Factors associated to chronic kidney disease in people living with HIV/AIDS

Objective: to analyze the factors associated to chronic kidney disease in people living with HIV (PLHIV). Method: a paired case-control study (4 controls for each case) carried out in a specialized care service in the Southeastern of Brazil, by analyzing PLHIV medical records. The sample consisted of 85 participants, corresponding to 17 cases and 68 controls. Pearson’s chi-square test (Χ2) and Fisher’s exact test, logistic regression, Odds Ratio (OR), 95% Confidence Interval (CI) and p<0.05 were used. SPSS version 25.0 and R Core Team, 2018 version 3.5.1 were used. Results: the factors associated with chronic kidney disease identified in this study were the following: presence of Systemic Arterial Hypertension [OR=5.8, CI (95%)=1.84-18.42, p=0.001] and use of nephrotoxic anti-retrovirals in the previous therapeutic regimen [OR=3.3, CI (95%)=1.105-10.221, p=0.028]. On the other hand, age below 40 years old [OR: 0.122, CI (95%)=0.015-0.981, p=0.022] was identified as a protective factor. Conclusion: the PLHIV under study have multi-factorial exposure associated with chronic kidney disease. However, knowing these factors helps to identify the existing risks and/or renal dysfunction, in addition to supporting the clinical decision of the health professionals who directly assist them.


Introduction
In the last three decades, the occurrence of AIDS is considered one of the greatest challenges for public health worldwide. AIDS is the most important and devastating contemporary epidemic (1) .
According to the most recent world report, until the year 2017, there were about 36.9 million people living with HIV/AIDS (PLHIV), of which 75% were aware of their serological status (2) . Among those who have already been diagnosed, four out of five are using Antiretroviral Therapies (ARTs) (79%). Among those who have already had access to the treatment, 81% had an undetectable viral load (2) .
Scientific and technological developments in the therapeutic field allowed for the advent of ART, enabling a better prognosis and, consequently, a reduction in morbidity and mortality (3) . After the success of combinations of anti-retroviral drugs (ARDs) to control viral replication, PLHIV have achieved better quality of life and greater longevity (4)(5) . This scenario, therefore, attributes to the HIV infection a chronic condition of the disease (5) .
However, PLHIV started to present high risks of developing comorbidities (cardiovascular, liver and kidney diseases), as a consequence of the complex association between immunodeficiency, chronic inflammation, aging, and toxicity of anti-retrovirals, expanding the focus of care for a new profile of PLHIV (6)(7) .
Faced with the new conjuncture of the health of PLHIV, previous studies have signaled a concern with chronic diseases, among them, chronic kidney disease (CKD) (7)(8) . The diverse causes and pathogenic mechanisms of kidney diseases found in these people are complex, multi-factorial and have as an aggravating factor the inflammatory processes resulting from HIV infection and the cumulative exposure of potentially nephrotoxic anti-retrovirals (8)(9)(10) .
CKD in PLHIV, therefore, presents an increasing and higher form in comparison to the general population (7,(11)(12) , which represents clinical, managerial and economic challenges for the health care of these individuals (13) .
A number of studies reveal a higher prevalence of CKD in PLHIV when compared to people not infected by the virus (11,(14)(15) , presenting an up to 20 times greater risk of progressing to Terminal Chronic Kidney Disease (TCKD) (15) .
The prevalence of CKD associated with HIV varies geographically, by population and by period of the year (13,(16)(17) , due to genetic heterogeneity, to the initiation of the ART (18) and to the different definition methods for CKD in each region, varying between 2% and 38% (13,19) . A study carried out in the Southeast region of Brazil showed that 35% of PLHIV using nephrotoxic ARDs for at least 6 months showed changes in the renal function (20) .
Therefore, the high number of PLHIV with CKD portrays an issue to be addressed by the health systems in developing countries that have a high prevalence of HIV and where access to CKD care is insufficient (13) . This increase in the number of cases leads to an increase in the use of the health resources and, consequently, to an increase in health care assistance costs (13) .
Due to the relevance of the matter (11)(12) and to the scarcity of research studies on this topic at the national level (20) , it is necessary to deepen studies on it and to expand the vision of comprehensive care for PLHIV, with the aim of preventing diseases, promoting health and timely treatment (20) . In view of the above, the objective of this study is to analyze the factors associated with CKD in PLHIV.

Method
In this study, a case-control design was analyzed, which was initially nested in a descriptive-analytical, The criterion for selecting the controls was for convenience, that is, the first medical record that met the inclusion criteria was selected (that is, after the identification of the cases, the first four medical records were selected immediately after the registration of the cases).
In order to obtain the eGFR using the CKD-EPI equation, it was first necessary to convert the conventional creatinine into Creatinine for Isotopic Dilution Mass Spectrometry (IDMS), considered the gold standard, in order to minimize its variability (30) .

Discussion
Among the 17 cases and 68 controls analyzed in this study, we found that the age, SAH, and nephrotoxic anti-retrovirals in a previous treatment regimen variable showed a statistically significant association with CKD.
Being less than 40 years old is a protective factor and, as associated factors, having SAH and making previous use of nephrotoxic ARDs are noted.
The main findings of this study indicate the importance of detecting the associated factors for traditional CKD, those intrinsically related to the fact of living with HIV and being treated with potentially nephrotoxic anti-retrovirals. International studies have addressed this issue in recent times due to its relevance in the population living with HIV (13,23,28,32) .
Chronic Kidney Disease has a low incidence of PLHIV, although it is considered an important worldwide public health problem and is more prevalent among PLHIV than in the general population (33)(34) . This fact justifies the need to investigate the main predictors for CKD in PLHIV using the case-control methodology. This study, therefore, is the first that addresses this type of design in this theme at the national level.
From the pre-established criteria for the definition of CKD, we found a prevalence of 6.5%, which is equivalent to the cases described in this study. Among A wide variation in the prevalence of CKD is found in different locations, which is justified by the heterogeneous population, regional, cultural, structures of access to health services and differences in diagnostic criteria (13,23,28) . Based on the first systematic review that provided prevalence estimates for CKD in PLHIV in various regions of the World Health Organization, using the CKD-EPI equation, an overall prevalence of 4.8% was identified (CI: 2.9-7.1), with the highest prevalence found in Africa and the lowest in Europe (13) .
While those who analyzed GFR<60 ml/min/1.73 m 2 and presence of proteinuria in more than one measure, in a recent study showed a global presence of 11.7% of CKD, with 7.6% being diagnosed only by the proteinuria criterion (38) . As well as what is represented in the Dutch (18.3%) (28) and Vietnamese cohorts (8.3%) (34) .
Data which show a high prevalence of the disease when using the two diagnostic criteria.
Being under the age of 40 has been shown to be a protective factor for CKD, that is, PLHIV under the age of 40 are less likely to develop CKD than those over 40 years old. This corroborates with other researchers who point out that, with increasing age there is a greater predisposition to lower eGFR, to greater regression of renal function and, consequently, to develop CKD (23)(24) .
Among the non-modifiable associated factors for developing CKD, advanced age is considered an independent marker of decline in renal function in PLHIV by several scholars (18,(27)(28)(38)(39) . The same is also identified in this study, in which the cases have a mean age of 61.4 years old and, in the controls, 49.9 years old.
The relationship between increasing age and CKD was also studied in a multi-center cohort carried out over nine years with 23,000 PLHIV, in which an increasing prevalence of CKD was identified with the advancing age groups in which these individuals are inserted. Among Pontes PS, Ruffino-Netto A, Kusumota L, Costa CRB, Gir E, Reis RK people aged between 50 and 60 years old, there was an increase from 5.2% to 7.2% while, among those over 60, there was an increase from 18.5% to 23.2% of CKD (32) .
However, the characteristic of premature aging among PLHIV causes middle-aged adults using ART to have a high inflammatory exposure and, therefore, premature onset can occur of chronic comorbidities, such as CKD (24,40) . This assertion is in line with the results found in a retrospective observational study over a six-year period, which revealed a reduction in the mean age among those who had CKD from 49.4 to 46.4 years old (p<0.0001) (40) .  (42)(43)(44)(45) .
Another variable that showed a significant association was the use of nephrotoxic anti-retrovirals in a previous therapeutic regimen. Individuals who used them were 3.3 times more likely to develop CKD compared to those who did not. This fact can be explained by the longer time of exposure to these specific ARDs in previous ART compared to the current one (7) .
A multi-center cohort study corroborates with this study by showing that the cumulative exposure of nephrotoxic ARDs during the first five years of followup shows a progression in renal impairment rates (7) . Therefore, PLHIV who had GFR>90 ml/min/1.73 m 2 and started the ART with Tenofovir, Atazanavir, Lopinavir enhanced by Ritonavir, and Darunavir showed a significant and growing association of CKD (7) .
Due to the nephrotoxicity of TDF recognized by the literature, the Ministry of Health recommends the discontinuation of this drug in a timely manner (six months of exposure) and its replacement by another ARD if, when using this drug, there is a 25% decline in baseline eGFR or GFR<60 ml/min/1.73 m 2 (5) .
By postponing the discontinuation of nephrotoxic ARDs, transient damage to renal structures can become permanent (26,28,46) . Both the high prevalence of the use of nephrotoxic ARDs in a previous and current scheme, and the cumulative exposure of these ARDs may justify the number of cases found in this study.
In this context, the nurse, as a member of a health team, is a professional who articulates, coordinates and conducts care interventions through goals, interventions and, consequently, obtaining satisfactory results. Its role is fundamental for the identification of the factors associated with CKD and problem solving (47) .
In addition, the nursing team must perform health education actions in the prevention, early detection, and management of CKD in order to change behaviors and lifestyle habits (48) . Thus, providing the protagonism of care for PLHIV from the knowledge of the risks to the chronic diseases that they are exposed to, CKD being an important comorbidity that can affect these individuals.
As for the limitations of the study, although there is methodological rigor from the preparation of the study model to the analysis of the data, some should be noted due to the retrospective nature of the study. Data collection was performed exclusively from secondary data in medical records of patients and, therefore, there were some gaps in obtaining the information.
Another limitation of the study concerns the unavailability of more than one result of 24-hour proteinuria or ACR tests. In view of this, the definition for CKD depended only on the criterion of eGFR<60 ml/ min/1.73 m 2 . Therefore, the identification of CKD stages 1 and 2 were impaired, whereas only the presence of albuminuria≥30 mg/24 hours or albuminuria/ proteininuria ratio (APR)>30 mg/g in more than one measure for more than three months characterizes such classifications.
Such limitations did not prevent the research from being carried out, as international studies also pointed out similar difficulties with access to proteinuria tests and, therefore, used the same definition adopted in this study (18,27,36) .

Conclusion
The factors associated with CKD in PLHIV were the presence of SAH and nephrotoxic anti-retrovirals in a previous therapeutic regimen. Another factor also associated, however, as protection for CKD in PLHIV was age below 40 years old.