Sahir Kalim1, Anders H Berg2, Subbian Ananth Karumanchi3, Ravi Thadhani1, Andrew S Allegretti1, Sagar Nigwekar1, Sophia Zhao1, Anand Srivastava4, Dominic Raj5, Rajat Deo6, Anne Frydrych7, Jing Chen8, James Sondheimer9, Tariq Shafi10, Matthew Weir11, James P Lash7. 1. Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 2. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 3. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 4. Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 5. Department of Medicine, Division of Renal Diseases and Hypertension, George Washington University School of Medicine, Washington, DC, USA. 6. Departments of Medicine and Epidemiology and Biostatistics, University of Pennsylvania Philadelphia, PA, USA. 7. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. 8. Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA. 9. Department of Medicine, Wayne State University, Detroit, MI, USA. 10. Department of Medicine, Johns Hopkins University Baltimore, MD, USA. 11. Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD, USA.
Abstract
BACKGROUND: Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established. METHODS: We conducted two nested case-control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study. RESULTS: At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9-32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0-11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN. CONCLUSIONS: Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation's association with mortality was smaller in this limited sample size.
BACKGROUND: Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established. METHODS: We conducted two nested case-control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study. RESULTS: At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9-32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0-11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN. CONCLUSIONS: Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation's association with mortality was smaller in this limited sample size.
Authors: J'Neka S Claxton; Pablo C Sandoval; Gary Liu; Chung-Lin Chou; Jason D Hoffert; Mark A Knepper Journal: PLoS One Date: 2013-12-26 Impact factor: 3.240
Authors: Anders H Berg; Christiane Drechsler; Julia Wenger; Roberto Buccafusca; Tammy Hod; Sahir Kalim; Wenda Ramma; Samir M Parikh; Hanno Steen; David J Friedman; John Danziger; Christoph Wanner; Ravi Thadhani; S Ananth Karumanchi Journal: Sci Transl Med Date: 2013-03-06 Impact factor: 17.956