Quick tip: in most patients the cause of AKI is pre-renal and multifactorial. If it’s not and there’s no hydronephrosis on imaging, consider rare causes.
When approaching AKI it is helpful to consider pre-renal, renal and post-renal causes.
- Pre-renal AKI accounts for >80% of AKI.
- Post-renal AKI accounts for >10% of AKI.
- Renal causes of AKI are relatively rare but are the ones that you don’t want to miss. Rapidly progressive glomerulonephritis requires urgent, specific treatment that can save a patient’s long-term kidney function and reduce their risk of dying.
Pre-renal causes (>80% of cases)
Quick-tip: Pre-renal AKI is usually multifactorial. Don’t stop at 1 cause – there are usually at least 3 contributing factors to find. If not, consider less common causes.
- The kidneys need blood to make urine. If blood pressure is low, then this IS the cause of the AKI until proven otherwise. Hypotension can be absolute hypotension (e.g. systolic <90 mmHg) or relative hypotension (decrease of 40 mmHg from baseline BP). Identifying relative hypotension can be difficult. Remember baseline BP is not the admission BP but the last documented BP when the patient was well (e.g. clinic letter; GP records).
- Remember that it takes time for creatinine to rise after an insult, and the rise lags behind the drop in eGFR. Commonly a patient has a prolonged hypotensive episode (e.g. intra-operative blood loss; sepsis on admission) but their AKI is only apparent 2-3 days later. It can be helpful to think of the kidneys having been “stunned” and taking time to recover.
- Even once normal circulation is restored, the creatinine may continue to rise. In this situation an increase in urine output from oliguria to polyuria is a reassuring sign that heralds the onset of recovery.
- Intravascular volume depletion (without hypotension)
- More common in patients with AKI risk factors (e.g. vascular disease, heart failure, liver disease, baseline CKD).
- Clinical history of volume loss (e.g. reported vomiting/poor intake) is often a more reliable indicator than examination findings (e.g. dry mucous membranes).
- Fluid status assessment may be challenging and typical examination findings may be unhelpful (e.g. peripheral oedema is less reliable as a marker of intravascular status in a patient with chronic lymphoedema). The best strategy is repeated volume status assessments over a period of days in combination with a trend in observations, daily weights and point of care ultrasound assessment (if possible).
- Sepsis (without shock)
- Even in the absence of shock, co-existent infection is a common cause of AKI.
- Cardiovascular drugs - ACE inhibitors e.g. ramipril, angiotensin receptor blockers e.g. losartan, mineralocorticoid receptor antagonists e.g. spironolactone, neprilysin-inhibtors e.g. sacubitril-valsartan– these medications are widely accepted to be contributory causes in pre-renal AKI, beyond just their blood pressure lowering effects. HOWEVER, these drugs have proven symptomatic and survival benefits in many settings (e.g. heart failure with reduced ejection fraction) and stopping these drugs is associated with increased risk of re-admission after AKI. So, while it is often appropriate to suspend these drugs in patients with AKI, it is vital that there is a clear plan regarding if and when these drugs should restart.
- Other antihypertensives – if absolute or relative hypotension all antihypertensive drugs should be suspended.
- Diuretics (e.g. furosemide; indapamide) – diuretics only contribute towards AKI if the patient is volume deplete - either in the setting of another contributing factor such as shock, or if the diuretic dose is too high (often referred to as ‘over-diuresed’). If a patient with AKI has fluid overload then continuing (or more likely increasing) their diuretics is appropriate.
- Aminoglycoside antibiotics (e.g. gentamicin; amikacin).
- Non-steroidal anti-inflammatories (e.g. ibuprofen; naproxen) – these medications contribute to pre-renal AKI, independent from their association with acute interstitial nephritis (see renal causes below).
- Iodinated contrast (e.g. for CT or angiograms)– We are now confident that the risk of AKI due to venous iodinated contrast alone is small and may not exist at all, especially when given intravenously. Nevertheless, most nephrologists would accept that CT contrast as a possible contributing factor in patients with multi-factorial pre-renal AKI.
Intrinsic renal causes (<5% of cases)
Quick tip: always get the urine dipstick and document it
Rapidly progressive glomerulonephritis (‘RPGN’)
- An umbrella term that refers to the clinical phenotype of a rapid fall in renal function over days to months almost always in the presence of an active urinary sediment (otherwise referred to as haematoproteinuria or ‘blood and protein’ on dipstick urinalysis).
- May be associated with haemoptysis and systemic features e.g. malaise, purpuric rash, generalised arthralgia, fever, raised inflammatory markers +/- episcleritis, epistaxis.
- The key challenge is identifying the possibility of a primary renal cause to allow appropriate immunological investigations to be sent and early discussion with renal to consider renal biopsy and empirical treatment.
- Given features often present which could be infective (cough, fever, high CRP) and treatment is with immunosuppression, perform a full infection screen including multiple blood cultures (NB, serum procalcitonin cannot reliably be used to differentiate active vasculitis from infection).
RPGN causes are autoimmune and include:
- Vasculitis e.g. ANCA-associated vasculitis, anti-GBM disease, cryoglobulinaemia
- Glomerulonephritis e.g. crescentic IgA nephropathy, post-infectious GN
- Lupus nephritis
What is the difference between glomerulonephritis and vasculitis?
Glomerulonephritis refers to inflammation within the glomeruli, which is seen on histology. Vasculitis is a systemic process that can cause glomerulonephritis, or can affect other organs without renal involvement.
Acute interstitial nephritis
- An “allergic” reaction within the kidney
- Can occur over days, weeks, months or years after the initial insult
- Consider AIN in any patient with unexplained AKI
- 80% are due to drug causes, of which proton-pump inhibitors, NSAIDs and antibiotics account for the majority of cases
- Other causes include infection (incl TB) and immune causes (Sjogrens, sarcoidosis)
- The “classic” features of fever, rash, arthralgia and peripheral eosinophilia are RARE
- Urinalysis may have ‘+’ blood and/or protein
- Diagnosed on renal biopsy (or clinically if AKI improves with cessation of offending drug)
Interpreting urine dipstick in setting of ‘?glomerulonephritis’:
- Blood and protein (everything else negative) – is it a catheter sample? If so it could be from trauma. Otherwise consider glomerulonephritis/vasculitis if clinically relevant. Haematoproteinuria is possible solely due to diabetic nephropathy, but most patients will require a renal biopsy to exclude other causes of intrinsic renal disease.
- Protein only – could be glomerulonephritis but if longstanding diabetes this might represent chronic diabetic nephropathy (check previous uACR).
- Blood only – could be glomerulonephritis but consider surgical causes first (e.g. stones, tumour). Depending on age, patient may require urological work up prior to renal referral (see referral criteria).
- Blood, protein, leucocytes +/- nitrites – either UTI (if symptoms) or chronic bacterial colonization. Unhelpful in differentiating likelihood of glomerulonephritis if clinically suspected.
- Negative or ‘bland’ urinalysis – essentially excludes possibility of rapidly progressive glomerulonephritis. Consider pre-renal causes. Could still be interstitial nephritis, thrombotic microangiopathy or myeloma.
Other causes of intrinsic ‘renal’ AKI:
- Rhabdomyolysis – check Creatine Kinase (CK); CK usually >10,000 for it to be the cause of AKI. May have history of ‘long-lie’, recreational drug use, or statin treatment. Also note that CK can be released during cardiac events so always review the clinical history and ECG.
- Myeloma – can present as AKI, with or without proteinuria, due to a variety of mechanisms. Anaemia and hypercalcaemia are suggestive. Send myeloma screen (see here for interpretation) in unexplained AKI especially if they are over 50.
- Thrombotic Microangiopathy – umbrella term that includes diagnoses such as: haemolytic urameic syndrome (HUS), atypical hameolytic uraemic syndrome (aHUS), thrombotic thrombocytopaenic purpura (TTP), scleroderma crisis and hypertensive emergency. Consider if low platelets, +/- low haemoglobin. Request urgent blood film (?fragments). Many of these conditions have disease-specific therapies so early discussion with renal and haematology is appropriate, which may include the national specialist aHUS referral team in Newcastle: http://www.atypicalhus.co.uk/contact-us/.
- Tumour lysis syndrome – recent chemo with hypocalcaemia, hyperphosphataemia and hyperkalaemia. Hyperkalaemia often disproportionate to degree of AKI. See for more.
- Hepato-renal syndrome – the vast majority (70%) of AKI in patients with decompensated liver disease is due to the ‘usual’ pre-renal causes. Where HRS is considered, discussion with both gastroenterology and renal is appropriate.
- Cholesterol-emboli syndrome – AKI, eosinophilia +/- typical rash. Often with history of vascular disease or recent vascular intervention.
- Bacterial endocarditis – can cause rapidly progressive glomerulonephritis and urine dip positive for blood and protein. Look for signs of endocarditis and discuss with cardiology.
- Drug toxicity - numerous drugs can cause AKI in overdose including paracetamol, NSAIDs, lithium, toxic alcohols.
Post-renal causes (~10%)
Quick tip: patients with AKI due to obstruction usually still pass urine! Anuria is an extremely late sign of obstruction.
Quick tip: 1/1000 people are born with a solitary kidney
Renal imaging should be considered in every patient with AKI in the first 24 hours (unless clear alternative cause or spontaneous improvement), or within 6 hours if an obstructed and infected renal tract is suspected.
Bladder outlet obstruction
- Most common cause of post-renal AKI. Early bladder scan is useful
- Can be acute or chronic
- Usually diagnosed with the insertion urethral catheter and documentation of a residual volume >400mls
- Results in bilateral hydronephrosis, which resolves in hours-days after urethral catheter placement
- Hydronephrosis chronicity can to some extent be determined by the appearance of the renal cortex. If echogenic and thin this raises the likelihood that obstruction is longstanding and renal recovery is less likely.
- Causes: prostatic enlargement (cancer or BPH), bladder cancer, neurogenic bladder, urethral stricture, urinary catheter malposition
- Diagnosed as hydronephrosis on imaging (ultrasound or CT) with an empty bladder.
- In order for ureteric obstruction to cause AKI it must be bilateral, occur in presence of pre-existing CKD or occur in the presence of a single functioning kidney (e.g. small kidney on imaging from previous obstruction of vascular disease, previous nephrectomy, congenital single kidney).
- Causes include; bladder cancer, stones, lymphadenopathy (usually malignant and may be first presentation), retroperitoneal fibrosis.