Miki Aihara

Tolvaptan Delays the Onset of End-Stage Renal Disease in a Polycystic Kidney Disease Model by Suppressing Increases in Kidney Volume and Renal Injury

Tolvaptan, a selective vasopressin V2 receptor antagonist, slows the increase in total kidney volume and the decline in kidney function in patients with the results of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Outcome (TEMPO) 3:4 trial. However, it was unclear which dose of tolvaptan was optimal or whether tolvaptan was able to delay progression to end-stage renal disease (ESRD). Here we examined the relationship with aquaresis and the inhibitory effect on cyst development in short-term treatment and mortality as an index of ESRD in long-term treatment with tolvaptan using DBA/2FG-pcy mice, an animal model of nephronophthisis. With short-term treatment from 5 to 15 weeks of age, tolvaptan (0.01–0.3% via diet) dose-dependently enhanced aquaresis, prevented increases in kidney weight and cyst volume, and was associated with significant reductions in kidney cAMP levels and extracellular signal–regulated kinase activity. Maximal effects of tolvaptan on aquaresis and the prevention of development of polycystic kidney disease (PKD) were obtained at 0.1%. Interestingly, tolvaptan also dose-dependently reduced urinary neutrophil gelatinase–associated lipocalin levels in correlation with the kidney volume. With long-term treatment from 5 to 29 weeks of age, tolvaptan significantly attenuated the increase in kidney volume by up to 50% and reduced urinary albumin excretion. Furthermore, tolvaptan significantly reduced the mortality rate to 20%, compared with 60% in the control group. These data indicate that tolvaptan may delay the onset of ESRD in PKD by suppressing the increases in kidney volume and renal injury, providing a promising treatment for PKD.

New rat model induced by anti‐glomerular basement membrane antibody shows severe glomerular adhesion in early stage and quickly progresses to end‐stage renal failure

The aim of the present study was to introduce a new anti‐glomerular basement membrane nephritis model in which plasma creatinine levels dramatically increased only 4 weeks after a single administration of rabbit antirat glomerular basement membrane antibody in Sprague–Dawley rats. According to renal morphology, glomerular lesions characterized by mesangial expansion and adhesion of the glomerular tuft to Bowmans capsule were observed in the early stage at day 7 after disease induction; adhesion was detected in approximately 90% of glomeruli 14 days after antibody injection. After 21 days the rats exhibited pronounced glomerulosclerosis/hyalinosis and severe tubulointerstitial lesions characterized by interstitial fibrosis. Urinary podocytes excreted in nephritis rats were studied and it was found that urinary podocyte loss might be closely related to progression of renal injury. Because this new model simply and reproducibly demonstrates development of end‐stage renal disease, it will be beneficial for elucidating mechanisms by which chronic renal injury irreversibly progresses, as well as for developing therapeutic agents for chronic renal failure.