What is acute tubular necrosis

Acute tubular necrosis is a kidney disorder involving damage to the tubule cells of the kidneys, which can lead to acute kidney failure. The term tubular necrosis is a misnomer, as true cellular necrosis is usually minimal and the alteration is not limited to the tubular structures ¹. 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 ².

Acute tubular necrosis is precipitated by an acute ischemic or toxic event or sepsis. 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 acute kidney injury (AKI). The reported cause 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 ¹. A Spanish multicenter study in 13 tertiary care hospitals in Madrid found the most frequent cause of acute kidney injury was acute tubular necrosis in 45% of the hospitalized patients ³.

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 acute kidney injury and acute tubular necrosis.

Acute tubular necrosis causes

Acute tubular necrosis is often caused by a lack of blood flow and oxygen to the kidney tissues (ischemia of the kidneys). Acute tubular necrosis may also occur if the kidney cells are damaged by a poison or harmful substance.

The internal structures of the kidney, particularly the tissues of the kidney tubule, become damaged or destroyed. Acute tubular necrosis is one of the most common structural changes that can lead to acute kidney failure.

Acute tubular necrosis is a common cause of kidney failure in people who are in the hospital.

Risks for acute tubular necrosis include:

• Blood transfusion reaction
• Injury or trauma that damages the muscles
• Low blood pressure (hypotension) that lasts longer than 30 minutes
• Recent major surgery
• Septic shock (serious condition that occurs when a body-wide infection leads to dangerously low blood pressure)

Liver disease and kidney damage caused by diabetes (diabetic nephropathy) may make a person more prone to develop acute tubular necrosis.

Acute tubular necrosis can also be caused by:

• Dye (contrast) used for x-ray (radiology) studies
• Medicines that are toxic to the kidneys (such as aminoglycoside antibiotics or amphotericin)

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 (DIC), 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:

1. Causing direct proximal tubular injury, tubular obstruction, or renal vasoconstriction
2. Crystal-induced nephropathy due to high cell turnover such as uric acid, calcium phosphate crystals in the setting of ongoing malignancy treatment
3. Light chains accumulation in multiple myeloma is directly toxic to the renal proximal and distal tubules

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 acute kidney injury (AKI) by renal vasoconstriction, and the release of inflammatory cytokines causing enhanced secretion of reactive oxygen species and leading to renal injury.

Acute tubular necrosis prevention

Promptly treating conditions that can lead to decreased blood flow as well as decreased oxygen to the kidneys can reduce the risk for acute tubular necrosis.

Blood transfusions are crossmatched to reduce the risk of incompatibility reactions.

Diabetes, liver disorders, and heart problems need to be managed well to reduce the risk for acute tubular necrosis.

If you know you’re taking medicine that can injure your kidneys, ask your provider about having your blood level of the medicine checked regularly.

Drink a lot of fluids after having any contrast dyes to allow them to be removed from the body and reduce the risk for kidney damage.

Acute tubular necrosis symptoms

Acute tubular necrosis symptoms may include any of the following:

• Decreased consciousness, coma, delirium or confusion, drowsiness, and lethargy
• Decreased urine output or no urine output
• Swelling in legs, ankles, and around the eyes due to fluid retention
• Nausea, vomiting
• Fatigue or tiredness
• Shortness of breath
• Confusion
• Nausea
• Seizures or coma in severe cases
• Chest pain or pressure

Acute tubular necrosis complications

Complications related to acute tubular necrosis are the same as related to acute kidney injury 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.

Acute tubular necrosis diagnosis

Your health care provider will perform a physical exam. Your health care provider may hear abnormal sounds when listening to the heart and lungs with a stethoscope. This is due to too much fluid in the body.

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.

Tests that may be done include:

• BUN (blood urea nitrogen) and serum creatinine
• Fractional excretion of sodium. 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 (acute tubular necrosis and prerenal acute kidney injury) having a value of less than 1% ⁴.
• Kidney biopsy
• Urinalysis. In prerenal disease, the urinalysis microscopy is normal or may contain hyaline casts. On the other hand, the urinalysis 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.
• 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 ⁵.
• Urine specific gravity and urine osmolarity
• Novel Biomarkers: Numerous biomarkers have evolved to detect acute kidney failure with 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 acute tubular necrosis from chronic kidney disease, urinary tract infection (UTI), and prerenal azotemia. Urinary biomarker neutrophil gelatinase-associated lipocalin (NGAL) is upregulated in the renal ischemia after distal tubular injury ⁶.

Acute tubular necrosis treatment

In most people, acute tubular necrosis is reversible. The goal of treatment is to prevent life-threatening complications of acute kidney failure

Treatment focuses on preventing the buildup of fluids and wastes, while allowing the kidneys to heal.

The mainstay of management of acute tubular necrosis 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 chronic kidney disease that can potentiate the effects of the acute tubular necrosis. The following are some of the high-risk procedures and conditions:

• Cardiogenic shock
• Hemorrhagic shock
• Pancreatitis
• Severe burns
• Sepsis
• Hypovolemia
• Major surgery (cardiac bypass, vascular surgery such as abdominal aortic aneurysm peripheral limb surgery, hepatobiliary surgery, emergent surgical exploration)

Interventions to decrease the risk of acute tubular necrosis in the above conditions include prevention of hypovolemia or hypotension including cessation of ACE inhibitor or angiotensin 2 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 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 is the preferred option ⁷.

Treatment may include any of the following:

• Identifying and treating the underlying cause of the problem
• Restricting fluid intake
• Taking medicines to help control potassium level in the blood
• Medicines taken by mouth or through an IV to help remove fluid from the body

Temporary dialysis can remove excess waste and fluids. This can help improve your symptoms so that you feel better. It may also make kidney failure easier to control. Dialysis may not be necessary for all people, but is often lifesaving, especially if potassium is dangerously high.

Dialysis may be needed in the following cases:

• Decreased mental status
• Fluid overload
• Increased potassium level
• Pericarditis (inflammation of the sac-like covering around the heart)
• Removal of toxins that are dangerous to the kidneys
• Total lack of urine production
• Uncontrolled buildup of nitrogen waste products

Acute tubular necrosis prognosis

Acute tubular necrosis can last for a few days to 6 weeks or more. This may be followed by 1 or 2 days of making an unusually large amount of urine as the kidneys recover. Kidney function often returns to normal, but there may be other serious problems and complications.

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. Despite aggressive treatment, some patients may end up with end stage renal disease requiring dialysis ⁸.

1. Hanif MO, Ramphul K. Acute Renal Tubular Necrosis. [Updated 2019 Mar 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507815[↩][↩]
2. Negi S, Koreeda D, Kobayashi S, Yano T, Tatsuta K, Mima T, Shigematsu T, Ohya M. Acute kidney injury: Epidemiology, outcomes, complications, and therapeutic strategies. Semin Dial. 2018 Sep;31(5):519-527[↩]
3. Bouchard J, Acharya A, Cerda J, Maccariello ER, Madarasu RC, Tolwani AJ, Liang X, Fu P, Liu ZH, Mehta RL. A Prospective International Multicenter Study of AKI in the Intensive Care Unit. Clin J Am Soc Nephrol. 2015 Aug 07;10(8):1324-31.[↩]
4. Lima C, Macedo E. Urinary Biochemistry in the Diagnosis of Acute Kidney Injury. Dis. Markers. 2018;2018:4907024[↩]
5. Legrand M, Le Cam B, Perbet S, Roger C, Darmon M, Guerci P, Ferry A, Maurel V, Soussi S, Constantin JM, Gayat E, Lefrant JY, Leone M., support of the AZUREA network. Urine sodium concentration to predict fluid responsiveness in oliguric ICU patients: a prospective multicenter observational study. Crit Care. 2016 May 29;20(1):165[↩]
6. Buonafine M, Martinez-Martinez E, Jaisser F. More than a simple biomarker: the role of NGAL in cardiovascular and renal diseases. Clin. Sci. 2018 May 16;132(9):909-923.[↩]
7. Karakala N, Tolwani AJ. Timing of Renal Replacement Therapy for Acute Kidney Injury. J Intensive Care Med. 2019 Feb;34(2):94-103[↩]
8. Kang R, Rovin B. Advances and Challenges on New Therapies and Clinical Targets of Acute Kidney Injury. Toxicol Pathol. 2018 Dec;46(8):925-929.[↩]