BMJ Learning

Acute renal failure

د. حسين محمد جمعة
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010

Key points

Acute renal failure describes an acute decline in renal function and is often characterised by a rising serum creatinine and plasma urea and a reduced urine output. Clinically there may be no symptoms or signs
Acute renal failure may happen as an isolated problem, but more commonly it occurs with circulatory disturbance, for example severe illness, sepsis, surgery, or trauma

Acute renal failure can have pre-renal causes secondary to inadequate renal perfusion, renal causes secondary to intrinsic renal disease, and post-renal causes secondary to obstruction. It is important to find out the cause when you suspect acute renal failure.

Clinical tips

Recognising and diagnosing acute renal failure and its cause early helps prompt investigations and appropriate treatment. Always consider obstruction as a cause of acute renal failure. It is a reversible cause and prompt treatment prevents permanent kidney damage and the need for dialysis.

Check the patient's potassium levels regularly because hyperkalaemia is a common and dangerous complication
Diuretics, mannitol, and low dose dopamine have not been proved to benefit patients with acute renal failure


Introduction
Acute renal failure is common. Many elderly patients have impaired renal function and most commonly develop "acute on chronic renal failure" in the setting of serious illness, prolonged hypotension, or major surgery .

You should always take note of the baseline level of renal function and any subsequent change in these patients. It is particularly important to identify patients who are at a higher risk of developing acute renal failure. This includes elderly patients and patients with diabetes mellitus, vascular disease, hypertension, and pre-existing renal impairment. These patients need careful monitoring of renal function and strict attention to fluid balance.

Many clinical laboratories now use various mathematical formulas such as the Modification of Diet in Renal Disease equation. This formula uses sex, age, and serum creatinine to calculate the estimated glomerular filtration rate. The level of baseline renal impairment or chronic renal disease in any patient may be classified as stage 1 to 5 according to the criteria in Table 1.

Patients with significant chronic renal disease are at increased risk of developing acute on chronic renal failure. You must pay careful attention to hydration and drug therapy in such patients. Note that the Modification of Diet in Renal Disease equation is not validated in the context of acute renal failure because the serum creatinine is highly variable in such circumstances. The serum creatinine may be used to track the level of renal dysfunction in acute renal failure.

Table 1. Classification of chronic renal disease

Stage of chronicrenal disease
Features
1
Normal glomerular filtration rate (>90 ml/min) but evidence of renal damage (eg proteinuria) or a renal structural abnormality (eg cystic renal disease)
2
Mild renal dysfunction (glomerular filtration rate 60-89 ml/min) plus evidence of renal damage (eg proteinuria) or a renal structural abnormality (eg cystic renal disease)
3
Moderate renal dysfunction (glomerular filtration rate 30-59 ml/min)
4
Severe renal dysfunction (glomerular filtration rate 15-29 ml/min)
5
Renal failure (glomerular filtration rate <15 ml/min); patient may be on renal replacement therapy


Definition of acute renal failure
There are over 30 definitions of acute renal failure and this complicates the interpretation and comparison of many clinical studies. Definitions have used various parameters, such as proportional or absolute changes in the serum creatinine and output of urine, or a combination of changes in serum creatinine and output of urine.

A recently published consensus paper examined the various definitions used and proposed a classification of different stages of acute renal failure that can be applied to critically ill patients. This RIFLE classification (Table 2) is denoted by:
Risk of renal dysfunction
Injury to the kidney
Failure of renal function
Loss of renal function
End stage renal disease.
This tells us the severity of the renal impairment.

Table 2. The RIFLE classification of acute renal failure

RIFLE
Serum creatinine criteria
Glomerular filtration rate criteria
Urine output criteria
Risk
Increased serum creatinine (1.5-fold)
Glomerular filtration rate decrease more than 25%
Urine output less than 0.5 ml/kg/hour for six hours
Injury
Increased serum creatinine (twofold)
Glomerular filtration rate decrease more than 50%
Urine output less than 0.5 ml/kg/hour for 12 hours
Failure
Increased serum creatinine (threefold) or serum creatinine more than 350 µmol/l
Glomerular filtration rate decreased by more than 75%
Urine output less than 0.3 ml/kg/hour for 24 hours or anuria for 12 hours
Loss
Persistent acute renal failure = complete loss of renal function for more than four weeks


End stage renal disease
End stage renal disease (more than three months)

Morbidity and mortality of acute renal failure

Acute renal failure has a significant morbidity and mortality. A recent review analysed the reported mortality rates in studies of acute renal failure published between 1970 and 2004 and found that they have remained constant at around 50%. Various factors may account for this including a change in the nature of patients who develop acute renal failure. Patients treated for acute renal failure in more recent years may be older patients with more comorbid disease.

The data reinforce the negative impact of acute renal failure on patient survival. On a more optimistic note, over 50% of patients with initial normal renal function who develop acute renal failure secondary to acute tubular necrosis in intensive care will regain renal function if they survive.
Only 10% of surviving patients have continuing severe renal dysfunction.

Causes of acute renal failure

There are many individual causes of acute renal failure but it is still instructive to classify these as:
• Pre-renal
• Renal
• Post-renal.

Pre-renal causes

Are the most common reason for renal failure. Patients are at increased risk of developing established acute tubular necrosis if not resuscitated in time. The most important pre-renal causes of acute renal failure are:
Hypovolaemia (severe diarrhoea, vomiting, severe bleeding, or loss of fluid into third spaces)
Hypotension and reduced renal perfusion (for example after a myocardial infarction)
Severe renovascular disease
Hepatorenal syndrome.


Intrinsic or renal causes
Acute tubular necrosis following:
Nephrotoxic drugs
Prolonged hypotension
Radiocontrast agents
Rhabdomyolysis with severe myoglobinuria following:
Trauma
Drug abuse
Delirium tremens
Excessive exercise

Acute glomerulonephritis:

Systemic lupus erythematosus
Wegener's granulomatosis
Goodpasture's syndrome
Thrombotic microangiopathy
Myeloma with tubular obstruction
Acute interstitial nephritis (commonly drug related but other causes include sarcoidosis)
Cryoglobulinaemia - although rare this condition may complicate lymphoproliferative diseases and infections such as hepatitis C.

Post-renal causes

Post-renal causes are due to obstruction of the genitourinary tract following:
Prostatic hypertrophy
Calculi
Retroperitoneal fibrosis
Pelvic malignancy.


There will be natural overlap between categories, as in septic patients who are hypotensive. There are countless causes of acute renal failure ranging from various infections (for example leptospirosis, HIV, or malaria), tissue injury (rhabdomyolysis), or obstruction (for example obstruction of a single functioning renal transplant).

In clinical practice it is common for patients to have several causes for the renal dysfunction. For example, a patient with hypertension and arthritis on long term treatment with angiotensin converting enzyme (ACE) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) continues to take these drugs after developing severe diarrhoea while on holiday.

ACE inhibitors impair the autoregulation of renal blood flow while the NSAID inhibits the generation of intrarenal vasodilatory prostaglandins.
The additional insult of hypovolaemia in this context is sufficient to result in acute tubular necrosis and acute renal failure, whereas the hypovolaemia may well have been tolerated in a patient receiving no ACE inhibitors or NSAIDs.

Drugs are a common cause of acute renal failure especially in hospital patients, and it is mandatory to scrutinise the drug prescription.
Table 3 provides a list of commonly used drugs that may cause acute renal failure. You should remember to regularly adapt drug dosages in the presence of a reduced glomerular filtration rate. Consult the British National Formulary and discuss the dose with a pharmacist if you have doubts.

Table 3. Commonly used drugs that may cause renal failure

Drug
Clinical feature
ACE inhibitors and angiotensin receptor blockers
Decline in renal function is most common in patients with significant renal artery stenosis, hypertensive nephrosclerosis, or cardiac failure. Renal function changes in first three to five days. A rise in creatinine of 20% is acceptable
Hyperkalaemia is common especially in patients with chronic renal failure. It may resolve with a lower dose
NSAIDs
Inhibition of renal prostaglandin synthesis can cause acute reduction in glomerular filtration rate. It is more common if the patient is hypovolaemic. This may also occur with cyclo-oxygenase-2 inhibitors
NSAIDs may cause:
• Acute interstitial nephritis. This usually resolves when the drug is stopped. Treatment with steroids may accelerate the resolution
• Nephrotic syndrome due to a minimal change disease
• Membranous nephropathy (less common)
Antibiotics:
Penicillins

Cause interstitial nephritis. Occurs after more than one week on antibiotics. Patients may have rash, fever, and eosinophilia. Should resolve on stopping drug
Aminoglycosides
Acute tubular necrosis occurs in 10-20% of patients. Elevated trough levels, pre-existing renal disease, and presence of additional nephrotoxins increase the risk. Usually reversible
Calcineurin inhibitors such as cyclosporin A and tacrolimus
High levels associated with elevation in creatinine. This is a common problem in renal transplant recipients


What should you do when you think your patient has acute renal failure?
You can glean much useful information from the history, examination, and focused investigations. Often, you can predict the underlying diagnosis. This allows you to prioritise further treatment and investigation.

History

At the beginning of acute renal failure there are no typical symptoms; later patients often have fatigue and nausea.
In your history taking you should seek answers to the following questions:

Is there a concomitant illness such as sepsis or pneumonia that makes acute renal failure more likely?
Has the patient pre-existing renal impairment?
Has the patient been exposed to nephrotoxic agents such as NSAIDs, aminoglycoside antibiotics, amphotericin, or radiographic contrast media? Don't forget to scrutinise the drug chart for potentially nephrotoxic drugs

Are there any symptoms, a skin rash, arthralgia, or haemoptysis, to suggest an underlying systemic disease?
Has the urine output slowly tailed off or has the patient become suddenly anuric? This would suggest a vascular event or complete obstruction
Did the patient have oliguria or excessive fluid losses over the last days? Fluid balance charts may indicate oliguria or excessive fluid losses such as diarrhoea, nasogastric aspirate, and fluids in a drain.

Examination

You should examine the patient carefully and accurately. The volume status of the patient is often the key aspect of the clinical assessment because many patients are volume depleted. Typical signs of intravascular fluid depletion include:
Tachycardia
Hypotension (you must interpret the blood pressure in the context of the patient's usual blood pressure)
Postural hypotension
A low jugular venous pressure.


It is worth investing time in assessing the jugular venous pressure because it is a useful parameter to follow during fluid resuscitation in patients who do not have central venous access. Although easy to assess in thin people, it is easy to confuse it with arterial pulsations. If you have identified the jugular venous pressure as visible with the patient sitting at 45°, ensure you can see it rising following gentle pressure over the liver (hepatojugular reflux). If you cannot see the jugular venous pressure, examine the patient flat or even "head down" until you identify it.

Other pertinent clinical findings include:

Fever (possibly caused by sepsis)
Skin rashes (possibly caused by systemic vasculitis or drug reactions)
Respiratory crackles (caused by infection, fluid overload, and pulmonary oedema, or pulmonary haemorrhage)
Palpable bladder (typical for prostatic obstruction).

Investigations

All patients need a comprehensive assessment of biochemistry and haematology tests including coagulation, although you should order the various immunological tests only if appropriate to the clinical context (Table 4). They would not be indicated in an uncomplicated case of renal tract obstruction or post-surgical acute tubular necrosis.

Also, serology for hepatitis B and C and HIV is necessary because the patient may need dialysis. A renal ultrasound is mandatory to assess renal size and exclude obstruction of the renal tract.
Patients with normal sized kidneys and unexplained renal failure usually need a diagnostic renal biopsy unless the clinical situation strongly suggests acute tubular necrosis.

Table 4. Useful investigations in patients with acute renal failure

Presenting features
Pertinent points
Haematology
Full blood count
Blood film
Coagulation (may need renal biopsy)
Anaemia (indicating chronic renal failure or myeloma)
Haemolysis (indicating thrombotic microangiopathy)
Biochemistry
Full biochemistry required including urea, electrolytes, bicarbonate, liver function tests, calcium, phosphate, and albumin
Creatine kinase
Immunoglobulin electrophoresis and Bence-Jones protein
Hypercalcaemia (indicating myeloma or malignant disease)
Marked increase in creatine kinase (diagnostic of rhabdomyolysis)
Immunology
Complement studies
Antinuclear antibodies and antidouble stranded antibodies
Antineutrophilic cytoplasmic antibodies
Antiglomerular basement membrane antibodies
Hypocomplementaemia (suggests lupus nephritis, cryoglobulinaemia, or chronic infection, for example endocarditis)
Suggests Goodpasture's syndrome
Microbiology
Blood cultures, urine microscopy and culture
Hepatitis and HIV serology
Antistreptococcal antibody titres (if recent infection)
Because underlying infections are common
Because dialysis may be required
Imaging
Renal ultrasound
Chest x ray
May need vascular imaging (Doppler, angiogram) if renovascular event suspected
To exclude obstruction
To see whether there is any evidence of fluid overload or pulmonary haemorrhage
Biopsy
Renal biopsy
Normal sized kidney and unexplained renal failure


Treating patients with acute renal failure
Specific treatment
This will depend on the diagnosis.
You should resuscitate patients with acute renal failure secondary to an inadequate circulating volume and reduced renal perfusion with appropriate fluids, such as blood (if bleeding), colloids, or normal saline, to restore normal tissue perfusion. This may prevent patients from developing established acute tubular necrosis

Patients with acute renal failure secondary to parenchymal renal disease other than acute tubular necrosis have a wide differential diagnosis. Treatments vary according to the underlying diagnosis. Patients with rapidly progressive glomerulonephritis need immunosuppressive treatment, for example prednisolone and cyclophosphamide.

You must treat patients with infection promptly and aggressively. In these patients you should take a comprehensive set of cultures and then choose the antibiotic therapy on a best guess basis.
You should treat patients with acute renal failure caused by obstruction by prompt relief of the obstruction, for example by inserting a urethral catheter or a nephrostomy.

It is important that you liaise with your nephrological (or urological) colleagues at an early stage to ensure that patients are managed appropriately. This is because some patients will need transfer to a renal unit for further investigation and treatment

Supportive care

Important and represents the mainstay of treatment. It is vital that you prevent further insults, such as giving nephrotoxic contrast agents. You must optimise fluid balance with appropriate fluid replacement. There has been debate about the best fluid to use in such circumstances but recent work suggests there is no major difference in outcome between giving normal saline and albumin.

In very unwell patients, patients who are at risk of fluid overload, and patients who are difficult to assess clinically, fluid replacement should be guided by invasive monitoring because this will ensure optimal perfusion of the kidneys.

Hyperkalaemia

Hyperkalaemia is a common complication in patients with acute renal failure. You should therefore monitor
potassium levels carefully.
Patients with hyperkalaemia need a 12 lead ECG.
The medical treatment of hyperkalaemia usually includes the administration of the following drugs:


Intravenous calcium to antagonise the effects of potassium on cardiac conduction (intravenously 5-10 ml 10% calcium gluconate or calcium chloride). This will provide only 30-60 minutes of protection and you may need to repeat this.

Intravenous glucose and insulin to drive potassium into the intracellular compartment (25 g glucose with 5 units Actrapid insulin). This will lower potassium levels for four to six hours.

Intravenous or nebulised salbutamol to drive potassium into the intracellular compartment (5-10 mg nebulised, 0.5 mg intravenous). This will lower potassium for about two hours. This may not work in patients on beta blockers or digoxin

Oral calcium resonium (an ion exchange resin) that acts to minimise the absorption of potassium from the gastrointestinal tract (15 g per mouth four times a day). Patients should receive adequate laxatives because this causes constipation.
Calcium resonium will take two to four hours to work, so is of little value in acute settings.

Intravenous loop diuretics such as furosemide will lower the potassium, if the patient is fluid overloaded and passing urine.
Haemodialysis is indicated if these measures fail to correct the hyperkalaemia because this will effectively remove potassium from the body.

Treating patients who need dialysis

Haemodialysis is the preferred means of treating acute renal failure in the UK. There are several types of haemodialysis, which may broadly be classified as either intermittent or continuous treatments.
Intermittent haemodialysis takes around four hours. Depending on the patient's size and biochemistry you should perform intermittent haemodialysis every day or on alternate days

Continuous renal replacement therapy is performed continuously, as the name suggests. Continuous renal replacement therapy may be more suitable for patients on intensive care units with acute renal failure who show cardiovascular instability. It is less challenging from the haemodynamic perspective than intermittent haemodialysis because the fluid is removed over a more prolonged period.

Continuous renal replacement therapy such as continuous venovenous haemofiltration may also remove injurious circulating pro-inflammatory mediators. Several trials have attempted to address whether the outcome of patients receiving continuous renal replacement therapy or intermittent haemodialysis differs. Recent studies suggest there is no significant difference in outcome.

The optimal dose of dialysis for a patient with acute renal failure is not known. Prolonged dialysis may improve biochemistry but also needs extended periods of anticoagulation and exposure of blood to a membrane that activates complement and leucocytes (despite being called "biocompatible"). The latter effects may affect events within the injured or recovering kidney.


Delivery of effective dialysis may also be hampered by vascular access problems, cardiovascular instability (hypotension may result in clotting of the dialysis filter), and hypercatabolism in severely ill patients.
There is some evidence that a daily haemodialysis may benefit patients on intensive care units compared with haemodialysis on alternate days.

Vascular access and anticoagulation

Dialysis requires a double lumen dialysis line to be inserted to allow blood to be removed and returned to the patient. A jugular position is preferable because subclavian lines can result in a subclavian stenosis.
This can jeopardise the successful development of an arteriovenous fistula if the patient does not recover renal function and needs long term dialysis.

If patients have a coagulopathy or are severely thrombocytopenic you should insert a dialysis catheter in the femoral vein because there is less risk of severe bleeding.
Femoral lines have an increased rate of infection.

During both intermittent haemodialysis and continuous renal replacement therapy patients need anticoagulation.
You should use heparin and monitor the activated clotting time. Complications of anticoagulation include bleeding and heparin induced thrombocytopenia.

You can use alternative agents such as prostacyclin in patients with the heparin induced thrombocytopenia syndrome.
The management of patients with acute renal failure mainly depends on the cause.
Table 5 gives an overview of typical findings in the history, examination, investigation, and treatment for different causes of acute renal failure.

Table 5. Findings and specific treatment for different causes of acute renal failure

Diagnosis
History
Examination
Key investigations
Specific treatment
Volume loss
Acute volume loss, for example:
Gastrointestinal bleeding
Diarrhoea
Trauma
Reduced skin turgor
Tachycardia
Hypotension
-
Fluid resuscitation with normal saline or colloid
Sepsis
Fever
Rigors
Information to localise site of infection
Pyrexia
Hypotension
Tachycardia
Vasodilatation
Blood and urine cultures
C-reactive protein, neutrophil count
Fluid resuscitation
May need inotropic support
Intravenous antibiotics directed at cause (on a best guess after extensive cultures taken)
Multiple myeloma
Bone pain
Fatigue
Weight loss
Pallor
Serum protein electrophoresis looking for monoclonal band
Bence-Jones protein in the urine
Hypercalcaemia is common
Bone marrow examination needed to confirm diagnosis
Hypercalcaemia treated with fluid resuscitation and bisphosphonates
Haematology review to determine specific treatment
The patient may need dialysis
Systemic vasculitis
Two to six months of malaise
Fevers
Arthralgia
Nasal discharge
Eye discomfort
Haemoptysis
Skin rash
Scleritis
Mononeuritis multiplex
Urine Dipstix (will have 3-4+ blood and protein)
ANCA (positive)
C-reactive protein and platelet count (elevated)
Renal biopsy
Immunosuppression typically with steroids and cyclophosphamide
Plasma exchange if dialysis needed
Lung haemorrhage may occur, which is a life threatening complication
Rhabdomyolysis
Crush injury in trauma patients
Elderly patients often lying on floor for a prolonged period after a fall
Commonly occurs in intravenous drug abusers who accidentally inject into artery leading to muscle damage
Compartment syndrome in arm or leg
Creatine kinase (massively elevated, usually >15 000 unit/l)
Fluid resuscitation with normal saline
Hyperkalaemia may be a significant early problem
Haemofiltration required early due to massive tissue injury
Cholesterol emboli
Pre-existing atheromatous disease with recent arterial imaging or surgery
Purpuric rash on the feet
Occasionally more significant emboli
Eosinophilia
Renal biopsy
No specific treatment
Renal function often does not recover
Renal tract obstruction
Prostatic symptoms in a man
Underlying malignant disease (such as cervical and bladder carcinoma) can obstruct the ureters
Known single kidney such as renal transplant
Known neurological problems
Palpable bladder for outlet obstruction
Ultrasound of kidney, ureter, and bladder
Urinary catheter where there is bladder outflow obstruction
Nephrostomy for ureteric obstruction with hydronephrosis


Preventive measures
Over the years a variety of agents has been proposed to be of benefit to patients with incipient or established acute renal failure. More recent studies and meta-analyses have indicated that these agents are of no significant benefit and may be harmful, for example furosemide may be ototoxic.

Dopamine

Doctors previously gave dopamine to patients to improve renal perfusion. There is no convincing evidence that renal dose dopamine has any beneficial effects, and giving dopamine is no longer indicated for oliguric patients.

Mannitol

The osmotic agent mannitol has been given to patients to promote urine flow and ameliorate oliguric renal failure. However, there are no convincing data that mannitol is useful in patients with acute renal failure.

Furosemide

Although most patients with acute renal failure exhibit a profound reduction in urine output (anuric or oliguric acute renal failure), some patients may develop renal failure despite maintaining a reasonable urine output.

The management of patients with such non-oliguric renal failure is slightly easier because they are less liable to develop peripheral and pulmonary oedema or hyperkalaemia. The diuretic furosemide has often been given to patients with acute renal failure following appropriate fluid resuscitation in an attempt to "convert" oligoanuric renal failure into non-oliguric renal failure to simplify patient management.

There is some scientific basis to support giving furosemide because inhibiting the sodium-chloride-potassium pump of the cells of the thick limb of the loop of Henlé reduces the energy requirements of the cells. This can protect them from hypoxic or ischaemic injury.

There are no convincing data to support the use of furosemide in acute renal failure. A recent meta-analysis of studies using furosemide to prevent or treat acute renal failure showed no clinical benefit: in hospital mortality, requirement for dialysis, number of dialysis sessions, and the proportion of patients with oliguria were unaffected by treatment with furosemide.

Preventing contrast nephropathy

Many radiological procedures need intravenous contrast and these agents may be nephrotoxic. Although more modern radiocontrast agents have diminished nephrotoxic effects, contrast nephropathy can still result in acute renal failure within 48 hours of exposure.


Although the acute renal dysfunction is typically mild and reversible, contrast nephropathy may necessitate dialysis. Patients with vascular disease and chronic renal failure (especially diabetic nephropathy) are at particular risk of developing contrast nephropathy.

As well as the common sense measures of minimising the dose of contrast agent and avoiding repetitive administration, several agents have been used to try to prevent contrast nephropathy including theophylline, fenoldopam, furosemide, intravenous hydration with a variety of fluids, and the antioxidant N-acetylcysteine. Many of the studies of these measures were small and underpowered.

The dose of N-acetylcysteine administered in studies has generally been a total of four oral doses of 600 mg taken before and after the radiological intervention. A recent meta-analysis indicated that giving N-acetylcysteine reduced the risk of contrast nephropathy (defined as an increase in serum creatinine of at least 44.2 mmol/l or of 25% of baseline values 48 hours after administering the contrast) compared with hydration alone during the procedure.

Other meta-analyses have been less conclusive and the quality of reviews varies.

All patients undergoing radiological interventions involving administration of contrast agents should be well hydrated and receive intravenous hydration if appropriate. Furosemide, mannitol, and dopamine do not have a role here. It is also reasonable to administer N-acetylcysteine .