Background
In April 2004, the South African National antiretroviral treatment (ART) guidelines were first implemented [
1,
2] and ART became universally accessible in the public sector for the first time. South Africa recently (01 September 2016) adopted the World Health Organization (WHO) “test and treat” approach, which was introduced as a possible means of controlling the global HIV epidemic [
3]. This approach entitles every patient who tests positive for HIV to a lifelong ART regardless of their CD4 count or clinical staging [
3]. With the successful rollout of ART in South Africa, the lifespan of people living with human immunodeficiency virus (HIV) has been prolonged thereby transforming HIV into a disease of chronicity [
4], adding to the burden of infectious and non-communicable diseases [
5]. Renal disease is a recognised complication of HIV infection and its incidence can be perpetuated by drug induced toxicity, comorbid diseases such as diabetes and hypertension and infectious diseases [
6]. Data from the USA suggest that at some stage of their HIV infection, 10% of patients will develop HIV-related renal disease [
7]. If this is extrapolated to the South African context, it is estimated that 650,000 patients may develop HIV-related renal disease [
7]. This large burden of chronic kidney disease (CKD) would place immense pressure on our resource-strained health system where access to renal biopsy, renal replacement therapies and nephrologists is limited [
8].
Mayosi et al. report a 67% increase in deaths related to nephritis/nephrosis in South Africa from 1999 to 2006 causally linked to the increasing HIV prevalence [
5]. In their systematic analysis, Stanifer et al. found that CKD is a prevalent and potentially growing disease in Sub-Saharan Africa with 24% of hypertensives, 18.9% of diabetics and 10% of HIV-infected patients having co-morbid CKD [
9]. The guidelines published by the
Infectious Diseases Society of America (IDSA) in 2014 recommend that all individuals be assessed for
kidney disease at the time of HIV diagnosis by way of a screening urinalysis for proteinuria and a calculated estimate of renal function in order to detect renal disease early [
10]. The South African ART guidelines incorporate this policy, and the recent implementation of ART initiation irrespective of CD4 allows for earlier access to ART before the onset of advanced disease [
3].
Despite the earlier initiation of ART and the screening for urinary abnormalities, renal disease in HIV infected patients is still prevalent [
11]. In addition, HIV-associated nephropathy (HIVAN) has become the third leading cause of end stage renal disease among HIV infected African-American patients [
12,
13]. To the best of our knowledge, this is the first systematic review that attempts to map the evidence of renal disease in people infected with HIV in South Africa post 2003 when ART became universally accessible to patients in the public sector. In light of the current upsurge of research and publications on the topic [
12,
14‐
17], the contribution of a systematic scoping review gains importance and relevance by demonstrating the current data in order to identify research gaps and suggest novel ideas for future research.
Discussion
We conducted a systematic scoping review of the available literature on the renal manifestations of HIV in the era of ART rollout in South Africa from 2004. This review provided a general overview of renal impairment (diagnostics, histological features and risk factors) in South African HIV-infected patients mainly prior to ART initiation. Most of what we know about HIV-related kidney disease has come from research performed in high income countries where the patient profiles and demographics are discordant to that of South Africa. The salient points unravelled by our review indicate a paucity of data on ART-related renal complications, specifically TDF nephrotoxicity; a deficiency of research on the impact of ART on AKI and CKD and the long-term outcomes of renal disease for patients on ART; and a relatively unknown prevalence of HIV-related kidney disease for patients on ART in South Africa. Bearing in mind that South Africa recently (1 September 2016) adopted the WHO “test and treat” approach to HIV prevention and management [
3], these findings has major implications for the near future.
TDF is widely used as first line ART in South Africa since April 2010 as part of National ART guidelines [
37]. A biopsy series revealed that TDF nephrotoxicity is essentially a reversible form of toxic acute tubular necrosis with features of mitochondrial injury [
38]. Numerous studies have demonstrated a decrease in kidney function with TDF usage and suggest monitoring of renal function to prevent TDF nephrotoxicity [
27,
39‐
41]. Early detection of proteinuria using accurate screening tests is important to decrease nephrotoxicity and improve outcomes in HIV-infected individuals [
27]. The current South African ART guidelines recommend routinely performing urine dipstick analysis on patients before and while on ART, as well as assessing the serum creatinine and eGFR at baseline (prior to ART initiation) and then at 3 months, 6 months and annually thereafter for patients on TDF. The rate of compliance to these guidelines, however, is not known.
The use of urine dipsticks alone as a screening tool has become a contentious issue with research both locally [
33] and overseas [
42] suggesting the poor validity of urine dipsticks in detecting proteinuria. Data from another South African study, Han et al., suggested that HIVAN is possible in patients without overt nephrotic syndrome and in patients who have only microalbuminuria. Therefore, microalbuminuria can be considered an early marker of HIVAN [
12]. Szczech et al. concluded that miroalbuminuria predicts the development of proteinuria in HIV-infected patients [
43]. Stanifer et al. showed that the prevalence of proteinuria when measured in people with HIV, hypertension or diabetes is substantial. However, the best method of urine protein detection is unknown [
9]. Currently, our urine dipstick analyses detect proteinuria only (not microalbuminuria). In other countries, alternate methods of urine analysis are already being sought. In a recent study set in Mexico City, a comparison was made between the protein reagent strip (PRS) and the urinary protein/creatinine ratio (uPCR) to detect proteinuria. It was concluded that there was a high concordance between the detection of urine protein by PRS and uPCR and therefore the PRS could be useful in low income countries to detect proteinuria [
44].
Two South African studies in our review demonstrated the importance of an early creatinine clearance, prior to 4 months after the initiation of TDF [
27,
32]. Both the CG equation (after correcting for bias) and the 4-v MDRD equation (without the ethnicity factor for African Americans) have been validated for the estimation of eGFR in Black South Africans [
30]. The production of creatinine is determined mainly by muscle mass and dietary intake [
45]. Therefore, using the ethnicity factor in the 4-v MDRD equation overestimates the eGFR in Black South Africans [
30] due to differences in diet, muscle mass and body composition between Black South Africans and African Americans [
30]. In the current review, the majority of the patients had mild to moderate renal dysfunction with a low prevalence of severe renal impairment prior to ART initiation. Similar findings were seen in a study by Overton et al. set in Washington [
46]. The prevalence of significant renal impairment in a South African study [
33] was slightly higher than that of a Kenyan study [
47], possibly because of the differences in the two African populations and because the eGFR method used in the South African study has not been validated for use in other African countries. Though the prevalence of chronic renal failure is low in the HIV-infected population, it has been shown to be higher than that of the general population in an American study [
46]. One South African study showed that approximately 6% of ART naïve outpatients who presented with proteinuria had HIV-related kidney disease [
12] and another study of 99 in-patients who underwent renal biopsy showed that 27 patients (27.3%) had HIVAN, only 3 of which were on ART [
17].
In the current review, HIVAN was the most common histology seen on renal biopsy [
15,
31]. Other histologies have been documented in various studies both locally [
12,
17,
22,
31] and overseas [
48]. The third leading cause of end stage renal disease (ESRD) in African Americans aged between 20 and 64 years was found to be HIVAN [
13]. HIVAN is commonly found in HIV-infected Black patients, suggesting a role of genetics in the development of HIVAN [
13]. Kasembelli et al. proved that Black South Africans who carried two copies of the APOL1 risk alleles were at higher risk of developing HIVAN [
28]. Lucas et al. demonstrated that ART can prevent or reduce the risk of developing HIVAN and, should it occur, patients on ART may have a slower course and lower mortality than patients not on ART [
49]. Following the diagnosis of HIVAN, patients can progress to end stage renal failure within months [
17]. In a South African study over a 10 year period of renal biopsies, the incidence of HIVAN increased from 6.6% in 2000 to 25.7% in 2009 [
22]. Furthermore, of the 27 patients diagnosed with HIVAN on renal biopsy in a study in South Africa, only 3 were on ART [
17]. This reaffirms the importance of renal biopsy in accurately diagnosing renal disease, particularly HIVAN [
12,
17,
48], so that ART can be initiated early to improve outcomes. Sadly, due to a lack of resources and specialists, access to renal biopsy is limited to urban tertiary hospitals in South Africa.
From September 2016, when ART will have been made universally available to all HIV-infected South Africans in accordance with WHO ART guidelines [
3], even patients with undiagnosed HIVAN will have been initiated on ART. We know from studies in other countries that renal function improves with ART. In a randomised ART trial in Uganda and Zimbabwe, there was stabilisation or a slight improvement in renal function after the initiation of ART [
50]. Another study demonstrated the resolution of renal disease with ART and the recurrence of renal disease after stopping ART [
51]. TDF-induced renal toxicity usually resolves after TDF cessation, but the TDF-related renal damage is not always completely reversible [
52]. Our systematic scoping review demonstrated that renal function essentially improved on ART [
15,
31,
32]. However, data on the long-term outcomes of renal function and CKD for patients on ART in South Africa is lacking. It was noted that 2015 had the most publications applicable to the topic of our scoping review, indicating a recent increase in interest on this subject in South Africa.
Recommendations for future research
The majority of the included studies were conducted in an urban setting where access to healthcare and laboratories is readily available. However, research shows the high HIV prevalence and fewer patients on ART, in rural South Africa [
53]. Females bear the brunt of the HIV epidemic in South Africa having a significantly higher prevalence of HIV than their male counterparts [
53]. In the current review, consensus was not reached regarding gender as a risk factor for renal dysfunction possibly because females predominated in most studies. Therefore, comparative studies to determine the differences in renal manifestations between HIV-infected males and females, preferably in rural settings, are recommended. We also need to recruit more males to participate in research.
Currently, our urine dipstick analyses detect only proteinuria and not microalbuminuria. This suggests a novel idea for research: looking at the significance of microalbuminuria versus proteinuria in our HIV-infected population, the outcome of which could guide future urine diagnostics in baseline screening for renal disease. Cost-effective methods for urine screening and estimating GFR are needed, especially for rural areas where access to laboratories is limited.
Considering that the majority of South African HIV-infected patients are Black and with a genetic predisposition to HIVAN, we anticipate that the prevalence of undiagnosed HIVAN will be significant. As far as we know, there are no prospective randomised controlled trials in South Africa investigating treatment options for HIVAN and no data on the actual prevalence of HIVAN.
Data on TDF nephrotoxicity and its impact on long-term renal function are lacking in South Africa. Prospective clinical trials focusing on TDF nephrotoxicity and its long-term renal outcomes are needed.
The overall prevalence of renal disease in South Africa is unknown. We urgently need epidemiological studies assessing the prevalence of renal disease and HIV-related renal disease in South Africa in order to efficiently plan and sustain an effective CKD programme. The establishment of renal registries will assist with much needed statistics on the morbidity and mortality of renal disease in general and specifically to HIV and ART.
Implications for practice
Risk factors associated with proteinuria and albuminuria in HIV-infected patients (low eGFR, older age, diabetes and HPT) [
54,
55] overlap with those for CKD patients [
56]. Stanifer et al. found that 24% of hypertensives, 18.9% of diabetics and 10% of HIV-infected patients have co-morbid CKD in Sub-Saharan Africa [
9]. With the high burden of HIV and non-communicable diseases such as CKD, hypertension and diabetes in South Africa, it would be wise for the Health Department to invest in CKD clinics in rural areas and nephrology outreach services as previously proposed by Madala et al. [
34]. All staff must be trained in screening for renal dysfunction and referral pathways and support systems must be in place for patients to access specialist care. In South Africa, the number of nephrologists per million population is estimated to be 1.1 [
57]. The lack of specialists must be addressed in order to have optimally functioning and widely accessible CKD facilities, as well as access to renal biopsy and renal replacement services. We must build on our current infrastructure.
Lastly, we need to empower our patients with knowledge regarding ART complications, and the monitoring and recognition of side effects. In over-burdened health facilities, it is not unusual for important management steps to be overlooked. Therefore, if we educate our patients, these can be avoided.
Strengths and limitations
An important strength of this study is the exhaustive search for relevant studies. Scoping review methodology is rigorous and methodical in its approach to examining the extent, range and nature of research activity in a particular field [
18]. The unavoidable limitation of this study was the exclusion of literature published in other languages other than the English language.
Conclusions
The findings of the review are in keeping with that of international literature. South Africa has recently adopted WHO policy and as of September 2016, all HIV-infected patients have access to ART irrespective of CD4 cell count. Though this is a victory for the millions still awaiting ART in South Africa (in this context, particularly patients with undiagnosed HIVAN), the impact on the current health infrastructure that this strategy will have is unknown. More patients on ART equates to a further increase in chronic disease in South Africa, mainly CKD, hypertension and diabetes. With a lack of dedicated CKD clinics and specialist renal services particularly in the rural settings, as well as a deficiency in knowledge on the long-term impact of ART on CKD, this may be a victory for which the healthcare system could be ill prepared.
More research is urgently needed on the impact of ART on renal disease, ART-related renal complications and the prevalence of CKD, as well as cost effective methods for routine screening of renal disease in resource-poor settings.