Diagnosis of AKI
NICE Clinical Guidance on AKI (22) recommends, “investigation for AKI, by measuring serum creatinine and comparing with baseline, in adults with acute illness, if any of the recognised risk factors and/or triggers are present”. Thus, recognition of the at risk patient is central to diagnosis of AKI. Having identified the at risk patient, criteria for diagnosis of AKI in primary care have been defined (5):
- A rise of serum creatinine of 26µmol/l or greater in 48 hours
- A 50% or greater rise in serum creatinine in 7 days
- A fall in urine output to less than 0.5ml/kg/hour for more than 6 hours in adults or 8 hours in children
- A fall of 25% or greater of eGFR in children and young people
Most patients will have no symptoms directly attributable to AKI. As urine output will be difficult to document accurately in most cases, measurement of serum creatinine is essential for diagnosis and staging of AKI.
Creatinine is one of many molecules cleared by the kidneys that will accumulate if renal function is impaired. It is used as the ‘standard’ measure of kidney function as it is cleared only by the kidneys and, within an individual, is produced at a fairly constant rate, largely unaffected by medications or intercurrent illness. Creatinine may increase by up to 25% in individuals with normal kidney function following a meat containing meal (43, 44). However, in routine clinical practice this is rarely relevant to interpretation of results. Urea is cleared also predominantly by the kidneys, but production is more significantly affected by a wider range of confounding factors including diet (protein load), hydration status and catabolic states. Thus, the specificity of serum creatinine versus urea as judged against isotope clearance is 95.7% versus 87%. Sensitivity of both markers is however poor.
If a patient is considered at risk of AKI, creatinine should be checked.
If intrinsic renal disease is the cause of AKI urgent referral to the renal unit is indicated
High serum concentrations of creatinine, in their own right, are not harmful. However, renal impairment significant enough to elevate plasma creatinine will cause accumulation also of other molecules cleared by the kidney. Vanholder et al characterized 90 such molecules in detail (45). In AKI potassium and urea are most important. In chronic kidney disease other molecules such as phosphate and possibly uric acid become important also.
Creatinine clearance consistently overestimates GFR (by approximately 15-20% at normal kidney function) due to tubular excretion of a small amount of creatinine, which is unrelated to glomerular function and therefore not affected by changes in glomerular haemodynamics. As tubular secretion is usually maintained as glomerular function is lost, in advanced CKD this route can account for up to 50% of creatinine clearance (46). Importantly, this tubular secretion is inhibited by a number of drugs of which trimethoprim (47, 48) and cimetidine are of most relevance to primary care. Thus, prescription of trimethoprim in patients at risk of AKI may elevate creatinine significantly causing diagnostic confusion. Although this effect does not represent a true fall in GFR it may be impossible to ascertain the relative contribution of tubular and glomerular effects, necessitating treatment as if ‘true’ AKI. Elevations in creatinine caused by these drugs are completely reversible on stopping these medications.
Urea and Potassium
Urea and potassium are not reliable for diagnosis of AKI, but are essential measurements in the patient with AKI due to the morbidity and mortality associated with elevation of their serum concentration. The term ‘uraemia’ is often used to describe the symptoms associated with kidney failure rather than specifically symptoms associated with elevated serum urea. Many organic waste products contribute to these symptoms. Mild symptoms of nausea and fatigue may be present when GFR falls below 60ml/min/1.73m2 BSA (49). Meyer (50) has reviewed the consequences of elevation of serum urea concentration and other metabolites that accumulate in renal failure. Urea is the most abundant of these solutes, but does not cause symptoms until the serum concentration rises above approximately 32mmol/l (51).
Hyperkalaemia is the most dangerous electrolyte disturbance seen in kidney disease. Although there is no universal definition of hyperkalaemia, a serum potassium concentration =5.5mmol/l is commonly used. The risk of arrhythmias increases with concentrations >6.5mmol/l. Emergency treatment is most often recommended if serum potassium is =6.5mmol/l with or without ECG changes. Detailed guidelines on treatment are available (52). These guidelines include recommendations for primary care, suggesting referral to secondary care for patients with K+ =6.5mmol/l and review of diet and medication with K+ 5.5-6.4 mmol/l. In keeping with advice on AKI in general, the guidelines suggest that renin-angiotensin agents (ACE-inhibitors, angiotensin II receptor blockers), potassium sparing diuretics, and/ or loop diuretics should be stopped during acute illness lasting > 24 hours, particularly when associated with hypovolaemia or hypotension (e.g. sepsis, diarrhoea and/or vomiting)
Recognition of intrinsic renal disease
In accordance with the NICE Guidelines on AKI, recognition of intrinsic renal disease as a cause for AKI is essential, as this should prompt urgent referral directly to the renal unit. Furthermore, urological causes may be indicated by the presence of haematuria. Thus, urinalysis should be performed in any patient with AKI. If urological causes for haematuria (microscopic or macroscopic) are excluded, intrinsic renal disease becomes likely. Microscopic haematuria with proteinuria >50mg/mmol is almost always due to intrinsic (parenchymal) renal disease and nephrology referral is appropriate (53).
It may be important to exclude urinary tract infection, as this is often considered as a cause for haematuria and proteinuria in a well patient. However, systematic review found that ‘there is no indication that asymptomatic UTI causes proteinuria or microalbuminuria’ (54). Accordingly, in accordance with NICE guidance, an MSU need not be sent to exclude infection in cases of asymptomatic haematuria and proteinuria, intrinsic renal disease being a more likely cause.
Intrinsic renal disease is almost always associated with hypertension, even without fluid overload. Thus, the presence of hypertension in a patient with abnormal urinalysis further increases the likelihood of underlying intrinsic renal disease. The fluid overload commonly seen in CKD may also cause hypertension in it’s own right or exacerbate the hypertension driven by the underlying kidney disease.
Diagnosis of AKI: Summary
- Most AKI occurs due to disease outside the kidney, with the kidney simply being an innocent bystander, often struggling to maintain function in the face of an external insult
- Acute kidney injury is best diagnosed by recognising those clinical situations where AKI is likely
- The fact that the primary diagnosis is most often not AKI, does not make recognition of AKI or the risk of AKI irrelevant, as if superimposed on other clinical situations morbidity and mortality is increased
- Limitation of AKI to stages 1 or 2 reduces the impact of AKI significantly
- It is essential to recognise a number of ‘must not miss’ situations where AKI is due to intrinsic renal disease or obstruction, requiring prompt specialist intervention in order to preserve renal function
- If AKI is due to intrinsic renal disease urinalysis will almost always reveal blood, protein or both and hypertension is likely.