The diagnostic criteria for AKI is based on an increase in serum creatinine or the presence of oliguria (see Table 17.1). Criteria have recently been introduced for the definition and staging of the condition; the acronym RIFLE is used (Risk, Injury, Failure, Loss and End-stage renal disease (ESRD)), which is now becoming established in clinical practice (see Fig. 17.1).

Table 17.1 Classification of acute kidney injury

Acute kidney injury type	Typical % cases	Common aetiology
Pre-renal	40–80	Reversible ↓ renal perfusion through hypoperfusion
Intra-renal (including ATN)	10–50	Renal parenchymal injury
Post-renal	<10	Urinary tract obstruction

ATN, acute tubular necrosis.

Fig. 17.1 The RIFLE criteria for the definition and staging of acute renal disease.

The large majority of cases of AKI occur in patients who are already hospitalised for other medical conditions; up to 7% of these sustain AKI and this increases to 30% or more in those who are critically ill. Most cases are caused by pre-renal AKI and are reversed with appropriate intervention. However, severe AKI, as defined by the requirement for dialysis treatment, is often associated with failure of one or more non-renal organs (this is called multi-organ failure); in this setting there is a mortality rate of 70% in patients with sepsis and AKI and 45% in patients without sepsis. AKI that occurs in the community is responsible for around 1% of all hospital admissions.

Classification and causes

AKI is not a single disease state with a uniform aetiology, but a consequence of a range of different diseases and conditions. The most useful practical classification comprises three main groupings: (i) pre-renal, (ii) renal, or (iii) post-renal. More than one category may be present in an individual patient. Common causes of each type of AKI are outlined in Table 17.1.

The kidneys are pre-disposed to haemodynamic injury owing to hypovolaemia or hypoperfusion. This relates to the high blood flow through the kidneys in normal function; the organs represent 5% of total body weight but receive 25% of blood flow. Furthermore, the renal microvascular bed is unique; firstly, the glomerular capillary bed is on the arterial side of the circulation; secondly, the peri-tubular capillaries are down-stream from the glomerular capillary bed. Finally, renal cells are highly specialised and are, therefore, pre-disposed to ischaemic and inflammatory injury.

Pre-renal acute kidney injury

This is caused by impaired perfusion of the kidneys with blood, and is usually a consequence of decreased intravascular volumes (hypovolaemia) and/or decreased intravascular pressures. Some of the commonest causes of pre-renal AKI are summarised in Fig. 17.2. Perfusion of the kidneys at the level of the microvascular beds (glomerular and tubulo-interstitial) is usually maintained through wide variations in pressure and flow through highly efficient auto-regulatory pathways, such as the renin–angiotensin–aldosterone system (RAAS) and regulated prostaglandin synthesis. However, when the systolic blood pressure (BP) drops below 80 mmHg, AKI may develop. In individuals with chronic kidney disease (CKD) or in the elderly, this may occur at higher levels of systolic BP. Drugs that inhibit the RAAS, such as angiotension converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs), or block the production of prostaglandins, such as non-steroidal anti-inflammatory drugs (NSAIDs), can pre-dispose to the development of pre-renal AKI. These are discussed in more detail below.

Fig. 17.2 Causes of pre-renal failure.

Hypovolaemia

This results from any condition that causes intravascular fluid depletion, either directly by haemorrhage or indirectly to compensate for extravascular loss. Examples of this include diarrhoea and vomiting, burns and excessive use of diuretics. Hypotension is a secondary effect of significant hypovolaemia.

Hypotension

In addition to hypovolaemia, hypotension can result from pump (cardiac) failure, of which there are a number of causes, the most common of which is ischaemic heart disease. Another important cause is septic shock, where there is peripheral vasodilatation and low peripheral resistance which leads to profound hypotension despite a high cardiac output.

Intra-renal acute kidney injury

This is caused by a variety of causes (see Tables 17.1 and 17.2), most commonly (in >80% of cases) acute tubular necrosis (ATN). ATN occurs usually as a consequence of a combination of factors, including hypotension, often in the setting of sepsis and nephrotoxic agents including drugs or chemical poisons, or endogenous sources such as myoglobin or haemoglobin.

Table 17.2 Common clinical factors known to cause acute tubular necrosis

Clinical factor	Mechanism
Hypoperfusion	Reduced oxygen/nutrient supply
Radiocontrast media	Medullary ischaemia may result from contrast media induced renal vasoconstriction. The high ionic load of contrast media may produce ischaemia particularly in diabetics and those with myeloma (who produce large quantities of light chain immunoglogulins)
Sepsis	Infection produces endotoxaemia and systemic inflammation in combination with a pre-renal state and nephrotoxins. The immunological response to sepsis involves release of vasoconstrictors and vasodilators (e.g. eicosanoids, nitric oxide) and damage to vascular endothelium with resultant thrombosis
Rhabdomyolysis	Damaged muscles release myoglobin, which can cause ATN through direct nephrotoxicity and by a reduction in blood flow in the outer medulla
Renal transplantation	The procedures and conditions encountered during renal transplantation can induce ischaemic ATN which can be difficult to distinguish from the nephrotoxic effects of immunosuppressive drug therapy used in these circumstances and rejection
Hepatorenal syndrome	Renal vasoconstriction is frequently seen in patients with end-stage liver disease. Progression to ATN is common
Nephrotoxins
Aminoglycosides	Aminoglycosides are transported into tubular cells where they exert a direct nephrotoxic effect. Current dosage regimens recommend once daily doses, with frequent monitoring of drug levels, to minimise total uptake of aminoglycoside
Amphotericin	Amphotericin appears to cause direct nephrotoxicity by disturbing the permeability of tubular cells. The nephrotoxic effect is dose dependent and minimised by limiting total dose used, rate of infusion and by volume loading. These precautions also apply to newer liposomal formulations
Immunosuppressants	Ciclosporin and tacrolimus cause intra-renal vasoconstriction that may result in ischaemic ATN. The mechanism is unclear but enhanced by hypovolaemia and other nephrotoxic drugs
NSAIDs	Vasodilator prostaglandins, mainly E₂, D₂ and I₂ (prostacyclin), produce an increase in blood flow to the glomerulus and medulla. In normal circumstances, they play no part in the maintenance of the renal circulation. However, increased amounts of vasoconstrictor substances arise in a variety of clinical conditions such as volume depletion, congestive cardiac failure or hepatic cirrhosis associated with ascites. Maintenance of renal blood flow then becomes more reliant on the release of vasodilatory prostaglandins. Inhibition of prostaglandin synthesis by NSAIDs may cause unopposed arteriolar vasoconstriction, leading to renal hypoperfusion
Cytotoxic chemotherapy	For example, cisplatin
Anaesthetic agents	Methoxyflurane, enflurane
Chemical poisons/naturally occurring poisons	Insecticides, herbicides, alkaloids from plants and fungi, reptile venoms

Acute tubular necrosis

ATN is a diagnosis made by renal biopsy; the findings can include damage to the proximal tubule and the ascending limb of the loop of Henle, interstitial oedema and sparse infiltrating inflammatory cells. Whilst severe and sustained hypoperfusion can lead to ATN, it usually develops when there is a combination of factors including the presence of one or more of a range of nephrotoxins. These may arise exogenously from drugs or chemical poisons, or from endogenous sources such as haemoglobin, myoglobin, crystals (uric acid, phosphate) and toxic products from sepsis or tumours (see Table 17.2). Some endogenous toxins may be released as a direct consequence of drug exposure. For example, myoglobin may be released (rhabdomyolosis) following muscle injury or necrosis, hypoxia, infection or following drug treatment, for example, with fibrates and statins, particularly when both are used in combination. The mechanism of the subsequent damage to renal tissue is not understood fully but probably results from a combination of factors including hypoperfusion, haem-catalysed free radical tubular cytotoxicity and haem cast formation and precipitation leading to tubular injury.

The vascular bed and development of acute tubular necrosis

Regional blood flow within the kidney varies, resulting in relatively hypoxic regions such as the outer medulla. This area is also the site of highly metabolically active parts of the nephron. Owing to the relatively poor oxygen supply and high metabolic demands, the outer medulla is at risk of ischaemia, even under normal conditions. The regulation of regional blood flow in the kidney, and therefore the oxygen supply to these areas, relies upon vasomotor mechanisms mediated in part by adenosine. Adenosine appears to exert either vasoconstrictor or vasodilator effects within the kidney depending upon the relative distribution of A₁ and A₂ receptors.

Clearly, any circumstance that interferes with the delicate balance of blood flow and, therefore, oxygen supply within the kidney can result in ATN because of ischaemia and a greater vulnerability to nephrotoxins. The likelihood of ATN is increased by underlying conditions that pre-dispose to ischaemia such as pre-existing CKD of any cause, atheromatous renovascular disease and cholesterol embolisation from upstream atheromatous plaque rupture.

Common causes of acute tubular necrosis

Table 17.2 shows a summary of some of the common factors encountered clinically that may cause ATN.

Differentiating pre-renal from renal acute kidney injury

It is sometimes possible to distinguish between cases of pre-renal and renal AKI through examination of biochemical markers (see Table 17.3). In renal AKI, the kidneys are generally unable to retain Na⁺ owing to tubular damage. This can be demonstrated by calculating the fractional excretion of sodium (FENa); in practice this is not often done because it lacks sensitivity and specificity and may be difficult to interpret in the elderly who may have pre-existing concentrating defects.

Table 17.3 Differentiating pre-renal from renal acute kidney injury

Laboratory test	Pre-renal	Renal
Urine osmolality (mOsm/kg)	>500	<400
Urine sodium (mEq/L)	<20	>40
Urine/serum creatinine (μmol/L)	>40	<20
Urine/serum urea (μmol/L)	>8	<3
Fractional excretion of sodium (%)	<1	>2

If FENa <1%, this indicates pre-renal AKI with preserved tubular function; if FENa >1% this is indicative of ATN. This relationship is less robust if a patient with renal AKI has glycosuria, pre-existing renal disease, has been treated with diuretics, or has other drug-related alterations in renal haemodynamics, for example, through use of ACE inhibitors or NSAIDs. One potential use of urinary electrolytes is in the patient with liver disease and AKI; where the diagnosis of hepato-renal syndrome is being considered, one of the diagnostic criteria is a urinary sodium <10 mmol/L

Post-renal acute kidney injury

Post-renal AKI results from obstruction of the urinary tract by a variety of mechanisms. Any mechanical obstruction from the renal pelvis to the urethral orifice can cause post-renal AKI; these can be divided into causes within the ureters (e.g. calculi or clots), a problem within the wall of ureter (malignancies, benign strictures) and external compression (e.g. retroperitoneal tumours). It is extremely unusual for drugs to be responsible for post-renal AKI. Practolol-induced retroperitoneal fibrosis resulting in bilateral ureteric obstruction is a rare example.

Clinical manifestations

The signs and symptoms of AKI are often non-specific and the diagnosis can be confounded by coexisting clinical conditions. The patient may exhibit signs and symptoms of volume depletion or overload, depending upon the precipitating conditions, course of the disease and prior treatment.

Acute kidney injury with volume depletion

In those patients with volume depletion, a classic pathophysiological picture is likely to be present, with tachycardia, postural hypotension, reduced skin turgor and cold extremities (see Table 17.4). The most common sign in AKI is oliguria, where urine production falls to less than 0.5 mL/kg/h for several hours. This is below the volume of urine required to effectively excrete products of metabolism to maintain a physiological steady state. Therefore, the serum concentration of those substances normally excreted by the kidney will rise and differentially applies to all molecules up to a molecular weight of around 50 kDa. This includes serum creatinine, which at a molecular weight of 113 Da is normally freely filtered by the kidneys but with loss of kidney function the serum level climbs. Whilst the term uraemia is still in widespread use, it merely describes a surrogate for the overall metabolic disturbances that accompany AKI; these include excess potassium, hydrogen ions (acidosis) and phosphate in blood. Most cases of AKI are first identified by an abnormal blood test, though some patients may have symptoms that are specifically attributable to AKI; these include nausea, vomiting, diarrhoea, gastro-intestinal haemorrhage, muscle cramps and a declining level of consciousness.

Table 17.4 Factors associated with acute kidney injury

	Volume depletion	Volume overload
History	Thirst	Weight increase
	Excessive fluid loss (vomiting or diarrhoea)	Orthopnoea/nocturnal dyspnoea
	Oliguria
Physical examination	Dry mucosae ↓ Skin elasticity	Ankle swelling Oedema
	Tachycardia	Jugular venous distension
	↓ Blood pressure	Pulmonary crackles
	↓ Jugular venous pressure	Pleural effusion

Acute kidney injury with volume overload

In those patients with AKI who have maintained a normal or increased fluid intake as a result of oral or intravenous administration, there may be clinical signs and symptoms of fluid overload (see Table 17.4).

Diagnosis and clinical evaluation

In hospitalised patients, AKI is usually diagnosed incidentally by the detection of increasing serum creatinine and/or a reduction in urine output.

The assessment of renal function is described in detail in Chapter 18. However, unless a patient is at steady state, measurement of serum creatinine does not provide a reliable guide to renal function. For example, serum creatinine levels will usually rise by only 50–100 μmol/L per day following complete loss of renal function in a previously normal patient. These changes in serum creatinine are not sufficiently responsive to serve as a practical indicator of glomerular filtration rate, particularly in AKI in critical care scenarios.

In the hospital situation, when AKI is detected incidentally, the cause(s) of the condition, such as fluid depletion (hypovolaemia), infection or the use of nephrotoxic drugs, are often apparent on close examination of the clinical history. The development of AKI in this setting is more likely to occur in people with pre-existing CKD. People with normal baseline kidney function usually need to sustain at least two separate triggers for the development of AKI; for example, hypovolaemia will rarely cause AKI in this setting, but when hypovolaemia occurs in the presence of nephrotoxic drugs then AKI may occur. In patients with pre-existing CKD, AKI (i.e. acute on chronic renal failure) can occur in patients with one trigger. By definition, the worse the baseline kidney function, the smaller the trigger required for the development of AKI. Irrespective of the presentation of AKI, it is wise to consider the complete differential diagnosis in all people; active exclusion of post-renal AKI and immune and inflammatory AKI should be considered in all cases. In AKI without an obvious precipitating pre-or post-renal cause, there is a greater need to consider these causes. Although the majority of patients have ATN, other causes such as rapidly progressive glomerulonephritis, interstitial nephritis, multiple myeloma or urinary tract obstruction must be screened for and systematically excluded. In addition to supportive care that is generic for all causes of AKI, disease-specific treatment may also be required. The investigation of AKI is outlined in Fig. 17.3.

Fig. 17.3 The investigations of acute kidney injury.

Various other parameters should be monitored through the course of AKI. Fluid balance charts that are frequently used may be inaccurate and should not be relied upon exclusively. Records of daily weight are more reliable but are dependent on the mobility of the patient.

Monitoring fluid balance in acute kidney disease

Maintaining appropriate fluid balance in AKI is a critical component of the clinical management of the patient. Detailed clinical assessment includes:

1. Measurement of BP which needs to be interpreted in respect of the baseline for the affected patient together with the patient’s heart rate.

2. Auscultation of the heart for the presence of 3rd (and 4th) heart sounds; the presence of these indicate cardiac strain associated with fluid overload.

3. Presence of added sounds in the chest, in particular fine inspiratory crackles that are found in some patients with pulmonary oedema.

4. A chest X-ray for the presence of pulmonary oedema.

5. Pulse oximetry to assess arterial oxygen saturation.

6. Whilst the presence of pitting oedema of the legs or sacrum indicates longer term fluid overload, it may be a useful marker of overall endothelial function and the potential for extravascular fluid accumulation.

7. Decreased skin turgor is a sign of fluid loss.

Intravascular monitoring

Central venous pressure (CVP) can be measured following insertion of a central venous catheter, and is a measure of the pressure in the large systemic veins and the right atrium produced by venous return. CVP assesses circulating volume and, therefore, the degree of fluid deficit, and reduces the risk of pulmonary oedema following over-rapid transfusion. CVP should usually be maintained within the normal range of 5–12 cmH₂O.

Most patients with AKI do not require invasive monitoring to the extent described above and recover with supportive care based on careful clinical observations.

Monitoring key parameters in acute kidney disease

Serum electrolytes including potassium, bicarbonate, calcium, phosphate and acid–base balance should be measured on a daily basis. In patients with severe AKI, acid–base balance may need assessing every few hours as this may direct fluid replacement, respiratory support and dialysis treatment.

Course and prognosis

Pre-renal acute kidney injury

The majority of cases will recover within days of onset following prompt correction of the underlying causes. The urine output improves and waste products of metabolism are cleared by the kidneys. Whilst the kidney function usually stabilises to the pre-event baseline, in some patients long-term kidney function resets to lower than previous values.

ATN may be divided into three phases. The first is the oliguric phase where patients have sustained pre-renal AKI and move from the potential for early reversibility to a situation where uraemia and hyperkalaemia develop and the patient may die unless renal replacement therapy (RRT) with dialysis is started. The oliguric phase is usually no longer than 7–14 days but may last for 6 weeks. This is followed by a diuretic phase, which is characterised by a urine output that rises over a few days to several litres per day. This phase lasts for up to 7 days and corresponds to the recommencement of tubular function. The onset of this phase is associated with an improving prognosis unless the patient sustains an intercurrent infection or a vascular event. Finally, the patient enters a recovery phase where tubular cells regenerate slowly over several months, although the glomerular filtration rate often does not return to initial levels. The elderly recover renal function more slowly and less completely.

The mortality rate of AKI varies according to the cause but increases when AKI occurs in patients with multi-organ failure, where mortality rates of up to 70% are seen. Higher mortality rates are seen in patients aged over 60 years.

Death resulting from uraemia and hyperkalaemia are very uncommon. Consequently, the major causes of death associated with AKI are septicaemia and intercurrent acute vascular events such as myocardial infarction and stroke. High circulating levels of uraemic toxins that occur in AKI result in general debility. These, together with the significant number of invasive procedures such as bladder catheterisation and intravascular cannulation which are necessary in the management of AKI, leave such patients prone to infection and septicaemia. Uraemic gastro-intestinal haemorrhage is a recognised consequence of AKI, probably as a result of reduced mucosal cell turnover.

Post-renal acute kidney injury

Prompt identification and relief of the obstruction is important. The prognosis is then dependent on the underlying cause of the obstruction of the renal tract and the baseline to which the kidney function returns after the obstruction has been relieved. If the underlying problem is benign then there may be no long-term adverse consequences. However, if the cause of the obstruction is due to an underlying malignancy then long-term survival is dependent on whether this can be cured.

ACE inhibitors and angiotensin receptor blockers in acute kidney injury

ACE inhibitors and ARBs are not directly nephrotoxic and can be used in most patients with kidney disease. However, profound hypotension can occur if they are initiated in susceptible patients such as those who are receiving high dose diuretics as treatment for fluid overload. This might result in the development of pre-renal AKI. It is, therefore, wise to monitor BP and carefully titrate dosages whilst monitoring renal function in such patients. Nonetheless, it is common to see increases in serum creatinine levels of up to 20% on initiation of an ACE inhibitor or ARB and this is not necessarily a cause for discontinuing therapy with these agents.

ACE inhibitor use is, however, absolutely contraindicated when a patient has bilateral renal artery stenosis, or renal artery stenosis in a patient with a single functioning kidney. If an ACE inhibitor or ARB is initiated under these circumstances then pre-renal AKI may ensue. This may occur since the renin–angiotensin system is stimulated by low renal perfusion resulting from stenotic lesions in the arteries supplying the kidneys, most often at the origin of the renal artery from the abdominal aorta. Angiotensin II is produced which causes renal vasoconstriction, in part, through increased efferent arteriolar tone. This creates a ‘back pressure’ which paradoxically maintains glomerular filtration pressure in an otherwise poorly perfused kidney. If angiotensin II production is inhibited by an ACE inhibitor, or the effect is blocked by an ARB, then efferent arteriole dilatation will result. Since increased efferent vascular tone maintains filtration in such patients, then the overall result of ACE inhibitor or ARB therapy will be to reduce or shut down filtration at the glomerulus and put the patient at risk of pre-renal AKI (see Fig. 17.4).

Fig. 17.4 The actions of ACE inhibition and angiotensin receptor blockade in patients with renal artery stenosis.

Management

The aim of the medical management of a patient with AKI is to prolong life in order to allow recovery of kidney function. Effective management of AKI depends upon a rapid diagnosis. If the underlying acute deterioration in renal function is detected early enough, it is often possible to prevent progression. If the condition is advanced, however, management consists mainly of supportive strategies, with close monitoring and appropriate correction of metabolic, fluid and electrolyte disturbances. Patients with severe AKI usually require renal replacement therapy with dialysis. Specific therapies that promote recovery of ischaemic renal damage remain under investigation. Patients with immune-mediated causes of AKI should be treated with appropriate immunosuppressant regimens to treat the underlying cause of the AKI.

Early preventive and supportive strategies

Identification of patients at risk

Any patient who has concurrent or pre-existing conditions that increase the risk of development and progression of AKI must be identified and this includes those with pre-existing CKD, diabetes, jaundice, myeloma and the elderly. These patients either have baseline impaired renal function or are sensitised to the development of AKI by the co-morbid condition. Meticulous attention to fluid balance, assessment of infection and the use of drugs is crucial to minimise the risk of development of AKI.

Withdrawal and avoidance of nephrotoxic agents

Irrespective of whether the aetiology of the AKI directly involves nephrotoxic drugs, the drug and treatment regimens should be examined so that potential nephrotoxins are withdrawn and avoided in the future in order to avoid exacerbating the condition. Particular care should be taken with ACE inhibitors, NSAIDs, radiological contrast media, and aminoglycosides. The doses should be adjusted of any drugs that are renally excreted or have active metabolites that are excreted renally.

Optimisation of renal perfusion

Initial treatment should include rapid correction of fluid and electrolyte balance to maximise renal perfusion. A central line may be considered to facilitate ease of fluid infusion and monitoring of intravascular volumes. In patients where it is difficult to assess fluid balance by use of clinical examination a urinary catheter may be placed in order that fluid losses may be measured easily. However, with the recent focus on the prevention of catheter-related bacteraemia, central lines are seldom used outside specialist renal and intensive care units.

A diagnosis of acute deterioration of renal function caused by renal underperfusion implies that restoration of renal perfusion would reverse impairment by improving renal blood flow, reducing renal vasoconstriction and flushing nephrotoxins from the kidney. The use of crystalloids in the form of 0.9% sodium chloride is an appropriate choice of intravenous fluid since it replaces both water and sodium ions in a concentration approximately equal to serum. The effect of fluid replacement on urine flow and intravascular pressures should be carefully monitored. However, fluid loading with 1–1.5 L saline at <0.5 L/h is unlikely to cause harm in most patients who do not show signs of fluid overload. There is no evidence that colloids such as gelofusin or albumin provide any additional benefit for volume expansion and renal recovery over the use of 0.9% sodium chloride.

The use of inotropes such as noradrenaline and cardiac doses of dopamine should be restricted to non-renal indications.

Establishing and maintaining an adequate diuresis

Whilst loop diuretics (most commonly furosemide) may facilitate the management of fluid overload and hyperkalaemia in early or established AKI, there is no evidence that these agents are effective for the prevention of, or early recovery from, AKI. It is reasonable to use these agents whilst the urine output is maintained as this provides space for intravenous drugs and parenteral feeding including oral supplements. In experimental settings, loop diuretics decrease renal tubular cell metabolic demands and increase renal blood flow by stimulating the release of renal prostaglandins, a haemodynamic effect inhibited by NSAIDs. However, there is no demonstrable impact on clinical outcomes. Indeed, diuretic therapy should only be initiated in the context of fluid overload. If not, any diuresis might produce a negative fluid balance and precipitate or exacerbate a pre-renal state.

Doses of up to 100 mg/h of furosemide can be given by continuous intravenous infusion. Higher infusion rates may cause transient deafness. The use of continuous infusions of loop diuretics has been shown to produce a more effective diuresis with a lower incidence of side effects than seen with bolus administration. Bolus doses of loop diuretics may induce renal vasoconstriction and be theoretically detrimental to function.

The addition of small oral doses of metolazone may also be considered. Metolazone is a weak thiazide diuretic alone but produces a synergistic action with loop diuretics. In this setting, it should be used with great care as it may initiate a profound diuresis and the patient can rapidly develop intravascular depletion and worsen renal failure

Mannitol

Mannitol has historically been recommended for the treatment of AKI. The rationale for using mannitol in AKI arises from the concept that tubular debris may contribute to oliguria. There is no evidence for mannitol producing benefit in AKI over and above aggressive hydration. Indeed, mannitol can cause volume overload. Consequently, mannitol is now not recommended for patients with AKI.

Dopamine

Historically, dopamine has been recommended at low dose to improve renal blood flow and urine output. Dopamine at low dose acts as a renal vasodilator in normal kidneys, but in renal failure it is a renal vasoconstrictor even at a low dose. This translates into no demonstrable clinical benefit and it should no longer be used. Dopamine has alpha and beta adrenergic effects. Recently, fenoldapam, a pure dopaminergic D₁ agonist has been investigated in small scale clinical trials; the results have shown a trend towards benefit in recovery of renal function from AKI. However, larger trials are needed to identify if fenoldapam has a role in routine clinical practice (Kellum et al., 2008).

Drug therapy and renal auto-regulation

Intra-renal blood flow is controlled by an auto-regulatory mechanism unique to the kidney called tubuloglomerular feedback (TGF). This mechanism produces arteriolar constriction in response to an increased solute load to the distal nephrons. Glomerular filtration rate and kidney workload are thus reduced. It has been proposed that oliguria is an adaptive response to renal ischaemia and therapy designed to improve glomerular filtration rate would increase solute load to the nephrons and might increase kidney workload and worsen AKI. Clearly, reversal of a pre-renal state with fluids is a logical therapeutic aim.

Non-dialysis treatment of established acute kidney injury

Uraemia and intravascular volume overload

In renal failure, the symptoms of uraemia include nausea, vomiting and anorexia, and result principally from accumulation of toxic products of protein metabolism including urea.

Unfortunately, since uraemia causes anorexia, nausea and vomiting, many severely ill patients are unable to tolerate any kind of diet. In these patients and those who are catabolic, the use of enteral or parenteral nutrition should be considered at an early stage.

Intravascular fluid overload must be managed by restricting NaCl intake to about 1–2 g/day if the patient is not hyponatraemic and total fluid intake to less than 1 L/day plus the volume of urine and/or loss from dialysis. Care should be taken with the so-called ‘low salt’ products, as these usually contain KCl, which will exacerbate hyperkalaemia.

Hyperkalaemia

This is a particular problem in AKI, not only because urinary excretion is reduced but also because intracellular potassium may be released. Rapid rises in extracellular potassium are to be expected when there is tissue damage, as in burns, crush injuries and sepsis. Acidosis also aggravates hyperkalaemia by provoking potassium leakage from healthy cells. The condition may be life-threatening causing cardiac arrhythmias and, if untreated, can result in asystolic cardiac arrest.

Dietary potassium should be restricted to less than 40 mmol/day and potassium supplements and potassium-sparing diuretics removed from the treatment schedule. Emergency treatment is necessary if the serum potassium level reaches 7.0 mmol/L (normal range 3.5–5.5 mmol/L) or if there are the progressive changes in the electrocardiogram (ECG) associated with hyperkalaemia. These include tall, peaked T waves, reduced P waves with increased QRS complexes or the ‘sine wave’ appearance that often presages cardiac arrest (see Chapter 18, Fig. 18.10).

Emergency treatment of hyperkalaemia consists of the following:

1. 10–30 mL (2.25–6.75 mmol) of calcium gluconate 10% intravenously over 5–10 min; this improves myocardial stability but has no effect on the serum potassium levels. The protective effect begins in minutes but is short lived (<1 h), although the dose can be repeated.

2. 50 mL of 50% glucose together with 8–12 units of soluble insulin over 10 min. Endogenous insulin, stimulated by a glucose load or administered intravenously, stimulates intracellular potassium uptake, thus removing it from the serum. The effect becomes apparent after 15–30 min, peaks after about 1 h and lasts for 2–3 h and will decrease serum potassium levels by around 1 mmol/L.

3. Nebulised salbutamol has also been used to lower potassium; however, this is not effective for all patients and does not permanently lower potassium. If used it is seen as a temporary emergency measure.

Acidosis

The inability of the kidney to excrete hydrogen ions may result in a metabolic acidosis. This may contribute to hyperkalaemia. It may be treated orally with sodium bicarbonate 1–6 g/day in divided doses (though this is not appropriate for acute metabolic acidosis seen in AKI), or 50–100 mmol of bicarbonate ions (preferably as isotonic sodium bicarbonate 1.4% or 1.26%, 250–500 mL over 15–60 min) intravenously may be used. The administration of bicarbonate in acidotic patients will also tend to reduce serum potassium concentrations. Bicarbonate will cause an increase in intracellular Na⁺ through activation of the cell membrane Na⁺/H⁺ exchanger, which promotes increased activity of Na-K ATPase producing increased intracellular sequestration of K⁺.

If calcium gluconate is used to treat hyperkalaemia, care should be taken not to mix it with the sodium bicarbonate (by giving this through the same intravenous access site) as the resulting calcium bicarbonate forms an insoluble precipitate. If elevation of serum sodium or fluid overload precludes the use of sodium bicarbonate, extreme acidosis (serum bicarbonate of less than 10 mmol/L) is best treated by dialysis.

Hypocalcaemia

Calcium malabsorption, probably secondary to disordered vitamin D metabolism, can occur in AKI. Hypocalcaemia usually remains asymptomatic, as tetany of skeletal muscles or convulsions does not normally occur until serum concentrations are as low as 1.6–1.7 mmol/L (normal 2.20–2.55 mmol/L). Should it become necessary, oral calcium supplementation with calcium carbonate is usually adequate, and although vitamin D may be used to treat the hypocalcaemia of AKI, it rarely has to be added. Effervescent calcium tablets should be avoided as they contain a high sodium or potassium load.

Hyperphosphataemia

As phosphate is normally excreted by the kidney, hyperphosphataemia can occur in AKI but rarely requires treatment. Should it become necessary to treat, phosphate-binding agents may be used to retain phosphate ions in the gut. The most commonly used agents are calcium containing such as calcium carbonate or calcium acetate and are given with food. For further information see Chapter18.

Infection

Patients with AKI are prone to infection and septicaemia, which can ultimately cause death. Bladder catheters, central catheters and even peripheral intravenous lines should be used with care to reduce the chance of bacterial invasion. Leucocytosis is sometimes seen in AKI and does not necessarily imply infection. However, pyrexia must be immediately investigated and treated with appropriate antibiotic therapy if accompanied by toxic symptoms such as disorientation or hypotensive episodes. Samples from blood, urine and any other material such as catheter tips should be sent for culture before antibiotics are started. Antibiotic therapy should be broad spectrum until a causative organism is identified.

Nutrition

There are two major constraints concerning the nutrition of patients with AKI:

• patients may be anorexic, vomiting and too ill to eat;

• oliguria associated with renal failure limits the volume of enteral or parenteral nutrition that can be given safely.

The introduction of dialysis or haemofiltration allows fluid to be removed easily and, therefore, makes parenteral nutrition possible. Large volumes of fluid may be administered without producing fluid overload. The use of parenteral nutrition is rare but where appropriate factors to be considered include fluid balance, calorie/protein requirements, electrolyte balance/requirements, and vitamin and mineral requirements.

The basic calorie requirements are similar to those in a non-dialysed patient, although the need for protein may occasionally be increased in haemodialysis and haemofiltration because of amino acid loss. In all situations, protein is usually supplied as 12–20 g/day of an essential amino acid formulation, although individual requirements may vary.

Electrolyte-free amino acid solutions should be used in parenteral nutrition formulations for patients with AKI as they allow the addition of electrolytes as appropriate. Potassium and sodium requirements can be calculated on an individual basis depending on serum levels. There is usually no need to try to normalise serum calcium and phosphate levels as they will stabilise with the appropriate therapy, or, if necessary, with haemofiltration or dialysis. Water-soluble vitamins are removed by dialysis and haemofiltration but the standard daily doses normally included in parenteral nutrition fluids more than compensate for this loss. Magnesium and zinc supplementation may be required, not only because tissue repair often increases requirements but also because they may be lost during dialysis or haemofiltration.

It is necessary to monitor the serum urea, creatinine and electrolyte levels daily to make the appropriate alterations in the required nutritional support. The glucose concentration should also be checked daily as patients in renal failure sometimes develop insulin resistance. The plasma pH should be checked initially to determine if addition of amino acid solutions is causing or aggravating metabolic acidosis. It is also valuable to check calcium, phosphate and albumin levels regularly, and when practical, daily weighing gives a useful guide to fluid balance.

Renal replacement therapy

Renal replacement therapy is indicated in a patient with AKI when kidney function is so poor that life is at risk. However, it is desirable to introduce renal replacement therapy early in AKI, as complications and mortality are reduced if the serum urea level is kept below 35 mmol/L. Generally, replacement therapy is urgently indicated in AKI to:

1. remove uraemic toxins when severe symptoms are apparent, for example, impaired consciousness, seizures, pericarditis, rapidly developing peripheral neuropathy

2. remove fluid resistant to diuretics, for example, pulmonary oedema

3. correct electrolyte and acid–base imbalances, for example, hyperkalaemia >6.5 mmol/L or 5.5–6.5 where there are ECG changes, increasing acidosis (pH < 7.1 or serum bicarbonate <10 mmol/L) despite bicarbonate therapy, or where bicarbonate is not tolerated because of fluid overload.

Forms of renal replacement therapy

The common types of renal replacement therapy used in clinical practice are:

• haemodialysis

• haemofiltration

• haemodiafiltration

• peritoneal dialysis

Although the basic principles of these replacement therapies are similar, clearance rates, that is, the extent of solute removal, vary.

In all types of renal replacement therapy, blood is presented to a dialysis solution across some form of semi-permeable membrane that allows free movement of low molecular weight compounds. The processes by which movement of substances occur are:

• Diffusion. Diffusion depends upon concentration differences between blood and dialysate and molecule size. Water and low molecular weight solutes (up to a molecular weight of about 5000) move through pores in the semi-permeable membrane to establish equilibrium. Smaller molecules can be cleared from blood more effectively as they move more easily through pores in the membrane.

• Ultrafiltration. A pressure gradient (either +ve or −ve) across a semi-permeable membrane will produce a net directional movement of fluid from relative high to low pressure regions. The quantity of fluid dialysed is the ultrafiltration volume.

• Convection. Any molecule carried by ultrafiltrate may move passively with the flow by convection. Larger molecules are cleared more effectively by convection.

Haemodialysis

In haemodialysis, the form of access used in AKI is a dialysis line. This is placed in a vein (the jugular, femoral or sub-clavian), which has an arterial lumen through which the blood is removed from the patient and a venous lumen by which it is returned to the patient after passing through a dialyser. The terms arterial and venous lumen can be misleading as both lumens are situated in the same vein. They are part of the same line which bifurcates and has two lumens, the longer lumen is the ‘arterial’ lumen and the shorter the ‘venous’ lumen. Heparin is added to the blood as it leaves the body to prevent the dialyser clotting. Blood is then actively pumped through the artificial kidney before being returned to the patient (Fig. 17.5). In those patients at high risk of haemorrhage, the amount of heparin used can be reduced or even avoided altogether. The dialyser consists of a cartridge comprising either a bundle of hollow tubes (hollow fibre dialyser) or a series of parallel flat plates (flat-plate dialyser) made of a synthetic semi-permeable membrane. Flat-plate dialysers are now rarely used. Dialysis fluid flows around the membrane countercurrent (opposite) to the flow of blood in order to maximise diffusion gradients. The dialysis solution is essentially a mixture of electrolytes in water with a composition approximating to extracellular fluid into which solutes diffuse. The ionic concentration of the dialysis fluid can be manipulated to control the rate and extent of electrolyte transfer. Calcium and bicarbonate concentrations can also be increased in dialysis fluid to promote diffusion into blood as replacement therapy. By manipulating the hydrostatic pressure of the dialysate and blood circuits, the extent and rate of water removal by ultrafiltration can be controlled.

Fig. 17.5 A typical dialysis circuit representing emergency dialysis via a dialysis catheter.

Haemodialysis can be performed in either intermittent or continuous schedules. The latter regimen is preferable in the critical care situation, providing 24-h control, and minimising swings in blood volume and electrolyte composition that are found using intermittent regimens. The haemodialysis described in this section is indistinguishable from that used as maintenance therapy for many patients with end stage renal failure, the method of access in this group is often via an arterio-venous fistula (see Chapter 18).

The capital cost of haemodialysis is considerable, requires specially trained staff, and is seldom undertaken outside a renal unit. It does, however, treat renal failure rapidly and is, therefore, essential in hypercatabolic renal failure where urea is produced faster than, for example, it could be removed by peritoneal dialysis. Haemodialysis can also be used in patients who have recently undergone abdominal surgery in whom peritoneal dialysis would be ill advised.

Haemofiltration

Haemofiltration is an alternative technique to dialysis where simplicity of use, fine fluid balance control and low cost have ensured its widespread use in the treatment of AKI.

Haemodiafiltration

Haemodiafiltration is a technique that combines the ability to clear small molecules, as in haemodialysis, with the large molecule clearance of haemofiltration. It is, however, more expensive than traditional haemodialysis, but does offer potential benefits. Whilst some studies suggest that haemodialfiltration may provide a clinical benefit compared to haemofiltration or haemodialysis, this is controversial (Rabindranath et al., 2006). However, enhanced combined control of fluid and solute removal provided by this technique is likely to be increasingly used over the next decade.

Acute peritoneal dialysis

Acute peritoneal dialysis is rarely used now for AKI except in circumstances where haemodialysis is unavailable. A semi-rigid catheter is inserted into the abdominal cavity. Warmed sterile peritoneal dialysis fluid (typically 1–2 L) is instilled into the abdomen, left for a period of about 30 min (dwell time) and then drained into a collecting bag (Fig. 17.6). This procedure may be performed manually or by semiautomatic equipment. The process may be repeated up to 20 times a day, depending on the condition of the patient.

Fig. 17.6 Procedure for peritoneal dialysis.

Acute peritoneal dialysis is relatively cheap and simple, does not require specially trained staff or the facilities of a renal unit. It does, however, have the disadvantages of being uncomfortable and tiring for the patient. It is associated with a high incidence of peritonitis and permits protein loss, as albumin crosses the peritoneal membrane.

Drug dosage in renal replacement therapy

Whether a drug is significantly removed by dialysis or haemofiltration is an important clinical issue. Drugs that are not removed may well require dose reduction to avoid accumulation and minimise toxic effects. Alternatively, drug removal may be significant and require a dosage supplement to ensure an adequate therapeutic effect is maintained. In general, since haemodialysis, peritoneal dialysis and haemofiltration depend on filtration, the process of drug removal can be considered analoguous to glomerular filtration. Table 17.5 gives an indication of approximate clearances of common renal replacement therapies, which for continuous regimens provide an estimate for the creatinine clearance of the system.

Table 17.5 Approximate clearances of common renal replacement therapies

Renal replacement therapy	Clearance rate (mL/min)
Intermittent haemodialysis	150–200
Intermittent haemofiltration	100–150
Acute intermittent peritoneal dialysis	10–20
Continuous haemofiltration	5–15

Drug characteristics that favour clearance by the glomerulus are similar to those that favour clearance by dialysis or haemofiltration. These include:

• low molecular weight

• high water solubility

• low protein binding

• small volume of distribution

• low metabolic clearance

Unfortunately, a number of other factors inherent in the dialysis process affect clearance; they include:

• duration of dialysis procedure

• rate of blood flow to dialyser

• surface area and porosity of dialyser

• composition and flow rate of dialysate

For peritoneal dialysis other factors come into play and include:

• rate of peritoneal exchange

• concentration gradient between plasma and dialysate

In view of the above, it is usually possible to predict whether a drug will be removed by dialysis, but it is very difficult to quantify the process except by direct measurement, which is rarely practical. Consequently, a definitive, comprehensive guide to drug dosage in dialysis does not exist. However, limited data for specific drugs are available in the literature, while many drug manufacturers have information on the dialysability of their products and some include dosage recommendations in their summaries of product characteristics. The most practical method for treating patients undergoing dialysis is to assemble appropriate dosage guidelines for a range of drugs likely to be used in patients with renal impairment and attempt to restrict use to these.

As drug clearance by haemofiltration is more predictable than in dialysis, it is possible that standardised guidelines on drug elimination may become available. In the interim, a set of individual drug dosage guidelines similar to those described above would be useful in practice.

Factors affecting drug use

How the drug to be used is absorbed, distributed, metabolised and excreted, and whether it is intrinsically nephrotoxic are all factors that must be considered. The pharmacokinetic behaviour of many drugs may be altered in renal failure.

Absorption

Oral absorption in AKI may be reduced by vomiting or diarrhoea, although this is frequently of limited clinical significance.

Metabolism

The main hepatic pathways of drug metabolism appear unaffected in renal impairment. The kidney is also a site of metabolism in the body, but the effect of renal impairment is clinically important in only two situations. The first involves the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (the active form of vitamin D) in the kidney, a process that is impaired in renal failure. Patients in AKI occasionally require vitamin D replacement therapy, and this should be in the form of 1α-hydroxycholecalciferol (alfacalcidol) or 1,25-dihydroxycholecalciferol (calcitriol). The latter is the drug of choice in the presence of concomitant hepatic impairment. The second situation involves the metabolism of insulin. The kidney is the major site of insulin metabolism, and the insulin requirements of diabetic patients in AKI are often reduced.

Distribution

Changes in drug distribution may be altered by fluctuations in the degree of hydration or by alterations in tissue or serum protein binding. The presence of oedema or ascites increases the volume of distribution while dehydration reduces it. In practice, these changes will only be significant if the volume of distribution of the drug is small, that is, less than 50 L. Serum protein binding may be reduced owing to either protein loss or alteration in binding caused by uraemia. For certain highly bound drugs the net result of reduced protein binding is an increase in free drug, and care is, therefore, required when interpreting serum concentrations. Most analyses measure the total serum concentration, that is, free plus bound drug. A drug level may, therefore, fall within the accepted concentration range but still result in toxicity because of the increased proportion of free drug. However, this is usually only a temporary effect. Since the unbound drug is now available for elimination, its concentration will eventually return to the original value, albeit with a lower total bound and unbound level. The total drug concentration may, therefore, fall below the therapeutic range while therapeutic effectiveness is maintained. It must be noted that the time required for the new equilibrium to be established is about four or five elimination half-lives of the drug, and this may be altered itself in renal failure. Some drugs that show reduced serum protein binding include diazepam, morphine, phenytoin, levothyroxine, theophylline and warfarin. Tissue binding may also be affected; for example, the displacement of digoxin from skeletal muscle binding sites by metabolic waste products that accumulate in renal failure result in a significant reduction in digoxin’s volume of distribution.

Excretion

Alteration in renal clearance of drugs in renal impairment is the most important parameter to consider when considering dosage. Generally, a fall in renal drug clearance indicates a decline in the number of functioning nephrons. The glomerular filtration rate can be used as an estimate of the number of functioning nephrons. Thus, a 50% reduction in the glomerular filtration rate will suggest a 50% decline in renal clearance.

Renal impairment, therefore, often necessitates drug dosage adjustments. Loading doses of renally excreted drugs are often necessary in renal failure because of the prolonged elimination half-life which leads to an increased time to reach steady state. The equation for a loading dose is the same in renal disease as in normal patients, thus:

The volume of distribution may be altered but generally remains unchanged.

It is possible to derive other formulae for dosage adjustment in renal impairment. One of the most useful is:

where DR_rf is the dosing rate in renal failure, DR_n is the normal dosing rate, RF is the extent of renal impairment = patient’s creatinine clearance (mL/min)/ideal creatinine clearance (120 mL/min) and F_eu is the fraction of drug normally excreted unchanged in the urine. For example, when RF = 0.2 and F_eu = 0.5, 60% of the normal dosing rate should be given.

An alteration in dosing rate can be achieved by either altering the dose itself or the dosage interval, or a combination of both as appropriate. Unfortunately, it is not always possible to obtain the fraction of drug excreted unchanged in the urine. In practice, it is simpler to use the guidelines for prescribing in renal impairment found in the British National Formularly. These are adequate for most cases, although the specialist may need to refer to other texts.

Nephrotoxicity

The list of potentially nephrotoxic drugs is long. Although the commonest serious forms of renal damage are interstitial nephritis and glomerulonephritis, the majority of drugs only cause damage by hypersensitivity reactions and are safe in many patients. Some drugs, however, are directly nephrotoxic, and their effects on the kidney are more predictable. Such drugs include aminoglycosides, amphotericin, colistin, the polymixins and ciclosporin. The use of any drug with recognised nephrotoxic potential should be avoided where possible. This is particularly true in patients with pre-existing renal impairement or renal failure. Figure 17.7 summarises the most important and common adverse effects of drugs on renal function, indicating the likely regions of the nephron in which damage occurs. Additional information on adverse effects can be found in Hems and Currie (2005).

Fig. 17.7 Common adverse effects of drugs on the kidney. The likely sites of damage to the nephron (stylised) are indicated.

Inevitably, occasions will arise when the use of potentially nephrotoxic drugs becomes necessary, and on these occasions constant monitoring of renal function is essential. In conclusion, when selecting a drug for a patient with renal failure, an agent should be chosen that approaches the ideal characteristics listed in Box 17.1.

Box 17.1 Characteristics of the ideal drug for use in a patient with renal failure

• No active metabolites

• Disposition unaffected by fluid balance changes

• Disposition unaffected by protein binding changes

• Response unaffected by altered tissue sensitivity

• Wide therapeutic margin

• Not nephrotoxic

Case studies

Case 17.1

Mrs J a 60-year-old widow, had long-standing hypertension that was unsatisfactorily controlled on a variety of agents. Her drug therapy included furosemide 40 mg once a day, amlodipine 10 mg daily and a salt restricted diet. Following a routine review of her therapy, ramipril 2.5 mg once daily was added to her treatment regimen in an attempt to improve blood pressure control.

Mrs J was recently diagnosed with gastroenteritis. A week after her diagnosis she presented to her local hospital accident and emergency unit, with ongoing diarrhoea. Her BP was found to be 100/60 mmHg and serum biochemistry revealed creatinine levels of 225 μmol/L (50–120 μmol/L, Na⁺ 125 mmol/L (135–145 mmol/l) and K⁺ 5.2 mmol/L (3.5–5.0 mmol/L).

Questions

1. What was the likely cause and underlying mechanism to this patients’s problem?

2. What treatment should be given?

Answers

1. ACE inhibitors reduce angiotensin II production, thus, attenuate angiotensin II mediated vasoconstriction of the efferent arterioles that contributes to the high-pressure gradient across the glomerulus necessary for filtration. It is not usually a problem in the majority of individuals; however, in patients with pre-existing compromised renal blood flow, such as renal artery stenoses, the kidney relies more heavily on angiotensin-mediated vasoconstriction of the postglomerular arterioles to maintain renal function. Hypovolaemia caused, for example, by diuretic use and a diarrhoeal illness would tend to exacerbate this problem. Moreover, it is likely that sodium depletion would render the kidney even more dependent upon vasoconstriction of efferent arterioles through activation of the tubuloglomerular feedback system, further sensitising the kidney to the effects of ACE inhibitors.

Mrs J might well have been suffering from incipient renal failure, but remained asymptomatic until her renal reserve diminished.

2. The inappropriate use of an ACE inhibitor should be stopped, as should the diuretic temporarily. Mrs J should be rehydrated using sodium chloride 0.9% and kidney function markers monitored in the hope that recovery will occur.

3. Investigations should be arranged to determine whether Mrs J has renal artery stenosis as a cause of her AKI after initiation of the ACE inhibitor (see Chapter 18).

Case 17.2

Mr B a known intermittent heroin and cocaine abuser, was discovered comatose in his room early in the morning. He was admitted to hospital as an emergency. An indirect history from an acquaintance indicated that Mr B had been drinking very heavily prior to the incident (probably more than a bottle of whisky in a 24-h period) and had smoked both heroin and cocaine of unknown source and purity.

On examination he was found to be dehydrated and serum biochemistry revealed the following:

		Reference range
Sodium	147 mmol/L	(135–145)
Potassium	6.1 mmol/L	(3.5–5.0)
Calcium	1.72 mmol/L	(2.20–2.55)
Phosphate	2.0 mmol/L	(0.9–1.5)
Creatinine	485 μmol/L	(50–120)
Creatinine kinase	120,000 IU/L	(<200)

Urine dipstick reacted positive for blood with no signs of red blood cells on microscopy. The urine was faintly reddish-brown in colour.

Question

What is likely to have occurred and how should it be treated?

Answer

Cocaine, heroin or alcohol abuse sometimes cause muscle damage resulting in rhabdomyolysis. The mechanism is unclear, but includes vasoconstriction, an increase in muscle activity, possibly because of seizures, self-injury, adulterants in the drug (e.g. arsenic, strychnine, amphetamine, phencyclidine, quinine) or compression (associated with long periods of inactivity). ATN may ensue from a direct nephrotoxic effect of the myoglobin released from damaged muscle cells, microprecipitation of myoglobin in renal tubules (as casts) or a reduction in medullary blood flow. The presence of myoglobin is suggested by the urine dipstick test, which reacts not only to red cells but also to free haemoglobin and myoglobin. Extremely high levels of myoglobinuria may result in urine the colour of Coca-Cola. High serum creatinine kinase levels are indicative of rhabdomyolysis together with the presence of free myoglobin in serum and urine. Serum levels of potassium and phosphate are elevated partly by the effects of incipient renal failure but also through tissue breakdown and intracellular release. Creatinine levels are often higher than expected because of muscle damage.

Treatment should involve fluid replacement with normal saline to reverse dehydration. Furosemide and other loop diuretics should be avoided as these decrease intra-tubular pH which may be a co-factor for cast precipitation. Indeed, in cases where urine pH is less than 6, administration of intravenous isotonic sodium bicarbonate may be of use. The patient’s ECG should be monitored, because of the risks involved with rapid elevation in serum potassium. Timely, appropriate corrective therapy must be instigated where necessary. In 50–70% of cases with rhabdomyolysis, dialysis is required to support recovery.

Case 17.3

Mr D is a patient who has been admitted to an intensive care unit with AKI, which developed following a routine cholecystectomy. His electrolyte picture shows the following:

		Reference range
Sodium	138 mmol/L	(135–145)
Potassium	7.2 mmol/L	(3.5–5.0)
Bicarbonate	19 mmol/L	(22–31)
Urea	32.1 mmol/L	(3.0–6.5)
Creatinine	572 μmol/L	(50–120)
pH	7.28	(7.36–7.44)