LOMERULAR FILTRATION RATE(GFR) is used in the diagnosis of chronic kidney disease (CKD) 1,2 and is an independent predictor of all-cause and cardiovascular mortality and kidney failure in a wide range of populations. [3][4][5][6] Clinical guidelines recommend reporting estimated GFR when serum creatinine level is measured 1,2 ; 84% of US laboratories report estimated GFR. 7 Although the Modification of Diet in Renal Disease (MDRD) Study equation is recommended for estimating GFR, 1,2,8,9 the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) has recently proposed an alternative equation, which applies different coefficients to the same 4 variables used in the MDRD Study equation (age, sex, race, and serum creatinine level). 10 The new CKD-EPI equation estimates measured GFR more accurately than the MDRD Study equation in most, [10][11][12][13][14][15][16][17][18] but For editorial comment see p 1976.Author Affiliations and a list of the investigators and collaborators for the Chronic Kidney Disease Prognosis Consortium appear at the end of this article.

Context Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial. Objective To evaluate possible effect modification (interaction) of age on the association of estimated GFR and albuminuria with clinical risk examining both relative and absolute risk. Design, Setting, Participants We investigated 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australesia, Europe, and North/South America conducted during 1972–2011 with mean follow-up time of 5.8 years (range 0–31 years). Main Outcome Measures Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholestserol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates. Results Mortality (112,325 deaths) and ESRD (8,411 events) risk were higher at lower eGFR and higher albuminuria in every age category. In general/high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age: e.g., adjusted HRs (95% CI) at eGFR 45 vs. 80 ml/min/1.73m2 were 3.50 (2.55–4.81), 2.21 (2.02–2.41), 1.59 (1.42–1.77), and 1.35 (1.23–1.48) in age categories 18–54, 55–64, 65–74 and 75+ years, respectively (P-values for age interaction <0.05). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0–12.8], 12.2 [10.3–14.3], 13.3 [9.0–18.6], and 27.2 [13.5–45.5] excess deaths per 1,000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age were less evident, while differences in absolute risk were higher in the older age categories (7.5 [95% CI, 4.3–11.9], 12.2 [7.9–17.6], 22.7 [15.3–31.6], and 34.3 [19.5–52.4] excess deaths per 1,000 person-years, respectively by age category, at ACR 300 mg/g compared to 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories. Conclusions Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risks differences at older age.

Background Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease (CKD). It is unknown, however, whether the association of the CKD measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status. Methods We performed a meta-analysis of 45 cohorts (25 general population, 7 high-risk and 13 CKD cohorts), including 1,127,656 participants (364,344 with hypertension). Adjusted hazard ratios (HRs) for all-cause mortality (84,078 deaths from 40 cohorts) and ESRD (7,587 events from 21 cohorts) by hypertensive status were obtained for each study and pooled using random-effects models. Findings Low eGFR and high albuminuria were associated with mortality in both non-hypertensive and hypertensive individuals in the general population and high-risk cohorts. Mortality risk was higher in hypertensives as compared to non-hypertensives at preserved eGFR but a steeper relative risk gradient among non-hypertensives than hypertensives at eGFR range 45-75 ml/min/1.73m2 led to similar mortality risk at lower eGFR. With a reference eGFR of 95 mL/min/1.73m2 in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min/1.73m2 was 1.77 (95% CI, 1.57-1.99) in non-hypertensives versus 1.24 (1.11-1.39) in hypertensives (P for overall interaction =0.0003). Similarly, for albumin-creatinine ratio (ACR) of 300 mg/g (vs. 5 mg/g), HRs were 2.30 (1.98-2.68) in non-hypertensives versus 2.08 (1.84-2.35) in hypertensives (P for overall interaction=0.019). Similar results were observed for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results in CKD cohorts were comparable to results in general and high-risk population cohorts. Interpretation Low eGFR and elevated albuminuria were more strongly associated with mortality among individuals without hypertension than in those with hypertension, but the associations with ESRD were similar. CKD should be considered at least an equally relevant risk factor for mortality and ESRD in non-hypertensive as it is in hypertensive individuals. Funding The US National Kidney Foundation (sources include Abbott and Amgen).

Background-No data are available on the absolute risk of either venous thromboembolism (VTE) or arterial thromboembolism (ATE) in patients with nephrotic syndrome. Reported risks are based on multiple case reports and small studies with mostly short-term follow-up. We assessed the absolute risk of VTE and ATE in a large, single-center, retrospective cohort study and attempted to identify predictive factors in these patients. Methods and Results-A total of 298 consecutive patients with nephrotic syndrome (59% men; mean age, 42Ϯ18 years)were enrolled. Mean follow-up was 10Ϯ9 years. Nephrotic syndrome was defined by proteinuria Ն3.5 g/d, and patients were classified according to underlying histological lesions accounting for nephrotic syndrome. Objectively verified symptomatic thromboembolic events were the primary study outcome. Annual incidences of VTE and ATE were 1.02% (95% confidence interval, 0.68 to 1.46) and 1.48% (95% confidence interval, 1.07 to 1.99), respectively. Over the first 6 months of follow-up, these rates were 9.85% and 5.52%, respectively. Proteinuria and serum albumin levels tended to be related to VTE; however, only the predictive value of the ratio of proteinuria to serum albumin was significant (hazard ratio, 5.6; 95% confidence interval, 1.2 to 26.2; Pϭ0.03). In contrast, neither the degree of proteinuria nor serum albumin levels were related to ATE. Sex, age, hypertension, diabetes, smoking, prior ATE, and estimated glomerular filtration rate predicted ATE (PՅ0.02). Conclusions-This study verifies high absolute risks of symptomatic VTE and ATE that were remarkably elevated within the first 6 months. Whereas the ratio of proteinuria to serum albumin predicted VTE, estimated glomerular filtration rate and multiple classic risk factors for atherosclerosis were predictors of ATE. (Circulation. 2008;117: 224-230.)

Key Points Question To what extent are established cardiovascular risk factors associated with risk of venous thromboembolism (VTE)? Findings In this analysis of individual participant data from the Emerging Risk Factors Collaboration and the UK Biobank including 1.1 million participants, among a panel of several established cardiovascular risk factors, older age, smoking, and greater adiposity were consistently associated with higher VTE risk. Meaning There is overlap in at least some of the major population determinants of important venous and arterial thrombotic diseases.

Fishbein I, Alferiev I, Bakay M, et al. Circulation 2008;117:2096-103. Conclusion: Sustained release of gene vectors is possible through reversible immobilization of adenovirus vectors on bare-metal surfaces of vascular stents.Summary: Polymer-coated stents facilitate local drug delivery to the vasculature and have proven efficacious in preventing in-stent restenosis. There are, however, concerns about the inflammatory effects of polymer coatings and late outcomes of drug-eluting stents. The authors investigated whether adenoviral vectors could be delivered from bare metal surfaces of stents using a synthetic complex for reversible vector binding. Three components of a gene vector-binding complex were synthesized: (1) a polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethylenimine (PEI) with pyridyldithio groups for amplification of attachments sites [PEI (PVT)], and (3) a bifunctional amine-reactive and thiol-reactive cross-linker with labile ester bond (HL).The HL-modified adenovirus attached to PABT/PEI(PDT)-treated steel surfaces and demonstrated in vitro sustained release for 30 days. They also demonstrated localized green fluorescent protein expression in rat arterial smooth muscle cell cultures. This expression was not sensitive to inhibition by neutralizing antiadenovirus antibodies or inactivation after storage at 37°C. In rat carotid studies, steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated site-specific arterial adenovirus green fluorescent protein expression and adenovirus-luciferase transgene activity by optical imaging. Adenovirus encoding inducible nitric oxide synthase delivered by a carotid stent resulted in significant inhibition of restenosis.Comment: This study investigated local delivery of gene therapy from bare-metal stent surfaces using reversible chemical attachment of vectors to the bare-metal stents. Adenovirus vectors on the surfaces of the stents demonstrated Ͼ1-month release kinetics and site-specific transduction of target cell types in vitro and in vivo in this rat model. Deployment of stents configured with 10 9 adenovirus vectors encoded for inducible nitric oxide synthase resulted in significant reduction of in-stent restenosis. It appears that the concept of gene-eluting stents is valid and may provide a mechanism of local and systemic delivery of gene products by the vasculature.

Context Microalbuminuria (albuminuria 30-300 mg per 24-hour urine collection) is a well-known risk marker for arterial thromboembolism. It is assumed that microalbuminuria reflects generalized endothelial dysfunction. Hence, microalbuminuria may also predispose for venous thromboembolism (VTE). Objective To assess whether microalbuminuria is associated with VTE. Design, Setting, and Participants Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. All inhabitants of Groningen, the Netherlands, aged 28 through 75 years (n=85 421) were sent a postal questionnaire and a vial to collect a first morning urine sample for measurement of urinary albumin concentration. Of those who responded (40 856), a cohort (8592 participants) including more participants with higher levels of urinary albumin concentration completed screening at an outpatient clinic. Screening data were collected on urinary albumin excretion (UAE) and risk factors for cardiovascular and renal disease. Main Outcome Measure Symptomatic and objectively verified VTE (ie, deep vein thrombosis, pulmonary embolism, or both) between study initiation and June 1, 2007. Results Of 8574 evaluable participants (mean [SD] age, 49 [13] years; 50% men), 129 experienced VTE during a mean (SD) follow-up period of 8.6 (1.8) years, corresponding to overall annual incidence of 0.14% (95% confidence interval [CI], 0.11%-0.19%). Annual incidences were 0.12%, 0.20%, 0.40%, and 0.56% in participants with UAE of less than 15 (n=6013), 15-29 (n=1283), 30-300 (n=1144), and greater than 300 (n=134) mg per 24-hour urine collection, respectively (P for trend Ͻ.001). When adjusted for age, cancer, use of oral contraceptives, and atherosclerosis risk factors, hazard ratios associated with UAE levels of 15-29, 30-300, and greater than 300 mg/24 h were 1.40 (95% CI, 0.86-2.35), 2.20 (95% CI, 1.44-3.36), and 2.82 (95% CI, 1.21-6.61), respectively, compared with participants with UAE of less than 15 mg/24 h (global P=.001). Adjusted hazard ratio for microalbuminuria vs normoalbuminuria (UAE Ͻ30 mg/24 h) was 2.00 (95% CI, 1.34-2.98; PϽ.001). Microalbuminuria-related number needed to harm was 388 per year. Conclusion Microalbuminuria is independently associated with an increased risk for VTE.

Long-term mortality and (aborted) SCD rates after ASA and myectomy are similarly low. Patients who undergo ASA have more than twice the risk of permanent pacemaker implantation and a 5 times higher risk of the need for additional septal reduction therapy compared with those who undergo myectomy.