Carbamylation in Renal Disease-modulation With Amino Acid Therapy
| Status: | Recruiting |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 7/11/2015 |
| Start Date: | January 2013 |
| End Date: | December 2016 |
| Contact: | Sahir Kalim, MD |
| Email: | skalim@partners.org |
| Phone: | 617-726-5050 |
Amino Acid Therapy to Modify Protein Carbamylation in End Stage Renal Disease
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).
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).
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.
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.
Inclusion Criteria:
- Informed of the investigational nature of the study and sign written informed consent
- Willing and able to adhere to all study-related procedures, including adherence to
study medication regimen
- ≥18 years old
- On stable medical therapy in the last 30 days before the study entry, defined as no
change, addition, or removal of medications
- Patients must satisfy the following criteria based on the initial screening
laboratory values:
- Serum albumin ≥ 3.0 g/dL (30 g/L)
- Dialysis adequacy recorded as Kt/ V > 1.2
- Women of childbearing potential must be practicing barrier or oral contraception, for
the duration of the study-related treatment, or be documented as surgically sterile
or one year post-menopausal
- If female, be non-nursing, non-pregnant and have a negative pregnancy test within two
weeks of starting study treatment
- On stable hemodialysis therapy for at least 90 days before the study entry, defined
as receiving thrice weekly dialysis and carrying a diagnosis of ESRD
- Prescribed a dialysis treatment time of 4 hours per session
Exclusion Criteria:
- Taking any type of amino acid supplementation within the last 90 days
- Received parenteral nutrition within last 90 days
- History of allergy to any amino acid compound
- Poorly controlled hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure > 110 mmHg during any of the previous 3 dialysis sessions (confirmed
by repeat)
- Severe hepatic impairment
- Condition with prognosis <1 year at time of study entry
- Current active treatment in another investigational study or participation in another
investigational study in the 1 month prior to screening
- Active malignancies or other serious concurrent or recent medical or psychiatric
condition which, in the opinion of the Investigator, makes the patient unsuitable for
participation in this study
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