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.