|Year : 2015 | Volume
| Issue : 2 | Page : 75-81
Prevalence and determinants of cognitive impairment in patients with chronic kidney disease: A cross-sectional study in Benin City, Nigeria
Oghenekaro Godwin Egbi1, Olubunmi Ogunrin2, Efosa Oviasu2
1 Department of Medicine, Niger Delta University Teaching Hospital, Okolobiri; Department of Medicine, Federal Medical Centre, Yenagoa, Bayelsa State, Nigeria
2 Department of Medicine, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria
|Date of Web Publication||19-Feb-2015|
Oghenekaro Godwin Egbi
Dialysis Unit, Federal Medical Centre, PMB 502, Yenagoa, Bayelsa State
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Chronic kidney disease (CKD) has become a public health concern and may be complicated by cognitive impairment (CI) contributing significantly to morbidity and poor prognosis. This hospital-based study aimed at determining the prevalence and the determinants of CI among CKD patients in Nigeria.
Materials and Methods: A total of 190 CKD patients and a 100 healthy control subjects completed this cross-sectional study. Sociodemographic data and history of common clinical features of CKD were obtained with the use of interviewer administered semi-structured questionnaires. The six-item cognitive impairment test was used for assessment of cognitive function of patients and controls.
Results: The prevalence of CI in Stages 3, 4, and 5 CKD patients were 24.0%, 41.6%, and 46.2%, respectively with overall prevalence of 35.3% while only 6.0% of controls had CI (P = 0.03). The most potent determinants of CI were low hematocrit (odds ratio [OR] =3.50), low serum bicarbonate levels (OR = 2.20), and high serum urea (OR = 2.11). Conclusion: CKD is associated with significant CI in Nigerian patients especially with progressive deterioration in renal function. There is a need for regular evaluation of CKD patients for cognitive deficits.
| Abstract in French|| |
Contexte: Insuffisance rιnale chronique (IRC) est devenue une préoccupation de santé publique et peut se compliquer de troubles cognitifs (CI), contribuant de maniθre significative ΰ la morbiditι et de mauvais pronostic. Cette ιtude en milieu hospitalier visant ΰ dιterminer la prιvalence et les dιterminants de la CI chez les patients IRC au Nigeria.
Matιriel et Mιthodes: A au total 190 patients CKD et un 100 sujets sains contrτle complιtι cette ιtude transversale. Donnιes sociodιmographiques et histoire de caractιristiques cliniques communes de CKD ont ιtι obtenus avec l'utilisation de questionnaires semi-structurιs intervieweur administrι. Le critθre de l'atteinte cognitive six ιlιments a ιtι utilisι pour l'ιvaluation des fonctions cognitives des patients et des contrτles.
Rιsultats: La prιvalence de la CI chez les patients CKD ιtapes 3, 4 et 5 ιtaient 24,0 %, 41,6 % et 46,2 %, respectivement, avec une prιvalence globale de 35,3 % alors que seulement 6,0 % des contrτles avaient CI (P = 0.03). les dιterminants plus puissants de la CI ont ιtι hιmatocrite faible (cotes [RC] = 3.50), un faible taux de bicarbonate sιrique (RC = 2.20) et de l'urιe sιrique ιlevι (RC = 2.11).
Conclusion: CKD est associι ΰ CI significative chez les patients nigιrians surtout avec une dιtιrioration progressive de la fonction rιnale. Il y a nιcessitι d'une ιvaluation rιguliθre des patients CKD pour dιficits cognitifs.
Mots-clιs: Chronic une maladie rιnale, cognition, Nigeria, prιvalence, le critθre de l'atteinte cognitive de six ιlιments
Keywords: Chronic kidney disease, cognition, Nigeria, prevalence, six-item cognitive impairment test
|How to cite this article:|
Egbi OG, Ogunrin O, Oviasu E. Prevalence and determinants of cognitive impairment in patients with chronic kidney disease: A cross-sectional study in Benin City, Nigeria. Ann Afr Med 2015;14:75-81
|How to cite this URL:|
Egbi OG, Ogunrin O, Oviasu E. Prevalence and determinants of cognitive impairment in patients with chronic kidney disease: A cross-sectional study in Benin City, Nigeria. Ann Afr Med [serial online] 2015 [cited 2020 Oct 29];14:75-81. Available from: https://www.annalsafrmed.org/text.asp?2015/14/2/75/149877
| Introduction|| |
Chronic kidney disease (CKD) has become a significant public health problem in recent times.  The negative impact of the disease on the quality of life of affected individuals has been reported in the literature. , Intact cognition is necessary for problem solving, decisions making, and forming judgments. The ability to understand the challenges associated with end stage renal disease (ESRD), to follow instructions and to keep scheduled appointments is crucial to ensuring improved outcomes.  Therefore, the presence of cognitive impairment (CI) may result in a deleterious effect on patients' compliance with their management. CKD patients with CIs may thus benefit from periodic review by the neuropsychologist and psychosocial interventional strategies.
The exact pathogenesis of CI in uremia is unknown. However, anatomic, physiologic and neurochemical disturbances of the brain are thought to develop secondary to renal insufficiency with consequent cognitive dysfunction.  Most patients with ESRD are anemic. Anemia may result in decreased cerebral oxygen utilization resulting in cognitive deterioration. The rise in cerebral blood flow observed in uremic patients can result in increased conveyance of uremic toxins to the brain. This phenomenon is also obvious in dialyzed patients with anemia. , Traditional predisposing vascular risk factors for chronic renal impairment such as diabetes and hypertension have been similarly linked with cognitive dysfunction. ,, Although a connection between acute stroke and CI in CKD has not been fully established, mild renal impairment is considered an independent risk factor for ischemic stroke. 
The incidence of CI among CKD patients as documented in literature is high and appears to increase with worsening renal function. ,, There is a dearth of information on the prevalence of CI in Nigerian patients with CKD. To the best of our knowledge, incidence and prevalence studies of CI in CKD have not been carried out in most African countries where the burden of CKD is high. The aim of this study was to determine the prevalence of CI among dialysis naive CKD patients in Nigeria and to identify its determinants.
| Materials and Methods|| |
The study population comprised of dialysis naïve CKD patients who consecutively attended the renal outpatient clinic of the University of Benin Teaching Hospital (UBTH).
University of Benin Teaching Hospital is a 600 bedded tertiary hospital located in Benin City, the capital of Edo State in Nigeria. The hospital runs specialist services in nephrology among other sub-specialties and specialties. The study duration was between December 2009 and July 2010. Patients who had a history of symptoms of renal disease lasting more than 3 months with estimated glomerular filtration rate (eGFR) of <60 ml/min using the Cockcroft-Gault (CG) equation were recruited as CKD participants. The CG equation was used in this study because of its simple mathematical formulation and bedside applicability. Furthermore, the CG, alongside the modification of diet in renal disease (MDRD) equation has been validated and used extensively in Nigerians. ,
The CKD patients were stratified into three groups according to level of eGFR namely, Stage 3 CKD: eGFR between 30 and 59 ml/min, Stage 4 CKD: eGFR between 15 and 29 ml/min and Stage 5 CKD: eGFR <15 ml/min.
The exclusion criteria for the study included subjects <18 years of age, patients who had received dialysis, and patients with a history of psychiatric illness and epilepsy, intracranial disorders, e.g., brain tumor, and presence of clinical signs of cardiac failure, alcohol intake above 120 g/week or 13 units/week, history of previous head injury with loss of consciousness and patients on anticholinergic medications. Patients found to be seropositive for human immunodeficiency virus (HIV) were also excluded from the study as well as patients presenting with severely elevated blood pressure (BP) >180/110 mmHg.
Apparently healthy controls were recruited from among the hospital staff and patients' relatives, and were age, sex, and level of education matched with the patients. Inclusion criteria for controls were the absence of symptoms of CKD, absence of hypertension, diabetes or other chronic ailments like HIV as well as eGFR >60 ml/min calculated from the serum creatinine with the same formula used for the CKD patients. The potential control subjects were encouraged to do the screening tests including the HIV testing as they were assured of privacy and confidentiality. The benefit of early detection of such illnesses was also explained to them. Those that agreed to the terms and that met the criteria were recruited as controls.
Interviewer-administered semi-structured questionnaires were used to obtain sociodemographic data including age, sex, and level of education as well as the presence of clinical features of CKD. BP was taken for both patients and control subjects using an Accoson® sphygmomanometer with subject in a sitting position. One measurement was taken after 5 min of resting quietly. If this reading did not indicate hypertension, then it was accepted, if it did indicate hypertension then a second reading was taken and this reading was reported for the purpose of this study.  The individual must not have taken caffeine or smoked tobacco at least 30 min prior. Laboratory investigations done for patients included hematocrit, serum urea, electrolytes and creatinine. Serum creatinine was similarly assayed for control subjects at recruitment and the eGFR calculated with the CG equation.
The test instrument
The six-item cognitive impairment test (6ICT) was used for assessment of cognitive function of the patients and controls. The 6ICT was developed in 1983 by regression analysis of the blessed information memory concentration scale. , It is an abbreviation of the latter. It consists of six questions meant to test memory, orientation, and concentration. It is brief, simple, easy to perform and can be translated linguistically and culturally. The total duration of the test is about 3-4 min. It uses an inverse score and questions are weighted to produce a total score of 28. Scores of 0-7 are normal while 8 and above meet the criteria for CI. The 6CIT was validated by Brooke et al. reported sensitivity and specificity rates of 90% and 100%, respectively at the 7 or 8 cut-off points with a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 83.33%. 
The 6ICT has been used by several authors in the evaluation of cognitive abilities of patients with chronic diseases. , However, it had not been validated among Nigerians. Hence, a pilot study was done using 30 CKD patients and 30 age, sex, and level of education-matched controls to validate the 6ICT and obtain a cut-off value for detection of CI among our patients using the receiver operating characteristic (ROC) analysis before proceeding with the main study.
Ethical approval was obtained from the Ethics and Research Committee of UBTH before the commencement of the study. Informed consent was obtained from all participants. To ensure confidentiality, serial numbers were used in data management in place of names or hospital numbers of participants.
Data were analyzed with the Statistical Package for Social Sciences (SSPS Inc, Chicago, IL) version 17.0 statistical software. Variables were descriptively analyzed with means, standard deviation, mode, and frequency distributions. The Student's t-test was useful in testing for differences between quantitative variables, while Chi-square tested for differences between proportions. The characteristics of CKD patients with and without CI were compared. Factors associated with CKD were tested with regression analysis. Unadjusted regression analysis examined the relationship between CI and all candidate covariates. Candidate covariates employed included traditional and biologically plausible factors such as age, gender, level of education, presence of hypertension, levels of hematocrit, serum urea, serum creatinine, serum bicarbonate as well as levels of eGFR. Adjustment of unconditional multivariate regression model included all covariates found to be significant in unadjusted analysis such as gender, level of education, levels of hematocrit, serum urea, serum creatinine, serum bicarbonate and levels of eGFR. All tests were two-tailed with a confidence interval set at 95% confidence limit and level of significance taken as P < 0.05. Results were presented in prose and tabular forms.
| Results|| |
A total of 240 CKD patients commenced the study, but only 190 completed it, giving a response rate of 79.2%. Similarly, a 100 control subjects completed the study out of 190 subjects initially recruited to match the patients giving approximately a 2:1 ratio of patients and controls. The relatively low number of controls was largely due to reluctance by some of the control subjects to do the HIV screening test. Only data of patients and controls that completed the study were included in the analysis.
Characteristics of participants
The mean ages of the CKD and control subjects were 46.7 ± 13.4 years and 44.2 ± 14.7 years, respectively with no statistically significant difference between them (t = 1.51, P = 0.13). The modal frequency (66; 34.7%) was the age group 45-54 years. There were 113 (61.6%) males and 73 (38.4%) females in the CKD group, while the control group had 60 (60.0%) males and 40 (40.0%) females. There was no significant difference between the sex distribution of patients and controls (χ2 = 0.07, P = 0.79).
73 (38.4%) of the CKD patients had primary level of education, 56 (29.5%) had secondary while 61 (32.1%) had tertiary level. Similarly, for the control group, 40 (40.0%) had primary level of education while 30 (30.0%) each had secondary and tertiary levels of education respectively. There was also no difference in the educational attainment of patients and controls (χ2 = 0.14, P = 0.93).
The categories of CKD based on eGFR showed that 75 (39.4%) patients were in Stage 3, 89 (46.9%) in Stage 4 and 26 (13.7%) in Stage 5. The etiologies of CKD were varied, with chronic glomerulonephritis, hypertension, and diabetic nephropathy accounting for majority, 151 (79.5%) of CKD patients in the study.
Prevalence of cognitive impairment
Using the ROC curve, a value of >8 for CI was obtained with a sensitivity of 70% and specificity of 96.67%, and PPV was 90% and the NPV was 72.4%.
Cognitive impairment was found in 67 (35.3%) of the CKD patients, but only 6 (6.0%) of the controls. The CKD patients thus performed significantly worse than the controls. 18 of the 75 Stage 3 CKD patients had CI while 37 out of 89 Stage 4 CKD patients and 12 out of the 26 Stage 5 CKD patients had CI giving prevalence rates of 24.0%, 41.6%, and 46.2%, respectively with a significant difference between them (P = 0.03).
Factors associated with cognitive impairment
The characteristics of CKD patients with and without CI are shown in [Table 1]. Compared with those without CI, CKD patients with CI had a lower level of education (P < 0.001), lower hematocrit (P < 0.001), higher serum urea (P = 0.006) and creatinine (P = 0.01), lower serum bicarbonate (P = 0.005) and lower eGFR (P = 0.02).
|Table 1: Characteristics of CKD patients with and without cognitive impairment|
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On binary logistic regression analysis, the following variables were significantly associated with CI in the CKD patients: Level of education, hematocrit, serum urea, and serum creatinine and serum bicarbonate. However, only hematocrit, serum urea and serum bicarbonate remained significantly associated with CI on multivariate analysis [Table 2].
|Table 2: Factors associated with cognitive impairment in the CKD patients|
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| Discussion|| |
This study revealed a high prevalence of global CI in CKD patients. There is a paucity of data on CI in the CKD population among Nigerian and indeed Africans to allow for adequate comparison. However, a recent study by Williams et al. similarly showed a high prevalence of CI among Nigerians using the community screening instrument for dementia) and the trail making tests A and B.  Our findings are higher than the 20% prevalence rates found in a London clinic  and the 17% and 22% found among predialytic and ESRD patients, respectively in California  Using the same neuropsychological tool as we did, Etgen et al. have reported a lower prevalence of 10.8% at baseline in their prospective cohorts who were inhabitants of Germany. It is therefore possible that there may be racial predisposition to CI. 
Studies in CKD patients have shown that the natural history of CI begins before the transition to ESRD. , Khatri et al., have reported a dose-response relationship between cognitive decline and CKD, which extended to those with mildly reduced eGFR and creatinine clearance in a multi-ethnic prospective study.  Our study also demonstrated a graded relationship between CI and severity of renal disease even though patients with GFR >60 ml/min were not included. Etgen et al., also demonstrated a similar relationship with a significantly progressively increasing risk of CI in mild, moderate, and severe kidney disease even though patient stratification based on GFR was slightly different. 
The most potent determinants of global CI in our patients were gender, decreased hematocrit level, decreased bicarbonate, and elevated serum urea. Female gender was associated with worse CI, which remained significant even after adjusting for other variables. Gender difference in cognitive performance has previously been described with males generally doing better in visuospatial and a few other tasks though they may be out-performed by their female counterparts in visual memory.  We however didn't look at the specific domains of CI in this study. The possible role of testosterone in enhancing performance in cognitive tasks has also been alluded to in previous work. 
Estimated GFR was significantly associated with CI in univariate analysis in our study. Although eGFR per se was not an independent predictor of CI in our study, patients with the least eGFR had the highest proportion of the cognitively impaired. In Yaffe's report though, this association remained significant even after multivariable adjustment.  However, the population they studied differed from ours as they consisted of older participants. Furthermore, while we estimated GFR with CG, MDRD was used in that study. Although Ogunrin et al., did not estimate GFR in their study, serum creatinine elevation was found to be associated with CI in the participants. 
Although low serum bicarbonate may not have had an established association with cognitive deficit in CKD patients in the existing literature, lactic acidosis has been related to neurological impairment in patients with mitochondrial myopathy, encephalopathy, and stroke episodes, thus suggesting a possible role for acidosis in cognitive decline.  Acidotic environments in vitro have also been shown to be toxic to neurons and glia cells.  Anemia may be linked with CI in patients with and without CKD. Denny et al., have reported a strong association between anemia and cognitive function by demonstrating a decrease in cognition among his cohorts over a 4-year period.  There is evidence to support improvement in cognitive function following correction of anemia  and after renal transplantation.  The resolution of azotemia and other metabolites of uremia after transplantation strongly suggest a causal role in cognitive dysfunction.
Higher level of education also showed a higher odd for global CI, which however ceased to be significant on multivariate analysis. The exclusion of patients with no formal education may have contributed to the lack of the strong association with CI as found in some other reports. 
Quite surprisingly, age and presence of hypertension showed no association with CI in our study unlike in the previous reports. , The fact that patients with severely elevated BPs were excluded from the study many have contributed to this finding. Furthermore, this finding is not exclusive. Etgen et al., similarly found no association between hypertension and development of incident CI using the same instrument as we did in our study.  It is therefore possible that CI in CKD patients may be mediated by mechanisms that are independent of BP. The reason for lack of significant association with age is not obvious and warrants further investigations. Several previous reports have suggested that CI may be more prevalent in older CKD patients. ,
The study had some limitations. The 6ICT measures global cognition and does not evaluate specific cognitive domains. The use of only one neuropsychological evaluation tool may also be a limitation.
Being a snap-shot study, serum creatinine was assayed only once in our patients. Ideally, kidney damage should persist for at least 3 months to meet the ideal criteria of definition for CKD. However, the presence of features of renal disease lasting over 3 months coupled with a reduced GFR makes CKD likely.
Despite these limitations, the findings of this study remain valid. There is a high prevalence of CI in CKD patients, which may be related to the severity of renal dysfunction. Patients with advanced CKD have worse cognitive function than those with moderate CKD. The effects of anemia, acidosis, and azotemia may contribute to the cognitive dysfunction in these patients. There is therefore need for routine screening of CKD patients for CI as well as adequate correction of anemia, acidosis, and azotemia in them.
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[Table 1], [Table 2]