Clinical trial NCT01989078: Losartan for Sickle Cell Kidney Disease
Official title: Losartan Treatment for Sickle Cell Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Sickle Cell Disease
Keywords: Kidney disorder
Blood disorder
Pediatrics
Lead sponsor: Emory University
Sponsor class: OTHER
First posted: 2013-11-20
Enrollment: 24
Sex: ALL
Minimum age (years): 9
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Participants will all receive the study medication in addition to the standard of care treatment. There is no control group for this pilot study.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in albumin/creatinine ratio (ACR)
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
measure: Change in glomerular filtration rate (GFR)
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
measure: Change in renal plasma flow (RPF)
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
measure: Change in glomerular permeability (GP)
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
Secondary outcomes:
Other outcomes:
measure: Association between changes in albumin/creatinine ratio (ACR) at one month and glomerular filtration rate (GFR) at 12 months
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
measure: Association between changes in albumin/creatinine ratio (ACR) at one month and renal plasma flow (RPF) at 12 months
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
measure: Association between changes in albumin/creatinine ratio (ACR) at one month and glomerular permeability (GP) at 12 months
timeFrame: Baseline, Month 1, End of treatment (12 to 24 months)
Locations:
city: Atlanta
country: United States
facility: Grady Health Systems
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
Study officials:
affiliation: Emory University
name: Marianne Yee, MD
role: PRINCIPAL_INVESTIGATOR
References: