Acute Tubular
Necrosis
Acute tubular necrosis (ATN) is one of the most common causes of acute
kidney injury (AKI), accounting for over 90% of intrarenal AKI. It is
characterized by a sudden decline in glomerular filtration rate (GFR) as a
result of direct tubular damage.
Pathophysiology
ATN is typically classified as
ischemic, septic, or toxic. Ischemic ATN occurs when there is a decrease in
renal perfusion that is severe and sustained enough to injure the tubular
epithelium. Such damage typically occurs in the setting of circulatory collapse
or massive hemorrhage.
Septic ATN involves direct
cytokine-induced damage to the renal tubules. Ischemic damage may also occur if
there is extensive systemic vasodilation.
Toxic ATN has been associated with
numerous toxins that damage the tubular epithelium through a variety of
mechanisms, which include production of free radicals, constriction of renal
microvasculature, and tubular obstruction (i.e., via formation of crystals
and/or casts). Major exogenous toxins include iodinated radiocontrast agents,
antibiotics (e.g., aminoglycosides), antivirals (e.g., cidofovir), antifungals
(e.g., amphotericin B), calcineurin inhibitors (e.g., cyclosporine and
tacrolimus), ethylene glycol, and toluene. Major endogenous toxins include
myoglobin, hemoglobin, oxalate, uric acid (i.e., in tumor lysis syndrome), and
myeloma light chains. In fact, the first cases of ATN, described in World War
II, were likely the result of excessive myoglobin released into the circulation
during crush injuries.
Although these agents injure the
tubular epithelium, the structural damage is often inadequate to explain the
dramatic decline in the overall glomerular filtration rate. In addition,
creatinine undergoes a far greater degree of filtration than secretion, but
serum concentrations are nonetheless markedly elevated. Thus three mechanisms
have been proposed to relate the physiologic findings to the histologic changes:
(1) tubuloglomerular feedback, (2) tubular obstruction, and (3) back leak.
The “tubuloglomerular feedback”
hypothesis argues that tubular damage results in decreased proximal
reabsorption of electrolytes, including sodium and chloride, which leads to
elevated concentrations of these solutes at the macula densa. Through the
mechanisms described in Plate 3-18, the macula densa triggers intense
vasoconstriction of the afferent arteriole, which reduces the filtration rate.
The “tubular obstruction”
hypothesis argues that sloughing of epithelial cells into the tubular lumen
pro- duces obstructive casts, which increase the hydrostatic pressure in
Bowman’s space and thereby decrease filtration.
The “back leak” hypothesis argues
that the damaged tubular epithelium and endothelium permits paracellular
reabsorption of filtered molecules, including creatinine, into the interstitium.
The prevailing opinion among
nephrologists is that the tubuloglomerular feedback hypothesis accounts for a
majority of the observed decline in filtration, although it is possible that all
three mechanisms contribute to some degree.
Presentation And Diagnosis
The clinical course is generally
divided into three phases: initiation, maintenance, and recovery. The
initiation phase corresponds to the period during which the
patient is exposed to the toxic insult and experiences an immediate decline in
GFR and urine output. The maintenance phase occurs after the renal injury is
established but before recovery occurs, and it is characterized by a stable but
low GFR. This phase has been reported to last between several hours and several
months, with a median length of 1 to 3 weeks. The recovery phase, if it occurs
at all, corresponds to regeneration of renal tubules and normalization of renal
function. This period is often associated with polyuria because of the impaired
concentrating ability of immature tubular cells. Eventually, reabsorption
capacity returns to normal, and polyuria ceases.
The first manifestation of disease
is typically a sharp increase in serum creatinine concentration on routine
laboratory examination. Recent exposure to a known nephrotoxin strongly
suggests the diagnosis of ATN, whereas hemodynamic compromise may cause either
prerenal state or ATN. Thus distinguishing between prerenal state and ATN is
often an important part of the differential diagnosis. As described in the
overview of AKI, the distinction between prerenal and intrarenal disease can
often be established based on the response to an intravenous fluid bolus, as
well as laboratory markers such as FENa and the BUN : creatinine ratio.
Microscopic analysis of urine may also facilitate the diagnosis. In the prerenal
state, urine either appears normal or contains hyaline casts, which form when
Tamm-Horsfall protein, secreted in the distal tubule, becomes concentrated and
aggregates. In contrast, ATN often features “muddy-brown” granular casts or
epithelial casts.
These laboratory indicators,
however, can sometimes be unreliable. Contrast-induced ATN, for example,
initially causes a high BUN : creatinine ratio and low FENa, which could be
misinterpreted as evidence of prerenal state. Instead, these values reflect the
intense renal vasoconstriction associated with contrast agents. For as long as
the tubular epithelium remains intact, such vasoconstriction causes increased
sodium reabsorption. As the ischemia persists, however, tubular cells become
injured and their ability to reabsorb sodium is lost, leading to laboratory
values more consistent with ATN.
The diagnosis of ATN is typically
established based on clinical and laboratory criteria. Renal biopsy is
generally not performed unless intrarenal AKI secondary to another cause, such
as rapidly progressive glomerulonephritis (see Plate 4-25), is suspected. Nonetheless,
ATN is associated with a spectrum of common pathologic findings, irrespective of
the cause, which can include shortening or loss of the proximal tubular brush
border, epithelial cell flattening and simplification, nucleolar prominence,
hypereosinophilia, and sloughing of tubular epithelial cells. Despite the name,
actual frank necrosis is only an occasional finding. The degree of injury is
often dependent on the severity of the expo- sure, rather than the identity of
the specific agent. These pathologic changes can occur in both proximal and
distal nephron segments.
Treatment
The treatment of ATN consists of
identifying and eliminating the underlying cause, as well as implementing
supportive measures and initiating renal replacement therapy when appropriate.
Supportive strategies include strict attention to fluids and electrolytes, as
well as limiting the administration of substances that undergo primarily renal
clearance. If these strategies are followed, dialysis can often be avoided in
cases of prolonged ATN. For example, furosemide can be used to increase
diuresis, which can treat volume overload and hyperkalemia. Likewise,
bicarbonate can be used to correct acidemia. Occasionally, severe cases of ATN
cannot be managed supportively, and dialysis must be initiated. The major
indications include acidosis, fluid overload, and hyperkalemia that are
refractory to medical management, as well as signs of uremia such as
pericarditis or encephalopathy. There are no proven therapies that “reverse”
ATN.
Prognosis
Because there are no effective
therapies that reverse the clinical or pathologic changes associated with ATN,
mortality remains high and, despite decades of intense research, has not
changed over the past 50 years. Mortality rates have been reported to be up to
40% in hospitalized patients with ATN and up to 80% in critically ill patients
with ATN.
Many patients who survive ATN
experience an eventual normalization of renal function. Some, however, sustain
moderate to severe tubulointerstitial scarring that leads to chronic kidney
disease (CKD), with about 5% to 10% ultimately requiring long-term
dialysis. Risk factors for nonresolving renal function after ATN include
persistent septic physiology, recurrent nephrotoxin administration, and
preexisting chronic kidney disease.
Prevention
The most effective prevention
strategy is to maintain euvolemia in hospitalized patients and to avoid
excessive exposure to nephrotoxic agents, especially in patients with
preexisting renal disease.
In situations where ATN could be
expected, such as during administration of intravenous radiocontrast, maintaining
euvolemia and limiting the dye load might be expected to reduce the risk of
this complication. Other measures including the use of antioxidants, natriuretic
peptides, and high dose furosemide/mannitol have not been shown to
consistently decrease the risk of ATN.
Multiple risk scores have been
devised to predict which patients are at highest risk for developing ATN and
which will have the poorest outcome. The risk factors overlap, and they include
variables that predict preexisting histologic damage and at predispose to renal
ischemia, including male sex, advanced age, comorbid illness, malignancy, vol
me depletion/oliguria, sepsis, and multiorgan failure.
