Molecular Predictors of Early Vaso-Occlusive Kidney Injury in Pediatric SCD

Abstract

Sickle cell disease (SCD) is a genetic blood disorder that slowly damages the kidneys over a lifetime, starting in early childhood. The damage is caused by SCD red blood cells shifting from a disc into a sickle shape. The sickle-shaped red blood cells clog the vessels of tissue and block blood and oxygen delivery downstream from occlusion. The kidney is sensitive to loss of oxygen because of its high energy demand. Left undetected, this damage progresses to kidney failure, which cuts a person's chance of survival in half. The clinical test used to detect kidney damage, urine microalbumin (UMA), only becomes abnormal after kidney cells have been permanently injured and lost. By that point, treatment slows further loss, but cannot undo damage. This study hypothesizes that urinary extracellular vesicles (uEVs), protein rich cell communication packages, contain PINK1, a marker for mitochondrial oxidative stress, to serve as a novel SCD early biomarker for kidney damage that identifies cellular stress preceding irreversible injury. From an IRB-approved cohort of urine samples from SCD pediatric patients at Children’s National Hospital, we isolated uEVs to evaluate PINK1 presence and other damage markers via Western blotting and Mass Spectrometry. PINK1 and podocalyxin were present on CD63+ uEVs in a majority of patients regardless of low or high UMA levels. Our findings demonstrate that PINK1+ uEVs represent a novel kidney damage marker where doctors could flag rising kidney risk long before permanent damage occurs, allowing for early intervention and prioritization of higher-risk children for advanced therapies.