The cardiorenal syndrome (CRS) involves both kidney failure and heart failure, with the failing organ initially being either the heart or the kidney; usually one failing organ leads to the failure of the other. While use of biomarkers and imaging techniques can assess cardiovascular function, the assessment of renal injury and function is complex in CRS patients. This article discusses some of the novel markers for the assessment of renal function and injury.
Renal dysfunction is an independent and significant contributor to poor heart failure outcomes. Serum creatinine (SCr), the most frequently used marker for clinical assessment of renal dysfunction and injury, is at best a retrospective window. Glomerular filtration rate, GFR, considered the best overall measure of renal function (RF), is similarly affected by multiple variables, but novel biomarkers of renal injury and function are now available. These biomarkers also have limitations but they address gaps in the information provided from use of conventional biomarkers
A marker of renal function: cystatin-C
Cystatin C, an endogenous proteinase inhibitor of low molecular weight (13-kDa), possesses many features that make it attractive as a surrogate marker of RF and GFR. It is synthesised and released into plasma by all nucleated cells at a constant rate, is freely filtered by the glomerulus and completely reabsorbed by the proximal tubules. It can be easily measured in the serum and plasma without the need for a urine sample or complex equations. It is not affected by changes in body mass, nutrition, age or gender, making it potentially more beneficial in critically ill patients, elderly and children. It has been validated as a marker of GFR in patients with pre-existing renal dysfunction and acute kidney injury (AKI) as levels increase before SCr. In congestive heart failure (CHF) Cys-C is superior to SCr based estimates, which underestimate GFR. This appears to extend to acure decompensated heart failure (ADHF) admissions without advanced RF. Cys-C also reflects myocardial stress and damage, reflects more advanced left ventricular diastolic and right ventricular systolic dysfunction and is an independent predictor of long-term prognosis after adjusting for myocardial factors. The advantage of Cys-C over SCr appears greater and more conclusive for ruling in renal injury in affected patients. Other benefits include predicting future CV events in intermediate-risk individuals, mainly through the identification of those unlikely to develop events; it is a stronger predictor of adverse events than conventional measurement of RF and, in combination with cardiac troponin T and N-terminal–pro-brain natriuretic peptide, it improves risk stratification for CV mortality (inclusive of HF) beyond models of established risk factors.
Novel assessments of renal injury
The potential to attenuate or reverse renal injury is far less likely when renal dysfunction is already evident, at least based on current assessment methods. Several promising AKI biomarkers arenow available.
Neutrophil gelatinase-associated lipocalin
Human neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein initially described to be bound to gelatinase in specific granules of the neutrophil, with recent evidence suggesting physiological activity in the kidney. It is expressed and secreted by immune cells, hepatocytes and renal tubular cells in various pathologic states. NGAL exerts bacteriostatic effects, which are explained by its ability to capture and deplete siderophores, small iron-binding molecules that are synthesised by certain bacteria as a means of iron acquisition and role in cell survival, inflammation and matrix degradation. NGAL is up regulated more than 10-fold in post ischaemic renal injury in a mouse model and secreted relatively early into the urine. Several recent studies in homogenous (adult and paediatric cardiac surgery), heterogeneous (intensive care and emergency department) and chronic kidney disease (CKD) populations have supported the use of NGAL as an important biomarker in early diagnosis and prediction of duration and severity of AKI. NGAL differentiates AKI from changes in GFR due to chronic disease progression, predicts duration of ICU stay and provides prognostic value. Specifically, a single urine level of NGAL in the emergency department differentiates AKI from normal function and from pre-renal azotaemia, and predicts poor in-patient outcome.
A recent multicentre pooled analysis of published data on 2322 critically ill children and adults with the cardiorenal syndrome revealed the surprising finding that approximately 20% of patients display early elevations in NGAL concentrations but never develop increases in serum creatinine. Importantly, this sub-group of ‘NGAL-positive creatinine-negative’ subjects encountered a substantial increase in adverse clinical outcomes, including mortality, dialysis requirement, ICU stay and overall hospital stay. Thus, early NGAL measurements can identify patients with sub-clinical AKI who have an increased risk of adverse outcomes, even in the absence of diagnostic increases in serum creatinine.
Among acute decompensated heart failure patients, high admission serum NGAL levels were associated with increased risk of worsening RF. In particular, patients with an NGAL of >140 ng/mL on admission had a 7.4-fold increased risk, with a sensitivity and specificity of 86% and 54%, respectively. NGAL values are also significantly increased and parallel the clinical severity of CHF. After a 2-year follow up, patients with baseline NGAL > 783 ng/mL had a significantly higher mortality. These findings may suggest that NGAL plays a pivotal role in the systemic adaptation to CHF. Elevated baseline serum levels in acute post-myocardial infarction and CHF correlated with clinical and neurohormonal deterioration and adverse outcomes. In a rat model of post-MI HF, NGAL/lipocalin-2 gene expression was increased in the non-ischaemic left ventricle segments, primarily located to cardiomyocytes. Strong NGAL immunostaining was found within cardiomyoctes in experimental and clinical HF. Furthermore interleukin-1β and agonists for toll-like receptors 2 and 4 were potent inducers of NGAL/lipocalin-2 in isolated neonatal cardiomyocytes supporting a role for the innate immune system in HF pathogensesis. Urinary NGAL also increases in parallel with the NYHA classes for HF and is also closely correlated with serum NGAL, Cys-C, SCr and eGFR. This suggests tubular damage may accompany renal dysfunction in CHF, which has prognostic consequences.
Evidence is continuing to accumulate and NGAL measurement appears to be of diagnostic and prognostic value. In a recent meta-analysis, NGAL levels predicted renal replacement therapy initiation and in-hospital mortality. Several recent studies showing the response of urinary levels to therapy suggest a future role for NGAL for follow up and monitoring the status and treatment of diverse renal diseases reflecting defects in the glomerular filtration barrier, proximal tubule reabsorption and distal nephrons. Thus the prospects of NGAL being used as a diagnostic tool, even beyond the realms of nephrology, are exciting but require further clinical research. The commercial availability of standardised clinical platforms for the accurate and rapid measurement of NGAL in the urine and plasma will facilitate future investigations as well as direct clinical applications.
Interleukin-18
Interleukin (IL)-18 is a proinflammatory cytokine which induces interferon-g production in T cells and natural killer cells. It is synthesised as a biologically inactive precursor, which requires cleavage into an active molecule by an intracellular cysteine protease similar to IL-1b. IL-18 is both a mediator and biomarker of ischaemic AKI. Several early studies demonstrate increases in patients with acute tubular necrosis, prerenal azotaemia, nephrotic syndrome, delayed graft function after renal transplantation, chronic renal insufficiency and urinary tract infections. In contrast nephropathy, cardiopulmonary bypass, critically ill children and kidney transplantation, urinary IL-18 rises two days earlier than SCr. Urine IL-18 increases four to six hours after cardiopulmonary bypass, peaks at over 25-fold at 12 hours, and remains elevated up to 48 hours later. IL-18 levels also predict graft recovery and need for dialysis up to three months later. There is also significant evidence that IL-18 contributes to clinical HF and other acute and chronic cardiovascular presentations. Presently there are no studies with patients with CRS.
Major concerns over IL-18 surround its discriminatory capacity and appropriate use. One concern is a spill over into the urine and its effects as a confounder, differentiating elevated cardiac as opposed to renal injury. Additionally, serum IL-18 may be increased in other disease states e.g. autoimmune disorders such as SLE, certain leukaemias, postoperative sepsis, chronic liver disease and acute coronary syndromes. On a positive note serum IL-18 levels were not different between those with and without AKI post paediatric cardiac surgery, and data suggesting its pathophysiological contribution to the renal damage observed during ischaemia/reperfusion are positive signs for its discriminatory values and causative effects in renal injury. Thus IL-18 appears to be a worthwhile addition to a biomarker panel in the assessment of AKI.
Kidney injury molecule-1
Kidney injury molecule-1 (KIM-1) is a transmembrane protein that is highly over expressed in proximal tubule cells after ischaemic or nephrotoxic AKI. Several studies have shown KIM-1 in urine and renal biopsy to be elevated from predominately ischaemic AKI and not from prerenal azotaemia, chronic renal disease, and contrast nephropathy. KIM-1 appears to play a role in the pathogenesis of tubular cell damage and repair in experimental and human kidney disease. KIM-1 is a sensitive marker for the presence of tubular damage. It is virtually undetectable in healthy kidney tissue, but tubular KIM-1 expression is strongly induced in acute and chronic kidney disease as well as transplant dysfunction, where it is significantly associated with tubulointerstitial damage and inflammation. Elevated urinary KIM-1 levels are strongly related to tubular KIM-1 expression in experimental and human renal disease, indicating that urinary KIM-1 is a very promising biomarker for the presence of tubulo-interstitial pathology and damage. Furthermore, urinary excretion of KIM-1 is an independent predictor of graft loss in renal transplant recipients, demonstrating its prognostic impact. Studies after cardiopulmonary bypass surgery have noted similar findings. KIM-1 also predicts adverse clinical outcomes in various forms of AKI. Data from non-diabetic proteinuric patients suggest that urinary excretion of KIM-1 may have the potential to guide renoprotective intervention therapy. KIM-1 could potentially provide additional prognostic data for tubular damage in CHF. Future studies will reveal whether the sensitive biomarker KIM-1 will become a therapeutic target itself. Kim-1/KIM-1 dipsticks can provide sensitive and accurate detection of Kim-1/KIM-1, thereby providing a rapid diagnostic assay for kidney damage and facilitating the rapid and early detection of kidney injury in preclinical and clinical studies. The primary limitation of KIM-1 is that time to peak is 12 to 24 hours after insult. While it may be of limited use as an early AKI biomarker, the ability to detect KIM-1 in urine makes it an attractive option, possibly in a biomarker panel togther with NGAL and IL-18.
L-FABP
The fatty acid-binding proteins (FABPs) are 15kDa cytoplasmic proteins. There are two types: heart type (H-FABP) located in the distal tubular cells and liver type (L-FABP) which is expressed in the proximal tubular cells. Both markers have been suggested as useful for the rapid detection and monitoring of renal injury. H-FABP has been tested as a marker for ischaemic injury in donor kidneys. L-FABP has been tested in progressive ESRD as well as renal injury post renal transplantation and cardiopulmonary bypass and more recently acute coronary syndromes. In patients undergoing PCI for unstable angina, urine L-FABP levels were significantly elevated after two and four hours and remained elevated for 48 hours. SCr did not change significantly during the study period. Among nondiabetic CKD patients, urine L-FABP levels correlated with urine protein and SCr levels. Notably, L-FABP levels were significantly higher in patients with mild CKD who progressed to more severe disease. Neither SCr nor urine protein differed between those same groups. H-FABP however is produced by myocardial damage and its clearance is determined by RF. The ratio of H-FABP to myoglobin after haemodialysis may be a useful marker for estimating cardiac damage and volume overload in haemodialysis. This may be an advantage for FABP in a panel of biomarkers to discrimnate background noise and cases where troponin levels can’t be interpreted. The main drawbacks are lack of evidence in the HF setting, small sample sizes in existing studies, and non-availability of a commercially usable assay. Additional longitudinal studies are needed to demonstrate the ability of L-FABP to predict AKI as well as CKD and its progression in cohorts with CKD of multiple aetiologies.
Biomarker panels
Each of these biomarkers has advantages and limitations. It will be a while yet before any of these biomarkers match serum troponin and act as a ‘standalone’ marker. However they do provide a safety mechanism initially to highlight anticipated risk, as well as additional information on likely renal pathophysiology. It may ultimately be that a panel of biomarkers is required. Candidates for inclusion are NGAL, IL-18, KIM-1, Cys C and L-FABP. The alternative may be selective use of markers when renal injury is anticipated, a strategy synonymous with acute coronary syndromes with serial cardiac enzymes, i.e.’serial renal enzymes’. Ultimately a point of care device would be ideal, and some kits are already in place. It is however clear that the learning paradigm is still ongoing. Future studies will need to validate these biomarker panels in a large heterogenous cohort.
The future of renal assessments in cardiovascular patients
Renal dysfunction is an independent and significant contributor to poor heart failure outcomes. Idiosyncracies in cardiorenal physiology and limitations of conventional diagnostic tools are factors in the poor prescribing of proven heart failure therapies in these patients. Novel biomarkers of renal injury and function are currently available. These biomarkers do have limitations but they address gaps in the information gained from conventional biomarkers i.e. improvements in injury chronology and functional accuracy. Significant limitations in how these markers are used as well as issues of availability and cost can only be addressed by further work. Future research studies should consider addressing these questions.
Reference
Abstracted with permission from Iyngkaran P et al. Cardiorenal syndrome – definition, classification and new perspective in diagnostics. Seminars in Nephrology 2012; 32: 3-17.
Maternal screening is offered to all expectant women during the first or second trimester of pregnancy. The purpose of this screening is to test for fetal abnormalities including chromosomal abnormalities such as Down’s syndrome, Trisomy 18 and neural tube defects such as spina bifida. Testing is performed by taking a blood sample from the patient’s arm which is then tested for a combination of biomarkers. Clinical results in addition to the maternal age are considered and used to calculate the risk of Down’s syndrome.
by Leah Hoencamp and Lynsey Adams
Down’s syndrome is a genetic condition and occurs when an individual inherits an extra copy of one chromosome. This means that affected people have three copies of chromosome 21, where there should be only two. The extra chromosome causes characteristic physical and intellectual features. The reasons why an extra copy of chromosome 21 causes Down’s syndrome are not known, which is why screening is so essential.
A combination of tests is used to screen for Down’s syndrome. Two types of screening are available and which is used depends on the stage of pregnancy of the patient. These stages are divided into first and second trimester.
First trimester screening includes:
• Free beta-hCG
• Pregnancy associated plasma protein (PAPP-A)
Second trimester screening includes:
• Double test AFP and hCG)
• Triple Test (AFP, hCG and uE3)
• Quadruple Test (AFP, hCG, uE3 and inhibin A)
If the results generated from this screening appear within the ‘higher risk’ category, more definitive tests are needed to confirm a diagnosis, such as amniocentesis or a chorionic villus sample. These tests provide a definitive result and involve taking samples of fluid from around the unborn baby. However, it is a highly invasive procedure and carries a small risk of miscarriage.
Internal quality control in maternal screening
Quality control (QC) is a crucial part of any clinical testing programme to ensure the accuracy and reliability of patient test results. Quality control is designed to detect, reduce and correct deficiencies in the laboratory’s internal analytical process prior to the release of patient results and to improve the quality of the results reported by the laboratory. Quality controls are manufactured to mimic a patient sample and contain one or more analytes of known concentration. They are made using a base material normally human serum, bovine serum, urine or spinal fluid. A laboratory will use quality controls to validate the patient samples. If QC results are within their target range then patient results should also be accurate. Once validated, the patient results can be used for diagnosis, prognosis and treatment planning. If QC values are outside the target range, it may indicate a number of issues including inaccurate calibration, instrument failure, operator error or reagent issues. In the field of maternal screening, the main aim is to minimise the risk of false positive and false negative results, ultimately ensuring results obtained are accurate and reliable.
In any type of screening the majority of errors take the form of false positive or false negative results. In other areas false negative results are of more concern as the patient will be perceived as healthy and will therefore not receive the required treatment. However, in prenatal screening, false positive results are also of major concern. If a patient tests positive they may have to undergo an invasive amniocentesis procedure with risk to the fetus in order to confirm if a chromosomal disorder like Downs’s syndrome is present. It is clear that such screening requires a robust and reliable quality control procedure in order to avoid potential errors.
To facilitate the increased screening for Down’s syndrome, trisomy 18 and neural tube defects, Randox has developed the only commercially available multi-analyte; tri-level control specifically designed to cover both first and second trimester prenatal screening, with the following benefits:
• The unique combination of inhibin A and PAPP-A in addition to AFP, total hCG, free B-hCG and uE3 reduce the need to purchase separate controls thus saving money
• Manufactured from 100% human serum providing a matrix similar to the patient sample while reducing cross reactivity and ultimately shifts in QC values
• Three distinct levels of control are available, accurately covering the complete clinical range. The level one control contains suitably low levels of AFP whereas the level three control contains high levels of hCG. Moreover, the uE3 levels are in line with those typically found during the first twenty weeks of pregnancy
• True third party control providing an unbiased, independent assessment of performance. Highly accurate instrument specific target values and ranges are provided for the most popular analysers used in maternal screening
• Excellent reconstituted stability of seven days at +2–8 oC
• Excellent vial-to-vial homogeneity (%CV <1 %)
• Suitable for first trimester double screen and second trimester triple and quad screens.
Internal quality control (IQC) will help ensure results are reliable. An inter-laboratory data management package such as Acusera 24.7 can be used to further ensure quality. An effective IQC and peer group reporting scheme will help improve your laboratory’s analytical performance, help meet regulatory requirements and most importantly ensure the accuracy and reliability of patient test results. Acusera 24.7 enables laboratories to monitor analytical performance, access peer group reports and compare results with other laboratories using the same quality controls, method and instrument.
External quality assessment in maternal screening
To further assess the performance of maternal screening tests, laboratories should also be involved in an external quality assessment (EQA)/proficiency testing (PT) scheme. External quality assessment (EQA) is an essential aspect of any laboratory operation. EQA measures a laboratory’s accuracy using ‘blind’ samples that are analysed as if they were patient samples. EQA provides a means of assessing the analytical performance of a laboratory compared to other laboratories utilising the same methods and instruments. Participation in an EQA scheme will help produce reliable and accurate reporting of patient results. Quality results will reduce time and labour costs, and most importantly provide accurate patient diagnosis and treatment. Such a scheme is of paramount importance during testing such as maternal screening.
Randox International Quality Assessment Scheme (RIQAS) offers a Maternal Screening Programme which is capable of monitoring all 6 parameters involved in first and second trimester screening. RIQAS is the world’s largest global EQA scheme with more than 20 000 participants in over 100 countries worldwide.
Effective screening is essential for the detection of fetal abnormalities including Down’s syndrome, trisomy 18 and spina bifida. However, equally important in this process for laboratories responsible for processing the results is quality control. Effective quality control will help reduce false positives and false negatives, thereby ensuring reliable results and improving care of the patient overall.
Abbreviations
AFP, alpha-fetoprotein; hCG, human chorionic gonadotropin; uE3, unconjugated estriol.
The authors
Leah Hoencamp BSc & Lynsey Adams BSc
Randox Laboratories
55 Diamond Road, Crumlin,
Co. Antrim, UK BT29 4QY
E-mail: marketing@randox.com
The ROMA (Risk of Ovarian Malignacy) algorithm uses the CA-125 and HE4 blood markers to determine the likelihood that a pelvic mass is malignant. The test has been shown to aid gynaecologists in referring women to gynaecologic oncologists for surgery.
by Dr Zivjena Vucetic
Ovarian cancer is the leading cause of death from gynaecologic malignancies in the United States with annual incidence of 22,000 cases. Estimated annual mortality rate is approximately 15,460 cases [1]. Ovarian cancer has a good prognosis if detected in its early stages and if treated by specialised gynaecologic oncology surgeons [2], however more than three-quarters of cases are diagnosed in the advanced stage and are associated with poor survival rates of 10-30% [3]. These poor outcomes reflect the lack of effective tools for early detection of ovarian cancer and the limitations of current treatment options for ovarian cancer, which generally include cytoreductive surgery followed by adjuvant chemotherapy.
Recent studies have shown that women with ovarian cancer develop non-specific symptoms, including pelvic or abdominal pain, increased abdominal size, bloating, urinary urgency and difficulty eating or feeling full quickly, months before diagnosis [4]. However, ovarian cancer is commonly discovered on surgery for an adnexal mass. It is estimated that 5–10% of women at some point in their lives will undergo surgical evaluation of an adnexal mass and up to one fifth of surgically removed masses will have a diagnosis of ovarian cancer [5]. In premenopausal women, the risk of a mass being malignant is 7-13%, while in the postmenopausal women is 30-40% [6]. Thus, the presence of symptoms and the findings of an adnexal mass increase the risk of malignancy and should prompt thorough diagnostic evaluation.
The primary goals of diagnostic evaluation of women who present with adnexal masses are to confirm that adnexal mass is of ovarian origin and to differentiate whether it is benign or malignant. In order to determine the most appropriate management strategy that would ensure the optimal outcome for the woman with adnexal mass it is essential to effectively triage the risk for malignancy. Combination of multiple diagnostic modalities improves the physician’s ability to preoperatively assess women with adnexal mass. Diagnostic techniques that are commonly used are: clinical exam and thorough medical history, imaging (e.g. transvaginal ultrasound) and serum tumour maker (e.g. CA125) measurements. According to a study by the US Agency for Healthcare Research and Quality, which assessed diagnostic strategies for distinguishing benign from malignant masses, all current diagnostic modalities showed significant trade-offs between sensitivity and specificity [7]. Although the serum CA125 test does not have FDA-cleared indication as preoperative diagnostic aid in women with ovarian masses that are suspected to be malignant, CA125 is commonly used and recommended by the American Congress of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) for this indication [8,9]. The main clinical disadvantage of CA125 for adnexal mass assessment is its insufficient sensitivity for detecting early stage cancer and decreased specificity, due to false elevations in benign obstetric-gynaecologic conditions such as endometriosis, leiomyomas, pelvic inflammatory disease and pregnancy [10].
HE4 – ovarian cancer specific biomarker
HE4 (Human epididymis protein 4) is a member of a family of four disulphide core (WFDC) domain proteins and the function of this protein is unknown [11]. The HE4 gene is elevated in serum from women with ovarian cancer and its expression in normal tissues, including ovary, is low [12]. Several studies have indicated that using HE4 alone or in combination with CA125 may improve the accuracy for detection of ovarian cancer. In a study by Moore et al that evaluated nine known biomarkers for ovarian cancer, HE4 showed the highest sensitivity at a set specificity for the detection of ovarian cancer, particularly in early stage disease [13]. In this study, the combination of HE4 and CA 125 was a more accurate predictor of malignancy than either marker alone, with a sensitivity of 76% and a specificity of 95%. Additional studies confirmed that measuring serum HE4 concentrations along with CA 125 concentrations may provide higher accuracy for detecting ovarian cancer, and may improve the accuracy for detection of ovarian cancer at an earlier stage.
Additionally, a number of studies demonstrated improved specificity of HE4 for discriminating ovarian cancers from benign gynaecologic disease. Huhtinen et al was first to report that serum concentration of HE4 was significantly higher in patients with endometrial and ovarian cancer than in patients with ovarian endometriomas or other types of endometriosis [14]. These results were later confirmed in studies reported by Montagnana et al and Holcomb et al [15,16]. Recently, in a large study of 1042 pre- and postmenopausal women with benign gynaecological disorders HE4 was found to be less frequently elevated than CA125 in several benign diseases [17]. For example, HE4 was elevated in only 3% of premenopausal women with endometriosis, while in the same group CA125 was elevated in 72% of women. Unlike CA125, which can be elevated in one fourth of pregnant women and a third of patients with pelvic inflammatory diseases (PID), HE4 is not elevated in pregnancy and PID [16,18]. In addition, in healthy premenopausal women HE4 does not appear to oscillate during the menstrual cycle [19].
ROMA test: an aid in determining the likelihood of malignancy in women who
present with an adnexal mass
In September 2011, the ROMA test received clearance from the FDA as an aid in assessing whether a premenopausal or postmenopausal woman who presents with an adnexal mass is at high or low likelihood of having a malignancy. ROMA is a qualitative serum test that combines the results of two biomarkers, HE4 + CA 125, and menopausal status into a single score and is indicated for women who meet the following criteria: over age 18 and adnexal mass present for which surgery is planned.
The effectiveness of ROMA to aid in estimating the risk of malignancy was determined in a prospective, multi-centre, blinded clinical trial of 461 women over 18 years old (240 pre- and 221 post-menopausal) presenting with an adnexal mass that required surgical intervention [20]. For each patient, an initial cancer risk assessment (ICRA) was completed by a non-gynaecological oncologist, providing the generalist’s assessment of the patient’s mass as benign (negative) or malignant (positive) based upon the information available to the generalist during his/her work-up of the patient. The corresponding histopathology reports were collected and the stratification into low and a high risk groups for finding malignancy on surgery was determined using ROMA. The incidence of ovarian cancers was 10%. ROMA achieved 100% sensitivity at 74.5% specificity, a positive predictive value (PPV) of 13.8% and a negative predictive value (NPV) of 100% for stratification of premenopausal women with epithelial ovarian cancer into low likelihood and high likelihood groups of having malignancy. In postmenopausal women, ROMA had 92.3% sensitivity at 76.8% specificity, a PPV of 50.0% and NPV of 97.5% for stratification into low and high likelihood groups of having malignancy. When considering all women together ROMA had a sensitivity of 93.8%, a specificity of 74.9% and a NPV of 99.0%.
In a separate prospective, multicentre trial conducted at 12 US tertiary care institutions, 566 women undergoing surgery for adnexal mass were classified using ROMA into high and low likelihood groups for having epithelial ovarian cancer [21]. The incidence of ovarian cancers in this cohort was 23%. In the postmenopausal group at specificity of 75.0%, ROMA had sensitivity of 92.3%. In the premenopausal group at the specificity of 74.8% ROMA provided a sensitivity of 76.5% for classifying into high likelihood and low likelihood groups for having malignancy.
Additionally, seven distinct, single centre, multinational studies were published that validated the use of ROMA for adnexal mass risk stratification [22-28]. Combined, these studies assessed over 4,000 women with adnexal mass that were scheduled to undergo surgery in the United States, Europe and Asia. The range of sensitivity for ROMA test was from 75 % – 94%, at specificity from 75% – 95%. ROMA demonstrated consistent and reliable performance for classifying women with adnexal mass into high risk and low likelihood groups for epithelial ovarian cancer.
Conclusions
In the US, women with adnexal masses present primarily to gynaecologists, primary care physicians or general surgeons for initial diagnostic evaluation. According to a Practice Bulletin from the American Congress of Obstetrics and Gynecology (ACOG) an important dilemma is faced by these physicians as to which patients are appropriate for referral to a gynaecologic oncologist, and/or to an institution experienced in gynaecologic cancer surgery. Several recent studies have demonstrated that ovarian cancer patients managed by gyneacologic oncologists and at high volume institutions are more likely to undergo complete surgical staging, and optimal cytoreductive surgery with fewer complications and better survival rates than patients treated by surgeons less familiar with the management of ovarian cancer. Based on the available clinical evidence, ROMA test represents an important tool for improved triage of women diagnosed with an adnexal mass which can ultimately lead to improved patient outcomes.
References
1. Jemal A et al. CA Cancer J Clin 2010; 60(5): 277-300.
2. Giede KC et al. Gynecol Oncol 2005; 99(2):447-61.
3. 1999-2006 National Cancer Institute –Surveillance Epidemiology and End Results (NCI-SEER)
4. Goff BA et al. Cancer 2007; 109: 221-27.
5. Trimble EL. Gynecol Oncol 1994 ; 55(3 Pt 2): S1-3.
6. Danforth’s Obstetrics and Gynecology, ed. B.Y.K. Ronald S. Gibbs, Arthur F. Haney, Ingrid Nygaard. 2008: Lippincott Williams & Wilkins.
7. Myers ER et al. 2006; 130: 1-145.
8. ACOG Practice Bulletin. Obstet Gynecol. 2007; 110: 201-213.
9. The Society of Gynecologic Oncologists. Gynecol Oncol 2000; 78(3 Pt 2): S1-13
10. Jacobs I, Bast RC Jr. Hum Reprod 1989; 4(1): 1-12
11. Bouchard D et al. Lancet Oncol 2006; 7: 167-74.
12. Drapkin R et al. Cancer Res 2006; 65: 2162-69.
13. Moore RG et al. Gynecologic Oncol 2008; 108: 402-408.
14. Hutinen K et al. Br J Cancer 2009; 100: 1315-1319.
15. Montagnana M et al. Br J Cancer 2009; 101(3): 548.
16. Holcomb K et al. Am J Obstet Gynecol Am J Obstet Gynecol 2011; 205(4): 358.e1-6.
17. Moore RG et al. Am J Obstet Gynecol 2012; 206(4): 351.e1-8.
18. Moore RG et al. Am J Obstet Gynecol 2012; 206(4): 349.e1-7.
19. Hallamaa M et al. Gynecol Oncol 2012 Mar 14. [Epub ahead of print]
20. Moore RG et al. Obstet Gynecol 2011; 118(2, Part 1): 280-288.
21. Moore RG et al. Gynecol Oncol 2009; 112(1): 40-6.
22. Van Gorp T et al. Br J Cancer 2011; 104(5): 863-870.
23. Jacob F et al. Gynecol Oncol 2011; 121(3): 487-491.
24. Lenhard M et al. Clin Chem Lab Med 2011 Sep 16.
25. Molina R et al. Tumour Biol 2011; 32(6): 1087-95.
26. Montagnana M et al. Clin Chem Lab Med 2011; 49(3): 521-525.
27. Ruggeri G et al. Clin Chim Acta 2011; 412(15-16): 1447-1453.
28. Kim YM et al. Clin Chem Lab Med 2011; 49(3): 527-534.
The author
Zivjena Vucetic, PhD
Fujirebio Diagnostics, Inc.
Although significant progress has been made to improve blood safety and efficiency, laboratories still face workforce challenges, and the lack of global standards and better quality controls in blood management and haemovigilance pose a threat to patient safety. To help address these challenges, a symposium was hosted at the 2011 American Association of Blood Banks Annual Meeting with key opinion leaders from the transfusion medicine departments of the Cleveland Clinic, Children’s Hospital Los Angeles and USC Medical Center.
The attending experts broadly agreed that the key to safe, efficient blood management boils down to the ‘5Rs’: ensuring the Right patient gets the Right donor unit at the Right time, the Right way and for the Right reason. Presentations at the symposium discussed how the transfusion laboratory can deliver on the 5Rs through improvements in blood management and haemovigilance practices.
by Scott Saccal
Improving blood safety
Laboratories strive to protect patients’ health and deliver safe blood and blood components to the right person at the right time, but they are under constant pressure to do more with less – including fewer skilled laboratory technicians and scarcer financial resources. To help in meeting these demands, blood bank laboratories are increasingly employing automation. For example, many blood banks are standardising across instrument platforms and implementing testing technologies such as Column Agglutination (CAT). These testing methods are easier to use, and help reduce the opportunity for error and variation among both technologists and tests because they provide stable and clear endpoints that deliver accurate, objective and consistent results.
Automation helps minimise the labor-intensive, time-consuming manual tests that require specialised skills and significant experience to master, such as patient and unit typing, antibody screening and cross-matching. Automation also increases the capacity of technologists so they can focus on priorities such as time-sensitive emergency situations, difficult patient workups and quality-improvement processes. For example, computerised physician order entries have been found to reduce errors related to labour-intensive tasks by 50 percent, and all errors in general by 80 percent [1,2]. Ultimately, automated testing can increase a lab’s capacity, potentially allowing it to serve more patients while helping it operate more efficiently.
New approaches to load management and haemovigilance
Quality controls help ensure the safety of the patient at the end of the bloodline by helping to assure that from the moment a donation is made, the right blood and blood products are delivered to the right patient at the right time, and in the right way for the right reason. While great strides have been made to implement quality controls for the highest level of patient safety, there remains much work to be done.
Across the globe, a total of 106 countries have national guidelines on blood management, yet no universal safety standards exist. Further, broken system links and human errors due to distraction, fatigue and inattention account for approximately 70 percent of lab errors and cause catastrophic consequences such as the inappropriate administration of blood and/or adverse reactions [3]. Giving the wrong donor unit or giving an inappropriate transfusion can lead to serious complications, disease transmission and even fatal haemolytic reactions [4].
To combat the high incidence of laboratory errors, many hospitals and clinics are appointing Transfusion Safety Officers (TSO), to oversee work outside of the laboratory to improve patient safety during transfusions [5]. The increase in demand for blood and blood components suggests that additional measures will be needed to promote transfusion safety across departments, oversee institution-wide haemovigilance and error and accident reporting, provide education on transfusion reactions, implement guidelines, perform safety training and identify new technology for enhanced safety.
Additionally, hospitals and healthcare institutions around the world are developing ways to meet new standards – both by instituting their own rigorous policies, and by understanding and implementing the guidelines from organisations that oversee the safety of transfusions. The UK’s Serious Hazard of Transfusion programme and the U.S. Centers for Disease Control (CDC) National Healthcare Safety Network (NHSN) suggest voluntary reporting structures to create a reliable source of information for the medical and scientific community about blood transfusion issues, including warning facilities about adverse events that could be systemic.
Industry groups also are striving to improve patient care and safety while maximising healthcare system efficiencies. For example, AABB collaborates with the U.S. Department of Health and Human Services on biovigilance activities, including programmes directed at a variety of different domains such as donor haemovigilance and transfusion recipient haemovigilance. Through the collaboration, the organisations are gathering and analysing data to help find trends and establish best practices for safer, more efficient transfusions and transplants [6]. Similarly, the International Society of Blood Transfusion (ISBT) and the European Haemovigilance Network (EHN) began a working group in 2004 focused on creating a common set of definitions for issues in the field, which would enable global benchmarking and is intended ultimately to increase the safety of blood donors and recipients around the world [7].
Shared commitment to patient safety
Protecting the precious life of a patient who will receive a unit of blood remains the focus of blood bankers everywhere. As the pressures and demands rise, labs are finding new ways to be efficient and haemovigilant, while never losing sight of the real person at the end of the bloodline. Despite the continued shortage of highly skilled technologists and scientists entering the laboratory science workforce, blood bankers are utilising automation and best practices to improve transfusion testing, and implementing new approaches to blood management and haemovigilance to deliver on the 5Rs of blood safety. Protecting the safety of patients through efficient blood management and haemovigilance is a commitment all of us share as part of the transfusion medicine community.
References
1. Bates DW et al. Effect of computerized order entry and a team intervention on prevention of serious medication errors. Journal of the American Medical Association 1998; 280: 1211-1212
2. Bates DW et al. The impact of computerized order entry on medication error prevention. Journal of American Medical Informatics Association 1999; 6: 313-332.
3. Kaplan HS. Getting the right blood to the right patient: the contribution of near-miss event reporting and barrier analysis. Transfusion Clinique et Biologique 2005; 2: 380-384.
4. Shulman Ira A. ‘Assuring That The Right Patient Gets The Right Donor Unit, At The Right Time, The Right Way, And For The Right Reason.’ Slide 6. AABB annual meeting. San Diego, CA. Ortho Clinical Diagnostics Blood Management Symposium. October 24, 2011
5. Davey Richard J. ‘The Safety of the Blood Supply.’ Food and Drug Administration Division of Blood Applications webinar. Available at: http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM245738.pdf. Accessed October 20, 2011.
6. Biovigilance – AABB program — http://www.aabb.org/programs/biovigilance/Pages/default.aspx
7. Haemovigilance – ISBT — http://www.isbtweb.org/fileadmin/user_upload/WP_on_Haemovigilance/ISBT_StandardSurveillanceDOCO_2008__3_.pdf
The author
Scott Saccal
Worldwide Marketing Director
Transfusion Medicine
Ortho Clinical Diagnostics
November 2024
Beukenlaan 137
5616 VD Eindhoven
The Netherlands
+31 85064 55 82
info@clinlabint.com
PanGlobal Media is not responsible for any error or omission that might occur in the electronic display of product or company data.