Intrarenal oxygen homeostasis in acute and chronic kidney disease

Sammanfattning: Renal hypoxia has been recognized as a common feature of acute and chronic kidney injury arising from varying etiologies. It has also been proposed to provide a driving mechanism for the transition from acute to chronic kidney disease (CKD). Acute kidney injury (AKI) is common in the critically ill patient, but no targeted therapies exist to treat and prevent kidney injury and the progression to chronic kidney injury. This thesis aims to describe the alterations in renal hemodynamics and oxygenation in the setting of acute and chronic kidney injury and elucidate if restoration of the oxygen supply/demand relationship can prevent kidney dysfunction in these settings. Disruption of the filtration barrier and back-leak of sodium into the proximal tubule, resulting in a futile transport cycle, has been proposed to provide an explanation for the disruption of the oxygen supply/demand relationship in AKI. By inhibiting proximal sodium transport using the drug acetazolamide in an ischemia reperfusion (IR) model of AKI in rats, sodium transport efficiency and glomerular filtration rate (GFR) were further impaired. This demonstrates that proximal tubular function is critical in the recovery from AKI. Hypoxia has been previously demonstrated to cause nephropathy. In a rat model of IR associated AKI we were able to demonstrate that further impairing renal oxygenation by subjecting rats to systemic hypoxia via alterations of inspired oxygen content. Conversely, by increasing the fraction of inspired oxygen and increasing renal oxygen tension kidney dysfunction could be prevented. This provides support for the theory that increasing renal oxygenation can ameliorate AKI. Diabetes is a leading cause of CKD and associated with renal hypoxia, especially in the real medulla. The diuretic furosemide inhibits sodium transport in the outer medulla and has previously been demonstrated to increase tissue oxygen tension in this region. However, the hemodynamic actions of furosemide on the kidney are still unclear. By administering furosemide to diabetic rats with intact and removed renal capsule we could show that the reduction in renal blood flow through increased vascular resistance was due to increased hydrostatic pressure and removing the renal capsule completely ameliorated the reduction in renal blood flow. Major haemorrhage is a clinically relevant cause of AKI. In a rat model of haemorrhage associated AKI, loss of kidney function was prevented by treatment with OR-1896, an active metabolite of levosimendan. OR-1896 restored renal oxygenation by increasing renal blood flow through reduced renal vascular resistance and completely ameliorated the reduction in GFR observed in untreated haemorrhaged animals. In summary, the results from the studies included in this thesis show that preventing renal hypoxia and restoring renal oxygenation has the potential to prevent loss of function in kidney disease.