A Systematic Review Exploring the Range of Renal Complications of Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) is a viral infection which progressively leads to acquired immunodeficiency syndrome (AIDS) in the absence of treatment. This happens through the destruction of crucial cells in the immune system, such as the helper T cells, dendritic cells, and macrophages. Since the first case was isolated in the 20th century, the disease has spread rapidly among humans, with significant renal, cardiovascular, respiratory, and neurological complications. It is predominantly sexually transmitted but non-sexual transmission. A relationship between HIV and renal diseases has been suggested for a long time, but only a few systematic studies have centered on this association. This systematic review aims to analyze the possible association between HIV and renal diseases as well as the range and pathogenesis of these renal diseases. HIV remains a critical infectious disease globally, inciting substantial morbidity and mortality. Studies have shown that people living with HIV (PLWH) are at increased risk of acute and chronic kidney disease. This review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Google Scholar, and Cochrane databases were searched exhaustively using the inclusion criteria of free full-text English papers that have exclusively studied humans in the last 20 years. Sixteen articles were selected including a systematic review, observational studies, and comprehensive narrative reviews on the role of HIV in the etiology of renal diseases, and were systemically reviewed and analyzed to elicit the wide range of possible renal complications resulting from HIV infection.

etiopathogenesis of HIV-1 begins when the virus gains entry to cells without causing immediate lethal damage. This access into cells triggers intracellular signal cascades, which then expedites the duplication of viral particles. The two envelope proteins, the external glycoprotein (gp120) and the transmembrane protein (gp41), establish the spikes on the virion's surface [7]. The external glycoprotein gp120 attaches to the cell membrane to facilitate entry by first binding to the CD4+ receptor [8]. This is followed by interactions between the virus and the chemokine co-receptors, which include C-C motif chemokine receptor 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4), thereby triggering irreversible conformational alterations [9]. This fusion event occurs within minutes by pore formation [10], and releases the viral core into the cell cytoplasm.
The next stage of genomic imprinting involves the reverse transcription of the viral genome into DNA by the virus' reverse transcriptase enzyme [4]. Other essential non-structural viral proteins such as Vpr, Tat, and Nef play crucial roles in the life cycle of HIV. Vpr is responsible for promoting nuclear importation of the viral pre-integration complex, a major phase in integrating viral particles into the host genetic makeup [11]. Tat increases the effectiveness of gene transcription and induces the expression of proinflammatory cytokines [12]. Nef plays crucial roles in T-cell activation, decreasing cell surface CD4 expression, viral transcription amplification, and stimulation of cell signaling pathways [13]. The dissimilarities between HIV-1 and HIV-2 viruses are seen in their genome structure. However, the basic organization, which is the presence of the three foundational genes (gag, pol, and env), is constant for all retroviruses. In addition to these three foundational genes, the HIV-1 and HIV-2 genomes possess a complex combination of additional regulatory genes [5]. While both viruses can cause AIDS, HIV-2 is less virulent and takes a longer clinical progression course to AIDS. Furthermore, HIV-1 causes central nervous system disease more regularly [11]. HIV entry into renal cells transpires in a CD4+-independent manner, due to the fact that neither podocytes nor renal tubular epithelial cells express CD4+ nor the co-receptors [14]. However, productive infection of renal cells has been shown in the setting of direct cell-cell interaction with both infected CD4+ T cells and macrophages [14].
Several mechanisms may contribute to kidney disease in people living with HIV (PLWH), including direct renal damage resulting from intrarenal HIV infection and gene expression, immune dysregulation, treatment toxicity, comorbidities, and co-infections [14]. Renal diseases have increasingly become a very important cause of morbidity and mortality in PLWH. This systematic review seeks to explore the wide range of renal diseases associated with HIV infection.

Review Methods
This systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [15].

Eligibility Criteria
We identified specific inclusion criteria to select the studies relevant to our systematic review. Studies evaluating the role of HIV in the etiopathogenesis of various renal diseases were selected as the primary target of our research. We selected studies published from 2003 to 2023, including systematic reviews, traditional reviews, case reports, reviews of literature, and observational studies. Articles published in languages other than English were excluded, along with studies unrelated to the topic, and abstracts with no access to full-text articles. In addition, animal studies, conference abstracts, and duplicated articles were also excluded.

Selection Strategy
Two reviewers selected the articles independently using the same search strategy in all three databases. At first, articles were screened from the title of articles and abstracts and then later by reading full-text articles. If contradicting results regarding the article's eligibility occurred, reviewers assessed the full-text article until the group reached a consensus.

Databases and Search Strategy
We searched electronic medical databases PubMed, Google Scholar, and Cochrane from January 2003 to January 2023 to elicit all English human studies assessing the role of HIV in the pathogenesis of renal diseases. Keywords used in all search engines included: 'HIV' or 'human immunodeficiency virus' or 'AIDS' or 'acquired immunodeficiency syndrome' AND 'renal failure' or 'kidney failure' or 'renal impairment' or 'kidney impairment' or 'renal insufficiency' or 'kidney insufficiency' or 'renal disease' or 'kidney disease' or 'acute kidney injury'.

Analysis of Study Quality/Bias
The full articles remaining were assessed for quality assessment and risk of bias using tools depending on the study type: Cohort Studies, Newcastle Ottawa Scale (NOS) [16]; Systematic reviews and Meta-analyses, Assessment of Multiple Systematic Reviews 2 (PRISMA 2020 Checklist) [15]; and Narrative reviews, Scale for the Assessment of Narrative Review Articles (SANRA) [17]. Each assessment tool had its criteria and different scoring, and each selected study was assessed for risk of bias by two reviewers independently using commonly used tools for each type of study, and only studies that scored more significantly than 70% were included in this review. A score of at least 70% for each assessment tool was accepted. Table 1 expatiates the questions used to assess the qualities of the papers included in the study.  [18] (arising from reporting biases)? 15) Did the review authors describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome? 16a) Did the review authors describe the search and selection process results, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram? 16b) Did the review authors cite studies that might appear to meet the inclusion criteria but which were excluded, and explain why they were excluded? 17) Did the review authors cite each included study and present its characteristics? 18) Did the review authors present bias risk assessments for each included study? 19) Did the review authors for all outcomes present for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g., confidence/credible interval), ideally using structured tables or plots? 20a) Did the review authors for each synthesis briefly summarise the characteristics and risk of bias among contributing studies? 20b) Did the review authors present the results of all statistical syntheses conducted? If meta-analysis was done, present for each the summary estimate and its precision (e.g., confidence/credible interval) and where the review protocol can be accessed or state that a protocol was not prepared? 24c) Did the review authors describe and explain any amendments to the information provided at registration or in the protocol? 25) Did the review authors describe sources of financial or non-financial support for the review and the role of the funders or sponsors in the review? 26) Did the review authors declare any competing interests of review authors? 27) Did the review authors report which of the following are publicly available and where they can be found template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review? Scored as 0,1.

Ottawa [16] Cohort
Eight items: 1) Representativeness of the exposed cohort, 2) Selection of the non-exposed cohort, 3) Ascertainment of exposure, 4) Demonstration that outcome of interest was not present at the start of study, 5) Comparability of cohorts based on the design or analysis*, 6). Assessment of outcome, 7) Was follow-up long enough for outcomes to

Results
The comprehensive and exhaustive database searches of PUBMED, Google Scholar, and Cochrane revealed 1419 potentially related titles based on the study inclusion criteria for this systematic review. Removal of duplicates left 1407 articles, after which all remaining records were screened using the title and abstract. A secondary review was then carried out by reading full-text articles and the use of detailed inclusion and exclusion criteria to eliminate irrelevant articles not possessing the required data for this systematic review. This holistic evaluation yielded 21 articles on our research question, which were further subjected to the screening tools. After a quality appraisal, we eliminated five studies, and the final 16 articles were included in our systematic review. These articles comprised two cohort studies, one systematic review, and 13 narrative reviews. We created a PRISMA flowchart for study identification and filtering the articles as shown in Figure 1 [15]. Table 2 discusses the characteristics of the papers included in the study.    . These disease entities result directly from viral nephrotoxic effect, leading to the histologic features of HIV-associated nephropathy (focal collapsing glomerulosclerosis), thrombotic microangiopathy, and immune complex glomerulonephritis, or indirectly due to antiretroviral medications such as indinavir and tenofovir, which have a nephrotoxic effect [30]. These, in turn, cause acute or chronic kidney disease. Acute renal failure is often a characteristic finding in HIV-infected patients. It is usually seen in advanced stages of HIV infection (i.e., CD4 cell count of <200 cells/mm 3 and HIV RNA level of >10,000 copies/mL), hepatitis C virus coinfection, and a history of antiretroviral treatment [30]. Furthermore, the cause of chronic renal failure in HIV-infected patients can be challenging to assess on clinical grounds alone and can usually only be determined by renal biopsy {30}.
This finding was buttressed by Islam et al., who conducted a systematic review and meta-analysis showing that the pooled relative risk of kidney disease among PLHIV was 3.87 (95%CI: 2.18-6.85) [34]. Jacobson et al. also reported in their study that the relative risk of kidney disease among 542 HIV-infected men with the clinical finding of abnormal proteinuria, having chronic kidney disease (CKD) stages 3-5, to be 5.1 (95%CI: 2.9-8.9), compared to 661 HIV-seronegative men [35]. Estimates were adjusted by age, race, hypertension, and diabetes. Bah et al. carried out an observational study to determine the frequency of renal diseases in HIV patients, with 45 (41.7%) demonstrating renal diseases. Renal complications in these cases consisted of acute renal failure in 24 cases (53.33%), chronic renal failure in 13 cases (28.89%), nephrotic syndrome in four cases (8.89%), and interstitial nephritis in four cases (8.89%) [36]. However, renal biopsy was not done for histologic diagnosis in these cases.
An observational study by Campbell et al. involved 3439 patients, 81 (2.4%) of whom were diagnosed with CKD. Patients with CKD were found to be older, showed lower basal CD4+ T-cell counts, and in addition, had more regularly experienced an AIDS-defining illness. HIV-associated nephropathy (HIVAN) is predominantly found in Blacks, supported by Campbell et al.'s study, in which HIVAN was diagnosed in 16 (62%) of 26 Black patients and none of 55 White/other ethnicity patients [22]. In addition, increasing age and comorbidities usually seen in CKD patients in the general population, such as diabetes mellitus, atherosclerosis, and hypertension, are also increasingly linked with CKD in HIV seropositive patients.

Pathogenesis of HIV Renal Disease
Gray areas remain in data concerning the pathogenesis of renal diseases associated with HIV infection. Current literature suggests that the host response to chronic HIV infection may include continuous antibody synthesis and atypical cell-mediated immune responses, which directly determine renal pathologic outcomes [33]. The release of proinflammatory cytokines by HIV-infected lymphocytes and renal cells may also play a crucial role in mediating kidney injury [33] The mechanism of entry of HIV-1 into renal cells is still poorly understood. This is because while HIV entry into renal cells occurs in a CD4-dependent manner; these renal cells do not possess the classic receptors and co-receptors required for viral entry, such as CXCR-4 or CCR5 (co-receptors for gp120), unlike macrophages, lymphocytes or dendritic cells [21].
Cell-to-cell interaction involving helper T cells has often been implicated in HIV infection of renal epithelial cells. Many studies describe the virological synapses that permit HIV to pass from infected CD4+ T cells to renal epithelial cells in a contact-dependent manner. This infective transfer is duplex and bidirectional as the renal epithelial cells can directly infect CD4+ T cells [37]. In keeping with this hypothesis, viral transmission occur more effectively when cells are infected in the presence of T cells, compared to cell-free viral inoculum [20]. Studies also showed that heparan sulfate proteoglycans (HSP), syndecan 1, and agrin might aid in this transfer, as using HSP inhibitors remarkably reduced infection of renal tubular epithelial cells [38].

Renal Complications of HIV infection
Several renal affectations occur with HIV infection, such as HIVAN, HIV-associated thrombotic microangiopathy (TMA), and HIV-associated immune-mediated glomerulonephritis [39].
HIVAN: Studies have shown that HIVAN is one of the major causes of end-stage renal disease (ESRD) in HIV seropositive patients, often progressing to ESRD without combined antiretroviral therapy (cART). Its clinical presentation is characterized by azotemia and proteinuria without significant peripheral edema in patients with advanced HIV infection. At the same time, the kidneys have a characteristic enlargement with loss of corticomedullary differentiation on ultrasound scans [40]. A systematic review conducted by Assaram et al.
involving 6595 participants concludes that HIVAN is the most common histological finding on renal biopsy. It is the third leading cause of ESRD among African Americans aged 20 to 64 years. This study also added that in 101 HIV-positive, ART-naive patients with renal failure, 57 presented with acute kidney injury (AKI), 21 with acute-on-chronic kidney disease, and 23 with CKD [19]. The histologic picture includes collapsing focal segmental glomerulosclerosis (FSGS), microcytic tubular dilation, fibrosis, and interstitial inflammation [40]. The collapsed glomerulus is often seen along with proliferation, hypertrophy, and hyperplasia of the superimposed glomerular epithelial cells (podocytes), which tend to fill the urinary space, giving rise to the classical histologic picture of podocyte effacement [18]. Glomerular collapse is defined as at least one glomerulus with the collapse of glomerular basement membranes accompanied by proliferated glomerular epithelial cells [32]. In addition, the podocytes may proliferate to form a pseudo-crescentic structure [27]. HIVAN occurs mainly in African Americans with apolipoprotein L1 (APOL1) risk alleles and is a leading cause of ESRD in African Americans [3]. Disease expression and renal complications, and subsequent kidney injury risk require two APOL1 risk alleles. The presence of high-risk genotypes in healthy populations points to the fact that this disease expression requires a "second hit," such as infections (e.g., HIV, viral hepatitis, and others), interferon, gene-gene interactions, illicit drug use, and other CKD risk factors [32]. It is also strongly linked with low CD4+ T-cell count and South African populations [18]. HIVAN affects 27% of seropositive individuals, and in the absence of highly active ART (HAART), it quickly progresses to ESRD [20]. A finding in HIVAN is also absent or minimal immune complex deposition [32]. Tubulointerstitial disease is also an important component of HIVAN and often appears out of proportion to glomerular disease, causing renal enlargement and a hyperechoic picture on ultrasonography [32].
Non-Collapsing FSGS: This is also known as FSGS not otherwise specified (NOS). Cases of non-collapsing FSGS usually have a less severe degree of podocyte effacement [32]. The main histologic finding is segmental sclerosis of capillary loops with matrix increase (with or without hyalinosis) within the glomerulus and adherence of capillary tuft to Bowman's capsule [18]. In addition, it possesses a different epidemiology as it is more commonly seen in Caucasians than in African Americans [18].
HIV-Associated Immune-Mediated Glomerulonephritis: Similar to non-collapsing FSGS, immune-mediated glomerulonephritis is more common in caucasian populations than African American populations. This collection of immune-mediated renal pathologies is also known as HIV immune complex kidney disease (HIVICK). Gernholtz et al. performed a retrospective study on 104 renal biopsies in Johannesburg, South Africa, and discovered that 20% of these biopsies were classified as HIVICK [41]. The limitation of this study is that it was a retrospective study, and the data was limited by selection bias and a small sample size. They possess similar characteristics with lupus nephritis, including immunologic, histologic, and ultrasonographic features such as immunoglobulin (IgG, IgA, and IgM) and complement (C3 and C1q) mesangial deposits; however, it occurs in patients without negative serological findings and no clinical evidence of systemic lupus erythematosus (SLE) [42]. Electron microscopy often reveals subendothelial, intramembranous, and mesangial electron-dense deposits [33]. A study of 60 biopsy specimens found that some form of immune complex-mediated glomerulonephritis was present in 37% of biopsy specimens. These histologic findings are classified into immune complex-mediated glomerulonephritis, IgA nephritis, mixed sclerotic/inflammatory disease, and lupus-like syndrome [30]. IgA nephritis's histopathology and immunologic picture encompass segmental or diffuse mesangial matrix expansion with sub-epithelial and peripheral intramembranous electron-dense deposits [33].
HIV-Associated TMA: This includes the clinical findings of hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Clinical features include microangiopathic hemolytic anemia, microangiopathic hemolytic thrombocytopenia, reduced haptoglobin, and schistocytes seen in peripheral blood smear [29]. Although the pathogenesis of HIV-related TMA is unknown, preliminary studies show that HIV infection causes injury to renal endothelial cells, leading to platelet activation and deposition in the renal microvasculature [25]. Coexisting infections, cytotoxins, deficiencies of platelet aggregation inhibitors, and coagulation cascade abnormalities have all been implicated in the pathogenesis of TMAs. [33]. Clinical presentation is proteinuria, hematuria complicated by rapid onset renal failure and damage, and multi-system organ dysfunction [29]. However, the incidence and prevalence have reduced since the advent of ART.

Other Renal Diseases in the Setting of HIV Infection
Renal diseases such as diabetic nephropathy and arterionephrosclerosis may occur in PLWH due to multiple risk factors. Studies have shown that HIV infection is associated with a four-fold increased risk of type 2 diabetes mellitus (T2DM) and poor glycemic control compared to uninfected people [18]. Conversely, T2DM can increase the risk and severity of renal manifestations in PLWH [18]. In addition, non-HIV-related kidney disease is also on the rise due to the aging patient population as a result of the prevalence of ARTs, which improve life expectancy. The life expectancy of highly educated PLWHs treated chronically with combined ART has reached that of the uninfected counterpart [43].

Limitations
This review was limited to studies written in the English language, and studies published after 2003. In addition, grey literature and non-free full texts were also excluded from the study, thereby reducing the amount of available data. We did not specify the locations of the studies. Also, there was a dearth of information on in-depth randomized clinical trials, clinical trials, and systematic reviews to demonstrate relationships between HIV infection and different aspects of renal diseases.

Conclusions
This was a critical analysis of the link between HIV and renal disease, discussing the pathogenesis of HIV in renal disease, the various implications of renal disease, and complication triggers. One study was a systematic scoping review, two were observational studies, and the rest were narrative reviews. We also discussed the increasing incidence of non-HIV-associated renal diseases in PLWH, such as diabetic and hypertensive nephropathy. This results from the increasing life expectancy in PLWHs with the increased use of ART. Hence, there is a need for more research in the future to elicit complications of HIV further as it remains a critical public health topic.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.