To the Editors:
Chronic kidney disease (CKD) in its different stages is independently related to higher risk of death, development of cardiovascular diseases, and higher hospitalization rates.1 It is currently considered a relevant and growing public health problem. Therefore, early diagnosis is crucial for the implementation of preventive measures.2
The regular use of combined antiretroviral therapy (CART) has had a substantial impact on the survival rate of human immunodeficiency virus (HIV)-infected patients, resulting in the aging of this population in which chronic pathologies can appear.3
The deterioration of renal function is clinically silent. Only through specific analyses it is possible to diagnose and evaluate the presence of CKD in the early stages.4 For all these, there is an increasing concern about renal dysfunction in HIV-infected patients.
A cross-sectional study was carried out on HIV-infected patients at a university hospital in Barcelona, Spain. All patients were 20 years or older. Exclusion criteria included evidence of clinical signs of active acquired immunodeficiency syndrome or no related acquired immunodeficiency syndrome infections in the 3 months before inclusion due to their possible impact on the anthropometric and biochemical parameters. A control group, adjusted by age, was recruited during the same period from the outpatient clinic of the hospital. These patients should have had a minimum follow-up of 3 consecutive visits during 1 year.
Estimated glomerular filtration rate (GFR) was ascertained according to the Modification of Diet in Renal Disease (MDRD-4) formula. CKD was defined as GFR <60 mL/min/1.73 m2 on at least 2 occasions separated by at least 3 months. In the control group, only age, sex, and GFR were recorded. For each HIV-infected patient, cardiovascular risk factors were evaluated according to the recommendations of Panel III of the National Cholesterol Education Program.5 We also recorded HIV exposure (mutually exclusive in the following order: intravenous drug use, homosexual or heterosexual activity), length of time from diagnosis, nadir lymphocyte CD4 cell count and the viral load before starting CART, HIV disease status according to the 1993 Centers for Disease Control and Prevention classification,6 exposure to antiretroviral treatment, classified as “naive” or “currently in treatment,” and hepatitis C coinfection. For those receiving CART, duration of exposure was also considered.
The physical examination included height and weight measurements and arterial pressure readings. Lipodystrophy was defined through the patient's own perception of changes in distribution of body fat and an evaluation by a single investigator.
We studied 854 patients. Seven hundred forty-seven (87.5%) received antiretroviral treatment, and of these, 156 (18.3%) were exposed to tenofovir (TDF). Average exposure to CART was 80 months.
In the control group (2134 HIV-negative patients), a prevalence of CKD was 5.6% [95% confidence interval (CI): 4.7 to 6.7], whereas in the HIV infected was 7.6% (95% CI: 6.0 to 9.6). In naive patients, CKD prevalence was 4.7% and in CART exposed was 8% (P: 0.3). Thus, in comparison to the control group, HIV-infected patients showed a greater prevalence of CKD [Odds ratio (OR): 1.40; 95% CI: 1.02 to 1.91; P: 0.04].
When we analyzed the factors potentially associated to CKD, TDF exposure was related to a high proportion of patients with CKD (9.3%); however, it did not reach statistical significance compared neither with naives nor patients exposed to other antiretroviral drugs (7.6%). In the univariate analysis, the factors associated with CKD were older age, female gender, hypertension, and diabetes mellitus. Other risk factors associated with CKD were being exposed to CART for more than 5 years, to have a symptomatic HIV infection (B+C category), and the presence of lipoatrophy. In the multivariate logistic regression model, classic risk factors, such as the presence of hypertension and diabetes mellitus, lost statistical significance. Only age (AOR: 3.19 per 10-year increment; 95% CI: 2.42 to 4.21), being female (AOR: 4.55; 95% CI: 2.46 to 8.40), the presence of lipoatrophy (AOR: 1.84; 95% CI: 1.03 to 3.27), and the symptomatic HIV infection [Adjusted odds ratio (AOR): 1.77; 95% CI: 1 to 3.14] appeared as factors independently associated with CKD (Table 1).
The prevalence of CKD among HIV-infected patients was higher than in the HIV-negative patients. However, when data were adjusted by age and gender, HIV infection did not result as an independent risk factor for CKD.
The Third National Health and Nutrition Examination Survey III conducted in the United States included 15,626 adults from the general population estimating a prevalence of CKD of 4.6% for GFR <60 mL/min.7 In Spain, the prevalence of CKD defined as GFR <60 mL/min is 5.7% in a population whose average age is 49.5 years.8 It must be stated that the HIV-negative population of the present study does not constitute the general population but rather individuals seeking outpatient care at our hospital. Moreover, this population has an average age nearly 10 years older than the population sample discussed in other studies, and for this reason, it could be possible that they have an increased burden of CKD risk factors. However, our results were very similar to those reported in the above mentioned studies carried out in the general population.
Data concerning the prevalence of CKD in the HIV-infected population are scarce. The study, which included the greatest number of patients, found a prevalence of 3.5% when using the Cockcroft-Gault equation or 4.7% using MDRD formula.9 A study that included a high proportion of black race patients found a prevalence of CKD of 15.5%.10 Our study group is representative of the Spanish population; the relatively low prevalence of CKD may be explained by the low proportion of black race patients.
In the logistic regression analysis, factors such as hypertension and diabetes mellitus lost statistical significance, perhaps due to the sample size and the young age of the studied population. Age maintained significance in the adjusted analysis, being a well-known factor in the general population.7 It is difficult to explain why female gender was a strong independent risk factor for CKD in the multivariate analysis. This association was not found in the EuroSida study.9 The most prevalent HIV exposure among women is to be intravenous drug users (data not shown) in our HIV-infected patients. Despite MDRD formula is not validated in this kind of patients, it could be possible that the lower body surface area in these women might be the explanation. Symptomatic HIV infection as a risk factor for CKD has been described in previous studies.11 Lipoatrophy as an independent variable associated with CKD has not been previously reported. This finding may partly be explained by the method used to estimate GFR, as the MDRD equation that expresses the GFR as a function of body surface, which in lipoatrophy could be severely affected. Exposure to TDF was not found to be related to the presence of CKD. These data are contradictory to that found in other studies.9 However, in controlled clinical trials12 and in cohort studies,13 TDF did not show differences in renal toxicity in comparison with other drugs.
Limitations of the present study are mainly related to the observational design and cross-sectional nature of the current analyses. In this respect, the results reported herein are only associations from which no conclusions regarding causality can be drawn. The present study is predominantly of white ethnic origin, and, therefore, our results may not be generalized to other populations at a higher risk of kidney disease. Another limitation is the lack of data on proteinuria and other important markers of CKD.
In conclusion, a relatively high prevalence of CKD has been described in HIV-infected patients using a confirmed estimation of GFR. The results of the factors associated with CKD, due to the possible inherent bias to a cross-sectional analysis, need to be confirmed by specific studies.
Although the substantial benefits of CART clearly outweigh the possible complications associated with this therapy, it must be kept in mind that with progressive aging of the HIV-infected population and the expected long-term use of CART, the need to prevent an increased incidence of CKD in this population will arise.
María L. Sorlí, MD
Ana Guelar, MD
Milagro Montero, MD
Alicia González, MD
Eva Rodriguez, MD
Hernando Knobel, PhD, MD
Hospital del Mar Barcelona, Spain
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