Acute tubular necrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayesha A. Khan, MD[2] Chandrakala Yannam, MD [3]

Acute tubular necrosis (ATN) defines a pathologic process rather than a clinical syndrome in which varying degrees of renal tubular injury occur. Clinically, ATN manifests as acute kidney injury although the terms have previously been used interchangeably. ATN is the most common cause of overt AKI. Despite the term, ATN does not necessarily imply cellular necrosis with evidence of non-necrotic injury observed more consistently. Furthermore, clinicopathologic correlation is often irrelevant with severe renal insufficiency sometimes seen with modest pathological findings.^[1] ATN can be either ischemic or toxin induced. Classically, ischemic ATN follows hypotension or hypovolemia with patchy involvement usually observed. On the other hand, toxic ATN is usually a dose-dependent injury seen with medications, diagnostic agents, and heavy metals with proximal tubule damage involving almost all nephrons.^[2]

Eric and beallduring was the first to publish a article on describing ATN in detail during world war II. In 1938, Councilman was the first to discover the association between systemic infections and the development of ATN.

Acute tubular necrosis may be classified based on mechanisms of tubular injury into three categories ischemic, toxin-induced, and mixed.

Classically the course of ischemic ATN has been divided into 3 phases: Initiation, maintenance, and recovery. During the initiation phase, immediately following the insult, sublethal cellular injury occurs, with loss of cell polarity and brush border. The maintenance phase is reached after the irreversible renal parenchymal injury has been established. During the last 2 phases, both tubular cell death and cell regeneration occur simultaneously. Apoptosis has been reported in the initial phase of acute tubular necrosis and during the recovery phase. With initial ischemic or cytotoxic injury, a number of tubular cells may undergo apoptosis. The ET-1 gene has also been shown to be upregulated during ischemic injuries. When exposed to ischemic stress, tubular cells are prone to loss polarity and even detachment of viable cells due to the disruption of key structural anchors. Several important proteins are required for tubular cells to maintain their structure and polarity including the actin cytoskeleton, microvilli, and junctional complexes such as tight junctions and adherens junctions. 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 commonly caused by renal ischemia resulting from conditions such as volume depletion, hypotension, septic shock, cirrhosis, and DIC. It is also caused by exposure to various nephrotoxic medications including aminoglycosides, amphotericin B, ACE inhibitors, NSAIDs, antiviral drugs, cytotoxic therapy,and also exposure to radio contrast substances.

Incidence of acute tubular necrosis is approximately 88 per 100,000 individuals worldwide. The mean age at diagnosis of acute tubular necrosis was 59.5 years. Mortality rate is high with acute tubular necrosis among hospitalized and ICU patients. Acute tubular necrosis affects men and women equally.

Common risk factors in the development of acute tubular necrosis include any condition that lead to decreased renal perfusion such as recent abdominal and cardiac surgery, marked hypovolemia, sepsis, hemorrhagic shock, severe pancreatitis, and diabetes mellitus. Nephrotoxic medications ( eg, ACE inhibitors, NSAIDs, aminoglycosides, radio contrast media) can also be a risk for developing acute tubular necrosis.

Screening for acute tubular necrosis is usually not recommended for asymptomatic individuals. Screening is usually recommended for patients who are at high risk for developing acute tubular necrosis. Screening evaluation includes measurement of serum creatinine, urine output, blood urea nitrogen, urinary and serum electrolytes.

Acute tubular necrosis may usually develop through 3 phases, initiation, maintenance and recovery. Common complications of acute tubular necrosis include electrolyte imbalance(eg, hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis), platelet dysfunction and altered consciousness or coma. Prognosis depends on the underlying etiology and severity of kidney damage. When compared to ischemic acute tubular necrosis, nephrotoxic and mixed acute tubular necrosis have the good prognosis.

There is no single diagnostic study of choice for the diagnosis of acute tubular necrosis, but acute tubular necrosis can be diagnosed based on serum creatinine and BUN levels, urinalysis, urine electrolytes (urine sodium, fractional excretion of sodium concentration), and ultrasonography with doppler imaging.

History taking is an important aspect in making a diagnosis of acute tubular necrosis. It provides clues to precipitating factors, causes and associated comorbid conditions leading to decreased renal perfusion and kidney injury. Most common symptoms of acute tubular necrosis include decreased or absent urinary output, postural dizziness, edema, excess thirst, tachycardia, altered mental status and easy fatiguability.

On physical examination, patients with acute tubular necrosis may show the findings of volume depletion. They usually appear ill, dehydrated, and lethargic. Common physical examinationfindings of acute tubular necrosis include orthostatic hypotension and other signs of hypovolemia (dry mucous membranes, sunken eyes, poor skin turgor and delayed capillary refill, and decreased jugular venous pressure).

CBC, urinalysis with sediment microscopy, urine electrolytes, osmolarity, serum electrolytes, blood urea nitrogen and serum creatinine, and urine dipstick are commonly performed in patients to evaluate acute tubular necrosis and other causes of acute renal failure. Urine sediment may show tubular epithelial cells and epithelial cell casts or brown muddy granular casts. Increased urine sodium concentration >40 mEq/L, urine fractional excretion of sodium greater than 2 percent along with elevated serum creatinine concentration at a rate greater than 0.3 mg/dL/day may be found in acute tubular necrosis. However, these tests may have some limitations.

There are no ECG findings associated with acute tubular necrosis. An ECG may be helpful in the diagnosis of electrolyte imbalance occurs as a complication of acute tubular necrosis.

There are no specific x-ray findings associated with acute tubular necrosis. However, an abdominal x-ray may be helpful in diagnosing renal calculi, and areas of obstruction.

Ultrasound with doppler imaging can be helpful in the diagnosis of acute tubular necrosis. Findings on an ultrasound include normal or increased kidney size, alterations in cortical echogenicityand increased RI. There are no echocardiography findings associated with acute tubular necrosis. However, an echocardiography may be helpful in the diagnosis of complications of acute tubular necrosis.

CT scan findings of patients with acute tubular necrosis may include alterations in kidney size, striate nephrogram, accumulation of fluid around kidneys. CT scan can also detect hydronephrosis that cannot be detectable on ultrasound.

There are no specific MRI findings associated with acute tubular necrosis. MRI may show alteration in kidney size, outflow obstruction areas that can not be clearly visible on ultrasound.

There are no other imaging findings associated with acute tubular necrosis.

Renal biopsy and detection of various novel biomarkers in the serum and urine can be helpful in diagnosing acute tubular necrosis.

According to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines, management approach of acute tubular necrosis include examination of all patients thoroughly to identify the cause, precipitating factors, and comorbid conditions leading to a rapid reduction in GFR, which may be reversible and regular monitor patients for serum creatinine, BUN, and urine output to assess the severity of renal damage.

Surgery is not the first-line treatment option for patients with acute tubular necrosis.

Effective measures for the primary prevention of acute tubular necrosis include identification of individuals who are at high risk and prompt treatment for underlying conditions, maintain volume status and adequate renal perfusion by proper hydration or isotonic fluid administration, monitoring fluid intake, urine output and serum creatinine levels regular intervals to ensure normal renal function and avoiding or decreasing dose of nephrotoxins and contrast media.

Secondary preventive measures of acute tubular necrosis are similar to primary prevention.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]

Acute tubular necrosis may be classified based on mechanisms of tubular injury into three categories including ischemic, toxin-induced, and mixed.

• Acute tubular necrosis may be classified into three categories based on the mechanisms of tubular injury involved.^[1]
  • Ischemic acute tubular necrosis
  • Nephrotoxic acute tubular necrosis
  • Mixed acute tubular necrosis
• Ischemic ATN resulting from conditions leading to inadequate blood flow and oxygenation to the kidneys during 48 hrs (eg, shock, sepsis, hemorrhage, volume loss, and hypotension) without nephrotoxin exposure that results in acute renal failure and rise in serum creatinine levels.
• Nephrotoxic ATN occurs as a result of exposure of kidneys to various nephrotoxic medications and chemicals (eg, aminoglycosides, radiocontrast media, ACE inhibitors, NSAIDs, cyclosporine, and sulfa drugs) during 72 hrs preceding the increase in serum creatinine.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Serge Korjian, Yazan Daaboul

Classically the course of ischemic ATN has been divided into 3 phases initiation, maintenance, and recovery. During the initiation phase, immediately following the insult, sublethal cellular injury occurs, with loss of cell polarity and brush border. The maintenance phase is reached after the irreversible renal parenchymal injury has been established. During the last 2 phases, both tubular cell death and cell regeneration occur simultaneously. Apoptosis has been reported in the initial phase of acute tubular necrosis and during the recovery phase. With initial ischemic or cytotoxic injury, a number of tubular cells may undergo apoptosis. The ET-1 gene has also been shown to be upregulated during ischemic injuries. When exposed to ischemic stress, tubular cells are prone to loss polarity and even detachment of viable cells due to the disruption of key structural anchors. Several important proteins are required for tubular cells to maintain their structure and polarity including the actin cytoskeleton, microvilli, and junctional complexes such as tight junctions and adherents junctions.

• Classically the course of ischemic ATN has been divided into 3 phases: Initiation, maintenance, and recovery.
• A fourth phase, an extension phase after the initiation phase has been proposed.^[1]

Initiation Phase

• During the initiation phase, immediately following the insult, sublethal cellular injury occurs, with loss of cell polarity and brush border.
• Renal function begins to decline, ATP depletion may be profound, and intrarenal protective mechanisms are activated.
• If the insulting factor is removed at this initiation phase, complete recovery would ensue.
• If not, the proposed extension phase is reached, characterized by significant cell necrosis, desquamation, inflammation, and tubular lumen obstruction.^[2]

Maintenance Phase

• The maintenance phase is reached after the irreversible renal parenchymal injury has been established.
• Despite the restoration of a normal blood flow to the kidneys, renal function remains significantly impaired.
• This phase lasts several weeks and may require close monitoring since it is associated with the most complications.

Recovery Phase

• During the last 2 phases, both tubular cell death and cell regeneration occur simultaneously.
• The balance between these 2 phenomena and the predominance of regeneration ushers in the recovery phase.
• The final phase is characterized by structural and functional renal recovery with a restored GFR.^[2]

• Apoptosis is a programmed cascade occurring secondary to intra- or intercelluar signaling which leads to cell death in the absence of an inflammatory response.
• In contrast, necrosis is due to cytotoxic cell injury and is characteristically associated with significant inflammation.
• Apoptosis has been reported in the initial phase of acute tubular necrosis and during the recovery phase.^[3]
• With initial ischemic or cytotoxic injury, a number of tubular cells may undergo apoptosis.
• This may be either due to insufficiently cytotoxic insults, or due to associated molecular cascades that release TNF-alpha or Fas (CD95).
• Classically with prolonged ATP depletion lasting more than 12 hours necrosis of tubular cells becomes more evident.
• However, both apoptosis and necrosis can be detected in biopsies of patients with ATN.
• During the recovery phase, apoptosis is thought to be a mechanism involved in the remodeling of the injured renal tubules.^[4]

• Many studies have demonstrated that following ischemia, the renal vasculature has increased sensitivity to vasoconstrictive stimuli particularly endothelin.
• Endothelin (ET-1) is a vasoactive substance release by endothelial cells and one of the most potent vasoconstrictors identified.
• The ET-1 gene has also been shown to be upregulated during ischemic injuries.^[5]
• In parallel, the initial insult following renal ischemia is endothelial dysfunction which contributes to the exacerbation of tissue hypoxia via several mechanisms.
• Endothelial injury disrupts normal vascular function and impairs reactivity and permeability of renal vessels causing maladaptive vasoconstriction and increased leukocyte recruitment.
• This is further exacerbated by an increase in vasoconstrictor substances, adhesion molecules, and inflammatory mediators.^[6]

• When exposed to ischemic stress, tubular cells are prone to loss polarity and even detachment of viable cells due to the disruption of key structural anchors.
• Several important proteins are required for tubular cells to maintain their structure and polarity including the actin cytoskeleton, microvilli, and junctional complexes such as tight junctions and adherens junctions.^[7]
• The initial tubular insult modifies the actin cytoskeleton causing a shift in many major structural and adherence proteins.
• The earliest finding in ATN is the loss of polarity and brush border membrane.^[8]
• Detachment later occurs mainly due to the displacement of integrins, the main adherence proteins, from a basolateral location to the apex of the cell.^[7]
• Furthermore, necrotic cell debris and apoptotic bodies can be seen in addition to detached viable cells within the tubular lumen.
• Cells with prolonged ATP depletion undergo necrosis with ensuing inflammation.
• Apoptosis has also been detected in early phases of renal between 12 and 48 hours after the initial insult.^[9]
• Accumulation of cells and cellular debris along with an overlying immune response within the tubular lumen causes significant obstruction that further aggravates a decreasing GFR.

• Other associated dysfunctions include tubular backleak and abnormal tubuloglomerular feedback.
• With detachment and cell death, loss of the tubular epithelial barrier occurs.
• This leads to some reabsorption of filtered solutes into the circulation leading to an increase in substances used to estimate GFR including creatinine and inulin.
• This is known as tubular backleak. However, the tubular backleack phenomenon has not been well substantiated in clinical ATN, and can only account for around 10% of the decrease in GFR.
• Another important associated dysfunction in ATN is the abnormal tubuloglomerular feedback occuring due to a decrease in the proximal tubular reabsorption of sodium.
• This leads to an increase in sodium chloride delivery to the macula densa activating the tubuloglomerular feedback.
• Counter-intuitively, a constriction of the afferent arteriole occurs leading to a decrease in GFR.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]

Acute tubular necrosis is commonly caused by renal ischemia resulting from conditions such as volume depletion, hypotension, septic shock, heart failure, cirrhosis, and DIC. It is also caused by exposure to various nephrotoxic medications including aminoglycosides, amphotericin B, ACE inhibitors, NSAIDs, antiviral drugs, and also caused by exposure to radio contrast substances.

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
• Life-threatening causes of acute tubular necrosis may include marked volume depletion, septic shock, DIC, and hypotension.

Acute tubular necrosis is commonly caused by renal hypoperfusion resulting in ischemia, nephrotoxic medications and nephrotoxic substance exposure.

• Ischemic acute tubular necrosis:
  • Volume loss:^[1]
    • Hemorrhage
    • Severe vomitings and diarrhea
    • Burns^[2]
    • Third space fluid sequestration (eg, fractures, crush injuries)
    • Extensive use of diuretics and osmotic diuresis
  • Profound hypotension^[3][4]
  • Sepsis^[5]
  • DIC^[6][7]
  • Heart failure^[8]
  • Cirrhosis^[9]
  • Drug adverse effects:
    • ACE inhibitors^[10]
    • NSAIDs^[11]

• Toxic acute tubular necrosis: Acute tubular necrosis can occur due to direct or indirect tubular cell toxicity secondary to medications or substance exposures.
  • Exogenous nephrotoxins:
    • Aminoglycosides^[12]
    • Amphotericin B^[13]
    • Contrast media^[14]
    • Cisplatin^[15]
    • Ifosfamide^[16]
    • Foscarnet^[17]
    • Pentamidine^[18]
    • Cidofovir^[19]
    • Tenofovir ^[20]
    • Acyclovir^[21]
    • Bisphosphonates^[22]
    • Cephalosporin^[23]
    • Naproxen^[24]
    • Tacrolimus^[25]
    • Mannitol^[26]
    • Intravenous immunoglobulins:^[27] These contain sucrose which is toxic to tubular cells.
    • Cyclosporine^[28]
    • Certain herbal medications^[29]
  • Endogenous nephrotoxins:
    • Multiple myeloma^[30]: In multiple myeloma, kidney injury and renal failure is mostly caused by accumulation of light chains in renal tubules leading to obstruction as well as direct toxic effect of light chains on tubules.
    • Heme pigment–associated kidney damage: Myoglobinuria and hemoglobinuria
      • Traumatic or non traumatic rhabdomyolysis leads to release of myoglobin, which may cause tublar blockage, direct tubular injury and vasoconstriction.
      • Hemolysis leads to hemoglobinuria.
    • Crystal induced nephropathy: May be seen in association with malignancies and cytotoxic therapy^[31][32], ethylene glycol poisoning^[33] and excessive intake of vitamin C^[34]

List the causes of acute tubular necrosis in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]

Incidence of acute tubular necrosis is approximately 88 per 100,000 individuals worldwide. The mean age at diagnosis of acute tubular necrosis was 59.5 years. Mortality rate is high with acute tubular necrosis among hospitalized and ICU patients. Acute tubular necrosis affects men and women equally.

• The incidence of acute tubular necrosis is approximately 88 cases per 100,000 individuals.^[1]
  • The incidence of acute tubular necrosis due to renal ischemia is approximately 12.7 cases per 100,000 individuals.^[2]
  • The incidence of acute tubular necrosis due to sepsis is approximately 24.7 cases per 100,000 individuals.
  • The incidence of acute tubular necrosis due to rhabdomyolysis and nephrotoxic medications is approximately 10.7 cases and 7.3 cases per 100,000 individuals.

• The prevalence of acute tubular necrosis is not known.
• Renal ischemia leading acute tubular necrosis and acute kidney injury is the most common cause of acute tubular necrosis.

• The case-fatality rate/mortality rate of acute tubular necrosis is approximately 37% among hospitalized individuals.

• Patients of all age groups may deveolp acute tubular necrosis.
• The mean age at diagnosis of acute tubular necrosis was 59.5 years.

• There is no racial predilection to acute tubular necrosis.

• Acute tubular necrosis affects men and woman equally.

• There is no specific regional distribution to acute tubular necrosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]

Common risk factors in the development of acute tubular necrosis include any condition that lead to decreased renal perfusion such as recent abdominal and cardiac surgery, marked hypovolemia, sepsis, hemorrhagic shock, severe pancreatitis, and diabetes mellitus. Nephrotoxic medications ( eg, ACE inhibitors, NSAIDs, aminoglycosides, radio contrast media) can also be a risk for developing acute tubular necrosis.

• Common risk factors in the development of acute tubular necrosis include:
  • Surgery^[1][2] (eg, abdominal aortic aneurysm surgery, cardiac surgery)
  • Septic shock^[3]
  • Hypovolemia
  • Hemorrhage
  • Severe acute pancreatitis^[4]
  • Drugs:^[5][6]
    • ACE inhibitors
    • Aminoglycosides
    • NSAIDs
    • Amphotericin B
    • Radio contrast media
    • Ethylene glycol poisoning
    • Antiviral drugs
  • Profound hypotension
  • Diabetes mellitus^[7]
  • Malignancy^[8] (eg, multiple myeloma)
  • Congestive heart failure
  • Cirrhosis^[9]
  • Tissue injury (eg, rhabdomyolysis)
  • Chronic renal disease^[10]
  • Morbid obesity
  • Disseminated intravascular coagulation
  • Peripheral vascular disease (atherosclerosis, intermittent claudication)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

• [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].
• [Disease name] must be differentiated from [differential dx1], [differential dx2], and [differential dx3].

• As [disease name] manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. [Subtype name 1] must be differentiated from other diseases that cause [clinical feature 1], such as [differential dx1] and [differential dx2]. In contrast, [subtype name 2] must be differentiated from other diseases that cause [clinical feature 2], such as [differential dx3] and [differential dx4].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chandrakala Yannam, MD [2]

Acute tubular necrosis may usually develop through 3 phases, initiation, maintenance and recovery. Common complications of acute tubular necrosis include electrolyte imbalance(eg, hyperkalemia, hyperphosphatemia, hypocalcemia, and metabolic acidosis), platelet dysfunction, uremia, and altered consciousness or coma. Prognosis depends on the underlying etiology and severity of kidney damage. When compared to ischemic acute tubular necrosis, nephrotoxic and mixed acute tubular necrosis have the good prognosis.

• Acute tubular necrosis may usually develop through 3 phases, include^[1]
  • Phase of initiation
  • Maintenance phase
  • Phase of recovery
• Renal injury by ischemia, hypoxia, and nephrotoxins can occur in initiation phase.
• After a renal injury, it may progress to renal failure depending upon the severity. once the acute renal failure is evident, there is marked decrease in glomerular filtration rate (GFR) resulting in oliguria.
• Oliguria leads to accumulation of metabolic waste products and uremia. Uremia may responsible for altered mental status, cognitive impairment, and other complications.
• The duration of maintenance phase may vary from days to weeks.
• Maintenance phase is followed by a recovery phase which may usually last upto 3-6 weeks. Polyuria can occur due to decreased concentration capacity of kidneys in the maintenance phase.
• Eventually kidney recovery may take place resulting in normal glomerular filtration rate (GFR).

• Common complications of acute tubular necrosis include:^[2]
  • Hyperkalemia
  • Hyponatraemia
  • Metabolic acidosis
  • Hypomagnesemia
  • Fluid retention
  • Hyperphosphatemia
  • Bleeding diathesis due to platelet dysfunction
  • Oliguria
  • Uremia
  • Pericarditis and pericardial effusion
  • Infection
  • Shock
  • Stupor or coma

• Prognosis of acute tubular necrosis depends on the underlying etiology responsible for the tubular damage.^[3][4]
• Prognosis is generally good in nephrotoxic acute tubular necrosis with mortality rate approximately 10%.
• Prognosis of ischemic acute tubular necrosis depends on early diagnosis and treatment of underlying condition causing renal ischemia with mortality rate approximately 30%.
• Poor prognostic factors associated with increased mortality include:^[5]
  • Mechanical ventilation
  • Hypotension
  • Oliguria
  • Cardiogenic shock
  • Coma
  • Sepsis
  • Parenteral nutrition

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