Inflammation in Chronic Kidney Disease and Cardiovascular Disease - The Role of Genetics and Interleukin-1 Receptor Antagonist (IL-1ra)

There has been an exponential growth in the number of people with Chronic Kidney Disease
(CKD) needing dialysis or transplantation, increasing from 209,000 in 1991 to 472,000 in
2004. This is highly concerning due to both the human cost and the burden that it represents
to the health care system. Recent comparison of the NHANES surveys showed that CKD prevalence
increased from 10% in 1988-1994 to 13% in 1999-2004. Patients with CKD are more likely to die
from premature cardiovascular death than to reach ESRD. In those that reach ESRD,
cardiovascular disease (CVD) accounts for over half of the deaths in dialysis. The prevalence
of CKD for the VA population is 20%, and 31.6% for diabetics, higher than in the general
population. These observations emphasize the need of risk stratification, early detection,
and prevention efforts with respect to CKD progression and the CVD burden that afflicts CKD
through targeted interventions in high-risk groups (personalized medicine).

CKD is multifactorial, however familial aggregation of end-stage renal disease (ESRD) and CKD
have been reported for all types of nephropathy underscoring "kidney disease genetic
susceptibility ". Genetic predisposition to ESRD is stronger in African Africans. African
Americans with a first-degree relative with ESRD have a 9-fold increase risk of ESRD vs. a
3-5 fold increase in whites.

Studies consistently show that CKD is an inflammatory process and that biomarkers of
inflammation increase since early stages of CKD. CVD is also an inflammatory process, and
genes that affect inflammation are associated with higher risk of CVD. Since inflammation is
a common denominator of both disease processes (CKD and CVD), it is likely that genes that
govern inflammation may be involved in both, the predisposition to CKD and the burden of CVD
attributable to CKD. Additionally if inflammation plays a central role in the burden of CVD
in CKD than drugs that modulate inflammation should impact both: CKD progression and
non-traditional CV risk factors and CVD.

The overall goal of this proposal is to study genetic predisposition to CKD, and CVD risk in
CKD through inflammatory pathways, and the effect that a potent anti-inflammatory
intervention like interleukin 1 receptor antagonist (IL-1ra), will have in inflame patients
with CKD stages 3&4. Specific Aims: 1) To determine if specific polymorphism/haplotypes,
genotype combinations and gene-environmental interactions that can affect inflammation,
available from the Third National Health and Nutrition Examination Survey (DNA data set),
specifically in the CRP,IL-1, IL-10 and TNF- genes, are associated with CKD. 2) To determine
if the specific polymorphisms and haplotypes studied in Aim 1 are associated with faster CKD
progression and CV outcomes in a longitudinal cohort from the African American Study of
Kidney Disease. 3)To determine if a targeted anti-inflammatory intervention, an IL-1 receptor
antagonist, will modulate systemic inflammation, endothelial function, oxidative stress and
urinary cytokines, the proposed surrogate markers of CVD and CKD progression in inflame
patients with CKD stages 3&4.