Papers by Andrew Lewington
Background
Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leadi... more Background
Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption.
Objectives
To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy.
Data sources
We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE, metaRegister of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report.
Review methods
The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis.
Results
The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck® (Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care.
Limitations
The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing.
Conclusions
Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, 2000
De novo CD44 and ligand expression at wound margins accompanies cellular proliferation and migrat... more De novo CD44 and ligand expression at wound margins accompanies cellular proliferation and migration that effect repair of injured mucosal and vascular endothelial tissues. To determine whether CD44 could play a role in recovery from acute ischemic renal injury, we characterized its renal expression and those of two of its ligands, hyaluronic acid and osteopontin. Although no expression is detectable in nonischemic kidneys, several mRNAs for CD44 are present within 1 day after injury. CD44 mRNA is expressed in proximal tubules undergoing repair. CD44 peptide is present in basal and lateral cell membranes. Hyaluronic acid is normally expressed in the interstitium of the renal papilla only. By 1 day postischemia, hyaluronic acid can be detected, in addition, in the interstitium surrounding regenerating tubules. Osteopontin, not normally expressed in the renal proximal tubule, is expressed in regenerating tubules by 3 days after induction of acute ischemic injury. Immunoreactive osteopontin peptide continues to be localized in those tubules still undergoing repair for as long as 7 days after the injury. Our data are consistent with a role for CD44-ligand interactions in the regenerating proximal tubule participating in the process of recovery after ischemic injury.
American Journal of Physiology Regulatory Integrative and Comparative Physiology, Nov 1, 2000
Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and i... more Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and increased intestinal permeability. A consequence of oxidative damage is the accumulation of DNA strand breaks and activation of poly(ADP-ribose) polymerase (PARP), which subsequently catalyzes ADP-ribosylation of target proteins. In this study, we assessed the role of PARP in the colitis seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mice demonstrated significant alterations in colonic cellular energy status in conjunction with increased permeability, proinflammatory cytokine release, and nitrosative stress. After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-alpha and interferon-gamma secretion, inducible nitric oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. Time course studies demonstrated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization of colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity results in a marked improvement of colonic inflammatory disease and a normalization of cellular metabolic function and intestinal permeability.
J Vasc Interven Radiol, 2010
Vascular problems, such as renal artery stenosis or renal vein thrombosis, are well recognized co... more Vascular problems, such as renal artery stenosis or renal vein thrombosis, are well recognized complications following renal transplantation. Interventional radiologic techniques are often used as diagnostic tools and as therapeutic options to prevent graft dysfunction (1). Renal vein stenosis is a rare vascular complication following renal transplantation. It usually occurs in the early postoperative stages, often as a consequence of malpositioning of the vein or extrinsic compression (2). Occasionally, renal vein stenosis may be pre-existing in the donor and remain unrecognized until after transplantation. Herein, we report two cases of early renal vein stenosis in the transplanted kidney that were successfully managed by using metallic self-expanding vascular stents. The institutional review board at our institution does not require approval for this type of project.
The Journal of thoracic and cardiovascular surgery, Jan 12, 2016
Acute kidney injury (AKI), defined as a rise in serum creatinine (functional AKI), is a frequent ... more Acute kidney injury (AKI), defined as a rise in serum creatinine (functional AKI), is a frequent complication after cardiac surgery. The expression pattern of acute tubular damage biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) has been shown to precede functional AKI and, therefore, may be useful to identify very early tubular damage. The term subclinical AKI represents acute tubular damage in the absence of functional AKI (biomarker positivity without a rise in serum creatinine) and affects hard outcome measures. This potentiates an tubular-damage-based identification of renal injury, which may guide clinical management, allowing for very early preventive-protective strategies. The aim of this paper was to review the current available evidence on NGAL applicability in adult cardiac surgery patients and combine this knowledge with the expert consensus of the authors to generate an NGAL based tubular damage score: The cardiac surgery-associated NGAL Score (CSA-N...
Transplantation, Jan 27, 2010
Late-onset proteinuria after renal transplantation has been universally associated with poor allo... more Late-onset proteinuria after renal transplantation has been universally associated with poor allograft outcomes. However, the significance of early low-grade posttransplant proteinuria remains uncertain. We analyzed the effect of proteinuria 3 months posttransplantation on death-censored graft loss, death with a functioning graft, vascular events within the graft's life, and estimated glomerular filtration rate at 5 years. Four hundred seventy-seven renal transplants from a single center (1988-2003) with a mean follow-up of 122 months were divided into four groups based on the median protein creatinine ratio (PCR) during the 3rd posttransplant month (PCR<0.15 [group 1, n=85]; PCR 0.15-0.5 [group 2, n=245]; PCR 0.5-1.00 [group 3, n=96]; PCR>1.00 [group 4, n=51]). Cox proportional hazards analysis was performed to study the impact of proteinuria on the various outcomes. Multivariate analysis revealed that even low-level proteinuria at 3 months predicted death-censored graft failure (group 1 [reference]--hazard ratio [HR]=1, group 2--HR=7.1, group 3--HR = 10.5, group 4--HR 16.0; P=0.001). The impact on death and the occurrence of vascular events was only significant for group 4 (HR: 2.6; P=0.01 for death and HR: 2.2; P=0.04 for vascular events). Estimated glomerular filtration rate at 5 years was group 1, 48.5 mL/min; group 2, 41.2 mL/min; group 3, 31.1 mL/min; and group 4, 24.5 mL/min (P<0.001). Continued observation of group 2 to 1 year revealed adverse outcomes with increasing proteinuria. Low-grade proteinuria at 3 months is associated with adverse clinical outcomes and identifies high-risk group of patients who may benefit from further intervention.
Journal of the Intensive Care Society, 2009
After a decision had been made among representatives of the contributing specialist societies to ... more After a decision had been made among representatives of the contributing specialist societies to develop this consensus, funding was required to cover reasonable travel expenses and working meals to enable the committee to meet in London venues, and to provide coffee, lunch and tea at the consensus meeting held at the Wingate Institute, Barts and the London School of Medicine. Costs have been kept to the minimum by the exclusive use of electronic communication. We are grateful to B Braun and Fresenius Kabi for their financial support in covering our expenses. We have been appreciative of the way both companies, throughout the process of its development, avoided attempting to influence the contents of the report,.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2015
Low-grade proteinuria and systolic hypertension (SHT) are risk factors for allograft failure. Bot... more Low-grade proteinuria and systolic hypertension (SHT) are risk factors for allograft failure. Both are dynamic variables and their relationship is not independent. We have simultaneously analyzed the effects of proteinuria and SHT on graft outcomes in 805 adult Kidney Transplant Recipients and impact of their changes over time. Proteinuria and systolic blood pressure (SBP) were recorded for years 1 and 3 posttransplantation. Subjects with proteinuria >1 g/day were excluded. Patients were divided into groups based on proteinuria (Absent(A) <150 mg/day or low-grade(P)150 mg-1 g/day) and blood pressure (Normotensive-SBP <140 mmHg or hypertensive-SBP ≥ 140 mmHg). Graft survival was assessed in all four groups over 10 years by multivariate analysis. At the three annual time points (Year 1, 2 and 3) hypertensive patients with proteinuria had the worst graft survival. Patients with persistent proteinuria between years 1-2 and 2-3 had the poorest graft survival with an improvement ...
British journal of hospital medicine (London, England : 2005), 2011
Nature reviews. Nephrology, 2009
Proteomics-based approaches are generating considerable data in clinical nephrology covering almo... more Proteomics-based approaches are generating considerable data in clinical nephrology covering almost all aspects of the discipline. Proteomic experiments commonly involve fractionation and protein separation, followed by mass spectrometric analysis to identify proteins and peptides. Biostatistical and bioinformatical input is essential in such experiments, from initial experimental design to analysis of data. Standardization of procedures is an important research objective. Depending on study design, results can lead to biomarker discovery, mechanistic insight and identification of potential avenues for therapeutic intervention and treatment evaluation. Understanding proteomic information and its place in current clinical research and practice is fundamental. This Review describes proteomic experimentation and the concepts behind it, and gives an overview of its application to important areas in clinical nephrology including acute kidney injury, chronic kidney disease, end-stage rena...
Transplantation, 2010
Late-onset proteinuria after renal transplantation has been universally associated with poor allo... more Late-onset proteinuria after renal transplantation has been universally associated with poor allograft outcomes. However, the significance of early low-grade posttransplant proteinuria remains uncertain. We analyzed the effect of proteinuria 3 months posttransplantation on death-censored graft loss, death with a functioning graft, vascular events within the graft&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s life, and estimated glomerular filtration rate at 5 years. Four hundred seventy-seven renal transplants from a single center (1988-2003) with a mean follow-up of 122 months were divided into four groups based on the median protein creatinine ratio (PCR) during the 3rd posttransplant month (PCR&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.15 [group 1, n=85]; PCR 0.15-0.5 [group 2, n=245]; PCR 0.5-1.00 [group 3, n=96]; PCR&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1.00 [group 4, n=51]). Cox proportional hazards analysis was performed to study the impact of proteinuria on the various outcomes. Multivariate analysis revealed that even low-level proteinuria at 3 months predicted death-censored graft failure (group 1 [reference]--hazard ratio [HR]=1, group 2--HR=7.1, group 3--HR = 10.5, group 4--HR 16.0; P=0.001). The impact on death and the occurrence of vascular events was only significant for group 4 (HR: 2.6; P=0.01 for death and HR: 2.2; P=0.04 for vascular events). Estimated glomerular filtration rate at 5 years was group 1, 48.5 mL/min; group 2, 41.2 mL/min; group 3, 31.1 mL/min; and group 4, 24.5 mL/min (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Continued observation of group 2 to 1 year revealed adverse outcomes with increasing proteinuria. Low-grade proteinuria at 3 months is associated with adverse clinical outcomes and identifies high-risk group of patients who may benefit from further intervention.
Transplantation, 2008
Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and ca... more Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.
Nephrology Dialysis Transplantation, 2001
Nephrology Dialysis Transplantation, 2014
Nephrology Dialysis Transplantation, 2012
Kidney International, 1998
Studies identifying genes that are differentially expressed following induction of acute ischemic... more Studies identifying genes that are differentially expressed following induction of acute ischemic injury have been useful in delineating the pathophysiology of acute renal failure. A differential cDNA library screening technique was used to identify genes that are differentially expressed in rat kidney following induction of acute ischemic renal injury. Levels of mRNA with a high homology to that coding for Siva, a human proapoptotic protein, were increased approximately 4.5-fold in kidneys obtained from rats within 12 hours following ischemia, compared to kidneys from sham-operated rats. A partial cDNA sequence for the rat protein (rat Siva) was determined that overlaps 92% of the human open reading frame. The cDNA sequence predicts a protein 177 amino acids in length with 76% homology to human Siva. Levels of rat Siva in kidneys were elevated at one, five and seven days post-ischemia were not different from those in kidneys from sham-operated controls. In situ hybridization demonstrated that rat Siva mRNA was expressed in cells lining damaged sections in the S3 segment of the proximal tubule at 12 hours and one day post-ischemia. At five and seven days, Siva mRNA was located in epithelial cells of regenerating tubules including in papillary proliferations. TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells colocalized with cells containing Siva mRNA. CD27, the receptor for Siva was localized by immunohistochemistry to sloughed cells in the lumens of damaged S3 segments at 12 hours post-ischemia and to cells within papillary proliferations at five days post-injury. Siva that is produced within the kidney could be a mediator of apoptosis post-ischemia via an interaction with CD27.
Kidney International, 2004
Background. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcriptio... more Background. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with multiple effects on target cell function. PPARc activity is regulated by extracellular signal-regulated protein kinase (ERK), mitogenactivated protein (MAP) kinase, and PPARc ligands have varying effects on activity of ERK. Different PPARc ligands have been shown to have both protective and detrimental effects in the kidney. Since transcriptional activation by different PPAR agonists is ligand-and depot-specific PPARc, we have examined the effects of different agonists on PPAR activity in the proximal tubule.
Journal of Vascular and Interventional Radiology, 2010
Vascular problems, such as renal artery stenosis or renal vein thrombosis, are well recognized co... more Vascular problems, such as renal artery stenosis or renal vein thrombosis, are well recognized complications following renal transplantation. Interventional radiologic techniques are often used as diagnostic tools and as therapeutic options to prevent graft dysfunction (1). Renal vein stenosis is a rare vascular complication following renal transplantation. It usually occurs in the early postoperative stages, often as a consequence of malpositioning of the vein or extrinsic compression (2). Occasionally, renal vein stenosis may be pre-existing in the donor and remain unrecognized until after transplantation. Herein, we report two cases of early renal vein stenosis in the transplanted kidney that were successfully managed by using metallic self-expanding vascular stents. The institutional review board at our institution does not require approval for this type of project.
Journal of the American Society of Nephrology, 2003
In nephrotic syndrome, large quantities of albumin enter the kidney tubule. This albumin carries ... more In nephrotic syndrome, large quantities of albumin enter the kidney tubule. This albumin carries with it a heavy load of fatty acids to which the proximal tubule cells are exposed at high concentration. It is postulated that exposure to fatty acids in this way is injurious to proximal tubule cells. This study has examined the ability of fatty acids to interact with peroxisome proliferator-activated receptors (PPAR) in primary cultures of human proximal tubule cells. Luciferase reporter assays in transiently transfected human proximal tubule cells were used to show that albumin bound fatty acids and other agonists activate PPAR␥ in a dose-dependent manner. One of the consequences of this activation is apoptosis of the cells as determined by changes in cell morphology, evidence of PARP cleavage, and appearance of DNA laddering. Overexpression of PPAR␥ in these cells also results in enhanced apoptosis. Both fatty acid-induced PPAR activation and apoptosis in these cells can be blocked by PPAR response element decoy oligonucleotides. Activation of PPAR␥ by the specific agonist PGJ 2 is associated with inhibition of cell proliferation, whereas activation by albumin bound fatty acids is accompanied by increased proliferation. However, the net balance of apoptosis/proliferation favors deletion of cells. These results implicate albumin-bound fatty acids as important mediators of tubular injury in nephrosis and provide fresh impetus for pursuit of lipid-lowering strategies in proteinuric renal disease.
Hemodialysis International, 2009
Use of depopulated bovine ureteric xenografts for hemodialysis vascular access has recently been ... more Use of depopulated bovine ureteric xenografts for hemodialysis vascular access has recently been described. Cellular components have been removed, giving a connective tissue matrix which can be neocellularized, retaining native biomechanics. A 24-year-old male with end-stage renal disease from focal segmental glomerulosclerosis presented with particularly difficult vascular access. A depopulated bovine ureteric xenograft was implanted from the left subclavian artery to innominate vein. It became massively aneurysmal, requiring emergency embolization. Biopsy of the graft stained positive for a-gal. We believe this is the first reported case of massive aneurysmal dilatation of a depopulated bovine ureteric xenograft.
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Papers by Andrew Lewington
Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption.
Objectives
To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy.
Data sources
We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE, metaRegister of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report.
Review methods
The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis.
Results
The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck® (Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care.
Limitations
The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing.
Conclusions
Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value.
Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption.
Objectives
To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy.
Data sources
We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE, metaRegister of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report.
Review methods
The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis.
Results
The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck® (Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care.
Limitations
The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing.
Conclusions
Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value.