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Rosuvastatin Preserves Renal Function and Lowers Cystatin C in HIV-infected Subjects on Antiretroviral Therapy: the SATURN-HIV Trial - heart, kidney, bone diseases, inflammation
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at CROI 2014-
Rosuvastatin Improves Hip Bone Mineral Density but Worsens Insulin Resistance - (03/07/14)
Rosuvastatin Reduces Immune Activation and Inflammation in Treated HIV Infection - (03/28/14)
Rosuvastatin Lowers Cystatin C in HIV-infected Subjects on Antiretroviral Therapy: SATURN-HIV - (03/28/14)
"Chronic kidney disease (CKD) is a common co-morbidity of HIV infection that is associated with substantial cardiovascular risk1......Both CKD and HIV infection are characterized by high levels of systemic inflammation.....Kidney disease is an independent risk factor for cardiovascular disease.....In conclusion, rosuvastatin 10mg daily reduces plasma cystatin C and slows eGFR decline compared to placebo over 24 weeks in HIV-infected patients on ART. HIV-infected subjects with elevated levels of inflammation despite effective ART are a sub-group of patients that may gain a protective renal benefit from statins. Furthermore, reductions in cystatin C with statin therapy correlate with reductions in T-cell activation, endothelial activation, and inflammation. Our study suggests that relationships between cystatin C, kidney function and cardiovascular risk in HIV are complex but may be mediated in part by inflammation. Future studies should evaluate whether other anti-inflammatory therapies improve cystatin C and/or glomerular function in patients with treated HIV infection.......Our study population is notably two-thirds African American......This study furthers our understanding of cystatin C as a predictor of cardiovascular risk in patients with treated HIV infection and the potential of statins to decrease that risk.....The highest cystatin C levels were seen in participants with the combination of brachial endothelial dysfunction, detectable coronary calcium, and carotid disease......the extent of inflammation, immune activation, and subclinical vascular disease in the study subjects were very well characterized."
Commentary [attached below] says: "In this issue of Clinical Infectious Diseases, Longenecker and colleagues report an analysis of cystatin C levels, and their relationship to an array of subclinical vascular and immune activation markers within a prospective randomized, placebo-controlled, double-blind, single center trial of a statin, rosuvastatin[9]. Participants.....had normal kidney function and no prior history of myocardial infarction......After 24 weeks, cystatin C levels fell compared to baseline in the rosuvastatin, but not in the placebo arm......They found significant, positive associations between cystatin C levels and common carotid artery intima-media thickness (IMT), an independent predictor of cardiovascular disease risk in population based studies,[11] and epicardial fat, a novel correlate of atherosclerosis that these investigators"
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Rosuvastatin Preserves Renal Function and Lowers Cystatin C in HIV-infected Subjects on Antiretroviral Therapy: the SATURN-HIV Trial
Clinical Infectious Diseases Advance Access published July 11, 2014 Chris T.
Longenecker1,2, Corrilynn O. Hileman1,3, Nicholas T. Funderburg4, Grace
A. McComsey1,2
Commentary
Abstract
Background. In chronic HIV-infection, plasma cystatin C may be influenced by factors other than glomerular filtration rate such as inflammation. Statins may improve cystatin C by improving glomerular function or by decreasing inflammation.
Methods. The Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV (SATURN-HIV) trial randomized 147 patients on stable antiretroviral therapy (ART) with LDL-cholesterol <130 mg/dL to blinded 10 mg daily rosuvastatin or placebo. We analyzed relationships of baseline and 0-24 week changes in plasma cystatin C concentration with measures of vascular disease, inflammation, and immune activation.
Results. Median (interquartile range) age was 46 (40-53) years; 78% were male, 68% African American. Tenofovir and protease inhibitors (PI) were used in 88% and 49% of subjects, respectively. Baseline cystatin C was associated with higher carotid intima-media thickness and epicardial adipose tissue independent of age, sex, and race. Biomarkers of endothelial activation and inflammation were associated with cystatin C in a multivariable model independent of eGFRcr. After 24 weeks, statin use slowed mean eGFRcr decline [+1.61 vs. -3.08 ml/min/1.73 m2, statin vs. placebo, p=0.033] and decreased mean cystatin C [-0.034 mg/L vs. +0.010 mg/L, p=0.008]. Within the statin group, changes in cystatin C correlated with changes in endothelial activation, inflammation, and T-cell activation.
Conclusions. Rosuvastatin 10 mg daily reduces plasma cystatin C and slows kidney function decline in HIV-infected patients on ART. Reductions in cystatin C with statin therapy correlate with reductions in inflammatory biomarkers. Relationships between cystatin C, kidney function and cardiovascular risk in HIV may be mediated in part by inflammation.
Background
Chronic kidney disease (CKD) is a common co-morbidity of HIV infection that is associated with substantial cardiovascular risk1. Traditional risk factors2 such as race and diabetes are associated with more rapid kidney function decline, as are HIV-specific factors such as active HIV-1 viral replication3 and certain antiretroviral therapy (ART) such as tenofovir and ritonavir-boosted protease inhibitors (PI)4. The accurate estimation of glomerular filtration rate (GFR) using endogenous filtration markers is critical for the clinical care of these patients, but is impaired in chronic HIV-infection by significant non-GFR determinants of creatinine and the novel marker cystatin C5-7.
Both CKD8 and HIV infection9 are characterized by high levels of systemic inflammation; however, whether inflammation is a significant non-GFR determinant of cystatin C levels that explains the strong associations of cystatin C with clinical outcomes in HIV infection is unclear7,10. Statins have anti-inflammatory effects in HIV-uninfected patients with CKD8,11, but the ability to slow GFR decline appears to be quite modest12. In HIV infection, statins have decreased inflammation and immune activation markers in some studies, with varying results depending on the biomarker studied and ART status13-18. To our knowledge, no study has evaluated the effect of statin therapy on glomerular function or cystatin C in HIV-infected patients.
The objectives of this study were two-fold. First, we aimed to examine the baseline cross-sectional associations of cystatin C levels with markers of inflammation and subclinical vascular disease among HIV-infected patients on ART enrolled in a randomized trial of statin therapy. Second, we studied the 24-week effect of rosuvastatin on cystatin C levels and estimated GFR and whether changes in cystatin C were related to changes in inflammation markers.
Discussion
In this randomized clinical trial of HIV-infected patients on ART, 10mg of daily rosuvastatin decreased plasma cystatin C levels and preserved creatinine-based eGFR. Interestingly, plasma cystatin C was associated with inflammation and endothelial activation at baseline independent of eGFRcr, and changes in cystatin C correlated with changes in inflammation, endothelial activation, and T-cell activation. This trial provides the first evidence in patients with HIV-infection that statin therapy may have salutary effects on kidney function, and also suggests that some of the effect on plasma cystatin C levels may be related to changes in systemic inflammation and immune activation. Statins substantially reduce the risk of cardiovascular events among patients with mild to moderate CKD in the general population30,31, although their effect on eGFR decline is less clear30-32. In JUPITER30, 20mg of rosuvastatin decreased the risk of the primary end-point by 45% and all-cause mortality by 44% among subjects with eGFRcr <60 ml/min/1.73m2. Hs-CRP reductions were similar in those with and without CKD. In contrast, 12-month median eGFRcr loss was no different for those with CKD (-3ml/min/1.73m2 for both statin and placebo). Furthermore, concerns about possible renal effects of rosuvastatin compared to atorvastatin in patients with known CKD have been raised by the PLANET 1 and 2 trials33,34. Among nondiabetic patients with CKD (mean eGFR of 75ml/min) in PLANET 2 (Prospective Evaluation of Proteinuria and Renal Function in Non-diabetic Patients With Progressive Renal Disease), atorvastatin 80mg daily decreased proteinuria and caused less 52 week mean eGFR decline (-1.74 ml/min) compared to rosuvastatin 10mg (-2.71ml/min) or rosuvastatin 40mg (-3.30ml/min)33. Similar results were seen among diabetic patients in PLANET 134.
In a combined analysis of pravastatin trials32, pravastatin 40mg daily decreased the rate of eGFR loss by 8% overall, and by 34% among those with moderate CKD (eGFR 30-60mL/min/1.73m2). In the CARE (Cholesterol and Recurrent Events) trial35, the most "inflamed" participants (highest tertile of CRP and sTNF-RI) derived the greatest renal benefit from pravastatin. Consistent with these findings from CARE, our study suggests that HIV-infected subjects with elevated markers of inflammation despite effective ART are a sub-group of patients that may gain a protective renal benefit from statins.
The extent to which cystatin C changes in our study were due to changes in eGFR is not clear. Although adjustment for eGFRcr attenuated the observed changes in cystatin C, there was still a trend towards statistical significance. It is possible that residual cystatin C changes were due to changes in true GFR that were not accurately captured by changes in eGFRcr. Alternatively, changes in cystatin C may have resulted from reductions in non-GFR determinants of cystatin C such as inflammation, since the anti-inflammatory properties of statins have been well-described8. The fact that changes in cystatin C within the statin arm of our study correlated with changes in T-cell activation and endothelial activation suggest that this may be the case. This interpretation is supported further by evidence that T-cell activation may partially explain the bias and inaccuracy of eGFRcys in HIV infection compared to measured GFR7. On the other hand, cystatin C and TNF-α receptor changes correlated similarly in both arms of our study, which cannot be attributed to the anti-inflammatory effect of statins. TNF-α receptors are primarily renally cleared and are more strongly correlated with glomerular function than other biomarkers of inflammation36. It is also possible that inflammation itself
(particularly endothelial activation) may be causally related to glomerular function8, an effect that may be more prominent among subjects of black race37. Our study population is notably two-thirds African American.
This study furthers our understanding of cystatin C as a predictor of cardiovascular risk in patients with treated HIV infection and the potential of statins to decrease that risk. Cystatin C and cystatin C based estimates of GFR are stronger predictors of cardiovascular events in HIV when compared to creatinine or creatininebased GFR10. The mechanism of this association between cystatin C levels and clinical events may be multifactorial and partly related to inflammation and/or abnormalities of vascular structure and function. Two studies have examined the relationship of cystatin C to subclinical carotid disease in HIV. Incipient renal disease (defined as eGFRcrcys <90ml/min/1.73m2 + >3% annual decrease in eGFR + albumin/creatinine ratio >5mg/g) was independently associated with carotid IMT in a Spanish cohort38. In the Study of Fat Redistribution and Metabolic Change (FRAM), cystatin C was a potent independent predictor of mortality39, but was not related to carotid intima media thickness after adjustment for age, sex, and race40. In our study, plasma cystatin C levels were associated with multiple measures of subclinical vascular disease in univariable analyses. Adjustment for age, sex, and race removed the association with some measures, although CCA-IMT and epicardial adipose tissue remained independently associated with cystatin C. Our study adds to these results by including endothelial function testing and coronary calcium scoring to provide a more complete phenotype of vascular structure and function. The highest cystatin C levels were seen in participants with the combination of brachial endothelial dysfunction, detectable coronary calcium, and carotid disease.
The major strength of our study was the double-blind, placebocontrolled randomized trial design. In addition, the extent of inflammation, immune activation, and subclinical vascular disease in the study subjects were very well characterized. The study was limited by the lack of a gold-standard direct measure of GFR. The study may have lacked power to detect an effect of statin therapy on cystatin C that is independent of eGFRcr. We chose to use the creatinine-based CKD-EPI equation to estimate GFR rather than the cystatin C-based or the combined equation, because we were testing the hypothesis that cystatin C is influenced by inflammation. We recognize that eGFRcr is biased by other non-GFR determinants of creatinine such as muscle mass, which may have influenced our findings. Finally, we did not account for the effect of other potentially nephrotoxic medications besides ART.
In conclusion, rosuvastatin 10mg daily reduces plasma cystatin C and slows eGFR decline compared to placebo over 24 weeks in HIV-infected patients on ART.
HIV-infected subjects with elevated levels of inflammation despite effective ART are a sub-group of patients that may gain a protective renal benefit from statins. Furthermore, reductions in cystatin C with statin therapy correlate with reductions in T-cell activation, endothelial activation, and inflammation. Our study suggests that relationships between cystatin C, kidney function and cardiovascular risk in HIV are complex but may be mediated in part by inflammation. Future studies should evaluate whether other anti inflammatory therapies improve cystatin C and/or glomerular function in patients with treated HIV infection.
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