Acute Tubular Necrosis
- Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Acute tubular necrosis (ATN) is the most common cause of acute kidney injury (AKI) in the renal category (that is, AKI in which the pathology lies within the kidney itself). See the ATN images below.
ATN follows a well-defined three-part sequence of initiation, maintenance, and recovery (see Pathophysiology). The initiation phase is characterized by an acute decrease in glomerular filtration rate (GFR) to very low levels, with a sudden increase in serum creatinine and blood urea nitrogen (BUN) concentrations.
The maintenance phase is characterized by a sustained severe reduction in GFR that persists for a variable length of time, most commonly 1-2 weeks. Because the filtration rate is so low during the maintenance phase, the creatinine and BUN levels continue to rise.
The recovery phase, in which tubular function is restored, is characterized by an increase in urine volume (if oliguria was present during the maintenance phase) and by a gradual decrease in BUN and serum creatinine to their preinjury levels.
The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Nephrotoxic mechanisms of ATN include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction (see Pathophysiology and Etiology). Most of the pathophysiologic features of ischemic ATN are shared by the nephrotoxic forms.
The history, physical examination, and laboratory findings, especially the renal ultrasonogram and the urinalysis, are particularly helpful in identifying the cause of ATN (see Presentation and Workup).
Acute tubular necrosis (ATN) follows a well-defined three-part sequence of initiation, maintenance, and recovery (see below). The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Most of the pathophysiologic features of ischemic ATN, as described below, are shared by the nephrotoxic forms.
Ischemic ATN is often described as a continuum of prerenal azotemia. Indeed, the causes of the two conditions are the same. Ischemic ATN results when hypoperfusion overwhelms the kidney’s autoregulatory defenses. Under these conditions, hypoperfusion initiates cell injury that often, but not always, leads to cell death.
Injury of tubular cells is most prominent in the straight portion of the proximal tubules and in the thick ascending limb of the loop of Henle, especially as it dips into the relatively hypoxic medulla. The reduction in the glomerular filtration rate (GFR) that occurs from ischemic injury is a result not only of reduced filtration due to hypoperfusion but also of casts and debris obstructing the tubule lumen, causing back-leak of filtrate through the damaged epithelium (ie, ineffective filtration).
The earliest changes in the proximal tubular cells are apical blebs and loss of the brush border membrane followed by a loss of polarity and integrity of the tight junctions. This loss of epithelial cell barrier can result in the above-mentioned back-leak of filtrate.
Another change is relocation of Na+/K+ -ATPase pumps and integrins to the apical membrane. Cell death occurs by both necrosis and apoptosis. Sloughing of live and dead cells occurs, leading to cast formation and obstruction of the tubular lumen (see the images below).
In addition, ischemia leads to decreased production of vasodilators (ie, nitric oxide, prostacyclin [prostaglandin I2, or PGI2]) by the tubular epithelial cells, leading to further vasoconstriction and hypoperfusion.
On a cellular level, ischemia causes depletion of adenosine triphosphate (ATP), an increase in cytosolic calcium, free radical formation, metabolism of membrane phospholipids, and abnormalities in cell volume regulation. The decrease or depletion of ATP leads to many problems with cellular function, not the least of which is active membrane transport.
With ineffective membrane transport, cell volume and electrolyte regulation are disrupted, leading to cell swelling and intracellular accumulation of sodium and calcium. Typically, phospholipid metabolism is altered, and membrane lipids undergo peroxidation. In addition, free radical formation is increased, producing toxic effects. Damage inflicted by free radicals apparently is most severe during reperfusion.
The maintenance phase of ATN is characterized by a stabilization of GFR at a very low level, and it typically lasts 1-2 weeks. Complications (eg, uremic and others; see Complications) typically develop during this phase.
The mechanisms of injury described above may contribute to continued nephron dysfunction, but tubuloglomerular feedback also plays a role. Tubuloglomerular feedback in this setting leads to constriction of afferent arterioles by the macula densa cells, which detect an increased salt load in the distal tubules.
The recovery phase of ATN is characterized by regeneration of tubular epithelial cells. During recovery, an abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not completely understood, but it may in part be due to the delayed recovery of tubular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) may also add to the problem.
Pathophysiologic mechanisms of selected types of nephrotoxicity
Nephrotoxicity can result from various drugs, such as aminoglycosides, amphotericin, calcineurin inhibitors, foscarnet, ifosfamide, cisplatin, and crystal-forming drugs. Additionally, conditions such as multiple myeloma and rhabdomyolysis can cause nephrotoxicity. Acute kidney injury (AKI) can result, and the pathophysiologic mechanism for renal injury differs among the agents and conditions.
AKI is observed in about 5% of all hospital admissions and in up to 30% of patients admitted to the intensive care unit (ICU). ATN is the most common cause of AKI in the renal category, and the second most common cause of all categories of AKI in hospitalized patients, with only prerenal azotemia occurring more frequently.
ATN is generally caused by an acute event, either ischemic or toxic.
Causes of ischemic acute tubular necrosis
Ischemic ATN may be considered part of the spectrum of prerenal azotemia, and indeed, ischemic ATN and prerenal azotemia have the same causes and risk factors. Specifically, these include the following:
Hypovolemic states: hemorrhage, volume depletion from gastrointestinal (GI) or renal losses, burns, fluid sequestration
Low cardiac output states: heart failure and other diseases of myocardium, valvulopathy, arrhythmia, pericardial diseases, tamponade
Systemic vasodilation: sepsis, anaphylaxis
Disseminated intravascular coagulation
Renal vasoconstriction: cyclosporine, amphotericin B, norepinephrine, epinephrine, hypercalcemia
Impaired renal autoregulatory responses: cyclooxygenase (COX) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs)
Causes of nephrotoxic acute tubular necrosis
The kidney is a particularly vulnerable target for toxins, both exogenous and endogenous. Not only does it have a rich blood supply, receiving 25% of cardiac output, but it also helps in the excretion of these toxins by glomerular filtration and tubular secretion.
Exogenous nephrotoxins that cause ATN include the following:
Aminoglycoside-related toxicity occurs in 10-30% of patients receiving aminoglycosides, even when blood levels are in apparently therapeutic ranges (risk factors for ATN include preexisting liver disease, preexisting renal disease, concomitant use of other nephrotoxins [eg, amphotericin B, radiocontrast media, cisplatin], advanced age, shock, female sex, and a higher aminoglycoside level 1 hour after dose; a high trough level has not been shown to be an independent risk factor)
Amphotericin B nephrotoxicity risk factors include male sex, maximum daily dose (nephrotoxicity is more likely to occur if >3 g is administered) and duration of therapy, hospitalization in the critical care unit at the initiation of therapy, and concomitant use of cyclosporine
Radiographic contrast media can cause contrast-induced nephropathy (CIN) or radiocontrast nephropathy (RCN) (commonly occurs in patients with several risk factors, such as elevated baseline serum creatinine, preexisting renal insufficiency, underlying diabetic nephropathy, congestive heart failure [CHF], or high or repetitive doses of contrast media, as well as volume depletion and concomitant use of diuretics, ACE inhibitors, or ARBs). The 2011 UKRA guidelines recommend that patients at risk of CIN should have a careful evaluation of volume status and receive volume expansion with 0.9% sodium chloride or isotonic sodium bicarbonate before the procedure. 
Cyclosporine and tacrolimus (calcineurin inhibitors)
Pentamidine, which is used to treat Pneumocystis jiroveci infection in individuals who are immunocompromised (risk factors for nephrotoxicity include volume depletion and concomitant use of other nephrotoxic antibiotic agents, such as aminoglycosides, which is common practice in the immunosuppressed)
Acyclovir and indinavir
Mammalian target of rapamycin (mTOR) inhibitors (eg, everolimus, temsirolimus) 
Endogenous nephrotoxins that cause ATN include the following:
In, myoglobinuria, rhabdomyolysis is the most common cause of heme-pigment associated AKI and can be caused by traumatic or nontraumatic injuries (most cases of rhabdomyolysis are nontraumatic, such as related to alcohol abuse or drug-induced muscle toxicity [statins alone or in combination with fibrates]).
In hemoglobinuria, AKI is a rare complication of hemolysis and hemoglobinuria, and most often, it is associated with transfusion reactions (in contrast to myoglobin, hemoglobin has no apparent direct tubular toxicity, and AKI in this setting is probably related to hypotension and decreased renal perfusion) 
Acute crystal-induced nephropathy occurs when crystals are generated endogenously due to high cellular turnover (ie, uric acid, calcium phosphate), as observed in certain malignancies or the treatment of malignancies, but this condition is also associated with ingestion of certain toxic substances (eg, ethylene glycol) or nontoxic substances (eg, vitamin C).
For patients with ATN, the in-hospital survival rate is approximately 50%, with about 30% of patients surviving for 1 year. Factors that are associated with an increased mortality rate include poor nutritional status, male sex, the presence of oliguria, the need for mechanical ventilation, acute myocardial infarction, stroke, or seizures.
The mortality rate in patients with ATN is probably related more to the severity of the underlying disease than to ATN itself. For example, the mortality rate in patients with ATN after sepsis or severe trauma is much higher (about 60%) than the mortality rate in patients with ATN that is nephrotoxin related (about 30%). The mortality rate is as high as 60-70% with patients in a surgical setting. If multiorgan failure is present, especially severe hypotension or acute respiratory distress syndrome, the mortality rate ranges from 50 to 80%.
Patients with oliguric ATN have a worse prognosis than patients with nonoliguric ATN. This probably is related to more severe necrosis and more significant disturbances in electrolyte balance. In addition, a rapid increase in serum creatinine (ie, >3 mg/dL) probably also indicates a poorer prognosis. Again, this probably reflects a more serious underlying disease.
Of the survivors of ATN, approximately 50% have some impairment of renal function. Some (about 5%) continue to undergo a decline in renal function. About 5% never recover kidney function and require dialysis.
A review of United States Renal Data System data (n = 1,070,490) for 2001 through 2010 found that although the incidence of end-stage renal disease (ESRD) attributed to ATN increased during that period, the prospects for renal recovery and survival also increased. Recovery of renal function was more likely in patients with ATN than in matched controls (cumulative incidence 23% vs. 2% at 12 weeks, 34% vs. 4% at 1 year), as was death (cumulative incidence 38% vs. 27% at 1 year). Hazards ratios for death declined in stepwise fashion to 0.83 in 2009-2010.
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|Finding||Prerenal Azotemia||ATN and/or Intrinsic Renal Disease|
|Fractional excretion of sodium (FENa)
|Fractional excretion of urea
|Urine sediment||Bland and/or nonspecific||May show muddy brown granular casts|