Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice.

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETA and ETB receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.

Association between Endothelial Dysfunction, Biomarkers of Renal Function, and Disease Severity in Sickle Cell Disease.

Background: Endothelial dysfunction (ED), as ascertained by brachial artery flow-mediated dilation (FMD), is a known feature of sickle cell disease (SCD), which is present both in crisis and in steady state. The assessment of FMD was introduced to examine the vasodilator function. Our objective was to establish the relationship between ED determined by FMD, biomarkers of renal dysfunction, and biomarkers of disease severity in SCD subjects asymptomatic of renal disease. Methods: We enrolled 44 patients with homozygous SCD in steady state and 33 age- and sex-matched controls between 2013 and 2014 in a tropical tertiary hospital. Ultrasonographic FMD of the right brachial artery, renal arterial Doppler, complete blood count, creatinine, fetal hemoglobin, soluble P-selectin, and cystatin C (Cys-C) levels were determined. Using the median FMD value of the control group, the SCD subjects were further classified into two groups for comparison. Results: The median FMD in SCD subjects of 3.44 (IQR, 0.00-7.08) was significantly lower than that of controls, which was 5.35 (IQR, 3.60-6.78; P=0.04). There was negative correlation between FMD and Cys-C levels (r=-0.372; P=0.01) along with renal artery resistivity index (RARI; r=-0.307; P=0.04) in SCD subjects. Additionally, Cys-C level was significantly higher in SCD subjects with FMD<5.35. Conclusions: Brachial artery FMD was significantly lower in SCD subjects compared with a control group. Cys-C and RARI show a negative correlation with FMD, indicating that renal function is related to ED in SCD.

Combined hydroxyurea and ETA receptor blockade reduces renal injury in the humanized sickle cell mouse.

AIM: The objective of this study is to determine if ambrisentan (ETA selective antagonist) and hydroxyurea (HU) treatment has a synergistic effect on renal injury in sickle cell nephropathy when compared to HU treatment alone. The premise of the study is based on recent studies showing that endothelin-1 (ET-1) contributes to the pathophysiology of nephropathy in sickle cell disease (SCD) and that ETA receptor blockade improves renal function and protects against renal injury. Hydroxyurea (HU) is commonly prescribed for the treatment of SCD and has been shown to reduce renal injury in patients with SCD. METHODS: Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2 weeks and renal structure and function were assessed. RESULTS: Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone. CONCLUSION: These findings indicate that HU and ETA receptor blockade produce similar reductions in renal injury in the humanized sickle mouse suggesting that both treatments may converge on the same mechanistic pathway.

The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait.

INTRODUCTION: Renal dysfunction is among the most common complication of sickle cell disease (SCD), from hyposthenuria in children to progression to overt chronic kidney disease (CKD) in young adults. Emerging evidence now suggests that sickle hemoglobin-related nephropathy extends to individuals with sickle cell trait (SCT). Areas covered: This review will highlight the pathophysiology, epidemiology, and management recommendations for sickle hemoglobin-related nephropathy in both SCD and SCT. In addition, it will focus on the major demographic and genetic modifiers of renal disease in sickling hemoglobinopathies. Expert commentary: Studies have elucidated the course of renal disease in SCD; however, the scope and age of onset of renal dysfunction in SCT has yet to be determined. In SCD, several modifiers of renal disease - such as α-thalassemia, hemoglobin F, APOL1 and HMOX1 - have been described and provide an opportunity for a precision medicine approach to risk stratify patients who may benefit from early intervention. Extrapolating from this literature may also provide insight into the modifiers of renal disease in SCT. Further studies are needed to determine the optimal treatment for sickle hemoglobin-related nephropathy.