Roles of glomerular endothelial hyaluronan in the development of proteinuria.

Vascular endothelial cells are covered with glycocalyx comprising heparan sulfate, hyaluronan, chondroitin sulfate, and associated proteins. Glomerular endothelial glycocalyx is involved in protecting against induction of proteinuria and structural damage, but the specific components in glycocalyx that represent therapeutic targets remain unclear. Anti-vascular endothelial growth factor (VEGF) therapy is associated with an increased risk of glomerular endothelial injury. This study investigated whether hyaluronan could provide a therapeutic target to protect against proteinuria. We conducted ex vivo and in vivo experiments to explore the effects of degrading glomerular hyaluronan by administering hyaluronidase and of supplementation with hyaluronan. We investigated hyaluronan expression using biotin-labeled hyaluronan-binding protein (HABP) in human kidney specimens or serum hyaluronan in endothelial injuries under inhibition of VEGF signaling. We directly demonstrated hyaluronan in glomerular endothelial layers using HABP staining. Ex vivo and in vivo experiments showed the development of proteinuria after digestion of hyaluronan in glomerular capillaries. Supplementation with hyaluronan after hyaluronidase treatment suppressed proteinuria. Mice in the in vivo study developed albuminuria after intraperitoneal injection of hyaluronidase with decreased glomerular hyaluronan and increased serum hyaluronan. In human kidneys with endothelial cell dysfunction and proteinuria due to inhibition of VEGF, glomerular expression of hyaluronan was reduced even in normal-appearing glomeruli. Serum hyaluronan levels were elevated in patients with pre-eclampsia with VEGF signaling inhibition. Our data suggest that hyaluronan itself plays crucial roles in preventing proteinuria and preserving the integrity of endothelial cells. Hyaluronan could provide a therapeutic target for preventing glomerular endothelial glycocalyx damage, including VEGF signaling inhibition.

Acute kidney injury caused by decompression illness successfully treated with hyperbaric oxygen therapy and temporary dialysis.

A 52-year-old Japanese male professional diver was referred to our hospital for decompression illness (DCI). After 1 h of diving operation at 20 m below sea level, he complained of dyspnea, chest pain, and abdominal pain. He dove again, intending to ease the symptoms, but the symptoms were never relieved. He dove for a total of 4 h. No neurological abnormalities were observed. Computed tomography images revealed portal venous gas and mesenteric venous gas, in addition to bubbles in the femoral veins, pelvis, lumbar canal, intracranial sinuses, and joints. Hyperbaric oxygen therapy (HBOT) was immediately administered. His symptoms improved after the first course of HBOT, however, the patient had anuria for almost 36 h after admission and exhibited acute kidney injury (AKI). Serum creatinine and creatine kinase (CK) levels were increased to maximal values of 6.16 mg/dL and 18,963 U/L, respectively. Blood flow signals were not detected on kidney Doppler ultrasound. We considered that AKI was caused by blood flow impairment and capillary leak syndrome due to DCI in addition to rhabdomyolysis secondary to arterial gas embolism in the skeletal muscles. Temporary dialysis was required to correct the acidemia and electrolyte disturbance. Diuretic phase was initiated, and the patient was put off dialysis on day 3. Serum creatinine and CK levels returned to normal on day 11. He was successfully treated without any complications. Although AKI is a rare manifestation, we should consider AKI risk in patients with severe DCI.