Lisa Crowley and Marlies Ostermann
Acute kidney injury (AKI) is a common and important clinical problem which affects 13-18% of patients admitted to hospital. It is associated with increased morbidity and mortality, a longer stay in hospital and high health care costs. (Chertow, 2005; Fischer, 2005; Lafrance, 2010). Survivors of AKI have an increased risk of short and long-term complications, including chronic kidney disease (Coca, 2009; Lo, 2009, Wald, 2009). The costs of AKI to the National Health Service are estimated to be between £434 -620 million per year which is more than the costs associated with the most common cancers (NICE AKI Guideline, 2013).
The RIFLE criteria for AKI (Bellomo, 2004)
In 2004, an international expert group of renal and intensive care clinicians proposed to change the term “acute renal failure” to “acute kidney injury” to better describe the spectrum of renal disease. In addition, they proposed a universal definition and staging system for AKI, termed RIFLE which incorporates 3 stages of severity (Risk, Injury and Failure) and 2 outcome criteria (Loss of renal function, End stage renal failure).
Figure: Rifle Criteria for Diagnosis of AKI
The purpose was to increase awareness about AKI and to improve the recognition and management at an earlier stage.
Acute Kidney Injury Network (AKIN) classification (Mehta, 2007)
In response to a large single center study which showed that even relatively small rises in serum creatinine of 0.3mg/dL or more (≥26.4μmol/L) were independently associated with an increased risk of dying, the RIFLE classification was revised by the AKI network.
The AKI Network proposed the following definition for AKI:
“An abrupt (within 48 hours) reduction in kidney function currently defined as an absolute increase in serum creatinine of ≥0.3mg/dl (≥26.4μmol/L), a percentage increase in serum creatinine of ≥50% (1.5 fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5ml/kg per hour for ≥6 hours).”
Once the criteria for AKI are fulfilled, three stages can be distinguished:
Increase in serum creatinine ≥26.2 μmol/L or increase to ≥150–199% (1.5- to 1.9 fold) from baseline; OR urine output <0.5 mL/kg/h for ≥6 h
Increase in serum creatinine to 200–299% (>2–2.9 fold) from baseline; OR UO <0.5 mL/kg/h for ≥12 h
Increase in serum creatinine to ≥300% (≥3-fold) from baseline OR serum creatinine ≥354 μmol/L with an acute rise of at least 44 μmol/L OR initiation of RRT (independent of serum creatinine) OR anuria >12h; OR UO <0.3 mL/kg/h for ≥24 h
KDIGO classification (KDIGO, 2012)
In 2012, the Kidney Disease Improving Global Outcomes (KDIGO) Group published the KDIGO classification for AKI in an attempt to harmonise the RIFLE and AKIN criteria.
As per KDIGO, AKI is defined as any of the following:
- Increase in serum creatinine by ≥0.3mg/dl (≥26.4 μmol/l) within 48 hours; OR
- Increase in serum creatinine to ≥ 1.5 times baseline which is known or presumed to have occurred within prior 7 days; OR
- Urine volume <0.5ml/kg/hour for 6 hours
If these criteria are met, the cause of AKI should be ascertained and AKI should be staged as follows:
Stage 1: serum creatinine 1.5–1.9 times baseline or >0.3 mg/dl (>26.5 mcmol/l) increase (or UO <0.5 ml/kg/h for 6-12h)
Stage 2: serum creatinine 2.0–2.9 times baseline (or UO <0.5 ml/kg/h for >12h)
Stage 3: serum creatinine 3.0 times baseline (or increase in serum creatinine to >4.0 mg/dl (353.6 mcmol/l); or initiation of renal replacement therapy
Or in patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m2 (or UO <0.3 ml/kg/h for >24h or anuria for >12 hours)
National Institute for Clinical Excellence (NICE, 2013)
In 2013, the National Institute for Health and Care Excellence (NICE) published an AKI guideline which recommends to use either the RIFLE, AKIN or KDIGO criteria to define AKI.
The NICE recommendation states:
Detect AKI in line with the RIFLE, AKIN or KDIGO definitions, by using any of the following criteria:
- Arise in serum creatinine of 26 μmol/l or greater within 48 hours;
- A50% or greater rise in serum creatinine known or presumed to have occurred within the past 7 days
- Afall in urine output to <0.5 ml/kg/hour for >6 hours in adults and >8 hours in children and young people
- A25% or greater fall in eGFR in children and young people within the past 7 days.
Importantly, the term AKI describes a large spectrum of diseases, all characterised by a rise in serum creatinine and/or fall in urine output. AKI is not a diagnosis and does not refer to any aetiology. Once AKI is diagnosed, it is still important to identify the exact aetiology.
The difficulty of defining AKI has been debated by Ostermann (2010).
The incidence of AKI is determined by its definition and the population studied. Before the use of the RIFLE, AKIN or KDIGO criteria, estimates were based on arbitrary criteria and often variable and conflicting. AKI is common in sicker patients, in particular in critically ill patients in the Intensive Care Unit (ICU) where it affects 30-60% of patients. Outcome is worse in patients with more severe AKI, especially if renal replacement therapy (RRT) is needed.
There is clear evidence that AKI is not always recognised in time (NCEPOD, 2009). NHS Kidney Care estimates that a large proportion of cases of AKI are preventable. If prevented, lives would be saved, complications avoided and healthcare costs reduced.
Thomas et al developed an electronic early warning system to spot AKI at an earlier stage (and treat appropriately) – though a mortality (36%) similar to the literature, was seen (Thomas, 2011). In another hospital-based study by Selby et al, a similar electronic reporting system was described in a large general hospital (Selby, 2012) The results showed that there were 3202 AKI episodes in 2619 patients during the 9-month study period (5.4% of hospital admissions).
The exact incidence of AKI in the community is not clear (Thomas, 2013). It has been shown that a large proportion of AKI cases start with an illness in the community. Future studies using electronic alerting based on the recent AKI definitions may give a better picture of the epidemiology of AKI in the community.
AKI can be simply classified into 3 groups: pre-renal, intrinsic and post-renal. Pre-renal is due to ineffective perfusion of the kidneys that are otherwise structurally normal. Intrinsic renal AKI results from structural damage to the glomeruli or renal tubules, or both. Post-renal is due to obstruction of the urinary tract anywhere from the calyces to the urethral meatus.
The pathogenesis of AKI is complicated. It has been summarised recently by Barratt and Ostermann (2012).
Pre-renal AKI, is caused by underperfusion of an otherwise normal kidney. The hallmark of pre-renal failure is that it is quickly reversible with appropriate therapy.
The Beautiful Glomerulus, part of'a good kidney looking at a bad world' in pre-renal AKI.
Pre-renal AKI and ischaemic acute tubular necrosis occur on a continuum of the same pathological process and together account for approximately 95% of hospital-acquired and 75% of community-acquired AKI (Lamiere, 2005).
Pre-renal AKI, in which the integrity of the renal tissue is preserved, is an appropriate physiological response to renal hypoperfusion associated with sepsis, hypovolaemia or cardiac failure (Prowle, 2009). Responses of the ageing kidney leave it more vulnerable to AKI. The kidney shrinks with age and with anatomical changes including:
• Cortical atrophy
• Decreased glomeruli
• Proximal tubule numbers
• Glomerular scarring
• Intimal thickening of renal arterioles
Functional changes include a decrease in renal blood flow and in GFR. Baseline 'normal' GFR is not known but in one study, median eGFR (using the MDRD equation) decreased from 90–100 ml/min (age 18–24 years) to 60–65 ml/min (age 85+ years) (Wetzels, 2007).
Pre-renal AKI is most often caused by volume depletion; eg gastrointestinal fluid loss, haemorrhage, poor oral intake, diuretic treatment, and 'third space' losses (eg pancreatitis). All of these cause 'true hypovolaemia'. Three other mechanisms can cause reduction in effective circulating volume ('pseudo-hypovolaemia'): poor cardiac output (heart failure), systemic vasodilatation (eg, anaesthetic drugs or sepsis) and afferent arteriolar vasoconstriction (often for haemodynamic reasons relating to drugs). Further examples are listed below. The urinalysis is bland and the urinary sodium level is low, but urine osmolality is high - ie the body is trying to retain Na and water.
Causes of Pre-renal AKI
• Renal losses (diuretics, polyuria)
• GI losses (vomiting, diarrhoea)
• Cutaneous losses (burns, Stevens-Johnson syndrome)
• Pancreatitis ('third-space' loss, ie pseudo-hypovolaemia)
Decreased cardiac output
• Heart failure
• Pulmonary embolus
• Acute myocardial infarction
• Severe valvular disease
• Abdominal compartment syndrome (tense ascites)
• Drug overdose
Afferent arteriolar vasoconstriction
• Drugs (NSAIDs, ACEi/ARBs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents)
• Hepatorenal syndrome
Pre-renal failure is often multifactorial, eg a patient may be septic and dehydrated post-operatively, on the background of a recent anaesthetic causing hypotension, and has just been given an NSAID. Therefore treatment of pre-renal failure has to address all these factors, eg IV fluids, adrenaline and antibiotics, and withdrawal of the nephrotoxic drug (NSAID). Treatment of all causes of pre-renal AKI is imperative, because continued renal hypoperfusion can progress to intrinsic renal failure.
Note: none of these treatments will be effective, if the underlying problem is not addressed (eg the patient needs an operation)
The kidney responds to changes in renal perfusion pressure by closely regulating renal blood flow. A decrease in perfusion leads to dilatation of afferent glomerular arterioles mediated through prostaglandins and vasoconstriction of efferent glomerular arterioles through angiotensin II - thereby maintaining hydrostatic pressure in the glomerulus and adequate filtration. Drugs that interfere with this regulatory mechanism can precipitate AKI.
Acute inhibition of cyclo-oxygenase (type I or II) by non-steroidal anti-inflammatory drugs (NSAIDs) results in decreased prostaglandins and an inadequate dilatation of the afferent arteriole. This loss of pre-renal blood flow leads to a decreased glomerular pressure and a reduced GFR. This is particularly common in these clinical situations: atherosclerotic cardiovascular disease in a patient older than 60 years, pre-existing CKD, and states of renal hypoperfusion (such as in sodium depletion, diuretic use, hypotension, and sodium-avid states such as cirrhosis, nephrotic syndrome, and congestive heart failure).
Hyperkalaemia, sometimes out of proportion to the degree of renal impairment, can occur when these patients are concomitantly treated with potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACEi), or angiotensin receptor blockers (ARBs). There is little evidence that NSAIDs can acutely impair renal function in otherwise healthy individuals.
Drugs that block the action of Angiotensin Converting Enzyme (ACE-i and ARBs) cause inadequate constriction of the efferent arteriole resulting in decreased hydrostatic pressure across the glomerulus and a decreased GFR - especially in patients with stenosis of the renal artery in a solitary kidney or with bilateral renal-artery stenosis. But patients with hypovolaemia, severe CCF, polycystic kidney disease, or intrarenal nephrosclerosis without renal artery stenosis are also at risk. The frequency of AKI induced by ACE inhibitors varies between 5% and 20% in patients with bilateral renal-artery stenosis and increases to 40% in patients with unilateral stenosis in a single kidney.
Once pre-renal and post-renal causes are ruled out, intrinsic renal failure is likely. There are a number of different causes:
• Acute tubular necrosis (ATN)
• Drugs (eg aminoglycosides, contrast nephropathy)
• Rhabdomyolysis (recreational drugs, alcohol, long lie), tumour lysis syndrome
• Acute glomerulonephritis/Vasculitis (eg Lupus nephritis, ANCA positive vasculitis)
• Interstitial nephritis (penicillins, cephalosporins, diuretics)
• Myeloma (should be actively excluded in all cases of AKI)
• Microangiopathic haemolytic anaemia (MAHA) (eg many causes including Haemolytic Uraemic Syndrome/Thrombotic Thrombocytopenic Purpura, HUS/TTP)
Intrinsic AKI, ie disease of the renal parenchyma, has many causes. Acute Tubular Necrosis (ATN) is the commonest. However, disorders may involve the glomeruli, tubules, or interstitium. Glomerular disease reduces GFR and increases glomerular capillary permeability to proteins; it may be inflammatory (glomerulonephritis) or the result of vascular damage from ischaemia or vasculitis. Tubules also may be damaged by ischaemia and may become obstructed by cellular debris, protein or crystal deposition, and cellular or interstitial oedema. Tubular damage impairs reabsorption of Na, so urinary Na tends to be elevated, which is helpful diagnostically. Interstitial inflammation (nephritis) usually involves an immunological or allergic phenomenon.
There are multiple processes that combine to result in ATN. These include a vascular component (intrarenal vasoconstriction, endothelial injury, microvascular disruption, vascular congestion in the outer medulla); and a tubular component (hypoxia and obstruction). New concepts such as sublethal cell injury, apoptosis, and cell repair after injury are emerging (see Lamiere, 2005).
ATN is most often the consequence of untreated prerenal AKI (renal hypoperfusion and renal ischaemia). Other causes include various endogenous nephrotoxic substances (eg myoglobin and haemoglobin after trauma; cellular products in tumour lysis syndrome; crystals of uric acid, calcium, or oxalate) and a host of exogenous substances.
If a patient develops ATN, all medication (prescribed and non-prescribed) must be reviewed for the possibility of nephrotoxicity. It should not be assumed that the 'usual suspects' (eg ACEi) are the cause. There may be more than one drug cause. If in doubt, stop most or all drugs.
ATN usually behaves in a particular way with 3 phases:
- Prodrome. This phase, with usually normal urine output, varies in duration depending on causative factors. Urea and creatinine rise acutely;
- Oliguria. In this phase, urine output is typically between 50 and 400 mL/day. It lasts an average of 10 to 14 days but varies from 1 day to 8 weeks. In an ICU study, the average duration of RRT was 7 days (Schiffl, 2005). However, many patients are never oliguric. Non-oliguric patients have lower mortality and morbidity and less need for dialysis;
- Recovery. In this post-oliguric phase, urine output gradually returns to normal, but serum creatinine and urea levels may not fall for several more days. Tubular dysfunction may persist and is manifested by Na wasting, polyuria (sometimes massive) unresponsive to vasopressin, and hyperchloraemic metabolic acidosis.
The phrase 'ATN' is now being rethought. In an autopsystudy of patients with septic shock by Hotchkiss (1999), only 1/20 (5%) patients hadpathological evidence ofnecrosis. The phrase 'acute tubular damage' has been suggested and may be more descriptive of this syndrome. This and other papers have been described by Langenburg (2008)in a review of septic AKI pathology.
AKI secondary to glomerulonephritis is the least common cause of AKI but beware rapidly progressive glomerulonephritis/vasculitis as this requires urgent treatment. Myeloma is more common and should be excluded with the same degree of urgency as glomerulonephritis/vasculitis.
Post-renal AKI is caused by obstruction of the urinary tract. This may occur anywhere along theurinary tractand includes:
• Prostate (malignancy, benign prostatic hypertrophy)
• Bladder (malignancy)
• Ureter (calculi, extrinsic compression egretroperitoneal fibrosis)
• Pelvic tumour
Obstructive nephropathy is more common in selected populations such as older men with prostatic disease; patients with a single kidney; or intra-abdominal cancer - particularly pelvic cancer. Severe ureteral obstruction is also caused by retroperitoneal fibrosis. This can be associated with neoplasia (eg lymphoma) orsmall inflammatory aortic aneurysms, or be idiopathic. If idiopathic, this type of obstruction can be successfully treated with corticosteroids.Ureteric stents are not alwaysnecessary. Most causes of post-renal AKI are amenable to therapy and the prognosis is generally good, depending on the underlying disease.
Important clinical sequelae of post-renal AKI are post-obstructive diuresis and the presence of hyperkalaemic renal tubular acidosis. Severe diuresis can occur after the release of the obstruction, especially if both kidneys, or a single functioning kidney, are completely obstructed. The period of total obstruction is short in most cases, a few days to a maximum of a week. Once the obstruction is relieved, the urine output generally ranges from 4 L to 20 L per day. This diuresis must be closely monitored as it can precipitate pre-renal AKI due to volume depletion, delaying renal recovery.
The development of hyperkalaemic hyperchloraemic tubular acidosis is indolent in most cases, and the abnormality tends to persist after correction of the obstruction. Patients in whom the hyperkalaemia is not corrected as their AKI is reversed by treatment of the obstructive lesion, should be investigated for the presence of tubular acidosis.
The pathophysiology of obstructive nephropathy is complicated. It affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 hours, the renal blood flow is reduced, and by 24 hours, it has fallen to < 50% of normal because of increased resistance of renal vasculature. Renovascular resistance may take up to a week to return to normal after relief of a 24 hour obstruction.
Treatment should focus on removing the obstruction. Techniques vary with the type of obstruction, but may include bladder catheterisation, nephrostomy and placement of urinary stents (either retrograde or antegrade).
The differential diagnosis of AKI is extensive. Therefore history and examination should aim to distinguish between pre-renal, intrinsic and post-renal causes.
An important skill is to recognise patients at risk of developing AKI. Consider recent events in the individual's history and highlight those that will put them at risk of AKI. For example, thepost-operative surgical patient may have suffered multiple nephrotoxic insults; such as volume depletion, sepsis, CT with contrast, and may be on nephrotoxic drugs. Often, predominant symptoms are those of the underlying illness, or those caused by the surgical complication that precipitated renal deterioration. Initially, weight gain and peripheral oedema may be the only findings.
Later, as nitrogenous products accumulate, symptoms of uraemia may develop, including anorexia, nausea and vomiting, weakness, myoclonic jerks, seizures, confusion, and coma; asterixis and hyperreflexia may be present on examination. A 'jittery' patient may be about to have a seizure. In causes of Micro-angiopathic Haemolytic Anaemia (MAHA) - especially pre-eclampsia, eclampsia and TTP- cerebral deterioration can occur rapidly, with very serious consequences. You may need to act quickly.
Often, the non-specific nature of the signs (and the fact that there may be few, or none) of AKI, is what puts juniors off the diagnosis. Blood tests alert them to a problem, sometimes not followed up appropriately.
Chest pain (typically worse with inspiration or when recumbent), a pericardial friction rub, and findings of pericardial tamponade may occur if uraemic pericarditis is present.
Symptoms of hypocalcaemia are rare but may be profound in patients with rhabdomyolysis, apparently because of the combined effects of Ca deposition in necrotic muscle, reduced calcitriol production, and resistance of bone to parathyroid hormone (PTH). During recovery from AKI, hypercalcaemia may supervene as renal calcitriol production increases, the bone becomes responsive to PTH, and Ca deposits are mobilised from damaged tissue.
Anuria. Complete anuria is very rare, and has only three common causes:
- Obstruction. Put a catheter in now
- Vascular catastrophe. Eg aortic dissection, or thromboembolism in a single kidney
- Acute severe glomerulonephritis/vasculitis
Note 1: unless it is 1, and can be rectified simply, a consultant needs to see the patient ASAP
Note 2: occasionally apatient with acute tubular necrosis will be anuric for a few hours
Symptoms related to hypovolaemia include increased thirst, decreased urine output and postural dizziness whilst simple causes of hypovolaemia are easy to explore – diarrhoea, vomiting, haemorrhage and reduced oral intake.
Drug history is vital. If you are going to do ONE thing .. TAKE A DRUG HISTORY.
The past medical history is important, particularly looking for conditions such as ischaemic heart diasease, cerebrovascular disease, peripheral vascular disease and diabetes mellitus that would suggest renovascular disease. These risk factors are especially important for prerenal causes.
ATN is suggested by prolonged renal failure and hypotension, symptoms of sepsis, exposure to nephrotoxic drugs and situations with potential for muscle injury – prolonged lying, seizures, alcohol and excessive exercise – that may lead to rhabdomyolysis.
Ask about recent procedures such as angiography or CT scans that may have exposed the patient to nephrotoxic contrast.
Clues to glomerular disease include upper respiratory tract infection, rash, fever, epistaxis and haemoptysis (pulminary-renal syndrome),and sore throat (post-streptococcal glomerulonephritis) whilst more systemic symptoms should be looked for in diseases such as Systemic Lupus Erythematous (SLE) and the vasculitides.
For post-renal AKI it is important to assess preceeding symptoms of prostatism (hesitancy, poor flow, dribbling and nocturia), lower abdominal pain, constipation and an inability to pass urine. Ask about a history of known abdominal and pelvic malignancy. Also look for symptoms suggesting covert malignancy such as weight loss and decreased appetite.
A comprehensive physical examination is vital focusing on an accurate assessment of fluid status. The JVP is the most important sign in nephrology. If the patient has an obese neck, measurement of CVP should be considered. Assess skin turgor, mucous membranes and closely monitor heart rate.
What is the blood pressure? This is a simple but vital observation.
If it is high, hypovolaemia is unlikely. If it is low, it is harder to make a generalisation. For example, in heart failure or, septic shock (with AKI) the patient can be fluid overloaded with low blood pressure. This is a Red Flag situation. The combination is always a sign of a major problem, and the patient will almost always need ITU care, and intropes.
Furthermore, normal blood pressure does not exclude hypovolaemia. A postural drop, when moving the patient from a lying to standing position, may demonstrate hypotension (and hypovolaemia) when the lying blood pressure is normal. This is not always easy in a frail, ill or obese patient. It may be easier to carry out a lying-to-sitting BP.
A high or low temperature (>38C or <36C) with tachycardia or tachypnoea defines the systemic inflammatory response syndrome (SIRS) and evidence of infection should make you strongly consider sepsis as your underlying cause for AKI. If in doubt, treat.
Systematically examine the different systems looking for complications of AKI such as pulmonary oedema, and causes of it (recent MI, AF). A palpable bladder suggests post-renal obstruction and necessitates a rectal examination looking for constipation and prostatic enlargement. Listen for adbominal and femoral bruits (reno-vascular disease).
Remember that AKI can be a complication of many systemic conditions (or their investigation and treatment); therefore clues to aetiology will be given by thorough examination.
Urea, Electrolytes and Creatinine
In the early stages of AKI, serum creatinine levels may rise within the ‘normal’ range despite a significant reduction in GFR - especially in an elderly patient, with poor muscle mass. Occasionally it is necessary to dialyse a patient with a creatinine that is in the normal range, or just above it.
A progressive daily rise in serum creatinine is diagnostic of AKI. Serum creatinine can increase by as much as 200 mcmol/L/day, depending on the amount of creatinine produced (which varies with lean body mass) and total body water. A rise of >200 mcmol/L per day suggests overproduction due to catabolic causes of AKI including rhabdomyolysis and tumour lysis syndrome.
Estimating GFR from serum creatinine should not be done, because the rise in serum creatinine concentration is a delayed response to GFR decline.
Serum urea may increase by 3.5 to 7 mmol per day. But the urea level may be misleading because it is frequently elevated in response to increased protein catabolism resulting from surgery, trauma, corticosteroids, burns, transfusion reactions, parenteral nutrition or GI or internal bleeding.
Note: the fact that it is inappropriately raised in dehydration is useful, though, as a diagnostic tool
Efforts to identify biomarkers to assist with the early diagnosis of AKI have yielded many promising candidates, such as KIM-1, NGAL, IL-18, Cys-C, clusterin, FABP, and osteopontin (Vaidya, 2010). None of these have reached clinical practice.
Whilst sending blood samples to the laboratory, also take a sample to go through the blood gas machine. This allows rapid evaluation of pH, potassium and lactate – all of which can signify the need for immediate intervention. Serum should be sent to haematology, biochemistry, immunology and microbiology. It is vital to know the potassium level as soon as possible.
Other laboratory findings are progressive metabolic acidosis, hypernatraemia or hyponatraemia, and anaemia. Acidosis is normally moderate, with a plasma HCO3 content of 15 to 20 mmol/L. Serum K concentration increases slowly, but when catabolism is markedly accelerated, it may rise by 1 to 2 mmol/L/day. Inappropriately high or rapidly rising K also suggests catabolic causes of AKI including rhabdomyolysis and tumour lysis syndrome.
Hyponatraemia, if present, is usually moderate (Na 125-135 mmol/L) and correlates with a surplus of water. If the patient is dehydrated,sodium can be very high (>160 mmol/L).
Mild normochromic-normocytic anemia with an haematocrit of 25 to 30% is typical. A rapidly falling or severe anaemia has three main causes:
- Haemolytic uraemic syndrome/thrombotic thrombocytopenia purpura (HUS/TTP).
In the latter case, a blood film should also be sent. There is no single diagnostic test for HUS/TTP. It is a clinical diagnosis, combined with characteristic (but non-specific) biochemical and haematological changes.ADAMTS-13 should be sent off. This will not change current management.
Raised inflammatory markers, ESR or CRP, imply infection or an underlying systemic disorder.Peripheral eosinophilia may be seen in interstitial nephritis. In sepsis, CRP can be normal in the elderly (and sometimesin the non-elderly) on day one. There is a lag time before it starts to rise. In Black patients a sickle cell screen should be performed.
Hypercalcaemia suggests myeloma, sarcoidosis (or TB) or malignancy. Hypocalcaemia is common and may be profound in patients with rhabdomyolysis.
Amylase, and Other 'False Positive' Tests
Mild hyperamylasaemia commonly is seen in AKI (2-3 times controls). Elevation of baseline amylase can complicate the diagnosis of pancreatitis in patients with AKI. Lipase, which commonly is not elevated in AKI, is often necessary to measure to make the diagnosis of pancreatitis. Pancreatitis has been reported as a concurrent illness with AKI in patients with atheroemboli, vasculitis, and sepsis from ascending cholangitis. Troponin T and D-dimer can also be falsely raised in AKI, complicating the diagnosis of myocardial disease and venous thromboembolism.
Urine dipstick should be done early. The presence of blood and protein is highly suggestive of glomerulonephritis or vasculitis whereas their absence almost excludes it. This sample should be sent for microscopy, culture and sensitivity. The presence of red cell casts is diagnostic of glomerulonephritis. Pyuria (the presence of white cells) is suggestive of urinary tract infection or tubulointerstitial nephritis.
Urine osmolality and electrolytes are helpful in distinguishing between pre-renal and intrinsic AKI. In intrinsic renal injury, there is an inability to concentrate urine. Therefore urine will be dilute (<300mOsm/kg) with a urinary sodium of <40 mmol/L. This compares to the concentrated urine of pre-renal kidney injury (>500mOsm/kg) (with increased sodium reabsorption), with a urinary Na of <10 mmol/L in a healthy adult, and <20 in the elderly. A urinary Na of 20-40 mmol/L is harder to interpret.
An ECG is important to look for changes of hyperkalaemia (absent p-wave, tall tented T-wave, wide QRS complex becoming sinusoidal) and those of pericarditis (diffuse saddle-shaped ST segments). A CXR is also important, looking for pulmonary oedema, pericardial and pleural effusion and pulmonary haemorrhage.
After immediate investigation and initial management has been implemented, a renal ultrasound is indicated. Early identification of AKI secondary to obstruction is essential. Dilatation of any part of the renal tract will indicate obstruction whilst bilateral small kidneys suggest chronic renal disease.
Renal ultrasonography, when used to detect obstruction, has a sensitivity and specificity of 90-95%. Unfortunately, it is also highly operator-dependent, so it should be performed by a highly experienced radiologist.
Note: the result of renal US should be known in no more than 24 hours ftom referral, preferably that day
Furthermore, false positives and negatives can occur. For example, false-negative results can occur if the obstruction is caused by retroperitoneal fibrosis or certain malignancies that encase the entire system. It might also fail to detect an obstruction in extremely volume-depleted patients who do not have enough fluid buildup to reveal the obstruction. Conversely, dilatation of the urinary tract can occur without obstruction (eg pregnancy, and in a transplant ureter).
Key point: a 'normal' renal US does not exclude obstruction, and dilatation (hydronephrosis) can occur without obstruction
In other words, non-dilated obstruction and non-obstructed dilatation, can occur. For thess reasons, specialist imaging techniques (eg cystoscopy and retrograde pyelograms) may be necessary. Then, if the diagnosis is still unclear, relieving the obstruction and seeing if renal function improves may be necessary.
Summary of Investigations
• Full Blood Count
- Eosinophilia (cholesterol emboli, vasculitis)
- Thrombocytopenia (with normal clotting, HUS/TTP; with deranged clotting, DIC)
• ESR, CRP
• Venous/arterial (if ?hypoxic) blood gas
Note: if you are going to do ONE test, do the VBG
• Urea and electrolytes
• LFTs (bilirubin raised in liver disease, and leptospirosis; low albumin in nephrotic syndrome, cirrhosis)
• Bone (hypercalcaemia in myeloma, sarcoidosis and malignancy)
• Creatinine kinase (rhabdomyolysis)
• Dipstick (proteinuria suggestive of glomerular disease? infection?)
• Microscopy (infection?)
• Culture and sensitivity
• Chest xray (pulmonary oedema or haemorrhage)
• ECG (hyperkalaemia)
Summary of Specialist Investigations (selected patients)
• Blood film (fragments in HUS/TTP and DIC; malarial parasites)
• Haemoglobin electrophoresis (sickle cell disease)
• LDH (raised in haemolysis, malignancy)
• Haptoglobins (reduced in haemolysis)
• Uric acid (raised in tumour lysis syndrome)
• Immunoglobulins (A, G, M) (IgA nephropathy, myeloma)
• Protein electrophoresis (myeloma)
• Serum free light chains (myeloma)
• ANA and dsDNA (SLE)
• Complement factors (C3 and C4):
- Low C3 and/or C4 (SLE)
- Low C4 (cryoglobulinaemia)
- Low serum complement activity (CH50) (post-infectious GN, Type II mesangiocapillary glomerulonephritis,cryoglobulinaemia, infective endocarditis, 'shunt' nephritis)
• Anti-neutrophil cytoplasmic antibodies MPO and PR3 (ANCA) (vasculitis)
• Anti-glomerular basement membrane antibodies (AGBM) (Goodpastures Syndrome)
• Anti-streptolysin O titre (ASOT) (post-infectious glomerulonephritis). This is done to test for exposure to streptococci. It has poor specificity
• Angiotensin converting enzyme (ACE) (raised in sarcoidosis)
Microbiology and virology
• Blood cultures
• Throat swab (post-infectious glomerulonephritis)
• Hepatitis B, C (cryoglobulinaemia, and transmission risk on haemodialysis)
• HIV (FSGS and increased risk of AKI on HAART)
• Bence-Jones protein (myeloma)
• Sodium and osmolality
• Microscopy (sediment: red cell casts (glomerulonephritis); eosinophiluria (interstitial nephritis))
• Leptospirosis, legionella
• Renal ultrasound
Consultant Decisions (minority of patients)
• Renal biopsy
• Renal angiogram
• Cystoscopy and retrograde pyelogram
• Occasionally CT-KUB (stones or sloughed papillae), CT abdomen or CT angiogram
Principles of Management
Prerenal failure is often multifactorial, eg a patient may be septic and dehydrated post-operatively, on the background of a recent anaesthetic causing hypotension, and has just been given a NSAID. Therefore treatment of pre-renal failure has to address all these factors, eg IV fluids, adrenaline and antibiotics, and withdrawal of the nephrotoxic drug (NSAID). Treatment of all causes of pre-renal AKI is imperative, because continued renal hypoperfusion can progress to intrinsic renal failure. None of these treatments will be effective, if the underlying problem is not addressed (eg the patient needs an operation).
Key point: in terms of treatment, removing the nephrotoxic event or agent(s) - whether it a bleeding source, or drug - is often the most important intervention. This may be a drug, incorrect IV therapy, untreated trauma, bleeding or sepsis. If there is an abscess, does the patient need an operation? 'Where there is pus, let it out'.
A nephrologist always looks at the front and back of the drug card, and the Emergency Department record. The nephrotoxins may be hidden. Ring the GP.
The Renal Pharmacy Group have published a toolkit to advise on which drugs to stop or reduce the dose of, in AKI.
Nephrotoxic drugs should be stopped. The dose of all drugs excreted by the kidneys (eg digoxin, some antibiotics) should be adjusted; serum levels are useful. Patients that need, or may need dialysis, should be transferred without delay to a renal ward (or ITU if unstable).
If the patient is fluid overloaded, daily water intake is restricted to a volume equal to the previous day's urine output plus measured extrarenal losses (eg vomit) plus 500 mL/day for insensible loss. Water intake may need to be increased in a dry patient, especially if hypernatraemic.
Na and K intake should be minimised in most patients. Don’t forget the importance of nutritional support to patients with AKI. They will often be hypercatabolic with high nutritional requirements. Elderly patients are at particular risk of malnutrition. An adequate diet should be provided, including daily protein intake of about 0.8-1 g/kg.
If oral or enteral nutrition is impossible, parenteral nutrition should be used. But it should be remembered in AKI, risks of fluid overload, hyperosmolality, and infection are increased by IV nutrition.
Calcium and Phosphate
Calcium salts (carbonate, acetate) before meals help maintain serum phosphate at < 1.8 mmol/L.
An indwelling bladder catheter is often needed, accepting the risks of UTI and urosepsis. It should be removed as soon as possible.
Treatment of Pulmonary Oedema
Pulmonary oedema must be managed very carefully. It can be directly due to AKI but is often present because of over-zealous fluid resuscitation. Initially give supplemental oxygen therapy and sit the patient upright. Pharmacological therapy including loop diuretics (furosemide), opiates (morphine) and nitrates is the next stage of management. If the patient is refractory to these treatments then they will need dialysis.
Treatment of Hyperkalaemia
Hyperkalaemia should be teated as needed with an IV infusion of 10 ml of 10% Calcium Gluconate (to stabilise the heart), and 50 mls of IV 50% Dextrose, containing 10 units of Insulin. Calcium Gluconate isa quick acting cardioprotective measure used as a prelude to dialysis. Nebulised Salbutamol 10 mg is also used.
These drugs do not reduce total body K. They move K back into the cells. So further (but slower acting) treatment with 15-30g of oral or rectal Calcium Resonium, to remove K from the body, is also needed. If K is not controlled (<6.5 mmol/L) by two rounds of insulin/dextrose, dialysis should be considered.
It is important to note that these treatments are not appropriate in an anuric-oliguric patient; as they are ‘temporary fixes’ to the problem of hyperkalaemia (and do not reduce the amount of K+ in the body).This seems rather obvious but it is something that gets overlooked, especially by juniors.
Treatment of Metabolic Acidosis
Metabolic acidosis is common in AKI. Correction of a high anion gap metabolic acidosis (which is the norm in AKI) with NaHCO3 is controversial. Small amounts of sodium bicarbonate can be given if serum bicarbonate falls below 15mmol/L but this should only be done under close supervision. When metabolic acidosis is not controlled by medical therapy, this is another indication for dialysis - especially if they are oligo-anuric or fluid overloaded.
There are acidotic circumstances (sometimes with normal renal function) that may be immediate indications for dialysis, eg Metformin (lactic acidosis), Aspirin and Ethylene glycol. Renal tubular acidosis is rare, and often missed. So nephrologists need to be on the 'look out' for it.
This is rule one of nephrology. Once venous access is established, if the patient is dry, an intravenous fluid challenge should be commenced to increase renal perfusion. A measured approach to initial fluid replacement should be taken depending on the patients heart rate, blood pressure, capillary refill time and venous filling. Overzealous fluid replacement can lead to pulmonary oedema especially in those with a cardiac history.
Aggressive fluid replacement (over-zealous fluid replacement)?
In a post hoc analysis of the Fluid and Catheter Treatment Trial (FACTT, 2006), which examined liberal versus conservative fluid management in intubated ICU patients, fluid balance and diuretic use were identified as prognostic factors for mortality in individuals with AKI (Grams, 2011). Specifically, greater cumulative fluid accumulation over an average of 6 days was associated with a higher mortality (10.2L vs 3.7L in the liberal vs conservative group), and higher furosemide use was associated with a lower mortality (cumulatively 562 mg vs 159 mg).
Note: high dose loop diuretics have no effect on outcome (dialysis or death), but can 'buy time' my maintaining urine output and controlling pulmonary oedema) (Bennett-Jones D, 2006) (Bagshaw, 2007).
Of note, more than one half of the individuals had Stage 1 AKI (AKIN criteria), so whether these results apply to more severe stages of AKI is not clear. One interpretation of this study is that patients who can be stabilised with less volume resuscitation fare better. From a practical standpoint, one conclusion is that aggressive prolonged volume resuscitation does not improve prognosis in AKI in the ICU setting.
Note: careful rather than aggressive fluid replacement may be preferable. This contradicts standard renal dogma (give alot of fluids to a patient with prerenal failure)
The failure of a response in urine output (minimum 0.5 ml/kg/hour) to the correction of hypovolaemia should make you consider an intrinsic or post-renal problem. If unsure, in the oliguric-anuric patient, pass a urinary catheter. If this produces a large residual volume then the patient has a lower-tract post-renal obstruction. This could be the cause (or partof the cause) of their AKI.
But. If the urinary catheter does not drain a significant volume of urine, then the diagnosis is either a pre-renal problem (that you have insufficiently corrected), an intrinsic renal problem, or upper-tract obstruction. So ..
Key Point: Both lack of diuresis post catheterisation and 'lack' of obstruction on ultrasound do not exclude obstruction. If in doubt, ask for a urological opinion (which may lead to a nephrostomy or ureteric stent placement).
Leave the catheter in-situ as accurate monitoring of urine output is vital. Furthermore, it may be necessary to dialyse the patient fora few days, to 'buy time' to make a diagnosis and/or start treating obstruction.
If the patient does not improve with this approach, and life-threatening complications of AKI are still present (eg fluid overload and hyperkalaemia) dialysis should be started, either in the form of haemodialysis or haemofiltration (which is usually carried out on ICU). There is no evidence that one form of RRT leads to better results than another.
Urea and creatinine levels alone are not the best guides for initiating dialysis in AKI. In asymptomatic patients who are not seriously ill, particularly those in whom return of renal function is considered likely, dialysis can be deferred until symptoms occur (or K is uncontrolled), thus avoiding placement of a dialysis catheter with its attendant complications. In these patients, daily bloods and senior review is necessary.
- Treat underlying cause
- Maintain BP
- Correct hyperkalaemia and metabolic acidosis
- Urinary catheter – exclude obstruction and monitor urine output
- Does this patient need dialysis?
Indications for Dialysis
- Pulmonary oedema unresponsive to medical treatment
- Hyperkalaemia (>6.5 mmol/L) unresponsive to treatment
- Metabolic acidosis (pH <7.2) unresponsive to treatment
Management of Specific Causes of AKI
Diuresis in Recovery Phase of ATN and Obstruction
In many patients, a brisk and even dramatic diuresis after relief of obstruction or recovery of ATN, is a physiologic response to the expansion of ECF during early stage of AKI. In some patients, polyuria accompanied by the excretion of large amounts of Na, K, Mg, and other solutes may cause hypokalaemia, hyponatraemia, hypernatraemia, hypomagnesaemia, or marked contraction of ECF volume with peripheral vascular collapse.
Therefore, in this post-oliguric phase, close attention to fluid and electrolyte balance is mandatory. When post-oliguric diuresis occurs, replacement of urine output (with the correct fluid for the patient, eg 0.45% saline) at about 75% of the previous day's urine output prevents volume depletion.
The prognosis of Sepsis-related AKI in the critically ill, is worse than non-sepsis related (Bagshaw, 2007). So, specific therapies should be considered in patients with sepsis-related AKI (Ronco C, 2008).
(Lameire, 2003) AKI can often be prevented by maintaining normal fluid balance, blood volume, and BP in patients with trauma, burns, or major haemorrhage and in those undergoing major surgery. Infusion of isotonic saline and blood may be helpful. Use of contrast agents should be minimised, particularly in at-risk groups (eg the elderly and those with pre-existing CKD, volume depletion, diabetes, myeloma or heart failure). However Katzberg (2010) has questioned the risk of AKI associated with contrast media.
If contrast agents are necessary, risk can be lowered by minimising volume of the IV contrast agent, using nonionic and low osmolar or iso-osmolar contrast agents, avoiding NSAIDs, and pretreating with normal saline at 1 ml/kg/h IV for 12 hours before the test. Isotonic NaHCO3 is used instead of normal saline in some patients. PO N-acetylcysteine 600 mg bd the day before and the day of IV contrast administration has been used to prevent contrast nephropathy, but reports of its efficacy are conflicting. Kelly (2008) carried out a meta-analysis oftheinterventions that have beenused to prevent contrast nephropathy, and considers n-acetylcysteine to be effective.
Before cytotoxic therapy is initiated in patients with certain neoplastic diseases (eg lymphoma, leukaemia), treatment with allopurinonol should be considered along with increasing urine flow by increasing oral or IV fluids to reduce urate crystalluria. Some units use IV Rasburicase,to prevent tumour lysis (Ueng, 2005). Making the urine more alkaline (by giving oral or IV NaHCO3 or acetazolamide) has been recommended by some but is controversial because it may also induce urinary Ca phosphate precipitation and crystalluria, which may cause AKI.
The renal vasculature is very sensitive to endothelin, a potent vasoconstrictor that reduces renal blood flow and GFR. Endothelin is implicated in progressive renal damage, and endothelin receptor antagonists have successfully slowed or even halted experimental renal disease. Anti-endothelin antibodies and endothelin-receptor antagonists are being studied to protect the kidney against ischaemic AKI.
Prognosis and Follow-up
Although many causes are reversible if diagnosed and treated early, the overall survival rate of dialysis-requiring AKI remains high about 50% (30% for non-ITU patients); perhaps because many patients with AKI have significant underlying disorders (eg sepsis, respiratory failure). Mortality may exceed 70% in patients that require ICU. Conversely, the mortality of AKI that does not require dialysis is approximately 10%. Death in all these patient groups, is usually the result of these disorders rather than the renal failure itself.
Factors Affecting Prognosis
- Older age
- Pre-existing CKD
- Cause of AKI (eg sepsis)
- Multiorgan failure (ie, the more organs that fail, the worse the prognosis). A useful 'rule of thumb' is that if a patient is on ICU, on a ventilator, and RRT, then their mortality is 70% (ie, 'two system failure', ie respiratory and renal). Every other major body system failure should add 10% mortality to the prognosis. So, if the patient is requiring inotropes (cardiac failure) and has liver dysfunction (liver failure) then the mortality is 90%
- Vasopressor support
Short-term Renal Outcomes
The duration and severity of AKI predicts the development of progressive chronic kidney disease (CKD). In a largeICU follow-up study, patients who have suffered AKI, 57% returned to normal renal function, 33%had mild to moderate CKD and 10% (Schiffl, 2005) severe renal failure.
In such ICU studies, selection bias may occur, as has been pointed out by Rifkin (2012); thus challenging the view that AKI leads to severe CKD and ESRD.
Even if serum creatinine returns towards baseline value but remains a poor marker of the residual tubular and vascular damage. The ensuing CKD is associated with an increase in cardiovascular disease.
Coca (2009) has published a very good meta-analysis of long-term outcomes in AKI. Mortality was 8.9 per 100 person-years in survivors of AKI and was 4.3 per 100 patient-years in survivors without AKI.The incidence rate of CKD after an episode of AKI was 7.8 per 100 patient-years and the rate of ESRD was 4.9 per 100 patient-years.
Key Point: All cases of AKI accepted by a renal service will require follow-up, within 4 weeks of discharge, by a nephrologist (or in some cases by the GP)
- Acute Kidney Injury (AKI)is traditionally referred to as a rapid decrease in renal function over hoursto days,resulting ina failure to regulatefluid, electrolyte and acid-base balance. Patients are at risk of a number of complications and have an increased mortality
- New definitions based on rises in serum creatinine or reductions in urine output have been proposed, which shouldprovide improved epidemiological data
- The most common forms of AKI are secondary to hypoperfusion injury, sepsis and nephrotoxins. Therapy is supportive and consists of rapid correction of hypovolaemia, prompt treatment of sepsis and withdrawal of nephrotoxic medication
- Prevention of AKI is of paramount importance and is dependent upon recognition of patients with risk factors. It has been estimated that 30% of cases of AKI could be prevented
- The cause of AKI must always be established to ensure that rarer forms (vasculitis) are not overlooked. Specific therapies are available and must be initiated as soon as possible
- The duration and severity of AKI predicts the development of progressive chronic kidney disease (CKD)
- Following AKI, serum creatinine may return towards the baseline value but remains a poor marker of the residual tubular and vascular damage. The ensuing CKD is associated with an increase in cardiovascular disease
- The mortality associated with AKI has remained unacceptably high. The mortality of dialysis-dependent AKI (if ITU patients are included) is 50% (and 30% if the ITU patients are not included). Aftre recovery, approximately 50% will have normalrenal function. a third mild-moderate CKD and 5-10% of patients will remain on dialysis
- The cost of AKI has been estimated to be £400-600m/year in the UK
- There is renewed interest in developing specific therapies to prevent AKI and major investment is occurring from thepharmaceutical industry (especially with regard to biomarkers)
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An account of AKI for junior doctors can be found in AcuteMed