NIDDK News

The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Study

Patients with chronic renal disease are at high risk for cardiovascular disease. Some of this elevated risk is due to a higher prevalence of established arteriosclerotic risk factors such as advanced age, hypertension, dyslipidemia, diabetes, and physical inactivity, but unique renal insufficiency/uremia-related risk factors may also exist. Prominent among these risk factors are elevated levels of homocysteine.

The Folic Acid for Vascular Outcome Reduction in Transplantation project, which began in August 2001 and will end January 31, 2006, will conduct a nationwide, multicenter clinical trial that will determine whether total homocysteine-lowering treatment with a high-dose combination of folic acid, vitamin B₁₂, and vitamin B₆ will reduce the rate of cardiovascular disease outcomes among stable renal transplant recipients with mild to moderately elevated total homocysteine levels. A total of 4,000 renal transplant recipients will be recruited over two years. Recruitment began in July 2002.

For several reasons, renal transplant recipients are a unique subpopulation for testing the hypothesis. They exhibit a high rate of new and recurrent cardiovascular disease outcomes. They display an excess prevalence of hyperhomocysteinemia despite the nationwide fortification of cereal grain flour that is credited with reducing homocysteine levels in the general population. In addition, their total homocysteine levels can be safely and successfully normalized with folic acid, vitamin B12, and vitamin B6. These overall conditions are representative of the population of people in the United States with chronic renal insufficiency (serum creatinine of 1.5 mg/dl or higher) who have not yet reached end-stage renal disease.

The randomized, double-masked study will be conducted at 20 major renal transplant centers in the United States and Canada. The primary outcome of the trial is recurrent or de novo arteriosclerotic cardiovascular disease, defined as nonfatal or fatal coronary heart, cerebrovascular, and peripheral vascular disease events: myocardial infarction, resuscitated sudden death, coronary artery revascularization, stroke, and peripheral or renovascular disease that requires an invasive procedure such as angioplasty, stenting, endarectomy, aneurysm repair, or lower extremity amputation for an arteriosclerotic complication.

The clinical trial is being conducted under a cooperative agreement. Andrew G. Bostom, M.D., M.S., will direct the clinical coordinating center at Rhode Island Hospital. Lloyd Chambless, Ph.D., will serve as principal investigator at the data-coordinating center at the University of North Carolina. Other participating institutions are University of Iowa, Albany Medical Center, Cedars Sinai Health System, Duke University Medical Center, Hennepin County Medical Center, Indiana University, London (Ontario, Canada) Health Sciences Center, Medical College of Wisconsin, Ohio State University, Oregon Health Sciences University, SUNY Downstate Medical Center, University of Alabama at Birmingham, University of California at Los Angeles, University of California at San Francisco, University of Maryland Medical Center, University of Michigan Medical Center, University of Toronto, University of Wisconsin, and Washington University.

NIDDK Project Officer: Dr. John W. Kusek, 301-594-7717

Focal Segmental Glomerulosclerosis (FSGS) in Children and Young Adults Interventional Study

Some children and young adults with nephrotic syndrome caused by focal segmental glomerulosclerosis (FSGS) are at high risk for kidney failure because they are resistant to or dependent on standard therapy with prednisone. No current treatment for this condition is satisfactory. The NIDDK has formed a collaborative network of research centers that will test the effects of cyclosporin or novel immune system modulation agents on reduction of proteinuria in these patients. The clinical sites are State University of New York, Stony Brook; Montefiore Medical Center; Seattle Children’s Medical Center; Medical City Dallas Hospital; and the University of North Carolina. The data-coordinating center is the Cleveland Clinic, and NephCare will perform ancillary studies.

Because the number of patients with FSGS who are followed at any one medical institution is likely to be insufficient to meet the recruitment goal for an individual regional clinical coordinating center, the network will have a central institution coordinating the recruitment, intervention, and follow-up of patients entered into the trial from other medical organizations and individual physicians. Approximately 400 children and young adults will be enrolled in the five-year study. Funding is $1.2 million for the first year and $2.4 million for each of the subsequent years.

The NIDDK-sponsored network was formed through a cooperative agreement, an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during performance of the trial.

NIDDK Project Officer: Dr. Marva Moxey-Mims, 301-594-7717

Dialysis Access Clinical Trials Consortium

Maintenance of vascular access for hemodialysis is one of the major challenges in the care of the hemodialysis patient. Access-related problems are among the most frequent reasons for hospitalization in the end-stage renal disease (ESRD) population, and the cost of vascular access placement and repair in the United States exceeds $700 million per year. Despite the substantial medical and economic impact of arteriovenous (AV) graft and fistula failure in hemodialysis patients, few randomized, controlled, clinical trials have been conducted that examine the effects of drugs and other therapies aimed at prolonging the survival of these types of vascular accesses.

To identify effective therapies that will reduce the rate of AV graft and fistula failure in hemodialysis patients, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established a multicenter consortium in September 2000 that will design and implement a series of randomized, controlled, clinical trials over a five-year period. Participating institutions are Boston University, University of Iowa, Duke University, Maine Medical Center, University of Alabama, University of Texas Southwestern Medical School, Washington University, and Cleveland Clinic Foundation.

Two randomized placebo-controlled clinical trials have been designed and are planned to begin recruitment in late 2002. The first trial will evaluate the effects of the anti-platelet agent, clopidogrel (Plavix), on prevention of early AV fistula thrombosis. A second clinical trial among hemodialysis patients with grafts will study Aggrenox (dipyridamole and aspirin), with the goal of preventing access stenosis. Because more than 40% of the new cases of end-stage renal disease (ESRD) are attributed to diabetes mellitus and both AV fistulas and grafts are more likely to fail in these patients, special emphasis has been given to recruit a study population that is at least 50% diabetic patients.

The recruitment goal for each study is approximately 1,200 subjects. It is anticipated that recruitment will begin in December 2002.

NIDDK Program Officers: Dr. Catherine Meyers and Dr. John Kusek, 301-594-7717

Family Investigation of Nephropathy of Diabetes (FIND) Consortium

Families of patients with diabetic nephropathy have an increased prevalence of renal disease, and certain populations appear to be more susceptible. Delineating the genetic loci associated with the development and progression of diabetic nephropathy could lead to improved outcomes; therefore, the NIDDK and the National Center for Minority Health and Health Disparities have established the Family Investigation of Nephropathy of Diabetes (FIND) Consortium.

FIND began in September 1999 and will conclude in September 2004. Eight investigator centers will conduct independent studies, using the facilities of a genetic analysis and data-coordinating center. The centers are Case Western Reserve University; University of California, Los Angeles; Harbor-University of California Los Angeles Medical Center; University of Texas Health Science Center at San Antonio; Wake Forest University School of Medicine; Johns Hopkins University; University of New Mexico School of Medicine; and NIDDK/ Phoenix.

Recruitment for the independent studies got underway in August 2000. Recruitment goals are 2000 sibpairs (1180 affected and 743 discordant) as well as approximately 1,000 cases and controls. The number of currently enrolled subjects is approximately 4,400.

In addition to conducting genetic and genomic studies, the FIND consortium will also establish a database that uniformly and accurately collects genetic and phenotypic information reflecting underlying susceptibility to variable courses and outcomes of diabetic nephropathy.

NIDDK Program Officer: Dr. Rebekah Rasooly and Paul Kimmel, 301-594-7717

Prospective Cohort Study of Chronic Renal Insufficiency (CRIC)

In recent years, a substantial number of studies have led to a greater understanding of end-stage renal disease (ESRD) and to significant improvements in the treatment and quality of life of ESRD patients. However, knowledge of the disease factors that precede ESRD — reduced renal function and chronic renal insufficiency — is far less advanced. In addition, very little is known about the incidence and risk factors for cardiovascular disease, which is 10 to 20 times higher in people with ESRD.

The Prospective Cohort Study of Chronic Renal Insufficiency (CRIC) will conduct annual studies of a cohort of 3,000 patients with chronic renal insufficiency to determine the risk factors for decline in renal function and for cardiovascular disease. Half of the subjects will have diabetes as the cause of their chronic kidney disease. The study will also assess health care issues and quality of life outcomes.

Funding for CRIC began in October 2001 and will continue for seven years. The study is scheduled to begin in April 2003 at seven clinical centers: University of Pennsylvania; University of Maryland-Johns Hopkins; University of Illinois; University of Michigan; University of California, San Francisco/Kaiser Permanente; Tulane University; and Case-Western Reserve University. The data-coordinating center is at the University of Pennsylvania.

NIDDK Project Officer: John Kusek, Ph.D., 301-594-7717

Polycystic Kidney Disease (PKD) Clinical Trials Network (HALT PKD)

Important advances in understanding the molecular basis of autosomal dominant polycystic kidney disease (PKD) —ADPKD1 and ADPKD2 — have generated intense interest and have provided investigators with new research opportunities. Building on these advances, the Division of Kidney, Urologic and Hematologic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases established a network in 2001 to design and implement clinical trials of treatments that will slow the progressive loss of renal function in PKD. Comprising a data-coordinating center and participating clinical centers, the network will develop and execute both pilot and feasibility trials and a large randomized controlled clinical trial on blockade of the renin-angiotensin-aldosterone axis in patients with PKD. The four clinical centers are University of Colorado, Mayo Clinic, Emory University, and Tufts University. The data will be coordinated at Washington University

Several years ago the NIDDK funded the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) to determine whether changes in anatomic characteristics of the kidneys of patients with PKD will be useful in providing surrogate measures for disease progression. Although final data from these studies are not presently available, findings from this group over the next several years will hopefully inform the designs of clinical trials in patients with PKD in the near future.

HALT PKD investigators began designing their protocol in the summer of 2002 and they plan to begin recruiting subjects for the main trial in the first half of 2003.

Program Officer: Catherine Meyers, 301-451-4901