Acute Tubular Necrosis

It is a reversible or irreversible medical condition which occurs either due to toxic injury or due to an ischemic injury to the renal tubular cells. During this disorder the cells from the basement membrane either die or detach from the tubules that results in dysfunction of the tubules.

Presentation

Patients suffering from ATN have no specific symptoms as such and most cases are found on incidental routine laboratory. Symptomatic patients may present with:

  • Pericardial rub
  • Pruritis due to increase in urea
  • Asterixis
  • Hypertension and edema

Besides these symptoms, there could be additional signs and symptoms pertaining to the underlying disease. For example, a patient with rhabdomyolysis may present with tender muscles with doughy consistency along with edema around the extremities involved. According to the 2011 UKRA AKI guidelines, a thorough physiological observation must be done on all patients suspected with AKI to be able to diagnose AKI and prevent from further deterioration. This also helps in prognosis and measures can be taken to keep it under control [4].

Complications of ATN

Besides these complications there are specific condition-related complications which are as follows:

  • Oliguric phase: In this phase of ATN, patients would have salt and water retention that leads to hypertension and edema. If not treated, this condition leads to heart failure.
  • Polyuric phase: This phase of ATN is characterized by hypovolemia. The hypovolemia results in prerenal azotemia and perpetuation of ATN.

Workup

Patients suspected of ATN should undergo the following diagnostic tests:

  • Urine analysis for determining the presence of infection and abnormal cells in the urine.
  • Blood urea nitrogen (BUN)
  • Blood tests to analyse sodium and creatinine levels. Any derangement in the kidneys reflects with increase or decrease in levels of sodium and creatinine. 
  • Renal biopsy may be necessary for further examination.
  • CT scan of the kidneys.

Treatment

For a better outcome, an early consult with a nephrologist or an intensivist is preferred. The goals to be achieved while treating ATN are:

  • To avoid any further damage to the kidneys.
  • Identify the underlying cause and treat it.
  • Identification of complications and efficient treatment.

Some of the issues sought during an ATN treatment are:

  • Adjustment of doses in such cases as the kidneys aren't functioning.
  • Consider the use of nephrotoxic drugs and use them only if necessary.
  • Other issues like intervention in electrolyte and acid base abnormalities.
  • Optimize the volume status by replacing it with fluids.

There is no special treatment outlined for ATN and most of it is supportive. The following steps are taken in treating ATN:

  1. The treatment usually revolves around maintaining the electrolyte acid-base balance and volume status [1]. Well perfused kidneys and stable hemodynamics are the pillars of ATN treatment. As per the guidelines of KDIGO (Kidney Improving Global Outcomes), vasopressors must be used concurrently with fluids in patients with vasomotor shock who are or maybe at risk for acute kidney injury (AKI) under special supervision.
  2. One of the treatment aspects of ATN is to avoid the use of nephrotoxins such as non-steroidal anti-inflammatory drugs, aminoglycosides, amphotericin B, etc. But if they must be used, their dose has to be reduced in a way that doesn't burden the kidneys or cause toxic effects on the kidneys.
  3. While trying to attain stable vitals and hemodynamic state with fluids, the real cause of volume depletion and blood loss should be investigated for. Fluids such as crystalloid (normal saline or lactated Ringer) work well in increasing the depleted volume. KDIGO guidelines give preference to usage of isotonic crystalloid over colloids (albumin or starches) for increasing the intravascular volume in patients that are at risk for AKI or at suffering from AKI when there is no hemorrhagic shock.
  4. In patients with contrast induced acute kidney injury (AKI), restoring the volume with normal saline with a target dose of 1 mL/kg/hour has proven helpful in decreasing the risk of contrast induced nephropathy in such patients [5]. A different radiological method should be sought. If contrast needs to be administered in such patients then the dose of contrast must be kept as minimum as possible. As per KDIGO guidelines, iso-osmolar or low-osmolar iodinated contrast media should be given and not the high-osmolar contrast media in patients with contrast induced acute kidney injury.

Renal replacement therapy

If a patient suffers from conditions such as severe acidosis, volume overload that don't respond to diuretics administered, increased potassium in blood or uremia treatment methods like hemodialysis, peritoneal dialysis and hemofiltration are opted.

Patients who have lost renal function and need more than supportive therapy are examined along with their hemodynamic and laboratory evidence by a nephrologist who outlines the type of care needed to restore or minimize the damage.

In patients that are hemodynamically stable, hemodialysis is preferred. While in critically ill patients, an early intervention along with increased dose, increased frequency and time have shown better prognosis [6] [7].

But patients that are hemodynamically unstable or those who can't tolerate a 4 to 6 hour ultra-filtration hemodialysis treatment are then advised continuous renal replacement therapy (CRPT). Continuous renal replacement therapy is of two types: a) arteriovenous and b) venovenous with continuous venovenous being the most frequently used technique. In a continuous venovenous treatment, a large double lumen catheter is inserted into the central venous system through the internal jugular vein or the femoral vein. Hence the most commonly used treatment are continuous venovenous hemofiltration (CWH), continuous venovenous hemodialysis (CWHD) and continuous venovenous hemodiafiltration (CWHDF).

Patients that have suffered septic shock or severe heart failure with volume overload cannot be treated with the conventional hemodialysis. In such patients CRPT have shown beneficial. Studies evaluating high clearance volumes and addition of a dialysis dose to CWH has shown better outcomes [8] [9] [10].

Prognosis

The prognosis of ATN depends largely on the necessity of intensive care unit.

  1. Patients not needing ICU have 32% mortality rate.
  2. Patients needing ICU have a 72% mortality rate.

Therefore an overall healthy patient suffering from ATN can have good prognosis when the main problem or the root cause is corrected. This can be seen with the serum creatinine level reaching normal in 1 to 3 weeks.

The predictors of prognosis of ATN are:

  1. Urine volume
  2. Severity of the underlying disease
  3. Any other co-morbid conditions
  4. Infection

The patients who suffer from ATN are predisposed to chronic kidney disease. Mortality is usually related to infection or the underlying disorder.

Etiology

Various reasons could cause ATN:

  • Physiological imbalance: Decreased blood flow to the kidneys most commonly caused due to hypotension or sepsis.
  • Drugs: Toxic drugs to kidney (Nephrotoxic drugs).
  • Surgery: Any major surgery can predispose or be the cause for ATN.
  • Burns: Any patient with a burn degree of more than 15% of body surface area which grades them as third degree burn are known to be at risk of ATN.
  • Heme products: Heme derivatives like myoglobin and hemoglobin can cause rhabdomyolysis which could lead to ATN.
  • Certain disorders like tumor lysis syndome or multiple myeloma can cause tubular degeneration and lead to ATN though it is very infrequent.
  • Poisons: Relatively uncommon poisons such as ethylene glycol could lead to ATN.
  • Other practices of medicine: Herbal and folk medicines could also pose threat and result in ATN. One of the common practice in Southeast Asia is the consumption of of fish gallbladder in folk medicine. Hence consider ATN in such cases.

Some of the most common nephrotoxic drugs are as follows [2]:

  • Antibiotics like aminoglycosides, amphotericin B, colistimethate.
  • Drugs used in chemotherapy like cisplatin.
  • Drugs used in radiological contrast imaging studies.
  • Anti-inflammatory drugs.
  • Drugs like cyclosporine, tacrolimus also pose toxic effects on kidney.

Risk factors

  • Patients that have suffered septic or hemorrhagic shock end up loosing a lot of blood. This results in hypovolemia and poor perfusion state and causes ATN.
  • Pancreatitis and advanced hepatobiliary disease are also known to affect the kidney tubules and cause ATN.
  • Co-morbidities like diabetes mellitus increases the chances of ATN.
  • Senile patients who would've undergone major surgery and have compromised kidneys are more likely to suffer from aminoglycoside toxicity that leads to ATN as opposed to the younger generation.
  • Patients with pre-existing chronic renal kidneys are at higher risk of ATN.

Epidemiology

It has been difficult to establish an appropriate occurrence rate of acute tubular necrosis due to changes in the definition and varied characteristics of examined patients. Acute renal failure (ARF) and acute tubular necrosis (ATN) are often used interchangeably even when they both are two different conditions [1]. The incidence rates of ARF also aren't well established but as per the National Hospital Discharge Survey Data for the year 2001 that included 29,039,599 hospitalizations, suggested that 19.2 cases of ARF are seen in every 1000 patient hospitalizations in the US [3].

Sex distribution
Age distribution

Pathophysiology

Acute tubular necrosis occurs in 3 stages namely initiation, maintenance, and recovery. Acute ischemia or toxic events usually are the cause for characteristic ATN features i.e tubular cell death. The ischemic ATN features overlap with the nephrotoxic forms as well.

Initiation phase

Prereneal azotemia is known to be a predisposing factor that causes ischemic ATN even though the causes of prerenal azotemia are different than those of ischemic ATN. Ischemic ATN occurs due to a hypoperfused kidney which can be an added burden to the kidneys existing auto-regulatory defenses. Hypoperfusion is the main factor that initiates the process of cell injury but isn't the cause of cell death.

In ATN, the tubular cellular injury is more common at the straight portion of the proximal tubules and in the thick ascending limb of loop of Henle since it is embedded in the medulla that is comparatively more hypoxic. The most common mechanism of ATN is reduction of the glomerular filtration rate that occurs due to two reasons:

  • Hypoperfusion of the kidneys.
  • Tubular lumen gets obstructed due to casts and debris.

This blockade in the tubular lumen causes the filtrate to go back in to the system through the damaged epithelial lining of the glomerulus disrupting the whole procedure of filtration.

Microscopically, the first change to occur in ATN are the apical blebs which is followed by loss of brush border in the tubule and loss of polarity. Cells also show loss of tight junctions in ATN. Finally the epithelial lining of the glomerulus that controls the filtration is also damaged and this causes the filtered and unfiltered materials to go back into the system.

ATN brings about a disturbance in the anatomy of the glomerulus and the tubules. It affects the Na+/K+ -ATPase pumps which tends to move away from their original position and integrins too move apart into the apical membrane. It eventually leads to cell death due to necrosis and apoptosis. The shedding of live as well as dead cells causes the formation of casts and obstructs the tubules.

Ischemia not only leads to ATN but also causes decreased production of vasodilators like nitric oxide, prostacyclin. The vasodilators are produced by the tubular cells of the kidney and a decrease in these causes more vasoconstriction and hypoperfusion.

Ischemia biochemically also causes a decline in adenosine triphosphate (ATP), an increase in the cytosolic calcium along with an increase in free radicals. The free radicals when increased pose a threat to cells since they have deleterious and toxic effect on the cells. This damage caused by free radicals is worse on reperfusion.

It also leads to an increase of membrane phospholipid metabolism wherein the phospholipid membrane undergoes change and the membrane lipids end up in peroxidation. It also affects the cell volume regulation. The reduction of ATP hinders the cellular function especially the active transport.

All of the above mentioned pathophysiological process results in cellular swelling and intracellular accumulation of Na and Ca.

Maintenance phase

This phase usually lasts for 1-2 weeks. As the name suggests the maintenance phase is the period when the glomerular filtration rate tries to come back to its original physiological state.

During this phase, the afferent arterioles of the glomerulus detect the increased salt retention in the tubules and this leads to constriction of the arterioles that is carried out by the macula densa cells. This is the tubuloglomerular feedback mechanism that helps overcome the injury.

Recovery phase

During this phase the damaged tubular cells begin to regenerate [3]. As they recover, physiological disturbance such as abnormal diuresis may occur resulting in salt and water loss and depletion of volume. Though the exact process behind the diuresis hasn't been established but it is presumed to be due to the late recovery of the tubules especially when there is an increase in glomerular filtration. This phase might worsens if diuretics are added from an external source which are usually given during the initiation and maintenance phase.

Prevention

ATN can be prevented by taking into following precautions:

  • When a patient suffers from co-morbid condition like diabetes, try to control their sugar levels to prevent complications.
  • Trying to keep the patient well hydrated by maintaining euvolemia and keeping the kidneys well perfused. This is important especially in ICU patients.
  • Try to avoid administering drugs that can be toxic to the kidney.
  • If in any case patients do need drugs that are nephrotoxic, renal function test should be monitored to avoid any complications.
  • Controlling the co-morbid conditions. e.g. controlling the blood glucose levels in a diabetic patient to avoid any complications or worsening of the existing condition.

It is difficult to comment on the efficacy of loop diuretics like mannitol or dopamine to help prevent ATN and no study has been able to prove it.

Summary

The kidney has two parts microscopically:

  1. Glomerulus
  2. Tubules

Acute tubular necrosis (ATN) is a condition affecting the tubules of the kidney which could be a reversible or an irreversible process, arising because of a toxic injury or an ischemic injury to the kidney. ATN occurs when the epithelial cells that line the tubule are damaged or die. ATN is known to be a very common disorder in acute kidney injury (AKI). The primary reasons for the occurrence of ATN are usually due to a toxin or decreased blood and oxygen flow to the tubules leading to ischemia.

ATN is difficult to diagnose since it doesn't present symptomatically. ATN is usually suspected when there are symptoms of AKI. These symptoms include decreased urine output, fluid retention, edema, nausea and vomiting, disoriented or decreased consciousness and lethargy. There are 2 types of ATN [1]:

  • Ischemic: This is commonly seen due to less blood flow to the kidney or hypoperfusion systemically.
  • Nephrotoxic: This occurs due to drugs that affect the kidneys, poisons, or due to radio-contrast media used in radiological studies.

Patient Information

Acute tubular necrosis is a kidney disorder that damages the tubular cells of the kidney and may causes an acute kidney failure.

Causes

Acute tubular necrosis (ATN) is primarily caused due to lack of oxygen to the kidney tissues also known as ischemia of the kidneys.

Other factors include:

  • Toxic drugs like aminoglycoside or amphotericin B are deteriorate the kidney functions in ATN.
  • Dye (contrast) x-ray.

On a cellular level, the tubules present in the kidney either get damaged or destroyed due to ATN. This change in structure of the tubules is the most common cause that lands patients into acute renal failure. The most common cause of kidney failure in hospitalized patients is ATN.

Some of the risks associated with ATN are enumerated below:

  • Blood transfusion reaction
  • Any injury or trauma damaging the muscles
  • If a patient suffers from low blood pressure (hypotension) longer than 30 minutes
  • Recent major surgery
  • Severe infection leading to septic shock
  • Co-morbid condition like diabetes predisposes a patient to kidney damage (diabetic nephropathy) that makes them susceptible to ATN
  • Liver disease also add to another risk for ATN

Symptoms

  • Very little or no urine output.
  • Swelling all over the body.
  • Fluid retention.
  • Feeling tired and lethargic.
  • Varying level of consciousness that could end up to being as severe as coma, delirium or confusion.

ATN usually doesn't present with a lot of symptoms and often goes undiagnosed, but it can have other symptoms of the underlying disorder that  are more pronounced.

Diagnosis

A routine physical examination is carried out to analyze the systems. The doctor tries to listen to the heart sounds to make sure all is well with the heart. Sometimes abnormal sounds in lungs and heart can be heard due to excess fluid overload in the body. If any abnormalities are found following tests are recommended:

  • BUN and serum creatinine
  • Fractional excretion of sodium
  • Kidney biopsy: A sample of the kidney is taken to visualize under the microscope for cellular level changes.
  • Urinalysis: This gives an overview of the functioning of the kidneys. The specific gravity and osmolarity of urine are checked along with leakage of substances which wouldn't be present otherwise in a healthy individual.
  • Urine sodium levels.

Treatment

ATN is a reversible disorder of the kidneys. The main aim in treating ATN is to prevent any further complications that are life-threatening complications of acute kidney failure.

The treatment goals for ATN are:

  1. To avoid excess fluid build up in the body. Keeping a close watch on the intake of fluid equaling to the output in urine.
  2. Maintain the hemodynamic state.
  3. Identify the underlying cause.
  4. Avoid medications that damage the kidney but if they are necessary then they are to be given in minute doses that the kidney can withstand.
  5. To minimize the use of substances that are usually excreted in the kidney and prevent their build up. For e.g. protein, sodium, potassium.
  6. Controlling the potassium levels in the blood.

Most of ATN treatment is supportive therapy, but if all of these fail and seem to not respond, dialysis may be the only option. Since ATN is a reversible disorder, the hemodialysis is temporary. Hemodialysis helps in removal of toxins and extra fluid. This technique decreases the burden of the kidneys and helps them to heal. Though it isn't necessary for all ATN patients to undergo dialysis but it has proven beneficial and is lifesaving especially in cases wherein the potassium levels are too high to manage.

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References

  1. Gill N, Nally JV Jr, Fatica RA. Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management. Chest. 2005; 128:2847-2863.
  2. Verghese E, Ricardo SD, Weidenfeld R, et al. Renal primary cilia lengthen after acute tubular necrosis. J Am Soc Nephrol. 2009 Jul 16.
  3. Liangos O, Wald R, O'Bell JW, et al. Epidemiology and outcomes of acute renal failure in hospitalized patients. Clin J Am Soc Nephrol. 2006; 1:43-51.
  4. Lewington A, Kanagasundaram S, UK Renal Association. Clinical Practice Guidelines: Acute Kidney Injury. Nephron Clin Pract. 2011; 118(1):c349-90.
  5. Barrett BJ, Parfey PS. Clinical practice. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006; 354:379-386.
  6. Paganini EP, Tapolyai M, Goormastic M, et al. Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis. 1996; 28: S81-S89.
  7. Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med. 2002; 346:305-310.
  8. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000; 356:26-30.
  9. Saudan P, Niederberger M, De Seigneux S, et al. Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int. 2006; 70:1312-1317
  10. Ronco C. Continuous renal replacement therapies for the treatment of acute renal failure in intensive care patients. Clin Nephrol. 1993; 40:187-198.

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