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.

Augmented NRF2 activation protects adult sickle mice from lethal acute chest syndrome.

Acute chest syndrome (ACS) mortality in sickle cell disease (SCD) rises sharply in young adult patients and mechanism-based prophylaxis is lacking. In SCD, haem oxygenase-1 (HO-1) declines with age and ACS is associated with low HO-1. To test if enhanced HO-1 can reduce ACS mortality, young SCD mice were treated with D3T (3H-1,2-dithiole-3-thione), an activator of nuclear-factor erythroid 2 like 2, which controls HO-1 expression, for 3 months. Following haem-induced ACS, all vehicle-treated mice succumbed to severe lung injury, while D3T-treated mice had significantly improved survival. Blocking HO-1 activity abrogated the D3T effect. Thus HO-1 may be targeted to reduce ACS severity in adult patients.

SARS-CoV-2 control on a large urban college campus without mass testing.

OBJECTIVE: A small percentage of universities and colleges conducted mass SARS-CoV-2 testing. However, universal testing is resource-intensive, strains national testing capacity, and false negative tests can encourage unsafe behaviors. PARTICIPANTS: A large urban university campus. METHODS: Virus control centered on three pillars: mitigation, containment, and communication, with testing of symptomatic and a random subset of asymptomatic students. RESULTS: Random surveillance testing demonstrated a prevalence among asymptomatic students of 0.4% throughout the term. There were two surges in cases that were contained by enhanced mitigation and communication combined with targeted testing. Cumulative cases totaled 445 for the term, most resulting from unsafe undergraduate student behavior and among students living off-campus. A case rate of 232/10,000 undergraduates equaled or surpassed several peer institutions that conducted mass testing. CONCLUSIONS: An emphasis on behavioral mitigation and communication can control virus transmission on a large urban campus combined with a limited and targeted testing strategy.