30 million US adults have chronic kidney disease (CKD) arising from diverse causes but commonly resulting in life-threatening complications such as cardiovascular disease (CVD) and progression to end stage renal disease (ESRD). Although we understand much about the epidemiology of CKD and its associations with CVD, the underlying mechanisms of CKD pathogenesis, progression, and complications remain less well understood. In this proposal we seek to comprehensively study a novel risk factor for the progression and complications of CKD known as protein carbamylation. Carbamylation describes a posttranslational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation increases with renal insufficiency and can change the charge, structure, and function of proteins, resulting in molecular and cellular dysfunction. Select carbamylated proteins have been shown to accelerate pathological biochemical processes such as atherosclerosis and renal fibrosis. We and others have characterized the associated morbidity and mortality risks of carbamylation in multiple ESRD cohorts, but the impact of carbamylation in the non-dialysis CKD population is unknown. The Chronic Renal Insufficiency Cohort (CRIC), an NIDDK- sponsored longitudinal study of 3,939 individuals with CKD that has stored biospecimens and adjudicated kidney and CV outcomes over an average of 6 years of follow-up, creates the ideal opportunity to meet our study's overall objective: we will rigorously quantify the impact of protein carbamylation (employing validated plasma markers of total body carbamylation burden such as carbamylated albumin, C-Alb) on key clinical outcomes in CKD using the CRIC biorepository. Our central hypothesis is that protein carbamylation independently associates with adverse renal and CV outcomes in people with CKD not yet on dialysis.
In Aim 1 of the study we will quantify the association between carbamylation load and clinical outcomes in CKD including CKD progression (defined as 50% reduction in eGFR or progression to ESRD); all-cause mortality; and CV events (heart failure, myocardial infarction, ischemic stroke, or peripheral artery disease events).
In Aim 2 we will classify which variables most significantly associate with carbamylation load, potentially identifying future therapeutic targets. Our approach includes assaying C-Alb in baseline samples from CRIC, analyzing outcomes in relation to these levels, and comparing various baseline covariates as predictors of C- Alb levels. The expected result of these studies is a comprehensive understanding of the pathophysiology of protein carbamylation in CKD and its relationship to important clinical outcomes. Such information could establish a modifiable risk factor in this vulnerable population. This proposal will boost the NIDDK's yield on its investment in CRIC while furthering its mission to understand the biology underlying CKD progression and its complications to ultimately advance effective treatment strategies.
The proposed research project is relevant to public health because it will establish the causes and effects of a harmful protein modification known as carbamylation, that rises with kidney disease and increases the risk for worsening kidney function and death in people with chronic kidney disease (CKD). By understanding the magnitude of carbamylation's impact and the key drivers of carbamylation, we can better design new therapeutic interventions. Thus, the proposed research is highly relevant to the NIDDK's mission to understand the biology underlying CKD progression and its complications in order to advance effective treatment strategies.