23rd June 2023

Acute Kidney Injury

Classification of acute kidney injury (AKI)

AKI definitions

Acute kidney injury is the term used to describe a rapid deterioration in renal function, generally over a period of hours to days. It is a common feature amongst hospital inpatients and is associated with adverse outcomes such as increased length of stay and increased mortality. It is a clinical syndrome with a separate underlying cause – identifying and managing this precipitating disorder is key to management.

Staging of acute kidney injury

Recommendations from NICE and the UK Renal Association suggest the use of the KDIGO (Kidney Disease: Improving Global Outcomes) criteria:

Pre-renal AKI

A pre-renal AKI is caused by a reduction in renal blood flow. Causes include:

• Reduced actual circulating volume:
  • Haemorrhage
  • Dehydration
  • Excess gastrointestinal or urinary losses, e.g. osmotic diuresis secondary to hyperglycaemia
  • Third-space loss of fluid, e.g. pancreatitis
  • Burns
• Reduced apparent circulating volume – may not necessarily be overall volume depletion, but effective circulating volume and, therefore, renal perfusion reduced for another reason
  • Peripheral vasodilatation e.g. sepsis
  • Reduced cardiac output
• Intrarenal haemodynamic changes
  • Non-steroidal anti-inflammatory drugs (inhibition of prostaglandin synthesis, reducing afferent artery dilatation)
  • ACE inhibitors (oppose efferent artery vasoconstriction, reducing perfusion pressure)

Intrinsic renal AKI

This encompasses disease processes which affect the renal parenchyma. Causes can be stratified by the location affected:

• Vascular
  • Large vessel disease – renal artery occlusion (e.g. cholesterol embolus, thrombosis), renovascular disease or renal vein pathology (e.g. thrombus)
  • Small vessel disease and glomerulonephritis – glomerulonephritides (see Glomerular diseases section), thrombotic microangiopathies (e.g. haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura), scleroderma, pre-eclampsia, malignant hypertension
• Tubulointerstitium
  • Acute tubular necrosis (see below), rhabdomyolysis, tumour lysis syndrome, cast nephropathy (e.g. due to myeloma), acute interstitial nephritis (e.g. drug-induced or secondary to infections), contrast nephropathy

Acute tubular necrosis (ATN)

Prolonged pre-renal AKI can lead to acute tubular necrosis; it can also be caused by intrinsic disorders, e.g. rhabdomyolysis, drugs, and contrast. The pathogenesis is complex, however centres around vascular supply to the renal tubules. Reduced blood flow results in vasoconstriction, leading to cell hypoxia; areas particularly vulnerable to this include the proximal convoluted tubule and the ascending loop of Henle. Cells die, and the resulting debris enters the tubular lumen, where it can form casts that cause obstruction. Other factors involved include backleak of filtrate through damaged tubules and injury to the vascular endothelium. Tubular structure and function can recover after some time once the blood supply has normalised; patients will frequently experience a period of polyuria before the tubules are able to concentrate urine again.

Post-renal AKI

A post-renal AKI is caused by an obstruction in the anatomy of the renal tract, preventing the free flow of urine. Resulting increased pressure on the kidneys can directly affect function, which can persist if the obstruction is not relieved in a timely manner. An impact on renal function is more likely in cases of obstruction of a single kidney or a process causing bilateral obstruction.

Common causes include:

• Prostate hypertrophy
• Haematuria causing clot retention
• Abdominal/pelvic masses
• Ureteric stones
• Neurological causes of urinary retention

Investigation of acute kidney injury

History and examination

A thorough history and examination of the patient will often provide some clues regarding diagnosis. Some example question and examination points to include below:

History

• Pre-renal – increased fluid losses/decreased fluid intake, cardiac issues, infection +/- sepsis.
• Intrinsic – symptoms of systemic connective tissue disease or vasculitis, full drug history, infections, malignancy, periods of prolonged immobility/trauma/limb ischaemia, source of emboli, cardiovascular disease or endovascular intervention
• Post-renal – abdominal pain, haematuria, lower urinary tract symptoms, history of prostatic symptoms

Examination

• Pre-renal – volume status assessment, urine output
• Intrinsic – signs of cardiovascular/peripheral vascular disease, rash, synovitis, mouth ulcers, uveitis, nail changes, epistaxis, pulmonary haemorrhage, signs of connective tissue disease
• Post-renal – palpable bladder, enlarged prostate, abdominal masses

Further investigations

Urinalysis

Urine dip

• If haematoproteinuria is present (and is not related to catheterisation or infection), it may indicate an active glomerulonephritis, vasculitis, or myeloma. It is useful to quantify this further with a urinary protein:creatinine ratio and sending an acute renal screen (see below).
• A ‘bland’ urine dip (i.e. no blood or protein) is more suggestive of a pre-renal AKI, post-renal AKI, interstitial nephritis or atheroembolic disease.
• Myoglobinuria will give a urine dip positive for blood.

Microscopy

• Red cells – cells can be dysmorphic in glomerular sources of bleeding
• White cells – infection, interstitial nephritis, atheroembolic disease
• Casts – various components: red cells (glomerulonephritis); white cells (pyelonephritis, interstitial nephritis); tubular cells (acute tubular necrosis); myoglobin
• Crystals (this requires examination under polarised light)

Urine biochemistry

• This is rarely performed in clinical practice. However, its role in recognising tubular function and differentiating ATN from pre-renal AKI remains a popular exam topic.
• In a pre-renal AKI, the concentrating ability of the renal tubules is maintained, and they act to retain salt, leading to a low urinary sodium or a fractional sodium excretion percentage (ratio of sodium clearance to creatinine clearance) of <1%.
• In ATN, the normal concentrating function of the tubules is lost, and the kidneys will not be able to concentrate urine, leading to a high urinary sodium or a fractional sodium excretion percentage of >2%. This can be affected by diuretics and other clinical states, such as hepatorenal syndrome, which will result in biochemistry in keeping with a pre-renal state.

Bloods

The choice of which investigations to send depends on the clinical scenario. Blood tests may help assess the severity of the AKI and identify serious/life-threatening problems or to identify the underlying cause.

Point of care testing

• A venous or arterial blood gas will quickly identify emergencies such as hyperkalaemia or severe acidosis.

Haematology

• Full blood count – anaemia (check for signs of haemolysis), thrombocytopenia (consider thrombotic microangiopathies (TMA), disseminated intravascular coagulation), raised white cell count (infection/sepsis, interstitial nephritis), bone marrow infiltration.
• Blood film – red cell fragments, thrombocytopenia (consider TMA).

Biochemistry

• Urea and electrolytes
• Liver function tests – raised bilirubin in conditions associated with haemolysis; raised transaminases may be from a muscle rather than a hepatic source, e.g. rhabdomyolysis.
• Bone profile – generally low calcium and high phosphate, but hypercalcaemia can be associated with specific causes, e.g. myeloma.
• Creatine kinase if suspected rhabdomyolysis; consider in cases of extreme exertion, crush injuries, compartment syndrome, and fall with a long lie.
• Others, e.g. CRP, urate

Renal screen

• Antinuclear antibodies (ANA) – specific subtypes include anti-double stranded DNA (anti-dsDNA)
• Anti-neutrophil cytoplasmic antibodies (ANCA) – two main patterns: cytoplasmic (c-ANCA, typically anti-proteinase 3) or perinuclear (p-ANCA, typically anti-myeloperoxidase)
• Anti-glomerular basement membrane antibody (anti-GBM)
• Antistreptolysin O titres – post-streptococcal glomerulonephritis
• Serum and urine protein electrophoresis – myeloma screen
• Immunoglobulins (IgG, IgA, IgM)
• Rheumatoid factor (RhF)– positive in vasculitis associated with rheumatoid arthritis, cryoglobulinaemia
• Complement levels – C3 and C4
• Cryoglobulins – consider only if suspicious clinical syndrome and/or risk factors such as hepatitis C
• Blood-borne virus screen – hepatitis B and C, and HIV can be associated with various forms of renal impairment. It is also useful to know status if haemodialysis is required as patients may need an isolated machine.

Imaging/tissue/other

Imaging

• Imaging of the renal tract (most easily performed via ultrasound) should be performed urgently, primarily for the purpose of ruling out obstruction. Another useful finding is kidney size; chronic renal impairment is suggested by kidneys that appear scarred and shrunken.
• Chest radiograph – consider if there is clinical suspicion of complications such as pulmonary oedema or pulmonary haemorrhage.
• Echocardiogram – to assist fluid status assessment and to assess for complications such as pericardial effusion secondary to uraemia.

Tissue

• A renal biopsy can be considered in cases of intrinsic AKI of unclear cause or where there is suspicion of a condition requiring specific treatment, e.g. a glomerulonephritis, thrombotic microangiopathy or tubulointerstitial nephritis. However, it is important to recognise that this is an invasive procedure, and risks/benefits need to be balanced carefully.

ECG

• An ECG in cases of hyperkalaemia is essential to rule out life-threatening arrythmias.

Management of acute kidney injury

General principles

Management of an acute kidney injury will depend on the underlying cause, however, principles that can be applied in all scenarios or until the cause is known include:

• Ensure obstruction has been excluded
• Review drug chart – hold nephrotoxic drugs and ensure renal dosing of necessary drugs such as antibiotics.
• Fluid status management – avoid hypotension, which could worsen a renal insult, and resuscitate a hypovolaemic patient with a likely pre-renal AKI (being careful to reassess regularly and avoid fluid overload).
• Fluid balance monitoring – consider a catheter, ensure fluid inputs/outputs are documented and weigh the patient daily.
• Regular blood tests to check urea and electrolytes
• Maintain good nutrition – consider referring to a dietitian

Specific complications

Hyperkalaemia

The degree of hyperkalaemia tolerated by a patient will vary – patients with a chronically raised potassium level may tolerate hyperkalaemia better than those with an acute kidney injury. Additional factors such as a very quick rise in serum potassium, low serum calcium and coexisting acidosis may also exacerbate the problem. The most serious consequence of hyperkalaemia is cardiac dysrhythmias; it is essential to perform an ECG to identify abnormalities from mild changes (peaking or ‘tenting’ of T waves, P wave flattening, prolonged PR interval) to those approaching life-threatening (widening of the QRS complex, sine wave pattern, ventricular fibrillation).

Management of hyperkalaemia focuses on initial stabilisation of the myocardium, followed by measures to lower serum potassium:

• Calcium – intravenous calcium, often in the form of calcium chloride or calcium gluconate, acts quickly to stabilise the myocardium. It should be given if the potassium level is very high (>6.5mmol/L) or if there are ECG changes present; it can be repeated after 5 minutes if there is no ECG improvement. Caution is advised in patients taking digoxin as toxicity can be induced. Time to effect = minutes, duration of effect = <1 hour.
• Insulin and glucose – insulin acts to move potassium into cells. Monitor for and treat any resulting hypoglycaemia. The effect is temporary and can result in rebound hyperkalaemia. Time to effect = 15-30 minutes, duration of effect = 4-6 hours.
• Salbutamol – nebulised beta-2 agonists will act to move potassium into cells. Caution in patients with underlying cardiac disease and note that salbutamol use can increase serum lactate levels. This should be considered in addition to insulin/glucose, not given alone.
• Sodium bicarbonate – serum potassium is inversely related to serum pH, therefore, correcting an acidosis can reduce serum potassium. However, caution should be taken with the accompanying salt and fluid load in a patient at risk of volume overload.
• Diuretics – can be helpful in removing potassium through the urine if a patient has urine output and if there is accompanying volume overload. Note that higher doses of drugs like furosemide will be required as GFR worsens.
• Gut – potassium binders such as calcium Resonium® will exchange other cations (sodium/calcium) for potassium in the gut and aid its removal. They can result in constipation which will reduce efficacy.
• Further steps include ensuring that intravenous fluid prescriptions do not contain potassium, that a dietitian is involved in care to ensure a low potassium diet and that offending drugs such as ACE-inhibitors have been suspended.

Pulmonary oedema

Pulmonary oedema is a significant risk in patients with poor urine output who will be prone to fluid retention. Alongside standard supportive measures, such as oxygen therapy, the mainstay of treatment is diuretics. Patients with renal impairment will often require a high initial bolus dose, which can be continued if it causes a diuresis. However, if a high bolus dose results in no effect, escalation of care will be required (see below).

Metabolic acidosis

A metabolic acidosis can contribute to cardiac instability and hyperkalaemia. If severe, it can be treated with sodium bicarbonate, but this does carry a risk of salt and fluid overload. It is also important to ensure that other causes of metabolic acidosis have been ruled out, e.g. ketoacidosis.

Indications for renal replacement therapy (RRT)

An element of clinical judgement is important here with regards to patient suitability for dialysis and which modality is most appropriate (e.g. intermittent haemodialysis, continuous haemofiltration, haemodiafiltration, etc.). However, RRT should be discussed in the following cases if refractory to first line medical management:

• Severe hyperkalaemia
• Volume overload
• Acidosis (pH <7.2)
• Uraemia complications – e.g. pericarditis, encephalopathy