Chronic Kidney Disease and associated factors among HIV/AIDS Patients on HAART at University of Gondar Referral Hospital, Northwest Ethiopia

Background In developing countries, both opportunistic infections and chronic diseases account a high HIV associated mortality and morbidity. Chronic kidney diseases (CKD) associated with HIV infection has got increased attention in sub-Saharan Africa as a result of the high HIV prevalence and due to the late diagnosis and initiation of HAART. Thus, this study was conducted to assess CKD and associated factors among HIV patients on HARRT in Northwest Ethiopia. Methods A hospital-based cross-sectional study with a secondary data review was conducted from February 01 to April 30, 2017, at the University of Gondar Referral Hospital, Northwest Ethiopia. The study participants were selected using a systematic random sampling technique. Socio-demographic and clinical data were collected using a semi-structured questionnaire by trained nurses. Venous blood and urine specimen was collected for serum creatinine and urine protein determination respectively. Glomerular �ltration rate was estimated using the CKD–EPI estimator. Data were entered into SPSS version 20 for analysis. Bivariate and multivariate logistic regression was employed and p-value < 0.05 was considered statistically signi�cant.


Background
Globally, an estimated 36.7 million people were living with Human immunode ciency virus (HIV) in 2016.
The majority of people living with HIV are in sub-Saharan Africa.In the era of combined antiretroviral therapy, the life expectancy of people living with HIV (PLWH) has increased [1][2][3].With longer life spans, however, PLWH is developing chronic medical conditions [4][5][6].The morbidity and mortality associated with HIV infection were due to opportunistic infections.However, in developed countries, opportunistic infections have been replaced by chronic diseases.whereas, in developing countries like Ethiopia both the opportunistic infections and chronic diseases account a high HIV associated mortality and morbidity [7].
One of the most commonly diagnosed chronic diseases is chronic kidney disease (CKD) [8][9][10].Chronic kidney disease is de ned as kidney damage or reduced kidney function that persists for more than three months [11,12].Chronic kidney diseases associated with HIV infection has got increased attention in sub-Saharan Africa as a result of the high HIV prevalence and due to the late HIV diagnosis and initiation of HAART.A research nding showed an increasing prevalence of kidney disease in PLWH compared with the general population, being related to increased mortality and morbidity [13][14][15].HIV infected patients are ve times more likely to develop kidney disease as compared to HIV non infected [16].A recent systematic review and meta-analysis in sub-Saharan Africa reported a 6.42% prevalence of CKD among HIV patients in which the majority of them were in stage 3 CKD [17].Chronic kidney disease prevalence is increasing globally and recognized as a global public health problem with major impact on health, health-care costs and productivity [11,18,19].The involved factors related to increased prevalence of kidney disease in PLWH were a direct effect of the virus itself, closely related to the immune status; prolonged use of antiretroviral therapy (tenofovir, indinavir, and others); frequent use of concomitant therapy with nephrotoxic drugs; an increase of comorbidities such as diabetes mellitus, dyslipidemia, and hypertension; high prevalence of coinfection with hepatitis B and C virus compared with general population [20][21][22][23][24][25][26].
Ethiopia is among countries where majority of CKD cases were under diagnosed and limited data both among the general population and high-risk groups such as PLWH.Hence, this study was conducted to assess CKD among HIV patients on HARRT in Northwest Ethiopia.

Aim
The aim of this study was to assess the prevalence of CKD among HIV/AIDS patients and its associated factors.

Study area, design, and population
A hospital-based cross-sectional study was conducted from February 01, to April 30, 2017 at the University of Gondar Referral Hospital (UOGRH), which is located in the North Gondar zone, 747 km from the capital city of the country, Addis Ababa.Gondar has an estimated population of more than 206,987 (98,085 males and 108,902 females) based on the 2008 central statistical agency data.at the time of data collection, there were about 13753 HIV patients and 5389 HIV patients on HAART.
Adult HIV/AIDS patients who received HAART in UOGRH were the study population.Those adult HIV/AIDS patients who received HAART for more than 6 months, visited UOGRH during the study period and consented to be involved in the study were included in the study.Whereas, patients who were seriously sick; and unable to give response, diabetic, and hypertension were excluded from the study.In addition, patients with incomplete laboratory and clinical data such as: baseline adherence, baseline drug regimen, HIV/AIDS WHO stage, weight, etc. were excluded from study.

Sample size determination and sampling technique
Based on single population formula and systematic random sampling technique with the following assumption, P = population proportion (estimated prevalence) = 0.5 to yield maximum sample size, precision d, 0.05, by assuming 95% con dence interval α = 0.05 and z (1-a/2) = 1.96was used for sample size determination.Including 10% non response rate, the nal sample size was 423.However, a total of 336 HIV patients on HARRT participated in the study (Fig. 1).
During the three-month data collection period, 1320 HIV/AIDS patients on HAART (> 6 months) were expected to visit the hospital for follow up.The average number of HIV/AIDS patients per day under follow up was 20 sampling intervals (K value) was calculated with 1320/423 = 3.12 = 3.Thus interviews, chart review and blood and urine specimen collection for chemistry analysis and urine dipstick were conducted at 3 intervals.To determine the rst-person, the lottery method was used at 1st day from the 20 patients who had under follow up.Then each 3rd client was selected for interview, chart review and blood chemistry and urine dipstick test.If the 3rd patient is not ful lling the inclusion criteria; the next person was taken as a study subject.

Data collection and laboratory methods
Socio-demographic characteristics and clinical data were collected by trained nurses using a semistructured questionnaire.The patient individual chart was also reviewed for relevant information.
Variables included age, gender, residence, education, occupation, viral load, CD4 count, co-infections, base line CD4 + count, regimen type, WHO stage, duration of follow up time, etc.About 3-5 ml of venous blood was collected aseptically from the patients and serum was separated after the sample clotted and centrifuged at 1000-2000 g for 10 minutes by trained laboratory technologist.A serum sample was immediately separated from the whole blood and transferred to nunc tube.The serum was kept frozen at -20 ºC until processed.A serum creatinine level was determined using Mindray BS-200 chemistry analyzer (Shenzhen Mindray Bio-Medical Electronics Co. Ltd, China) and reported in mg/dL.About 5 ml of urine specimen was collected using clean, dry and leak proof urine cup for urine protein level determination.Chemical analysis of urine specimens was performed immediately after sample collection using urine dipsticks test (Multistix® Henry Schein, Inc.https://www.henryschein.com/medical-multistix.aspx).Urine protein level was reported semiquantitatively as negative, or + 1, to + 4. Glomerular ltration rate (GFR) was estimated using CKD-EPI question [27].Chronic kidney disease was de ned using eGFR and presence of albuminuria and classi ed into ve stages according to the classi cation of Kidney Disease Improving Global Outcomes (KDIGO) [28].

Variables' de nition
Chronic kidney disease is de ned as abnormalities of kidney structure or function, present for ≥ 3 months, with implications for health and CKD is classi ed based on cause, GFR category, and proteinuria category [29].
HAART experienced: taking HAART for more than 6 months which is composed of two NRTIs plus an NNRTI [30].
Hypertension: de ned as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg or taking medication for blood pressure-lowering [32].

Data processing and analysis
The completeness of the data was checked and entered into SPSS version 20 for analysis.During analysis, descriptive statistics such as percentage, mean and standard deviation were used.Bivariate logistic regression was used to assess the crude association between independent and dependent variables, and with p-value ≤ 0.20 were considered for multivariate logistic regression.Finally, logistic regression was used to identify independent predictors of CKD and p-value < 0.05 was considered statistically signi cant.

Socio-demographic characteristics
A total of 336 HIV/AIDS patients who received HAART were enrolled in the study.Of these, 215(64%) of them were females and 121(36%) were males.The mean (SD) age of the participants was 39.7 (± 9.7) years, range 18-69 years.One hundred thirty-three (39.6%) of the study participants were within the age group of 30-39 years.At the time of study almost half of patients, 170 (50.6.4%) were married and

Discussion
The current study assessed the prevalence and associated factors of CKD in HIV patients on HAART using the commonest estimator of kidney function method CKD-EPI.The nding of this study revealed a high frequency of CKD and the related risk factors mostly being male, occupation merchant and patients with VL > 1000.The prevalence of CKD, 16.1%was consistency with the previous study conducted in Ethiopia, 12.1% [33], Ghana, 14.5% [35], Nigeria, 15.3%[36] and Tokyo, 13% [37].However, the result was higher as compared to a study conducted in Uganda, 6% [38], Nigeria, 6.9% [39], Brazil, 8.4% [40], Southwest Ethiopia, 7.6% [41], Tanzania, 1.1% [42], and Lesotho, 5.5% [43].The observed differences could be due to study design, study area and their lifestyle, and the method used to estimate GFR.
This study showed, male gender was signi cantly associated with renal impairment and was 2.05 times more likely to have chronic kidney disease as compared with its comparison group female.The nding agrees with the study ndings conducted in France [44], and South Africa [45].The lower prevalence of CKD in females may be due to the possible protective role promoted by estrogens hormone or due to the absence of the pro brotic effects caused by testosterone [46,47].This study also showed that being occupation merchant was independently and signi cantly associated with chronic kidney disease.
Merchant patients were 2.9 times high risk than the comparative group housewife.In the current study more than half, (51%) of the occupation, merchant participant group were male.Since the higher prevalence of CKD on male than females might be due to the possible CKD protective role promoted by estrogens hormone in females or due to the absence of the pro brotic effects caused by testosterone hormone in females compared to males [46,47].
In the current study patients who have had VL > 1000 were three times more likely to have chronic kidney disease compared with its comparison group patents who have had viral load < 20 copies/mm 3 respectively.This result is agreed with the study conducted in America [5,48] and Thailand [49].High viral replication increased renal damage may be occurred due to destruction of kidney cells and the nephrons.Viral suppression would improve renal function [22,50,51].
In conclusion, the prevalence of CKD in our study based on glomerular ltration rate using CKD-EPI method was high (16.1%).Male gender, merchant, and VL > 1000 were associated factors of chronic kidney diseases CKD among HIV patients on HARRT.Hence, HIV patients on HARRT should be regularly screened for early diagnosis and management of CKD.Those patients with high viral load and male patients should be closely followed.

Consent for publication
Not applicable

Data Availability
The data used to support the ndings of this study are available from the corresponding author upon request

Competing interests
We declare that we do not have any con ict of interests.
Authors' contribution GAM: study design, data collection, analysis and interpretation, and manuscript write-up.DDA and WNA: data analysis and interpretation, study design and supervision.All authors have read and approved the nal manuscript.

Funding
University of Gondar

Declarations
Ethics approval and consent to participateEthical clearance was acquired from the Research and Ethical Review Committee of School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar.The permission letter was taken from the clinical director of the University of Gondar specialized referral hospital and head of the ART clinic.The privacy of personal information was protected and kept con dential.For the purpose of the study, codes were used instead of any personal identi ers.Data were collected after full written consent had been obtained from each participant.Patients with abnormal test results were linked to consulting physicians for further diagnosis and treatment accordingly.

Table 1
Sociodemographic characteristics of HIV/AIDs patients on HARRT at the University of Gondar Referral Hospital, 2017.

Table 2
Clinical characteristics of HIV/AIDs patients on HARRT at the University of Gondar Referral Hospital, 2017.

Table 3
Stages of kidney functions using the CKD-EPI estimator among HIV/AIDs patients on HARRT at the University of Gondar Referral Hospital, 2017.

Table 4
Bivariate and multivariate analysis of chronic kidney disease associated factors among HIV/AIDs patients on HARRT at the University of Gondar Referral Hospital 2017.