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Abstract
Infection of the kidneys by human immunodeficiency virus (HIV) is known to cause kidney disease. HIV-associated nephropathy occurs with variable prevalence rates in various communities and is found to be higher among sub-Saharan Africans. The disease has not been studied in Northeastern Nigeria. This study was aimed at comparing the prevalence, clinical and histo-pathologic features of kidney disease among highly active antiretroviral therapy (HAART)-experienced and HAART-naive patients in northeastern Nigeria. Four hundred HIV-infected (200 HAART-experienced and 200 HAART-naïve) patients were recruited consecutively from the ART clinic. Their socio-demographic and laboratory data including CD4+ cell counts and viral loads were obtained and documented. Out of the 200 study participants in the HAART-experienced arm, 21 (10.5%) had kidney disease whereas 61 (30.5%) participants in the HAART-naïve group had kidney disease. Their mean ages were 41.43 ± 11.04 years and 37.42 ± 9.96 years in the HAART-experienced and HAART-naïve groups, respectively. The mean serum creatinine (SCr), CD4+ cell counts, and viral load were 185.67 ± 221.80 μmol/L, 493.26 ± 241.97/mm3, and 8,856.79 ± 19,747.11/mL in the HAART-experienced group, respectively. In the HAART-naïve group, the mean SCr, CD4+ cell count, and viral load were 141.88 ± 130.56 μmol/L, 270.00 ± 154.65 cells/mm3, and 139,217.70 ± 12,598.50/mL. Focal segmental glomerulosclerosis (FSGS) was the most common histologic diagnosis in 64.7% of kidney biopsies. Risk factors for chronic kidney disease among the study population included age, low weight and body mass index, high human immunodeficiency virus (HIV)-1 viral load, low CD4+ cell counts, low hemoglobin (Hb), and proteinuria. The prevalence of kidney disease is higher among HAART-naïve HIV-infected patients than in patients who are HAART-experienced patients. Factors associated with development of kidney disease included advanced age, low CD4+ cell counts, high viral load, proteinuria, and HAART-naivety. FSGS is the most common histologic diagnosis in our study population.
Introduction 
Human immunodeficiency virus (HIV) infection is associated with a broad spectrum of clinical manifestations ranging from asymptomatic carrier state to severe immuno-deficiency.[1] HIV infection has continued to affect millions of people worldwide. In Nigeria, the prevalence of HIV infection is about 3.4% with slight variation from one region of the country to another.[2]
Before the advent of highly active antiretroviral therapy (HAART), opportunistic infections were the most common complications. However, with the attainment of nearuniversal HAART coverage in most developed countries of the world, patients survive longer, and therefore, long-term complications, such as renal diseases and cardiomyopathy, are becoming more prevalent.[3]
Renal disease is a relatively common complications in patients with HIV disease, presenting as acute kidney injury, glomerulonephritis (GN), or toxic effects of drugs. Prerenal azotemia may result from loss of volume due to diarrheal diseases and vomiting that are prominent in these patients.[4],[5]
HIV-associated nephropathy (HIVAN) is almost exclusively found in sub-Saharan Africans.[6] It is now the third most common cause of end-stage renal disease [after diabetes mellitus (DM) and hypertension (HTN)] among African Americans aged between 20 and 64 years.[6],[7] Genetic factors have been determined to contribute to the high burden of kidney disease among Africans such as APOL1 gene variants and low CD4+ cell counts.[8],[9]
Although focal segmental glomerulosclerosis (FSGS) has been reported to be the predominant lesion in HIV-associated kidney disease,[10] other histological abnormalities seen in patients with HIV infection include immunoglobulin A nephropathy, amyloidosis, and a lupus-like immune complex GN.[6],[11],[12]
Only a few studies have examined chronic kidney disease and its histological manifestations in HIV-infected patients in Northeastern Nigeria. Therefore, given the paucity of information in this regard, a study on chronic kidney disease in HIV-infected patients in our environment is quite imperative.
The aims of this study were to compare the prevalence, risk factors, and histological features of kidney disease among HIV-infected subjects on HAART and HAART-naïve receiving care at a tertiary health facility in Maiduguri, northeastern Nigeria.
Materials and Methods The study was carried out at the University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Northeastern Nigeria, between January 2012 and December 2014. This was an analytical cross-sectional study. Four hundred consecutive adult patients aged ≥18 years who met the inclusion criteria were recruited at the University of Maiduguri Teaching Hospital ART Clinic over the study period. Two hundred were newly diagnosed (<2 weeks) HAART-naive HIV-infected patients, and 200 patients had been on HAART for ≥1 year. The data were collected and entered manually into a computer and analyzed using the Statistical Package for the Social Sciences (SPSS) version 16.0 (SPSS Inc., Chicago, Illinois, USA). Excluded from the study were patients <18 years of age, patients with DM, HTN, hepatitis C virus (HCV), and hepatitis B virus (HBV) infection. Patients with preexisting renal disease as well as those who had been on HAART for <1 year were also excluded from the study. Ethical clearance was obtained from the Research Ethics Committee of the University of Maiduguri Teaching Hospital, Maiduguri. Informed, written consent was also obtained from each participant before being recruited. The diagnosis of HIV infection was made using the Alere™ Determine™ HIV 1/2 and Trinity Biotech Uni-Gold™ HIV test kits. CD4+ cell counts were determined using PARTEC™ (GmbH Görlitz, Germany) flow cytometer, with an excitation light source of 488 nm or 532 nm. The AMPLICOR® HIV-1 MONITOR test v1.5 (Roche Molecular Systems, Inc., Branchburg, NJ 08876, USA) was used to quantify HIV viral load. Serum electrolytes, urea, creatinine, and cholesterol were measured using the COBAS C 311 chemistry auto-analyzer. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease equation. Renal biopsy was performed under ultrasound guidance on patients who had estimated GFR <60 mL/min and/or proteinuria >1 g/24 h. Tissues obtained were fixed in 10% formalin, prepared on slides, stained, and examined under light microscopy by two pathologists.
Results Out of a total of 400 patients recruited into the study, there were 276 (69%) females. The mean age of the study population was 35.65 ± 8.94 years with an age range of 18–61 years. [Table 1] shows the sociodemographic and biochemical characteristics of the two groups. The mean ages of patients on HAART and treatment-naive groups were 36.34 ± 9.07 and 34.92 ± 8.75 years, respectively (P = 0.103).
Table 1: Comparison of sociodemographic feature between patients on HAART and HAART naiveCharacteristics of patients with kidney disease among HAART-experienced and HAART-naïve patients
Out of 200 HAART-naïve study participants, 61 (30.5%) had kidney disease compared with 21 (10.5%) patients in the HAART-experienced group. Their socio-demographic and clinical features are compared in [Table 2].
Table 2: Comparison between HAART-experienced and HAART-naїve patients with kidney disease.The prevalence ratio
The prevalence of HIVAN in HAART-naïve patients/prevalence of HIVAN in HAART-experienced patients was 30.5/10.5, i.e., 2.9.
Renal ultrasonographic findings of patients with kidney disease
Out of the 82 patients who had biochemical evidence of kidney disease, 61 (74.4%) patients had normal kidney sizes, with a mean size of 9.3 ± 1.01 × 4.2 ± 0.34 cm and 9.6 ± 1.11 × 3.9 ± 0.45 cm on the right and left, respectively. Twelve (14.6%) had enlarged kidneys and nine (11.0%) patients had shrunken kidneys.
Histologic features
Out of 68 patients who had kidney biopsy, sufficient renal tissue was obtained in 66 patients. As shown in [Table 3], various histologic features were seen. FSGS collapsing variant with tubulocystic dilatation was the common histologic finding, seen in 44 (64.7%) patients. [Figure 1] shows the histology of FSGS with collapsing changes stained with hematoxylin and eosin. Significant tubulocystic dilatation and thyroidization of the tubules were also seen, as shown in [Figure 2] and [Figure 3], respectively. Minimal change disease (MCD) and membranoproliferative GN (MPGN) were seen in four (5.9%) patients each.
Figure 1: Light microscopic appearance a glomerulus with collapsing focal segmental glomerulosclerosis (×40).
Figure 2: Tubulocystic dilatation in a patient with human immunodeficiency virus-associated nephropathy (×40).
Figure 3: Thyroidization of renal tubules in a patient with human immunodeficiency virusassociated nephropathy.Risk factors for kidney disease
[Table 4] shows that age, Hb levels, body mass index (BMI), weight, and HAART are factors associated with development of kidney disease.
Table 4: Correlation between glomerular filtration rate and risk factors for kidney disease. Discussion The study compared the prevalence, risk factors, and histopathologic features of kidney disease in HAART-experienced and HAART-naive patients in a tertiary health facility in northeastern Nigeria.
The mean age of patients in this study is similar to that of other studies conducted among HIV-infected patients.[11],[12],[13] HIV largely affects sexually active young people, hence the age range in this study agrees with similar studies among African-Americans.[7],[10]
The low literacy rate in this study is a reflection of the northeastern sub-region’s literacy rates coupled with protracted insurgency which has bedeviled the region for over a decade.
The majority of patients with biochemical and histological evidence of kidney disease were asymptomatic in the study. The mean systolic and diastolic blood pressures were normal in patients with HIV-associated kidney disease. This finding is in tandem with findings of several other studies that HTN is not a feature of HIVAN.[11],[14] This finding is thought to result from the tendency of the kidneys in HIVAN to lose salt and water.
The mean weight of patients on HAART was higher than that of patients in the treatment-naive group. Patients who developed HIVAN had lower mean weight than patients who had normal renal function. Similarly, the mean BMI of patients on HAART was higher than that of patients in the treatment-naive group. Moreover, patients who developed HIVAN had lower BMI when compared with those with normal renal function. This finding is in concordance with findings from various other studies.[11]’[14] A plausible explanation is the fact that HIVAN develops on the background of advanced HIV disease when these patients have profound weight loss.
About one-third of the study participants had mild proteinuria. The rate of proteinuria in the setting of HIVAN is quite variable as reported by several other studies.
The mean Hb of patients with HIVAN was lower than those with normal renal function. Furthermore, there was a direct relationship between Hb levels and GFR among HIVAN patients in the study, which is consistent with other studies. This may perhaps be due to impaired erythropoietin release as in most patients with impaired renal function. Other causes of anemia in HIV-infected patients include depression of the bone marrow by HIV and parvovirus B19, as well as iron and folate malabsorption.[15],[16],[17],[18]
The mean serum cholesterol was significantly higher in patients with HIVAN than in those with normal renal function. Serum cholesterol has been found to be associated with progression of kidney disease in both HIV-associated and non-HIV-associated kidney diseases.[15],[19]
The mean CD4+ cell count of HAART-experienced participants was significantly higher than those of HAART-naive subjects. The mean viral load was higher among the treatment-naïve subjects than treatment-experienced patients. The viral load was also higher among patients who developed HIVAN than those with normal renal function. HIVAN occurs in the setting of severe immunosuppression, and many studies found lower CD4 counts in those patients.[13],[19] Treatment with antiretroviral drugs replenishes the depleted CD4+ cell pool and hence improves the immune system.
Majority of the patients had normal-sized kidneys with increased echogenicity. This finding is consistent with that reported by Di Fiori et al.[20] Few patients with shrunken kidneys in the study may have developed HIV GN.
As reported in other studies, increased echogenicity was a common finding in this study. A study by Garko et al[21] in northeastern Nigeria also found increased echogenicity in 98% of patients.
Majority of the patients had focal segmental glomerular sclerosis on renal biopsy in this study. This finding is similar to those reported by several other studies.[22],[23],[24]
Proliferative GN, MPGN, and MCD were also seen in this study though not in substantial proportions.
This study has further demonstrated that HIVAN was 2.9 times common among treatment-naïve patients than their HAART-experienced counterparts. Since HIVAN occurs partly due to the direct effect of HIV on the kidneys, antiretroviral drugs may improve renal functions by viral suppression.
The mean GFR inversely correlates with age in this study. This simply means that HIVAN develops in older patients than younger ones. It is known that renal function declines with age at the rate of about 1 mL/min/year; therefore, the cumulative effects of disease and age may explain this finding. Gender had little influence on the development of HIVAN in this study. Even though many studies have found that male sex was associated with development of HIVAN, many of these studies had almost 1:1 male:female ratio as compared to this study which found a larger proportion of females than males among HIV-infected patients.[9,],[11],[12],[13],[25],[26] Low hemoglobin was found to correlate with GFR. This may perhaps be due to the fact that both advanced HIV disease and impaired renal function may both individually and collectively result in low Hb levels. Furthermore’ studies have shown that low HB may further worsen renal function.[25],[26]
The study is limited by the lack of electron microscope and immunofluorescence stain to further elucidate the histologic findings.
Conclusion The findings from this study have shown that kidney disease is more common among HAART-naïve HIV-infected patients than HAART-experienced patients. This may suggest that HAART is therapeutic for HIV-associated kidney diseases. The index study also showed that FSGS is the most common histologic finding in HIV patients in Northeastern Nigeria.
Conflict of interest: None declared.
References 
Correspondence Address:
Mohammad Maina Sulaiman
Department of Medicine, University of Maiduguri, Maiduguri, Borno State
Nigeria
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.367828
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