Severe vacuolization of tubular cells in injured tubular epithelium (hematoxylin and eosin, original magnification X 400). The vacuoles reflect cell injury and derangement of homeostatic mechanisms that maintain the normal intracellular milieu. In this case, the vacuoles developed on exposure to intravenous immunoglobulin in a sucrose vehicle; the morphology is reminiscent of the severe changes produced by osmotic agents. While generally a nonspecific marker of cell injury, a distinctive pattern of "isometric" vacuolization, in which there are numerous intracellular vacuoles of uniform size (not shown here) is very typical of cyclosporine/FK506 effect .
FIGURE 9-19 (see Color Plate)
Necrotic tubular cells and cell debris in tubular lumina. One tubule shows extensive cell loss, with tubular epithelium lined only by a very flattened layer of cytoplasm. The dilated lumen contains numerous necrotic tubular cells with pyknotic nuclei. Several tubules contain cell debris and one contains red blood cells (hematoxylin and eosin, original magnification X 250). Such changes are more often seen with toxic than with ischemic injury , unless the latter is very severe.
This micrograph shows sites of cell exfoliation, attenuation of remaining cells, and reactive and regenerative changes (hema-toxylin and eosin, original magnification X 400). Exfoliation occurs with disruption of cell-cell and cell-substrate adhesion, and may involve viable as well as non-viable cells . Reactive and regenerative changes may include basophilia of cell cytoplasm, increased nuclear:cytoplasmic ratio, heterogeneity of nuclear size and appearance, hyperchromatic nuclei and mitotic figures.
FIGURE 9-21 (see Cole
Outer medulla shows in situ cell necrosis and loss in medullary thick ascending limb (hematoxylin and eosin, original magnification X 250). Tubules contain cells and cell debris. Changes reflect ischemic injury. Impaction of cells and cast material may lead to tubular obstruction, especially in narrow regions of the nephron. Adhesion molecules on the surface of exfoliated cells may contribute to aggregation of cells within the tubule and adhesion of detached cells to in situ tubular cells .
FIGURE 9-22 (see Color Plate)
Fine-needle aspirate showing acute tubular cell injury and necrosis. A, The aspirate shows scattered tubular epithelial cells with swelling and focal degenerative changes, and a minimal associated inflammatory infiltrate. There is no significant background cell debris (May-Grunwald Giemsa, original magnification X 40). B, One tubular cell is degenerated with reduction in cell size, condensed gray-blue
cytoplasm, and a pyknotic nucleus. Another cell has more advanced necrosis with additional cytoplasmic disruption and a very small pyknotic nucleus. Compare the adjacent swollen damaged tubular cell which has not yet undergone necrosis (May-Grunwald Giemsa, original magnification X 160).
Urine sediment from a patient with acute tubular injury showing tubular cells and cell casts (Papanicolaou stain, original magnifica tion X 250). Many of these cells are morphologically intact, even by electron microscopy. Studies have shown that a significant percentage of the cells shed into the urine may exclude vital dyes, and may even grow when placed in culture, indicating that they remain viable. Such cells clearly detached from tubular basement membrane as a manifestation of sub-lethal injury .
(original magnification X 250). These casts may obstruct the nephron, especially with dehydration and low tubular fluid flow rates. Rhabdomyolysis with formation of intrarenal myoglobin casts may also occur with severe trauma, crush injury, or extreme exercise.
Apoptosis of tubular cells following tubular cell injury. Note the shrunken cells with condensed nuclei and cytoplasm in the central tubule. The patient had presumed ischemic injury (hematoxylin and eosin, original magnification X 400). The role of apoptosis in injury to the renal tubule remains to be defined. The process may be difficult to quantitate, since apoptotic cells may rapidly disintegrate. In experimental models, the degree of apoptosis versus coaggulative necrosis occurring following injury is related to the severity and duration of injury, with milder injury showing more apoptosis .
Apoptosis-schematic of histologic changes in tubular epithelium. The process begins with condensation of the cytoplasm and of the nucleus, a process which involves endonucleases, which digest the DNA into ladder-like fragments characteristic of this process. The cell disintegrates into discrete membrane-bound fragments, so-called "apoptotic bodies." These fragments may be rapidly extruded into the tubular lumen or phagocytosed by neighboring epithelial cells or inflammatory cells. (Modified from Arends, et al. ; with permission.)
Tubular cell injury
Tubular cell injury
Upregulation of adhesion molecules
Tubular cell swelling
Compression of peritubular capillaries
Loss of surface area and cell polarity
Loss of normal transport function
Vacuolization of smooth muscle cells
Increased epithelial permeability
Loss of tubular integrity
Loss of distal flow
Aggregation of erythrocytes,fibrin and/or leukocytes in peritubular capillaries
Increased renal vascular resistance
Changes of repair and regeneration
In situ necrosis
Impaction in the tubules
"Backleak" of filtrate
Reduced renal blood flow
Decrease in glomerular filtration rate
Increased intratubular pressure i=>
A schematic showing the relationship between morphologic and functional changes with injury to the renal tubule due to ischemia or nephrotoxins. Morphologic changes are shown in italics.
Histology reflects the altered hemodynamics, epithelial derangements, and obstruction which contribute to loss of renal function. (Modified from Racusen ; with permission.)
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