Trial of 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: | 3/22/2019 |
| Start Date: | February 2016 |
| End Date: | December 2020 |
| Contact: | Sahir Kalim, MD, MMSc |
| Email: | skalim@mgh.harvard.edu |
| Phone: | 617-726-5050 |
Amino Acid Therapy to Modify Protein Carbamylation in End Stage Renal Disease: A Randomized Trial
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.
Evidence suggests that high levels of carbamylated proteins may be linked to adverse outcomes
in dialysis patients. This is a randomized, open-label study to evaluate the effects of amino
acid supplementation on levels of carbamylated proteins in ESRD patients. Secondary
objectives will be to determine whether this intervention can modify intermediate markers of
inflammation, cardiac stress, and erythropoietin responsiveness in this population. Sixty
ESRD patients on dialysis will be randomized into two groups of 30 patients each. Group 1
will receive intravenous supplementation with an FDA-approved amino acid solution (250 mL of
NephrAmine®, 5.4% amino acids) during regular dialysis sessions (3 times weekly for 8 weeks);
Group 2 will be treated according to standard-of-care (no amino acid supplementation). During
the 8 weeks of therapy and for 4 weeks of follow-up, blood will be drawn from patients'
existing hemodialysis access ports (~20 mL once per month) to measure levels of carbamylated
albumin, amino acids, selected biomarkers, and standard laboratory values. Patients
randomized to Group 1 will have fluid volume equivalent to the amino acid therapy removed by
ultra-filtration to avoid net fluid gain. All patients will be monitored for safety (adverse
events) and for changes in hemodynamics and dialysis prescription.
interact with blood proteins and change their structure by a process known as carbamylation.
Evidence suggests that high levels of carbamylated proteins may be linked to adverse outcomes
in dialysis patients. This is a randomized, open-label study to evaluate the effects of amino
acid supplementation on levels of carbamylated proteins in ESRD patients. Secondary
objectives will be to determine whether this intervention can modify intermediate markers of
inflammation, cardiac stress, and erythropoietin responsiveness in this population. Sixty
ESRD patients on dialysis will be randomized into two groups of 30 patients each. Group 1
will receive intravenous supplementation with an FDA-approved amino acid solution (250 mL of
NephrAmine®, 5.4% amino acids) during regular dialysis sessions (3 times weekly for 8 weeks);
Group 2 will be treated according to standard-of-care (no amino acid supplementation). During
the 8 weeks of therapy and for 4 weeks of follow-up, blood will be drawn from patients'
existing hemodialysis access ports (~20 mL once per month) to measure levels of carbamylated
albumin, amino acids, selected biomarkers, and standard laboratory values. Patients
randomized to Group 1 will have fluid volume equivalent to the amino acid therapy removed by
ultra-filtration to avoid net fluid gain. All patients will be monitored for safety (adverse
events) and for changes in hemodynamics and dialysis prescription.
As human kidney function declines, so does the kidney's ability to excrete urea, the chief
end product of nitrogen metabolism. Excess urea may accelerate 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 such as collagen and low density lipoproteins (LDLs), when
carbamylated, have been shown to induce the characteristic biochemical events of
atherosclerosis progression. This research aims to evaluate whether amino acid
supplementation can attenuate such processes that are known to contribute to morbidity in
patients with ESRD.
Percent carbamylated albumin (C-Alb) level will be used as a measure of overall carbamylation
burden. Previous studies conducted by MGH Investigators have shown a negative correlation
between %C-Alb and circulating amino acids, suggesting that free amino acids may actively
scavenge reactive isocyanate. Further, ex vivo studies show that amino acid supplementation
reduces the carbamylation reaction. The MGH Investigators recently demonstrated an
association between markers of cardiac stress, heart failure and carbamylation in patients
with ESRD and found that %C-Alb was strongly associated with erythropoietin resistance in
dialysis patients. Additionally, using validated measures of total-body carbamylation, these
and other Investigators have reported that elevated protein carbamylation was linked with
higher mortality in several distinct ESRD cohorts. Finally, preliminary data from a recent
pilot study at MGH (NCT01612429) suggests that amino acid supplementation in patients with
ESRD undergoing maintenance hemodialysis can attenuate carbamylation of proteins.
The proposed randomized study will directly evaluate the impact of amino acid supplementation
on: (1) the burden of carbamylation in terms of %C-Alb; and (2) selected intermediate
determinants of clinical outcomes, i.e., markers of inflammation, cardiac stress, and
erythropoietin responsiveness.
end product of nitrogen metabolism. Excess urea may accelerate 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 such as collagen and low density lipoproteins (LDLs), when
carbamylated, have been shown to induce the characteristic biochemical events of
atherosclerosis progression. This research aims to evaluate whether amino acid
supplementation can attenuate such processes that are known to contribute to morbidity in
patients with ESRD.
Percent carbamylated albumin (C-Alb) level will be used as a measure of overall carbamylation
burden. Previous studies conducted by MGH Investigators have shown a negative correlation
between %C-Alb and circulating amino acids, suggesting that free amino acids may actively
scavenge reactive isocyanate. Further, ex vivo studies show that amino acid supplementation
reduces the carbamylation reaction. The MGH Investigators recently demonstrated an
association between markers of cardiac stress, heart failure and carbamylation in patients
with ESRD and found that %C-Alb was strongly associated with erythropoietin resistance in
dialysis patients. Additionally, using validated measures of total-body carbamylation, these
and other Investigators have reported that elevated protein carbamylation was linked with
higher mortality in several distinct ESRD cohorts. Finally, preliminary data from a recent
pilot study at MGH (NCT01612429) suggests that amino acid supplementation in patients with
ESRD undergoing maintenance hemodialysis can attenuate carbamylation of proteins.
The proposed randomized study will directly evaluate the impact of amino acid supplementation
on: (1) the burden of carbamylation in terms of %C-Alb; and (2) selected intermediate
determinants of clinical outcomes, i.e., markers of inflammation, cardiac stress, and
erythropoietin responsiveness.
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
- Carbamylated albumin (C-Alb) > 7.7 mmol/mol
- 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
- HIV positive
- Condition with prognosis <1 year at time of study entry
- Body Mass Index (BMI) <18 or >30
- 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
- Presence of asthma
We found this trial at
2
sites
185 Cambridge Street
Boston, Massachusetts 02114
Boston, Massachusetts 02114
617-724-5200
Principal Investigator: Sahir Kalim, MD
Phone: 617-726-5050
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