Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease

It is well recognized that sickle cell disease (SCD) is characterized by a vasculopathy, with
involvement of multiple organs including the brain, lung, spleen, and kidney. This results in
multiple clinical complications, including ischemic stroke, pulmonary hypertension,
autosplenectomy, as well as albuminuria and chronic renal disease. Several recent studies
have confirmed the association of both albuminuria and renal dysfunction with
echocardiographically-defined pulmonary hypertension and other vasculopathic complications in
SCD, suggesting that they may share a similar pathophysiology. Despite the high prevalence of
albuminuria in patients with SCD and the known association of renal failure with increased
mortality, the pathophysiology and treatment of albuminuria in this setting remain poorly
defined.

The treatment options for nephropathy in SCD are limited. Although Angiotensin converting
enzyme (ACE) inhibitors are the "standard of care" in the treatment of patients with
proteinuria, there are to date no controlled, long-term studies confirming their efficacy and
safety in this setting.

In this study, the investigators will evaluate the efficacy and safety of atorvastatin in SCD
patients. At the completion of this trial, the investigators will have an improved
understanding of the contribution of endothelial dysfunction to the pathophysiology of
albuminuria in SCD. If the data support the hypothesis that atorvastatin is safe and
effective in this population, the investigators plan on carrying out adequately powered
studies to more definitively evaluate its safety and efficacy in the treatment and/or
prevention of albuminuria in SCD.

Inclusion Criteria:

1. Sickle cell anemia (HbSS) or Sickle-beta0 thalassemia (HbS-beta0thal) between ages of
18 and 60;

2. albuminuria (micro- or macroalbuminuria, defined as =/> 30mg/g creatinine);

3. serum alanine aminotransferase (ALT) gamma-glutamyl transferase (GGT)
4. platelet count > 150,000 cu/mm;

5. normal baseline coagulation profile (PT, International Normalized Ratio (INR), and
PTT);

6. non-crisis, steady state with no severe pain episodes during the preceding 4 weeks,
and no documented infection in the 2 weeks prior to enrollment;

7. ability to understand the requirements of the study;

8. if a woman of childbearing potential, must use an adequate method of contraception;
and

9. if receiving hydroxyurea, ACE inhibitors or angiotensin blockers (ARB), should be on a
stable dose for at least 3 months.

Exclusion Criteria:

1. hypersensitivity to any component of atorvastatin, or history of adverse reaction to
statins;

2. pregnant or breastfeeding;

3. on statin therapy;

4. history of metastatic cancer;

5. current history of alcohol abuse;

6. history of diabetes mellitus or poorly controlled systemic hypertension;

7. end-stage renal disease;

8. total cholesterol level < 80 mg/dL and LDL cholesterol > 130 mg/dL;

9. on a chronic transfusion program;

10. ingested any investigational drugs within the past 4 weeks;

11. prior history of any myopathy;

12. allergy to nitroglycerin;

13. taking any of the following drugs: phosphodiesterase-5 inhibitors (e.g., sildenafil),
cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors (e.g., cyclosporine, protease
inhibitors), macrolide antibiotics (e.g., clarithromycin, erythromycin), fibric acid
derivatives (e.g. gemfibrozil), niacin, colchicines, antifungal agents (azole
derivatives), amiodarone, danazol, daptomycin, diltiazem, verapamil, eltrombopag,
everolimus, fosphenytoin, or lanthanum.

Patients will also be encouraged to avoid grape fruit juice and red yeast rice for the
duration of the study.

Atorvastatin is contraindicated during pregnancy and breast-feeding.