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.
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.
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.
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.
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.