HCQ for the CVD in CKD

Cardiovascular disease (CVD) is the most prominent cause of morbidity and mortality among
patients with chronic kidney disease (CKD), and end stage kidney disease (ESKD).
Unfortunately at the present time, the investigators do not have an effective treatment to
reduce the high CVD mortality in these populations. Accelerated atherosclerosis,
inflammation, and vascular stiffness are prominent factors contributing to CVD in CKD.
Interventions that can effectively counter these factors may provide significant benefits for
the management of CVD in CKD. Hydroxychloroquine (HCQ) is an inexpensive and safe
anti-inflammatory drug that has been in clinical use for over 4 decades even in patients with
CKD and ESKD. In recent times, multiple in vitro, in vivo, and human cohort based data have
shown that HCQ benefits multiple parameters of CVD, including inflammation, endothelial
function, metabolic syndrome, insulin sensitivity and atherosclerosis. Recently the
investigators through the animal studies validated that HCQ indeed has significant
anti-atherosclerosis and vasculoprotective effects in CKD milieu. The investigators further
conducted a small, human, feasibility study that shows a potential for HCQ on parameters
relevant to CVD in CKD. As the next step, the investigators propose to conduct a
proof-of-concept, randomized controlled trial (RCT) to ascertain the effects of HCQ on the
structural, functional, and biochemical measures of atherosclerosis and CVD. The
investigators will enroll 100 albuminuric, stage 3b CKD subjects in a with 1:1 allocation
(HCQ : placebo) and treat for a duration of 18 months. The investigators' three specific aims
are as follows: Specific Aim (SA) 1 will evaluate the ability of HCQ, compared to placebo, to
slow the progression, or reverse atherosclerosis through serial examination of carotid
atherosclerosis through non-contrast MRI performed at baseline and after 9 and 18 months of
treatment with HCQ or placebo. The investigators will measure the change in total carotid
plaque volume (TPV) as the primary outcome measure, and changes in total plaque surface area,
maximal stenosis, and the type (fibrous, stable, or unstable), and stability of plaques as
secondary outcome measures. SA2 will evaluate the impact of HCQ vs. placebo on inflammation
(SA2a), and vascular stiffness (SA2b) at baseline, and at 6, 9, 12, and 18 months as
secondary outcome measures. The investigators will quantify inflammation through
high-sensitivity C-reactive protein (SA2a) and vascular stiffness through measurements of
aortic pulse wave velocity (SA2b). Specific Aim 3 will examine the effect of HCQ and placebo
on the trends of hard cardiac and renal outcomes and drug safety. The results of this trial
will provide critical preliminary data to justify and plan a definitive, multicenter RCT to
examine the effects of HCQ on hard outcomes of CVD in CKD. Additionally, this study may
provide insights into the importance of select inflammatory and vascular factors in CVD with
wider future implications for those with CKD and perhaps the general population.

Inclusion Criteria:

- Veteran

- Stage 3b CKD with an eGFR of 30 to 45 mL/min/m2

- Albuminuria defined as urine albumin/creatinine ratio (UACR) of 30 mg/g

Exclusion Criteria:

- G6PD deficiency or known hypersensitivity to 4-aminoquinoline

- Conventional contraindications for non-contrast MRI examination including

- Permanent pacemaker

- Automatic Implantable Cardioverter Defibrillator

- Significant fear of closed space

- Claustrophobia that prevents patients from participating

- Inability to lie down

- Severe or morbid obesity defined as BMI > 35

- Abnormal liver functions or diagnosis of cirrhosis

- AST and ALT more than 1.5 times the normal or INR without being anti-coagulated
greater than 1.4

- History of documented non-adherence to therapy

- Inability to attend treatment or follow-up scheduling

- Less than 6 months since initiation of 'Statins'

- Prior history of any dialysis, or history of diagnosed AKI in the prior three months

- History of acute cardiovascular event defined as:

- myocardial infarction

- stroke or new diagnosis of congestive heart failure or heart failure related
admission in prior 3 months

- History of prolonged QTc interval 450

- Known chronic active infections like HIV, Hepatitis B or Hepatitis C positive, chronic
osteomyelitis etc.

- Recent serious infection including requiring hospitalization within 3 months or Recent
minor infection such as skin, soft tissue or respiratory infections within 30 days of
enrollment

- Active or recently treated (< 1 year in remission) malignancy, transplantation, or
systemic inflammatory diseases

- Patients with localized squamous cell carcinoma of the skin are eligible

- Use of systemic corticosteroids or other immunosuppression within last 3 months (acute
course of steroid for a gouty arthritis or chronic obstructive pulmonary disease is
eligible if > 1 month ago)

- Pregnancy, breastfeeding or planning to become pregnant during the course of the study

- Life expectancy less than 12 months or uncontrolled congestive heart failure (CHF)

- defined as more than 2 admissions in prior 6 months)

- Any other condition the PI determines may put the research subject in jeopardy during
the course of the study

- Recent unexplained weight loss or vision changes