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Serum Levels of Neutrophil Gelatinase–Associated Lipocalin Are Associated With Microalbuminuria in HIV-Infected Patients

2012; Lippincott Williams & Wilkins; Volume: 59; Issue: 2 Linguagem: Inglês

10.1097/qai.0b013e31823f35a7

1944-7884

Jan Kristian Damås, Morten Bækken, Thor Ueland, Ingjerd W. Manner, Ingrid Os, Arne Yndestad, Trude H. Flo, Olav Øktedalen, Pål Aukrust,

Muscle and Compartmental Disorders

To the Editors: With improved survival after the introduction of antiretroviral therapy (ART), cardiovascular and hepatic diseases represent an increasing burden for HIV-infected individuals.1 Renal diseases have also emerged as significant causes of morbidity and mortality in these patients.1 HIV-associated nephropathy has been the most common cause of renal failure in HIV-infected persons of African descent who are not receiving ART. However, other causes of kidney disease related to ART, its metabolic complications, or comorbid conditions such as diabetes and high blood pressure seem also to be of major importance in the pathogenesis of renal disease in HIV-infected patients in the ART era.2 In addition, chronic inflammation has recently been implicated in the pathogenesis of renal dysfunction during HIV infection, even in patients with successful ART.3,4 Neutrophil gelatinase–associated lipocalin (NGAL), also known as lipocalin 2, is a 25-kDa secretory glycoprotein that was originally identified in mouse human neutrophil granules and has been implicated in the acute phase response to infection.5–7 However, NGAL is not solely a product of activated neutrophils. Hence, epithelial cells, hepatocytes, adipocytes, and macrophages have all been found to release NGAL during inflammation or injury.8–10 Recent reports also suggest that NGAL might be a sensitive biomarker for early renal injury, at least partly, reflecting increased synthesis in distal nephron during renal impairment.11 Based on its role as a sensitive marker of kidney injury and its ability to reflect inflammation, we investigated if serum levels of NGAL were related to impaired renal function in HIV-infected patients with and without ongoing ART. The present study is a substudy of the Microalbuminuria in a HIV-positive population in Oslo study, including 221 HIV-infected patients (187 males and 34 females, 46 ± 11 years); 148 received ART (CD4+ T-cell count: 0.45 ± 0.31×109/L; HIV RNA level: 4.4 ± 21.6 × 103 copies/mL plasma) and 73 were without treatment (CD4+ T-cell count: 0.48 ± 0.29 × 109/L; HIV RNA level: 112 ± 159 × 103 copies/mL plasma). According to the albumin/creatinine ratio, patients were categorized as having normoalbuminuria (<2.5 mg/mmol) or microalbuminuria (2.5–30 mg/mmol). Hypertension was defined as previously described.12 Data on blood pressure, creatinine, estimated glomerular filtration rate, β-2-microglobulin, lipids, and HbA1c were obtained as previously reported.12 NGAL was measured in serum by enzyme immunoassays.13 For NGAL analyses, 30 sex-matched and age-matched healthy individuals served as control subjects. The study was approved by the The National Committee for Medical and Health Research Ethics. For statistical comparisons, the Kruskal–Wallis test, the Mann–Whitney U test, and the Spearman rank test were used as appropriate. Probabilities are 2-sided and considered to be significant when P < 0.05. HIV-infected patients (n = 221) had significantly raised serum levels of NGAL as compared with healthy control subjects (n = 30) independent on ongoing ART (Fig. 1A). There was no association between NGAL and CD4+ T-cell counts, HIV RNA levels, or duration of disease (data not shown). However, when patients were dichotomized with regard to absence/presence of microalbuminuria, we found significantly higher NGAL levels in relation to the presence of microalbuminuria (Fig. 1B). Moreover, NGAL was significantly correlated to several other parameters of renal function in the HIV-infected patients such as albumin/creatinine ratio (r = 0.27, P < 0.01), serum creatinine (r = 0.20, P < 0.01), and estimated glomerular filtration rate (r = −0.21, P < 0.01). There was also a significant association between NGAL levels and total leukocyte count (r = 0.35, P < 0.001), β2-microglobulin (r = 0.16, P < 0.05), and total cholesterol (r = 0.16, P < 0.05) in HIV-infected patients. We found no association between NGAL and blood pressure, age, gender, or body mass index in these patients (data not shown).FIGURE 1: A, Serum levels of NGAL in 221 HIV-infected patients [148 received antiretroviral therapy (ART+) and 73 were without antiretroviral therapy (ART−)] and in 30 sex-matched and age-matched healthy control subjects (controls). B, Serum levels of NGAL in 221 HIV-infected patients dichotomized with regard to absence/presence of MA (2.5–30 mg/mmol). A total of 35 patients had micoalbuminuria (27 with and 8 without ongoing ART). *P < 0.05, **P < 0.01, ***P < 0.001 versus controls, and ###P < 0.05 versus patients without microalbuminuria (MA−). Data are mean ± SEM. MA, microalbuminuria.Herein, we show a significant association between NGAL and microalbuminuria and with other parameters of renal impairment in HIV-infected patients, independent on ongoing ART. Our findings may suggest that NGAL could be a useful biomarker for early detection of renal injury during HIV infection. Others have shown that NGAL is a reliable biomarker for acute kidney injury. In cardiopulmonary bypass-induced acute renal injury and cisplatin-induced nephrotoxic injury, a sharp increase in NGAL levels is observed both systemically and in urine.14,15 NGAL could also be a sensitive marker of chronic renal dysfunction. Recently, Viau et al16 identified NGAL as a critical marker of chronic kidney disease in a genome-wide expression study, with particularly high expression in patients who rapidly progressed to end-stage renal failure. According to our current data, serum NGAL levels should be further investigated as a potential sensitive marker of early renal impairment in HIV-infected patients. An increased urinary albumin excretion rate is an independent risk factor for cardiovascular disease, and this has also been seen in HIV-infected patients.17 Enhanced expression of NGAL has been found in patients with myocardial infarction and chronic heart failure.18 Moreover, Haase et al19 recently reported that NGAL detects patients with subclinical kidney dysfunction and predicts adverse outcomes in patients with cardiorenal syndrome. Thus, it could be hypothesized that the combination of increased microalbuminuria and high NGAL serum levels could represent a potential promising predictor for cardiovascular events also in HIV-infected individuals. In fact, the ability of NGAL to mirror renal injury and systemic inflammation as 2 interaction processes in the pathogenesis of cardiovascular disorders should make it as an interesting marker of cardiovascular disease, in particular, in patients with additional inflammatory disorders such as HIV infection.