Acute Kidney Injury

1. Acute Kidney Injury
2. Pre-Renal Failure
3. Acute Tubular Necrosis
   
   • Pre-Renal Acute Kidney Injury vs Acute Tubular Necrosis
4. Intrinsic Renal Failure
   
   • Acute Interstitial Nephritis 
5. Post-Renal Failure
6. Investigations
7. Management
   
   • Indications for Dialysis
8. Quiz

• Acute kidney injury is an acute decline in the actual glomerular filtration rate (the true rate at which the kidneys filter blood, not an estimate). It is defined by either an increase in serum creatinine (a waste product measured in the blood) or a decrease in urine output. It is staged using either the serum creatinine or the urine output, with higher stages having an increased mortality risk.
• Acute kidney injury can be split into pre-renal (before the kidney, from poor blood flow), intrinsic (within the kidney itself) and post-renal (after the kidney, from blocked urine outflow) causes of renal failure.
• The symptoms of renal failure are non-specific (they do not point to one cause) and many patients have none, so AKI is usually identified on blood tests. When symptoms occur they include fatigue, loss of appetite, vomiting, nausea and confusion.
• Pre-renal failure is caused by reduced perfusion to the kidneys leading to a decreased filtration rate, even though the kidneys still retain their function and can reabsorb salt and water. Causes of pre-renal failure include hypovolaemia (low circulating blood volume), hypotension, cardiac failure, sepsis, angiotensin-converting enzyme (ACE) inhibitors (a class of blood pressure drug), non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen) and renal artery occlusion (blockage).
• Acute tubular necrosis (damage to the tubules, the small tubes in each nephron that process the filtered fluid) is the most common cause of intrinsic renal failure. The kidneys are unable to reabsorb salt and water effectively resulting in a loss of salt and water from the body. Acute tubular necrosis is caused by ischaemia, nephrotoxins (substances that damage the kidney) and sepsis.
• Intrinsic AKI includes injury to glomerular, tubular, interstitial (the tissue between the tubules) or vascular (blood vessel) structures. In tubular injury, impaired reabsorption and urine concentration typically produce higher urine sodium and lower urine osmolality (more dilute urine) than uncomplicated pre-renal AKI. This pattern is not universal across intrinsic AKI, and urinary indices must be interpreted in the clinical context. Causes include glomerular disease, nephrotoxins and renal ischaemia.
• Post-renal failure occurs when the ureter or urethra is obstructed. Back pressure builds up in the urinary tract and reaches the kidneys. This damages them and stops waste products and water leaving the body. Causes of post-renal failure include benign prostatic hyperplasia (non-cancerous enlargement of the prostate), renal stones and urological malignancy (cancer of the urinary tract).
• Acute kidney injury is investigated through urinalysis (testing the urine), serum biochemistry (blood tests) and imaging. Ultrasound is the usual first scan, with CT or MRI used if an obstruction is still suspected.
• Management of acute kidney injury depends on the cause and includes assessment of volume status, perfusion, medicines and complications. Give fluid resuscitation for hypovolaemia when appropriate, with repeated reassessment; additional fluid can harm an overloaded patient. Review potentially harmful medicines and adjust doses for reduced renal clearance. Refer immediately for renal replacement therapy (dialysis or a similar treatment that does the work of the kidneys) when any of the following do not respond to medical management: hyperkalaemia (high blood potassium), metabolic acidosis (blood that has become too acidic), complications of uraemia (a build-up of waste products such as urea in the blood), fluid overload or pulmonary oedema (fluid in the lungs).

Acute Kidney Injury

Acute kidney injury (AKI) is a clinical syndrome where there is an acute decline in the actual glomerular filtration rate (GFR), meaning the true rate at which the kidneys filter blood rather than an estimate. This disturbs the volume of fluid outside the cells (extracellular fluid), the balance of electrolytes (salts such as sodium and potassium) and acid-base homeostasis (the balance of acid and base in the blood), and allows nitrogenous waste (waste products that contain nitrogen, such as urea) to build up. Acute kidney injury can be split into pre-renal (before the kidney, from poor blood flow), intrinsic (within the kidney itself) and post-renal (after the kidney, from blocked urine outflow) causes of renal failure.

• If a decline in GFR persists for between 7 days and 3 months, then it is defined as acute kidney disease, but if the decline in GFR remains after 3 months then it is defined as chronic kidney disease.
• Around 15% of patients admitted to hospital will have an AKI, and about one in five emergency admissions are associated with AKI (source), with the percentage increasing the sicker patients get.

AKI is clinically defined as:

• An increase in serum creatinine by ≥ 26.5μmol/L within 48 hours (NICE gives this figure as 26 μmol/L),
• An increase in serum creatinine by ≥ 1.5x baseline levels within 7 days, or
• Urine output of < 0.5ml/kg/hour for 6 hours (NICE specifies more than 6 hours in adults, and more than 8 hours in children and young people)

AKI is staged using creatinine and urine output, assigning the highest stage reached by either measure. These staging criteria apply to a patient who meets the AKI definition.

• Stage 1 - 1.5–1.9 times baseline creatinine or an increase of ≥26.5 μmol/L; urine output <0.5 ml/kg/hour for 6–12 hours.
• Stage 2 - 2.0–2.9 times baseline creatinine or urine output <0.5 ml/kg/hour for ≥12 hours.
• Stage 3 - ≥3.0 times baseline creatinine, a creatinine of ≥353.6 μmol/L together with an acute rise (26.5 μmol/L or more within 48 hours, or 1.5 times baseline within 7 days), initiation of renal replacement therapy, urine output <0.3 ml/kg/hour for ≥24 hours, or anuria (almost no urine, defined below) for ≥12 hours. In patients under 18 years, a fall in eGFR (estimated GFR) to <35 ml/min/1.73 m² also meets Stage 3.

Even a modest rise in serum creatinine (stage 1 AKI) is potentially associated with a higher risk of death.

The patient’s urine output is used to help define the stage as well as the cause of the AKI. There are three main descriptions of urine output that are used:

• Oliguria - where the patient produces a reduced volume of urine. NICE describes it as a urine output of less than 0.5ml/kg/hour, the same cut-off used to define AKI. In absolute terms it is often given as < 500ml of urine per day or < 20ml per hour.
• Anuria - where the patient produces a very reduced volume of urine. It is defined as < 100ml of urine per day. This usually indicates blockage of urine flow or very severe damage to the kidneys.
• Non-oliguria - where the patient produces a normal volume of urine (800 to 2000 ml per day).

The symptoms of renal failure are non-specific (they do not point to one cause), and many people have none, especially if the AKI is mild. Some patients pass much less urine than usual. Other symptoms of renal failure include:

• Fluid retention and oedema
• Fatigue
• Loss of appetite
• Nausea
• Vomiting
• Shortness of breath
• Confusion

Pre-Renal Failure

Pre-renal failure results from decreased renal perfusion leading to a reduction in the glomerular filtration rate. This causes acute kidney injury as there is reduced flow to the kidneys which decreases the filtration of blood and decreases urine output. The kidneys are not yet impaired in pre-renal failure. They are just unable to maintain adequate blood flow. They will therefore often respond to careful fluid resuscitation (giving the patient intravenous fluids), provided the patient is hypovolaemic (has a low circulating blood volume) and does not have contraindications (reasons not to give fluid) such as fluid overload or decompensated (worsening and no longer controlled) heart failure. This will increase the blood volume and therefore increase blood flow to the kidney.

In pre-renal AKI, there is reduced blood flow to the kidneys, so they are unable to maintain the GFR. They work to restore the blood flow and raise the filtration rate back to normal through a variety of mechanisms. The kidneys act as if the body was in hypovolaemia, and so they increase the reabsorption of salt and water through the activation of the renin-angiotensin-aldosterone system (a hormone system that raises blood pressure and makes the kidneys keep salt and water) and the release of anti-diuretic hormone (a hormone that makes the kidneys keep water). This leads to urine becoming more concentrated with low sodium, as the body reabsorbs sodium and water. Concentrated urine with a low sodium level can help to distinguish pre-renal failure from other causes of AKI.

With ageing, the body’s ability to maintain normal kidney perfusion decreases meaning it is unable to respond appropriately to changes in blood pressure. This explains why elderly patients are more susceptible to the pre-renal causes of AKI: their kidneys adapt poorly to changes in kidney perfusion.

Causes of pre-renal failure include:

• Hypovolaemia
• Hypotension
• Renal artery occlusion
• Cardiac failure
• Systemic vasodilation - causes include sepsis, cirrhosis and anaphylaxis.
• Impaired renal autoregulation (the kidney keeping its own blood flow and filtration steady) - this can be caused by angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and non-steroidal anti-inflammatory drugs (NSAIDs).
  
  • ACE inhibitors and angiotensin receptor blockers prevent vasoconstriction of the efferent arteriole (the small vessel carrying blood away from the glomerulus) and so prevent the kidney from increasing the glomerular capillary pressure. This stops the kidney from increasing the GFR.
  • NSAIDs block the production of prostaglandins. Prostaglandins normally widen (vasodilate) the afferent arteriole (the small vessel carrying blood into the glomerulus), which raises the glomerular capillary pressure and the GFR. Without them the afferent arteriole stays narrower, so the pressure and the GFR fall.

Pre-renal failure can be distinguished from other types of acute kidney injury by the response to a fluid challenge. This involves giving the patient intravenous fluids to increase the perfusion to the kidney, which will cause an improvement in renal function in patients with pre-renal failure. Patients with other types of AKI will not respond as well.

Acute Tubular Necrosis

Acute tubular necrosis (ATN) is the most common cause of intrinsic renal failure (where the pathology lies within the kidney itself). Despite its name, there is typically minimal necrosis to the kidney tubules. ATN is commonly seen in hospital and is associated with a high morbidity and mortality so needs to be identified quickly.

In ATN there is damage to the tubule cells of the nephron that is either reversible or irreversible. It is caused by ischaemia, nephrotoxins or sepsis, often being a combination of two or more of these. The damaged cells are unable to reabsorb salt and water effectively. This inability can help to tell whether a patient has a pre-renal AKI or ATN.

There are three phases in ATN: initiation, maintenance and recovery. In the initiation phase, there is a decrease in the glomerular filtration rate (i.e. the patient develops AKI). In the maintenance phase the reduction in GFR persists, often for days to weeks, depending on the severity and cause. The recovery phase is characterised by the return of normal tubular function with urine output returning to pre-ATN levels.

Ischaemic causes of ATN are very similar to pre-renal causes of AKI, as they reduce the blood flow to the kidney and cause ischaemia. Some examples include hypovolaemia (e.g. dehydration, haemorrhage, diuretics), heart failure (a weakened heart pumps less blood to the kidneys) and anaphylaxis.

In sepsis, systemic vasodilation and the release of toxins occur which together cause ATN. Each of these can damage the kidneys, either by direct damage to the tubule cells or by causing ischaemia of these tubule cells.

Nephrotoxins damage the tubule cells to cause cell injury and cell death. The risk of acute tubular necrosis is increased if there is decreased perfusion to the kidney alongside the nephrotoxic damage. Nephrotoxins can either be endogenous (made in the body) or exogenous (from outside the body). Endogenous nephrotoxins include urate (a salt of uric acid), bilirubin and myoglobin (the oxygen-carrying protein in muscle; high levels released in rhabdomyolysis, the breakdown of muscle tissue, are a well-known cause of ATN). Exogenous nephrotoxins include aminoglycosides (a class of antibiotics that includes gentamicin), radiographic contrast media (the dye used in some scans), cisplatin (a chemotherapy drug), aciclovir (an antiviral drug) and calcineurin inhibitors (immunosuppressant drugs such as ciclosporin).

Recovery from acute tubular necrosis can take several weeks and the treatment is mainly supportive, via maintaining kidney perfusion, avoiding nephrotoxins and treating any identifiable cause.

Pre-Renal Acute Kidney Injury vs Acute Tubular Necrosis

Pre-renal AKI and acute tubular necrosis can present very similarly. Some key differences can help to tell them apart, particularly the urine osmolality (how concentrated the urine is) and urinary sodium levels. However, these are not always reliable in isolation. Pre-renal AKI has a high urinary osmolality and a low urinary sodium whereas ATN has a low urine osmolality and a high urinary sodium. Pre-renal AKI has a low urinary sodium as the body tries to retain sodium to increase the blood pressure and so there is an increased reabsorption of sodium. In ATN, the damaged tubule cells cannot reabsorb sodium so it is lost in the urine.

Table - Typical differences between pre-renal AKI and tubular injury. These patterns can support assessment but do not establish the cause on their own; urinary indices may overlap and are affected by medicines and the clinical setting.

SimpleMed original by Dr. Thomas Burnell

Intrinsic Renal Failure

Intrinsic renal failure is an AKI where something damages the glomerulus, the tubules, the interstitium (the tissue between the tubules) or the blood vessels of the kidney, causing tissue injury and so decreasing the glomerular filtration rate. Some examples of intrinsic AKI causes include glomerulonephropathies (diseases of the glomeruli, e.g. immunoglobulin A (IgA) glomerulonephritis), nephrotoxins, renal ischaemia, systemic lupus erythematosus (an autoimmune disease that can affect many organs) and infection.

With intrinsic AKI due to tubular injury, damaged tubular cells reabsorb sodium less effectively and lose some ability to concentrate urine. A higher urine sodium and lower urine osmolality than in uncomplicated pre-renal AKI are therefore typical. These findings are not universal across intrinsic AKI: glomerular and interstitial disease may differ, and medicines and the clinical setting can affect urinary indices. Interpret them alongside volume status and urine microscopy.

Acute Interstitial Nephritis

Acute interstitial nephritis is acute immune-mediated inflammation of the renal tubule interstitium (the tissue between the kidney tubules). It presents similarly to other causes of acute renal failure, so acute interstitial nephritis can be difficult to distinguish from other causes of AKI. If a patient is thought to have acute interstitial nephritis then it is important to identify potential causes and manage them appropriately, such as stopping the medicine that triggered it. Drug-induced acute interstitial nephritis is usually an idiosyncratic (unpredictable) delayed hypersensitivity reaction (an immune reaction that develops over days), rather than a direct toxic effect on the kidney.

Acute interstitial nephritis is caused by:

• Medications - examples include penicillin, proton pump inhibitors (acid-reducing drugs such as omeprazole), NSAIDs and furosemide (a diuretic).
• Infections - examples include acute bacterial pyelonephritis (kidney infection), renal tuberculosis and fungal nephritis.
• Autoimmune Diseases - examples include systemic lupus erythematosus, granulomatosis with polyangiitis (an autoimmune inflammation of small blood vessels) and Sjögren’s syndrome (an autoimmune condition mainly affecting the tear and salivary glands).

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