Impaired renal function and associated risk factors in newly diagnosed HIV-infected adults in Gulu Hospital, Northern Uganda

Human immunodeficiency Virus (HIV) is a leading cause of morbidity and mortality especially in sub-Saharan Africa. The HIV-infected individuals may suffer both HIV-associated and non HIV-associated kidney disease which may worsen their prognosis. Non HIV-associated kidney disease may follow hypertension, diabetes mellitus, infections and many other causes while HIV-associated kidney disease may occur as HIV-associated nephropathy, nephropathy due to opportunistic infections, immune complex mediated glomerulonephritis, thrombotic microangiopathy, interstitial nephritis and various electrolyte disturbances among others [1-4]. Globally, the prevalence of renal disease among the HIV-infected adult population has been estimated to range between 5 and 30% [5-7]. In sub-Saharan Africa, the prevalence is estimated between 6 and 48.5% [6,8]. In Uganda, the incidence of renal disease in HIV-infected persons is expected to increase, even though highly effective antiretroviral therapy is increasingly available.

Screening for renal disease is recommended for all HIV-infected individuals at diagnosis of the infection and at initiation of antiretroviral therapy (ART) [9]. If not detected and managed timely and appropriately, AIDS-associated renal disease may progress to end-stage renal disease (ESRD) requiring renal replacement therapy [10]. Renal dysfunction at the time of initiation of ART or during ART is associated with complications such as faster progression to AIDS, high blood pressure, bone demineralization and anemia [10] which present significant challenges to HIV management especially in resource limited settings. Early initiation of ART may improve the treatment outcomes of individuals with HIV-associated kidney disease [11].

Although current guidelines recommend determination of renal function prior to ART initiation, this is often not performed due to resource constraints in many areas in sub-Saharan Africa. Moreover, there is enormous evidence that HIV-infected patients receiving ART are surviving longer. Currently recommended ART regimens include 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor as first line therapy and 2 NRTIs plus a protease inhibitor as second line therapy. Some of these drugs are known to cause kidney toxicity such as tenofovir, indinavir and atazanavir, underscoring the need to screen and monitor HIV-infected patients for kidney disease pre and during ART. Several studies have demonstrated ART associated renal toxicity with underlying risk factors such as pre-existing renal disease, untreated and advanced HIV disease, administration of other renal toxic drugs, female gender and older age, longer duration on ART, dehydration, opportunistic infections and African-American ethnicity [12].

Despite the high prevalence of HIV/AIDS in Northern Uganda, little is known about the status of renal function in the HIV-infected individuals in this resource limited region. Renal function pre-ART and during ART is not routinely performed. The cost of chronic renal replacement therapy is exorbitant for majority of people in this setting. An emphasis should be placed on early detection and management of HIV-infected individuals. Interventions such as avoidance of nephrotoxic drugs and substances, blood pressure and glucose control can be used to slow progression and prevent development of end stage renal disease. We aimed to determine the status of renal function and factors associated with impaired function in newly diagnosed HIV-infected adults in Gulu Regional Referral Hospital in Northern Uganda.

Table 2 summarizes the overall socio-demographic characteristics of the study participants. The same table also shows comparison of these characteristics between the patients with and without renal impairment. Three hundred sixty five (365) ART naïve HIV-infected patients were enrolled into the study. Four patients had incomplete records (age, serum creatinine or gender which we needed to calculate eGFR) and were excluded from the analysis. However, data were missing on occupation for 2 subjects. Of the 361 patients analyzed, 63.7% (230/361) were female. The majority, 90.4% (327/361) of the patients were in early stages of HIV infection (WHO clinical stages I and II). The majority of the patients were non smokers and were not taking alcohol 86.1% (311/361) and 74.9% (274/361) respectively. Very few patients, 5.3% (19/361) had attained education beyond secondary level as the majority had only attained primary education. There were no differences in the socio-demographic categorical variables between the participants with impaired renal function and those with normal renal function as shown in Table 2.

We aimed to determine renal function status and factors associated with impaired function in newly diagnosed HIV-infected adults in Gulu Regional Referral Hospital in Northern Uganda. Defining renal impairment as eGFR <90 mL/min/1.73 m², we found a high prevalence of renal insufficiency of 36.9%. This finding is similar to that from a study done in Zambia where renal impairment was found in 33.5% of the HIV-infected patients initiating ART [17], and from studies in Nigeria where prevalence was 38% and 39% [8,18] who used the same cut off of eGFR <90 mL/min/1.73 m² to define renal impairment. However, both the Zambian and Nigerian studies used Cockroft and Gault formula for calculating eGFR. When renal impairment was defined as eGFR < 60 mL/min/1.73 m², 14.4% of our newly diagnosed HIV-infected participants had renal dysfunction. Our finding compares very well with the study done in Kenya by Kaloustian et al. [19] which recorded a prevalence of 11.5% using the same definition with MDRD formula which compares very well with CKD-EPI. However, our finding is lower than the recent finding of 24% in Nigeria% [18] and higher than findings by Wyatt et al. [20] in Rwanda and by Ekat et al. [21] in Brazaville, Congo of 2.7% and 7.9% respectively. The low prevalence of renal impairment in Wyatt et al. study used a population of only HIV positive women while our study included both men and women. Our finding of 14.4% is almost less than half the finding of Onodugo et al. possibly of two reasons. First, most (almost 40%) of the patients with eGFR < 60 mL/min/1.73 m² in the Nigerian study were in chronic kidney disease stage 5 where as only 11.5% of our participants with eGFR < 60 mL/min/1.73 m² were in chronic kidney disease stage 5. It could also be because of the different method used to estimate the GFR in this study. Our present prevalence of 14.4% is almost twice that found in Brazaville yet majority (90.6%) of our participants were in early disease stages (I & II) of HIV infection and majority (70.8%) of the participants in Ekat et al. study were in advanced disease stages (III & IV) [21]. The disparity in prevalence between studies seems to be explained mainly by the definitions of the impaired renal function and characteristics of studied patients. There is a chance that the prevalence of renal failure would have been higher than this if we had more of our participants in advanced stages of HIV-infection since the risk of failure increases with advancing clinical stage [22-24].

There was high prevalence of proteinuria among our study participants (n = 189, 52.4%), similar to findings from Nigeria [8]. This finding is higher than that by Chioma et al. [25] who found prevalence of proteinuria of 38.1%. The difference could be due to the fact that we used one spot urine sample while Chioma et al. used two serial urine samples four weeks apart to diagnose proteinuria. Longo et al. [26] found a lower prevalence of proteinuria of 20.5% and Kaloustian et al. found much lower prevalence of 6.2% [19]. From our study we observed that proteinuria (3+) detects renal impairment in 100% of the HIV-infected adults who are ART naïve in this resource limited region (Table 3).

Notable in this study is the very high prevalence of mild renal impairment in the study population. Although dose adjustment of medication or additional monitoring may not be necessary in HIV patients with mild renal impairment, and they may improve on antiretroviral therapy, it is important that such patients be identified [14,27]. Mild renal insufficiency has been reported to be associated with increased risk of mortality [28].

For resource limited settings, screening for renal impairment could be limited to individuals who do not immediately qualify for ART. This will detect those that will commence ART due to renal impairment. This because studies have shown that in settings where renal insufficiency is diagnosed but the etiology is unknown; provision of ART in itself improves renal function [29]. This is very important considering the rapid and severe clinical course associated with HIVAN which can improve, with preservation of long-term renal function, by a trial of empiric ART [30].

Studies done in Africa have found renal insufficiency to be associated with increased risk for death [17,19]. We found a significant association between estimated GFR and CD4 cell counts implying that individuals with advanced immune suppression as measured by the CD4 count had more advanced renal impairment as measured by the GFR. Our finding is similar to findings in South Africa, Malawi and India [22-24] where low CD4 cell count below 350cells/μL was an independent predictor for impaired renal function. However, Wyatt et al. did not find a significant association between these two parameters [20]. This high prevalence of renal impairment has significant implications for HIV treatment in this area where tenofovir is the preferred NRTI for first-line ART. Guidelines recommend tenofovir dose adjustments to prevent further renal damage when creatinine clearance is below 50 mL/min [31,32]. Approximately 12% of participants in our study would have required tenofovir dose adjustments and nearly 3% would have benefited from serial creatinine monitoring if they were to initiate tenofovir-based ART. While a strategy of routine screening will increase costs of HIV care in resource constrained settings, it must be balanced against the risk of worsening renal impairment following ART initiation regardless of renal function consideration. Similar concerns should be raised if HIV-infected individuals are to receive other ART drugs with known renal toxicities, such as indinavir and atazanavir.

Majority of our study participants were categorised as WHO clinical stage I and II and had CD4 count greater than 350 cells/μL compared to findings in some studies where ART naïve newly diagnosed HIV-infected patients were found with very low CD4 counts [6,15] signifying advanced immune suppression at start of HIV care. For example in Ekat et al. [6], study, 70.8% of HIV-infected adults in advanced disease stage (III & IV) while in our study only 9.4% of the participants in advanced disease stage. Our findings imply that adults in this region possibly seek HIV testing and care services early compared to other settings. Uganda has been implementing the routine counseling and testing program for more than five years. All individuals presenting to a health facility are offered HIV counseling and testing. This could also possibly explain the early HIV diagnosis in this population. More than one third of participants were eligible for ART according to national guidelines at the time the study was conducted which has significant implications for ART provision in Uganda.

Our study had some limitations; both creatinine and proteinuria were measured at a single point in time; therefore, we may have included short term, reversible causes of renal impairment. We did not assess for microalbuminuria although it has been shown to be the earliest marker of renal disease. Furthermore, estimation of eGFR and creatinine clearance is affected by medications, diet, protein intake, circulating cortisol levels, and muscle wasting, factors that this study did not explore.

The prevalence of impaired renal function was high in HIV-infected individuals in Northern Uganda, a region which is limited resources. So, screening for renal disease in HIV is recommended at the time of HIV diagnosis. We also recommend use of urine dipstick to detect proteinuria which is a good proxy of renal impairment especially moderate (2+) and severe (3+).