Acute kidney injury

Definitions

Progress in understanding AKI has been hampered by the lack of a universal definition. Over 35 different definitions have been used to define ARF in the literature. Major advances towards developing a universally accepted definition were taken in 2002 when the ADQI proposed the Risk, Injury and Failure, Loss of function and End-stage kidney disease (RIFLE) staging system (Table 1). The classification thus includes three levels of increasing kidney dysfunction and two outcomes. Categorisation into a particular stage depends upon rises in SCr from baseline or reductions in glomerular filtration rate (GFR) within a one-week time interval or reductions in urine output.

Further studies subsequently demonstrated that relatively small increments in SCr are associated with a significant increase in patient mortality. This prompted proposals by AKIN in 2005,² to modify the RIFLE staging system to produce an interim staging system allowing additional data to be gathered and research initiatives proposed (Table 1). Further refinement of the definition based upon the results of future studies is anticipated.

Epidemiology

The incidence of AKI depends upon the definition used and the cohort studied. Accurate assessment is difficult due to the lack of a standardised registry. Based on previous studies, AKI has been estimated to occur in 3–7% of hospitalised patients.⁵ More recently, a study using the RIFLE staging system identified that 18% of patients admitted to a large urban medical centre had evidence of AKI.⁶ The incidence of AKI on the intensive care unit (ICU) has been characterised more clearly due to established data collection systems and estimated at 25–30%.⁵ The RIFLE staging system has demonstrated a wide ranging incidence of AKI dependent upon the population case mix.⁵

Aetiology

The aetiology of AKI is best considered divided into three main categories (Table 2):

• pre-kidney

• intrinsic kidney, and

• post-kidney.

This division allows the clinician to consider the cause of the injury systematically for the purposes of diagnosis and management. The frequency of aetiology type will depend upon the cohort studied. Outside the ICU the aetiology of patients with AKI is generally recognised as pre-kidney 55–60%, intrinsic 35–40% and post-kidney <5%.⁷ In contrast, on the ICU most critically ill patients with multi-organ failure will have potentially reversible ischaemic intrinsic AKI secondary to kidney hypoperfusion.

Pre-kidney and ischaemic intrinsic AKI may be considered as two extremes of a spectrum of injury that is the result of hypoperfusion of the kidneys. In pre-kidney AKI there is a reduction in GFR without overt tubule cell injury. Restoration of adequate kidney perfusion will result in rapid recovery of GFR. However, if the hypoperfusion is sustained, ischaemic tubule cell injury occurs resulting in ATN from which recovery will be delayed.

Pathophysiology

The pathophysiology of AKI will depend upon the underlying aetiology. This article considers only ATN secondary to kidney hypoperfusion. ATN is strictly a histopathological diagnosis, often used interchangeably with ischaemic AKI. Significant kidney hypoperfusion results in the preferential shunting of blood away from the already relatively ischaemic environment of the outer medulla.⁸ Therefore most ischaemic injury is sustained by the proximal tubules and medullary thick ascending limbs of the distal tubules which lie in the outer medulla.

Paradoxically, kidney biopsy studies have failed to demonstrate frank tubule cell necrosis despite marked kidney dysfunction. A number of mechanisms have been proposed to explain the marked reduction in GFR. These include:

• a decrease in the filtration pressure in the glomerulus secondary to afferent arteriolar vasoconstriction and proximal tubular obstruction, and

• back leak of glomerular filtrate across denuded basement membrane and disrupted tubule cell tight junctions.

Recovery of kidney function is possible, involving tubule cell proliferation and differentiation and may take up to six weeks to complete.⁹

Research into the pathophysiology of ischaemic ATN has allowed the discovery of novel biomarkers of kidney injury.¹⁰ Investigators have identified a number of genes and their gene products that are upregulated in the kidney following ischaemic injury and then secreted into the blood and urine. Such biomarkers may ultimately offer clinicians the opportunity to detect AKI at an earlier stage and enable appropriate therapeutic intervention. Neutrophil gelatinase-associated lipocalin is highly upregulated following ischaemic injury in the human and rapidly excreted into the urine and blood.¹¹ The results of a large randomised controlled trial (RCT) are awaited to assess its clinical applicability.

Clinical presentation

Early differentiation of AKI from chronic kidney disease (CKD) must be performed. The clinician must consider the cause of AKI (Table 2). If intrinsic AKI is diagnosed clinically it must be determined whether this is ischaemic intrinsic AKI or a more esoteric diagnosis. Clinical suspicion of a more esoteric diagnosis (eg vasculitis, intestinal nephritis) should be aroused in patients without a clearly defined insult or who have systemic symptoms. Establishing the diagnosis depends on taking a thorough history (Table 3(a)) and performing a comprehensive clinical examination (Table 3(b)).

Investigations

Baseline investigations include those listed in Table 4. More specialised investigations (Table 5) may be requested if indicated by the clinical presentation. Urine chemistry may help to differentiate pre-kidney AKI and ATN are shown in Table 6.

Management

The best form of management of AKI is prevention. This involves careful clinical evaluation of patients and risk stratification (Tables 3(a) and 3(b)). Patients identified to be at risk should have their cardiovascular status and intravascular volume optimised and nephrotoxic drugs avoided. Optimisation of fluid status remains a medical challenge and requires meticulous consideration of the patient's fluid status and requirements. A thorough review is given in the recent British Consensus Guidelines For Intravenous Fluid Therapy In Adult Surgical Patients (GIFTASUP).¹²

High-risk patients with an estimated GFR below 60 ml/min/1.73 m² undergoing contrast studies should receive volume expansion with 0.9% sodium chloride at 1 ml/kg/hr for 12 hours before the procedure and for several hours afterwards.¹³ There is no compelling evidence to support the use of sodium bicarbonate or N-acetylcysteine to prevent contrast-induced nephropathy,¹⁴ and similarly none to justify the use of dopamine, loop diuretics or mannitol for the prevention or treatment of AKI.