Video by Dr Patrick Harnett - Consultant physician and nephrologist (2:57)
An acute kidney injury (AKI) is a clinical syndrome in which there is a rapid reduction in kidney function leading to a rise in serum creatinine and/or reduced urine output (oliguria). This leads to an inability to maintain electrolyte, acid-base and fluid homeostasis which can result in the following signs and symptoms:
Electrolyte imbalance: The patient may present with hyperkalaemia, hypo- or hyper-natraemia, acid-base disorders and arrythmia.
Uraemia: This can lead to nausea, vomiting, fatigue, anorexia, weight loss and headache.
Impaired fluid homeostasis: Pulmonary and peripheral oedema may develop.
This page will cover the aetiology and diagnosis of AKI.
2019 guidelines by the National Institute of Health and Care Excellence (NICE) defines the presence of an AKI with any one of the following criteria:
A rise in serum creatinine of 26 micromol/litre or greater within 48 hours.
A 50% or greater rise (>1.5x baseline) in serum creatinine known or presumed to have occurred within the past 7 days.
A fall in urine output to less than 0.5 ml/kg/hour for more than 6 hours in adults and more than 8 hours in children and young people.
A 25% or greater fall in eGFR in children and young people within the past 7 days.
The causes of AKI are commonly divided into three major categories based on the anatomical location of pathophysiology behind the syndrome.
The hallmark of a prerenal AKI is reduced renal perfusion. The most common cause is secondary to hypovolaemia (a decrease in circulating volume). Other causes include cardiogenic shock, distributive shock, impaired autoregulation, renal vessel occlusion and hepatorenal syndrome. There is no structural abnormality to the kidney and therefore a prerenal AKI will respond to a restoration of renal perfusion. It is the most common type of AKI.
A prolonged reduction in renal perfusion may lead to ischaemia and an acute tubular necrosis (see intrinsic AKI). This may not respond to a restoration of renal perfusion.
The first part of the renal nephron is known as the renal corpuscle. It consists of the glomerulus (a densely packed cluster of capillaries) and the Bowman’s capsule. Blood flows into the glomeruli via afferent arterioles and exits via efferent arterioles.
The hydrostatic pressure of the fluid on the capillary walls in the glomerulus causes filtration of blood plasma into the Bowman’s capsule. The hydrostatic pressure is determined by the blood pressure in the glomerulus. As a result, if there is decreased perfusion of blood into the glomeruli, whether this be due to hypovolaemia or hypotension, there will be a lower filtration pressure in the glomerulus and hence a drop in the eGFR.
This leads to reduced excretion of electrolytes, fluid and metabolic waste leading to the signs and symptoms of an acute kidney injury.
A reduction in circulating volume results in a decreased flow of plasma into the glomeruli. Hypovolaemia may be caused by four main mechanisms:
Dehydration: This is a common cause in those with cognitive impairment who are unable to source oral fluids for themselves, such as delirium or dementia.
Bodily fluid loss: This may be due to vomiting, diarrhoea, haemorrhage, excessive sweating and burns.
Diuresis: Excessive loss of water in the kidneys. This may be due to use of pharmacological diuretics or endocrine diseases such as Addison’s disease, diabetes mellitus and diabetes insipidus.
Third space losses: Third space losses: This is loss of fluid into extravascular compartments, such as in acute pancreatitis hypoalbuminaemia and in distributive shock (see below).
If the blood pressure in the glomerulus drops, so does hydrostatic pressure and the filtration rate. In addition to hypovolaemia, are five major mechanisms by which this may occur:
Cardiogenic shock: Shock (a sudden drop in blood pressure) is where there is an impairment of left ventricular function to effectively perfuse the organs of the body. This may be due to cardiac mechanical dysfunction (such as following a myocardial infarction), arrhythmia or a cardiomyopathy.
Distributive shock: Shock caused by improper distribution of blood flow resulting in inadequate perfusion of certain tissues and organs, such as the kidneys and alimentary canal. Causes include sepsis, pancreatitis, anaphylaxis, burns, and in adrenal insufficiency crisis.
Impaired autoregulation: A stable glomerular filtration rate is maintained by the mechanism of tubuloglomerular feedback and regulation of the renin-angiotensin system (RAS). Use of non-steroidal anti-inflammatory drugs (NSAIDs) or angiotensin-converting-enzyme (ACE) inhibitors interfere with this and reduce the eGFR.
Renal vessel occlusion: Partial or complete obstruction of blood flow to the kidney which may occur in renal artery stenosis, or thrombosis of the artery or vein.
Hepatorenal syndrome: Patients with cirrhosis or fulminant liver failure are at risk of developing hepatorenal syndrome, a syndrome in which there is a rapid development of a prerenal AKI due to decreased renal blood flow.
The macula densa, located at the junction of the thick ascending limb and the distal convoluted tubule of the renal nephron, senses the concentration of sodium chloride (NaCl) in the nephron and helps regulate glomerular filtration via a mechanism known as tubuloglomerular feedback.
A low NaCl is indicative of poor glomerular filtration. The cells in the macula densa detect this and through signalling pathways cause smooth muscle in afferent arterioles to relax, causing vasodilation. In addition, there will be production of prostaglandin E2 which acts to cause renin release from juxtaglomerular cells. The renin-angiotensin system (RAS) causes systemic vasoconstriction. In the kidneys, its vasoconstrictive effect on the efferent arterioles is much more profound then on the afferent ones. The combined effect of afferent arteriole vasodilation and efferent arteriole vasoconstriction leads to an increase in glomerular filtration.
A high NaCl is indicative of effective glomerular filtration. The cells in the macula densa detect this and signal to afferent arteriole smooth muscle cells to cause arteriole vasoconstriction. In addition, the macula densa signals to inhibit renin release from juxtaglomerular cells. The reduced activity of the renin-angiotensin system (RAS) leads efferent arteriole vasodilation. This combined effect of afferent arteriole vasoconstriction and efferent arteriole vasodilation leads to a decrease in glomerular filtration.
Both NSAIDs (which inhibit prostaglandin E2 production) and ACE inhibitors (which inhibits activity of the renin-angiotensin system) lead to a decrease in glomerular filtration predisposing patients to AKI.
In renal artery stenosis (renovascular disease), there is narrowing of the renal arteries due to atherosclerosis (90% cases) or fibromuscular dysplasia (an angiopathy in which there is abnormal growth of smooth muscle and collagen in the arterial wall).
This leads to a glomerular hypotension and reduced glomerular filtration. As a consequence of tubuloglomerular feedback (see the “impaired autoregulation” box above) there will be increased activity of the renin-angiotensin system (RAS); vasoconstriction of efferent arterioles will be essential to maintaining glomerular filtration. As a result of the increased RAS activity on other arteries in the body, patients with renal artery stenosis will have renovascular hypertension.
Use of an ACE inhibitor will cause efferent arteriole vasodilation as it impedes the effect of the RAS. This will result in a decrease in glomerular filtration. As a result, ACE inhibitors pose a significant risk to developing AKI in those with renal artery stenosis.
Intrinsic (renal) AKI
Intrinsic, or renal AKI is caused by structural injury to the kidney. As a result, restoration of renal perfusion will have no impact on its resolution. Injury may occur at the glomerulus, the renal tubule, the renal interstitium or the small vessels surrounding the nephrons. The damage may affect excretion and/or reabsorption of water, electrolytes and waste products leading to the features of AKI.
Glomerulonephritis an umbrella term used for many different diseases which cause inflammation of the glomeruli and surrounding structures.
The renal corpuscule is made up of the glomerular capillaries which are surrounded by intraglomerular mesangial cells. A basement membrane envelopes the mesangium, separating it from the podocyte foot processes which make up the inner epithelial lining of the Bowman’s capsule.
Glomerular diseases cause injury to these structures. Proteins may pass through the cell membranes and into the Bowman’s capsule resulting in what is known as nephrotic syndrome (proteinuria, hypoalbuminaemia, oedema and hyperlipidaemia).
Inflammation can result in basement membrane thinning and the creation of pores in the podocytes. This may allow further substances such as red blood cells to pass through and the patient will present with a nephritic syndrome (features of nephrotic syndrome + hypertension, haematuria, oliguria and/or uraemia). There is a marked reduction in glomerular filtration resulting in an intrinsic AKI.
The causes of glomerular disease may be classified by their histopathological effects:
Non-proliferative glomerular disease
These diseases do not cause cell proliferation. They tend to present with a bephrotic syndrome. Causes include minimal change disease, focal segmental glomerulosclerosis, diabetic glomerulosclerosis (Kimmelstiel-Wilson syndrome), amyloidosis and membranous nephropathy.
The latter disease can progress into a membranous glomerulonephritis in which there is inflammation of the glomerular basement membrane. This may present with a nephritic syndrome.
These diseases cause proliferation of the glomerular mesangium. They tend to present with a nephritic syndrome as the basement membrane and podocytes are also commonly affected.
Mesangial proliferative glomerulonephritis is a focal glomerulonephritis which primarily affects the mesangium.
Diffuse glomerulonephritides include membranoproliferative glomerulonephritis, post-infection glomerulonephritis, lupus nephritis and rapidly progressive (crescentic) glomerulonephritis.
Acute tubular necrosis
Acute tubular necrosis (ATN) is a disease in which there is death of tubular epithelial cells of the nephron. It is the most common reason for an intrinsic AKI. It can sometimes be difficult to reverse; the best management is to treat the aetiological factor:
Ischaemia: A prolonged prerenal AKI can lead to ischaemia of the nephron and cell death.
Exogenous nephrotoxins: Nephrotoxic mediations such as gentamicin and vancomycin may directly cause cell death. NSAIDs can cause a prolonged prerenal AKI which leads to ischaemia (see “prerenal AKI”).
Endogenous nephrotoxins: Some disease produce toxigenic substances can damage renal tubules. Examples include light-chains in myeloma, myoglobin in rhabdomyolysis and uric acid in haematological malignancy and tumour lysis syndrome.
Acute tubulointerstitial nephritis
Tubulointerstitial nephritis describes inflammation of the tubular interstitium, that is the space in between the renal tubules and capillaries. It is an inflammatory reaction that is almost always caused by drugs, such as antibiotics, proton pump inhibitors, NSAIDs and monoclonal antibodies. The patient may present with a fever, rash or arthralgia and will often have an eosinophilia.
Small vessel disease
Systemic small vessel disease can affect the capillaries surrounding the renal tubules. Causes include vasculitis, malignant hypertension, and thrombotic microangiopathies such as thrombotic thrombocytopaenic purpura and haemolytic uraemic syndrome.
Note that small vessel disease may affect the glomerulus. ANCA-associated vasculitides for example can cause a type III rapidly progressive glomerulonephritis.
Postrenal AKI is caused by downstream obstruction to the flow of urine. As a result, there is swelling of the kidney (hydronephrosis), an increase in intratubular pressure and a decrease in glomerular filtration. Immediate relief of the obstruction will lead to a restoration of glomerular filtration with no structural damage.
Causes are usually mechanical in nature; however, they may also be secondary to pharmacological effects:
Luminal obstruction: Obstruction of the inner tube of the urethra. This may be due to urolithiasis (renal stones), blood clots in frank haematuria or an obstructed urinary catheter.
Mural obstruction: Obstruction caused by pathology in the wall of the urethra. Fibrosis secondary to scarring, urethral strictures and malignancy are common causes.
Extramural obstruction: External compression of the urethra may be seen in prostatic hypertrophy and pelvic malignancy.
Trauma: Trauma to the urethra, whether this be by an external (a “straddle” injury) or internal (traumatic catheterisation) cause, will cause inflammation +/- scarring of the urethra. Trauma may also lead frank haematuria and blood clots.
Medication: Certain medications, such as those with anticholinergic properties, may inhibit bladder activity leading to urinary retention.
Note that a prolonged obstruction can cause glomerular, tubular and interstitial damage resulting in an intrinsic AKI.
Investigation of AKI must be tailored towards your differential diagnosis (see the “other investigations” box) below. As prerenal AKI is the most common cause of AKI, often fluid resuscitation is enough to manage the condition. However, in unresolving AKI a urine dipstick test, ultrasound scan and renal biopsy should be strongly considered.
An ECG will help identify or detect early signs of electrolyte abnormality.
Blood tests are essential for both detection of AKI and narrowing your differential diagnosis. A renal profile is essential in staging your AKI and detecting electrolyte abnormalities. Other tests you should consider are:
Venous blood gas: For acid-base assessment and quick identification of electrolyte abnormality.
Full blood count and C-reactive protein: Raised inflammatory markers are pertinent in assessment of a septic patient. An eosinophilia may point toward tubulointerstitial nephritis.
Liver profile and clotting: Useful in patients with known liver disease to exclude hepatorenal syndrome or identification of hypoalbuminaemia in those with suspected nephrotic syndrome.
Serology: Detection of complement and antibodies in patients with suspected glomerulonephritis or vasculitis.
Amylase: If pancreatitis is suspected.
ESR and serum electrophoresis: If myeloma is suspected.
Blood film: If a thrombotic microangiopathy is suspected.
A urine protein:creatinine or albumin:creatinine ratio will be essential for diagnosis of a nephrotic syndrome. Urine sodium, creatinine and osmolality can help differentiate between a prerenal and intrinsic AKI.
If myeloma is suspected, consider urine electrophoresis.
Chest X-ray: To identify pulmonary oedema.
CT kidneys, ureter and bladder: If urolithiasis is suspected.
Urethrogram: If urethral injury is suspected/
In addition to renal ultrasound, you may wish to consider:
This may be indicated if malignancy is suspected or, if there is urinary obstruction and a urethral/suprapubic catheterisation is contraindicated.
A urine dip will give information on urinary levels of blood, protein, leucocytes, nitrites and glucose. This will help to detect conditions such as glomerulonephritis (proteinuria, haematuria) and acute tubulointerstitial nephritis (haematuria, leucocytes).
An ultrasound scan will identify any hydronephrosis and postrenal AKI.
In AKI with no identifying cause, the NICE guideline development group recommend performing an ultrasound scan within 24 hours of assessment. If infection is also suspected, then the scan should be performed within 6 hours of assessment.
If prerenal and postrenal causes of AKI have been excluded, then a discussion with a nephrologist should be had. They may suggest performing a renal biopsy, which is the most useful test in identifying the cause of an intrinsic AKI.
NICE recommends monitoring serum creatinine, monitoring urine output and using trigger systems (such as the National Early Warning Score 2) in all persons with or at risk of developing AKI.
Risk factors for developing an acute kidney injury include but are not limited to those with:
Increasing age (particularly those aged ≥65).
Chronic kidney disease (particularly in children or in adults with an estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2).
Heart failure, liver disease, diabetes mellitus or diabetes insipidus.
Sepsis and hypovolaemia.
Nephrotoxic drugs or use of iodine-based contrast media.
Very young age or cognitive impairment leading to reduced oral fluid access.