Role of leukocytes and leukocyte adhesion molecules in renal ischemic-reperfusion injury

Hamid Rabb, M.D.

Division of Nephrology and Hypertension, J. A. Haley VA Hospital & University of South Florida, Tampa, FL 33612

Received 12/07/95; Accepted 12/25/95; On-line 1/1/95

3. Leukocytes and renal reperfusion injury

There is a considerable body of evidence that leukocytes are involved in the process of renal IRI. In postischemic human and rat kidneys, an increase in the number of leukocytes was noted in the ascending vasa recta in the outer and inner medulla (6,7). Willinger et al quantified polymorphonuclear cells (PMNs) in the post-ischemic rat kidney and found a greater than 9-fold increase in the total number of PMN 2 hours after a 45 minute clamping of the renal artery (8). At this time point, increased neutrophils were seen in the renal cortex, outer medulla and also the inner medulla using a modified Leder stain. In a seperate study, an increase in the number of rat peritubular neutrophils was observed 24 hours after the renal artery was clamped for 60 min (9). In mice, a greater than 10-fold increase in the number of peritubular PMNs was observed 24 hours after the renal pedicle was clamped for 30 minutes (10). Using a myeloperoxidase assay as a measure for the neutrophil influx, Kelly et al found a significant increase in the renal tissue myeloperoxidase activity as early as 4 hours after renal ischemia (11). This activity peaked at 24 hours after the ischemic episode (11). Thus, one may need special stains or biochemical assays to adequately quantify the increased PMNs in the postischemic kidney.

The increase in PMNs in the postischemic organ may be involved in the healing process or may potentially contribute to the tissue damage. Consistent with the latter possibility, neutrophil depletion reduced the postischemic injury to heart, liver, and gut (12-15). Thus PMNs may have a pathophysiologic role in renal IRI. Depletion of rat neutrophils by a rabbit antiserum to neutrophils afforded marked protection in ischemia-induced renal dysfunction and tubular necrosis 24 hours after the renal pedicle was clamped for 45 minutes (5). In addition, the neutropenia was associated with less increase in the amount of renal vein leukotriene B4 and thromboxane B2 after ischemia. Hellberg and Kallskog demonstrated that the post-ischemic tubular leakage in rat kidneys can in part be limited by depletion of neutrophils (16). In a series of studies by Linus et al using isolated perfused rat kidneys there has been further demonstration that neutrophils have an adverse effect on renal IRI. PMNs can lead to a more severe compromise in GFR and tubular sodium reabsorption postischemia (17). The contribution of neutrophils was shown to be dependent on the duration of renal ischemia and the state of PMN activation (18). More recently, these investigators have found that IRI leads to neutrophil retention, thereby further compromising kidney function (19). It should be noted that these studies by Linus et al evaluated the effects of human neutrophils on the isolated rat kidneys.

Despite this strong evidence supporting the adverse role of leukocytes in renal IRI, this issue is not settled yet. Morphologic examination of the post-ischemic human kidney as well as reports from animal models of experimental ischemic acute renal failure have only infrequently reported an increase in the number of neutrophils (19,20). In addition, it is well recognized in clinical practice that neutropenic patients can develop acute renal failure. Forty minutes of renal artery occlusion produced similar worsening of renal function in rats depleted of neutrophils and in control rats (4). Nevertheless induction of neutropenia with nitrogen mustard, was associated with a higher inulin clearance after IRI (4). In another study, anti-neutrophil serum did not confer functional or morphologic protection after either 29 minutes or 37 minutes of renal artery occlusion (21). These findings cast doubt whether neutrophils play a major role in the pathogenesis of renal injury after ischemia.