In most countries with broad access to antiretroviral therapy, chronic kidney disease (CKD) in people living with HIV infection is now more likely to be the result of non-HIV associated conditions,1,2 and it might have a higher prevalence and earlier onset than in age-matched uninfected individuals.3–5 Although there is a low overall risk of developing end-stage renal disease,6,7 decreasing GFR is related to a significantly increased risk of cardiovascular events and mortality.8,9

Even patients with milder grades of renal dysfunction already have sizable medical costs that can be attributed to renal function impairment.10 Moreover, a considerable number of the antiretroviral drugs and antibiotics undergo renal elimination and demand dose-adjustments according to kidney function.11 Lastly, the increasing exposure to some antiretroviral drugs can lead to progression to kidney disease, even in individuals with initially normal renal function.12 Therefore, in clinical practice, it is important for the attending physician to identify the presence of incremental baseline risk factors and intervene where they are potentially modifiable and as early as possible.

Several studies have already been published evaluating the presence of risk factors for CKD stage ≥3.7,13–18 However, there is a lack of information regarding the factors associated with earlier stages of renal dysfunction, also associated with increased risk of complications,9,19 but in which preventive actions would be more feasible.

The aim of the present study is therefore to assess the influence of sex, type of antiretroviral therapy (ART), and the classical risk factors on mildly decreased renal function (CKD EPI eGFR 60–89mL/min/1.73m2) among an urban population of stable patients with HIV-infection in a large Spanish cohort.

The eligible population consisted of 4493 patients. After excluding 116 subjects with chronic kidney disease, 11 patients in dialysis, eight recipients of kidney transplantation, and 21 recipients of hepatic transplantation, 4337 individuals were included for analysis (Fig. 1).

Fig. 1.

Flow diagram of the studied population.

(0.11MB).

The overall median age was 44 years-old (range 18–85), 47 (18–85) for females and 44 (18–83) for males.

The overall prevalence rate of mildly reduced renal function (eGFR 60–89mL/min per 1.73m2) was 25.0% (1083 patients). The median eGFR among patients with normal renal function was 103.5 (IQR 97.3–110.3)mL/min/1.73m2; the median eGFR among patients with mildly reduced renal function was 79.7 (IQR 73.0–85.1)mL/min/1.73m2.

The main findings of this study, which involved a large sample of patients with well-controlled HIV-infection, were: (a) one quarter of the patients had mildly decreased renal function; (b) women appear to be more susceptible to changes in renal function than men; and (c) traditional and non-traditional risk factors were associated with this outcome.

Renal involvement among patients with HIV-infection is highly variable, but there is a higher risk of developing end-stage renal disease (ESRD) in comparison with the non-infected population. A recent report from the North American AIDS Cohort Collaboration on Research and Design (NAACCORD) in USA and Canada, including 38,354 HIV-infected adults from 2000 to 2009, showed a three-fold higher incidence of ESRD than in the general population. Patients with HIV-infection and ESRD were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, or have a prior AIDS-defining illness.24 In the same way, in Europe, a German cohort study of 9198 patients observed that the incidence of ESRD was more than two times that of the general population. Risk factors for ESRD were black ethnicity, use of injecting drugs, and HCV-coinfection. Interestingly, the prevalence of ESRD increased over time, especially among Caucasian patients, and ESRD was associated with a high overall mortality.25 The overall prevalence of ESRD ranged from 0.3% to 0.5%.20,25

There is significant clinical information on moderate chronic renal failure (GFR<60mL/min) among patients with HIV-infection.13–18,26 However, there is scant information on milder degrees of renal function impairment, especially with GFR 60–89mL/min.9,27 The reason is the relatively recent use of the estimated glomerular filtration rate (eGFR) with the MDRD-equation which is not validated to discriminate GFR over 60mL/min. In addition, the eGFR with the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation allows for more detailed analysis of renal function and discriminates patients with mildly reduced GFR (60–89mL/min/1.73m2).20

In the present analysis, there was a significant prevalence of mildly reduced renal function (eGFR 60–89mL/min/1.73m2) in 25% of the patients. The overall prevalence of mild renal impairment found in this study is in accordance with the rates of 25–40% found in other urban, ambulatory and well-controlled populations in the modern era of antiviral therapy.28–30 Due to the asymptomatic character of this condition, these patients were often not recognized as having kidney disease by the caring clinicians and thus missed opportunities for early preventive measures.

The risk factors associated with the presence of mildly reduced renal function in HIV-infected patients have been poorly studied. In the last several years, there has been growing attention to sex in HIV epidemiology, prevention and treatment. Although the association of female sex and chronic kidney disease was not found in the classic EuroSida study,31 several other publications,32,33 including a modern prospective analysis of the large cohort from the D:A:D study,34 have found contrary results. Several reasons may explain why female sex was a strong independent risk factor for mildly impaired renal function in the multivariate analysis. Firstly, in the present study, women presented a higher prevalence of black race and injecting drug use. Although not sex-specific, these factors may interact with sex and create a structural barrier to prevention, testing, and treatment services, as already addressed in a recent review.35 The higher prevalence of prior AIDS events and lower nadir CD4 cell count support this affirmation, as they indicate more advanced stages of HIV-infection at diagnosis. Finally, there are sex differences in the antiretroviral pharmacokinetic parameters, and in general, women have been found to be more susceptible than men to developing ART-associated toxicities.36 In fact, the longer duration of HIV-infection in women, and the more frequent exposure to boosted-PI with or without tenofovir disoproxil-fumarate are in accordance with this hypothesis.

Consistent with other studies,16,26,27,33,34 older age was the most important risk factor for the occurrence of renal dysfunction. On the one hand, as HIV patients are living longer, they are also getting older. In 2013, individuals aged 55 and older comprised 26% of the people living with HIV in the USA.37 Moreover, although much attention has been paid to preventing HIV-infection in young people, many patients are infected later in life. For example, 12.9% of newly reported cases of HIV in Western Europe in 2007 were in people aged 50 years or older.38 On the other hand, chronic HIV-infection is associated with accelerated aging despite apparent viral control, manifested as increased genetic instability, enhanced T-cell senescence, diminished naïve T-cell regeneration, and altered intracellular communication. It is therefore, associated with early onset of diseases linked to aging, including renal impairment.39,40

In this cohort, coinfection with HCV was not found to be an independent risk factor for renal dysfunction. Among male patients, this condition was even regarded as a protective variable. Certainly, this topic remains an unsolved issue. A pooled analysis of more than 18,000 patients with HIV-infection found a 50% increased risk of chronic kidney disease among individuals with HCV-coinfection,41 and a more recent meta-analysis of more than 13,000 subjects confirmed these findings.42 However, both authors acknowledged that all the available studies were retrospective and subject to heterogeneity in the design and in the quality of data, as many confounding variables were not reported. Although some investigators have linked HCV to atherosclerosis and atherosclerotic diseases at the extra-hepatic level including kidneys,43 and although there is an association between HCV infection and several types of glomerulonephritis,44 the often observed association between HCV infection and increased risk for kidney disease may still reflect confounding variables such as older age, injecting drug use, poor socioeconomic status, and exposure to nephrotoxic medications.

In this study, experiencing HIV-suppression was a strong independent risk factor for renal impairment. It is true that, on the one hand, an untreated HIV-infection may be related to acute and chronic kidney disease due to direct viral kidney injury (HIVAN and other manifestations), chronic inflammation, opportunistic infections, and their potentially nephrotoxic treatments. However, on the other hand, to achieve adequate control of HIV-infection, patients are exposed to prolonged periods on potentially nephrotoxic antiretrovirals and accumulate several adverse events.45

Tenofovir disoproxil-fumarate, the first-choice standard of care treatment, constitutes a risk factor even for milder grades of renal dysfunction.16,46 The primary mechanism by which tenofovir causes renal toxicity may involve drug accumulation within proximal renal tubules, leading to mitochondrial injury and depletion. Tenofovir renal injury may present as partial or full Fanconi syndrome and acute tubular necrosis, eventually leading to tubulointerstitial scarring, which may account for the lack of reversibility of tenofovir renal toxicity in some individuals.47 Nephrotoxicity due to protease inhibitors (PIs), mainly indinavir and atazanavir, is related to the formation of urolithiasis and intratubular precipitation, obstructive nephropathy, and acute or chronic interstitial nephritis. Ritonavir toxicity is more likely the result of drug interactions than of a direct kidney effect.48 Other PIs such as nelfinavir, amprenavir, saquinavir, ritonavir, and darunavir have also been reported to cause urolithiasis.49

This finding has strong implications for clinical practice. Women and middle-aged patients are a population associated with an increased risk of alterations in renal function even in the initial stages of renal injury. This new scenario involves performing a specific clinical management in this group of patients, especially with the use of certain antiretroviral drugs with potentially nephrotoxic effects (as tenofovir disoproxil-fumarate or ritonavir-boosted protease-inhibitors), and intensifying the control of cardiovascular risk factors. Prospective studies are needed to assess whether it is possible to stabilize or reverse the mild decline of renal function in HIV-infected patients.

Our study has two limitations: first, currently most patients are being treated with tenofovir alafenamide, which can improve renal failure.50 We have not evaluated in our study the impact of occult chronic renal failure of the switching from tenofovir disoproxil-fumarate to tenofovir alafenamide. Second, in this study protease-inhibitors were boosted with ritonavir and now cobicistat is the booster agent. We do not know if cobicistat can also enhance tenofovir tubular toxicity as ritonavir does.50 Finally, due to the retrospective nature of the study, and due the fact that information was obtained from databases, ii should acknowledged that some information could have been missed (for example, minor information regarding hypertensive patients, once hypertension diagnosis was based on the use of antihypertensive medication).

This study found a 25% prevalence of already established renal impairment, albeit in the initial stages, among stable, ambulatory patients with well-controlled HIV-infection. Older subjects and female patients are the most susceptible population. Modifiable risk factors, such as hypertension and dyslipidemia, and exposure to potentially nephrotoxic antiretrovirals, such as tenofovir disoproxil-fumarate and ritonavir-boosted protease-inhibitors, were also associated with this outcome. It remains to be determined whether early interventions including antiretroviral therapy switch (tenofovir alafenamide, cobicistat) or improving comorbidities management will improve the course of mild chronic kidney disease.

The authors declare no conflicts of interest.