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Chronic Renal Insufficiency Cohort (CRIC) Study

ESRD-A Public Health Problem

ESRD is an important medical and public health problem in the United States that disproportionately affects racial and minority populations. According to the United States Renal Data System (USRDS), at the end of 1997 over 300,000 patients were receiving treatment for ESRD and nearly 80,000 new patients started ESRD treatment during the same year.

The number of ESRD patients is steadily increasing. From 1988 to 1997, the absolute number of ESRD patients more than doubled and the incidence rate doubled. Two important factors associated with this dramatic rise are the increasing prevalence of diabetes and the continuing high rates of uncontrolled high blood pressure observed in the United States. Despite the prominence of diabetes and hypertension in increasing the risk of developing chronic renal disease, the factors responsible for accelerating decline in renal function once chronic renal disease has been established are considerably less well defined.

Although there has been substantial interest during the past two decades to better understand the risk factors for progression of chronic renal disease (i.e., accelerated decline in renal function), only a small number of epidemiological studies examining this issue have been conducted. All of the studies have had important shortcomings, including retrospective study design, small sample size, short-term follow-up, use of select populations such as clinical trial participants, lack of ethnic and racial diversity of the study populations, exclusion or low rates of female participants, use of crude measures of renal function, limited assessment of potential risk factors, and inclusion of only select causes of renal disease, among others. Therefore, it is not surprising that the demographic, clinical, and laboratory factors examined in these studies explain only a small percentage of the variability in renal function decline between patients. This suggests that a significant number of important patient-, genetic-, environmental-, and health-care-utilization-related risk factors for rapid loss of renal function in persons with established chronic renal disease remain unidentified.

The survival of ESRD patients is significantly poorer when compared to patients with other major illnesses such as prostate and colon cancer. In 1996 the adjusted death rate (adjusted for age, race, sex, and primary cause of ESRD) for all incident ESRD patients was 19.8 per 100 patient years at risk for patients in the first year of ESRD therapy. The death rate for ESRD patients with renal disease due to diabetes is even higher.

High Cardiovascular Mortality Rates

Strikingly, cardiovascular disease mortality rates among all ESRD patients are approximately 10 to 20 times those in the general population. Cardiac arrest of unknown cause, acute myocardial infarction, and all other cardiac causes account for nearly one-half of the deaths in hemodialysis patients older than age 20. In contrast to the many studies of cardiovascular disease in ESRD patients, most notably in those undergoing hemodialysis, there is a noticeable lack of epidemiological studies documenting the occurrence of and risk factors for cardiovascular disease in persons with chronic renal insufficiency in the United States.

However, several small retrospective and prospective studies conducted in Europe suggest that the incidence rate of cardiovascular disease is at least three times more frequent among patients with chronic renal insufficiency resulting primarily from non-diabetic renal disease compared to the general population. In contrast, a recent report from the Framingham Heart Study found that among women, mild chronic renal insufficiency was not associated with an increased risk for cardiovascular events or all-cause mortality in men and in women, whereas in men there was an increase in all-cause mortality but not cardiovascular events.

The impact of chronic renal disease on morbidity and mortality in diabetic patients is especially striking. For example, in insulin-dependent diabetic patients with overt nephropathy, the excess mortality may be up to one hundred times that of an otherwise matched normal population. Much of this mortality burden is due to an excess of cardiovascular deaths, which is over several hundred times higher in young insulin-dependent diabetic patients on renal replacement therapy compared with a normal population. Likewise, the impact of cardiovascular disease among non-insulin dependent diabetics with nephropathy is substantial.

The reasons for the increased risk for cardiovascular disease among diabetic and non-diabetic patients with nephropathy are unclear. Although traditional risk factors such as hypertension, hyperlipidemia, hyperglycemia, tobacco use, and physical inactivity are considered important risk factors for cardiovascular disease in patients with chronic renal insufficiency, the relative importance of each of these risk factors compared to nontraditional risk factors (i.e., chronic inflammation, infection, oxidative stress, elevated homocysteine levels, fibrinogen, etc.) is not known.

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. One type of study that has played an important role in defining risk factors for a wide-range of diseases is the prospective cohort study. To determine the risk factors for rapid decline in kidney function and development of cardiovascular disease, the NIDDK established the Chronic Renal Insufficiency Cohort (CRIC) Study in 2001.

The CRIC Study

The CRIC study is a longitudinal cohort study of 3,000 persons, ages 21 to 74, with mild to moderate chronic renal insufficiency. The cohort will be racially and ethnically diverse (40% white/Caucasian, 40% African American, and 20% other), and approximately half will have a diagnosis of diabetes mellitus. Participants in this seven-year prospective, multiethnic, multiracial study reflect the racial, ethnic, and gender composition of the U. S. ESRD patient population.

Data and specimens obtained in this study will serve as a national resource for investigating chronic renal disease and cardiovascular disease. Establishing this cohort of patients and following them prospectively will also provide an opportunity to examine genetic, environmental, behavioral, and nutritional factors in this population. The study will also assess health care issues and quality of life outcomes.

The study hypotheses are as follows:
  • A set of nontraditional risk factors is associated with both progression of chronic renal insufficiency and development of end-stage renal disease.
  • A set of nontraditional risk factors is associated with cardiovascular disease and measures of cardiovascular disease progression in the setting of chronic renal insufficiency.

During the study, patients will continue to receive general health care from their own clinicians. However, at the same time, CRIC investigators will monitor the health of each patient and perform standard blood, urine, and other tests measuring kidney, heart, and blood vessel health. Participants will be followed up for approximately 5 years with annual in-clinic visits and interim telephone contact. A sub-cohort of 1,000 participants will have their kidney function measured with radio-labeled iothalamate. Another sub-cohort of a similar size will also undergo electron beam tomography to assess coronary calcification. All study participants will have an echocardiogram at year 1 and year 4 of follow-up. Establishing this cohort of patients and following them prospectively will also provide an opportunity to examine genetic, environmental, behavioral, and nutritional factors in this population. The study will also assess health care issues and quality of life outcomes.

The study began in April 2003 at seven clinical centers: University of Pennsylvania, Philadelphia; University of Maryland-Johns Hopkins, Baltimore; University of Illinois at Chicago Clinical Centers; University of Michigan, Ann Arbor; Kaiser Permanente of Northern California/ University of California, San Francisco; Tulane University, New Orleans; and Case Western Reserve University, Cleveland. The data- coordinating center is at the University of Pennsylvania.

The CRIC Study design was published in the Journal of the American Society of Nephrologists (Feldman H et al. J Am Soc Nephrol 2003,14 (Suppl 2): S148-153). Program Officers: Thomas Hostetter, M.D. and John Kusek, Ph.D., 301-594-7717

Last Updated: 4/29/2004

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