Hemopexin deficiency promotes acute kidney injury in sickle cell disease.

Acute kidney injury (AKI) is a major clinical concern in sickle cell disease (SCD). Clinical evidence suggests that red cell alarmins may cause AKI in SCD, however, the sterile inflammatory process involved has hitherto not been defined. We discovered that hemopexin deficiency in SCD is associated with a compensatory increase in α-1-microglobulin (A1M), resulting in an up to 10-fold higher A1M-to-hemopexin ratio in SCD compared with healthy controls. The A1M-to-hemopexin ratio is associated with markers of hemolysis and AKI in both humans and mice with SCD. Studies in mice showed that excess heme is directed to the kidneys in SCD in a process involving A1M causing AKI, whereas excess heme in controls is transported to the liver as expected. Using genetic and bone marrow chimeric tools, we confirmed that hemopexin deficiency promotes AKI in sickle mice under hemolytic stress. However, AKI was blocked when hemopexin deficiency in sickle mice was corrected with infusions of purified hemopexin prior to the induction of hemolytic stress. This study identifies acquired hemopexin deficiency as a risk factor of AKI in SCD and hemopexin replacement as a potential therapy.

Hemolysis scavenger proteins and renal function marker in children with sickle cell disease at steady state: A cross-sectional study.

Background and Aims: Hemolysis is a fundamental feature of sickle cell disease (SCD) contributing to the vaso-occlusive crisis of patients. The objectives of the study were to assess the link between hemolysis proteins and hematological parameters, and to validate cystatin C (CYS C) as a potent renal marker in diagnoising SCD. Method: Here, a cross-sectional study carried out at the pediatric SCD clinic of the Komfo Anokye Teaching Hospital comprised 90 SCD children (HbSC, HbSF, and HbSS). ANOVA, t-test, and Spearman's rank correlation analysis were done. Elevated proteins levels were compared to standard values; alpha-1 microglobulin (A1M) (1.8-65 µg/L), CYS C (0.1-4.5 µmol/L), and haemopexin (HPX) (500-1500 µg/mL). Results: The mean (standard deviation) age of participants was 9.830 (±0.3217) years, and 46% of them were males. From simple descriptive analysis, we observed that all but one patient had their HPX level below the reference range (<500 µg/mL). Here, A1M levels were shown to be within the appropriate reference range for all the patients except few patients. CYS C levels were also all within the required reference values. A Spearman's rank correlation test between full blood count and HPX generally suggested a weak but positive correlation; RBC (coef. = 0.2448; p = 0.0248), HGB (coef. = 0.2310; p = 0.030), hematocrit (coef. = 0.2509; p = 0.020), and platelet (coef. = 0.1545; p = 0.160). Mean corpuscular volume (coef. = -0.5645; p = 0.610) had a stronger but negative correlation with HPX. This study depicts a positive and stronger association between CYS C and HPX levels (coef. = 0.9996; p < 0.0001), validating the use of CYS C as a useful marker of renal function in persons with SCDs. Conclusion: In the present study, we show that A1M levels were normal for most of the patients, hence CYS C levels are not alarming in this study. Further, there exists a correlation between hemolysis scavenger proteins and hematological parameters.