P0546EARLY, BUT NOT LATE, CONTRALATERAL NEPHRECTOMY OVERCOMES PROGRESSION TO CKD AFTER UNILATERAL ISCHEMIC INJURY

Abstract

Abstract Background and Aims It is increasingly clear that acute kidney injury (AKI) can result in the development of chronic kidney disease (CKD) in humans. Murine renal unilateral ischemia-reperfusion injury (UIRI) models this AKI-to-CKD progression in the injured kidney in the presence of its healthy counterpart (Le Clef et al, Plos One 2016). In mice, we and others demonstrated that contralateral nephrectomy (Nx), when performed shortly after UIRI (i.e. 3 days), is able to significantly attenuate the progression to CKD. Although non-translatable, Nx can be considered an experimental therapeutic intervention that incites inherent physiological recovery mechanisms in the kidney. Here, we investigate in rats to what extent contralateral Nx is able to attenuate or revert CKD progression when performed well beyond the acute injury phase, i.e. with increased Nx delay time after UIRI. Method AKI was induced in male Wister rats by left UIRI for 60 min at 35°C core body temperature after which contralateral Nx was performed 3, 10 or 20 days later, or no Nx was performed. Control animals underwent sham-UIRI and sham-Nx 3 days later. Renal function was assessed by serum creatinine and transcutaneous GFR measurement 24h and 72h after Nx and weekly thereafter. Rats were euthanized 11 weeks after Nx. Kidneys were weighed and histology was evaluated by PAS stain for overall morphology and Sirius Red stain for interstitial fibrosis. Results When no Nx was performed, renal function of the injured kidney decreased 44% compared to control animals at week 11. Nx at day 3 induced full functional recovery from week 5 after Nx on, whereas Nx at day 10 and 20 both lead to a persistent 20% loss of renal function at week 9 after Nx (p<0.05). Nx at day 3 was able to attenuate renal atrophy and fibrotic tubulointerstitial expansion. Nx at day 10 and 20 were less efficient and led to 1.6 (p>0.05) and 2.6 (p<0.05) fold increase of tubulointerstitial area compared to controls. Nx at day 3 and 10 induced a significant increase in renal mass-to-body weight ratio compared to control from 2.9±0.1 mg/g (control) to 4.6±0.4 mg/g (day 3) and 4.8±0.3 mg/g (day 10) respectively. When Nx was performed at day 20 or no Nx was performed, renal mass-to-body weight ratio did not differ significantly from control animals, however, parallel with renal function, histopathology was considerably worse. Conclusion Early contralateral Nx after UIRI rescues renal function and morphology, whereas delayed Nx does not allow full recovery of the injured kidney. There was no additional functional loss when Nx was performed on day 20 versus day 10, though, histopathology aggravated. These results imply that a damaged kidney loses its intrinsic (compensatory) recovery potential over time and that an early intervention is crucial for averting CKD outcome after AKI.