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Objective- Albuminuria is an important risk factor for cardiovascular disease in diabetes mellitus. We determined whether albuminuria associates with alterations in the proteome of HDL (high-density lipoprotein) of subjects with type 1 diabetes mellitus and whether those alterations associated with coronary artery calcification. Approach and Results- In a cross-sectional study of 191 subjects enrolled in the DCCT (Diabetes Control and Complications Trial)/EDIC study (Epidemiology of Diabetes Interventions and Complications), we used isotope dilution tandem mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that 8 proteins associated with albuminuria. Two of those proteins, AMBP (α1-microglobulin/bikunin precursor) and PTGDS (prostaglandin-H2 D-isomerase), strongly and positively associated with the albumin excretion rate ( P<10 -6 ). Furthermore, PON (paraoxonase) 1 and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (95% CI, 0.43-0.92; P=0.018) for PON1 and 0.59 (95% CI, 0.40-0.87; P=0.0079) for PON3. Only 1 protein, PON1, associated with both albumin excretion rate and coronary artery calcification. Conclusions- Our observations indicate that the HDL proteome is remodeled in type 1 diabetes mellitus subjects with albuminuria. Moreover, low concentrations of the antiatherosclerotic protein PON1 in HDL associated with both albuminuria and coronary artery calcification, raising the possibility that alterations in HDL protein cargo mediate, in part, the known association of albuminuria with cardiovascular risk in type 1 diabetes mellitus. Visual Overview- An online visual overview is available for this article.

Purpose of Review: Treatment of end-stage renal disease with peritoneal dialysis is associated with an obligatory absorption of carbohydrates with both glucose and icodextrin-based dialysate. In this review, we examine the evidence linking this obligatory absorption with adverse systemic effects., Recent Findings: Systemic glucose absorption is associated with worse glycemic control; this can be ameliorated with glucose-sparing peritoneal dialysis regimens. The studies examining the benefit of glucose-sparing regimens on dyslipidemia are inconsistent and the magnitude of benefit is potentially small. There are no studies demonstrating any improvement in clinically meaningful patient outcomes with glucose-sparing regimens., Summary: Although it is conceivable that the obligatory carbohydrate absorption with peritoneal dialysis increases systemic cardiovascular risk, this premise has not been systematically or rigorously examined to date, there are no robust biomarkers to measure the risk, modification of which may favorably improve outcomes, and whether glucose-sparing peritoneal dialysis regimens will lower the putative risk is currently unknown. Hence, there is a compelling need to bridge our gap in understanding the role of systemic glucose absorption with peritoneal dialysis on the health of individuals undergoing peritoneal dialysis.

Background: The safety and efficacy of different types of β-blocker therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of systolic HF with carvedilol is efficacious and safe in adults with CKD., Methods and Results: We performed a post hoc analysis of pooled individual patient data (n=4217) from 2 multinational, double-blinded, placebo-controlled, randomized trials, CAPRICORN (Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction Study) and COPERNICUS (Carvedilol Prospective Randomized, Cumulative Survival study). Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, HF mortality, first HF hospitalization, the composite of cardiovascular mortality or first HF hospitalization, and sudden cardiac death. Non-dialysis-dependent CKD was defined by estimated glomerular filtration rate ≤60 mL/min/1.73 m(2), using the abbreviated Modification of Diet in Renal Disease equation. CKD was present in 2566 of 4217 (60.8%) of the cohort, 50.4% of whom were randomly assigned to carvedilol therapy. Within the CKD group, treatment with carvedilol decreased the risks of all-cause mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63 to 0.93; P=0.007), cardiovascular mortality (HR, 0.76; 95% CI, 0.62 to 0.94; P=0.011), HF mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P=0.003), first hospitalization for HF (HR, 0.74; 95% CI, 0.61 to 0.88; P=0.0009), and the composite of cardiovascular mortality or HF hospitalization (HR, 0.75; 95% CI, 0.65 to 0.87; P<0.001) but was without significant effect on sudden cardiac death (HR, 0.76; 95% CI, 0.56 to 1.05; P=0.098). There was no significant interaction between treatment arm and study type. Carvedilol was generally well tolerated by both groups of patients, with an increased relative incidence in transient increase in serum creatinine without need for dialysis and other electrolyte changes in the CKD patients. However, in a sensitivity analysis among HF subjects with estimated glomerular filtration rate <45 mL/min/1.73 m(2) (CKD stage 3b), the efficacy of carvedilol was not significantly different from placebo., Conclusions: This analysis suggests that the benefits of carvedilol therapy in patients with systolic left ventricular dysfunction with or without symptoms of HF are consistent even in the presence of mild to moderate CKD. Whether carvedilol therapy is similarly efficacious in HF patients with more advanced kidney disease requires further study.

Purpose of Review: Chronic kidney disease is now recognized as an independent risk factor for cardiovascular events, and cardiovascular disease is the major cause of mortality in patients with the disease. Recent studies have attempted to evaluate the utility of biomarkers for assessing cardiovascular risk in patients with chronic kidney disease. This review will summarize these studies and critically assess the utility of cardiovascular risk biomarkers for clinical practice., Recent Findings: Traditional cardiovascular risk factors including dyslipidemia, hypertension, smoking and diabetes mellitus are highly prevalent in patients with chronic kidney disease. Although prediction models using traditional risk factors underestimate cardiovascular disease risk in these patients, nontraditional biomarkers (i.e. markers of inflammation, endothelial dysfunction, myocardial necrosis, and left ventricular remodeling) have been associated with increased cardiovascular event rates and mortality risk in populations with and without chronic kidney disease. Moreover, a high prevalence of biomarkers that are directly attributable to loss of kidney function is observed in patients with the disease., Summary: Recent studies suggest only limited utility of either single or multiple biomarkers of cardiovascular risk as prognostic tools in patients with and without chronic kidney disease. Novel approaches for biomarker development capturing augmented information through a systems biology approach are urgently needed to improve the usefulness of cardiovascular risk biomarkers.

Background: Chronic kidney disease patients have a high prevalence of inflammation and oxidative stress, and this has been associated with the excess cardiovascular morbidity and mortality observed in this population. Because maintenance hemodialysis is ineffective in controlling these factors, we hypothesized that restoration of kidney function by transplantation would be required to improve uremic inflammation and oxidative stress., Methods: This was a prospective cohort study evaluating time-dependent changes in biomarkers of inflammation and oxidative stress before and after renal transplantation. Nineteen end-stage renal disease (ESRD) patients (age 38.3+/-13.7 years, 58% male, 95% white, 21% diabetic) undergoing living-donor renal transplantation were enrolled. C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, protein-associated carbonyl content, and F2-isoprostanes were assessed at 1 week pretransplantation and at 1 week and 2 months posttransplantation., Results: Pretransplant levels of the pro-inflammatory proteins IL-6, TNF-alpha, and CRP, as well as the oxidative stress markers plasma protein carbonyls and F2-isoprostanes, were significantly elevated in ESRD patients compared with healthy control subjects. We observed rapid and significant declines in all of these biomarkers after transplantation that persisted for 2 months., Conclusions: Our findings indicate that restoration of renal function by transplantation improves the chronic inflammation and increased oxidative stress associated with uremia, which may contribute to the improved survival afforded to ESRD patients by renal transplantation.

Purpose of Review: The HEMO study is a randomized clinical trial using a 2x2 factorial design to assign patients to a standard or high dose of dialysis and to a low flux or a high flux dialyzer. This study is the largest, most comprehensive, randomized clinical trial ever performed in the maintenance hemodialysis population. This review analyzes the results of the study and discusses how the HEMO study results affect efforts to lower morbidity and mortality in the hemodialysis population., Recent Findings: The primary outcome of the HEMO study was death from any cause. This outcome was not significantly influenced by treatment assignment for the dose of dialysis or for the flux of the dialysis membranes used. The main secondary outcomes also did not differ significantly in either the dose groups or the flux groups., Summary: The results of the HEMO study support current clinical practice guidelines for the delivery of thrice-weekly dialysis, but the results do not support conventional attempts to lower the high morbidity and mortality in hemodialysis patients. Current efforts are being focused on increasing dialysis time and/or frequency, improving phosphate control, and lowering traditional and nontraditional risk factors for adverse cardiovascular events in this patient population.

Purpose of Review: Oxidative stress has been described as 'a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. In uremic patients, an increase in oxidative stress may occur because of the loss of residual renal function, and may be exacerbated by dialysis. This review will focus on the emerging biochemical evidence of an increase in oxidative stress in uremic patients, the relationship with renal replacement therapy, and the potential linkages to acute-phase inflammation, malnutrition, and adverse cardiovascular outcomes in uremic patients., Recent Findings: Many studies from multiple research laboratories around the world have recently utilized in-vivo biomarkers to describe increased oxidative stress in uremic patients. An emerging literature suggests that there are links between an increase in oxidative stress, endothelial dysfunction, an increase in acute-phase inflammation, and an accelerated risk of cardiovascular complications in dialysis patients. Additional uremia-associated metabolic abnormalities, including hyperhomocysteinemia, intravenous iron exposure, and biocompatibility changes related to dialysis, may contribute to an increase in oxidative stress. Finally, two well-conducted pilot clinical randomized trials have suggested that antioxidant therapy may have efficacy in reducing cardiovascular events in uremic patients., Summary: The implications of the findings of a generalized increase in oxidative stress associated with uremia have led to the suggestion that antioxidative therapy may be efficacious in reducing cardiovascular complications. Pilot studies have suggested potential efficacy for this approach. However, further large-scale randomized clinical trials will be required to establish a compelling, evidence-based approach to the use of antioxidants in patients with uremia.

Data from this retrospective study indicate that a positive two-color T and/or B cell flow cytometric crossmatch (FCXM) is predictive of early renal allograft loss (less than 2 months) in cadaveric kidney donor recipients who had a negative crossmatch by the antihuman globulin complement-dependent cytotoxicity technique. Among 90 cadaveric kidney donor recipients (67 primary, 23 regrafts), 14 (8 primary, 6 regrafts) lost their renal allografts within 2 months, and 10 of the 14 were FCXM positive and HLA sensitized. The remaining 76 allografts survived beyond 2 months, 12 of which were FCXM-positive. Thus, the FCXM sensitivity rate for detecting early graft loss was 71%, and the specificity rate was 84%. Cadaveric graft-loss rates at 2 months were 33% for primary and 60% for FCXM-positive regrafts in contrast to 7% for primary and 0% for FCXM-negative regrafts. The difference in early graft loss between FCXM-positive and FCXM-negative recipients was statistically significant (P less than 0.0001). Subset analyses of FCXM-positive graft recipients indicate: (1) previous early graft loss contraindicates transplantation of an FXCM-positive regraft (P = 0.03); and (2) panel reactive antibody (PRA) less than or equal to 10% at crossmatch is not associated with early graft loss (P = 0.04). There was no significant difference in 1-year graft survival between primary and regrafts in either FCXM-negative recipients (85% vs. 77%, respectively) or FCXM-positive recipients (67% vs. 40%). All 12 of the FCXM-positive primary and regrafts that survived 2 months continued to function at 2 years. Stepwise logistic regression analysis of 5 independent predictor variables (FCXM status, gender, primary vs. regraft status, PRA level, and HLA mismatched antigens) indicated that the FCXM test was the best predictor of early graft loss. When FCXM results of the 90 cadaveric graft recipients were ranked in three groups, an FCXM channel shift of 29 or greater (third tertile) on a 1024 channel log scale was associated with a 7.0-fold (95% confidence interval 1.9-25.5) increased risk of early graft failure when compared to the first two tertiles. These data indicate that the FCXM offers an additional approach for identifying sensitized patients at risk of early renal allograft loss.