Preventing Sickle Cell Kidney Disease
| Status: | Recruiting |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), Renal Impairment / Chronic Kidney Disease, Anemia, Endocrine, Nephrology |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology, Hematology, Nephrology / Urology |
| Healthy: | No |
| Age Range: | 5 - 25 |
| Updated: | 5/3/2018 |
| Start Date: | April 2015 |
| End Date: | April 2020 |
| Contact: | Jeffrey Lebensburger, DO, MSPH |
| Email: | jlebensburger@peds.uab.edu |
Chronobiology and Chronopharmacology to Prevent Sickle Cell Kidney Disease
Untreated hypertension and renal injury are risk factors for increased morbidity and
mortality in sickle cell disease, yet early markers of progressive disease have not been
identified and therapies to prevent the development of adverse cardiovascular outcomes have
not been defined. Circadian blood pressure, as defined by 24 hour blood pressure monitoring,
is more accurate than clinic blood pressure in defining secondary hypertension and abnormal
nocturnal blood pressured dipping and nocturnal hypertension have been linked to progressive
renal disease in other diseases.
Methodology/Aims: A randomized feasibility trial of losartan will be conducted among
adolescent HbSS and SB0 thalassemia patients (11-19 years) with abnormal nocturnal blood
pressure dipping. During this six month feasibility trial, two dosing strategies of losartan
(titrated to keep clinic BP <95th percentile vs. <75th percentile) will be analyzed for
safety and effect on restoring normal circadian blood pressure.
A prospective cohort study among HbSS and SB0 thalassemia patients (6-19 years) will also be
conducted to evaluate the incidence of hypertension and role of monitoring potential
biomarkers of kidney injury and hypertension. Cohort participants will undergo annual
evaluations of hypertension(24 hour blood pressure monitoring for participants ≥ 11yrs,
clinic BP in all participants) and markers of kidney injury/hypertension.
Expected Results: At the completion of the feasibility trial, vital background information
will be obtained to design a definitive multicenter trial of hypertension in sickle cell
disease. At the completion of the cohort study, the incidence of pediatric hypertension will
be identified and the role for monitoring blood and urine biomarkers will be better
understood.
As therapy for patients with renal failure is dismal, it is imperative that SCD patients at
risk are identified early and that therapeutic trials are conducted that prevent progression.
mortality in sickle cell disease, yet early markers of progressive disease have not been
identified and therapies to prevent the development of adverse cardiovascular outcomes have
not been defined. Circadian blood pressure, as defined by 24 hour blood pressure monitoring,
is more accurate than clinic blood pressure in defining secondary hypertension and abnormal
nocturnal blood pressured dipping and nocturnal hypertension have been linked to progressive
renal disease in other diseases.
Methodology/Aims: A randomized feasibility trial of losartan will be conducted among
adolescent HbSS and SB0 thalassemia patients (11-19 years) with abnormal nocturnal blood
pressure dipping. During this six month feasibility trial, two dosing strategies of losartan
(titrated to keep clinic BP <95th percentile vs. <75th percentile) will be analyzed for
safety and effect on restoring normal circadian blood pressure.
A prospective cohort study among HbSS and SB0 thalassemia patients (6-19 years) will also be
conducted to evaluate the incidence of hypertension and role of monitoring potential
biomarkers of kidney injury and hypertension. Cohort participants will undergo annual
evaluations of hypertension(24 hour blood pressure monitoring for participants ≥ 11yrs,
clinic BP in all participants) and markers of kidney injury/hypertension.
Expected Results: At the completion of the feasibility trial, vital background information
will be obtained to design a definitive multicenter trial of hypertension in sickle cell
disease. At the completion of the cohort study, the incidence of pediatric hypertension will
be identified and the role for monitoring blood and urine biomarkers will be better
understood.
As therapy for patients with renal failure is dismal, it is imperative that SCD patients at
risk are identified early and that therapeutic trials are conducted that prevent progression.
Feasibility Trial of Losartan to Correct Abnormal Circadian Blood Pressure. Cohort
participants (below) identified with in-clinic hypertension and abnormal nocturnal dipping on
24 hour ABPM will be asked to participate in a feasibility trial of losartan. Participants
will be offered a consultation with Pediatric Nephrology prior to study enrollment.
Participants that consent /assent will undergo repeat 24 hour ABPM to confirm abnormal
circadian blood pressure prior to receiving losartan. At baseline, participants will undergo
evaluation for biomarkers of kidney injury and hypertension. Participants will start on
losartan at 25mg of losartan and randomized to titrate clinic BP <95th or 75th percentile
based on NHLBI BP tables. Participants will be followed monthly x 6 months and receive
standard of care labs. ABPM and blood/urine biomarkers of kidney injury, buccal swab for
circadian genes, and hypertension will be repeated at 3 and 6 months. Participants will
undergo monthly evaluation for adherence through pill counting and questionnaires. Safety of
dosing will be monitored by internal review and external review (DSMB).
Prospective Pediatric Cohort to Evaluate Hypertension and Kidney Injury. Patients with HbSS
or SB0 thalassemia, ages ≥ 6 years and have signed informed consent will undergo clinic BP,
annual ABPM and biomarkers to determine the incidence of HTN and potential role for
biomarkers as monitors for the development of hypertension or kidney injury/disease. Urine
will be collected annually and evaluated for current known biomarkers of kidney disease and
stored for future analysis of relevant biomarkers. Uric acid will be processed from collected
blood annually.
participants (below) identified with in-clinic hypertension and abnormal nocturnal dipping on
24 hour ABPM will be asked to participate in a feasibility trial of losartan. Participants
will be offered a consultation with Pediatric Nephrology prior to study enrollment.
Participants that consent /assent will undergo repeat 24 hour ABPM to confirm abnormal
circadian blood pressure prior to receiving losartan. At baseline, participants will undergo
evaluation for biomarkers of kidney injury and hypertension. Participants will start on
losartan at 25mg of losartan and randomized to titrate clinic BP <95th or 75th percentile
based on NHLBI BP tables. Participants will be followed monthly x 6 months and receive
standard of care labs. ABPM and blood/urine biomarkers of kidney injury, buccal swab for
circadian genes, and hypertension will be repeated at 3 and 6 months. Participants will
undergo monthly evaluation for adherence through pill counting and questionnaires. Safety of
dosing will be monitored by internal review and external review (DSMB).
Prospective Pediatric Cohort to Evaluate Hypertension and Kidney Injury. Patients with HbSS
or SB0 thalassemia, ages ≥ 6 years and have signed informed consent will undergo clinic BP,
annual ABPM and biomarkers to determine the incidence of HTN and potential role for
biomarkers as monitors for the development of hypertension or kidney injury/disease. Urine
will be collected annually and evaluated for current known biomarkers of kidney disease and
stored for future analysis of relevant biomarkers. Uric acid will be processed from collected
blood annually.
Inclusion Criteria:
- Pts with HbSS or SB0 thalassemia
- Hypertension from clinic BP readings (defined by NHLBI BP tables)
- Abnormal nocturnal dipping (systolic or diastolic) as defined by <10% dip or abnormal
nocturnal BP load (>25% of sleep BP readings >95th percentile as defined by AHA ABPM
guidelines)
- Signed Informed Consent
Exclusion Criteria:
- Patient already on BP lowering medication
- Hyperkalemia
- Pregnancy
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