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Endothelial cell autoantibodies in predicting declining renal function, end-stage renal disease, or death in adult type 2 diabetic nephropathy.

Zimering MB, Zhang JH, Guarino PD, Emanuele N, McCullough PA, Fried LF, Investigators for the VA NEPHRON - Front Endocrinol (Lausanne) (2014)

Bottom Line: A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals.In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017).Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 - 95% confidence intervals (CI 1.84-6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine).

View Article: PubMed Central - PubMed

Affiliation: Medical Service, Department of Veterans Affairs New Jersey Health Care System , East Orange, NJ , USA ; Rutgers-Robert Wood Johnson Medical School , New Brunswick, NJ , USA.

ABSTRACT
Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 - 95% confidence intervals (CI 1.84-6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine). These results suggest that anti-endothelial cell antibodies interact significantly with albuminuria in predicting the composite endpoint of death, ESRD, or substantial decline in renal function in older, adult type 2 diabetic nephropathy.

No MeSH data available.


Related in: MedlinePlus

Hazard ratio of time to primary endpoint occurrence by AECA-mediated cell survival, albuminuria subgroup is shown. The hazard ratio (bar height) and 95% confidence intervals (brackets) were computed from Cox regression survival analysis of time to first post-randomization primary endpoint occurrence using albuminuria <1 g/g creatinine, AECA-mediated cell survival >80% as the (Ref) – reference group.
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Figure 1: Hazard ratio of time to primary endpoint occurrence by AECA-mediated cell survival, albuminuria subgroup is shown. The hazard ratio (bar height) and 95% confidence intervals (brackets) were computed from Cox regression survival analysis of time to first post-randomization primary endpoint occurrence using albuminuria <1 g/g creatinine, AECA-mediated cell survival >80% as the (Ref) – reference group.

Mentions: Fifty-eight primary end points were experienced by the 305 participants. In Cox regression analysis, there was a significant interaction effect of baseline AECA-mediated cell survival and baseline albuminuria level on the hazard rate (HR) for primary composite endpoint occurrence (P = 0.017) (Table 2). Compared to reference participants with low baseline albuminuria level ( <1 g/g creat) and lacking strongly inhibitory anti-EC antibodies ( >80% cell survival), patients with albuminuria >1 g/g and lacking strongly inhibitory anti-EC antibodies ( >80% cell survival) had a significantly higher hazard for the primary endpoint, HR, 3.41 (CI, 1.84–6.33; P < 0.001); whereas participants with strongly inhibitory antibodies and higher baseline albuminuria ( ≥1 g/g creatinine) or those with strongly inhibitory antibodies and lower baseline albuminuria ( <1 g/g creatinine) had a non-significant hazard for primary endpoint occurrence HR, 1.44 (CI, 0.63–3.28) and HR, 1.53 (CI, 0.72–3.27), respectively (Figure 1; Table 2).


Endothelial cell autoantibodies in predicting declining renal function, end-stage renal disease, or death in adult type 2 diabetic nephropathy.

Zimering MB, Zhang JH, Guarino PD, Emanuele N, McCullough PA, Fried LF, Investigators for the VA NEPHRON - Front Endocrinol (Lausanne) (2014)

Hazard ratio of time to primary endpoint occurrence by AECA-mediated cell survival, albuminuria subgroup is shown. The hazard ratio (bar height) and 95% confidence intervals (brackets) were computed from Cox regression survival analysis of time to first post-randomization primary endpoint occurrence using albuminuria <1 g/g creatinine, AECA-mediated cell survival >80% as the (Ref) – reference group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127944&req=5

Figure 1: Hazard ratio of time to primary endpoint occurrence by AECA-mediated cell survival, albuminuria subgroup is shown. The hazard ratio (bar height) and 95% confidence intervals (brackets) were computed from Cox regression survival analysis of time to first post-randomization primary endpoint occurrence using albuminuria <1 g/g creatinine, AECA-mediated cell survival >80% as the (Ref) – reference group.
Mentions: Fifty-eight primary end points were experienced by the 305 participants. In Cox regression analysis, there was a significant interaction effect of baseline AECA-mediated cell survival and baseline albuminuria level on the hazard rate (HR) for primary composite endpoint occurrence (P = 0.017) (Table 2). Compared to reference participants with low baseline albuminuria level ( <1 g/g creat) and lacking strongly inhibitory anti-EC antibodies ( >80% cell survival), patients with albuminuria >1 g/g and lacking strongly inhibitory anti-EC antibodies ( >80% cell survival) had a significantly higher hazard for the primary endpoint, HR, 3.41 (CI, 1.84–6.33; P < 0.001); whereas participants with strongly inhibitory antibodies and higher baseline albuminuria ( ≥1 g/g creatinine) or those with strongly inhibitory antibodies and lower baseline albuminuria ( <1 g/g creatinine) had a non-significant hazard for primary endpoint occurrence HR, 1.44 (CI, 0.63–3.28) and HR, 1.53 (CI, 0.72–3.27), respectively (Figure 1; Table 2).

Bottom Line: A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals.In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017).Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 - 95% confidence intervals (CI 1.84-6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine).

View Article: PubMed Central - PubMed

Affiliation: Medical Service, Department of Veterans Affairs New Jersey Health Care System , East Orange, NJ , USA ; Rutgers-Robert Wood Johnson Medical School , New Brunswick, NJ , USA.

ABSTRACT
Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 - 95% confidence intervals (CI 1.84-6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine). These results suggest that anti-endothelial cell antibodies interact significantly with albuminuria in predicting the composite endpoint of death, ESRD, or substantial decline in renal function in older, adult type 2 diabetic nephropathy.

No MeSH data available.


Related in: MedlinePlus