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ABSTRACT: Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta-analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty.
Journal of Clinical Lipidology 07/2012; 6(4):303-9. · 1.58 Impact Factor
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ABSTRACT: Valvular and vascular calcification are important early aging phenotypes and represent risk factors for cardiovascular morbidity and mortality. Klotho is a gene primarily expressed in the kidney that has an important role in calcium-phosphate homeostasis. The functional KL-VS variant of Klotho has been associated with aging and cardiovascular disease in human studies, but its role in valvular and vascular calcification remains unknown. We performed a candidate gene study in the Framingham Offspring Cohort to evaluate the effect of KL-VS variant of the Klotho gene on valvular calcification.
We analyzed the Klotho KL-VS genotype (rs9536314) from the Affymetrix 550K genome-wide dataset, distributed by dbGAP, on 1389 cases and 2139 controls from the Framingham Heart Study Offspring Cohort. Allele and genotype frequencies were compared between cases and controls. Valvular calcification was defined as presence of calcification on the mitral annulus or the aortic valve as determined by echocardiography. A sensitivity analysis of coronary artery calcification by electron beam computed tomography was performed on 1363 patients.
The frequency of the TT versus the TG allele was not different between the cases and the controls (39 versus 41%). The KL-VS variant of Klotho was not associated with valvular or vascular calcification, despite adequate power to detect association (86% for odds ratios ≥1.2). In sensitivity analyses, no association (P > 0.001) between other common variants of Klotho, β-Klotho or fibroblast growth factor-23 and the end points of valvular or vascular calcification was observed.
In our adequately powered candidate gene study, we did not observe an association with the functional KL-VS variant of Klotho and presence of valvular or vascular calcification. Future studies aimed at combining cohorts with echocardiographic phenotypes need to be conducted to identify genetic variants associated with valvular calcification.
Nephrology Dialysis Transplantation 05/2011; 26(12):3998-4002. · 3.40 Impact Factor
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ABSTRACT: The utility of the Framingham risk score among individuals infected with HIV is poorly understood. We examined the association of Framingham risk scores with surrogate markers of atherosclerosis in a carefully characterized cohort of adults infected with HIV.
We calculated Framingham risk scores and measured carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) scores in 334 participants from the Nutrition for Healthy Living study. Cardiovascular risk factors, c-IMT and CAC scores were assessed for each Framingham risk subgroup (low versus intermediate/high risk). We used adjusted and unadjusted linear and logistic regression to examine the association between clinical factors and Framingham risk group with c-IMT and CAC scores.
Patients with intermediate/high Framingham risk scores were more likely to have internal c-IMT ≥ 1.0 mm (26% versus 12%; P=0.003) and common c-IMT ≥ 0.8 mm (22% versus 5%; P < 0.001). These patients were also more likely to have detectable CAC (78% versus 48%; P < 0.001). Intermediate/high Framingham risk scores were significantly associated with internal c-IMT ≥ 1.0 mm (odds ratio 2.65 [95% confidence interval 1.37-5.13]) and common c-IMT ≥ 0.8 mm (odds ratio 5.24 [95% confidence interval 2.39-11.50]). Intermediate/high Framingham risk scores were also significantly associated with detectable CAC (odds ratio 3.84 [95% confidence interval 2.05-7.16]). The addition of HIV-related variables did not improve the accuracy of the Framingham risk score.
Our study shows that increased Framingham risk scores are associated with abnormal early and late surrogate markers of atherosclerosis in adults infected with HIV, and might predict the risk of cardiovascular complications in this population.
Antiviral therapy 01/2011; 16(1):1-8. · 3.16 Impact Factor
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ABSTRACT: Background. Serum creatinine (Scr)-based equations lack accuracy in predicting glomerular filtration rate (GFR) in patients with liver disease. Cimetidine has been shown to improve the performance of Scr-based GFR formulae. Methods. We evaluated the use of cimetidine on the performance of GFR-estimating equations in 39 liver transplant recipients. The patients received oral cimetidine (800 mg tid) during a 24-h urine collection. The next day, the patients underwent radionucleotide GFR (rGFR) determination and Scr was measured for creatinine clearance (CrCl) and GFR estimation using the Cockcroft-Gault, Nankivell and modified diet in renal disease (MDRD) equations. Data were analysed using the Pearson correlation statistic and Bland-Altman plots. Results. The mean rGFR was 65 +/- 26.4 mL/min. The use of cimetidine increased the bias between rGFR and the Nankivell and MDRD equations. The combined root mean square error for the CrCl, Cockcroft-Gault, Nankivell and MDRD equations without cimetidine were 20.2, 15.6, 17.0 and 15.5 and cimetidine-aided were 28.2, 23.2, 23.7 and 24.3, respectively. Conclusions. All the tested equations without using cimetidine predicted GFR with modest accuracy. The addition of cimetidine decreased the precision and increased the bias of all the GFR-estimating equations. In the absence of accurate GFR-estimating equations, rGFR should be used to monitor kidney function in liver transplant recipients.
Nephrology Dialysis Transplantation 04/2010; 25(4):1285-9. · 3.40 Impact Factor
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ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the leading hereditary cause of ESRD in the United States. Because of the renal and extrarenal manifestations of ADPKD, specific challenges exist caring for these patients once they reach ESRD. In this article, we report the overall outcomes of individuals with ADPKD after ESRD as compared with non-ADPKD patients. We also review the available literature concerning issues specific to dialysis or kidney transplantation. For the ADPKD patient on dialysis, we address the use of peritoneal dialysis, the management of renal cystic, and extrarenal complications, and we discuss the significance of the relative polycythemia often observed in this population. For the ADPKD patient undergoing kidney transplantation, we highlight issues of anemia management and aneurysm screening pretransplant, the indications for nephrectomy of the native ADPKD kidneys, the potential benefits of select immunosuppressive agents, the role for combined kidney-liver transplantation, and renal and extrarenal complications of ADPKD postkidney transplantation. In general, patients with ADPKD have more favorable outcomes after ESRD as compared with those with other causes of kidney failure. Most of our knowledge, however, is based on case series and observational studies. Although these reports have certainly been valuable to our understanding, there still remains considerable uncertainty and ambiguity in many aspects of ADPKD patient care as it relates to ESRD. Particular focus needs to be placed on performing clinical trials with the goal of enhancing outcomes and quality of life of patients with ADPKD.
Advances in chronic kidney disease 03/2010; 17(2):164-72. · 2.42 Impact Factor
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ABSTRACT: The catecholaminergic pathway is important in the physical stress response; however, its role is not well understood in acute kidney injury (AKI). We studied single nucleotide polymorphisms (SNPs) of phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholaminergic pathway, and their association with adverse outcomes in AKI.
We performed a case-control study of 961 Caucasian subjects (194 with AKI and 767 controls). The PNMT promoter G-161A (rs876493) and coding A+1543G (rs5638) SNPs were genotyped and haplotypes generated. The outcomes of interest were the development of AKI, in-hospital mortality, dialysis requirement, oliguria, and hemodynamic shock. Urine catecholamines were measured in cases to explore genotype-phenotype correlations.
The PNMT +1543 G allele was associated with AKI [odds ratio (OR) 2.19, 95% confidence interval (CI): 1.04-4.60]. For AKI cases, each PNMT -161 A allele was associated with lower mortality (OR 0.58, 95% CI: 0.35-0.99) and hemodynamic shock (OR 0.63, 95% CI: 0.40-1.00). The PNMT +1543 G allele was associated with oliguria (OR 3.35, 95% CI: 1.13-9.95). Urine adrenaline was associated with increased hemodynamic shock and mortality, but was lowest in PNMT -161 A/A carriers.
In Caucasians, PNMT SNPs are associated with the development of AKI, disease severity, and in-hospital mortality. The adrenergic pathway provides another area of focus in the study of AKI.
Nephron Clinical Practice 01/2010; 114(4):c253-9. · 2.04 Impact Factor
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Clinical Journal of the American Society of Nephrology 07/2009; 4(7):1154-5. · 5.23 Impact Factor
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ABSTRACT: In this study we evaluated the use of cimetidine on the performance of glomerular filtration rate (GFR) estimating equations and 24-hour creatinine clearance (24-hour CrCl) against radionuclide GFR in 43 heart transplant recipients with stable renal function. Pearson correlation coefficients for the 24-hour CrCl, Cockcroft-Gault, Nankivell and Modification of Diet in Renal Disease study (MDRD) equations without cimetidine were 0.76, 0.70, 0.81 and 0.76, and cimetidine-aided coefficients were 0.82, 0.80, 0.80 and 0.72, respectively. All the tested equations without cimetidine use predicted GFR with moderate accuracy in this population. The addition of cimetidine improved the predictive ability of the 24-hour CrCl and Cockcroft-Gault formulas, but not the Nankivell and MDRD GFR estimating equations, in heart transplant recipients.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2008; 27(8):905-9. · 3.54 Impact Factor
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ABSTRACT: Chronic kidney disease is associated with increased mortality among nonrenal organ transplant recipients. End-stage renal disease (ESRD) is a serious complication after orthotopic liver transplantation (OLT). It is unclear if the outcomes of these individuals are different from nontransplant patients requiring dialysis or a kidney transplant.
We report the incidence of ESRD in OLT recipients and compare their outcomes to matched dialysis controls. We analyzed 4186 patients who received an OLT in Canada between January 1981 and December 2002 and 228 matched, nontransplant, chronic dialysis controls.
The incidence of ESRD after OLT was 2.9% (n=120). The unadjusted mortality rate for those who required chronic dialysis was 49.2% compared with 26.8% in those who did not develop kidney failure (P<0.0001). The survival of OLT recipients on dialysis was lower than the matched chronic dialysis cohort (log-rank test, P=0.01). A kidney transplant was performed in 24% of the OLT recipients and 21% of the matched dialysis cohort, and their overall survival was similar. The OLT patients who remained on dialysis had a significantly lower survival when compared with matched dialysis patients who did not receive a kidney transplant (log-rank test, P=0.0002).
Mortality was greater for OLT recipients on dialysis than would be expected from a matched, nontransplant, dialysis cohort. Kidney transplantation may abrogate some of this increased mortality risk.
Transplantation 05/2008; 85(9):1277-80. · 4.00 Impact Factor
