Research Project

Biomarkers of acute kidney injury in children with sickle cell anemia and vaso-occlusive crisis

Globally about 300,000 children are born with sickle cell anemia (SCA) annually with 80% of the affected children born in Africa. In Uganda, an estimated 15,000 children are born with SCA each year and approximately 70-80% of these children with SCA will die before reaching five years of age. Vaso-occlusive pain crises (VOC) are a common complication in children with SCA and a risk factor for acute kidney injury (AKI); with the incidence of AKI ranging from 2.3% in uncomplicated painful crisis to 13.0% in children with severe acute chest syndrome. AKI is defined by reduced urine output or increases in serum creatinine. However, creatinine is affected by factors such as age and nutritional status. Further, glomerular hyperfiltration in SCA reduces creatinine levels and limits detection of AKI. These limitations highlight the need for biomarkers to improve early detection of AKI in SCA.

Biomarkers can provide insight into etiology, and pathophysiology of AKI. For example, biomarkers can differentiate between reduced glomerular filtration (Creatinine, Cystatin C) and tubulointerstitial injury (neutrophil gelatinase-associated lipocalin(NGAL), and kidney injury molecule 1 (KIM-1). There is urgent need to explore how AKI biomarkers perform in children with SCA, and to evaluate pathophysiology of AKI associated with VOC. During vaso-occlusive SCA episodes, nitric oxide bioavailability can be quenched by increases in cell-free hemoglobin contributing to microvascular dysfunction. Impaired nitric oxide bioavailability is a risk factor for AKI following cardiopulmonary bypass, and increased cell-free hemoglobin during cardiac surgery is a risk factor for development of AKI. There is evidence that iron scavengers, e.g. haptoglobin, may have a renal protective role during acute hemolytic episodes. We hypothesize that increased plasma levels of cell-free hemoglobin and reduced haptoglobin may contribute to AKI in children with SCA during VOCs. Further, we hypothesize novel AKI biomarkers may improve our ability to detect AKI in a population of children where creatinine-based diagnosis of AKI is problematic.

Research Significance

Renal disease contributes to significant morbidity and mortality in children with SCA, and new tools to identify AKI are urgently needed. There are limited data on alternative biomarkers of AKI in children with SCA, and the results from this study will determine whether these biomarkers are promising candidates to improve AKI diagnosis. Further, data on cell-free hemoglobin and haptoglobin will be useful in understanding the pathophysiology of AKI in children with SCA and may lead to potential therapeutics

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Publications

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Mentors

• • Chandy C. John, MD, MS
  • Andrea L. Conroy, PhD

Research Project

Transcranial blood flow velocity, stroke risk, and chronic kidney disease in children with sickle cell anemia following hospitalization with vaso-occlusion

Globally, an estimated 300,000 children are born with sickle cell anemia (SCA) annually, with 80% of the affected children residing in Africa. SCA contributes to 5% of under 5 child deaths (3). The two main pathophysiological mechanisms for complications in SCA are vaso-occlusion with ischaemia-reperfusion injury and haemolytic anaemia. Both vaso-occlusion and haemolysis can lead to endothelial activation and dysfunction, increased cerebral blood flow velocities and a corresponding increase in the risk of stroke. In Uganda, the prevalence of stroke in children with SCA is 5.7% and about 18.1% of children have elevated Transcranial Doppler (TCD) flow velocities. Children with TCD velocities of >200 cm/s have a 10% risk for overt stroke per year in the first 3–4 years immediately following the abnormal TCD (7). This highlights the need for prevention of both primary and secondary stroke in children with SCA. Vaso-occlusion crises (VOC) are a risk factor for acute kidney injury (AKI) and chronic kidney disease (CKD). Estimates of the prevalence of AKI in children with VOC range from 8-17% in high-income countries, and we identified AKI in 27% of children with SCA and VOC in the proposed cohort(9, 10). Risk factors for stroke in SCA include vaso-occlusion and vascular dysfunction. In addition, AKI and CKD have been found to increase the risk of stroke although data on the association between stroke in SCA with AKI and CKD are limited.

Preliminary results from our studies show that 36.2% of the children hospitalised with SCA and VOC develop AKI. From the results, children in VOC have higher levels of Angiopoietin-2 (p<0.001), a marker of endothelial activation/dysfunction, compared to children in steady state. AKI is a well-established risk factor for CKD, it is thus important to evaluate CKD in the children following AKI to identify modifiable risk factors to facilitate early recognition of CKD and prevent disease progression in these children. Identification of markers of endothelial dysfunction associated with elevated transcranial Doppler velocity may also facilitate early identification of children at increased risk of stroke to enable targeted therapies to prevent both primary stroke and stroke recurrence (e.g. early initiation of hydroxyurea, transfusion protocols).

We hypothesize that children with high angiopoietin-2 levels at hospitalization will have higher transcranial Doppler (TCD) flow velocities. Further we hypothesize that children with history of stroke have persistent elevated angiopoitin-2 levels and cerebral vasculopathies that increase the risk for stroke recurrence. We also hypothesize the incidence of CKD will be higher in children with a history of documented AKI during hospitalization compared to children without AKI and children who were in steady state.

Research Significance

SCA is associated with high morbidity and mortality in children. Common complications occur due to vaso-occlusion, hemolysis and ischaemia-reperfusion injury. Serious clinical complications associated with a substantial increased risk of mortality or long-term neurodisability in children with SCA are kidney disease and stroke.

Currently there is a critical need to evaluate different risk factors and tools to facilitate prevention, early recognition and management of CKD and stroke in children with SCA. Our prospective study will generate data on the role of AKI as a risk factor for CKD in SCA, and identify modifiable factors to prevent CKD and stroke. Our study will further evaluate biomarkers of vascular dysfunction (angiopoietin-2) in predicting abnormal transcranial blood flow velocities. The transcranial blood flow velocities are important predictors for stroke in children with SCA.

Publications

View on PubMed

Mentors

• • Chandy John, MD, MS
  • Andrea Conroy, PhD
  • Robert Opoka, MD, MPH, PhD