L-arginine for Prevention of Kidney Damage in Liver Transplant Recipients
Chronic renal insufficiency is a common and important health problem that causes morbidity and mortality among patients who have undergone liver transplantation. It is mainly caused by drugs (calcineurin inhibitors) that are used to prevent or treat rejection and once established, there is no effective treatment. This research investigates whether L-arginine can reverse the effects of calcineurin inhibitors on the kidneys and thus prevent renal insufficiency in liver transplant recipients.
Although liver transplantation (LTx) is now well-established as a means of restoring health in patients with liver failure, there remain opportunities to further optimize its outcome. One of the major sources of mortality and morbidity in LTx recipients is renal insufficiency associated with nephrotoxicity of immunosuppressant agents, particularly calcineurin inhibitors (i.e., cyclosporine and tacrolimus). These agents are also associated with hypertension and diabetes among LTx recipients, contributing to further reduction in renal function. In a report based on nationwide data, 18% of LTx recipients developed renal failure within 5 years.
Most of the decline in renal function after LTx occurs in the first few months. This is in part because patients are exposed to the highest levels of calcineurin inhibitors in the early post-LTx period, when the risk of acute cellular rejection is the greatest. Calcineurin inhibitors produce intense renal vasoconstriction, which may be reversible early on. Over time, however, irreversible changes, such as vascular angiopathy, tubular atrophy and eventually interstitial fibrosis, contribute to permanent reduction in renal perfusion and glomerular filtration. Thus, interventions to preserve renal function after LTx would be most effective in the early post-LTx period, when most reduction in renal function occurs and when renal vascular changes are potentially reversible.
Existing evidence and our preliminary data indicate that impairment of vasodilatory response mediated by nitric oxide (NO) plays an important role in the pathogenesis of calcineurin inhibitor nephrotoxicity. Our overall hypothesis is that L-arginine supplement provides protection against calcineurin inhibitor nephrotoxicity. L-arginine, a naturally occurring amino acid, is the main substrate of the NO synthase enzyme and exogenous supplementation of L-arginine may improve renal perfusion by inducing renal vasodilation via increased NO production. Although L-arginine has been shown to prevent renal damage from calcineurin inhibitors in experimental animals, its efficacy in preserving renal function has not been studied in human LTx recipients.
In this application, we propose to conduct a pilot, randomized, double-blinded, placebo-controlled trial to explore the use of prophylactic L-arginine supplement in preserving renal function in LTx recipients. Twenty-four (24) LTx recipients recovering uneventfully from the procedure will be recruited for the study. Subjects will be randomized 1:1 to receive 9g per day of L-arginine or placebo given orally for 7 days between 14 and 21 days after LTx, followed by open-label maintenance with L-arginine. The aims of the study are as follows:
AIM 1. To determine the effect of oral L-arginine supplement on glomerular filtration rate in LTx recipients. We will compare changes in GFR, as estimated by the eGFRcys equation, before and after a 7-day trial of L-arginine versus placebo. The eGFRcys equation has recently been shown to be the most accurate GFR estimator incorporating serum cystatin-C and creatinine concentrations, age, gender and race.
AIM 2. To determine the effect of L-arginine supplement on secondary efficacy endpoints. We will compare plasma L-arginine concentrations and urinary cyclic-GMP, the latter being a key metabolite of renal NO, between the L-arginine and placebo groups.
AIM 3. To evaluate the safety of oral L-arginine supplement in liver transplant recipients. We will compare the frequency and severity of adverse events between the L-arginine and placebo groups.
AIM 4. To determine the effect of maintenance open label L-arginine on GFR. After the 7-day trial, participants will be offered an open label L-arginine for 13 additional weeks. We will compare their GFR determined by iothalamate clearance before and after the maintenance use of L-arginine supplement.
Our hypothesis is that L-arginine will promote the release of NO in the renal vascular bed, increasing renal blood flow and glomerular filtration rate (AIM 1). We believe it is critical that we test this in patients early after LTx before irreversible vascular and glomerular damage is established. Once this proof of concept is attained, we would like to link the observation with plasma L-arginine concentration and urinary c-GMP excretion (AIM 2). Based on extensive experience at Mayo Clinic of using oral L-arginine, we expect to demonstrate no clinically significant adverse events with L-arginine (AIM 3). The data from the open label maintenance phase (AIM 4) will help gauge whether the short term benefit shown in AIM 1 is sustainable for a longer time frame.
The significance of these studies is based on several factors: (1) Calcineurin inhibitor-induced renal insufficiency is a major source of morbidity and mortality among LTx recipients; (2) Once it is established, there is no effective treatment for calcineurin inhibitor-induced renal insufficiency; and (3) If the results of this study support our hypothesis, we will be able to embark upon a full scale, randomized trial of long-term oral L-arginine supplement using GFR as the end point. Such a study will be able to answer whether a simple amino acid supplement may prevent calcineurin inhibitor nephrotoxicity, making a fundamental difference in morbidity, mortality and quality of life of our patients, who have undergone a life-changing procedure, namely liver transplantation.
Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
Liver Transplant Recipients
Results (where available)
- Source: http://clinicaltrials.gov/show/NCT00587418
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Non-cadaveric providers of organs for transplant to related or non-related recipients.
Identification of the major histocompatibility antigens of transplant DONORS and potential recipients, usually by serological tests. Donor and recipient pairs should be of identical ABO blood group, and in addition should be matched as closely as possible for HISTOCOMPATIBILITY ANTIGENS in order to minimize the likelihood of allograft rejection. (King, Dictionary of Genetics, 4th ed)
Immunoglobulin preparations used in intravenous infusion, containing primarily IMMUNOGLOBULIN G. They are used to treat a variety of diseases associated with decreased or abnormal immunoglobulin levels including pediatric AIDS; primary HYPERGAMMAGLOBULINEMIA; SCID; CYTOMEGALOVIRUS infections in transplant recipients, LYMPHOCYTIC LEUKEMIA, CHRONIC; Kawasaki syndrome, infection in neonates, and IDIOPATHIC THROMBOCYTOPENIC PURPURA.
An enzyme that activates arginine with its specific transfer RNA. EC 188.8.131.52.
An enzyme that catalyzes the phosphorylation of the guanidine nitrogen of arginine in the presence of ATP and a divalent cation with formation of phosphorylarginine and ADP. EC 184.108.40.206.
Antirejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent their bodies from rejecting the new organ. Long-term use of these d...
The purpose of this study is to determine whether the switch from tacrolimus to cyclosporine microemulsion benefits post-transplant diabetes management (in terms of glycogenic control and...
To determine the safety and efficacy of early corticosteroid discontinuation in liver transplant recipients more than 90 days post transplant, utilizing a combination of two drugs (tacroli...
The purpose of this study is to compare kidney function, long term patient and graft survival, and incidence of acute rejection in liver transplant recipients between one group receiving t...
The study is being done to study the impact of prophylactic administration of antiviral therapy as compared to initiation of antiviral therapy at the time of clinical recurrence of hepatit...
Patients who have received liver transplant are at increased risk of skin complications due to long-term immunosuppression regimen. The aim of this study was to analyze the incidence and risk factors...
Our aim was to analyze the differences in quality of life and mental health among liver transplant recipients with better (G(1)) and worse (G(2)) perceived health and decompensated cirrhotic patients...
Our objectives are to examine the incidence of new-onset diabetes mellitus after transplant (NODAT) and to identify its risk factors in pediatric liver transplant recipients using the Organ Procuremen...
Over the past decade, the use of induction therapy in organ-transplant recipients to intensify immunosuppression during the peritransplantation period has contributed to a reduction in early rejection...