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Acute Tubular Necrosis
Arthur H. Cohen
Introduction/Clinical Setting
Acute tubular necrosis (ATN) is a pathologic process that manifests clini- cally as acute renal failure. Although the term implies cellular death (necro- sis), it should be appreciated that frank necrosis is not a constant finding;
evidence of sublethal cellular injury is common. Furthermore, there is often a lack of clinical-pathologic correlation, with severe acute renal failure sometimes associated with trivial morphologic findings (1,2).
Broadly speaking, ATN may be the result of one of two mechanisms:
ischemia or toxin induced. The structural changes in each are reasonably distinctive, and pathogenic mechanisms are also considered different. Tra- ditionally, ischemic ATN follows hypotension or hypovolemia or both (3,4). There may be many causes of this circulatory state; these include extensive trauma with rhabdomyolysis and myoglobinuria, incompatible blood transfusions, pancreatitis, septic shock in a variety of settings, ex tensive hemolysis as in malaria (blackwater fever), and shock following administration of barbiturates, morphine, and sedatives. Toxic ATN is a dose-dependent injury with extensive tubular cell necrosis normally limited to a specific portion of the nephron and usually involving almost all neph- rons. This is obviously in sharp contrast to ischemic tubular necrosis in which the changes are considerably more subtle and patchy. Many thera- peutic and diagnostic agents, industrial chemicals, heavy metals, and plants may be responsible for this lesion. The classic agent is mercuric chloride;
the changes are quite prominent and impressive.
Ischemic Acute Tubular Necrosis
Light Microscopy
The pathologic changes in ischemic ATN are often subtle but are easily discernible with well-fixed tissue. Both proximal and distal tubules are affected. The proximal tubules are dilated and the lining cells flattened.
crystals is most commonly observed in ethylene glycol poisoning. Overt or extensive necrosis of tubular cells is neither common nor regularly observed.
Instead, loss of individual cells, manifested by incomplete epithelial lining of tubules, is present. This change requires well-fixed tissue and a practiced eye to demonstrate. It is often referred to as the “nonreplacement” phe- nomenon. There are often desquamated cells or cellular debris in the lumina (Fig. 15.2).
Ischemic tubular necrosis is frequently associated with disruption of tubular walls (including cell loss and basement membrane disruption) with spillage of contents into the adjacent interstitium. It also may be associated with localized inflammation, sometimes in the form of granulomata.
However, inflammation is not constantly present. The interstitium is dif- fusely edematous and infiltrated by a small number of lymphocytes and monocytes. The outer medullary vasa recta often contain large numbers of nucleated circulating cells including lymphocytes and monocytes, both
Figure 15.1. Tubular cells are flattened and many proximal cells lack brush border staining; lumina are relatively dilated [periodic acid-schiff (PAS) stain].
mature and immature forms, and granulocyte precursors. These cells are in greater concentrations in the vasa recta than in other renal vascular beds. The glomerular capillary tufts are usually unaltered. However, there are several reasonably common abnormalities: there may be some degree of capillary collapse and dilatation of Bowman’s space. Additionally, tubular metaplasia (“tubularization”) of parietal epithelial cells may be evident in recovery. Solez and colleagues (5) assessed these morphologic changes as to their frequency in active renal failure, recovery phase, and normal controls. In their landmark study, they noted that the follow- ing were more common in biopsies from patients with renal failure: vasa recta leukocyte accumulation, tubular cell necrosis, regeneration (mitotic fi gures), dilatation of Bowman’s spaces, loss of brush border staining, tubular casts, and interstitial edema and inflammation. However, only cel- lular necrosis and loss of brush border staining distinguished biopsies from patients with acute renal failure from those of patients in recovery from renal failure.
Electron Microscopy
Ultrastructural observations have indicated a reduction in brush border formation for most proximal tubules; this ranges from slight to almost complete loss of microvilli. There is also simplification of basolateral cell surfaces. Overt necrosis is also noted. Disintegration of cells, characterized by extreme lucency of cytoplasm together with disruption of plasma mem- brane, nuclear membrane, or organelles, may affect single cells, with only minor abnormalities to neighboring cells. Apoptosis, characterized by condensation and increased density of cytoplasm and closely aggregated organelles, dilated vacuoles, cisternae and mitochondria, and folding of nuclear membrane with clumped chromatin, affects single cells, and is Figure 15.2. One tubule contains cells and debris in lumen and is incompletely lined by epithelium (PAS stain).
the necrotic cells are partially desquamated and the lumina are filled with cellular debris. At 7 to 9 days, most of the luminal contents are no longer present in the proximal tubules but are in more distal parts of the nephron.
The proximal tubules are dilated and lined by flattened and basophilic cells with numerous mitotic figures. At 2 weeks, the proximal tubules are lined by cuboidal epithelium; tubular calcifications are not infrequent. In general, tubular basement membranes are intact, and interstitial edema with a vari- able mononuclear leukocytic infiltrate is evident. This sequence of events is reasonably constant for other agents, although the degree of overt necro- sis rarely achieves that of mercuric chloride. There are some morphologic features that are reasonably characteristic of certain toxins; they may be observed by light or electron microscopy depending on the poison. For example, gentamicin may result in ultrastructurally defined myeloid bodies (lysosomes with phospholipid), lead is characterized by intranuclear inclu- sions (consisting of lead and lead-binding protein) as is bismuth, and gold accumulates in lysosomes in tubular cells as dense filamentous structures (aureosomes).
Etiology/Pathogenesis
The pathogenesis of acute renal failure in ATN has been studied exten- sively and, at least in humans, no clear, coherent, and universally accept- able explanation exists at present. Increased tubular permeability to glomerular filtrate (backleak) through an injured tubular wall (cells) probably plays a role in more severe ischemic and toxic ATN, but likely is unimportant in mild to moderate acute renal failure. Tubule obstruction, because of luminal casts, debris, cells, and/or crystals, may have some role in altering renal function (6). Reduction in renal cortical and glomerular blood flow is documented and is responsible for the gross autopsy findings of cortical pallor. Its mechanism may be related to vasoconstrictive humoral factors. Medullary blood flow reduction has also been documented, espe- cially at the corticomedullary junction, affecting juxtamedullary nephrons.
This regional hypoxia could explain the apparent susceptibility of the
straight portion of the proximal tubule (S3) to ischemia; the medullary thick ascending limb may also be affected similarly. Tubuloglomerular feedback activation is implicated in some phases of acute renal failure, although its extent and the importance of vasoactive substances are not clarified. Rosen, Brezis, and coworkers (7,8), in a series of studies on experimentally induced acute renal failure, documented the regular occur- rence of necrosis of cells of the thick ascending limb of Henle (TALH).
The lesions affected only a few cells of this portion of the nephron and therefore are often difficult to detect in many biopsies unless sufficient medullary tissue is available. Because the cells of TALH are involved with feedback control of glomerular filtration and with production of Tamm- Horsfall protein as casts that may obstruct the nephron, injury to these cells may well be directly responsible for acute renal failure. These inves- tigators have maintained that necrosis of thick ascending limb cells is the primary and, indeed, pathophysiologically important lesion in ATN with acute renal failure. The other changes of cells in different segments of the nephron are viewed, perhaps correctly so, as secondary lesions. The work of Brezis, Rosen, and colleagues points out the importance of reduced renal blood flow to the inner strip of the medulla and the thick ascending limb of Henle in animals and suggests its applicability to human acute renal failure, including the lesion known as “lower nephron nephrosis.”
References
1. Kashgarian M. Acute tubular necrosis and ischemic renal injury. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of the Kidney, 5th ed. Philadelphia: Lippincott-Raven, 1998:863–889.
2. Olsen S, Solez K. Acute tubular necrosis and toxic renal injury. In: Tisher CC, Brenner BM, eds. Renal Pathology with Clinical and Functional Correlations, 2nd ed. Philadelphia: Lippincott, 1994:769–809.
3. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 334:1448–1460, 1996.
4. Nadasdy T, Racusen LC. Renal injury caused by therapeutic and diagnostic agents and abuse of analgesics and narcotics. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of the Kidney, 5th ed. Philadelphia:
Lippincott-Raven, 1998:811–862.
5. Solez K, Morel-Maroger L, Sraer JD. The morphology of “acute tubular necro- sis” in man: analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine 58:362–376, 1979.
6. Molitoris BA, Marrs J. The role of cell adhesion molecules in ischemic renal failure. Am J Med 106:583–592, 1999.
7. Brezis M, Rosen S. Hypoxia of the renal medulla—its implications for disease.
N Engl J Med 332:647–655, 1995.
8. Rosen S, Heyman SN. Difficulties in understanding human “acute tubular necrosis”: limited data and flawed animal models. Kidney Int 60:1220–1224, 2001.
