To date, the most traditional diagnostic test for renal impairment is creatinine. However, although most commonly used, problems can arise when implementing this test as a number of factors are not considered. On this World Kidney Day, Randox will explore the potential utility of H-FABP as a clinical diagnostic marker for cardiac surgery-associated acute kidney injury.

Acute Kidney Injury (AKI) is defined as an acute decline in renal function that can lead to structural changes. It involves a sudden drop in kidney function that usually arises due to a complication of another serious illness such as impaired renal perfusion, exposure to nephrotoxins, outflow obstruction or intrinsic renal disease. As a result, a patient can experience effects such as impaired clearance and regulation of homeostasis, altered acid/base and electrolyte regulation and impaired volume regulation.¹

The mortality rate associated with AKI varies depending on severity, patient related factors and setting including whether the patient is in intensive care (ICU) or not.² In the UK, AKI has been found to affect 1 in 5 people admitted to hospital as an emergency and has been found to be deadlier than a heart attack, contributing to around 100,000 deaths each year. Conversely, in the US, age-standardized rates of acute kidney injury hospitalisations increased by 139% among adults with diagnosed diabetes and by 230% among those without diabetes.^{3, 4}

The rising incidence of AKI comes at price. Patients tend to survive ICU but will be discharged with various degrees of chronic kidney disease (CKD), placing an increasing strain on the health care system. At present, the cost to the NHS is estimated to be between £434 and £620 million, which is more than the costs associated with breast cancer, or lung and skin cancer combined. However, this increased cost and strain could be unnecessary, as research has shown that 30% of the reported 100,000 deaths in the UK could have been prevented with the right care and treatment.^3,4

These unfavourable statistics are the result of late detection of AKI, as to date, a superior method of detection has not been found.

Cardiac surgery-associated acute kidney injury (CSA-AKI)

CSA-AKI is a well-recognised postoperative complication of cardiac surgery and is the second most common cause of AKI in the intensive care unit, occurring in up to 30% of patients.^5,6 Of these patients, an estimated 1% will require dialysis and the majority will remain dependent on dialysis leading to an increase in mortality. Certain patient groups are more susceptible to CSA-AKI and vulnerability can depend on age, sex, pre-existing cardiac dysfunction, pre-existing CKD, previous cardiac surgery or comorbidity.⁷

The pathogenesis of AKI involves multiple pathways including hemodynamic, inflammatory and nephrotoxic factors that overlap  leading to kidney injury.⁶ Figure 1 illustrates the pathophysiology of AKI following cardiac surgery. It shows that there are multiple physiological processes that are associated with the development of AKI as a result of cardiac surgery.⁸

What is H-FABP?

Fatty acid-binding proteins (FABPs) are small cytoplasmic proteins that are abundantly expressed in tissues with an active fatty acid metabolism, with their primary function being the facilitation of intracellular long-chain fatty acid transport.⁹ Elevated FABP serum concentrations are related to a number of common comorbidities including heart failure, CKD, diabetes mellitus and metabolic syndrome, which represent important risk factors for postoperative AKI.¹⁰

H-FABP is most commonly associated with being a marker for acute coronary syndrome (ACS) as its concentrations peak at approximately 6-8 hours after symptom onset, making it easier to detect. Recently studies have highlighted H-FABP as a potential biomarker for the detection of AKI after cardiac surgery. This potential would mean earlier diagnosis of patients, reducing the mortality rate and costs to the health service.

Potential Mechanism for the release of H-FABP in AKI

There are a number of hypotheses regarding the release of H-FABP, with myocardial injury being considered the major reason for an increased level. The mechanisms involved in this increase have been found to differ depending on the severity of a patients ACS situation including whether they are in ICU.¹¹

One possible explanation for the release of H-FABP is the effects of ischemic stress. Ischemic stress induced by non-cardiogenic shock is a type of mechanical stretching which can lead to the leakage of small amounts of macromolecules. This process would lead to the release of H-FABP into the blood. In non-cardiac patients, minor myocardial injury alone may not adequately explain this observed increase. Other factors such as a reduction in the amount of skeletal muscle tissue, lipid disorders, release of free radicals and an increase in free acids produced by the catabolism of glycogen could also contribute to a rise in H-FABP levels.¹¹

One final process that could lead to increased H-FABP is the damage of vital organ functions which occurs in almost all non-surgical intensive care patients. The degree of leakage of H-FABP may vary depending on the severity of a patient’s condition and whether they have suffered from multiple organ failure or vital organ damage. AKI is a component of multiple organ failure suggesting that serum H-FABP levels may increase in AKI patients as a result. Also, serum H-FABP is excreted by renal tubular cells and patients with an acutely diminished renal function are unable to clear large amounts of H-FABP resulting in increasing levels. These potential mechanisms of H-FABP and its release during AKI provide further confirmation that the measurement of serum H-FABP is an effective biomarker in patients with AKI.¹¹

Comparison of H-FABP Measurement Against Traditional Acute Kidney Disease Measurement Tools

For years, no standard method for definition or diagnosis  was in place for AKI. The RIFLE classification was introduced in 2004, which defined and staged renal failure over seven days into five classes of increasing severity including; risk, injury, failure, loss and end-stage kidney disease.

The RIFLE criteria were then revised by the Acute Kidney Injury Network (AKIN) and introduced four main changes including replacing the period of seven days for serum creatinine (SCr) with forty eight  hours and implementing SCr changes as low as 0.3 mg/dL as the lowest measure considered as AKI. However, despite these changes the Kidney Disease Improving Global Outcome (KDIGO) proposed that AKI is defined when any of the three criteria are met including increase in SCr by 50% in seven days, increase in SCr > 0.3 mg/dL or oliguria.⁷

However, despite these advances, identification and management of AKI is still difficult for two main reasons. The change of SCr does not occur until two to three days after the initial insult. Also, serum creatinine can rise for a variety of reasons such as tubular injury, hemodynamic alterations or cardio-renal interactions.

The utility of SCr as biomarker for CSA- AKI is questionable as changes occur 48 hours to seven days after the original insult.⁵ The delays in diagnosis of CSA-AKI may have detrimental effects as prolonging the diagnosis period may result in the disease already being well established.¹²

Also, a main issue concerning the AKI criteria established is its relevance to the perioperative period. Many surgical patients arrive in hospital without preoperative SCr concentrations being measured, potentially leading to over-diagnosis of AKI. However, when patients do arrive with a preoperative SCr concentration, the opposite can occur and immediate postoperative period SCr concentrations can be lower than baseline as a result of haemodilution.  A comparison of the postoperative and preoperative values can lead to under-diagnosis of AKI and consequently delayed treatment.¹²

The research conducted has illustrated that SCr is not the most appropriate biomarker for diagnosis of AKI. Studies have demonstrated that H-FABP has more clinical utility and is released less than thirty minutes after myocardial injury and renally excreted within 24 hours, showing that as a biomarker it responds faster than creatinine.¹²

How Randox can Help

The Randox H-FABP test tests utilises an immunoturbidimetric method, offers a wide measuring range and is available liquid ready-to-use for convenience and ease of use.

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