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Creatinine eGFR and all that, an update
PATHOLOGY UPDATE 2010 ABSTRACTS
Tamoxifen and its main active metabolite endoxifen are selective oestrogen-receptor modulators used in the treatment of breast cancer. Endoxifen is generated by CYP2D6 action on tamoxifen. Recently, interest has focussed on the influence of reduced CYP2D6 enzyme activity on tamoxifen efficiency in breast cancer treatment. Study data suggest that carriers of CYP2D6 poor metaboliser alleles benefit less from tamoxifen therapy.1 Reduced concentrations of tamoxifen and endoxifen have been demonstrated in this setting. It has, however, not been demonstrated that drug levels are relevant for treatment outcome. This must not necessarily be the case since tamoxifen shows receptor targeting even without metabolic activation eventually leading to sufficient receptor blockade even at lower concentrations. Prospective study data are missing and published studies show some bias.2 Aromataseinhibitors, the current standard of treatment in postmenopausal women, are not subject to CYP2D6 metabolism. Switch protocols involving tamoxifen may be less beneficial for CYP2D6 poor metabolisers. At present, patients should be informed about possible implications of their CYP2D6 status. Optimised choices can then still be made within approved regimens. References 1. von Ahsen N, et al. J Lab Med 2009, DOI: 10.1515/JLM.2009.048et. 2. Lash, Lien EA, Sørensen HT, et al. Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol 2009; 10: 825–33.
NEW AND BETTER BIOMARKERS OF ACUTE KIDNEY INJURY John W. Pickering, Zolta´n H. Endre Christchurch Kidney Research Group, Department of Medicine, University of Otago, Christchurch, New Zealand Acute kidney injury (AKI) affects 50% of critically ill patients and has a high mortality rate. Diagnosis with plasma creatinine leads to 48–72 hour delays in treatments. Future treatment modalities may follow the paradigm of early intervention following triage with an injury biomarker or biomarker panel.1 We compared six potential urinary biomarker candidates for early detection of AKI measured on entry to an intensive care unit in 528 patients: gammaglutamyl transpeptidase (GGT), alkaline phosphatase (AP), cystatin C (CysC), neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18). The composite biomarker (GGTxAP) was used to triage a higher at risk group to a randomised control trial of erythropoietin within 6.3 + 4.2 hours of admission. The prognostic performance of GGTxAP in predicting AKI (in patients not treated with EPO and without AKI on admission) depended on the time from insult to first sample. The maximum area under the receiver operator characteristic curve (AUC) was at 6–12 hours post-insult, AUC ¼ 0.69 (95%CI 0.55–0.82). The prognostic performance of the other biomarkers depended similarly on timing in relation to injury. Reference 1. Pickering JW, Endre ZH. Secondary prevention of acute kidney injury. Curr Op Crit Care 2009; 15: 488–97.
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ROLE OF 25 HYDROXYVITAMIN D AND PTH IN CHRONIC RENAL FAILURE: NEW TARGETS AND NEW THERAPIES Paul Glendenning Endocrinologist and consultant Chemical Pathologist, Royal Perth Hospital, and Clinical Associate Professor, Schools of Medicine, Pharmacology, Pathology and Laboratory Medicine, University of Western Australia, Australia Suboptimal levels of 25 hydroxyvitamin D (25OHD) are common in haemodialysis patients (CKD-5D) and may be associated with reduced muscle strength, increased falls risk and fractures. Reasons for suboptimal 25OHD in CKD-5D will be explored in this presentation and the association between 25OHD, 1,25 dihdroxyvitamin D, PTH and renal function will be examined. The increased risk of hip fracture in dialysis patients will be demonstrated and data exploring the hypothesis that 25OHD levels may be independently associated with falls risk in CKD-5D will be examined. Whilst supplementation with calcium and cholecalciferol reduces hip and other non-vertebral fractures in elderly individuals, in part attributable to reduction in falls, the relationship between 25OHD and falls risk has not been investigated in CKD-5D in the past. Consequently, in addition to the traditional endocrine role for vitamin D, that requires renal conversion of 1,25 (OH)2D, circulating levels of 25OHD may play a more important and direct auto/paracrine role in muscle metabolism, both in people with normal renal function and those on dialysis.
CREATININE eGFR AND ALL THAT, AN UPDATE Graham Jones Department of Chemical Pathology, SydPath, St Vincent’s Hospital, Sydney, NSW, Australia The introduction of routine reporting of eGFR is now part of the health landscape in Australia and many countries worldwide. There are well known limitations to this process and it is appropriate to keep working to address these issues. Some areas of new activity include the development of a new formula, the CKD-EPI formula; consideration of common reference intervals for serum creatinine; estimation of GFR for drug monitoring purposes and racial effects. To date there has also been little co-ordinated progress for the paediatric population with regard to creatinine measurement, reference intervals and GFR estimation. The joint working party of the Royal College of Pathologists of Australasia, the Australasian Association of Clinical Biochemists (AACB) and Kidney Health Australia plans to address these issues during 2010.
A METABOLOMIC APPROACH TO LIPIDOPATHIES Peter J. Meikle Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Metabolomics is the systematic quantification and characterisation of the complement of small molecules
Tamoxifen and its main active metabolite endoxifen are selective oestrogen-receptor modulators used in the treatment of breast cancer. Endoxifen is generated by CYP2D6 action on tamoxifen. Recently, interest has focussed on the influence of reduced CYP2D6 enzyme activity on tamoxifen efficiency in breast cancer treatment. Study data suggest that carriers of CYP2D6 poor metaboliser alleles benefit less from tamoxifen therapy.1 Reduced concentrations of tamoxifen and endoxifen have been demonstrated in this setting. It has, however, not been demonstrated that drug levels are relevant for treatment outcome. This must not necessarily be the case since tamoxifen shows receptor targeting even without metabolic activation eventually leading to sufficient receptor blockade even at lower concentrations. Prospective study data are missing and published studies show some bias.2 Aromataseinhibitors, the current standard of treatment in postmenopausal women, are not subject to CYP2D6 metabolism. Switch protocols involving tamoxifen may be less beneficial for CYP2D6 poor metabolisers. At present, patients should be informed about possible implications of their CYP2D6 status. Optimised choices can then still be made within approved regimens. References 1. von Ahsen N, et al. J Lab Med 2009, DOI: 10.1515/JLM.2009.048et. 2. Lash, Lien EA, Sørensen HT, et al. Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol 2009; 10: 825–33.
NEW AND BETTER BIOMARKERS OF ACUTE KIDNEY INJURY John W. Pickering, Zolta´n H. Endre Christchurch Kidney Research Group, Department of Medicine, University of Otago, Christchurch, New Zealand Acute kidney injury (AKI) affects 50% of critically ill patients and has a high mortality rate. Diagnosis with plasma creatinine leads to 48–72 hour delays in treatments. Future treatment modalities may follow the paradigm of early intervention following triage with an injury biomarker or biomarker panel.1 We compared six potential urinary biomarker candidates for early detection of AKI measured on entry to an intensive care unit in 528 patients: gammaglutamyl transpeptidase (GGT), alkaline phosphatase (AP), cystatin C (CysC), neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18). The composite biomarker (GGTxAP) was used to triage a higher at risk group to a randomised control trial of erythropoietin within 6.3 + 4.2 hours of admission. The prognostic performance of GGTxAP in predicting AKI (in patients not treated with EPO and without AKI on admission) depended on the time from insult to first sample. The maximum area under the receiver operator characteristic curve (AUC) was at 6–12 hours post-insult, AUC ¼ 0.69 (95%CI 0.55–0.82). The prognostic performance of the other biomarkers depended similarly on timing in relation to injury. Reference 1. Pickering JW, Endre ZH. Secondary prevention of acute kidney injury. Curr Op Crit Care 2009; 15: 488–97.
S21
ROLE OF 25 HYDROXYVITAMIN D AND PTH IN CHRONIC RENAL FAILURE: NEW TARGETS AND NEW THERAPIES Paul Glendenning Endocrinologist and consultant Chemical Pathologist, Royal Perth Hospital, and Clinical Associate Professor, Schools of Medicine, Pharmacology, Pathology and Laboratory Medicine, University of Western Australia, Australia Suboptimal levels of 25 hydroxyvitamin D (25OHD) are common in haemodialysis patients (CKD-5D) and may be associated with reduced muscle strength, increased falls risk and fractures. Reasons for suboptimal 25OHD in CKD-5D will be explored in this presentation and the association between 25OHD, 1,25 dihdroxyvitamin D, PTH and renal function will be examined. The increased risk of hip fracture in dialysis patients will be demonstrated and data exploring the hypothesis that 25OHD levels may be independently associated with falls risk in CKD-5D will be examined. Whilst supplementation with calcium and cholecalciferol reduces hip and other non-vertebral fractures in elderly individuals, in part attributable to reduction in falls, the relationship between 25OHD and falls risk has not been investigated in CKD-5D in the past. Consequently, in addition to the traditional endocrine role for vitamin D, that requires renal conversion of 1,25 (OH)2D, circulating levels of 25OHD may play a more important and direct auto/paracrine role in muscle metabolism, both in people with normal renal function and those on dialysis.
CREATININE eGFR AND ALL THAT, AN UPDATE Graham Jones Department of Chemical Pathology, SydPath, St Vincent’s Hospital, Sydney, NSW, Australia The introduction of routine reporting of eGFR is now part of the health landscape in Australia and many countries worldwide. There are well known limitations to this process and it is appropriate to keep working to address these issues. Some areas of new activity include the development of a new formula, the CKD-EPI formula; consideration of common reference intervals for serum creatinine; estimation of GFR for drug monitoring purposes and racial effects. To date there has also been little co-ordinated progress for the paediatric population with regard to creatinine measurement, reference intervals and GFR estimation. The joint working party of the Royal College of Pathologists of Australasia, the Australasian Association of Clinical Biochemists (AACB) and Kidney Health Australia plans to address these issues during 2010.
A METABOLOMIC APPROACH TO LIPIDOPATHIES Peter J. Meikle Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Metabolomics is the systematic quantification and characterisation of the complement of small molecules