Losartan for Sickle Cell Kidney Disease (SCD-Losartan)

Sickle cell nephropathy (SCN) is a progressive complication of sickle cell disease (SCD) that begins in childhood and results in renal (kidney) failure and early mortality in nearly 12% of adults with hemoglobin SS (HbSS). The potential for prevention and reversal of kidney damage in SCD is not known. Albuminuria is a commonly used biomarker of glomerular damage; however the correlations of albuminuria with specific measurements of glomerular function and pathophysiology have not been determined. The investigators hypothesize that in patients with persistent albuminuria despite treatment of SCD with hydroxyurea, losartan will reverse kidney dysfunction in early stage nephropathy and ameliorate progressive kidney dysfunction in more advanced nephropathy. The primary aim is to study the acute and longer-term effects of losartan (study drug) on specific glomerular functions in children and adults with SCD who have persistent albuminuria. Research glomerular function tests will be done at study entry (prior to taking losartan), 1 month, and 1 to 2 years after starting losartan therapy (participants may take losartan for up to 24 months). In addition, participants are seen each month in clinic and assessed by their regular clinical team. The second aim is to assess the correlation of changes in albuminuria after 1 month of losartan with changes in direct measurements of glomerular function at 12-24 months, thus determining if the magnitude of the initial decrease in albuminuria in response to losartan predicts sustained improvements in renal function.

Sickle cell nephropathy (SCN) is a progressive complication of sickle cell disease (SCD) that begins in childhood and results in renal (kidney) failure and early mortality in nearly 12% of adults with hemoglobin SS (HbSS). The potential for prevention and reversal of kidney damage in SCD is not known. Albuminuria is a commonly used biomarker of glomerular damage; however the correlations of albuminuria with specific measurements of glomerular function and pathophysiology have not been determined. The investigators hypothesize that in patients with persistent albuminuria despite treatment of SCD with hydroxyurea, losartan will reverse kidney dysfunction in early stage nephropathy and ameliorate progressive kidney dysfunction in more advanced nephropathy. Losartan is an FDA-approved drug to treat blood pressure to protect the kidneys in people who have diseases like diabetes and blood pressure. It is not specifically labeled for use in sickle cell disease. Participants will be enrolled from Children's Healthcare of Atlanta (pediatric subjects) or Grady Memorial Hospital (adult subjects) and will be in the study for 1 to 2 years (depending on when the final renal function tests can be preformed). The primary aim of this pilot study is to evaluate the acute and longer-term effects of losartan (study drug) on renal function in children and adults with SCD who have persistent albuminuria. The renal function tests will be done at study entry (prior to taking losartan), 1 month, and 1 to 2 years after starting losartan therapy. In addition, participants are assessed monthly by their regular clinical team. The second aim of this study is to assess the correlation of changes in albuminuria after 1 month of losartan with changes in direct measurements of renal function at 12-24 months, thus determining if the magnitude of the initial decrease in albuminuria in response to losartan predicts sustained improvements in renal function.

Participants will all receive the study medication in addition to the standard of care treatment. There is no control group for this pilot study.

Participants taking losartan, in addition to taking hydroxyurea therapy, as prescribed per standard of care

Adults and Children >50 kg: Those with systolic blood pressure (SBP) ≥ 100 mm Hg at entry will start with 50 mg of oral losartan once daily. At the week 2 visit, losartan will be increased to 100 mg daily. Those with SBP <100 mm Hg at entry will start with 25 mg of oral losartan once daily. Participants will return after 1 week for titration to 50 mg daily, if tolerated (i.e. SBP not lower than pre-losartan measurement by 10 mm Hg or more), and after 2 weeks to monitor blood pressure. Children <50 kg weight: Treatment will start with 25 mg oral Losartan once daily given as a morning dose. At the 2 week visit, Losartan will be increased to 50 mg daily. The dose will be increased to 100 mg once a body weight of 50 kg is achieved.

Association between changes in albumin/creatinine ratio (ACR) at one month and glomerular filtration rate (GFR) at 12 months

For the exploratory aims, the relationship between the degree of short-term change in albumin/creatinine ratio (ACR) and longer-term changes in glomerular filtration rate (GFR) will be examined. The mean change in urinary ACR after 1 month of treatment with losartan will be associated with the long-term mean changes in GFR after 12 months of treatment.

Association between changes in albumin/creatinine ratio (ACR) at one month and renal plasma flow (RPF) at 12 months

For the exploratory aims, the relationship between the degree of short-term change in albumin/creatinine ratio (ACR) and longer-term changes in renal plasma flow (RPF) will be examined. The mean change in urinary ACR after 1 month of treatment with losartan will be associated with the long-term mean changes in RPF after 12 months of treatment.

Association between changes in albumin/creatinine ratio (ACR) at one month and glomerular permeability (GP) at 12 months

For the exploratory aims, the relationship between the degree of short-term change in albumin/creatinine ratio (ACR) and longer-term changes in glomerular permeability (GP) will be examined. The mean change in urinary ACR after 1 month of treatment with losartan will be associated with the long-term mean changes in GP after 12 months of treatment.

Inclusion Criteria: SCD genotype HbSS or HbS/beta-0-thalassemia Age greater than or equal to 9 years old Urinary albumin/creatinine ratio (ACR) greater than or equal to 30 mg/gram creatinine on greater than or equal to 2 occasions separated by one month or more Current treatment with hydroxyurea and a sustained hematologic response for 6 months or more prior to enrollment Exclusion Criteria: End-stage renal failure (estimated GFR <30 ml/min/1.73 m2) Known co-existent medical conditions that could affect the kidneys, such as diabetes mellitus, systemic lupus erythematosus (SLE), or human immunodeficiency virus (HIV) positive Chronic therapy (daily use for ≥8 weeks) with non-steroidal anti-inflammatory drugs (NSAIDs) Females who are pregnant Pre-existing hyperkalemia (serum potassium > 5.5 milliequivalents per liter (mEq/L)) Current chronic transfusion therapy