Proximal Tubular Injury Attenuates Outer Medullary Hypoxic Damage: Studies in Perfused Rat Kidneys

Abstract

The straight segment (S3) of the proximal tubule is predominantly damaged during renal ischemia-reflow, whereas medullary thick ascending limbs (mTALs) are principally affected in other models of hypoxic acute tubular necrosis (ATN). Since the latter injury pattern largely depends on the extent of reabsorptive activity during hypoxic stress, we hypothesized that proximal tubular damage might attenuate downstream mTAL injury by means of diminished distal solute delivery for reabsorption. In isolated rat kidneys perfused for 90 min with oxygenated Krebs-Henseleit solution, mTAL necrosis developed in 75 ± 3% of tubules in the mid-inner stripe of the outer medulla. By contrast, S3 segments in the outer stripe were minimally affected, with tubular fragmentation involving some 5 ± 2% of tubules. In kidneys subjected in vivo to proximal tubular injury and subsequently used for isolated perfusion studies, the injury pattern was inverted: following 20 and 30 min ischemia and reflow for 24 h, S3 fragmentation rose to 18 ± 16% and 72 ± 13%, while mTAL damage was reduced to 33 ± 10 and 24 ± 8%, respectively. In kidneys subjected in vivo to D-serine S3 necrosis rose to 100%, while mTAL damage fell to 1 ± 1% (p < 0.001). Substantial S3 tubular collapse (involving approximately 30% of tubules) and inner stripe interstitial hemorrhage were also noted, exclusively in kidneys subjected to ischemia-reflow. Proximal tubular necrosis alone or in combination with collapse inversely correlated with mTAL necrosis (R = –0.51 and –0.72, respectively, p < 0.003). This cogent inverse association might imply that disruption of the proximal nephron attenuates downstream mTAL necrosis by a reduction of distal tubular reabsorptive workload.