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15

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,
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.

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.

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Brush border staining is reduced or absent (Fig. 15.1). This combination


of changes causes proximal tubules to resemble distal tubules (“distaliza-
tion”) and is also known as simplification of tubules so that one nephron
segment cannot easily be differentiated from another. Distal tubules,
including the thick ascending limb of Henle, are dilated and lined by flat-
tened cells. Tamm-Horsfall protein containing casts, sometimes incorpo-
rating granular material, are frequently present but are not specific for
ATN. In addition, pigmented (tan-brown) granular casts are characteristic;
many studies have concluded that heme pigment is responsible for this
appearance. Oxalate crystals are commonly present and are located in the
thick ascending limb, distal tubule, and collecting duct. It should be noted
that the crystals are usually not numerous; marked accumulation of oxalate
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].
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

increased compared to normal. The above-mentioned nonreplacement


phenomenon is identified as a defect in epithelial lining corresponding to
loss of a single cell; the intact basement membrane may be covered by a
thin projection of cytoplasm from an adjacent cell.

Toxic Acute Tubular Necrosis


Pathologic Findings
The basic morphologic findings in toxic ATN, rarely observed today, are
best illustrated in mercuric chloride poisoning. At 3 days following expo-
sure, there is extensive necrosis of cells of the proximal convoluted tubules;
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
15. Acute Tubular Necrosis 157

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
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JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of the
Kidney, 5th ed. Philadelphia: Lippincott-Raven, 1998:863–889.
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Brenner BM, eds. Renal Pathology with Clinical and Functional Correlations,
2nd ed. Philadelphia: Lippincott, 1994:769–809.
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334:1448–1460, 1996.
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agents and abuse of analgesics and narcotics. In: Jennette JC, Olson JL, Schwartz
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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.
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necrosis”: limited data and flawed animal models. Kidney Int 60:1220–1224,
2001.