Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease

Abstract

Background and objectives: The mechanisms underlying erythropoietin resistance are not fully understood. Carbamylation is a post-translational protein modification that can alter the function of proteins, such as erythropoietin. The hypothesis of this study is that carbamylation burden is independently associated with erythropoietin resistance.

Design, setting, participants, & measurements: In a nonconcurrent prospective cohort study of incident hemodialysis patients in the United States, carbamylated albumin, a surrogate of overall carbamylation burden, in 158 individuals at day 90 of dialysis initiation and erythropoietin resistance index (defined as average weekly erythropoietin dose [U] per kg body weight per hemoglobin [g/dl]) over the subsequent 90 days were measured. Linear regression was used to describe the relationship between carbamylated albumin and erythropoietin resistance index. Logistic regression characterized the relationship between erythropoietin resistance index, 1-year mortality, and carbamylation.

Results: The median percent carbamylated albumin was 0.77% (interquartile range=0.58%-0.93%). Median erythropoietin resistance index was 18.7 units/kg per gram per deciliter (interquartile range=8.1-35.6 units/kg per gram per deciliter). Multivariable adjusted analysis showed that the highest quartile of carbamylated albumin was associated with a 72% higher erythropoietin resistance index compared with the lowest carbamylation quartile (P=0.01). Increasing erythropoietin resistance index was associated with a higher risk of death (odds ratio per unit increase in log-erythropoietin resistance index, 1.69; 95% confidence interval, 1.06 to 2.70). However, the association between erythropoietin resistance index and mortality was no longer statistically significant when carbamylation was included in the analysis (odds ratio, 1.44; 95% confidence interval, 0.87 to 2.37), with carbamylation showing the dominant association with death (odds ratio for high versus low carbamylation quartile, 4.53; 95% confidence interval, 1.20 to 17.10).

Conclusion: Carbamylation was associated with higher erythropoietin resistance index in incident dialysis patients and a better predictor of mortality than erythropoietin resistance index.

Figures

Figure 1.

Histogram of percent carbamylated albumin with quartiles. Distribution of percent carbamylated albumin levels in the study population (n=158). Dashed lines separate quartiles. Q1, lowest quartile; Q2, quartile 2; Q3, quartile 3; Q4, highest quartile.

Figure 2.

Erythropoietin dose and hemoglobin by quartile of carbamylation. Median weekly erythropoietin dose (units) and median hemoglobin (g/dl) values between days 90 and 180 across quartile of percent carbamylated albumin. Bars are interquartile range.

Figure 3.

Odds ratio for death by erythropoietin resistance index. Odds ratios represent odds per unit change in natural log-erythropoietin resistance index. Bars are 95% confidence interval. Multivariable model includes systolic BP, diastolic BP, vascular access (catheter versus no catheter), albumin, phosphorous, and IL-6.