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
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