Relationship Between The Clinical And Cellular Phases Of Ischemic Acute Renal Failure

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Clinical Phases

Cellular Phases

Prerenal azotemia

Vascular and cellular adaptation

Initiation

ATP depletion, cell injury

Maintenance

Repair, migration, apoptosis, proliferation

4

4

Recovery

Cellular differentiation

induced by ischemia can be mimicked by F-actin disassembly mediated by cytochalasin D [11]. Although these correlations are highly suggestive of a central role for actin alterations in the pathophysiology of ischemia-induced surface membrane damage they fall short in providing mechanistic data that directly relate actin cytoskeletal changes to cell injury.

Proximal tubule cell injury during ischemia is also known to be principally responsible for the reduction in GFR. Figure 13-5 illustrates the three known pathophysiologic mechanisms that relate proximal tubule cell injury to a reduction in GFR. Particularly important is the role of the cytoskeleton in mediating these three mechanisms of reduced GFR. First, loss of apical membrane into the lumen and detachment of PTC result in substrate for cast formation. Both events have been related to actin cytoskeletal and integrin polarity alterations [12-15]. Cell detachment and the loss of integrin polarity are felt to play a central role in tubular obstruction (Fig. 13-6). Actin cytoskeletal-mediated tight junction opening during ischemia occurs and results in back-leak of glomerular filtrate into the blood. This results in ineffective glomerular filtration (Fig. 13-7). Finally, abnormal proximal sodium ion reabsorption results in large distal tubule sodium delivery and a reduction in GFR via tubu-loglomerular feedback mechanisms [2,16,17].

In summary, ischemia-induced alterations in proximal tubule cell surface membrane structure and function are in large part responsible for cell and organ dysfunction. Actin cytoskeletal dysregulation during ischemia has been shown to be responsible for much of the surface membrane structural damage.

FIGURE 13-1

Relationship between the clinical and cellular phases of ischemic acute renal failure. Prerenal azotemia results from reduced renal blood flow and is associated with reduced organ function (decreased glomerular filtration rate), but cellular integrity is maintained through vascular and cellular adaptive responses. The initiation phase occurs when renal blood flow decreases to a level that results in severe cellular ATP depletion that, in turn, leads to acute cell injury. Severe cellular ATP depletion causes a constellation of cellular alterations culminating in proximal tubule cell injury, cell death, and organ dysfunction [2]. During the clinical phase known as maintenance, cells undergo repair, migration, apoptosis, and proliferation in an attempt to re-establish and maintain cell and tubule integrity [3]. This cellular repair and reorganization phase results in slowly improving cell and organ function. During the recovery phase, cell differentiation continues, cells mature, and normal cell and organ function return [18].

FIGURE 13-2

PT

PT

F

Ischemic acute renal failure in the rat kidney. Light A, B, transmission electron, C, D, and immunofluorescence E, F, microscopy of control renal cortical sections, A, C, E, and after moderate ischemia induced by 25 minutes of renal artery occlusion, B, D, F. Note the extensive loss of apical membrane structure, B, D, in proximal (PT) but not distal tubule cells. This has been shown to correlate with extensive alterations in F-actin as shown by FITC-phalloidin labeling, E, F. G, Drawing of a proximal tubule cell under physiologic conditions. Note the orderly arrangement of the actin cytoskeleton and its extensive interaction with the surface membrane at the zonula occludens (ZO, tight junction) zonula adherens (ZA, occludens junction), interactions with ankyrin to mediate Na+, K+-ATPase [2] stabilization and cell adhesion molecule attachment [5,8]. The actin cyto-skeleton also mediates attachment to the extracellular matrix (ECM) via integrins [12,15]. Microtubules (MT) are involved in the polarized delivery of endocytic and exocytic vesicles to the surface membrane. Finally, F-actin filaments bundle together via actin-bundling proteins [19] to mediate amplification of the apical surface membrane via microvilli (MV). The actin bundle attaches to the surface membrane by the actin-binding proteins myosin I and ezrin [19,20].

Proximal tubule cell

Proximal tubule cell

Renal [ithelial Cell

Fate of an injured proximal tubule cell. The fate of a proximal tubule cell after an ischemic episode depends on the extent and duration of the ischemia. Cell death can occur immediately via necrosis or in a more programmed fashion (apoptosis) hours to days after the injury. Fortunately, most cells recover either in a direct fashion or via an intermediate undifferentiated cellular pathway. Again, the severity of the injury determines the route taken by a particular cell. Adjacent cells are often injured to varying degrees, especially during mild to moderate ischemia. It is believed that the rate of organ functional recovery relates directly to the severity of cell injury during the initiation phase. ECM—extracellular membrane; Na+—sodium ion; K+—potassium ion; P1—phosphate.

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