Rheumatoid Factor: The Most Remarkable Autoantibody in Rheumatoid Arthritis
The Most Remarkable Autoantibody in Rheumatoid Arthritis
Celebrating World Arthritis Day (WAD)
Rheumatoid Factor: The Most Remarkable Autoantibody in Rheumatoid Arthritis
World Arthritis Day (WAD) is celebrated on 12th October to help raise global awareness of the existence and impact of rheumatic and musculoskeletal diseases (RMDs). It is estimated that over one-hundred million people are currently undiagnosed impacting their quality of life and participation in society – including their ability to work and lead a normal life. As a result this increases dependency on state welfare, the healthcare system and the required support from their family and friends.
The European League Against Rheumatism (EULAR) launched the ‘Don’t Delay, Connect Today’ campaign focusing on the importance of early diagnosis and access to care.
Randox Reagents fully supports the importance of early diagnosis – to aid in the early implementation of effective treatment plans, aiding in improved health outcomes – it’s the ethos of our business. This blog delves deeper into rheumatoid factor (RF), the most remarkable autoantibody in rheumatoid arthritis.
Pathobiology of Rheumatoid Arthritis (RA)
The pathophysiology of RA involves various signaling pathways and immune modulators (effector cells and cytokines) as indicated in figure 1. Joint destruction is caused by the intricate interactions of immune modulators, beginning at the synovial membrane and encompassing most IA structures, with synovitis caused by both or individually, the local activation or influx of mononuclear cells, including: B cells, T cells, dendritic cells, plasma cells, mast cells and macrophages. Consequently, “the synovial lining becomes hyperplastic, and the synovial membrane expands and forms villi”. The neutrophils, chondrocytes and synoviocytes secrete enzymes that degrades the cartilage in the joint whereas the osteoclast-rich area of the synovial membrane destroys the bone 4.
Rheumatoid arthritis (RA), “the most common systemic inflammatory autoimmune disease” affecting 1% of the global population, is characterised by fatigue, synovial joint pain, stiffness, swelling and destruction, with severe symptoms resulting in disability. Whilst the exact cause of RA is unknown, it is believed that genetic and environmental factors play a role in triggering the disease 2, 3. Differences in the human leukocyte antigen (HLA)-DRB1 alleles (proteins with a critical role in the immune system) have been identified as a genetic variant for RA, observed in >80% of patients, particularly in those testing positive for RF. Moreover, those with variations in the HLA-DRB1 who smoke, increase their risk of RA. As RA is more common in women (2-fold increased risk in women compared to men), hormonal influences are an area of active research, however, an inverse correlation with breastfeeding has been identified. Women who breastfeed for >13 months aids in reducing the risk of RA compared to women who have never breastfed 3, 4.
Figure 1: Schematic view of (a) a normal joint and (b) a joint affected by RA 4
Clinical Significance of Rheumatoid Factor (RF)
Interestingly, elevated levels of RF have been observed in other autoimmune conditions such as Sjögren syndrome and systemic lupus erythematosus (SLE) as well as non-autoimmune conditions including old age and chronic infections. Despite this, RF in RA patients can be distinguished from RF in healthy individuals. RF in RA patients displays affinity maturation whereas RF in healthy individuals has low affinity and are polyreactive 2.
RF is a class of immunoglobulin (Ig) autoantibodies that are directed against the fragment crystallizable region (Fc region), the tail region of the IgG antibody. In RA, RF are produced by the B cells present in lymphoid follicles and the germinal center(GC)-like structures that mature in inflamed synovium. Most RF are IgM antibodies, but may also be IgG or IgA isoforms. IgM RF are detected in 60% to 80% of RA patients. “RF testing in RA patients has a sensitivity of 60% to 90% and a specificity of 85%” (5). RF is a highly valuable biomarker in RA 5, 2.
Key Features of the Randox Rheumatoid Factor Assay
The Randox automated latex enhanced immunoturbidimetric rheumatoid factor assay provides an accurate assessment of RF titre as the Randox rheumatoid factor calibrator is standardised against the primary WHO material, 1st British Standard 64/2. With a wide measuring range of 6.72 – 104lU/ml for the comfortable detection of clinically important results, the Randox RF assay is available in a liquid ready-to-use format for the comfortable detection of clinically important results. The Randox rheumatoid factor assay does not suffer from interference from C1q complement and is stable until expiry date. With dedicated calibrator and controls for a complete testing package, Randox offer applications, detailing instrument-specific settings for the convenient use of the Randox rheumatoid factor assay on a wide range of clinical chemistry analysers.
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Alzheimer’s Disease: The Role of Apolipoprotein E
Raising awareness of Alzheimer’s Disease
Every year we celebrate Alzheimer’s Day on 21st September to help raise awareness around dementia. Dementia is the medical name attributed to a set of symptoms affecting the brain, including: difficulties with problem solving, thinking, language and memory loss. AD is the most common form of dementia accounting for 60 – 80% of cases and it is believed that half of patients with Alzheimer’s dementia (dementia due to AD) have Alzheimer’s disease 1, 2.
About Alzheimer’s Disease (AD)
AD is one of the most devastating and complex diseases characterised by:
- Neurodegeneration resulting in memory loss 2
- Neurofibrillary tangles composed of tau amyloid fibrils which associates with synapse loss 2
- Accumulation of β-amyloid (Aβ) plaques 2
- Other cognitive functions 2
Figure 1: Alzheimer’s Disease Demographic, 2019 3
It is believed that AD is expected to begin 20 years prior to symptom onset, as the small changes in the functioning of the brain are unnoticeable to the person affected. Overtime, the symptoms progress and begin to interfere with the patient’s ability to perform everyday tasks. The final stages of AD leaves the patient bed-bound, requiring 24/7 care. Ultimately, AD is fatal. Age has been identified as a risk factor for AD with 10% of people over the age of 65 affected. Moreover, AD has been recognised as a leading cause of morbidity and the sixth leading cause of mortality, but the fifth leading cause of death in over 65’s in the US .3
Physiological Significance of Apolipoprotein E
Apolipoprotein E (Apo E) is a lipoprotein composed of 299 amino acids with a molecular weight of 34kDa. Apo E is responsible for the regulation of homeostasis through the mediation of lipid transport from and to bodily cells and tissues. Apo E comprises of three common isoforms: apo E2, apo E3 and apo E4. The apo E isoforms differ due to differences in either the 112 and 158 amino acids, whether either arginine (ARG) or cysteine (CYS) is present 4.
Apo E3 is the parent form of apo E and is responsible for the clearance of triglyceride-rich lipoproteins. Apo E3 is associated with normal lipid plasma concentrations. Apo E2 is the rarest of the apo E isoforms and differs slightly compared to the apo E3 isoform through the substitution of a single amino acid, ARG158Cys, located near the low-density lipoprotein receptor (LDLR) recognition site.
Apo E2 displays impaired binding to the receptor, prohibiting the clearance of triglyceride-rich lipoprotein remnant particles. Apo E2 is strongly associated with type-III hyperlipoproteinemia. Apo E3 also differs from apo E4, again through the substitution of a single amino acid, Cys112Arg. The main difference between apo E3 and apo E4 is that apo E4 is unaffected by the binding of the isoform to LDLR. However, apo E4 is strongly associated with dyslipidemia 5. Fig. 2 provides a visual representation of the variations in the Apo E isoforms.
Figure 2: Variations in the Apo E Isoforms 4
Apo E is expressed in numerous bodily organs with the liver presenting with the highest expression followed by the brain. Astrocytes and, to a lesser extent, microglia are the major cells responsible for the expression of apo E in the brain. In the brain, apo E, apo J and apo A-1 are predominantly expressed on distinct high-density-like lipoprotein particles. Whilst apo A-1 is the major apolipoprotein of high-density lipoproteins (HDL), in the central nervous system (CNS), apo E is the predominant apolipoprotein of HDL-like lipoproteins. HDL-like lipoproteins are the only lipoproteins present in the CNS. It is believed that the cholesterol released from apo E supports synaptogenesis 6.
Clinical Significance of Apolipoprotein E in Alzheimer’s Disease
Whilst apo E3 is the most abundant of the three isoforms, apo E4 has been known for decades to be the most significant genetic risk factor for late-onset AD. Inheriting the one copy of the apo E4 gene increases the risk of AD 2-3-fold, whilst inheriting two copies increases the risk of AD up to 12-fold 7. Whilst the underlying mechanism of apo E’s contribution to AD risk is still unclear and debatable, apo E has been identified as promoting amyloid β (Aβ) deposition and clearance as well as neurofibrillary tangles in the brain. Interestingly, Aβ-independent pathways exist for apo E in AD, which led to the unearthing of the new roles of apo E including the most recent, iron metabolism and mitochondria dysfunction 8, 9. Captivatingly, sex-related hormones may play a role in AD in apo E4 carriers as AD has been recognised to be more pronounced in women 10. Apo E4 has also been identified as impairing lipid transport, microglial responsiveness, glucose metabolism, synaptic plasticity and integrity, and cerebrovascular function and integrity. Some of these pathogeneses are independent of Aβ pathways. Furthermore, therapeutic strategies are aiming to modulate the quantity, lipidation, structural properties, Aβ interaction and receptor expression of Apo E 11.
Key Features of the Randox Apolipoprotein E Assay
Randox are one of the only manufacturers to offer the apo E assay in an automated clinical chemistry format. Utilising the immunoturbidimetric method, the Randox apo E assay is available in a liquid ready-to-use format. Not only does the Randox apo E suffer from limited interferences from bilirubin, haemoglobin, intralipid® and triglycerides for truly accurate results, it has an excellent measuring range of 1.04 – 12.3mg/dl for the comfortable detection of clinically important results. Moreover, apolipoprotein calibrator and controls are available for a complete testing package. Applications are available detailing instrument-specific settings for the convenient use of the Randox apo E assay on a wide range of clinical chemistry analysers.
Biochip Technology – Alzheimer’s Array
Utilising the Biochip Technology, Randox have developed an array to identify the risk of Alzheimer’s disease in just 3 hours with one effective test. In addition to a rapid and accurate diagnosis, this also introduces both cost and time-saving benefits. The apo E4 array is a research use only product developed for the Evidence Investigator, a semi-automated benchtop immunoassay analyser which can process up to 2376 test per hour as well as up to 44 analytes screened per biochip. The apo E4 array measures both total apo E protein levels and apo E4 protein levels directly from plasma samples as well as using a ratio, it can classify patients as negative or positive for apo E4. In turn, we can then assess their risk for the development of Alzheimer’s disease.
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 Alzheimer’s Society. Alzheimer’s disease. [Online] [Cited: September 2, 2019.] https://www.alzheimers.org.uk/about-dementia/types-dementia/alzheimers-disease.
 Gaugler, Joseph, et al. 2019 Alzheimer’s Disease Facts and Figures. s.l. : Alzheimer’s Association, 2019.
 2014 Update of the Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception. Weiner, Michael W, et al. 6, San Francisco : Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2015, Vol. 11.
 Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Liu, Chia-Chen, et al. 2, Fujian : Nature Reviews Neurology, 2013, Vol. 9.
 Apolipoprotein E isoforms and lipoprotein metabolism. Phillips, Michael C. 9, Philadelphia : IUBMB Journals, 2014, Vol. 66.
 The Role of Apolipoprotein E in Alzheimer’s Disease. Kim, Jungsu, Basak, Jacob M and Holtzman, David M. 3, St Louis : Neuron, 2009, Vol. 63.
 Dacks, Penny. What ApoE Means For Your Health. Cognitive Vitality. [Online] November 16, 2016. [Cited: September 11, 2019.] https://www.alzdiscovery.org/cognitive-vitality/blog/what-apoe-means-for-your-health.
 The Complex Role of Apolipoprotein E in Alzheimer’s Disease: an Overview and Update. Mahoney-Sanchez, Laura, et al. 3, Parkville : Journal of Molecular Neuroscience, 2016, Vol. 60.
 Understanding the Role of ApoE Fragments in Alzheimer’s Disease. Muñoz, SS, Gerner, B and Ooi, L. 6, Wollongong : Neurochemical Research, 2019, Vol. 44.
 ApoE4: an emerging therapeutic target for Alzheimer’s disease. Affieh, Mirna, Korczyn, Amos D and Michaelson, Daniel M. 64, s.l. : BMC Medicine, 2019, Vol. 17.
 Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Yamazaki, Yu, et al. 9AB, s.l. : Nature Reviews Neurology, 2019, Vol. 15.
SARS-CoV-2 (COVID-19), a highly contagious disease, primarily manifests as an acute respiratory illness, however, for those with health complications, including: autoimmune diseases, asthma, heart disease and diabetes, the risk of developing serious illness and adverse outcomes is much greater. It is estimated that 1 in 6 will experience adverse outcomes that could be life-threatening 1. The spread and devastation of COVID-19 highlights the vital role laboratory diagnostics plays in the diagnosis and management of suspected and affected patients. As the COVID pandemic continues, it is imperative that fast and accurate diagnostic testing strategies are implemented for effective risk stratification and monitoring of treatment and recovery.
In this article, we will review how Randox Reagents can aid in diagnosing and managing SARS-CoV-2 adverse outcomes.
The immune system activates a pro-inflammatory response to enhance host immunity against viruses and decrease colonisation and infection, but only if the pro-inflammatory response is controlled. Uncontrolled pro-inflammatory responses can result in a cytokine storm 2. A cytokine storm is a serious complication associated with SARS-CoV-2, which can trigger life-threatening pneumonia, acute respiratory distress syndrome (ARDS) and multiple organ failure 3, 4. Cytokine storms occur in 5% of severe COVID-19 cases, with several inflammatory cytokines observed at high levels. Due to the elevation of several pro-inflammatory and anti-inflammatory cytokines, a multiplex immunoassay approach can offer several advantages over the widely utilised single ELISA tests. The simultaneous detection of multiple cytokines from a single patient sample will provide clinicians with a comprehensive overview of cytokine markers and complete patient profile, facilitating a personalised treatment plan to be implemented 5, 6.
In COVID-19 patients, CRP testing has proved to perform well in discriminating disease severity and predicting adverse outcomes 7. Elevated CRP levels have been identified in 86% of patients admitted to hospital. CRP measurements are useful in diagnosis, prognosis and monitoring for clinical improvements or deterioration. Moreover, the acute phase reactant, ferritin, has been observed to increase in approximately 60% of COVID-19 patients. In the critically ill COVID-19 patients, extremely elevated ferritin concentrations were recorded, which could be attributed to a cytokine storm and secondary haemophagocytic lymphohistiocytosis (a hyper-inflammatory syndrome associated with multi-organ failure) 8.
Acute kidney injury (AKI) is a common complication in diabetic patients who test positive for COVID-19. Regardless, the National Institute for Health and Care Excellence (NICE) recommend AKI testing in all COVID-19 patients upon hospital admission and their condition monitored throughout their stay 9.
The most commonly utilised screening test for renal impairment is serum creatinine (SCr); however, it is important to consider the accuracy and reliability of the method. Two commercially available methods exist for SCr determination: Jaffe and enzymatic. Whilst the Jaffe method is less expensive, it is more susceptible to interferences which can lead to the misdiagnosis of patients, which isn’t ideal in the current pandemic 7. Moreover, the sensitivity of SCr, regardless of method, in the early detection of renal disease is poor, as SCr is insensitive to small changes in glomerular filtration rate (GFR). Up to 50% of renal function can potentially be lost before significant SCr levels become detectable 8, 9. In comparison, cystatin C (CysC) is a superior marker of renal function and is useful in the determination of the extent of renal damage, as well as distinguishing those with severe and mild COVID-19 10.
Abnormal liver function tests significantly increases a COVID-19 patients risk of developing severe disease and complications such as pneumonia 11. Bilirubin levels, 3 times the upper limit have been observed in COVID-19 patients 11, 12. Whilst the diazo method is commonly utilised in bilirubin testing, superior methods exist. The vanadate oxidation (VO) method offers several advantages particularly in haemolytic and lipemic samples. These advantages are particularly evident in neonatal and infant populations where haemolysis is extremely common. Moreover, the VO method offers a wider analytical measurement range for the comfortable detection of clinically important results 13.
Other liver function markers are known to be elevated in COVID-19 patients including both AST and ALT, with markers like albumin decreased.
The Importance of Lp(a) Testing
Lipoprotein(a) / Lp(a), a strong independent marker of cardiovascular disease risk has recently been identified as a key risk marker of cardiovascular complications in COVID-19 patients. Those with either baseline elevated or elevated levels of Lp(a) following COVID-19 infection may be at a significantly increased risk of developing thromboses. Consideration should be given to measurement of Lp(a) and prophylactic anticoagulation of infected patients to reduce the risk. Elevated Lp(a) levels may also cause acute destabilization of pre-existing but quiescent, atherosclerotic plaques, which could induce an acute myocardial infarction (AMI) or cerebrovascular accident (CVA) (stroke) 14.
The size heterogeneity of apo(a) isoforms represents the biggest challenge faced by laboratories in accurately measuring Lp(a). The variable numbers of repeated KIV-2 units in act as multiple epitopes, and so standardisation across calibrators is vital. Unless the calibrants have the same range of isoforms as test samples, those with higher numbers of the KIV-2 repeat, will represent with an overestimation in Lp(a) concentrations and those with smaller numbers of the KIV-2 repeat, will represent with an underestimation. The smaller isoforms are strongly associated with higher Lp(a) concentrations 15.
Lp(a) assays that are standardised to the WHO/IFCC (World Health Organization/International Federation of Clinical Chemistry) reference material, transferring values from mg/dl to nmol/l are more uniform. The assay considered the most reliable commercially available Lp(a) assay is so because: 15
1. The isoform size variations are reduced as a range of calibrators from separate pools of serum used, which covered a range of Lp(a) concentrations.
2. The isoform size and concentrations are inversely correlated, better matching calibrants with test samples.
3. Methods are calibrated in nmol/l and traceable to WHO/IFCC reference material and give acceptable bias compared with the Northwest Lipid Metabolism and Diabetes Research Laboratory (NLMDRKL) gold standard method.
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 Complications coronavirus can cause. https://www.webmd.com/lung/coronavirus-complications#1 (accessed 22 July 2020).
 Sinha P, Matthey MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA 2020; (): 1-3. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2767939#:~:text=Why%20has%20the%20%E2%80%9Ccytokine%20storm,and%20associated%20with%20adverse%20outcomes.&text=Several%20early%20case%20series%20in,elevated%20above%20the%20normal%20range. (accessed 22 July 2020).
 Del Valle DM, Kim-Schulze S, Huang HH, Beckmann M, Nirenberg S, et al. An inflammatory cytokine signature helps predict COVID-19 severity and death. The Preprint Server for Health Sciences https://www.medrxiv.org/content/10.1101/2020.05.28.20115758v1.full.pdf (accessed 24 July 2020).
 The Royal College of Pathologists. Guidance on the use and interpretation of clinical biochemistry tests in patients with COVID-19 infection. https://www.rcpath.org/uploads/assets/3f1048e5-22ea-4bda-953af20671771524/G217-RCPath-guidance-on-use-and-interpretation-of-clinical-biochemistry-tests-in-patients-with-COVID-19-infection.pdf (accessed 14 June 2020).
 Dhungana N, Morris C, Krasowski MD. Operational impact of using a vanadate oxidase method for direct bilirubin measurements at an academic medical center clinical laboratory. Practical Laboratory Medicine 2017; 8(2017): 77-85.
 Moriarty PM, Gorby LK, Stroes ES, Kastelein JP, Davidson M, et al. Lipoprotein(a) and its potential association with thrombosis and inflammation in COVID-19: a testable hypothesis. Current Atherosclerosis Reports 2020; 22(48): 1-8.
Featured Reagent | Microalbumin
What is Microalbumin?
Albumin is the most common protein found in the blood and is produced in the liver, it helps your body maintain fluid balance. To prevent fluid from leaking out of the blood vessels a proper balance of albumin is needed. Albumin also carries vital nutrients and hormones, and provides your body with the proteins it needs to maintain growth and repair tissues.
A urine microalbumin test is a test to detect very small levels of albumin in the urine. This test can detect early signs of kidney damage. Microalbumin tests are recommended for people with an increased risk of kidney disease, such as those with type 1 diabetes, type 2 diabetes or high blood pressure.
Healthy kidneys filter waste from your blood and hang on to the healthy components, including proteins such as albumin. Kidney damage can cause proteins to leak through your kidneys and exit your body in your urine. Albumin is one of the first proteins to leak when kidneys become damaged.
Features of Microalbumin
Liquid ready-to-use reagents
Stable to expiry at 2-8°C
Measuring range 5.11-234 mg/l
Applications available for a wide number of clinical chemistry analysers. Please contact us at email@example.com for more information.
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Featured Reagent | Complement C4
What is Complement C4?
The complement system is one of the major mechanisms of innate immunology consisting of more than 30 plasma and membrane-associated serum proteins which evokes cytolytic immune responses to pathogens, including viruses, bacteria and anything that is classified as foreign to the body.
Complement c4 works alongside Complement c3 to accurately diagnose and monitor autoimmune disorders. Low levels of complement c4 levels are associated with the risk of developing disorders such as rheumatoid arthritis and Systematic Lupus Erythematosus (SLE), due to the cell-bound levels of processed complement activation products. On the other hand, higher levels of complement c4 are highlighted in patients with autoimmune haemolytic anaemia.
Liquid ready-to-use reagents – for convenience and ease of use
Exceptional correlation with standard methods – Our assay showed a correlation coefficient of r=0.98 when compared against other commercially available methods
Wide measuring range – 2.90 – 152 mg/dl comfortably detecting levels outside the healthy range of 7 – 49 mg/dl
Excellent stability – Stable to expiry when stored at +2°C – + 8°C
Applications available for a wide number of clinical chemistry analysers. Please contact us at firstname.lastname@example.org for more information.
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Featured Reagent | Complement C3
What is Complement C3?
Complement C3 is a complex biological system which works in conjunction with antibodies and other factors to protect the body from invasion by pathogens. When activated by either the classical or alternative pathway Complement acts on biological membranes and may cause cell death. Complement C3 and complement C4 levels are important in determining inherited or acquired deficiencies.
Complement testing can be used to help diagnose the cause of recurrent microbial infections, unexplained swellings or inflammation. In addition, low levels of complement C3 can be found in patients diagnosed with Systemic Lupus Erythematosus (SLE), a form of lupus, which is a chronic autoimmune disease that triggers inflammation in different organs and tissues of the body and can cause widespread inflammation and tissue damage in the affected organs. Periodic tests should be carried out to help monitor known long term diseases that affect the complement system.
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Featured Reagent | Cystatin C
Kidney disease is a huge global health crisis, increasing healthcare costs, mortality and morbidity rates. The global prevalence of chronic kidney disease (CKD) has continued to rise during a short lifespan. In 2016, 1 in 10, equivalent to 10 percent of the global population were identified with having CKD with the highest prevalence’s reported in Europe, the Middle East, East Asia and Latin America, estimated at 12 per cent and the lowest in South Asia, estimated at 7 percent1.
The early risk assessment of renal function is vital. In 1990, CKD was ranked the 27th leading cause of death in the Global Burden of Disease study2, rising to 18th 3 in 2010, 13th in 20132 and 12th by 2015. From 2005-2015, the overall CKD mortality rate has risen by 31.7 percent, accounting for 1.1 million deaths globally in 20154.
Inadequacies of Traditional CKD Biomarkers
The most commonly used screening test for renal impairment is creatinine. When testing for CKD using creatinine, certain factors must be taken into consideration, including: age, gender, ethnicity, and muscle mass. As such, black men and black women will present with higher creatinine levels compared to white men and white women respectively5.
Serum creatinine is not an adequate screening test for renal impairment in the elderly (65 years of age and over) due to their decreased muscle mass. As such, patients are misdiagnosed, thus, patients with severe renal failure are receiving suboptimal care6.
The main disadvantage of using creatinine to screen for renal impairment is that up to 50 percent of renal function can be lost before significant creatinine levels become detectable as creatinine is insensitive to small changes in the glomerular filtration rate (GFR). Consequently, treatment is not provided at the appropriate time which can be fatal, thus, an earlier and more sensitive biomarker for renal function is vital7.
Cystatin C is a small (13 kDa) cysteine proteinase inhibitor, produced by all nucleated cells at a constant rate. Cystatin C travels through the bloodstream to the kidneys where it is freely filtered by the glomerular membrane, resorbed and fully catabolised by the proximal renal tubes. Consequently, cystatin C is the ideal biomarker of GFR function8.
Clinical Significance of Cystatin C
The National Institute for Health and Care Excellence (NICE) (2014) guidelines recommend cystatin C testing due to its higher specificity for significant disease outcomes than those based on creatinine. As such, eGFR cystatin C measurements will significantly reduce the number of misdiagnosed patients, thus reducing the overall CKD burden9.
In 2017, a systematic literature search found 3,500 investigations into cystatin C as a marker of GFR. The study concluded that eGFRcystatinc was a significantly more superior than eGFRcreatinine10.
Benefits of Cystatin C
The Randox cystatin C assay utilises the latex enhanced immunoturbidimetric method offering numerous key features:
A niche product from Randox meaning that Randox are one of the only manufacturers to provide the cystatin C test in an automated biochemistry format
An automated assay which removes the inconvenience and time consumption associated with traditional ELISA testing
Applications are available detailing instrument-specific settings for the convenient use of the Randox cystatin C assay on a wide range of biochemistry analysers
Liquid ready-to-use reagents for convenience and ease-of-use
Latex enhanced immunoturbidimetric method delivering high performance
Extensive measuring range for the detection of clinically important results
Complementary controls and calibrators available offering a complete testing package
Limited interference from Bilirubin, Haemoglobin, Intralipid® and Triglycerides
Cystatin C does not suffer from a ‘blind area’ like creatinine due to cystatin C’s sensitivity to small changes in GFR enabling the early detection renal impairment
An exceptional correlation coefficient of r=1.00 when compared against standard methods
 Bello, AK, et al. Global Kidney Health Atlas: A report by the Internal Society of Nephrology on the current state of organization and structures for kidney care across the globe. Brussels : Internal Society of Nephrology, 2017.
 Bikbov, Boris. Chronic kidney disease: impact on the global burden of mortality and morbidity. The Lancet. [Online] 2015. http://www.thelancet.com/campaigns/kidney/updates/chronic-kidney-disease-impact-on-global-burden-of-mortality-and-morbidity.
 National Kidney Foundation. Global Facts: About Kidney Disease. National Kidney Foundation. [Online] National Kidney Foundation, 2015. https://www.kidney.org/kidneydisease/global-facts-about-kidney-disease#_ENREF_1.
 Neuen, Brendon Lange, et al. Chronic kidney disease and the global NCDs agenda. s.l. : BMJ Global Health, 2017.
 Lascano, Martin E and Poggio, Emilio D. Kidney Function Assessment by Creatinine-Based Estimation Equations. Cleveland Clinic. [Online] August 2010. [Cited: May 16, 2018.] http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/kidney-function/.
 Swedko, Peter J, et al. Serum Creatinine Is an Inadequate Screening Test for Renal Failure in Elderly Patients. Research Gate. [Online] February 2003. [Cited: May 6, 2018.] https://www.researchgate.net/publication/8243393_Serum_Creatinine_Is_an_Inadequate_Screening_Test_for_Renal_Failure_in_Elderly_Patients.
 Mishra, Umashankar. New technique developed to detect chronic kidney disease. Business Line. [Online] May 07, 2018. [Cited: May 17, 2018.] https://www.thehindubusinessline.com/news/science/new-technique-to-detect-chronic-kidney-disease/article23803316.ece.
 Chew, Janice SC, et al. Cystatin C-A Paradigm of Evidence Based Laboratory Medicine. NCBI. [Online] May 29, 2008. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533150/.
 National Institute for Health and Care Excellence. Chronic kidney disease in adults: assessment and management: 2 Implementation: getting started. NICE. [Online] January 2015. [Cited: April 19, 2018.] https://www.nice.org.uk/guidance/cg182/chapter/implementation-getting-started.
 Grubb, Anders. Cystatin C is Indispensable for Evaluation of Kidney Disease. NCBI. [Online] December 28, 2017. [Cited: April 19, 2018.] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746836/.
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Reagent | Apolipoprotein E (ApoE)
A Genetic Risk Factor for CVD & Alzheimer’s Disease
Benefits of the Randox ApoE Assay
A correlation coefficient of r=1.00 was displayed when the Randox apoE assay was compared to commercially available methods.
The Randox apoE assay displayed a precision of <2.79% CV.
Extensive measuring range
The Randox apoE assay has a measuring range of 1.04 – 12.3mg/dl for the comfortable detection of clinically important results.
The apoE assay is available in a liquid ready-to-use format for convenience and ease-of-use.
Dedicated calibrator and controls available
Randox offer dedicated apolipoprotein calibrator and controls for a complete testing package.
Applications available detailing instrument-specific settings for the convenient use of the Randox apoE assay on a variety of clinical chemistry analysers.
The apolipoproteinE (APOE) gene provides instructions for the production of the apolipoprotein E (apoE) protein. The apoE protein binds with lipid forming lipoproteins which are responsible for the transportation of cholesterol and other lipids through the bloodstream 1.
Apolipoprotein E (apoE) is a multifunctional glycoprotein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. ApoE has three major isoforms (apoE2, apoE3, and apoE4) all of which have different effects on lipid and neuronal homeostasis (fig 1). The key function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalise apoE-containing lipoprotein particles and so apoE participates in the distribution or redistribution of lipids among various tissues and bodily cells. The e3 allele is the most of the three and may be considered an ancestral allele. The e4 allele is more common in those of Northern European ancestry and lower in those of Asian ancestry 3.
Both apoE2 and apoE4 alleles are associated with cardiovascular disease (CVD).
As apoE2 binds defectively to LDL receptors, apoE2 homozygosity can precipitate type III hyperlipoproteinemia, however, only occurs when another condition, including: diabetes, oestrogen deficiency, hypothyroidism, or obesity, leads to the overproduction of VLDL or fewer LDL receptors, overwhelming the limited ability of apoE2 to mediate the clearance of triglyceride-rich and cholesterol-rich β-VLDL. Other dominant and recessive mutations in apoE that affect residues in or around the receptor binding region also causes type III hyperlipoproteinemia 3.
ApoE3 increases LDL levels in plasma and the risk of atherosclerosis. The lipoprotein-binding preference of apoE4 to large (30-80nm), triglyceride-rick VLDL, is associated with elevated levels of LDL. The enrichment of VLDL with apoE4 accelerates their clearance from the plasma by receptor-mediated endocytosis in the liver and consequently, LDL receptors are downregulated, and LDL levels rise 3.
ApoE4 is the major genetic risk factor, or causative gene, for Alzheimer’s disease (AD) and other neurological disorders, including poor clinical outcomes following traumatic brain injury, stroke, frontotemporal dementia, Down syndrome, certain patients with Parkinson’s disease, and Lewy body disease 3.
Apo E4 drastically affects AD with 65-80% of all AD patients carrying at least one apoE4 allele. ApoE4 increases the risk of developing AS 4-fold (one allele) and 14-fold (two allele). Carrying one e4 allele is not uncommon with approximately 25% of people worldwide having at least one E4 allele. Fig. 2 illustrates the apoE-mediated pathogenic pathways leading to AD, with amyloid β playing a key role 3.
 Huang Y, Mahley RW. Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiology of Disease 2014; 72(Part A): 3-12.
 Genetics Home Reference. APOE gene: apolipoprotein E. https://medlineplus.gov/genetics/gene/apoe/ (accessed 9 October 2020).
 Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. Journal of Molecular Medicine (Berlin, Germany) 2016; 94: 739-746.
 Liao F, Yoon H, Kim J. Apolipoprotein E metabolism and functions in brain and its role in Alzheimer’s disease. Current Opinion in Lipidology 2017; 28(1): 60-67.
Reagent | Immunoglobulin (IgE)
A Marker of Allergic Diseases
A correlation coefficient of r=1.00 was displayed when the Randox methodology was compared against commercially available methods.
The Randox IgE assay displayed a precision < 4.0% CV.
Excellent measuring range
The Randox IgE assay has a measuring range of 19.6 – 1007IU/ml for the comfortable detection of clinically important results.
The Randox IgE assay is available in a liquid ready-to-use format for convenience and ease-of-use.
Calibrator and controls available
Dedicated IgE calibrator and specific protein controls available for a complete testing package.
Applications available detailing instrument-specific settings for the convenient use of the Randox IgE assay on a variety of clinical chemistry analysers.
Immunoglobulin E (IgE) is one of five classes of immunoglobulins (IgA, IgD, IgE, IgG and IgM). IgE was the last immunoglobulin to be discovered. However, since it’s discovery, vast amounts of research have been aimed at characterising its physiological and clinical significance’s. Whilst IgEs chemical structure is unique compared to the rest of the immunoglobulin family (lacks a ‘hinge’ region in the centre of the molecule and gets replaced by the C-epsilon2 domain), it has an array of physiological functions. For immunoglobulin E to fulfil its function, the Fc portion of the antibody must bind to a given cellular receptor located on certain cell types, such as eosinophil or mast cells. Whilst many an array of cellular receptors have been identified, the main ones are Fc-epsilon-RI, Fc-epsilon-II and CD23. Fc-epsilon-RI is the high affinity receptor located on basophils, dendritic cells, eosinophils, mast cells and macrophages and is responsible for immediate hypersensitivity reactions, enhanced cytokine production, parasitic immunity, and antigen presentation 1.
It is believed that immunoglobulin E evolved as a defence mechanism against parasitic infestation. The major sites of parasitic invasion are the gut, respiratory tract and skin, the typical allergic response sites. IgE antibodies play a key role in the early recognition of foreign material or a general potentiation of the immune system response through improved antigen presentation. An allergy triggered by IgE could be beneficial to the host as the typical allergic reactions include: sneezing, coughing, inflammation, bronchoconstriction and vomiting, to expel allergenic proteins from the body. Different allergens stimulate the production of corresponding allergen-specific immunoglobulin E antibodies 2. The antigen-dependent activation of tissue mast cells that have specific immunoglobulin E bound to their surface is the central event in acute allergic reactions. IgE specific allergens include: allergic or atopic asthma, atopic dermatitis (eczema), food allergies such as peanut and shellfish, allergic rhinitis (hay fever), house dust mite, latex allergy, dog or cat allergies 2, 3.
Specific Proteins Controls