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Proteinuria and Endothelial Dysfunction in Stable HIV-Infected Patients: A Pilot Study
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JAIDS Journal of Acquired Immune Deficiency Syndromes:Volume 45(5)15 August
2007pp 596-598
[Letters to the Editor]
Gupta, Samir K MD*; Mather, Kieren J MD; Agarwal, Rajiv MD; Saha, Chandan K PhD; Considine, Robert V PhD; Dube, Michael P MD*
*Division of Infectious Diseases Indiana University School of Medicine Indianapolis, IN Division of Endocrinology and Metabolism Indiana University School of Medicine Indianapolis, IN Division of Nephrology Indiana University School of Medicine Indianapolis, IN Division of Biostatistics Indiana University School of Medicine Indianapolis, IN
from Jules: There were 2 studies at the 2007 Lipodystrophy Workshop,one from Mike Dube, both finding ART was not associated with endothelial dysfunction. The 4-week study by Torriani and the ACTG found endothelial function impaired by HIV but improved after 4 weeks on HAART. Here are links to reports:
Effects of 4 weeks of atazanavir, lopinavir/ritonavir, or placebo on endothelial function and insulin sensitivity in healthy men - (07/20/07)
Relationship of body composition, antiretroviral use, and HIV disease factors to endothelial dysfunction in HIV-infected subjects: lipoatrophy associated with endothelial dysfunction - (07/20/07)
To the Editor:
There is an increasingly recognized need to identify HIV-infected patients at higher risk for cardiovascular events using easily obtainable and inexpensive markers. One such marker may be proteinuria, which predicts future cardiovascular events in the general population.1 Proteinuria has historically been associated with HIV-associated nephropathy (HIVAN), which typically affects those of African descent.2 Recent investigations have documented that HIV-related proteinuria (and albuminuria, which may be a more specific marker of glomerular function) is commonly found in blacks and whites, however, and even in those without diabetes or marked hypertension.3
The development of systemic endothelial dysfunction is an early step in the progression of atherosclerosis and has been suggested as the mechanistic link between the presence of proteinuria and the development of cardiovascular disease.4 HIV itself5 and its therapies6 have been associated with endothelial dysfunction. We therefore hypothesized that proteinuria may be associated with endothelial dysfunction in HIV-infected patients, including those without other traditional cardiovascular risk factors.
We performed a pilot cross-sectional study evaluating flow-mediated dilation (FMD) as a measure of endothelial function in prospectively enrolled HIV-infected subjects with and without persistent proteinuria (defined as 2 consecutive spot urine protein-to-creatinine ratios obtained during screening visits 4-8 weeks apart of at least 25.0 mg/mmol each and without pyuria). Exclusion criteria included age <18 years, known vascular or renal disease, serum creatinine >124 μmol/L, hemoglobin <80 g/L, temperature >38.0C, or suspected active infection of any kind (other than HIV) at the time of each screening and study visit. To reduce confounding from traditional risk factors for proteinuria and endothelial dysfunction, subjects were excluded if they had uncontrolled hypertension or known diabetes mellitus. Subjects then underwent standardized endothelial function testing7 using a single technician within 4 weeks of the second screening urine test. All measurements were made by a single investigator (SKG), who was blinded to the subjects' proteinuria status. This study was approved by the Clarian Health (Indiana University School of Medicine) Institutional Review Board. Written informed consent was obtained prospectively from all subjects.
The characteristics of the 34 subjects (28 nonproteinuric and 6 proteinuric) enrolled into this study are shown in Table 1. The mean FMD and nitroglycerin-mediated dilation (NTGMD) in the overall group were 5.1% and 17.2%, respectively. There were no significant differences between groups in terms of baseline diameters, flow measurements, or other endothelial function parameters. Interestingly, multivariable linear regression analysis of the entire study cohort suggested that the strongest predictor of greater FMD was the use of lopinavir/ritonavir (n = 8, ƒÀ-coefficient = 3.089 [SE = 1.608]; P = 0.06). Neither proteinuria nor albuminuria was associated with FMD in univariable or multivariable analyses using the entire cohort. In contrast to most forms of proteinuric nephropathies, albuminuria was generally not the major component of the total proteinuria observed in this cohort, accounting for only a small proportion (median = 8%, interquartile range [IQR]: 5%-16%) of the total proteinuria observed.
Similar to other investigations,5 we found low FMD results with intact NTGMD in the current study. Contrary to our expectations, however, we did not observe any associations between markers of renal impairment and endothelial dysfunction in this group. Endothelial function associated with HIV has been attributed to HIV infection itself or to its therapies, especially protease inhibitors. For example, Stein et al6 enrolled subjects primarily receiving indinavir, which was commonly used at the time that study was performed. Moreover, this agent may directly impair endothelial function.8 No subject in this current study, however, was using indinavir. Interestingly, we noted a possible benefit to the receipt of lopinavir/ritonavir, which is consistent with a recent report9 of improved endothelial function in healthy HIV-uninfected men receiving this agent. These results suggest that there may be marked heterogeneity in regard to the effects on endothelial function within the protease inhibitor class of antiretrovirals.
Although proteinuria10 and albuminuria11 have been associated with impaired FMD in other populations, we could not confirm this relation in stable HIV-infected patients without diabetes, uncontrolled hypertension, or advanced chronic kidney disease. It is unlikely that misclassification bias accounted for the lack of association between proteinuria and FMD in this study, because proteinuria was strictly defined as persistent elevations of protein/creatinine ratios without evidence of pyuria over the 1- to 2-month screening period. Although we cannot exclude the possibility that the negative relations found between proteinuria and albuminuria with FMD were attributable to the small sample size in this study, we identified no trends relating proteinuria or albuminuria with FMD in categoric or continuous variable analyses. In fact, FMD was nominally higher in the proteinuric subjects, although this finding did not reach statistical significance.
Albuminuria accounted for only a small portion of the total proteinuria in this study, which corroborates another recent investigation suggesting that tubular proteins may be the predominant components of total proteinuria in HIV-infected patients without diabetes or hypertension.12 In contrast, albuminuria does seem to be the major component of proteinuria in HIV-infected patients with diabetes or marked hypertension.13 This suggests that in the absence of conditions classically associated with glomerular impairment and endothelial dysfunction, treated HIV infection may result primarily in tubular proteinuria. This finding may explain why total proteinuria does not seem to be a reliable identifier of more impaired FMD in the current study. Nevertheless, we cannot exclude the possibility that proteinuria may be significantly associated with endothelial dysfunction in HIV-infected subjects with diabetes or hypertension.
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