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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,
extensive 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.
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154 A.H. Cohen
Figure 15.1. Tubular cells are flattened and many proximal cells lack brush border
staining; lumina are relatively dilated [periodic acid-schiff (PAS) stain].
15. Acute Tubular Necrosis 155
Figure 15.2. One tubule contains cells and debris in lumen and is incompletely
lined by epithelium (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
figures), 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
156 A.H. Cohen
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
15. Acute Tubular Necrosis 157
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.