Nigerian Postgraduate Medical Journal

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 25  |  Issue : 4  |  Page : 197--203

Assessment of iron deficiency anaemia and its risk factors among adults with chronic kidney disease in a tertiary hospital in Nigeria


Yemi Raheem Raji1, Samuel Oluwole Ajayi1, Titilola Stella Akingbola2, Olupelumi A Adebiyi3, Kayode S Adedapo4, Batunde Lawal Salako5,  
1 Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
2 Department of Haematology, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
3 Department of Community Medicine and Prevention, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
4 Department of Chemical Pathology, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
5 Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Oyo State; Department of Clinical Sciences, Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria

Correspondence Address:
Dr. Yemi Raheem Raji
Department of Medicine, College of Medicine, University of Ibadan and University College Hospital, Ibadan, Oyo State
Nigeria

Abstract

Introduction: A substantial proportion of patients with chronic kidney disease (CKD) develop iron deficiency anaemia (IDA). Despite the association of IDA with adverse cardiovascular outcomes, it remains underdiagnosed and poorly managed. Up to 70% of patients with CKD are anaemic at the time of initiating dialysis, while the predictors of IDA in these patients in our setting are unknown. This study aimed to determine the prevalence and risk factors for IDA in patients with CKD. Materials and Methods: This is a case–control study of 157 patients with CKD and 157 age and gender matched subjects without CKD. Information obtained from the participants were socio-demographic details, aetiology of CKD, medication history and features of IDA. All participants had serum ferritin, total iron binding capacity (TIBC), transferrin saturation (TSAT), highly sensitive C-reactive protein, serum creatinine and complete blood count determined. Results: The median estimated glomerular rate (22.7 [3.4–59.5] vs. 110.2 [60.3–152.8] ml/min/1.73 m2, P < 0.01), the mean haemoglobin concentration (9.3 ± 2.6 vs. 11.4 ± 1.7 g/dl, P < 0.01), and TSAT (27.9% ± 6.4% vs. 34.8% ± 8.1%, P < 0.04) were significantly lower in patients with CKD. The mean age, serum ferritin and TIBC were similar in both groups. The prevalence of absolute (24.8% vs. 13.4%, P < 0.01) and relative (17.8% vs. 7.6%, P < 0.01) iron deficiencies were higher among individuals with CKD compared to the controls. Female gender (odd ratio [OR]:1.50, 95% confidence interval [CI]:1.0267–4.1163, P < 0.04) and severity of CKD (OR: 3.43, 95% CI: 1.5568–7.8324, P < 0.02) were independently associated with IDA. Conclusion: IDA is common among individuals with CKD while female gender and severity of CKD were factors that independently predicted IDA.



How to cite this article:
Raji YR, Ajayi SO, Akingbola TS, Adebiyi OA, Adedapo KS, Salako BL. Assessment of iron deficiency anaemia and its risk factors among adults with chronic kidney disease in a tertiary hospital in Nigeria.Niger Postgrad Med J 2018;25:197-203


How to cite this URL:
Raji YR, Ajayi SO, Akingbola TS, Adebiyi OA, Adedapo KS, Salako BL. Assessment of iron deficiency anaemia and its risk factors among adults with chronic kidney disease in a tertiary hospital in Nigeria. Niger Postgrad Med J [serial online] 2018 [cited 2019 Aug 22 ];25:197-203
Available from: http://www.npmj.org/text.asp?2018/25/4/197/248204


Full Text

 Introduction



Chronic kidney disease (CKD) is a disease of public health importance associated with rising prevalence, high morbidity and mortality and the exorbitant cost of treatment.[1],[2] The prevalence of CKD worldwide is between 10% and 20% of the world population.[2],[3],[4] In Nigeria, findings from various population-based screening across the country estimated CKD prevalence to be between 8% and 30%.[5],[6],[7],[8],[9] Anaemia is a common finding in patients with CKD and usually, the degree of anaemia corresponds with the severity of the kidney disease.[10],[11] Renal anaemia starts early in the disease process and becomes progressive if not promptly treated.[12] Using the World Health Organisation criteria, up to 90% of patients with an estimated glomerular filtration rate (eGFR) <25 ml/min/1.73 m2 have anaemia, many of whom have haemoglobin levels <10 g/dl. It was further reported that even at CKD stages 1–2, approximately a quarter of patients have a haemoglobin concentration ≤12 g/dL.[13],[14],[15] Anaemia of CKD is an independent risk factor for both cardiovascular morbidity and mortality.[16],[17] The single most important mechanism of anaemia in CKD is reduced production of erythropoietin by the failing kidneys, other mechanisms include shortened red blood cell half-life, chronic blood loss, hyperparathyroidism, bone marrow depression, iron, folate and Vitamin B-12 deficiencies among others.

Normochromic normocytic anaemia is the most common type of anaemia in CKD, however a larger percentage of CKD patients have iron deficiency anaemia (IDA), especially with the use of erythropoiesis-stimulating agents (ESA), indeed IDA affects patients at all stages of CKD.[10],[18],[19] Iron deficiency could be absolute or functional, in absolute iron deficiency there is inadequate iron store while in functional iron deficiency there is the inadequate availability of iron for erythropoiesis despite adequate iron store. Data from the third National Health and Nutritional Examination Survey (NHANES III) confirmed that approximately 60% of males and 70% of females with reduced eGFR had low iron status.[20] Despite the association of IDA with adverse cardiovascular outcomes, rapid progression to end-stage renal disease (ESRD), diminished quality of life and high mortality, it remains underdiagnosed and poorly managed, with up to 70% of patients with CKD are having anaemia at the time of initiating dialysis.[20],[21] In addition, only few studies[22],[23] have assessed the correlates of IDA among patients with CKD in Nigeria and such studies are characterised by small sample sizes. This study, therefore, aimed to determine the prevalence and risk factors for IDA among patients with CKD.

 Materials and Methods



Ethical consideration

Ethical approval was obtained from the Joint University of Ibadan and University College Hospital Ethics Committee, Ibadan and the ethical approval was gotten on the 7 May, 2015 with the approved protocol number UI/EC/14/0314. The study adhered to the Declaration of Helsinki and written informed consent was obtained from all participants.

Study design and participants

This is a case–control study of 157 patients with CKD and 157 age and matched apparently healthy controls who were individuals without CKD. The patients with CKD were recruited from the renal clinic, medical wards and the dialysis centre of the University College Hospital, Ibadan, Oyo State, South West Nigeria. The CKD cases were consecutively presenting and consenting adults while the controls were age and gender matched volunteers. The study was carried out between 1 June, 2015 and 31 July, 2016.

Subject selection

Inclusion criteria for the CKD patients were individuals aged 18 years and above, diagnosis of CKD and haemoglobin concentration of <12 g/dl in women and <13.5 g/dl in men. Included as controls were age and gender matched individuals who were 18 years and above and had no history of kidney disease. Those excluded from the study were individuals with other causes of anaemia (sickle cell disease, leukaemia, multiple myeloma and Human Immunodeficiency Virus infection), on-going blood loss, current febrile illness or those with history suggestive of inflammatory diseases and malignancy, while patients with highly sensitive C– reactive protein (hsCRP) >3 ng/L, were excluded from the analysis. The controls were recruited from volunteers who were staff and students of the University College Hospital and College of Medicine, University of Ibadan, Ibadan.

Sample size determination

The minimum sample size was calculated using standard statistical formula for case–control study.[24]

[INLINE:1]

N-Sample size calculated

r-ratio of cases to controls = 1

P–Prevalence of IDA in CKD population (0.56%)[25]

Zβ–Power set at 80% with value equals 0.84

Zα/2–Level of significance at 0.05 with value equals 1.96

P1–P2–Expected differences in cases and control 10%

[INLINE:2]

N = 81

Using a prevalence of IDA of 56.1% among patients with CKD reported by Arogundade et al.,[25] the minimum sample size with estimated nonresponse rate of 30% was 105 each in both the case and control groups. For this study, we enrolled a total of 157 each as cases and controls.

Data collection

Data were obtained using a standard case report form and the information obtained from the participants included socio-demographic details, duration of diagnosis of CKD, aetiology of CKD, duration on maintenance dialysis, current medications, history of oral iron intake, lifestyles and presence of comorbidity. Other information obtained were symptoms and signs of iron deficiency, and history of blood transfusion. Anthropometric measurements obtained from all participants were weight, height, waist and hip circumferences, in addition to the blood pressure check and examination for signs of iron deficiency (palor, angular stomatitis, glossitis and koilonychia).

Laboratory measurements

Ten millilitres of venous blood and 10 ml of spot urine were collected from each participant. The blood sample was analysed for full blood count, serum iron, ferritin, transferrin, hsCRP, electrolytes, urea and creatinine while the spot urine was used to determine the urinary albumin-creatinine ratio. Serum iron was determined using spectrophotometric method using a semi-autoanalyser (Jenway Spectrophotometer 6305 series, United Kingdom). Ferrozine methods of direct iron measurement was carried out and using surfactant to prevent protein precipitation,[26] with Iron-Ferrozine kit (Fortress Diagnostic, United Kingdom). Serum ferritin and transferrin were assayed using enzyme-linked immunosorbent assay (ELISA) kit (Cloud-Clone Corporation, United Kingdom).[27],[28] Serum hsCRP were assayed using ELISA kits[28] (Cloud-Clone Corporation, United Kingdom), All the ELISA assays were analysed using Emax ELISA Reader (Molecular Device, United States). Total iron binding capacity (TIBC) and transferrin saturation (TSAT) were calculated from the obtained serum iron, ferritin and transferrin, using iron indices equations.[29] eGFR was estimated from the serum creatinine using CKD Epidemiology Collaboration equation.[30]

Definition of terms

Anaemia was defined as haemoglobin concentration of <12 g/dl in females and <13.5 g/dl in males.[14] Functional iron deficiency was defined as serum ferritin >100 ng/ml and TSAT <20% while absolute iron deficiency was defined as serum ferritin <100 ng/ml and TSAT <20%.[14] Overall iron deficiency was defined as the presence of either absolute or functional iron efficiency.[14] An hsCRP >3 mg/L was taken as suggestive of an on-going infection or inflammatory process.[31] CKD was defined as eGFR <60 ml/min/1.73 m2 and/or albuminuria >30 mg/mmol lasting at least 3 months or the presence of markers of CKD at presentation, these markers include radiological or histological evidence of kidney damage.[32]

Statistical analysis

Data obtained was analysed using Statistical Package for Social Sciences Version 20 (IBM, Armonk, New York (NY), USA). Continuous variables were presented as means with standard deviation while categorical variables were presented as percentages and proportions. The difference between the means of continuous variables was determined using independent Student's t-test while those between categorical variables was tested using Chi-square statistics. For data that were not normally distributed Man–Whitney U-test and Kruskal–Wallis statistics were used for analysis. Independent risk factors for IDA were determined using multiple logistic regression statistics. In all situations a P < 0.05 was considered statistically significant.

 Results



A total of 314 participants were enrolled in the study, equal halves were individuals with CKD and age- and gender-matched controls. The mean ages were similar in both groups (CKD cases 45.5 ± 14.4 years vs. controls 46.0 ± 15.5 years, P < 0.75). Female participants were 56.3% of the cases and 50.1% of the controls. Majority of the participants had secondary school education or more, 82.8% in cases and 78.3% among the controls, P < 0.62, [Table 1]. Chronic glomerulonephritis was the leading cause of CKD (37.6%) among the participants with CKD while half of the participants with CKD were in stage 3 and one-third were ESRD on maintenance haemodialysis. A significantly higher proportion of patients with CKD were on oral (83.4% vs. 14.6%, P < 0.01) or intravenous iron therapy (37.5% vs. 0, P < 0.01) and ESA (18.5% vs. 0, P < 0.01) [Table 1].{Table 1}

The mode and range of the serum creatinine (282.9 [106.1–362.5] vs. 79.6 [44.2–309.4] mg/dl, P < 0.01) and urea (20.4 [10.6–49.8] vs. 6.7 [4.3–13.3] mg/dl, P < 0.01) were significantly higher among the CKD cases compared to the controls while the mode and range for eGFR (22.7 [3.4–59.5] vs. 110.2 [60.3–152.8] ml/min/1.73 m2, P < 0.01) was lower in the CKD group. The mean haemoglobin concentration (9.3 ± 2.6 vs. 11.4 ± 1.7 g/dl, P < 0.01), packed cell volume (27.8 ± 8.7 vs. 38.7 ± 5.2%, P < 0.01) and TSAT (27.9 ± 6.4 vs. 34.8 ± 8.1%., P < 0.04) were significantly lower in the CKD groups compared to the controls [Table 2]. The mean serum iron (102.8 ± 11.8 vs. 106 ± 13.3 μg/dl, P < 0.28), ferritin (320.5 ± 21.2 vs. 289.3 ± 18.9 ng/mL, P < 0.09) and TIBC (247.3 ± 13.1 vs. 256.6 ± 15.4 μg/dl, P < 0.53) were similar in both groups.{Table 2}

The prevalence of absolute (24.8% vs. 13.4%, P < 0.01), functional (17.8% vs. 7.6%, P < 0.01) and overall (42.6% vs. 21.0%, P < 0.01) IDA were significantly higher among the CKD group compared to the controls [Table 3]. Among all patients with IDA, absolute and functional IDA were observed in 58.2% and 41.8%, respectively. On bivariate analysis, age >45 years, female gender, severity of CKD, patients on haemodialysis and patients who were receiving weekly ESA were significantly associated with IDA [Table 4], while on multivariate analysis only female gender (odd ratio [OR]:1.50, 95% confidence interval [CI]: 1.0267–4.1163, P < 0.04) and severity of CKD (OR: 3.43, 95% CI: 1.5568–7.8324, P < 0.02) were independently associated with IDA [Table 5].{Table 3}{Table 4}{Table 5}

 Discussion



This study observed high prevalence of IDA (42.7%) among patients with CKD, of which almost three fifths had absolute iron deficiency while a little over two-fifths had functional IDA. Factors independently associated with IDA were gender and severity of CKD. The high prevalence of iron deficiency was despite high rate of oral iron intake among patients with CKD. The high prevalence of IDA (42.7%) among our patients was similar to reports by and Arogundade et al.[25] and Waziri et al.[33] who reported iron deficiency prevalence of 56.1% and 56.6%, respectively, among patients with CKD in Nigeria. Similarly, the prevalence of IDA was similar to the findings from the NHANES 1988–2004 data, where iron deficiency was observed in majority of participants with a creatinine clearance of <60 mL/min (CKD stages 3–5), the prevalence of absolute IDA was 57.8%–58.8% in men and 69.9%–72.8% in women.[20],[21] However, the prevalence of iron deficiency in our study was higher than 15% and 28.4% reported by Iimori et al.[34] and Post et al.[35] among nondialysis patients with CKD. The disparity in prevalence could be explained by the fact that latter studies included only the pre-dialysis CKD, unlike our study that included both pre-dialysis and dialysis patients with CKD. The lower prevalence in the studies also supports the progressive nature of IDA with worsening severity as the patients become dialysis dependent. Second, the exclusion of participants with evidence of inflammation (elevated hsCRP) in our study may have contributed to the high prevalence of iron deficiency among our patients.

The proportion of CKD patients with absolute iron deficiency observed in our cohort was 58.2%, and this agrees with 50.3% and 61% reported by Waziri et al.[33] and Łukaszyk et al.,[36] respectively. The low proportion of participants with functional iron deficiency in our study may not be unconnected with the exclusion of participants with evidence of an on-going inflammation (elevated hsCRP). Female gender was independently associated with IDA among patients with CKD and this agrees with findings from similar studies.[37],[38] Pre-menopausal women are at a higher risk of iron deficiency because of blood loss from monthly menstruation. Expectedly, IDA among the patients with CKD was independently associated with the severity of kidney disease. The findings in our study agree with the observation from other similar studies of iron evaluation in CKD.[31],[32],[33],[35] Worsening kidney disease is associated with poor dietary iron intake, inadequate iron absorption and the use of ESA among the patients. Surprisingly, being on maintenance dialysis was not independently associated with IDA, this may be explained by the fact that the dialysis status has a direct relationship to kidney disease severity spectrum. Furthermore, frequency and adequacy of dialysis are factors critical to the development of anaemia among patients on maintenance haemodialysis.

There was high use of oral iron therapy (83.4%) among our patients, but despite this, the prevalence of IDA was high. The explanation for this could be that oral iron was ineffective among patients with CKD as previously demonstrated by earlier studies,[39],[40] or the occurrence of impaired iron absorption due to gut oedema and the use of ESA in some of the patients. Furthermore, we found no association between the use of erythropoietin and IDA, this may be because most of our patients were not getting adequate dosing of ESA, as most patients pay out of pockets for medications and care. Over two-fifths of the patients with IDA in our study were functional, this form of IDA is attributed to inability to utilise iron despite adequate iron store (serum ferritin >100 ng/dl and TSAT <20%). Functional iron deficiency is often due to concomitant inflammation or infection and the cause which needs to be identify and treated appropriately, to obtain adequate response to anaemia treatment. Surprisingly, a substantial proportion of individuals with IDA in our study were with low hsCRP, perhaps there are other causes of functional IDA that are not related to infection or inflammation, which our study may have missed.

Our study has highlighted, high burden of IDA among patients with CKD and once again emphasised the need to routinely screen for iron deficiency among this group of patients. Treatment of IDA with parenteral iron therapy may be the preferred mode of treatment, as a substantial proportion of our patients had iron deficiency despite being on oral iron therapy. The treatment with parenteral iron therapy will be more appropriate for patients who are taking ESA, which predisposes them to IDA.[19],[40] This study is not without limitations, despite the use of hsCRP as a means of excluding participants with infection and tissue reaction, it is still possible that we may have inadvertently included some patients with an on-going inflammation. Most patients with ESRD on maintenance dialysis in our setting are over-transfused and this frequent transfusion may be responsible for the underdiagnosis of IDA in this group.

 Conclusion



This study showed a high prevalence of IDA among individuals with CKD, and three fifths of those with iron deficiency had absolute iron deficiency. Female gender and severity of CKD were factors independently associated with occurrence of IDA. Routine screening for IDA and prompt treatment in this cohort of patients will improve the quality of life and at the same time reduce cardiovascular morbidity and mortality associated with IDA.

Acknowledgements

The authors would like to acknowledged the contributions of Mr. Sakiru Najimu, Mr. Oyewumi Titilayo and Mr. Olomu Satar, the former was involved in data collection while the latter two carried out the laboratory analyses.

Financial support and sponsorship

The study was supported by the College of Medicine, University of Ibadan, Early Career Research Grant 2015.

Conflicts of interest

There are no conflicts of interest.

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