Inflammation in Chronic Kidney Disease and Cardiovascular Disease - The Role of Genetics and Interleukin-1 Receptor Antagonist (IL-1ra)
Information source: Department of Veterans Affairs
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Chronic Kidney Disease; Cardiovascular Disease
Intervention: Rilonacept (Drug); Placebo (Drug)
Phase: N/A
Status: Completed
Sponsored by: Department of Veterans Affairs Official(s) and/or principal investigator(s): Adriana M Hung, MD MPH, Principal Investigator, Affiliation: Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
Summary
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 CV 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.
Clinical Details
Official title: Inflammation in CKD and CVD - The Role of Genetics and IL-1ra
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: High Sensitivity C-Reactive Protein (hsCRP)
Secondary outcome: Interleukin-6 (IL-6)
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- 18 years of age or older;
- eGFR between 15-60 mL/min/1. 73m2;
- Must be on stable regimens of medications that can affect inflammatory axis (ASA,
TZDs, statins);
- Willing and able to comply with clinic visits and study-related procedures;
- Provide signed informed consent.
Exclusion Criteria:
- Recent infection or hospitalization (within one month);
- History of active or chronic hepatitis B, history of active or chronic hepatitis C,
human immunodeficiency virus (HIV), history of tuberculosis (patient must be PPD
negative);
- Patients taking TNF inhibitors, TNF blocker, IL-6 blockers or IL-1 blocking drugs;
- Patients on steroids or receiving any other immunosuppressive agent or
anti-inflammatory drug (aspirin up to 325 mg a day is allowed) one month prior;
- Have clinically significant chronic lymphopenia (low white blood cell count);
- History of malignancy in the prior 5 years. Any history of melanoma or lymphoma;
- Life expectancy less than six months;
- Intolerance to the study medication;
- The use of any other investigational drug 30 days prior to enrollment or within five
half-lives of the medication used;
- Live vaccinations within 3 months prior to the start of the trial, during the trial,
and up to 3 months following the last dose;
- Currently receiving parenteral iron or scheduled to receive parenteral iron during
the study;
- Uncontrolled diabetes mellitus (HbA1c > 10);
- hsCRP <2mg/L or >30 mg/L;
- BMI > 40;
- Known diagnosis of severe congestive heart failure with documented EF < 35%;
- Pregnant or breast-feeding women;
- Sexually active men* or women of childbearing potential** who are unwilling to
practice adequate contraception during the study (adequate contraceptive measures
include stable use of oral contraceptives or other prescription pharmaceutical
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device
[IUD]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam,
or jelly, or diaphragm plus contraceptive sponge, foam, or jelly).
- Contraception is not required for men with documented vasectomy.
**Postmenopausal women must be amenorrheic for at least 12 months in order not
to be considered of child bearing potential. Pregnancy testing and
contraception are not required for women with documented hysterectomy or tubal
ligation.
Locations and Contacts
Tennessee Valley Healthcare System Nashville Campus, Nashville, TN, Nashville, Tennessee 37212-2637, United States
Vanderbilt University, Nashville, Tennessee 37232, United States
Additional Information
Starting date: January 2013
Last updated: July 20, 2015
|