Carbamylation in Renal Disease-modulation With Amino Acid Therapy (CarRAAT)
This is a pilot study to evaluate the effects of amino acid supplementation on the structure of certain proteins in the blood of dialysis patients. Patients with end stage renal disease (ESRD) usually have high levels of urea that may interact with blood proteins and change their structure by a process known as carbamylation. The investigators are interested in determining whether carbamylation is linked to adverse outcomes in dialysis patients and have hypothesized that supplementation with a balanced formulation of amino acids can reduce the amount of carbamylation that occurs. In this study, dialysis patients (n= up to 30) will receive intravenous supplementation with an FDA-approved amino acid solution (NephrAmine®, 5.4% amino acids) during regular dialysis sessions (3 times weekly for 6 weeks). During the 6 weeks of therapy and for 2 weeks of follow-up, blood will be drawn from patients' existing hemodialysis access ports (~60 ml total per month) to measure levels of carbamylated albumin, amino acids, and standard laboratory values. Patients will be closely monitored for safety and tolerability of the amino acid therapy. For each treated subject, we will follow an additional individual that is not receiving treatment to serve as a control (no intervention).
End Stage Renal Failure on Dialysis
Dietary Supplement: Amino acid supplementation
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Amino Acid Therapy to Modify Protein Carbamylation in End Stage Renal Disease|
- Change from baseline in plasma carbamylated albumin levels [ Time Frame: Baseline and 6 weeks ] [ Designated as safety issue: No ]
- Number of patients with adverse events [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]6 weeks of therapy and 2 weeks of follow-up post-therapy
|Study Start Date:||January 2013|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
Experimental: Amino acid supplementation
Up to 500 mL of 5.4% amino acid solution (NephrAmine) by intravenous infusion 3 x weekly for 6 weeks.
Dietary Supplement: Amino acid supplementation
Single arm study in which dialysis patients will receive up to 500 mL of NephrAmine® (5.4% amino acids for injection; B. Braun Medical, Inc) containing 26.8 grams of essential amino acids at 125 mL/h during each dialysis session (3 times weekly for 6 weeks)
Other Name: NephrAmine®
As human kidney function declines so does the ability to excrete urea, the chief end product of nitrogen metabolism. Though elevated blood urea levels denote a loss of kidney function, they may also serve as a source for the pathophysiological consequences of kidney failure. Urea spontaneously dissociates to form cyanate, which in its unprotonated form can react with protein amino groups in a process known as carbamylation. Carbamylation-induced protein alterations may be involved in the progression of various diseases by changing the structure, charge, and function of enzymes, hormones, receptors, and amino acids. For example, proteins as diverse as collagen and low density lipoproteins (LDLs), are shown to induce the characteristic biochemical events of atherosclerosis progression when carbamylated. Our research seeks to examine how protein carbamylation contributes to the pathological sequelae of end stage renal disease (ESRD) and determine if novel therapeutics can attenuate this process.
Percent carbamylated albumin level can be used as a measure of overall carbamylation burden. Our preliminary work shows a negative correlation between subjects' percent carbamylated albumin level and circulating amino acids, suggesting that free amino acids may be active scavengers for reactive isocyanate. Furthermore, ex vivo studies show that amino acid supplementation attenuates the carbamylation reaction from occurring. To better assess the biologic pathways affecting carbamylation in dialysis patients and to bring discoveries closer to clinical and therapeutic application, we aim to conduct a pilot study evaluating the effect of amino acid supplementation on carbamylation in participants with ESRD undergoing maintenance hemodialysis. We believe elevated urea and amino acid deficiencies may play dominant roles in the carbamylation of proteins in ESRD and protein carbamylation may be modifiable by amino acid therapy. The proposed pilot study will directly assess this concept.
The specific aims of the study are to evaluate the effect of amino acid supplementation on carbamylation in ESRD patients undergoing maintenance hemodialysis: (1) by evaluating safe and optimal amino acid supplement dosing and (2) by investigating the effect of amino acid supplementation on plasma carbamylated albumin levels.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01612429
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|Principal Investigator:||Ravi Thadhani, MD, MPH||Massachusetts General Hospital|