Prolonged renal hypoperfusion after ischemia-reperfusion injury in conscious, chronically instrumented rats

Introduction
Ischemia-reperfusion (IR) injury is a major cause of acute kidney injury (AKI) and the subsequent development of chronic kidney disease (CKD). Although plasma creatinine (PCr) often returns toward baseline within days after IR, previous studies indicate that significant renal dysfunction can persist well beyond the recovery of PCr. Most prior studies used cross-sectional or anesthetized preparations, limiting insight into dynamic hemodynamic adaptations during recovery. The goal of this pilot study was to generate the first longitudinal measurements of systemic and renal hemodynamics in conscious, chronically instrumented rats before and for 14 days after bilateral renal IR injury.
Methods
Male Sprague–Dawley rats (n=9; 8-9-weeks-old) were implanted with a blood pressure radiotelemeter (HD-S10, DSI), a transit-time ultrasonic flow probe (1PRB, Transonic) positioned on the left renal artery, and an FITC-inulin pump. After a 1-week recovery, baseline measurements of mean arterial pressure (MAP) and renal blood flow (RBF) were obtained (500 Hz) for 2-4 hours across 3 consecutive days in conscious rats. Renal vascular resistance (RVR) was calculated as MAP/RBF. Baseline measurements of glomerular filtration rate (GFR) via FITC-inulin clearance, hematocrit (Hct), and PCr were also obtained. Rats then underwent 35 min bilateral IR (n=5) or sham IR (n=4) under anesthesia. For 2 weeks post-surgery, MAP and RBF were measured daily and GFR, Hct, and PCr every 3 days starting on day 2 of recovery in conscious rats. Hemodynamic data were expressed as the percentage of average baseline data. Group comparisons were made using a 2-way repeated measures ANOVA with Tukey post hoc test. Data are mean ± SEM and P<0.05 was considered significant.
Results
PCr increased 3.7-fold 2 days after IR but returned near sham levels thereafter (Fig. 1A). Hct fell from a baseline level of 46±1% to 35±2% by day 14 following IR (Fig. 1B) and was significantly lower in IR vs. sham rats on days 8 and 14 of recovery (P<0.05). MAP was higher in IR vs. sham rats on day 1 of recovery (P<0.05) but not thereafter (Fig 2A). RBF fell to 70±6% (Fig 2B) and RVR rose to 140±11% (Fig 2C) of baseline on day 1 following IR. By day 14 of recovery, RBF rose to 89±15% and RVR declined to 113±15% of baseline. Both RBF and RVR were significantly different in IR vs. sham IR rats throughout the majority of the 14-day recovery period. GFR fell to 40±14% of baseline 2 days following IR (Fig 2D), partially recovered to 67±14% from days 5-11, and reached 85±25% of baseline on day 14 of recovery.
Conclusion
Bilateral IR injury is associated with a sustained increase in RVR and decrease in RBF for nearly two weeks, revealing a previously underappreciated period of renal vulnerability that may inform strategies to mitigate the development of CKD after AKI. The decline in Hct after IR may, in part, represent an adaptive response to the greater reduction in GFR (oxygen demand) relative to RBF (oxygen delivery).