CYBA Gene Polymorphisms and Adverse Outcomes in Acute Kidney Injury: A Prospective Cohort Study

Background: NADPH oxidase is an important enzyme involved in the generation of reactive oxygen species in acute kidney injury (AKI). Its key subunit, p22phox, is encoded by the highly polymorphic CYBA gene. Methods: We examined the associations of CYBA gene polymorphisms across the CYBA locus (rs8854, rs3794624, rs4673, rs4782390, and rs1049255) with dialysis requirement or in-hospital death in 256 hospitalized adults with AKI. Dominant and haplotype multivariable logistic regression analyses were performed, adjusted for sex, race, age, and severity of illness. Results: The baseline characteristics of the patients were not different among genotype groups with the exception of a lower prevalence of sepsis and shock in the CYBA rs8854 A-allele group; a higher prevalence of shock in the CYBA rs4782390 T-allele group, and a higher APACHE II score in the CYBA rs1049255 G-allele group. The CYBA rs8854 A-allele had an adjusted odds ratio (OR) of 0.41 (95% confidence interval, CI, 0.18–0.96) for the outcome of dialysis requirement or in-hospital death. The CYBA rs4673 T-allele and rs1049255 G-allele had unadjusted ORs of 1.69 (95% CI 1.03–2.79) and 1.66 (95% CI 1.01–2.73) for the composite outcome, respectively, which became non-significant after multivariable adjustment. The remaining 2 polymorphisms were not associated with the outcomes of interest. Finally, the presence of the CYBA A-A-G-G haplotype (generated from rs4782390, rs4673, rs3794624, and rs8854, all in Hardy-Weinberg equilibrium) was associated with an elevated OR of 1.81 (95% CI 1.07–3.08) for dialysis requirement or in-hospital death, which was attenuated after multivariable adjustment (OR 1.80; 95% CI 0.99–3.29). Conclusion: This study identifies several polymorphisms spanning the entire CYBA gene locus and a common haplotype as risk markers for dialysis requirement or in-hospital death in patients with AKI. Additional studies are needed to validate these findings

Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community

AbstractObjectivesThe goal of this study was to determine whether the level of kidney function is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) outcomes in the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study of subjects aged 45 to 64 years.BackgroundThe level of kidney function is now recognized as a risk factor for ASCVD outcomes in patients at high risk for ASCVD, but it remains unknown whether the level of kidney function is a risk factor for ASCVD outcomes in the community.MethodsCox proportional-hazards regression was used to evaluate the association of glomerular filtration rate (GFR) with ASCVD after adjustment for the major ASCVD risk factors in 15,350 subjects. We searched for nonlinear relationships between GFR and ASCVD.ResultsDuring a mean follow-up time of 6.2 years, 965 (6.3%) of subjects had ASCVD events. Subjects with GFR of 15 to 59 ml/min/1.73 m2(n = 444, hazard ratio 1.38 [1.02, 1.87]) and 60 to 89 ml/min/1.73 m2(n = 7,665, hazard ratio 1.16 [1.00, 1.34]) had an increased adjusted risk of ASCVD compared with subjects with GFR of 90 to 150 ml/min/1.73 m2. Each 10 ml/min/1.73 m2lower GFR was associated with an adjusted hazard ratio of 1.05 (1.02, 1.09), 1.07 (1.01, 1.12), and 1.06 (0.99, 1.13) for ASCVD, de novo ASCVD, and recurrent ASCVD, respectively. A nonlinear model did not fit the data better than a linear model.ConclusionsThe level of GFR is an independent risk factor for ASCVD and de novo ASCVD in the ARIC study

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy:An Individual Participant Meta-analysis

Rationale & Objective: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a metaanalysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. Study Design: Individual patient-level metaanalysis. Setting & Study Populations: Individual data of 1,037 patients from 12 randomized trials. Selection Criteria for Studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. Analytical Approach: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. Results: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R-2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R-2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. Limitations: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. Conclusions: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN

A New Panel-Estimated GFR, Including beta(2)-Microglobulin and beta-Trace Protein and Not Including Race, Developed in a Diverse Population

RATIONALE AND OBJECTIVE: GFR estimation based on creatinine and cystatin C (eGFR(cr-cys)) is more accurate than eGFR based on either creatinine or cystatin C alone (eGFR(cr) or eGFR(cys)), but the inclusion of creatinine in eGFR(cr-cys) requires specification of a person’s race. Beta-2-microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine. STUDY DESIGN: Study of diagnostic test accuracy. SETTING AND PARTICIPANTS: Development in pooled population of seven studies with 5017 participants with and without chronic kidney disease. External validation in a pooled population of seven other studies with 2245 participants. TESTS COMPARED: Panel eGFR using B2M and BTP in addition to cystatin C (three-marker panel) or creatinine and cystatin C (four-marker panel) with and without age and sex or race. OUTCOMES: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of Cr-EDTA RESULTS: Mean measured GFR was 58.1 and 83.2 ml/min/1.73m(2) and the proportion of blacks was 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared to equations without age and sex, but addition of race did not further improve the performance. In validation, the four-marker panels were more accurate than the three-marker panels (p<0.001). The three-marker panel without race was more accurate than eGFR(cys) [1- P(30) of 15.6 vs 17.4% (p=0.014)], and the four-marker panel without race was as accurate as eGFR(cr-cys) [1- P(30) of 8.6 vs 9.4% (p=0.17)]. Results were generally consistent across subgroups. LIMITATIONS: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe. CONCLUSIONS: The four-marker panel eGFR is as accurate as eGFR(cr-cys), without requiring specification of race. A more accurate race-free eGFR could be an important advance

Electro-thermal modelling for plasmonic structures in the TLM Method

This paper presents a coupled electromagnetic-thermal model for modelling temperature evolution in nano-size plasmonic heat sources. Both electromagnetic and thermal models are based on the Transmission Line Modelling (TLM) method and are coupled through a nonlinear and dispersive plasma material model. The stability and accuracy of the coupled EM-thermal model is analysed in the context of a nano-tip plasmonic heat source example

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression

Background: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. Methods: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. Results: The mean acute effect across all studies was 20.21 ml/min per 1.73 m2 (95% confidence interval, 20.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, 22.50 to 12.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. Conclusion: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD