18 and Silverberg et al19 in hemodialysis and pre-dialysis CKD patients respectively. However, contrary to this finding, iron therapy is known to reduce total white blood cell count as it transiently causes leucopoiesis and megakaryopoiesis decline.20,21

Serum ferritin and TSAT were also increased among participants and is similar to findings of the FIND-CKD11 and DRIVE12studies. Parenteral iron is known to rapidly improve iron stores as well as circulating iron and delays the need for commencement of erythropoiesis stimulating agents (ESA) as well as reducing ESA dose when required.22Parenteral iron therapy has also been reported to improve cardiac health in heart failure which is a common complication in CKD.23Iron sucrose used is safe with little or no reported incidence of adverse drug event and is comparable in safety to newer iron formulations.24 In this study, one (4%) participant reported nausea during parenteral iron administration which was noticed 20 minutes after commencement of the first iron dose, this is in contrast with the study by Arogundade et al17who reported moderate adverse drug events in 24.9% of study participants. The reason for this may be the use of iron dextran in the study by Arogundade et al,17which has poor tolerability compared to iron sucrose and its use is now obsolete.25

Parenteral iron administration in this study was given as an intravenous bolus injection which involved administering small doses of iron over a period of 5 weeks. On the other hand, parenteral iron administered in the study by Arogundade et al17 was by total dose infusion, where calculated iron required for each patient is given in a single hospital visit. The advantage of the total dose infusion over the intravenous bolus injection is lower cost in terms of time spent in the hospital and transportation. On the other hand, the incidence of adverse drug reactions will be increased with the total dose infusion.

Age, gender, stage of CKD, baseline PCV, folic acid and vitamin B12 did not significantly influence the response to parenteral therapy. A 2-year retrospective study in the United Kingdom (UK) reported better Hb response following parenteral iron therapy in those with lower baseline PCV and later CKD stages 3-5 compared to those with stages 1-2.26This report is different from the finding of this present study. This difference may be explained by the relatively small sample size compared to the study done in UK. However, Chukwu et al26 did not find significant influence of age and gender on Hb response as seen in this study. Iron deficiency affects metabolic pathways of vitamin B12 and folate and their serum levels has been reported to increase following iron therapy in non-CKD population.27

The higher mean EPO among non-responders may be related to poor iron utilisation due to the effect of hepcidin and will need further exploration.

In conclusion, the mean PCV, red cell indices, serum ferritin and TSAT significantly improved in iron deficient anaemic pre-dialysis patients with CKD after 5 weeks of parenteral iron therapy, response to parenteral iron therapy was generally inadequate. The use and safety of parenteral iron sucrose therapy in pre-dialysis CKD patients cannot be over-emphasized. It is however recommended that total iron dosage be calculated for individual patient so as to achieve optimal response.

Acknowledgements: We acknowledge all study participants for their willingness to participate in the study

Conflict of interest: None declared

Funding: Self-funded

Table1: Socio-demographic characteristics, stage and Aetiology of CKD

	CKD WITH IDA (n=23)
Age group (years)
<50	7 (30.4)
≥50	16 (69.6)
Mean age   Gender	58.1±14.9
Male	9 (39.1)
Female	14 (60.9)
Education
Primary	3 (13.0)
Secondary	12 (39.2)
Tertiary	8 (34.8)
CKD Aetiology
DM	11 (47.8)
HTN	9 (39.2)
CGN	2 (8.7)
ADPKD	1 (4.3)
CKD Stage
Stage II	1 (4.3)
Stage III	6 (29.1)
Stage IV	10 (43.5)
Stage V	6 (26.1)

IDA- iron deficiency anaemia, DM-diabetes mellitus, HTN- hypertension, CGN- chronic glomerulonephritis, ADPKD- autosomal dominant polycystic kidney disease

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 2: Pre- and Post- Iron Therapy parameters (N= 23)

	Pre - Iron therapy n = 23	Post - Iron therapy n = 23	P value
	Mean ± SD	Mean ± SD
Hb (g/dl)	9.5 ±1.6	10.3 ± 1.4	<0.001
PCV (%)	28.4 ± 4.7	30.4 ± 3.7	<0.001
RBC (x 106cells/mm3)	3.6 ± 0.8	3.8 ± 0.6	0.027
MCV (fl)	82.0 ± 8.4	85.1 ± 4.9	0.003
MCH (pg)	27.1 ± 2.8	28.4 ± 2.2	0.006
MCHC (g/dl)	33.7 ± 1.4	33.2 ±1.8	0.067
RDW (%)	16.6 ± 3.1	13.8 ± 2.2	0.001
WBC (x 103cells/mm3)	5.8 ± 2.3	5.6 ± 1.6	0.525
GRA (%)	61.0 ± 11.5	65.4 ± 6.7	0.002
Lymphocyte (%)	31.4 ± 11.1	28.2 ± 6.9	0.015
Monocytes (%)	7.8 ± 2.7	6.6 ± 2.7	0.020
Platelets (x 103cells/mm3)	249.0 ± 129.5	248.8 ± 95.5	0.991
Ferritin (ng/ml)	120.4 ± 46.9	211.2 ± 36.7	0.001
TSAT (%)	20.5 ± 6.0	27.9 ± 16.9	0.011

Hb- haemoglobin, PCV- packed cell volume, RBC- red blood cell, MCV- mean corpuscular volume, MCHC- mean corpuscular haemoglobin concentration, MCH- mean corpuscular haemoglobin , RDW- Red cell distribution width, WBC- white blood cell, GRA-granulocytes, TSAT-transferrin saturation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3: Association between age, gender, stage of CKD and response to iron therapy (N= 23)

	Optimal responders n= 3	Inadequate responders n= 16	Non responders n= 4	P value
Age group(years)
<50	2 (66.7)	5 (31.3)	0 (0.0)
≥50	1 (33.3)	11 (68.7)	4 (100.0)	0.228
Gender
Male	1 (33.3)	6 (37.5)	2 (50.0)	0.685
Female	2 (66.7)	10 (62.5)	2 (50.0)
Stage of CKD
II	0 (0.0)	1 (6.3)	0 (0.0)
III	0 (0.0)	6 (37.5)	0 (0.0)	0.237
IV	0 (0.0)	7 (43.8)	3 (75.0)
V	3 (100.0)	2 (12.5)	1 (25.0)

CKD-chronic kidney disease

 

Table 4: Factors influencing response to iron therapy (N=23)       

	Optimal responders n=3	Inadequate responders n=16	Non responders n=4	P value
	Mean ± SD	Mean ± SD	Mean ± SD
Baseline PCV (%)	26.4 ± 1.7	31.0 ± 3.8	31.1 ± 3.0	0.143
CRP (ng/ml)	5.1 ± 3.6	4.6 ± 2.4	7.0 ± 0.4	0.203
Folate (ng/ml)	2.5 ± 2.0	3.8 ± 3.5	2.6 ± 3.1	0.702
Vitamin B12 (pg/ml)	210.8 ± 33.6	219.5 ± 155.3	178.1 ± 76.0	0.867
EPO (miu/l)	124.0 ± 12.0	143.9 ± 56.2	281.9 ± 308.4	0.161

PCV- packed cell volume, CRP-C reactive protein, EPO- erythropoietin

Ethical Consideration

Ethical Committee of University of Benin Teaching Hospital approved the study protocol with a reference number of ADM/E 22/A/Vol.VII/148220. Written informed consent was obtained from all study participants and information obtained was treated with utmost confidentiality.

 

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