Publications by authors named "Karen L Price"

36 Publications

Free 25-hydroxyvitamin-D concentrations are lower in children with renal transplant compared with chronic kidney disease.

Pediatr Nephrol 2020 06 22;35(6):1069-1079. Epub 2020 Jan 22.

Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Total serum 25-hydroxyvitamin D [25(OH)D] is considered the best marker of vitamin D status and used routinely in clinical practice. However, 25(OH)D is predominantly bound to vitamin D-binding protein (VDBP), and it has been reported that the free-25(OH)D and 25(OH)D loosely bound to albumin fraction correlates better with clinical outcomes.

Methods: We assessed total-25(OH)D, measured free-25(OH)D, and calculated free-25(OH)D and their relationship with VDBP and biomarkers of mineral metabolism in 61 children (22 CKD 2-3, 18 dialysis, and 21 post-transplant).

Results: Total-25(OH)D concentrations were comparable across the three groups (p = 0.09), but free- and bioavailable-25(OH)D (free- and albumin-25(OH)D) were significantly lower in the transplant group (both: p = 0.01). Compared to CKD and dialysis patients, the transplant group had significantly higher VDBP concentrations (p = 0.03). In all three groups, total-25(OH)D concentrations were positively associated with measured free-, calculated free-, and bioavailable-25(OH)D. Multivariable regression analysis showed that total-25(OH)D was the only predictor of measured free-25(OH)D concentrations in the dialysis group (β = 0.9; R = 90%). In the transplant group, measured free-25(OH)D concentrations were predicted by both total-25(OH)D and VDBP concentrations (β = 0.6, - 0.6, respectively; R = 80%). Correlations between parathyroid hormone with total-25(OH)D and measured and calculated free-25(OH)D were only observed in the transplant group (all: p < 0.001).

Conclusions: In transplanted patients, VDBP concentrations were significantly higher compared to CKD and dialysis patients, and consequently, free-25(OH)D concentrations were lower, despite a comparable total-25(OH)D concentration. We suggest that free-25(OH)D measures may be required in children with CKD, dialysis, and transplant, with further research required to understand its association with markers of mineral metabolism.
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http://dx.doi.org/10.1007/s00467-020-04472-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184055PMC
June 2020

Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease.

Elife 2019 12 6;8. Epub 2019 Dec 6.

Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis; a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.
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http://dx.doi.org/10.7554/eLife.48183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948954PMC
December 2019

Vangl2, a planar cell polarity molecule, is implicated in irreversible and reversible kidney glomerular injury.

J Pathol 2018 12;246(4):485-496

Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.

Planar cell polarity (PCP) pathways control the orientation and alignment of epithelial cells within tissues. Van Gogh-like 2 (Vangl2) is a key PCP protein that is required for the normal differentiation of kidney glomeruli and tubules. Vangl2 has also been implicated in modifying the course of acquired glomerular disease, and here, we further explored how Vangl2 impacts on glomerular pathobiology in this context. Targeted genetic deletion of Vangl2 in mouse glomerular epithelial podocytes enhanced the severity of not only irreversible accelerated nephrotoxic nephritis but also lipopolysaccharide-induced reversible glomerular damage. In each proteinuric model, genetic deletion of Vangl2 in podocytes was associated with an increased ratio of active-MMP9 to inactive MMP9, an enzyme involved in tissue remodelling. In addition, by interrogating microarray data from two cohorts of renal patients, we report increased VANGL2 transcript levels in the glomeruli of individuals with focal segmental glomerulosclerosis, suggesting that the molecule may also be involved in certain human glomerular diseases. These observations support the conclusion that Vangl2 modulates glomerular injury, at least in part by acting as a brake on MMP9, a potentially harmful endogenous enzyme. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282744PMC
December 2018

Lithium induces mesenchymal-epithelial differentiation during human kidney development by activation of the Wnt signalling system.

Cell Death Discov 2018 Dec 7;4:13. Epub 2018 Feb 7.

Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.

Kidney function is directly linked to the number of nephrons which are generated until 32-36 weeks gestation in humans. Failure to make nephrons during development leads to congenital renal malformations, whilst nephron loss in adulthood occurs in progressive renal disease. Therefore, an understanding of the molecular processes which underlie human nephron development may help design new treatments for renal disease. Mesenchyme to epithelial transition (MET) is critical for forming nephrons, and molecular pathways which control rodent MET have been identified. However, we do not know whether they are relevant in human kidney development. In this study, we isolated mesenchymal cell lines derived from human first trimester kidneys in monolayer culture and investigated their differentiation potential. We found that the mesenchymal cells could convert into osteogenic, but not adipogenic or endothelial lineages. Furthermore, addition of lithium chloride led to MET which was accompanied by increases in epithelial () and tubular () markers and downregulation of renal progenitor (, , ) and mesenchymal markers (, ). Prior to phenotypic changes, lithium chloride altered Wnt signalling with elevations in , GSK3β phosphorylation and β-catenin. Collectively, these studies provide the first evidence that lithium-induced Wnt activation causes MET in human kidneys. Therapies targeting Wnts may be critical in the quest to regenerate nephrons for human renal diseases.
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http://dx.doi.org/10.1038/s41420-017-0021-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841285PMC
December 2018

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases.

J Am Soc Nephrol 2016 Jan 2;27(1):69-77. Epub 2015 Jun 2.

Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom;

Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1(nl/nl) mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1(nl/nl) mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3(+) pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1(nl/nl) mice. These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1(cpk/cpk) mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.
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http://dx.doi.org/10.1681/ASN.2014090856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696565PMC
January 2016

Incorporation of individual-patient data in network meta-analysis for multiple continuous endpoints, with application to diabetes treatment.

Stat Med 2015 Sep 30;34(20):2794-819. Epub 2015 Apr 30.

Division of Biostatistics, University of Minnesota, Minneapolis, MN, 55405, U.S.A.

Availability of individual patient-level data (IPD) broadens the scope of network meta-analysis (NMA) and enables us to incorporate patient-level information. Although IPD is a potential gold mine in biomedical areas, methodological development has been slow owing to limited access to such data. In this paper, we propose a Bayesian IPD NMA modeling framework for multiple continuous outcomes under both contrast-based and arm-based parameterizations. We incorporate individual covariate-by-treatment interactions to facilitate personalized decision making. Furthermore, we can find subpopulations performing well with a certain drug in terms of predictive outcomes. We also impute missing individual covariates via an MCMC algorithm. We illustrate this approach using diabetes data that include continuous bivariate efficacy outcomes and three baseline covariates and show its practical implications. Finally, we close with a discussion of our results, a review of computational challenges, and a brief description of areas for future research.
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http://dx.doi.org/10.1002/sim.6519DOI Listing
September 2015

Genetic Background is a Key Determinant of Glomerular Extracellular Matrix Composition and Organization.

J Am Soc Nephrol 2015 Dec 20;26(12):3021-34. Epub 2015 Apr 20.

Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom;

Glomerular disease often features altered histologic patterns of extracellular matrix (ECM). Despite this, the potential complexities of the glomerular ECM in both health and disease are poorly understood. To explore whether genetic background and sex determine glomerular ECM composition, we investigated two mouse strains, FVB and B6, using RNA microarrays of isolated glomeruli combined with proteomic glomerular ECM analyses. These studies, undertaken in healthy young adult animals, revealed unique strain- and sex-dependent glomerular ECM signatures, which correlated with variations in levels of albuminuria and known predisposition to progressive nephropathy. Among the variation, we observed changes in netrin 4, fibroblast growth factor 2, tenascin C, collagen 1, meprin 1-α, and meprin 1-β. Differences in protein abundance were validated by quantitative immunohistochemistry and Western blot analysis, and the collective differences were not explained by mutations in known ECM or glomerular disease genes. Within the distinct signatures, we discovered a core set of structural ECM proteins that form multiple protein-protein interactions and are conserved from mouse to man. Furthermore, we found striking ultrastructural changes in glomerular basement membranes in FVB mice. Pathway analysis of merged transcriptomic and proteomic datasets identified potential ECM regulatory pathways involving inhibition of matrix metalloproteases, liver X receptor/retinoid X receptor, nuclear factor erythroid 2-related factor 2, notch, and cyclin-dependent kinase 5. These pathways may therefore alter ECM and confer susceptibility to disease.
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http://dx.doi.org/10.1681/ASN.2014040419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657824PMC
December 2015

Bayesian modeling of cost-effectiveness studies with unmeasured confounding: a simulation study.

Pharm Stat 2014 Jan-Feb;13(1):94-100. Epub 2013 Nov 13.

Department of Statistical Science, Baylor University, Waco, TX, USA.

Unmeasured confounding is a common problem in observational studies. Failing to account for unmeasured confounding can result in biased point estimators and poor performance of hypothesis tests and interval estimators. We provide examples of the impacts of unmeasured confounding on cost-effectiveness analyses using observational data along with a Bayesian approach to correct estimation. Assuming validation data are available, we propose a Bayesian approach to correct cost-effectiveness studies for unmeasured confounding. We consider the cases where both cost and effectiveness are assumed to have a normal distribution and when costs are gamma distributed and effectiveness is normally distributed. Simulation studies were conducted to determine the impact of ignoring the unmeasured confounder and to determine the size of the validation data required to obtain valid inferences.
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http://dx.doi.org/10.1002/pst.1604DOI Listing
October 2014

Experimental renal progenitor cells: repairing and recreating kidneys?

Pediatr Nephrol 2014 Apr 13;29(4):665-72. Epub 2013 Nov 13.

Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford Street, London, UK.

Strategies to facilitate repair or generate new nephrons are exciting prospects for acute and chronic human renal disease. Repair of kidney injury involves not just local mechanisms but also mobilisation of progenitor/stem cells from intrarenal niches, including papillary, tubular and glomerular locations. Diverse markers characterise these unique cells, often including CD24 and CD133. Extrarenal stem cells may also contribute to repair, with proposed roles in secreting growth factors, transfer of microvesicles and exosomes and immune modulation. Creating new nephrons from stem cells is beginning to look feasible in mice in which kidneys can be dissociated into single cells and will then generate mature renal structures when recombined. The next step is to identify the correct human markers for progenitor cells from the fetus or mature kidney with similar potential to form new kidneys. Intriguingly, development can continue in vivo: whole foetal kidneys and recombined organs engraft, develop a blood supply and grow when xenotransplanted, and there are new advances in decellularised scaffolds to promote differentiation. This is an exciting time for human kidney repair and regeneration. Many of the approaches and techniques are in their infancy and based on animal rather than human work, but there is a rapid pace of discovery, and we predict that therapies based on advances in this field will come into clinical practice in the next decade.
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http://dx.doi.org/10.1007/s00467-013-2667-5DOI Listing
April 2014

Guidance on the implementation and reporting of a drug safety Bayesian network meta-analysis.

Pharm Stat 2014 Jan-Feb;13(1):55-70. Epub 2013 Aug 30.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA.

The Drug Information Association Bayesian Scientific Working Group (BSWG) was formed in 2011 with a vision to ensure that Bayesian methods are well understood and broadly utilized for design and analysis and throughout the medical product development process, and to improve industrial, regulatory, and economic decision making. The group, composed of individuals from academia, industry, and regulatory, has as its mission to facilitate the appropriate use and contribute to the progress of Bayesian methodology. In this paper, the safety sub-team of the BSWG explores the use of Bayesian methods when applied to drug safety meta-analysis and network meta-analysis. Guidance is presented on the conduct and reporting of such analyses. We also discuss different structural model assumptions and provide discussion on prior specification. The work is illustrated through a case study involving a network meta-analysis related to the cardiovascular safety of non-steroidal anti-inflammatory drugs.
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http://dx.doi.org/10.1002/pst.1592DOI Listing
October 2014

Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease.

J Am Soc Nephrol 2014 Jan 5;25(1):33-42. Epub 2013 Sep 5.

Cardiovascular Division, King's College London, London, United Kingdom;

Vascular growth factors play an important role in maintaining the structure and integrity of the glomerular filtration barrier. In healthy adult glomeruli, the proendothelial survival factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 are constitutively expressed in glomerular podocyte epithelia. We demonstrate that this milieu of vascular growth factors is altered in streptozotocin-induced type 1 diabetic mice, with decreased angiopoietin-1 levels, VEGF-A upregulation, decreased soluble VEGF receptor-1 (VEGFR1), and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria, nephromegaly, hyperfiltration, glomerular ultrastructural alterations, and aberrant angiogenesis. We subsequently hypothesized that restoration of angiopoietin-1 expression within glomeruli might ameliorate manifestations of early diabetic glomerulopathy. Podocyte-specific inducible repletion of angiopoietin-1 in diabetic mice caused a 70% reduction of albuminuria and prevented diabetes-induced glomerular endothelial cell proliferation; hyperfiltration and renal morphology were unchanged. Furthermore, angiopoietin-1 repletion in diabetic mice increased Tie-2 phosphorylation, elevated soluble VEGFR1, and was paralleled by a decrease in VEGFR2 phosphorylation and increased endothelial nitric oxide synthase Ser(1177) phosphorylation. Diabetes-induced nephrin phosphorylation was also reduced in mice with angiopoietin-1 repletion. In conclusion, targeted angiopoietin-1 therapy shows promise as a renoprotective tool in the early stages of diabetic kidney disease.
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http://dx.doi.org/10.1681/ASN.2012121218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871771PMC
January 2014

Bayesian methods for design and analysis of safety trials.

Pharm Stat 2014 Jan-Feb;13(1):13-24. Epub 2013 Jul 30.

Eli Lilly and Company, Indianapolis, IN, USA.

Safety assessment is essential throughout medical product development. There has been increased awareness of the importance of safety trials recently, in part due to recent US Food and Drug Administration guidance related to thorough assessment of cardiovascular risk in the treatment of type 2 diabetes. Bayesian methods provide great promise for improving the conduct of safety trials. In this paper, the safety subteam of the Drug Information Association Bayesian Scientific Working Group evaluates challenges associated with current methods for designing and analyzing safety trials and provides an overview of several suggested Bayesian opportunities that may increase efficiency of safety trials along with relevant case examples.
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http://dx.doi.org/10.1002/pst.1586DOI Listing
October 2014

Albuminuria is associated with too few glomeruli and too much testosterone.

Kidney Int 2013 Jun 27;83(6):1118-29. Epub 2013 Feb 27.

Nephro-Urology Unit, UCL Institute of Child Health, London, UK.

Normally, the glomerular filtration barrier almost completely excludes circulating albumin from entering the urine. Genetic variation and both pre- and postnatal environmental factors may affect albuminuria in humans. Here we determine whether glomerular gene expression in mouse strains with naturally occurring variations in albuminuria would allow identification of proteins deregulated in relatively 'leaky' glomeruli. Albuminuria increased in female B6 to male B6 to female FVB/N to male FVB/N mice, whereas the number of glomeruli/kidney was the exact opposite. Testosterone administration led to increased albuminuria in female B6 but not female FVB/N mice. A common set of 39 genes, many expressed in podocytes, were significantly differentially expressed in each of the four comparisons: male versus female B6 mice, male versus female FVB/N mice, male FVB/N versus male B6 mice, and female FVB/N versus female B6 mice. The transcripts encoded proteins involved in oxidation/reduction reactions, ion transport, and enzymes involved in detoxification. These proteins may represent novel biomarkers and even therapeutic targets for early kidney and cardiovascular disease.
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http://dx.doi.org/10.1038/ki.2013.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674403PMC
June 2013

Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis.

PLoS One 2013 8;8(2):e56273. Epub 2013 Feb 8.

Nephro-Urology Unit, UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.

Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056273PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568077PMC
July 2013

Comparison of Bayesian and frequentist meta-analytical approaches for analyzing time to event data.

J Biopharm Stat 2013 ;23(1):129-45

Institute for Health Care Research and Improvement, Baylor Health Care System, Dallas, Texas 75201, USA.

Using meta-analysis in health care research is a common practice. Here we are interested in methods used for analysis of time-to-event data. Particularly, we are interested in their performance when there is a low event rate. We consider three methods based on the Cox proportional hazards model, including a Bayesian approach. A formal comparison of the methods is conducted using a simulation study. In our simulation we model two treatments and consider several scenarios.
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http://dx.doi.org/10.1080/10543406.2013.737210DOI Listing
October 2013

Identifying potential adverse events dose-response relationships via Bayesian indirect and mixed treatment comparison models.

J Biopharm Stat 2013 ;23(1):26-42

Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

Patients and prescribers need to be fully informed regarding the safety profile of approved medications. This includes knowledge and information regarding whether an adverse event of interest exhibits a potential dose-response relationship. In order to thoroughly evaluate whether an adverse event rate increases with increasing dose level, evidence from multiple clinical trials needs to be combined and analyzed. The various clinical trials that need to be combined often include different dose levels. If one evaluates the dose-response relationship by including only the trials with all of the common dose levels, this will lead to the exclusion of potentially several clinical trials as well as dose levels, and thus the loss of important information. Other methods, such as crudely pooling patients on the same dose level across different studies, are subject to bias due to the breakdown of randomization. It is preferable to include all studies and relevant dose levels, even if all studies do not contain the same dose levels. Bayesian methodology has been shown to be useful in the context of indirect and mixed treatment comparison methods, to combine information from different therapies in different studies in order to make treatment effect inferences. This type of approach is foundational to the models presented here, but instead of modeling different dose arms in different studies, we extend the methodology to allow for assessment of the dose-response relationship across multiple clinical trials. In this paper, we propose three Bayesian indirect/mixed treatment comparison models to assess adverse event dose-response relationships. These three models are designed to handle binary responses and time to event responses. We apply the methods to real data sets and demonstrate that our proposed methods are useful in discovering potential dose-response relationships.
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http://dx.doi.org/10.1080/10543406.2013.735761DOI Listing
October 2013

Modified citrus pectin reduces galectin-3 expression and disease severity in experimental acute kidney injury.

PLoS One 2011 Apr 8;6(4):e18683. Epub 2011 Apr 8.

Nephro-Urology Unit, UCL Institute of Child Health, London, United Kingdom.

Galectin-3 is a β-galactoside binding lectin with roles in diverse processes including proliferation, apoptosis, inflammation and fibrosis which are dependent on different domains of the molecule and subcellular distribution. Although galectin-3 is known to be upregulated in acute kidney injury, the relative importance of its different domains and functions are poorly understood in the underlying pathogenesis. Therefore we experimentally modulated galectin-3 in folic acid (FA)-induced acute kidney injury utilising modified citrus pectin (MCP), a derivative of pectin which can bind to the galectin-3 carbohydrate recognition domain thereby predominantly antagonising functions linked to this role. Mice were pre-treated with normal or 1% MCP-supplemented drinking water one week before FA injection. During the initial injury phase, all FA-treated mice lost weight whilst their kidneys enlarged secondary to the renal insult; these gross changes were significantly lessened in the MCP group but this was not associated with significant changes in galectin-3 expression. At a histological level, MCP clearly reduced renal cell proliferation but did not affect apoptosis. Later, during the recovery phase at two weeks, MCP-treated mice demonstrated reduced galectin-3 in association with decreased renal fibrosis, macrophages, pro-inflammatory cytokine expression and apoptosis. Other renal galectins, galectin-1 and -9, were unchanged. Our data indicates that MCP is protective in experimental nephropathy with modulation of early proliferation and later galectin-3 expression, apoptosis and fibrosis. This raises the possibility that MCP may be a novel strategy to reduce renal injury in the long term, perhaps via carbohydrate binding-related functions of galectin-3.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072992PMC
April 2011

Corticosteroid-induced kidney dysmorphogenesis is associated with deregulated expression of known cystogenic molecules, as well as Indian hedgehog.

Am J Physiol Renal Physiol 2010 Feb 9;298(2):F346-56. Epub 2009 Dec 9.

Nephro-Urology, University College London Institute of Child Health, London, United Kingdom.

An intact genome is essential for kidney growth and differentiation, but less is known about whether, and how, an altered fetal milieu modifies these processes. Maternal low-protein diets perturb growth of the metanephros, the precursor of the mature kidney. Fetal corticosteroid overexposure may, in part, mediate this, because such diets downregulate placental 11beta-hydroxysteroid dehydrogenase-2, which degrades maternal corticosteroids. We report that glucocorticoid and mineralocorticoid receptors are expressed in mouse metanephric epithelia. Metanephroi maintained in organ culture with hydrocortisone (1.4 or 14 microM) underwent a dose-dependant deceleration of overall growth accompanied by cyst formation. Dexamethasone, a glucocorticoid, reproduced these outcomes, but aldosterone, a mineralocorticoid, did not. Hydrocortisone upregulated transcripts levels of cadherin-11 and downregulated prospero-related homeobox-1, hence mimicking reported effects of maternal low-protein diet. Hydrocortisone also upregulated transcripts encoding Na(+)-K(+)-ATPase subunits and ligands for the epidermal growth factor receptor, all previously implicated in renal cyst growth. The most upregulated transcript, however, was indian hedgehog, and the encoded protein was immunodetected in metanephric cysts. Furthermore, in the presence of hydrocortisone, cystogenesis, but not whole organ growth, was significantly reduced by cyclopamine, a drug downregulating hedgehog signaling. Finally, both glucocorticoid receptor and indian hedgehog proteins were detected by immunohistochemistry in cystic tubules within human dysplastic kidneys, consistent with the hypothesis that these molecules modify the severity of this congenital malformation. Collectively, our observations raise the possibility that enhanced hedgehog signaling is an important stimulus for renal cyst formation. Furthermore, pharmacological inhibition of this pathway should be explored as a potential therapy for renal cystic diseases, starting with relevant animal models.
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http://dx.doi.org/10.1152/ajprenal.00574.2009DOI Listing
February 2010

Sphingosine kinase-1: a potential mediator of renal fibrosis.

Kidney Int 2009 Oct;76(8):815-7

University College London, Institute of Child Health, UK.

Renal fibrosis contributes to glomerulosclerosis and tubulointerstitial damage in chronic kidney disease. A well-established pathway implicated in the progression of fibrosis is the induction of connective tissue growth factor by transforming growth factor-beta, resulting in the accumulation of extracellular matrix proteins. Ren and colleagues demonstrate that sphingosine kinase-1 is involved in the regulation of this pathway in the glomerulus. This raises the possibility of targeting sphingosine kinase-1 to prevent fibrosis in chronic kidney disease patients.
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http://dx.doi.org/10.1038/ki.2009.310DOI Listing
October 2009

Unraveling the genetic landscape of bladder development in mice.

J Urol 2009 May 19;181(5):2366-74. Epub 2009 Mar 19.

Nephro-Urology Unit, University College London Institute of Child Health, London, United Kingdom.

Purpose: To better understand the pathobiology of human congenital bladder abnormalities and disorders associated with dedifferentiation, such as bladder cancer, we must first unravel the biology of normal bladder development. Therefore, we performed microarray analysis focusing on determining the gene expression profile at the initiation of bladder development.

Materials And Methods: RNA was extracted from embryonic day 13 and 18 mouse bladders (anatomically equivalent to 7 and 13 weeks of human gestation) and gene expression was evaluated using microarrays. Alterations in select genes of biological interest were confirmed using real-time quantitative polymerase chain reaction and localization was determined by immunohistochemistry.

Results: The genetic profile in the initiating mouse bladder at embryonic day 13 was dominated by transcription factors, retinoic acid signaling genes, Eph/ephrin bidirectional signaling molecules and genes associated with regulating cell cycle and differentiation. Later in development at embryonic day 18 genes associated with smooth muscle, innervation and epithelial differentiation were up-regulated. In addition, we examined the functional role of midkine, which was highly expressed at embryonic day 13, using organ culture and to our knowledge we provide the first evidence that this growth factor up-regulates molecules associated with bladder smooth muscle differentiation.

Conclusions: These data provide novel insights into molecules that orchestrate bladder development and highlight genes that may be involved in diseases associated with abnormal differentiation.
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http://dx.doi.org/10.1016/j.juro.2009.01.001DOI Listing
May 2009

Primary cultures of renal proximal tubule cells derived from individuals with primary hyperoxaluria.

Urol Res 2009 Jun 13;37(3):127-32. Epub 2009 Mar 13.

Institute of Urology and Nephrology, University College London, London, UK.

The primary hyperoxalurias, PH1 and PH2, are inherited disorders caused by deficiencies of alanine:glyoxylate aminotransferase and glyoxylate reductase, respectively. Mutations in either of these enzymes leads to endogenous oxalate overproduction primarily in the liver, but most pathological effects are exhibited in the kidney ultimately leading to end-stage renal failure and systemic oxalosis. To provide a non-invasive means of accessing kidney cells from individuals with primary hyperoxaluria, we have derived primary cultures of renal proximal tubule cells from the urine of these patients. The cells stain positively for the epithelial markers pan-cytokeratin and zonula occludens 1 and the proximal tubule marker gamma-glutamyl transpeptidase. Mutation analysis confirmed that the cultured cells had the same genotype as the leucocytes of the patients and also expressed glyoxylate reductase at the mRNA level, illustrating their potential value as a source of renal material from these individuals.
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http://dx.doi.org/10.1007/s00240-009-0185-5DOI Listing
June 2009

Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury.

Kidney Int 2008 Aug 14;74(3):300-9. Epub 2008 May 14.

Nephro-Urology Unit, University College London, Institute of Child Health, London, UK.

The loss of interstitial capillaries is a feature of several experimental models of renal disease and this contributes to secondary kidney injury. Angiopoietin-1 is a secreted growth factor which binds to Tie-2 present on endothelia to enhance cell survival thereby stabilizing capillary architecture in-vitro. Previous studies showed that angiopoietin-1 prevented renal capillary and interstitial lesions following experimental ureteric obstruction. We tested here the effect of angiopoietin-1 treatment on capillary loss and associated tubulointerstitial damage known to follow recovery from folic acid-induced tubular necrosis and acute renal injury. We found that delivery of angiopoietin-1 by adenoviral vectors stabilized peritubular capillaries in folic acid nephropathy but this was accompanied by profibrotic and inflammatory effects. These results suggest that the use of endothelial growth factor therapy for kidney disease may have varying outcomes that depend on the disease model tested.
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http://dx.doi.org/10.1038/ki.2008.179DOI Listing
August 2008

Correlation of vibratory quantitative sensory testing and nerve conduction studies in patients with diabetes.

Muscle Nerve 2007 Dec;36(6):821-7

Department of Neurology, Indiana University, Indianapolis, Indiana, USA.

Monitoring the course of diabetic peripheral neuropathy (DPN) remains a challenge. Besides clinical examination, nerve conduction studies (NCS) and quantitative sensory testing (QST) are the most commonly used methods for evaluating peripheral nerve function in clinical trials and population studies. In this study the correlation between vibratory QST and NCS was determined. Patients (N = 227) with diabetes mellitus participated in this multicenter, single-visit, cross-sectional study. QST of vibration measured with the CASE IV system was compared with a composite score of peroneal motor and tibial motor NCS and with individual attributes of peroneal, tibial, and sural nerves. The correlation between QST and composite score of NCS was 0.234 (Pearson correlation coefficient, P = 0.001). The correlations between QST and individual attributes of NCS ranged from 0.189 to 0.480 (Pearson correlation coefficients, P < 0.001). The low to moderate correlation between QST and NCS suggests that these tests cannot replace each other but are complementary.
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http://dx.doi.org/10.1002/mus.20880DOI Listing
December 2007

Factors that impact symptomatic diabetic peripheral neuropathy in placebo-administered patients from two 1-year clinical trials.

Diabetes Care 2007 Oct 10;30(10):2626-32. Epub 2007 Jul 10.

Diabetes Research Unit, Royal Hallamshire Hospital, Q Floor, Room 26, Glossop Road, Sheffield S102JF, UK.

Objective: The purpose of this study was to evaluate the change in neuropathy symptoms and disease progression in placebo-administered patients from two 1-year studies in which the impact of ruboxistaurin (RBX) in mild diabetic peripheral neuropathy (DPN) was tested.

Research Design And Methods: Data from 262 placebo-administered patients from two identical phase 3, randomized, double-blind trials were combined and analyzed.

Results: After 1 year, change in the neuropathy impairment score of lower limbs [NIS(LL)] (-0.63 points; P = 0.005), vibration detection threshold (VDT) (-0.42 just noticeable difference units; P = 0.003), and Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire (-3.73 points; P < 0.001) improved, whereas some electrophysiology measures and heart rate deep breathing (HRDB) (-0.78 beats; P = 0.003) worsened compared with baseline values. There was a small but significant worsening of A1C (0.28%; P < 0.001), and a greater percentage of patients were using analgesics at the end of the trials (33.6%; P = 0.003). At 1 year, the change in NTSS-6 directly correlated with changes in NIS(LL) and VDT and inversely correlated with the peroneal nerve conduction velocity. On logistic regression analyses, a > or = 50% reduction in NTSS-6 score was less likely in patients who used antihypertensive or chronic symptom medication at baseline.

Conclusions: In placebo-administered patients with mild symptomatic DPN, there was a progressive improvement in symptoms over 12 months, whereas nerve conduction studies and HRDB declined, and clinically significant worsening of DPN would require > 1 year of observation.
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http://dx.doi.org/10.2337/dc07-0608DOI Listing
October 2007

Clinical safety of the selective PKC-beta inhibitor, ruboxistaurin.

Expert Opin Drug Saf 2006 Nov;5(6):835-45

Washington University School of Medicine, 660 S. Euclid, Campus Box 8127, St. Louis, MO 63110, USA.

The aim of this manuscript is to report the safety profile of patients treated with ruboxistaurin mesylate (RBX; LY333531), a selective protein kinase C-beta (PKC-beta) inhibitor, for up to 4 years. Data from patients with diabetes (1396 RBX 32 mg/day; 1408 placebo) were combined from 11 placebo-controlled, double-masked studies. The proportion of patients who reported one or more serious adverse events was greater in the placebo group than in the RBX-treated group (23.2 versus 20.8%, respectively). There were 51 deaths (21 RBX; 30 placebo) reported in this patient cohort; none of the deaths was attributed to study drug by the investigators. Common adverse drug reactions (> or = 1/100 - < 1/10 patients) that were reported in the RBX-treated patients were dyspepsia and increased blood creatine phosphokinase. In controlled, randomised clinical trials, RBX had an adverse event profile comparable to placebo, and was well tolerated.
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http://dx.doi.org/10.1517/14740338.5.6.835DOI Listing
November 2006

Microarray interrogation of human metanephric mesenchymal cells highlights potentially important molecules in vivo.

Physiol Genomics 2007 Jan 19;28(2):193-202. Epub 2006 Sep 19.

Nephro-Urology, University College London Institute of Child Health, London, United Kingdom.

Many molecules have been implicated in kidney development, often based on experimental animal studies with organ cultures and cell lines. There are very few studies, however, that have directly addressed equivalent living human embryonic tissues. We generated renal mesenchymal cell lines from normal human metanephroi and used a microarray strategy to define changes in gene expression after stimulation with growth factors which enhance nephrogenesis in rodents. Changes were observed in 1) genes modulating diverse general cellular processes, such as matrix metalloproteinase 1 and stanniocalcin 1; 2) genes previously implicated in organogenesis e.g., sprouty 4 and midline 1; and 3) genes involved in blood vessel growth, including angiopoietin 1 and 4. Expression of these same genes was subsequently confirmed in vivo. Our novel data have identified several previously unhighlighted genes that may be implicated in differentiation programs within early human nephrogenesis.
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http://dx.doi.org/10.1152/physiolgenomics.00147.2006DOI Listing
January 2007

Vascular endothelial growth factor administration does not improve microvascular disease in the salt-dependent phase of post-angiotensin II hypertension.

Am J Physiol Renal Physiol 2006 Dec 27;291(6):F1248-54. Epub 2006 Jun 27.

Section of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida, USA.

Renal microvascular injury and tubulointerstitial inflammation may provide a potential mechanism for the development of salt-sensitive hypertension. Therefore, we hypothesized that vascular endothelial growth factor (VEGF) administration would prevent the development of salt-sensitive hypertension induced by ANG II. Infusion of ANG II in rats for 2 wk led to an elevation in blood pressure and an increase in blood urea nitrogen. Prominent tubular injury, focal areas of peritubular capillary loss accompanied by a decrease in urinary nitrites, thickening of the afferent arteriole, and an elevation in systemic and renal VEGF protein levels also occurred. In separate studies, animals were infused with ANG II and then placed on a low-salt diet for 1 wk. At this point, the animals were paired on the basis of weight and blood pressure and treated with either VEGF(121) or vehicle subcutaneously for 8 wk while being fed a high-salt diet. During the treatment period, a spontaneous improvement in many parameters, including both renal function and healing of the peritubular capillaries, occurred to the same degree in both vehicle- and VEGF(121)-treated rats. VEGF(121) significantly reduced blood pressure and accelerated the recovery of tubular injury. In contrast, vehicle-treated rats demonstrated a persistent increase in afferent arteriolar media-to-lumen ratio, which was further enhanced in rats treated with VEGF(121). Therefore, VEGF therapy has only limited benefits on the healing of renal lesions in the salt-dependent phase of post-ANG II-mediated hypertension.
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http://dx.doi.org/10.1152/ajprenal.00096.2006DOI Listing
December 2006

Human vascular smooth muscle cells express a urate transporter.

J Am Soc Nephrol 2006 Jul 14;17(7):1791-5. Epub 2006 Jun 14.

Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida, USA.

An elevated serum uric acid is associated with the development of hypertension and renal disease. Renal regulation of urate excretion is largely controlled by URAT1 (SLC22A12), a member of the organic anion transporter superfamily. This study reports the specific expression of URAT1 on human aortic vascular smooth muscle cells, as assessed by reverse transcription-PCR and Western blot analysis. Expression of URAT1 was localized to the cell membrane. Evidence that the URAT1 transporter was functional was provided by the finding that uptake of 14C-urate was significantly inhibited in the presence of probenecid, an organic anion transporter inhibitor. It is proposed that URAT1 may provide a mechanism by which uric acid enters the human vascular smooth muscle cell, a finding that may be relevant to the role of uric acid in cardiovascular disease.
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http://dx.doi.org/10.1681/ASN.2006030264DOI Listing
July 2006

Loss of nitric oxide and endothelial-derived hyperpolarizing factor-mediated responses in aging.

Kidney Int 2005 Nov;68(5):2154-63

Section of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, USA.

Background: Aging has considerable structural and functional effects on the vascular system of the kidney. One such effect is an alteration in vascular tone which potentially will initiate renal damage. Vascular tone is determined by the balance between vasoconstrictors and vasodilators. Therefore, we hypothesized that aging attenuates vasodilatory responses in the kidney. These changes may be mediated by a loss of nitric oxide and endothelial-derived hyperpolarizing factor (EDHF).

Methods: The systemic and renal responses of nitric oxide and EDHF were investigated in aging (18 months old) and young (3 months old) Sprague-Dawley rats.

Results: We demonstrated a general loss of vasodilatory responses in the aging kidney. In addition, nitric oxide levels were reduced in the serum and kidney cortex of aging versus young animals, although this was not accompanied with a loss of endothelial nitric oxide synthase (eNOS) protein in the kidney cortex. Aging animals also exhibited a loss in EDHF-mediated vasodilation following stimulation with either acetylcholine or bradykinin in the isolated perfused kidney.

Conclusion: These findings indicate that not only a defect in the nitric oxide pathway, but also a loss of EDHF-mediated responses may be responsible for impaired vasodilation in the aging kidney. This may result in enhanced vasoconstrictive responses in aging which potentially will cause renal damage and ultimately a loss in glomerular filtration rate (GFR).
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http://dx.doi.org/10.1111/j.1523-1755.2005.00671.xDOI Listing
November 2005

Development and validity testing of the neuropathy total symptom score-6: questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy.

Clin Ther 2005 Aug;27(8):1278-94

Lilly Research Laboratories, Indianapolis, Indiana, 46285, USA.

Objective: The aim of this study was to develop and validate a neuropathy sensory symptom scale, the Neuropathy Total Symptom Score-6 (NTSS-6), which evaluates individual neuropathy sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN) in clinical trials, with the intent of distinguishing a response to therapy.

Methods: The NTSS-6 questionnaire was developed to evaluate the frequency and intensity of individual neuropathy sensory symptoms identified frequently by patients with DPN (ie, numbness and/or insensitivity; prickling and/or tingling sensation; burning sensation; aching pain and/or tightness; sharp, shooting, lancinating pain; and allodynia and/or hyperalgesia). The NTSS-6 was administered 8 times over a 1-year period to DPN patients. The NTSS-6's reliability (determined by internal consistency and test-retest reproducibility), construct validity, convergent validity, and minimally clinically important differences (MCIDs) were determined.

Results: The NTSS-6 was administered to a total of 205 patients at 10 centers in the United States, Canada, Belgium, Germany, Hungary, Croatia, Slovenia, and the United Kingdom. Internal consistency was demonstrated at all 8 visits (Cronbach's alpha > 0.7). Test-retest reproducibility (intraclass correlation coefficient >0.9) was observed during the baseline period and at end point. Construct validity was demonstrated by statistically significant correlations between the NTSS-6 total score and the Neuropathy Symptoms and Change (NSC) score (r = 0.773-0.885, P < 0.001). Convergent validity was demonstrated by statistically significant correlations between the change in NTSS-6 total scores and the following: change in NSC scores (r = 0.519-0.708, P < 0.001); change in Neuropathy Impairment Score of the Lower Limbs and composite nerve function scores (r = 0.188-0.202, P < 0.007), and categories of the Clinical Global Impressions (r = 0.402, P < 0.001). The within- and between-groups MCIDs for the total NTSS-6 total scores were -1.26 and 0.97 points, respectively. The mean (SD) within-group MCID for all patients who improved on the Clinical Global Impression was -2.29 (3.4) points.

Conclusions: The NTSS-6 provided a valid assessment of neuropathy sensory symptoms in this sample of patients with DM and DPN, which suggests that it may be useful for symptom evaluation in clinical trials and practice. The NTSS-6 showed internal consistency, test-retest reliability, and construct validity. There was also convergent validity of the scores, indicating that the NTSS-6 may be a suitable questionnaire for clinical trials that evaluate symptoms of DPN in this well-defined patient population.
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http://dx.doi.org/10.1016/j.clinthera.2005.08.002DOI Listing
August 2005