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.
Biomarkers in the management of cardiorenal syndrome
, /in Featured Articles /by 3wmediaThe 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.
Helping elite athletes to give a peak performance
, /in Featured Articles /by 3wmediaAccording to applied physiologist Dr Brian Moore, and Dr Andrew Hodgson, Consultant Physician (Haematology) – co-founders of the Irish company ORRECO – one of the most difficult elements of competing in sport at a world class level is to balance training hard whilst ensuring adequate recovery. Dr Moore and his integrated team of high performance practitioners advised Olympic medalists and competitors at the last three Olympic games, and will do the same at the London Olympic games this year. CLi spoke to Dr Moore and his team to find out more about ORRECO’s mission and the methods it uses to help athletes reach peak performance without overtraining.
Q. Could you first tell us a little about your company. What inspired you to set up ORRECO and what did you hope to achieve? Briefly how does the company operate?
ORRECO was founded with the aim of joining the disciplines of clinical and sports haematology to deliver a unique proposition for world sport. We facilitate blood and saliva analysis for some of the world’s best athletes from an administrative base on Ireland’s western coast – the Innovation Centre at the Institute of Technology, Sligo.
Analysis occurs through a global network of partner laboratories that are located close to training (altitude, warm weather) and competition (World Cup, Championship, Olympic) venues. Results are reported in real time through our software solution DAVE (Download, Analyse, Validate and Export your results) to allow team physicians, coaches and performance staff to review information immediately and compare the results to an athlete’s performance. We cross-reference the results with training and competition data, (e.g. speed and power, GPS tracking) to understand the individual’s adaptation to training.
Recognising that testing and result reporting are just one part of the solution; we also provide a consultancy service for elite athletes and their teams. Our performance staff assists in interpretation and comparison of results against sports-specific reference ranges, as well as provides practical guidance and interventions where needed. This includes nutritional support, training-plan modification and more. Rather then rely on one specific biomarker, we use multiple assays that are aggregated by our bio-statisticians and map the athlete on a range from ‘well’ to ‘unwell’, and, from ‘peak performance’ to ‘over-reached’ or ‘over trained.’
Q. Tough training programmes are integral to sporting success, but what are the main problems that can occur if athletes over train?
We know that in the elite sport world, very small margins exist between defeat and victory. To succeed, an athlete must train extremely hard, and there are situations when a training programme requires an athlete, player or squad to be selectively overreached or overloaded for a short time period. With a subsequent, controlled reduction in training volume, a super-compensation occurs, allowing for a positive adaptation to the intense training dose and overall improved performance.
However, if athletes train too hard for too long in their pursuit of success, they will eventually fatigue and follow the performance continuum [Figure 1], which leads to injury and increased frequency of illness, such as upper-respiratory tract infections, immunosuppression, disturbed sleep patterns and depressed mood states. Biomarker analysis can help navigate the fine line required to balance adequate load with sufficient recovery.
Q. How did you establish which biomarkers were the most important for monitoring athletes in training and how do you carry out analysis of these biomarkers?
Our starting point is leveraging clinical markers that are routinely used for general health and wellness. In the context of training, we rely on biomarkers found in blood and saliva that are known signs of a normal process (e.g. adaptation), abnormal process (e.g. maladaptation), a particular condition (e.g. under performance syndrome) or disease (e.g. infection).
Biomarkers may be used to see how well the body responds to an intervention/process (e.g. training modification), a treatment (e.g. recovery solution) or a stress inducer (e.g. game, match). Our specialist team includes former speed and power coach to the New Zealand ‘All Blacks’ and Americas Cup sailing team, Dr Christian Cook; the first team physiologist to Real Madrid, Dr Carlos Gonzalez-Haro; the former Director of the Australian Institute of Sport Haematology Lab, Robin Parisotto; and Clinical and Performance Nutritionist to the British Olympic Team, Nathan Lewis (MSc). We have significant collective experience of applying, analysing and interpreting biomarkers across a range of elite sports at the very highest level of world competition. We facilitate analysis of markers that have been applied and validated in the world of elite sport. Our combined experience of working with thousands of elite athletes and monitoring them at key times during the season means we can discern trends that are consistent with either peak, or, at times, underperformance. We are especially interested in athletes’ cell counts, inflammatory markers, trace metal status, immunoglobulins and hormonal profiles.
Q. Are you satisfied with the methods and equipment used?
We are constantly looking for improvement and searching for markers that can give us objective information about an athlete’s response capabilities and/or status. For example, we utilise the routine parameters, including the differential WBC, haemoglobin and reticulocyte counts, available on the Siemens Healthcare Diagnostics ADVIA 2120 Haematology System, to give us rapid insights into an athlete’s health and wellness. We also rely on additional parameters available on this platform, such as the cellular haemoglobin of the reticulocyte (CHr) and the percentage hypochromasia of both the reticulocytes and mature red cells (%hypor and %hypom). These parameters are also routinely utilised in renal medicine to deliver specific information about the quality of erythropoiesis.
Historically, we would have used ferritin to assess the iron stores, but given the acute phase response of the parameter, we interpret the result in concert with the white cell counts and creatine kinase (CK), as we know the parameter is elevated in infection and inflammation. This information is especially important when an athlete is undertaking altitude or endurance training, as we can ensure enough iron is being made available to the developing red cells and they benefit from all their hard work. We can also pick up a functional or pre-latent iron deficiency before it impacts upon performance and track the responses to prescribed iron supplementation. Thus, in addition to looking for new techniques, we also seek to apply established principles in new ways.
Q. How do you see the future for sports medicine in general and ORRECO in particular?
As explained by our colleague, Dr Bruce Hamilton, sports medicine is no longer focused on just treating injury and illness in athletes. Increasingly, early recognition and prevention of injury and illness is the goal. Particularly when working with elite athletes, being able to identify athletes at risk of developing problems is a constant challenge, and vast amounts or research and resources are being directed at this task. Despite this, we are only just beginning to understand the risk factors behind even common injuries (e.g. hamstring muscle strains) and techniques that may be used to prevent them. Similarly, while illness and fatigue have been recognised as significant limitations to elite athletic performance for many years, to date, the understanding of risk factors and the ability to identify athletes at risk has been limited by both our knowledge base and our technical ability. The goal of tools, such as those developed by ORRECO, are to facilitate the identification and prevention of illness in highly tuned athletes, thereby allowing them to compete to the best of their ability. This is consistent with the aspirations of modern sports medicine around the world.
By integrating sports haematology and biochemistry with knowledge and expertise in clinical and performance nutrition, applied physiology, speed and power physiology, biostatistics and cellular nutrition across our team, whole avenues of possibility open up to performance science in general. ORRECO aims to provide a global resource for real-time sports haematology and biochemistry results for athletes training and competing around the world.
For more information go to www.orreco.com. An introductory video can be seen at http://vimeo.com/41485500.
Siemens Healthcare Diagnostics
Book Review
, /in Featured Articles /by 3wmediaParasitology: An Integrated Approach
Ed. by Alan Gunn and Sarah Jane Pitt, Pub. by Wiley-Blackwell 2012, 456 pp, €41.80
www.wiley.co.ukThis book provides a concise, student-friendly account of parasites and parasite relationships that is supported by case studies and suggestions for student projects. The book focuses strongly on parasite interactions with other pathogens and in particular parasite-HIV interactions, as well as looking at how host behaviour contributes to the spread of infections. There is a consideration of the positive aspects of parasite infections, how humans have used parasites for their own advantage and also how parasite infections affect the welfare of captive and domestic animals. The emphasis of the book is on recent research throughout and each chapter ends with a brief discussion of future developments. This text is not simply an updated version of typical parastitology books but takes an integrated approach and explains how the study of parasites requires an understanding of a wide range of other topics from molecular biology and immunology to the interactions of parasites with both their hosts and other pathogens
Clouds in the lab
, /in Featured Articles /by 3wmediaLike much in healthcare IT, the development of Laboratory Information Management Systems (LIMS) has been an uneven mix of technology-push and user-pull, coupled with regulatory efforts at streamlining the two. Today, the new vista of cloud computing is rapidly opening up new LIMS opportunities, especially for smaller labs.
The demand for LIMS began in the late 1970s after the proliferation of electronic lab equipment and an explosion in data. The then-emerging technology of ‘minicomputers’ offered LIMS the first realistic alternative to expensive/inaccessible mainframes. Minicomputers, however, were only a brief interlude in computing technology, before the advent of personal computers. Most minicomputer vendors (e.g Data General, Wang, Norsk Data etc.) have since disappeared. By the late 1980s, personal computers enabled LIMS users to leverage relational databases. The arrival of client/server architecture and the Internet in the 1990s expanded the reach of LIMS outside laboratories, providing novelties such as 24×7 analysis from offshore locations. The past decade has expanded the footprint of LIMS further via Wi-Fi, mobile access and standards like XML.
However, much of this has been a mixed blessing. As the LIMS community proliferated, so too did concerns about data security and systems complexity. Competition among LIMS vendors led to a blizzard of new features, ranging from those required to comply with regulations, to a swathe of pureplay ‘business’ applications such as inventory and personnel management, workflow sequencing etc. The result: an escalation in user expectations, and in entry-level costs.
In spite of the recent centralisation of healthcare, most labs are still relatively small. In the US, the largest 50 account for one-third of the industry’s total revenues of about 40 billion dollars; over 7,500 labs share the rest. With commercial LIMS systems beyond their budgets, several labs have sought to develop their own, but almost always ended up with huge cost-overruns, and performance problems. One reason lies in the very essence of information technology, namely the steady fall in unit costs of processing power, with savings harnessed by commercial vendors to bundle additional features. The second reason: any mission-critical IT system needs to handle peak load requirements, often several multiples of the median; healthcare is no exception.
Cloud computing technology may answer both the above challenges, and LIMS seems an especially promising area. At its most basic, cloud computing is akin to an electricity grid, pooling computing horsepower across locations to enable scale-up on demand; the parallel is particularly close in terms of load balancing – the ability to adjust database, server and networking capacity to fluctuating demand.
In May 2010, a headline feature by the American Chemical Society titled ‘LIMS in the Cloud’ emphasised how cloud computing was opening up LIMS to small labs, which had ‘not been particularly well served’ by vendors. Indeed, cloud-based LIMS pioneers such as LabLynx have acquired over 1,000 customers in less than two years of launch. The recent entry of IT giants such as Microsoft, Oracle and Google into cloud computing promises to galvanise the industry further, with LIMS applications likely to remain at the forefront.
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, /in Featured Articles /by 3wmediaThe fight against blood doping in sport
, /in Featured Articles /by 3wmediaBlood doping benefits endurance athletes (notoriously, but not only, cyclists) by raising the red blood cell (rbc) count or haematocrit, and so increasing the oxygen supply to the muscles. It is one of the most difficult types of drug abuse to detect. Awareness of blood doping was raised in the popular press recently when comments were made about the impressive nature of China’s Ye Shiwen’s Olympic gold medal wins and with Lance Armstrong’s (cycling’s famous winner of seven Tours de France after surviving advanced testicular cancer) sudden decision to drop his fight against the US Anti-Doping Agency’s drug charges. Hematocrit levels can be raised by a variety of methods ranging from legal altitude training, to the banned use of autologous blood transfusions and erythropoietin (EPO) injections.
Detection of these banned methods is extremely difficult and the fight against them is being waged in a number of ways. The UCI’s (cycling’s governing body) lines of defence include simply demonstrating possession of banned substances and monitoring hematocrit levels, with a limit set at 50% (normal being 41–50% for men).
Some early success was had with testing urine to distinguish pharmaceutical EPO from the nearly identical natural hormone by isolectric focusing, though its accuracy has been questioned with claims that it is not possible to distinguish pharmaceutical EPO from other unrelated proteins that are present in urine after strenuous exercise or as the result of sample degradation and bacterial contamination.
At present, tests that provide indirect evidence of autologous blood transfusion (where the athlete withdraws and then re-injects his own blood) are under development and involve looking at the ratio of immature to mature red blood cells and might also include the measurement of 2,3-bisphophoglycerate (2,3-BPG). As 2,3-BPG degrades over time, stored blood used for autologous transfusions would have less than fresh blood and so levels of 2,3-BPG lower than normal may then indicate blood doping by this method. The presence of plasticizers in the blood (from the IV bags in which blood is stored) has also been used as evidence of blood doping.
While these advances in the detection of blood doping are being made it is tempting to think that we have got there, that the cheats will be caught. However, in the high-stakes world of elite athletes this would be a naive hope: the possibility of athletes subjecting themselves to EPO gene therapy – so called gene doping – has been suggested and methods for the detection of transgenic DNA following in vivo gene transfer are already being developed.
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