AbstractA major challenge in paediatric urology is determining which children with antenatally detected hydronephrosis and pelvi-ureteric junction obstruction (PUJO) need a pyeloplasty to relieve obstruction, and which do not. In part this is because the pathophysiology underpinning why children develop ‘safe’ or ‘damaging’ PUJO is not well understood. This research investigates whether aquaporins, as mediators of water-reabsorption from the renal tract, explain the mechanism behind these differing clinical outcomes. Furthermore, this research explores whether urinary aquaporin levels are good biomarkers to direct surgical management. A dual approach was employed involving interrogating an in vivo neonatal rat partial unilateral ureteric obstruction model, and implementing a complementary childhood PUJO study.
The rodent model demonstrated that kidneys with moderate hydronephrosis had normal renal architecture and raised intra-renal pelvis pressure, whereas severely hydronephrotic kidneys displayed obstructive nephropathy. While renal aquaporin isoform expression was maintained in moderate hydronephrosis, several, but not all, renal aquaporin isoforms were downregulated in severe hydronephrosis. Following characterisation of the aquaporin isoforms expressed by whole normal rodent and human renal pelvis, aquaporins 1 and 3 were localised to the vascular endothelium and the urothelium in both species respectively. The rat model established that aquaporins 1 and 3 were downregulated in obstructed renal pelvis. Downregulation was inversely related to hydronephrosis severity and, contrary to renal expression, was exhibited in both moderate and severe hydronephrosis. These findings may indicate that reduced urothelial aquaporin expression diminishes the urinary tract’s ability to mitigate pressure rises, ultimately leading to severe hydronephrosis and renal damage. Rodent urinary aquaporin 1 excretion was unchanged between obstructed and sham rats, questioning the ability of this test as a non-invasive biomarker in the management of PUJO. A childhood PUJO study with full ethical approval is currently underway, having recruited 18 patients thus far. This study will investigate the same parameters as the rodent model, confirming whether results translate to the human scenario.
In conclusion, improving our understanding of the mechanism of renal injury through studies such as this will enable earlier diagnosis and better management of this important condition through the development of novel biomarkers and new therapies.
|Date of Award||25 Sep 2018|
|Supervisor||Mark Woodward (Supervisor), Gavin I Welsh (Supervisor) & Richard J M Coward (Supervisor)|