Could H-FABP Have Potential Benefits in Diagnostics Beyond Cardiac Health Problems?
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
Figure 1 Illustrates the pathophysiology of AKI following cardiac surgery and the various mechanisms that contribute.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.
Want to know more?
Contact us or visit the Randox H-FABP Site
- National Kidney Foundation. Acute Kidney Injury (AKI). National Kidney Foundation. [Online] National Kidney Foundation. [Cited: February 3, 2019.] https://www.kidney.org/atoz/content/AcuteKidneyInjury.
- Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges. Geus, de, MG, Betjes and J , Bakker. 2, s.l. : NCBI, 2012, Vol. 5.
- Kidney Care UK. A range of useful facts and stats about kidneys. Kidney Care UK. [Online] Kidney Care UK. [Cited: February 15, 2019.] https://www.kidneycareuk.org/news-and-campaigns/facts-and-stats/.
- Centers for Disease Control and Prevention. Trends in Hospitalizations for Acute Kidney Injury — United States, 2000–2014. Centers for Disease Control and Prevention. [Online] Centers for Disease Control and Prevention, March 16, 2018. [Cited: February 22, 2019.] https://www.cdc.gov/mmwr/volumes/67/wr/mm6710a2.htm.
- Cardiac Surgery-Associated Acute Kidney Injury. Mao, h, et al. s.l. : Karger, 2013, Vol. 3.
- Acute Kidney Injury Associated with Cardiac Surgery. Rosner, Mitchell and Okusa, Mark. 1, s.l. : Clinical Journal of American Society of Nephrology, 2016, Vol. 1.
- Cardiac surgery-associated acute kidney injury. Loubon, Christian, et al. 4, s.l. : NCBI, 2016, Vol. 19.
- Acute kidney injury following cardiac surgery: current understanding and future directions. O’Neal, Jason, Shaw, Andrew and Billings, Frederic. s.l. : NCBI, 2016, Vol. 20.
- Heart-type fatty acid-binding protein predicts long-term mortality after acute coronary syndrome and identifieshigh-risk patients across the range of troponin values. Kilcullen, N, et al. 20, s.l. : Epub, 2012, Vol. 50.
- Preoperative serum h-FABP concentration is associated with postoperative incidence of acute kidney injury in patients undergoing cardiac surgery. Oezkur, Mehmet, et al. 117, s.l. : BMC Cardiovascular Disorders, 2014, Vol. 14.
- The serum heart-type fatty acid-binding protein (HFABP) levels can be used to detect the presence of acute kidney injury on admission in patients admitted to the non-surgical intensive care unit. Shirakabe, A, et al. 1, s.l. : NCBI, 2016, Vol. 16.
- Perioperative acute kidney injury. Goren, O and Matot, I. 2, s.l. : British Journal of Anaesthesia, 2015, Vol. 115.
On 8th March 2018, Randox Reagents are supporting World Kidney Day! World Kidney Day is an annual campaign and partnership to raise awareness of the importance of our kidneys to our overall health and to reduce the frequency and impact of kidney disease and its associated health problems worldwide.
This year, the World Kidney Day theme is: “Kidney Disease and Women’s Health: Include, Value, Empower”. Chronic kidney disease affects approximately 195 million women worldwide and it is currently the 8th leading cause of death in women, with close to 600,000 deaths per year.
Chronic kidney disease in women has increased over the years. Women over the age of 50 and African American women have seen the highest rise of kidney failure. This has been attributed to obesity, diabetes and high blood pressure. It is important that women are screened for renal impairment as although treatment of kidney disease in men and women are the same, the complications associated with renal impairment in women is greater than in men. The complications women are faced with due to renal impairment include: irregular periods, diminished sex drive and difficulties conceiving. Whilst it is difficult for a woman with renal impairment to conceive, it is not impossible, however, 50% of babies born to women on dialysis survived with most being born prematurely due to high blood pressure. There are several measures that women can take to reduce their likelihood of developing renal impairment or manage their symptoms including; lifestyle changes, medication to control associated problems, dialysis and kidney transplant.
The standard marker for renal functional is creatinine as creatinine clearance gives a measure of the glomerular filtration rate (GFR), however, creatinine levels are unreliable in individuals who are obese, malnourished, have liver cirrhosis or reduced muscle mass. Due to this, Randox developed an automated test for Cystatin C, a superior marker of kidney dysfunction.
The Randox Cystatin C assay
Cystatin C is a small (13kDa) cysteine proteinase inhibitor that is produced at a constant rate by all nucleated cells. The small molecular weight of cystatin C allows it to be completely removed and broken down by the kidneys. Therefore, levels remain steady if the kidneys are working efficiently and the Glomerular Filtration Rate (GFR) is normal.
There are several studies that have documented the superiority of cystatin C compared to creatinine as a marker of GFR function. Unlike creatinine, cystatin C does not have a ‘blind area’ meaning it is extremely sensitive to very small changes in GFR and therefore capable of detecting early reductions in GFR. Up to 50% of renal function can be lost before significant creatinine levels are detected. GFR estimates based on cystatin C are less influenced by diet or muscle mass compared to GFR estimates based on creatinine, therefore, Cystatin C is also beneficial if the patient is overweight, elderly or has a lot of muscle mass. Cystatin C is also beneficial if previous kidney function tests were inconclusive.
World Kidney Day and Randox are working towards improving healthcare globally. With continuous investment into R&D, Randox are striving to develop the earliest biomarker for renal function to prevent serious complications.
On 9 March 2017, Randox Reagents are celebrating World Kidney Day! World Kidney Day is a global campaign aimed at raising awareness of the importance of our kidneys to our overall health. It aims to reduce the frequency and impact of kidney disease and its associated health problems worldwide.
This year, the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviours an affordable option.
With this in mind, throughout the week we have been sharing on social media some interesting facts on diagnostic tests which can help aid an early risk assessment of kidney disease in obese patients, allowing preventative action to be taken before any serious damage occurs. The tests of focus this week included cystatin C, adiponectin and microalbumin…
The creatinine test is routinely run for patients who are suspected for deteriorating kidney function, however this test has limitations. Cystatin C is an alternative test, and is particularly useful in patients where creatinine measurements are not suitable e.g. individuals who are obese, malnourished, have liver cirrhosis or reduced muscle mass. Importantly, unlike creatinine, cystatin C does not have a ‘blind area’ – up to 50% of kidney function can be lost before significant creatinine elevation occurs. Cystatin C is extremely sensitive to very small changes in kidney function and is therefore capable of detecting early stage kidney dysfunction. The cystatin C test therefore allows preventative measures to be taken much earlier and before significant kidney function decline.
There is substantial evidence that excess visceral fat is the main driving force for almost all of the disorders associated with the metabolic syndrome, including CKD.1,2 The adiponectin test from Randox can accurately assess levels of abdominal visceral fat, independent of age, race or fitness level.3,4 Assessing adiponectin, and therefore visceral fat levels, can help assess risk of CKD, as well as a range of other illnesses such as pre-diabetes, CVD and various cancers.
The microalbumin test detects very low levels of a blood protein called albumin, in urine. The detection of albumin in urine can be an indicator of kidney injury and can result in irreversible damage if left untreated. Low albumin concentrations in the urine are the earliest marker of kidney damage and therefore enable preventative measures to be taken. Microalbumin testing can identify individuals with diabetic nephropathy approximately 5-10 years earlier than proteinuria tests helping reduce the frequency of end stage renal disease.
Both World Kidney Day and Randox are working towards improving healthcare worldwide. With continuous investment in R&D, Randox are helping with the risk assessment and earliest detection of renal function problems. By assessing one’s risk of kidney problems (with the adiponectin test), it can give patients (obese and other) the tools to prevent kidney problems further on down the line. With early diagnosis (through the cystatin C and microalbumin tests) it will be possible to keep kidney problems from getting worse, therefore lowering the number of those diagnosed with CKD worldwide.
World Kidney Day is a global campaign aimed at raising awareness of the importance of our kidneys to our overall health. It aims to reduce the frequency and impact of kidney disease and its associated health problems worldwide.
The main objectives of World Kidney Day are to educate all medical professionals about their key role in detecting and reducing the risk of Chronic Kidney Disease (CKD), particularly in high risk populations, and to stress the important role of local and national health authorities in controlling the CKD epidemic. On World Kidney Day all governments are encouraged to take action and invest in further kidney screening.
World Kidney Day highlights the need for more accurate kidney function testing for better diagnosis and monitoring of kidney function to assist in the development of appropriate treatment plans. As such, Randox have invested in the development of more sensitive and specific renal function tests such as cystatin C, which may be requested if kidney function is found to be borderline using the more routinely run creatinine test. Doctors may request cystatin C to check for early kidney disease and/or to monitor known impairment over time.
Cystatin C is a particularly useful marker of renal function in patients where creatinine measurements are not suitable e.g. individuals who are obese, malnourished, have liver cirrhosis or reduced muscle mass. Importantly, unlike creatinine, cystatin C does not have a ‘blind area’ – up to 50% of renal function can be lost before significant creatinine elevation occurs. Cystatin C is extremely sensitive to very small changes in GFR and is therefore capable of detecting early stage kidney dysfunction.
Both World Kidney Day and Randox are working towards improving healthcare worldwide. With a comprehensive panel of high performance reagents, Randox are helping with the detection and characterisation of renal function problems. With early diagnosis it will be possible to keep kidney problems from getting worse, therefore lowering the number of those diagnosed with CKD worldwide.
If you are a clinician or lab interested in running renal function assays, Randox offers a large range of high quality routine and niche assays including: Cystatin C, Creatinine Enzymatic and Jaffe, Microalbumin, Urinary Protein, Urea, Sodium, Potassium, Albumin, Ammonia, β2- Microglobulin, Calcium, Chloride, Glucose, HbA1c, IgG, LDH, Magnesium, Phosphorus (Inorganic), and Uric Acid. These can be run on most automated biochemistry analysers.