Summary

AKI (formerly more commonly Acute Renal Failure) is a sudden decline in renal function significant enough to produce uraemia, and also often oliguria – a urine output of <400ml/day. It normally occurs over a period of days or week, and is often reversible.  Diagnosis is usually based on serum urea and/or creatinine levels.

Severe AKI is defined as a creatinine level of >500umol/L
Acute renal failure is a medical emergency and can cause death.

Epidemiology

AKI superimposed on CRF comprises 50% of community-acquired cases that are admitted to hospital. The approximate incidence of AKI is 180 per 1 million; before the age of 50, this value is 17 per 1 million, but as high as 950 per 1 million in those over 80.

Causes

These can be divided into three main categories: prerenal, intra-renal and post-renal. There may be multiple causes of SKI in an individual patient.  In the hospital situation, the most common cause of AKI is sepsis
Prerenal causes – here, there is impaired blood flow to the kidney, and this may be a result of hypovolemia↓BP↓COvascular disease, or a combination of any of these.
Clinical signs are probably more important than laboratory tests in the determination of prerenal causes, and those that suggest prerenal uraemia are history of blood/fluid loss, sepsis leading to vasodilation, cardiac disease, postural hypotension, weak, rapid pulse and low JVP
Intra-Renal causes
  1. Acute tubular necrosis (ATN) – by far the most common cause of AKI where toxicity and/or ischaemia results in ↓GFR
  2. Nephrotoxicity – caused by aminoglycosides, contrast nephropathy
  3. Renal parenchymal disease – a result of ATN

Investigations

  • Urine dipstick
  • Urine microscopy – look particularly for the presence of red cell casts and red cells.
  • Blood tests – U+E’s (particularly Cr and K+, FBC, free haemoglobin and myoglobin.
  • Kidney function is monitored through urine output analysis and creatinine clearance monitoring – creatinine clearance monitoring is the ideal, i.e. it is a more precise indication of GFR than serum urea monitoring alone!
  • Check if the patient is on any nephrotoxic drugs.

Management

This is based on careful monitoring of signs and symptoms, e.g. treatment of hypovolaemia whilst avoiding fluid overload, and seeking specialist help if hyperkalaemia, pulmonary oedema, bleeding, acidosis or sepsis are present.

Renal replacement therapy

This is indicated if any of the following cannot be controlled: fluid overload, hyperkalaemia, hypocalcaemia, metabolic acidosis, pericarditis, uremic symptoms, GFR <15ml/min/1.73 m2, or poisoning. Different options include haemodialysis, peritoneal dialysishaemofiltration, and renal transplantation.

Further Information

Definition

Acute renal failure is a sudden decline in renal function significant enough to produce uraemia, and also often oliguria – a urine output of <400ml/day, which is the minimum volume required to remove waste products from the blood.
Uraemia – this is where there is enough urea in the blood to cause clinical symptoms, which may include anorexia and lethargy, and later, possible decrease in mental capacity leading to coma. The term azotaemia is sometimes used to describe levels of urea above normal but not high enough to cause clinical signs.
It normally occurs over a period of days or week, and is often reversible.
Diagnosis is usually based on serum urea and/or creatinine levels.
Acute renal failure is a medical emergency and can cause death.
The distinction between acute and chronic can sometimes be difficult to make.  In some cases, acute renal failure may present on top of a history of chronic disease.
Be suspicious of ARF – particularly in the elderly! A combination of low muscle mass, and low dietary meat intake can result in a falsely low creatinine, masking ARF. Also, be wary in patients with CRF: ARF is likely to become apparent.
Fluid input and output monitoring of at-risk patients is a good idea, but isn’t always accurate, e.g. they may urinate in a toilet and not report this, they may be too, they may spill a drink, etc.  To ensure accuracy, such patients should be weighed on a daily basis.
Serum urea, creatinine and electrolytes are monitored on a regular basis in most hospitalised patients. Abrupt onset of ARF can therefore be detected through these means.

Epidemiology

The actual incidence of ARF is difficult to quantify given varied definitions of the condition and different populations studies.
ARF superimposed on CRF comprises 50% of community-acquired cases that are admitted to hospital.
The approximate incidence is 180 per 1 million; before the age of 50, this value is 17 per 1 million, but as high as 950 per 1 million in those over 80.
Severe ARF is defined as a creatinine level of >500umol/L, with an incidence of about 130 per 1 million.
  • Mortality is about 5-10% in those with isolated ARF which does not normally require admission to ITU.
  • In those with other organ failure that then go into ARF, mortality is about 50-70%.
  • The presence of sepsis translates into a much worse prognosis.

Diagnosis

Before diagnosing acute renal failure, 3 questions need to be asked:
  1. Is the renal failure acute? Is there is a previous test of renal function that proved normal? It is unlikely that a baseline measure is at hand, but suspect chronic renal failure if:
    1. There is co-existing diabetes.
    2. There is increased blood pressure, and other signs of chronic disease.
    3. Small kidneys are apparent on ultrasound (<9cm), with increased echogenicity.
  2. Is there urinary tract obstruction? This is a cause of ARF, and should always be considered because generally treatment is quick and easy and will prevent any permanent renal damage from occurring. Obstruction should be considered in those with a history of renal calculi, a single functioning kidney, or previous surgery in this region. Examine for a palpable bladder, pelvic/abdominal mass, and enlarged prostate.
    1. 25% of cases of severe ARF are due to obstruction, most commonly caused by prostatic hypertrophy.
    2. The main test for obstruction is USS of the kidneys. The results are highly variable depending on the patient and the operator. Also, renal USS will not detect obstruction, but dilation of the calyces – and in 5% of cases such dilation may not be detected, culminating in a false negative result.
    3. In order to relieve obstruction the following procedures may be carried out:
      1. Catheterization – this is a relatively quick and straightforward technique that carries with it few risks – not withstanding the risk of infection!
      2. Percutaneous nephrostomy
      3. Surgery to allow implant of stents whilst consideration of how to treat the underlying cause is undertaken.
  3. Is there something rare that might be causing the ARF? E.g. glomerulonephritis, vasculitis, or interstitial nephritis. Do a dipstick test on anyone with suspected ARF, and if there are any irregular findings, send off for urgent analysis. Often there will be haematuria and/or proteinuria.

Other investigations

  • Dipstick
  • Urine microscopy – look particularly for the presence of red cell casts and red cells.
  • Blood tests – U+E’s – particularly creatinine and potassium. Also check for free haemoglobin and myoglobin.
  • Check if the patient is on any nephrotoxic drugs.

Causes

Pre-renal failure and acute tubular necrosis account for 80% of cases.
Causes of ARF can be divided into three main categories:  prerenal, intra-renal and post-renal. There may be multiple causes of ARF in an individual patient.
In the hospital situation, the most common cause of ARF is sepsis.  But proceed with caution – treatment with gentamycin or vanomycin is contraindicated as these are nephrotoxic agents!

Prerenal causes

Here, there is impaired blood flow to the kidney, and this may be a result of:
  1. Hypovolaemia –  which may be due to reduced blood volume
  2. Hypotension
  3. Decreased cardiac output
  4. Vascular disease – limiting renal blood flow
  5. Combinations of any of the above
 
  • Normally the kidney is able to maintain sufficient perfusion despite alterations in these conditions through autoregulation.  However, in extreme circumstances, it cannot, thus GFR will fall. This is known as prerenal uraemia.
    • ACE inhibitors and NSAID’s impair autoregulation; for that reason they predispose to prerenal uraemia.
  • Excretory function of the kidney improves once normal perfusion has been restored.
The following parameters are used to differentiate between prerenal and intra-renal causes:
Prerenal Intrarenal
Urine specific gravity >1.020 <1.010
Urine osmolarity (mOsm/kg) >500 <350
Urine sodium (mmol/L) <20 >40
Urine specific gravity and urine osmolarity are measures of the concentration of solutes in urine. They are quick and easy to carry out, but are unreliable in the presence of glycosuria or other unrelated conditions that disturb urine concentration.
Confirming diagnosis –clinical signs are probably more important than laboratory tests in the determination of prerenal causes, and those that suggest prerenal uraemia are:
  • History of blood/fluid loss
  • Sepsis – leading to vasodilation)
  • Cardiac disease
  • Postural hypotension
  • Weak, rapid pulse
  • Low JVP

Intra-Renal causes

Acute tubular necrosis (ATN)
This term is contentious. In many cases, necrosis of tubular cells exists, although it is difficult to confirm.  Structurally, the glomerulus and vessels are often normal. Generally, the term “acute tubular necrosis” refers to ARF where there are signs of renal damage as a result of renal ischemia, or nephroptoxins.  There is often more than one precipitating factor.
The kidneys are particularly susceptible to ischaemic damage and cholestatic jaundice.
  • Vulnerability is also increased when there is more than one factor contributing to the ischaemia. For example, there are many conditions that cause hypotension which directly cause renal artery occlusion, aggravating the damage to a localised area. Such conditions, which perpetuate renal ischemia, include gram-negative septicaemia, pre-eclampsia  and other complications of pregnancy
Treatment of ATN is based on increasing renal perfusion, whilst treating the underlying condition, e.g. glomerulonepthritis, if one is present.
Varying degrees of ATN are seen after almost all cases of circulatory compromise.
 

Aetiological factors

  • Myoglobinaemia and haemoglobinaemia as a result of muscle injury – this is also often present in trauma.
  • Heroin use – this probably contributes, as above, to the formation of myoglobin or haemoglobin casts that occlude the renal artery.
  • Liver failure
    • Interestingly, a kidney donated from a patient suffering liver failure with coexisting oliguria will function normally after transplantation into a healthy recipient!
  • ACE-inhibitors – this is complicated situation. ACE-inhibitors can lead to dilation of the efferent arteriole, thus lowering glomerular pressure, resulting in a reduced GFR.  In patients with renal disease, this exacerbates the condition.
  • NSAID’s – reduce prostaglandin production. Protaglandins are vasodilators – thus inhibition of their production may lead to vasoconstriction of the afferent arteriole, thereby causing reduced renal and reduced GFR.

Pathology

The kidneys are the first organ system to be jeopardised when systemic circulation is compromised. There are two main causes for this: toxicity and ischaemia.
There is a well-defined sequence of events that culminates in ATN.  Initially there will be a rapid reduction in GFR followed by a rapid increase in serum creatinine and urea.  This is followed by an extended period, typically 1 to 2 weeks, where there is continued poor kidney function while serum creatinine and urea continue to rise. Finally (and hopefully!), there is restoration of kidney function, where GFR rises, whilst serum creatinine and urea fall.
In ATN, a combination of the following factors exists:
  • Intra-renal vasoconstriction on a microvascular level due to:
    • Decreased vasodilation occuring in the presence of other factors, including endothelial damage, e.g. in trauma or in infection, where leukocyte activation and release of PGE2 (prostaglandin 2), ACh and bradykinin occurs.
    • Increased vasoconstriction
  • Tubular cell injury – ischemia initiates rapid utilisation of intracellular ATP stores which, once depleted, will cause the cell to die by necrosis or apoptosis.  Adjacent cells will thereby lose their adherent qualities (perhaps due to lack of polarity, lack of membrane integrity and other effects), and desquamate. As a result, RBCs are able to escape into the tubule, squishing together to form casts. Casts can then block the renal tubule, forming a back-up of tubular fluid.  Consequently, there may also be a leak of tubular fluid into the interstitium, reducing the total filtered volume. The necrosis is worst in the ascending loop of Henle – especially when it lies in a relatively poorly perfused medulla – and the proximal tubule.  This type of cell injury also leads to decreased production of prostaglandins and nitric oxides which are vasodilators, causing vasoconstriction, and reducing perfusion of tubular cells even further!
    • Tubular cell recovery – tubular cells have the ability to regenerate very quickly, and can rapidly repair the damaged basement membrane. This may explain why ATN is reversible. Numerous growth factors are released during cell injury to assist in the regeneration process, such as insulin-like growth factor, epidermal growth factor, and hepatocyte growth factor.
Ischaemia results in a reduction of GFR in various ways:
  • Glomerular contraction – resulting from increased solute delivery to the macula densa, glomerular contraction reduces the surface area available for filtration. Increased solute delivery is caused by reduced sodium reabsoprtion due to loss of tight-junction integrity, and reduction in the number and function of Na+/K+ potassium pumps.
  • Back-leak of filtration – due to tubular damage (described above).
  • Obstruction of the tubule by debris – such as casts.

Progression of the condition

ATN has a well defined sequence of events, and these will vary depending on the severity of the disease.  Initially there will be a rapid reduction in GFR followed by a rapid increase in serum creatinine and urea. And there may or may not be oliguria. Oliguria is associated with a worse prognosis than when there is a higher urinary output.  This will be followed by an extended period – typically 1 to 3 weeks – where there is continued poor kidney function, and serum creatinine and urea continue to rise. Any recovery possible at this stage will be delayed by sepsis.  Also, during this prolonged phase, some patients may have a massive urine output of up to many litres per day due to tubular damage resulting in insignificant reabsorption of filtrate.  Finally (and hopefully!) there will be restoration of kidney function, and the GFR will rise, whilst the serum creatinine and urea will fall.
There are no known treatments that will reduce the duration of ATN once it has begun. Treatment will essentially involve keeping the patient alive until the condition rectifies itself!
  • There is no evidence to suggest the use of mannitol, furosemide or dopamine is beneficial, however often one of these is given if correction of pre-renal causes produces no benefit.

Chemical and biochemical features

  • Hyperkalaemia – this is particularly common, especially following trauma, i.e. muscle related injury.
  • Metabolic acidosis – this is usually present.  Some patients may bypass this situation by vomiting, i.e. to reduce H+ ion concentration, or aspirating gastric contents.
  • Hyponatraemia – many patients will drink significant amounts in the presence of oliguria, leading to ‘dilution’ of body fluids to the extent that hyponatraemia occurs.
  • Pulmonary oedema – as a result of salt and water retention.  This is quite common but not always present.  Just as above complication, this condition is often the result of medical intervention – where patients have over-enthusiastically been given fluid infusion, e.g. 0.9% saline in this situation, without adequate monitoring of fluid volume.
  • Hypocalcaemia and hyperphosphateaemia
  • General symptoms of uraemia – these include anorexia, nausea, vomiting, fits, coma and haemorrhagic episodes.
Avoid causing acquired infections. Medical interventions, such as catheterisation and cannulation, can lead to acquired infection, which is already likely due to immune system compromise in the setting of uraemia.  Take extra precautions such as not leaving a catheter in for too long a period, or changing a cannulation site according to hospital policy.
 

Nephrotoxicity

Many substances are known to be nephrotoxic. The risk of nephrotoxicity increases with age, duration of treatment, combinations of nephrotoxic drugs, high dosage, underlying renal dysfunction and renal ischaemia.
Often, ARF will appear within 2 weeks of taking a nephrotoxic drug. It will usually present as mild oliguria, with possible proteinuria.

Amnioglycosides

These are a class of antibiotics that are most commonly associated with nephrotoxicity.  Generally, reserve the use of these drugs when other suitable treatments are not effective or cannot be used.  Examples of these drugs include gentamycin, vanomycin, kanamycin and streptomycin. Remember, though, that there are many other nephrotoxins that do not fall into this class of drugs.  Often, the presentation can appear worse due to the presence of infection (which is obviously what the drugs were prescribed for in the first place!)

Contrast nephropathy

In patients with impaired renal function, the use of iodinated contrast media can cause nephrotoxicity.  Patients at particular risk are those with diabetic nephropathy.  It is thought that the toxic effect is caused both by direct toxicity, and by the vasoconstricting effect of the contrast. The effect is dose-dependent and is therefore most commonly seen in procedures that utilise significant doses, such as angiography.  In most patients, the effect is mild and transient, and is of no clinical significance.  The risk is minimised by using the lowest dose possible, by using a low-osmolality contrast, and also by infusing saline solution before the procedure.  But be careful not to cause fluid overload!
In patients with CKD, who need a coronary angiography, giving haemofiltration is a good preventative measure.
The symptoms of the nephrotoxicity when it occurs within a couple of hours of injection of the contrast medium can be difficult to distinguish from those of atheromatous embolization – which carries a worse prognosis.
Renal parenchymal disease
This is actually a result of acute tubular necrosis.

Managing ARF

Kidney function is monitored through urine output analysis and creatinine clearance monitoring.  Creatinine clearance monitoring is the ideal, i.e. it is a more precise indication of GFR than serum urea monitoring alone!
Note that there are many non-renal causes of raised serum urea, such as GI bleed where blood is broken down by bacteria in the GI tract and reabsorbed as urea.
The lowest rate of urination in a healthy individual is ½ ml/KG/hour.  In a normal person, i.e. 75 kg, this translates into 35ml/hour.
Signs and symptoms must carefully be monitored! Monitor BP, urine output, JVP, and central venous pressure every hour.   Detecting hypovolaemia isn’t as easy as it sounds, so look for…
  • JVP – may or may not be invisible
  • Low BP
  • Low urine output
  • Poor tissue turgor
  • Fast, weak pulse

In order to avoid fluid overload also look for…

  • Raised BP
  • Peripheral oedema
  • Lung crepitations
  • Gallop rhythm heard on heart sounds
Replace fluidsif hypovolaemia andor hypotension are suspected, but be careful! In many cases, prerenal and intrarenal causes co-exist, and loading the patient with fluids can result in massive oedema.  The oedema will be particularly apparent in the hips.
Call for specialist help!  And whilst waiting the junior doctor should…
  • Palpate the bladder –if there is a palpable bladder, then the underlying cause is most likely post-renal!  However, the absence of a palpable bladder does not rule out obstruction as a cause.
  • Order an urgent USS – the presence of small kidneys suggests CKD
  • Put a catheter in to monitor urine output
  • Stop all nephrotoxic drugs – this includes NSAID’s, ACE inhibitors, gentamycin, vanomycin, and if creatinine is >150mmol/L then stop metformin also.
  • Take cultures and then use an appropriate antibiotic to treat any sepsis present.
  • Nutrition is very important – aim for a normal calorie intake, and if oral feeding is difficult, then consider early naso-gastric feeding.
  • Treat hyperkalaemia early and quickly!! –values of above 6mmol/L are particularly dangerous as this may lead to arrhythmias, particularly ventricular fibrilliation, or cardiac arrest.
    • In the setting of VF, the ECG may demonstrate…
      • Tall tented T waves
      • Small or absent P waves
      • Wide QRS complex – normal QRS is 0.12 which can increase 0.24, predisposing to MI.
      • Asystole
      • Sine wave pattern
    • If VF is present, the following is imperative:
      • Calcium gluconate – this is cardio-protectiveGive a 10ml dose of 10% solution every 2 mins until the ECG improves.
      • Insulin – this stimulates the uptake of glucose within a cell – and as glucose is taken up it is taken up in co-transport with potassiumGiving insulin will lower serum K+ by 1-2mmol/L over 1 hour. Check glucose level about 30 minutes after initial administration as rendering the patient hypoglycaemic poses great dangers!
      • Consider haemodialysis if the patient is anuric, i.e. producing no urine. This is often the only way the acutely hyperkalaemic patient can be managed. The treatment is often employed for only a few days in the ARF patient whilst they recover.
  • Give the following if pulmonary oedema is present:
    • Venodilator,e.g. morphine
    • Oxygen – sit the patient upright
    • Loop diuretic, i.e. furosemide.  Although higher doses may be required, loop diuretics are indicated in this instance as they remain effective in the setting of renal failure despite reduced GFR.
    • If there is no response as a result of the above interventions, then urgent haemodialysis or haemofiltration is needed. 
  • Give plasma and platelets if bleeding is marked. In most instances where bleeding is apparent only a straightforward blood transfusion is required as blood loss is often detected before the situation becomes life-threatening.
  • Consider dialysis if any of the following indications are present:
    • Pulmonary oedema
    • Persistent hyperkalaemia, i.e. K>7mmol/L
    • Severe metabolic acidosis, i.e. pH <7.2, or base excess <10
    • Uraemic encephalopathy
    • Uraemic pericarditis, aka “uraemic rub” 
  • Manage any acidosis – Treat this with sodium bicarbonate; this intervention will also help to lower the level of free potassium.
    • BE CAREFUL!  If NaHCO3 is administered too quickly, the patient may become hypocalcaemic, which often causes tetany. 
  • Treat any sepsis – this needs to be treated quickly, but remember not to use nephrotoxic drugs, e.g. vanomycin, gentamycin.  Prophylactic antibiotics and barrier nursing are not always deemed necessary.
Fluid and electrolyte balance
Once the patient has a normal balance, then fluid intake should equal urine output + vomit + fistulae losses + 500 ml extra allowance.  Patients with fever will require an additional allowance.
  • Assess electrolytes daily.
  • Check for signs of fluid overload constantly.
  • Monitor weight – rapid fluctuations are indicators of fluid loss or gain.
Diet
Restrict sodium and potassium intake.  Other dietary modifications are controversial:
  • Protein intake – some recommendations restrict intake to 40g/day; however, this can lead to excessive metabolism of endogenous protein, thus causing a negative nitrogen balance. To prevent this, a high calorie intake, alongside low protein intake, is recommended.
  • Patients treated with haemodialysis require 70g protein daily to prevent negative nitrogen balance.
Vitamin D supplements are usually required.
Patients may have to be fed parenterally if vomiting or diarrhoea are problematic.

 

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