The most common cause of acute kidney injury (AKI) is acute tubular necrosis (ATN) when the pattern of injury lies within the kidney (intrinsic disease). The term tubular necrosis is a misnomer, as true cellular necrosis is usually minimal and the alteration is not limited to the tubular structures. Acute tubular necrosis is most common in hospitalized patients and is associated with high morbidity and mortality. The pattern of injury that defines acute tubular necrosis includes renal tubular cell damage and death. Intrarenal vasoconstriction or a direct effect of drug toxicity is caused by an ischemic event, nephrotoxic mechanism, or a mixture of both.
Acute tubular necrosis is precipitated by an acute ischemic or toxic event or sepsis.
Ischemic-Induced Acute Tubular Necrosis
Prerenal azotemia and ischemic acute tubular necrosis have the same spectrum of causes. In fact, any factor that leads to prerenal azotemia can lead to ischemic acute tubular necrosis. Some common causes include hypovolemic states such as diarrhea, vomiting, bleeding, dehydration, burns, renal losses via diuretics or osmotic diuresis, and third fluid sequestration. Edematous states such as heart failure and cirrhosis cause reduced kidney perfusion. Sepsis or anaphylaxis leads to systemic vasodilation. Coagulopathy, such as disseminated intravascular coagulation, can also cause acute tubular necrosis.
Nephrotoxic-Induced Acute Tubular Necrosis
The kidney clears and metabolizes many drugs. Some of these drugs behave as exogenous toxins and can cause direct renal tubular injury or crystal-induced acute kidney injury (AKI), leading to acute tubular necrosis. Drugs such as aminoglycoside, amphotericin B, radiocontrast media, sulfa drugs, acyclovir, cisplatin, calcineurin inhibitors (tacrolimus, cyclosporine), mammalian target of rapamycin mTOR inhibitors (everolimus, temsirolimus), foscarnet, ifosfamide, cidofovir, and IV immunoglobulin containing sucrose all can cause acute tubular necrosis.
Heme pigment-containing proteins such as hemoglobin and myoglobin can behave as endotoxins in 3 ways:
Sepsis-Induced Acute Tubular Necrosis
Sepsis also plays a role in causing acute tubular necrosis because of systemic hypotension and renal hypoperfusion. Other mechanisms which are incompletely understood include endotoxemia leading to AKI by renal vasoconstriction, and the release of inflammatory cytokines causing enhanced secretion of reactive oxygen species and leading to renal injury.
The landmark PICARD (Program to improve care in acute renal disease) study conducted in five United States medical institutions included a cohort of 618 patients in the intensive care unit (ICU) with AKI. The reported etiology of 50% of those patients with acute renal failure was found to be acute tubular necrosis from ischemic causes, and the other 25% were nephrotoxic acute tubular necrosis leading to renal failure. A Spanish multicenter study in 13 tertiary care hospitals in Madrid found the most frequent cause of AKI was acute tubular necrosis in 45% of the hospitalized patients.
Decreased glomerular filtration rate (GFR) is associated with acute tubular necrosis, leading to 3 possible mechanisms of injury to the renal tubular epithelial cells:
These injury patterns lead to the following 4 phases clinically:
The initiation phase is characterized by an acute decrease in GFR and a sudden increase in serum creatinine and BUN concentrations.
The extension phase consists of 2 major events:
These events are more pronounced in the corticomedullary junction of the kidney. In this phase, damage to the renal vascular endothelial cell is responsible for the ischemia of the renal tubular epithelial cell. The cells in the outer medulla continue to undergo injury and death with the combination of both necrosis and apoptosis. While in the outer cortex, the blood flow returns to near normal, leading to cellular repair. As the injury worsens in the cortico-medullary junction (CMJ), the GFR falls due to the continuous release of cytokines and chemokines enhancing the inflammatory cascade.
The maintenance phase is established by cellular repair, apoptosis, migration, and proliferation to maintain cellular and tubule integrity. The cellular function improves slowly as the cells repair and reorganize. The blood flow returns to normal range, and the cells establish intracellular homeostasis.
Because it is a histological finding, acute tubular necrosis is diagnosed on a clinical basis. A biopsy is only performed when there is suspicion of an entity other than acute tubular necrosis causing AKI. Histopathological findings include:
Ischemic Acute Tubular Necrosis
Nephrotoxic Acute Tubular Necrosis
The nephrotoxic agents that lead to acute tubular necrosis can manifest as different features of histological damage, including:
The history and physical examination give a lot of clues in identifying a person with prerenal disease and acute tubular necrosis which is caused by decreased renal perfusion. Events such as diarrhea, vomiting, sepsis, dehydration, or bleeding that leads to tissue hypoxia can indicate a risk of acute tubular necrosis. Hospitalized patients with events such as hypotension, sepsis, intraoperative events, use of nephrotoxic agents such as radiocontrast media or a nephrotoxic antibiotic help in identifying the clinical picture causing AKI and acute tubular necrosis.
Physical findings such as tachycardia, dry mucous membrane, decreased skin turgor, and cool extremities are findings that can be present in patients with volume depletion and hypotension. Fever and hypotension are common manifestations of sepsis. Muscle tenderness is present in the setting of rhabdomyolysis. Intraabdominal hypertension that causes abdominal distension due to abdominal compartment syndrome also impedes renal perfusion and raises the concern for acute tubular necrosis.
The workup is usually to differentiate acute tubular necrosis from prerenal AKI and other causes of AKI. Major tests that help to differentiate include urinalysis (UA), response to fluid repletion, urinary sodium concentration, fractional excretion of sodium (FENa), and fractional excretion of urea in patients who get diuretics and novel biomarkers.
In prerenal disease, the UA microscopy is normal or may contain hyaline casts. On the other hand, the UA of acute tubular necrosis shows muddy brown casts or renal tubular epithelial cells secondary to the sloughing of tubular cells into the lumen due to ischemia or toxic injury.
Fractional excretion of sodium (FENa)
This is a good test to differentiate between acute tubular necrosis and prerenal disease with a value less than 1% favoring prerenal disease and more than 2%, acute tubular necrosis. However, these values are not always accurate as in chronic prerenal states such as congestive heart failure and cirrhosis in which there is an overlap between both (ATN and prerenal AKI) having a value of less than 1%.
Urine sodium concentration
This test determines that the kidney is sodium avid in hypovolemic states (prerenal) where kidneys try to conserve sodium or lose sodium due to tubular injury with values more than 40 to 50 mEq/L indicating acute tubular necrosis and less than 20 mEq/L suggestive of prerenal disease. 
Numerous biomarkers have evolved to detect AKI/acute tubular necrosis early as compared to serum creatinine. These biomarkers include serum cystatin C to be an early and reliable marker of renal injury as compared to serum creatinine which is often witnessed 48 to 72 hours after the initial insult. Other markers include urinary alpha one microglobulin, beta-2 microglobulin, urinary liver-type fatty acid-binding protein (L-FABP) and kidney injury molecule 1 (KIM-1) for the detection of proximal tubular damage, urinary interleukin-18 (IL-18) is known to differentiate ATN from CKD, urinary tract infection (UTI), and prerenal azotemia. Urinary biomarker neutrophil gelatinase-associated lipocalin (NGAL) is upregulated in the renal ischemia after distal tubular injury.
The mainstay of management is the prevention of acute tubular necrosis by identifying the patients undergoing high-risk procedures and having comorbidities such as diabetes mellitus, heart failure, advanced malignancy, atherosclerosis, and CKD that can potentiate the effects of the acute tubular necrosis. The following are some of the high-risk procedures and conditions:
Interventions to decrease the risk of acute tubular necrosis in the above conditions include prevention of hypovolemia or hypotension including cessation of ACEI or angiotensin II receptor blocker in patients with low blood pressure, and optimization of volume status via intravenous (IV) fluids, such as crystalloids, to ensure adequate renal perfusion. Nephrotoxic medications that can lead to acute tubular necrosis should be avoided, including NSAIDs, antibiotics such as amphotericin B, aminoglycosides, vancomycin, piperacillin/tazobactam, and radiocontrast agents.
Diuretics are used only to manage the volume status but are not recommended for the treatment of acute tubular necrosis in the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines. Other pharmacological agents such as dopamine, fenoldopam, and atrial natriuretic peptide do not provide any survival benefit in patients with acute tubular necrosis.
Renal replacement therapy (RRT) has the same indications and is used in volume overload refractory to diuretics, hyperkalemia, signs of uremia, and metabolic acidosis. In critically ill hemodynamically unstable patients, the use of continuous renal replacement therapy (CRRT) is the preferred option.
The mortality in patients with acute tubular necrosis depends on the underlying condition that leads to acute tubular necrosis. Some factors that lead to poor survival in such patients include oliguria, poor nutritional status, male gender, the need for mechanical ventilation, stroke, seizures, and acute myocardial infarction. The mortality rate is higher in oliguric patients than in non-oliguric patients signifying the amount of damage done leading to necrosis. Mortality is high (about 60%) in sepsis and surgical patients, causing multiple organ failure.
Complications related to acute tubular necrosis are the same as related to AKI which include acid-base and electrolyte disturbances such as hypocalcemia, hyperkalemia related to the metabolic acidosis, and hyperphosphatemia. Volume overload is related to anuria or oliguria. Uremic complications lead to pericarditis, bleeding diathesis, and altered mental status.
The diagnosis and management of ATN is best done with a multidisciplinary team that includes a nephrologist, pharmacist, internist, cardiologist and an intensivist. The mainstay of management is the prevention of acute tubular necrosis by identifying the patients undergoing high-risk procedures and having comorbidities such as diabetes mellitus, heart failure, advanced malignancy, atherosclerosis, and CKD that can potentiate the effects of the acute tubular necrosis. ATN is not a benign disorder and the outcomes depend on the cause. Factors that lead to poor survival in such patients include oliguria, poor nutritional status, male gender, the need for mechanical ventilation, stroke, seizures, and acute myocardial infarction. The mortality rate is higher in oliguric patients than in non-oliguric patients signifying the amount of damage done leading to necrosis. Mortality is high (about 60%) in sepsis and surgical patients, causing multiple organ failure. Despite aggressive treatment, some patients may end up with end stage renal disease requiring dialysis.
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