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Alison J Armitage
Charlie Tomson
Definitions
ARF is defined as a reduction in glomerular filtration rate (GFR)
occurring over days or weeks. This is an imprecise definition, with
respect to both the change in GFR required and the length of time
over which the change develops. However, it is useful for practical purposes. In routine clinical practice, measurement of serum
creatinine is used to follow changes in GFR. Common working
definitions of ARF are as varied as:
an increase in serum creatinine of > 50 mol/litre
an increase in serum creatinine of > 50% from baseline
a reduction in calculated creatinine clearance of > 50%
need for dialysis.
Considerable caution is required in interpreting measurements of
serum creatinine in ARF, for several reasons as follows.
Creatinine production depends on muscle mass, and though
normally constant can increase in patients with acute muscle injury
(as in rhabdomyolysis).
Creatinine concentration may exhibit a modest decrease as a
result of dilution during rapid fluid resuscitation (e.g. an increase
in extracellular fluid volume from 12 litres to 14 litres reduces
serum creatinine from 300 to 257 mol/litre).
Because of the reciprocal relationship between creatinine concentration and GFR, small changes in GFR close to the normal
range have much less effect on serum creatinine than small changes
when GFR is already significantly reduced (Figure 1).
Changes in serum creatinine concentration lag behind changes
in GFR. Creatinine concentration may continue to increase for
Epidemiology
The incidence of severe ARF (defined as an acute increase in
serum creatinine to > 500 mol/litre) is about 140/million/year.
In Scotland, the incidence of ARF requiring dialysis was recently
estimated at about 130/million/year. Less severe ARF (defined
as an increase in serum creatinine to 177 mol/litre or by 50%
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Pathophysiology
Pre-renal ARF is an appropriate physiological response to effective
or true hypovolaemia, resulting in intense renal conservation of
sodium and water at the expense of decreased GFR. Urea clearance
decreases more than creatinine clearance as a result of the action of
antidiuretic hormone (ADH). By definition, renal function returns
to normal rapidly once the underlying cause is corrected. Reduction in renal arterial perfusion pressure below the level at which
autoregulation of GFR occurs is an important contributor. However,
in hypovolaemic or septic patients (in whom mean arterial blood
pressure may be maintained at normal levels by intense systemic
vasoconstriction), pre-renal ARF may still occur as a result of intrarenal vasoconstriction from increased sympathetic tone, increased
intra-renal production of angiotensin II, and the contribution of
venous pressure receptors to the afferent limb of the reflexes that
cause pre-renal ARF. The early phase of sepsis causes peripheral
vasodilatation and increased cardiac output, as a consequence of
the production of nitric oxide by inducible nitric oxide synthase.
In the renal circulation, however, this leads to feedback inhibition
of constitutive endothelial nitric oxide synthase, resulting in renal
vasoconstriction.
Aetiology
Pre-renal ARF is defined as a reduction in GFR caused by impaired
renal perfusion as a result of hypotension or hypovolaemia that is
rapidly reversed by correction of the underlying cause.
Intrinsic renal disease: the principal causes of ARF caused by
intrinsic renal disorders are listed in Figure 2. ATN and drug
nephrotoxicity are the most common causes in this group.
Post-renal ARF: obstructive nephropathy is more often subacute
or chronic than acute, but often presents as an emergency and
is treated as a form of ARF because it is at least partially reversible on relief of obstruction. The most common cause is benign
or malignant prostatic bladder outflow obstruction; other causes
include infiltrative bladder cancer (causing bilateral vesicoureteric obstruction), other pelvic malignancies, radiation fibrosis,
bilateral stone disease, and retroperitoneal fibrosis with or without
abdominal aortic aneurysm.
Complete bilateral obstruction causes anuria, but is rare. Partial
chronic bilateral obstruction commonly leads to an increase in
urine flow rate as a result of impaired salt and water reabsorption.
Symptoms are very variable. In patients with high-pressure chronic
retention causing renal failure, presenting symptoms may include
nocturnal enuresis and voiding lower urinary tract symptoms (e.g.
poor stream). Chronic back pain is a feature of retroperitoneal
fibrosis. The initial investigation of choice is renal ultrasonography,
which shows bilateral hydronephrosis and may help to identify
the level of obstruction. In rare cases, however, obstructive renal
damage occurs without significant dilatation of the pelvicalyceal
system; this usually results from encasement by tumour.
Acute tubular necrosis (ATN): acute tubular necrosis is an inaccurate term, because necrosis is seldom seen in renal biopsies
taken from patients with this syndrome. It results from the insults
that cause pre-renal ARF, but lasting long enough to cause ischaemic injury to renal tubules. This leads to a long-lasting reduction
in GFR that sometimes persists for weeks after correction of the
initiating insult. This is caused by a combination of:
persistent, intense intra-renal vasoconstriction caused by
endothelin, other autocrine mediators and increased intracellular calcium
loss of polarity of tubular cells, leading to loss of function
loss of adherence of tubular cells, leading to desquamation into
the tubular lumen
formation of tubular casts, blocking the lumen and preventing
urine flow
tubuloglomerular feedback (reflex reduction of glomerular
perfusion caused by high sodium concentration in the distal
tubule)
back-leak of tubular filtrate as a result of loss of tubular viability
and obstructing casts
reperfusion injury, causing oxidant stress.
These observations have led to many attempts to alter the natural history of ATN using, for example, vasodilators, natriuretic
peptides, diuretics and growth factors, but almost all have been
unsuccessful.
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Renal embolism
Endocarditis, cardiac thrombus
Nephrotoxicity
Including aminoglycosides and amphotericin
Hypercalcaemia
Sarcoidosis, milkalkali syndrome
Contrast nephropathy
A specific form of nephrotoxicity characterized by renal
vasoconstriction and avid sodium retention
Intravenous immunoglobulin
Probably results from osmotic damage to proximal tubular
cells caused by sucrose in some intravenous immunoglobulin
preparations
Urate nephropathy
Complicating chemotherapy of acute leukaemia or lymphoma
Myeloma
Cast nephropathy, light-chain deposition disease, amyloidosis,
sepsis and hypercalcaemia can all cause renal damage
Hepatorenal syndrome
Reversible intense renal vasoconstriction and sodium retention
complicating cirrhosis
Malignant hypertension
Untreated primary (essential) hypertension or complicating
chronic glomerulonephritis
Poisoning
Including paracetamol, often after recovery from liver damage
Rhabdomyolysis
Following crush injury, drug overdose, status epilepticus
Acute pyelonephritis
Seldom causes acute renal failure, but ?more likely to do so in
the elderly and in those taking non-steroidal
anti-inflammatory drugs
Infection in patients with diabetes and partial obstruction
(e.g. from papillary necrosis) may cause emphysematous
pyelonephritis and acute renal failure
Investigations
Renal ultrasonography: as discussed above, ultrasonography
assesses renal size and echogenicity and the presence or absence
of hydronephrosis (Figure 3). Occasionally, other appearances may
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Management
Fluid resuscitation: aggressive, early fluid resuscitation is the
intervention most likely to ameliorate the course of pre-renal ARF
and ARF caused by ATN. It must be guided by regular clinical
assessment of the patients circulating volume, aided if there is
any doubt by measurements of central venous pressure (CVP) or
even pulmonary capillary wedge pressure.
Measurement of input and output strict fluid balance charts
are often demanded in patients with ARF. It is useful to know the
Abnormality
Eosinophilia
Very high creatine kinase,
phosphate, K+
Elevated lactate
dehydrogenase
Antineutrophil cytoplasm
antibodies
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Antiglomerular basement
membrane antibody
Low C4 complement
Antinuclear antibody,
anti-dsDNA
Cryoglobulin
Plasma urate
Serum (and urine)
electrophoresis
Suggested underlying
disorder
Acute interstitial nephritis
Cholesterol embolism
Rhabdomyolysis
Renal infarction/embolism
Systemic vasculitis causing
rapidly progressive
glomerulonephritis
Goodpastures disease
Systemic lupus erythematosus,
cholesterol embolism,
cryoglobulinaemia
Systemic lupus erythematosus
Cryoglobulinaemia
Urate nephropathy
Myeloma
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input and output, but these charts are often inaccurate because of
the difficulties of measuring all sources of fluid loss (e.g. insensible
losses, diarrhoea, vomitus, blood loss) and fluid gain (e.g. oral
intake, water generated from metabolism). Over-reliance on fluid
balance charts also carries the danger that fluid administration
will be adjusted according to recent output rather than the clinical
state of the patient; for example, it would be possible to clamp
a patient in a severely hypovolaemic state simply by matching
input to output. Positive fluid balance is a necessary part of the
resuscitation of patients with effective or true hypovolaemia.
Another reason for measuring urine output is to assess renal
function. Anuria and severe oliguria are diagnostic of severe ARF,
but urine volume is of little help in any other situation. The following is an extreme example.
A GFR of 100 ml/minute (6000 ml/hour) normally gives a urine
flow rate of about 60 ml/hour because of reabsorption of 99%
of the filtrate delivered to the renal tubules. However, a GFR of
1 ml/minute combined with complete failure of tubular reabsorption (resulting from tubular damage, as in ATN, or from high
doses of drugs that inhibit tubular reabsorption, e.g. dopamine,
furosemide) would also give a urine output of 60 ml/hour.
Changes in urine flow rate are therefore a very poor guide to
changes in GFR, and must be interpreted along with all the other
available clinical information.
Urethral catheters are often placed to enable accurate measurement of urine flow rate. For the reasons discussed above,
this is seldom as helpful as it appears. Urethral catheters are the
single most important source of hospital-acquired Gram-negative
septicaemia they should not be placed without good reason, and
should be removed as soon as possible.
Fluid challenges are often given in the hope that they will
stimulate diuresis as if a head of pressure would help to improve
renal perfusion. It is illogical (and dangerous) to give further fluid
to a patient who has already been fully resuscitated; if the patient
remains oliguric, the extra fluid load may cause life-threatening
pulmonary oedema. It is equally illogical to give 500 ml fluid
boluses to a hypovolaemic patient. The only rational use of fluid
boluses is in combination with CVP measurement; administration
of a fluid bolus to a hypovolaemic patient causes only a transient
increase in CVP, compared with a more sustained rise in patients
approaching euvolaemia.
Dopamine and loop diuretics low-dose dopamine is widely
used in the belief that it restores renal blood flow and improves
GFR. There is mounting evidence (including a recent large randomized controlled trial, Bellomo et al.) that this treatment is of
no benefit. The only setting in which dopamine is justified is as an
inotropic agent. Loop diuretics are also widely used. The rationale is that they may lessen tubular hypoxic damage by inhibiting
energy-dependent transport processes and flushing out tubular
casts. However, there is no clinical evidence that loop diuretics
improve outcome in ARF (Lassnigg et al.).
Loop diuretics and dopamine can both increase urine output
by reducing tubular reabsorption of filtrate, and this can fool the
unwary into believing that GFR has improved. The ability to mount
a diuresis in response to either drug probably identifies patients in
whom the prognosis is better, but there is no evidence that either
drug improves prognosis. Unless the patient is significantly volumeoverloaded, the diuresis caused by these drugs can exacerbate ATN
by causing further hypovolaemia.
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REFERENCES
Bellomo R, Chapman M, Finfer S et al. Low-dose Dopamine in Patients
with Early Renal Dysfunction: A Placebo Controlled Randomised Trial.
Australian and New Zealand Intensive Care Society (ANZICS) Clinical
Trials Group. Lancet 2000; 356: 213943.
Lassnigg A, Donner E, Grubhofer G et al. Lack of Renoprotective Effects of
Dopamine and Furosemide during Cardiac Surgery. J Am Soc Nephrol
2000; 11(1): 97104.
Phu N H, Hien T T, Mai N T et al. Haemofiltration and Peritoneal Dialysis
in Infection-associated Acute Renal Failure in Vietnam. N Engl J Med
2002; 347: 895902.
Sort P, Navasa M, Arroyo V et al. Effect of Intravenous Albumin on Renal
Impairment and Mortality in Patients with Cirrhosis and Spontaneous
Bacterial Peritonitis. N Engl J Med 1999; 341: 4039.
van den Berghe G, Wouters P, Weekers F et al. Intensive Insulin Therapy
in the Surgical Intensive Care Unit. N Engl J Med 2001; 345:
135967.
FURTHER READING
Alderson P, Schierhout G, Roberts I et al. Colloids versus Crystalloids for
Fluid Resuscitation in Critically III Patients. Cochrane Database Syst
Rev 2000; 2: CD000567.
Blantz R C. Pathophysiology of Pre-renal Azotemia. Kidney Int 1998;
53(2): 51223.
Esson M L, Schrier R W. Diagnosis and Treatment of Acute Tubular
Necrosis. Ann Intern Med 2002; 137(9): 74452.
Human Albumin Administration in Critically III Patients: Systematic
Review of Randomised Controlled Trials. Cochrane Injuries Group
Albumin Reviewers. BMJ 1998; 317: 23540.
Lameire N, Vanholder R. Pathophysiologic Features and Prevention of
Human and Experimental Acute Tubular Necrosis. J Am Soc Nephrol
2001; 12: (Suppl. 17): S2032.
Metcalfe W, Simpson M, Khan I et al. Acute Renal Failure requiring Renal
Replacement Therapy: Incidence and Outcome. Q J Med 2002; 95:
57983.
Star R A. Treatment of Acute Renal Failure. Kidney Int 1998; 54(6):
181731.
Follow-up: patients with ARF who do not recover normal excretory function, or who had pre-existing renal impairment, should
not be discharged without a long-term plan for management of
CRF (see page 52). Patients who make a full recovery do not
require follow-up unless required for the underlying condition
that caused the ARF.
Practice points
Always discuss the patient with a nephrologist if in doubt
Beware of missing parenchymal renal disease; irreversible
renal damage may occur if appropriate specific treatment is not
initiated rapidly
Central venous catheters are more useful than urethral catheters
in the treatment of sick patients
The choice of resuscitation fluid is less important than the speed
and completeness of correction of hypovolaemia
Prevention
The fact that 50% of cases of ARF occur after admission to hospital
suggests a potential for prevention. This is largely by avoidance,
or early aggressive treatment, of sepsis and hypovolaemia, and
avoidance (when possible) of nephrotoxic drugs.
u
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