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Original article
DOI: 10.1016/j.bjid.2018.05.001
Prevalence and risk factors of mild chronic renal failure in HIV-infected patients: influence of female gender and antiretroviral therapy
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Marina Pontello Cristellia,1,
Corresponding author
ninacristelli@yahoo.com.br

Corresponding author.
, Joan Carles Trullàsb,1, Federico Cofánc, Naira Ricod, Christian Manzardoe, Juan Ambrosionie, Josep Lluis Bedinid, Asunción Morenoe, Fritz Diekmannc, Jose Maria Miroe, the CKD-H. Clinical Investigators 2
a Universidade Federal de São Paulo, Hospital do Rim, Divisão de Transplante Renal, São Paulo, SP, Brazil
b University of Girona, Medical Sciences Department, Hospital de Olot, Internal Medicine Service, Girona, Spain
c University of Barcelona, Hospital Clinic – Institut D’Investigacions Biomèdiques August Pi i Sunyer, Nephrology and Renal Transplantation Service, Barcelona, Spain
d Hospital Clínic, Biomedical Diagnosis Center, Core Laboratory, Barcelona, Spain
e University of Barcelona, Hospital Clinic – Institut D’Investigacions Biomèdiques August Pi i Sunyer, Infectious Diseases Service, Barcelona, Spain
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Received 28 February 2018, Accepted 01 May 2018
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Tables (4)
Table 1. Demographic and HIV-related characteristics of the global cohort and comparative analysis regarding the presence of mildly-reduced eGFR (glomerular filtration rate, estimated by CKD-EPI creatinine equation, between 60 and 89mL/min/1.73m2).
Table 2. Antiretroviral treatment used by patients with normal eGFR and with mildly-reduced eGFR.
Table 3. Demographic and HIV-related characteristics according to sex.
Table 4. Multivariate analysis of risk factors independently associated with mildly decreased renal function in patients with HIV-infection.
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Abstract
Background

In people living with HIV, much is known about chronic kidney disease, defined as a glomerular filtration rate under 60mL/min. However, there is scarce data about prevalence and risk factors for milder impairment (60–89mL/min).

Objective

The present study aims to assess the influence of sex, antiretroviral therapy, and classical risk factors on the occurrence of mild decreased renal function in a large Spanish cohort of HIV-infected patients.

Methods

Cross-sectional, single center study, including all adult HIV-1-infected patients under antiretroviral treatment with at least two serum creatinine measures during 2014, describing the occurrence of and the risk factors for mildly decreased renal function (eGFR by CKD-EPI creatinine equation of 60–89mL/min).

Results

Among the 4337 patients included, the prevalence rate of mildly reduced renal function was 25%. Independent risk factors for this outcome were age older than 50 years (OR 3.03, 95% CI 2.58–3.55), female sex (OR 1.23, 95% CI 1.02–1.48), baseline hypertension (OR 1.57, 95% CI 1.25–1.97) or dyslipidemia (OR 1.48, 95% CI 1.17–1.87), virologic suppression (OR 1.88, 95% CI 1.39–2.53), and exposure to tenofovir disoproxil-fumarate (OR 1.67, 95% CI 1.33–2.08) or ritonavir-boosted protease-inhibitors (OR 1.19, 95% CI 1.03–1.39).

Conclusions

Females and patients over 50 seem to be more vulnerable to renal impairment. Potentially modifiable risk factors and exposure to tenofovir disoproxil-fumarate or ritonavir-boosted protease-inhibitors are present even in earlier stages of chronic kidney dysfunction. It remains to be determined whether early interventions including antiretroviral therapy changes (tenofovir alafenamide, cobicistat) or improving comorbidities management will improve the course of chronic kidney disease.

Keywords:
HIV-infection
Antiretroviral drugs
Chronic kidney disease
Glomerular filtration rate estimates
Full Text
Introduction

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.

MethodsStudy design

This was an observational, cross-sectional, single center study. The study project was reviewed and approved by the Institutional Review Board (CEIC Hospital Clinic i Provincial, Barcelona, Spain, IRB# 2014/1080). Eligible patients were all adult HIV-1-infected patients (>18 years old) with at least two serum creatinine measures during the calendar year of 2014. A description of the prevalence of the various stages of CKD of the entire cohort was published elsewhere.20 For the current analysis, patients were excluded if they presented an estimated GFR above 181mL/min/1.73m2, a diagnosis of chronic kidney disease (eGFR<60mL/min per 1.73m2), dialysis and/or kidney transplantation, or if they were recipients of a hepatic allograft.

The main objectives of our study were to describe the occurrence of mildly decreased renal function, defined as two consecutive measures of eGFR between 60 and 89mL/min/1.73m2 over at least three months, and to determine the variables associated with a higher risk of this event. eGFR was obtained using the CKD-EPI creatinine equation.21 As in other publications, we considered the African-American coefficient factor as not applicable to black patients from Africa, Europe and Antilles.22,23

The following demographic, clinical and laboratory parameters were abstracted from the HIV clinical database: age, sex, race, body mass index, hypertension (use of anti-hypertensive medication at CKD diagnosis), diabetes mellitus (glucose intolerance requiring pharmacological intervention), hyperlipidemia (use of hypolipidemic medication at CKD diagnosis), prior cardiovascular event, viruses, time of HIV-infection diagnosis, mode of transmission, AIDS stage, CD4 and viral load (current and nadir), current and previous antiretroviral treatment, hepatitis B coinfection (positive serology) and hepatitis C coinfection (positive serology+detectable HCV-RNA). Urinalysis for proteinuria was not available for the present study.

Data analysis

Demographic, clinical and laboratory parameters were described for patients with and without mildly decreased renal function. Quantitative variables were expressed as median and interquartile range. Analysis of normality of quantitative variables was performed using the Kolmogorov–Smirnov test, and because none of them displayed a normal distribution, nonparametric tests were used to compare these variables. Categorical variables were expressed as number, percentage, and 95% CI; the Chi-square test was used for comparisons. For all tests, statistical significance is considered if the p-value<0.05. To identify risk factors associated with mildly decreased renal function, we performed a stepwise binary logistic regression analysis. Variables included in the model were those with a p-value<0.05 in univariate analysis, or those considered relevant by other published studies. Statistical analyses were performed using the Predictive Analytics Software Statistics for Windows, v21.0 (SPSS Inc, Chicago, IL).

Results

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.
(0.11MB).

Flow diagram of the studied population.

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.

Univariate analysis

Compared with patients with normal renal function, patients with mildly reduced eGFR were older, had a higher percentage of females, higher body mass index, higher proportion of heterosexuality, more prior AIDS events, and more comorbidities like hypertension, dyslipidemia, diabetes, and prior cardiovascular disease. They were also prone to longer durations of HIV-infection, higher initial and peak viral loads, lower nadir of CD4+ cell count, higher frequency of prior AIDS events, but a higher proportion of patients presented viral suppression on treatment (Table 1). The overall length of exposure to any regimen, as well as the total exposure to protease inhibitors (boosted or not), tenofovir disoproxil-fumarate, and PI plus tenofovir disoproxil-fumarate were higher among individuals with mildly reduced eGFR (Table 2).

Table 1.

Demographic and HIV-related characteristics of the global cohort and comparative analysis regarding the presence of mildly-reduced eGFR (glomerular filtration rate, estimated by CKD-EPI creatinine equation, between 60 and 89mL/min/1.73m2).

Variable  Global cohort  Normal eGFR  Mildly-reduced eGFR  p-value 
Number of patients  4337  3254  1083  – 
Age, yearsa  44 (14)  43 (14)  50 (13)  <0.001 
Female gender, n (%)  819 (18.9)  580 (17.8)  239 (22.1)  0.002 
Black race, n (%) (n=2729)  55 (2.0)  40 (1.8)  15 (2.5)  0.281 
Body mass index, kg/m2a(n=1373)  22.9 (3.5)  22.8 (3.4)  23.2 (3.3)  0.040 
Hypertension, n (%)  530 (12.2)  296 (9.1)  234 (21.6)  <0.001 
Diabetes mellitus, n (%)  199 (4.6)  120 (3.7)  79 (7.3)  <0.001 
Dyslipidemia, n (%)  528 (12.2)  302 (9.3)  226 (20.9)  <0.001 
Cardiovascular events, n (%)  168 (3.9)  97 (3.0)  71 (6.6)  <0.001 
HBV coinfection, n (%)  145 (3.3)  100 (3.1)  45 (4.2)  0.325 
HCV coinfection, n (%) (n=4329)  951 (22.0)  708 (21.8)  243 (22.5)  0.639 
Duration of HIV infection, yearsa(n=4313)  10.7 (13.9)  9.6 (13.7)  14.1 (12.6)  <0.001 
Route of HIV acquisition, n (%)
Heterosexual  1116 (25.7)  788 (24.2)  328 (30.3)  <0.001 
Homosexual  2590 (59.7)  1997 (61.4)  593 (54.8)  <0.001 
Injecting-drug abuse  602 (13.9)  445 (13.7)  157 (14.5)  0.681 
Another route  48 (1.1)  37 (1.1)  11 (1.0)  0.778 
Unknown  228 (5.3)  175 (5.4)  53 (4.9)  0.536 
Prior AIDS events, n (%)  837 (19.3)  578 (17.8)  259 (23.9)  <0.001 
HIV suppression, n (%)
On treatment  3840 (88.5)  2825 (86.8)  1015 (93.7)   
Without treatment  29 (0.7)  23 (0.7)  6 (0.6)  <0.001 
No suppression  468 (10.8)  406 (12.5)  62 (5.7)   
Viral load, copies/mLa         
First  23,622 (116,567)  22,300 (105,867)  28,670 (160,438)  0.018 
Higher  67,951 (233,350)  62,934 (209,910)  88,730 (286,825)  <0.001 
CD4 cell count, cells/mm3
Lower (nadir)  252 (237)  264 (237)  219 (240)  <0.001 
Current  633 (375)  634 (372)  626 (394)  0.991 
a

Results expressed as median and interquartile range (IQR).

HCV, hepatitis C virus; HBV, hepatitis B virus. Significant p<0.05.

Table 2.

Antiretroviral treatment used by patients with normal eGFR and with mildly-reduced eGFR.

Variable  Global cohort  Normal eGFR  Mildly-reduced eGFR  p-value 
Number of patients  4337  3254  1083   
Currently on ART, n (%)  4199 (96.8)  3132 (96.3)  1067 (98.5)  <0.001 
Time under current ART regimen, yearsa  1.3 (3.6)  1.2 (3.5)  1.5 (3.9)  <0.001 
Current ART regimen, n (%)
No treatment  138 (3.2)  112 (3.7)  16 (1.5)   
NNRTI-based  2336 (53.9)  1759 (54.1)  577 (53.3)  0.005 
PI-based  136 (3.1)  102 (3.1)  34 (3.1)   
Boosted PI-based  1257 (29.0)  930 (28.6)  327 (30.2)   
Integrase Inh-based  439 (10.1)  316 (9.7)  123 (11.4)   
Other  31 (0.7)  25 (0.8)  6 (0.6)   
Patients currently using, n (%)
Tenofovir  2825 (65.1)  2169 (66.7)  656 (60.6)  <0.001 
Indinavir  – 
Atazanavir  308 (7.1)  237 (7.3)  71 (6.6)  0.419 
Darunavir  808 (18.6)  586 (18.0)  222 (20.5)  0.068 
Boosted PI  1024 (23.6)  755 (23.2)  269 (24.8)  0.272 
Patients having used, n (%)
Lopinavir/ritonavir  2010 (23.5)  711 (21.9)  309 (28.5)  <0.001 
Amprenavir  44 (1.0)  27 (0.8)  17 (1.6)  0.035 
Atazanavir  923 (21.3)  632 (19.4)  291 (26.9)  <0.001 
Darunavir  1069 (24.6)  771 (23.7)  298 (27.5)  0.011 
Fosamprenavir  182 (4.2)  126 (3.9)  56 (5.2)  0.065 
Indinavir  692 (16.0)  429 (13.2)  263 (24.3)  <0.001 
Nelfinavir  462 (10.7)  296 (9.1)  166 (15.3)  <0.001 
Ritonavir  1788 (41.2)  1285 (39.5)  503 (46.4)  <0.001 
Saquinavir  431 (9.9)  313 (9.6)  118 (10.9)  0.224 
Tenofovir  3670 (84.6)  2711 (83.3)  959 (88.6)  <0.001 
Tipranavir  58 (1.3)  39 (1.2)  19 (1.8)  0.168 
Any PI  2496 (57.6)  1769 (54.4)  727 (67.1)  <0.001 
Boosted PI  2156 (49.7)  1554 (47.8)  602 (55.6)  <0.001 
Previous/current treatment with TEN, n (%)  3670 (84.6)  2711 (83.3)  959 (88.6)  <0.001 
Previous/current treatment with boosted PI, n (%)  2156 (49.7)  1554 (47.8)  602 (55.6)  <0.001 
Previous/current PI or boosted PI plus TEN, n (%)  1865 (43.0)  1313 (40.4)  552 (51.0)  <0.001 
Previous/current PI or boosted PI without TEN, n (%)  291 (6.7)  241 (7.4)  50 (4.6)  0.001 
Previous/current NNRTI plus TEN, n (%)  2144 (49.4)  1615 (49.6)  529 (48.8)  0.654 
Previous/current NNRTI without TEN, n (%)  192 (4.4)  144 (4.4)  48 (4.4)  0.992 
Previous/current Integrase Inh plus TEN, n (%)  381 (8.8)  269 (8.3)  112 (10.3)  0.037 
Previous/current Integrase Inh without TEN, n (%)  58 (1.3)  47 (1.4)  11 (1.0)  0.287 
Duration of the treatment, yearsa
Lopinavir/ritonavir  2.40 (3.8)  2.450 (3.8)  2.30 (3.8)  0.534 
Amprenavir  1.50 (2.1)  1.20 (2.4)  1.75 (2.0)  0.642 
Atazanavir  2.90 (4.1)  2.90 (4.1)  3.00 (3.9)  0.555 
Darunavir  2.0 (2.3)  1.90 (2.3)  2.20 (2.6)  0.242 
Fosamprenavir  1.90 (3.8)  1.80 (3.5)  2.30 (4.7)  0.358 
Indinavir  1.70 (2.4)  1.60 (1.9)  1.90 (2.9)  0.015 
Nelfinavir  1.80 (2.5)  2.00 (2.7)  1.70 (2.1)  0.114 
Ritonavir  2.60 (4.2)  2.40 (4.0)  3.00 (4.7)  0.002 
Saquinavir  1.80 (2.8)  2.00 (2.9)  1.70 (2.3)  0.264 
Tenofovir  3.20 (4.4)  3.00 (4.1)  3.90 (4.9)  <0.001 
Tipranavir  1.80 (2.9)  2.00 (2.8)  1.20 (2.9)  0.716 
Any PI  4.00 (5.8)  3.90 (5.6)  4.30 (6.2)  0.008 
Boosted PI  3.30 (5.0)  3.10 (4.7)  3.75 (5.2)  0.004 
a

Results expressed as median and interquartile range (IQR). Significant p<0.05.

ART, antiretroviral therapy; NNRTI, non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitors; Inh, inhibitors; TEN, tenofovir disoproxil fumarate. All PIs were boosted with ritonavir.

Sex disparities

The median eGFR was 94.9 (IQR 81.3–105)mL/min/1.73m2 for females and 96.6 (IQR 84.2–106.3)mL/min/1.73m2 for males (p=0.005). Females had a significantly higher proportion of mildly impaired renal function compared to males (29.2% vs. 23.9%, p=0.002, Table 3).

Table 3.

Demographic and HIV-related characteristics according to sex.

  Female patientsp-value  Male patientsp-value  p-valueb 
  Global femaleb  Normal eGFR  Mildly-reduced eGFR    Global maleb  Normal eGFR  Mildly-reduced eGFR     
Number of patients, n (%)  819  580  239 (29.2)  –  3518  2674  844 (23.9)  –  0.002 
Age, yearsa  47 (11)  45 (11)  51 (13)  <0.001  44 (15)  42 (15)  50 (13)  <0.001  <0.001 
Black race, n (%)  23 (5.3)  18 (5.4)  5 (4.8)  0.802  32 (1.4)  22 (1.2)  10 (2.0)  0.147  <0.001 
Body mass index, kg/m2a  22.4 (5.8)  22.6 (6.5)  22.1 (4.9)  0.240  23.0 (3.3)  22.8 (3.3)  23.4 (3.1)  0.004  0.269 
Hypertension, n (%)  112 (13.7)  58 (10.0)  54 (22.6)  <0.001  418 (11.9)  238 (8.9)  180 (21.3)  <0.001  0.158 
Diabetes mellitus, n (%)  39 (4.8)  24 (4.1)  15 (6.3)  0.191  160 (4.5)  96 (3.6)  64 (7.6)  <0.001  0.792 
Dyslipidemia, n (%)  89 (10.9)  46 (7.9)  43 (18.0)  <0.001  439 (12.5)  256 (9.6)  183 (21.7)  <0.001  0.204 
Prior cardiovascular event, n (%)  21 (2.6)  12 (2.2)  8 (3.3)  0.363  147 (4.2)  84 (3.1)  63 (7.5)  <0.001  0.031 
HBV coinfection, n (%)  13 (1.6)  9 (1.6)  4 (1.7)  0.979  132 (3.8)  91 (3.4)  41 (4.9)  0.236  0.019 
HCV coinfection, n (%) (n=4329)  268 (32.8)  176 (30.4)  92 (38.7)  0.022  683 (19.4)  532 (19.9)  151 (17.9)  0.196  <0.001 
Duration of HIV infection, yearsa  17.5 (11.8)  17.0 (12.9)  17.7 (10.1)  0.022  9.2 (13.1)  8.4 (12.5)  12.5 (13.0)  <0.001  <0.001 
HIV acquisition, n (%)
Heterosexual  559 (68.3)  398 (68.6)  161 (67.4)  0.688  557 (15.8)  390 (14.6)  167 (19.8)  0.001  <0.001 
Homosexual  25 (3.1)  19 (3.3)  6 (2.5)  0.695  2565 (72.9)  1978 (74.0)  587 (69.5)  0.013  <0.001 
Drug abuse  175 (21.4)  115 (19.8)  60 (25.1)  0.229  427 (12.1)  330 (12.3)  97 (11.5)  0.710  <0.001 
Other route  27 (3.3)  24 (4.1)  3 (1.3)  0.086  21 (0.6)  13 (0.5)  8 (0.9)  0.289  <0.001 
Unknown  51 (6.2)  38 (6.6)  13 (5.4)  0.549  177 (5.0)  137 (5.1)  40 (4.7)  0.366  0.167 
Prior AIDS events, n (%)  192 (23.4)  132 (22.8)  60 (25.1)  0.263  645 (18.3)  446 (16.7)  199 (23.6)  <0.001  0.001 
HIV suppression, n (%)
On treatment  721 (88.0)  504 (86.9)  217 (90.8)  0.199  3119 (88.7)  2321 (86.8)  798 (94.5)  <0.001  0.008 
Without treatment  1 (1.5)  8 (1.4)  4 (1.7)    17 (0.5)  15 (0.6)  2 (0.2)     
No suppression  86 (10.5)  68 (11.7)  18 (7.5)    382 (10.9)  338 (12.6)  44 (5.2)     
CD4 cell count, cells/mm3a
Nadir  196 (204)  207 (208)  178 (183)  0.002  266 (245)  277 (240)  232 (249)  <0.001  <0.001 
Current  624 (406)  618 (394)  638 (434)  0.331  635 (371)  638 (369)  625 (377)  0.631  0.204 
Currently on ART, n (%)  797 (97.3)  565 (97.4)  232 (97.1)  0.783  3402 (96.7)  2567 (96.0)  835 (98.9)  <0.001  0.369 
Time under current ART regimen, yearsa  1.7 (4.2)  1.7 (4.1)  1.7 (4.6)  0.337  1.2 (3.4)  1.2 (3.3)  1.4 (3.7)  <0.001   
Current ART regimen, n (%)
No treatment  22 (2.7)  15 (2.6)  7 (2.9)  0.978  116 (3.3)  107 (4.0)  9 (1.1)  0.001  <0.001 
NNRTI-based  356 (43.5)  253 (43.6)  103 (43.1)    1980 (56.3)  1506 (56.3)  474 (56.2)     
PI-based  41 (5.0)  30 (5.2)  11 (4.6)    95 (2.7)  72 (2.7)  23 (2.7)     
Boosted PI-based  290 (35.4)  207 (35.7)  83 (34.7)    967 (27.5)  723 (27.0)  244 (28.9)     
Integrase inhibitor-based  105 (12.8)  72 (12.4)  33 (13.8)    334 (9.5)  244 (9.1)  90 (10.7)     
Other  5 (0.6)  3 (0.5)  2 (0.8)    26 (0.7)  22 (0.8)  4 (0.5)     
Patient currently using, n (%)
Tenofovir  476 (58.1)  355 (61.2)  121 (50.6)  0.005  2349 (66.8)  1814 (67.8)  535 (63.4)  0.017  <0.001 
Indinavir  –  –  – 
Atazanavir  85 (10.4)  60 (10.3)  25 (10.5)  0.961  223 (6.3)  177 (6.6)  46 (5.5)  0.224  <0.001 
Darunavir  161 (19.7)  116 (20.0)  45 (18.8)  0.701  647 (18.4)  470 (17.6)  177 (21.0)  0.026  0.402 
Boosted PI  220 (26.9)  159 (27.4)  61 (25.5)  0.579  804 (22.9)  596 (22.3)  208 (24.6)  0.155  0.015 
Previous or current treatment with tenofovir, n (%)  686 (83.8)  487 (84.0)  199 (83.3)  0.804  2984 (84.8)  2224 (83.2)  760 (90.0)  <0.001  0.449 
Previous or current treatment with boosted PI, n (%)  496 (60.6)  347 (59.8)  149 (62.3)  0.503  1660 (47.2)  1207 (45.1)  453 (53.7)  <0.001  <0.001 
PI or boosted PI plus TEN, n (%)  430 (52.5)  297 (51.2)  133 (55.6)  0.247  1435 (40.8)  1016 (38.0)  419 (49.6)  <0.001  <0.001 
PI or boosted PI without TEN, n (%)  66 (8.1)  50 (8.6)  16 (6.7)  0.357  225 (6.4)  191 (7.1)  34 (4.0)  0.001  0.087 
NNRTI plus TEN, n (%)  321 (39.2)  234 (40.3)  87 (36.4)  0.293  1823 (51.8)  1381 (51.6)  442 (52.4)  0.714  <0.001 
NNRTI without TEN, n (%)  35 (4.3)  19 (3.3)  16 (6.7)  0.028  157 (4.5)  125 (4.7)  32 (3.8)  0.279  0.813 
Integrase inhibitors plus TEN, n (%)  96 (11.7)  64 (11.0)  32 (13.4)  0.341  285 (8.1)  205 (7.7)  80 (9.5)  0.093  0.001 
Integrase inhibitors without TEN, n (%)  9 (1.1)  8 (1.4)  1 (0.4)  0.230  49 (1.4)  39 (1.5)  10 (1.2)  0.554  0.510 
a

Results expressed as median and interquartile range (IQR). Significant p<0.05.

b

p-value for comparisons between global female and global male.

HBV, hepatitis B virus; HCV, hepatitis C virus; ART, antiretroviral; PI, protease inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors; TEN, tenofovir disoproxil fumarate. All PIs were boosted with ritonavir.

Compared to men, women were older, had higher proportion of black race, higher prevalence of HCV-coinfection, longer duration of HIV-infection, higher proportion of heterosexual route of acquisition, of drug injecting drugs and prior AIDS events, a lower nadir of CD4+ cell count, a more frequent exposure to PI or boosted-PI with tenofovir disoproxil-fumarate, and a higher proportion of current therapy with PI, but a lower proportion of current ART with tenofovir disoproxil-fumarate.

Multivariate analysis

After multivariate adjustment for demographics, traditional risk factors for kidney disease, and HIV-related characteristics, female sex was associated with a 23% increased risk for renal dysfunction (Table 4). Individuals older than 50 years had a three-fold higher risk for mildly reduced eGFR compared to the under 50s. Hypertension and dyslipidemia were also independently associated with this outcome. Subjects under virological suppression had an almost 2.0-fold greater risk of renal impairment. Previous tenofovir disoproxil-fumarate and protease-inhibitor exposure were also significant risk factors for mild impaired renal function.

Table 4.

Multivariate analysis of risk factors independently associated with mildly decreased renal function in patients with HIV-infection.

Risk factors  OR (95% CI)  p-value 
Baseline age
≤50 y  1.00 (reference)  – 
>50 y  3.03 (2.58–3.55)  <0.001 
Gender
Male  1.00 (reference)  – 
Female  1.23 (1.02–1.48)  0.031 
Baseline hypertension  1.57 (1.25–1.97)  <0.001 
Diabetes mellitus  0.99 (0.71–1.37)  0.955 
Dyslipidemia  1.48 (1.17–1.87)  0.001 
Previous cardiovascular events  0.77 (0.53–1.13)  0.186 
HCV coinfection  0.84 (0.69–1.01)  0.387 
Duration of HIV infection (years)a  1.01 (0.99–1.02)  0.283 
HIV suppression
No  1.00 (reference)  – 
Yes  1.88 (1.39–2.53)  <0.001 
CD4+ cell count nadir  1.00 (0.99–1.00)  0.467 
Current and/or previous exposure to tenofovira  1.67 (1.33–2.08)  <0.001 
Current and/or previous exposure to boosted PIb  1.19 (1.03–1.39)  0.023 

HCV, hepatitis C virus; PI, protease inhibitors.

a

Tenofovir disoproxil fumarate.

b

All PIs were boosted with ritonavir. Significant p<0.05.

Analyses were also stratified by sex to evaluate possible effect modification: among men, older age (OR 2.57; 95% CI 2.17–3.04), dyslipidemia (OR 1.56; 95% CI 2.17–3.04), viral suppression (OR 2.05; 95% CI 1.47–2.84), each additional year of exposure to tenofovir disoproxil-fumarate (OR 1.08; 95% CI 1.05–1.11), and coinfection with hepatitis B (OR 1.48; 95% CI 1.01–2.17) remained independently associated with increased risk for mild renal impairment, whereas coinfection with hepatitis C (OR 0.74; 95% CI 0.57–0.95) was related to a lower risk for this event. On the other hand, among women, older age (OR 2.84; 95% CI 2.07–3.89), hypertension (OR 1.62; 95% CI 1.05–2.50), viral suppression (OR 2.19; 95% CI 1.20–4.03), and each additional year of exposure to protease inhibitors (OR 1.05; 95% CI 1.01–1.08) remained as independent variables associated with renal dysfunction.

Discussion

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).

Conclusion

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.

Conflicts of interest

The authors declare no conflicts of interest.

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Equivalent contribution.

CKD-H. Clinic Investigators: Federico Oppenheimer, Nephrology and Renal Transplantation Service, Hospital Clinic – IDIBAPS; Aleix Cases, Nephrology and Renal Transplantation Service, Hospital Clinic – IDIBAPS; Esteban Poch, Nephrology and Renal Transplantation Service, Hospital Clinic – IDIBAPS; Esteban Martinez, Infectious Diseases Service, Hospital Clinic – IDIBAPS; José Luís Blanco, Infectious Diseases Service, Hospital Clinic – IDIBAPS; Felipe García, Infectious Diseases Service, Hospital Clinic – IDIBAPS; Josep Mallolas, Infectious Diseases Service, Hospital Clinic – IDIBAPS; Josep María Gatell, Infectious Diseases Service, Hospital Clinic – IDIBAPS.

Copyright © 2018. Sociedade Brasileira de Infectologia
The Brazilian Journal of Infectious Diseases

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