What is the most common cause of acute kidney injury?

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.[rx]

Introduced by the KDIGO in 2012,^[rx] specific criteria exist for the diagnosis? of AKI.

AKI can be diagnosed if any one of the following is present:

• Increase in SCr by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or
• Increase in SCr to ≥1.5 times baseline, which has occurred within the prior 7 days; or
• Urine volume < 0.5 ml/kg/h for 6 hours.

Staging

The RIFLE criteria, proposed by the Acute? Dialysis Quality Initiative (ADQI) group, aid in assessment of the severity of a person’s acute kidney injury. The acronym RIFLE is used to define the spectrum of progressive kidney injury seen in AKI:^[rx][rx]

• Risk: 1.5-fold increase in the serum creatinine?, or glomerular filtration rate (GFR) decrease by 25 percent, or urine output <0.5 mL/kg per hour for six hours.
• Injury: Two-fold increase in the serum creatinine?, or GFR decrease by 50 percent, or urine output <0.5 mL/kg per hour for 12 hours.
• Failure: Three-fold increase in the serum creatinine?, or GFR decrease by 75 percent, or urine output of <0.3 mL/kg per hour for 24 hours, or no urine output (anuria) for 12 hours.
• Loss: Complete loss of kidney function (e.g., need for renal? replacement therapy) for more than four weeks.
• End-stage kidney disease: Complete loss of kidney function (e.g., need for renal? replacement therapy) for more than three months.

Causes of Acute? Kidney Injury

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. 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.[rx]
• 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 intravenous immunoglobulin containing sucrose all can cause acute tubular necrosis.[rx]

Decreased blood flow

Some diseases and conditions can slow blood flow to your kidneys and cause AKI.

These diseases and conditions include:

• Low blood pressure (called “hypotension”) or shock
• Blood or fluid loss (such as bleeding, severe diarrhea)
• Heart attack, heart failure, and other conditions leading to decreased heart function
• Organ failure (e.g., heart, liver)
• Overuse of pain medicines called “NSAIDs”, which are used to reduce swelling or relieve pain from headaches, colds, flu, and other ailments.  Examples include ibuprofen, ketoprofen, and naproxen.
• Severe allergic reactions
• Burns
• Injury
• Major surgery

Direct Damage to the Kidneys

Some disease and conditions can damage your kidneys and lead to AKI. Some examples include:

• A type of severe, life-threatening infection called “sepsis”
• A type of cancer called “multiple myeloma”
• A rare condition that causes inflammation and scarring to your blood vessels, making them stiff, weak, and narrow (called “vasculitis”)
• An allergic reaction to certain types of drugs (called “interstitial nephritis”)
• A group of diseases (called “scleroderma”) that affect the connective tissue that supports your internal organs
• Conditions that cause inflammation or damage to the kidney tubules, to the small blood vessels in the kidneys, or to the filtering units in the kidneys (such as “tubular necrosis,” “glomerulonephritis, “vasculitis” or “thrombotic microangiopathy”).

Blockage of the urinary tract

In some people, conditions or diseases can block the passage of urine out of the body and can lead to AKI.

Blockage can be caused by:

• Bladder, prostate, or cervical cancer
• Enlarged prostate
• Problems with the nervous system that affect the bladder and urination
• Kidney stones
• Blood clots in the urinary tract

Heme pigment-containing proteins such as hemoglobin and myoglobin can behave as endotoxins in 3 ways

• Causing direct proximal tubular injury, tubular obstruction, or renal vasoconstriction.
• Crystal-induced nephropathy due to high cell turnover such as uric acid, calcium phosphate crystals in the setting of ongoing malignancy treatment.
• Light chain 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 that 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.[rx]

Decreased glomerular filtration rate (GFR) is associated with acute tubular necrosis, leading to 3 possible mechanisms of injury to the renal tubular epithelial cells:

• Afferent arteriolar vasoconstriction in response to tubuloglomerular feedback
• Backlink of glomerular filtrate
• Tubular obstruction

Clinical Phases

These injury patterns lead to the following 4 phases clinically:

Initiation

The initiation phase is characterized by an acute decrease in GFR and a sudden increase in serum creatinine and BUN concentrations.

Extension

The extension phase consists of 2 major events:

• Ongoing hypoxia following the ischemic event
• An inflammatory response

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.

Maintenance

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 the normal range, and the cells establish intracellular homeostasis.

Recovery

The recovery phase is the continuation of the maintenance phase in which cellular differentiation continues, and epithelial polarity is reestablished, improving the renal function.[rx][rx]

Symptoms of Acute Kidney Injury 

Signs and symptoms of acute kidney injury differ depending on the cause and may include:

• Too little urine leaving the body
• Swelling in legs, ankles, and around the eyes
• Fatigue or tiredness
• Shortness of breath
• Confusion
• Nausea
• Seizures or coma in severe cases
• Chest pain or pressure
• Not enough urine
• Swelling in your legs, ankles or feet
• Feeling tired
• Trouble catching your breath
• Feeling confused
• Pain or pressure in your chest

In some cases, AKI causes no symptoms and is only found through other tests done by your healthcare provider.

Diagnosis of Acute Kidney Injury

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

• Early: Changes range from swelling of the cell to focal tubular epithelial necrosis and apoptosis with desquamation of cells into the tubular lumen; dilated proximal tubules with loss or thinning of brush border; granular, hyaline, and pigmented cases especially in distal and collecting ducts; white blood cells in dilated vasa recta; interstitial edema; and eosinophilic hyaline casts of Tamm-Horsfall protein
• Later: Regeneration of epithelia (dilated tubular lumina, flattened epithelium, large nuclei with prominent nucleoli and mitotic activity)

Nephrotoxic Acute Tubular Necrosis

The nephrotoxic agents that lead to acute tubular necrosis can manifest as different features of histological damage, including:

• Ethylene glycol: Calcium oxalate crystals in tub[rx]
• Hemoglobin/myoglobin: Deeply pigmented, red-brown cast in the distal and collecting tubule.
• Carbon tetrachloride: Neutral lipid accumulation in injured cells followed by necrosis.
• Indinavir: Clear intraluminal crystals with mononuclear reaction.
• Lead: Intranuclear, dark inclusions, and necrosis.
• Mercury: large acidophilic inclusions.
• Tenofovir: Proximal tubular eosinophilic inclusions that represent giant mitochondria.
• Vancomycin: Acute interstitial nephritis with eosinophilic and lymphocytic infiltrate and acute tubular necrosis.[rx]

History and Physical

The history and physical examination give a lot of clues in identifying a person with the 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 antibiotics 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.

Lab Test and Imaging

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.

• Urinalysis (UA) – 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.
• Blood tests – Blood tests will help find levels of creatinine, urea nitrogen phosphorus and potassium should be done in addition to blood tests for protein in order to look at kidney function.
• Creatinine – is a waste product in your blood that’s made by muscle activity. Normally, it’s removed from your blood by your kidneys. But if your kidneys stop working, your creatinine level rises.
• Urea nitrogen – is another waste product in your blood. It’s created when protein from the foods is broken down. Like creatinine, your kidneys remove this from your blood. When your kidneys stop working, your urea nitrogen levels rise.
• Serum potassium – is a substance found in your blood that balances water levels in your bloodstream. Kidney disease can cause either high or low potassium levels.
• Serum sodium – is another substance in your blood that helps with fluid balance in your body.  High sodium levels can mean that your kidneys aren’t working properly because your body can’t get rid of the right amount of sodium.
• GFR – Your blood test will also help find your GFR (glomerular filtration rate) to estimate the decrease in kidney function
• 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%.[rx]
• 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. [rx]
• Novel Biomarkers – 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 renal ischemia after distal tubular injury.[rx][rx]
• Urine output measurement. This measures how much urine you pass in 24 hours. You will get a container to take home, pee into, and then return to the lab after a full 24 hours. It can help your doctor determine why you’re having kidney failure.
• Removing a sample of kidney tissue for testing. In some situations, your doctor may recommend a kidney biopsy to remove a small sample of kidney tissue for lab testing. Your doctor inserts a needle through your skin and into your kidney to remove the sample.

Treatment of Acute Kidney 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 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 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.[rx]

• Diet. Your doctor will limit the amount of salt and potassium you get until your kidneys heal. That’s because both of these substances are removed from your body through your kidneys. Changing how and what you eat won’t reverse acute kidney failure. But your doctor may change your diet while they treat the conditions that caused it. This may mean treating a health problem like heart failure, taking you off certain medications, or giving you fluids through an IV if you’re dehydrated. If your doctor has put you on a low potassium diet, you’ll need to cut back on high-potassium foods like bananas, spinach, oranges, potatoes, and tomatoes.  On the other hand, you can eat more low-potassium foods like apples, strawberries, grapes, and cauliflower.
• Dialysis. If your kidney damage is severe enough, you may require hemodialysis until your kidneys can heal. Dialysis does not help kidneys heal but takes over the work of kidneys until they do. If your kidneys don’t heal, dialysis could be long-term.

Treating complications until your kidneys recover

Your doctor will also work to prevent complications and allow your kidneys time to heal. Treatments that help prevent complications include:

• Treatments to balance the amount of fluids in your blood. If your acute kidney failure is caused by a lack of fluids in your blood, your doctor may recommend intravenous (IV) fluids. In other cases, acute kidney failure may cause you to have too much fluid, leading to swelling in your arms and legs. In these cases, your doctor may recommend medications (diuretics) to cause your body to expel extra fluids.
• Medications to control blood potassium. If your kidneys aren’t properly filtering potassium from your blood, your doctor may prescribe calcium, glucose or sodium polystyrene sulfonate (Kionex) to prevent the accumulation of high levels of potassium in your blood. Too much potassium in the blood can cause dangerous irregular heartbeats (arrhythmias) and muscle weakness.
• Medications to restore blood calcium levels. If the levels of calcium in your blood drop too low, your doctor may recommend an infusion of calcium.
• Dialysis to remove toxins from your blood. If toxins build up in your blood, you may need temporary hemodialysis — often referred to simply as dialysis — to help remove toxins and excess fluids from your body while your kidneys heal. Dialysis may also help remove excess potassium from your body. During dialysis, a machine pumps blood out of your body through an artificial kidney (dialyzer) that filters out waste. The blood is then returned to your body.

Lifestyle and home remedies

During your recovery from acute kidney failure, your doctor may recommend a special diet to help support your kidneys and limit the work they must do. Your doctor may refer you to a dietitian who can analyze your current diet and suggest ways to make your diet easier on your kidneys.

Depending on your situation, your dietitian may recommend that you:

• Choose lower potassium foods. Your dietitian may recommend that you choose lower potassium foods. High-potassium foods include bananas, oranges, potatoes, spinach and tomatoes. Examples of low-potassium foods include apples, cauliflower, peppers, grapes and strawberries.
• Avoid products with added salt. Lower the amount of sodium you eat each day by avoiding products with added salt, including many convenience foods, such as frozen dinners, canned soups and fast foods. Other foods with added salt include salty snack foods, canned vegetables, and processed meats and cheeses.
• Limit phosphorus. Phosphorus is a mineral found in foods, such as whole-grain bread, oatmeal, bran cereals, dark-colored colas, nuts and peanut butter. Too much phosphorus in your blood can weaken your bones and cause skin itchiness. Your dietitian can give you specific recommendations on phosphorus and how to limit it in your particular situation.

As your kidneys recover, you may no longer need to eat a special diet, although healthy eating remains important.

Complications

Potential complications of acute kidney failure include:

• Fluid buildup. Acute kidney failure may lead to a buildup of fluid in your lungs, which can cause shortness of breath.
• Chest pain. If the lining that covers your heart (pericardium) becomes inflamed, you may experience chest pain.
• Muscle weakness. When your body’s fluids and electrolytes — your body’s blood chemistry — are out of balance, muscle weakness can result.
• Permanent kidney damage. Occasionally, acute kidney failure causes permanent loss of kidney function, or end-stage renal disease. People with end-stage renal disease require either permanent dialysis — a mechanical filtration process used to remove toxins and wastes from the body — or a kidney transplant to survive.
• Death. Acute kidney failure can lead to loss of kidney function and, ultimately, death.

Prevention

Acute kidney failure is often difficult to predict or prevent. But you may reduce your risk by taking care of your kidneys. Try to:

• Pay attention to labels when taking over-the-counter (OTC) pain medications. Follow the instructions for OTC pain medications, such as aspirin, acetaminophen (Tylenol, others), ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve, others). Taking too much of these medications may increase your risk of kidney injury. This is especially true if you have pre-existing kidney disease, diabetes or high blood pressure.
• Work with your doctor to manage kidney and other chronic conditions. If you have kidney disease or another condition that increases your risk of acute kidney failure, such as diabetes or high blood pressure, stay on track with treatment goals and follow your doctor’s recommendations to manage your condition.
• Make a healthy lifestyle a priority. Be active; eat a sensible, balanced diet; and drink alcohol only in moderation — if at all.

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