Professor David Kavanagh
Professor of Complement Therapeutics / Honorary Consultant Nephrologist
- Email: email@example.com
- Telephone: +44 (0) 191 241 8634
- Fax: +44 (0) 191 241 8666
- Address: Institute of Genetic Medicine
International Centre for Life
Newcastle upon Tyne
1995 BSc (Immunology), University of Glasgow
1998 MB ChB, University of Glasgow
2004 Clinical Research Fellow, Newcastle University
2007 PhD, Newcastle University
2007 Post-doctoral research fellow, Washington University School of Medicine, St Louis, USA
2008 Kidney Research UK clinical training fellow, Edinburgh University
2008 Clinical Lecturer in Renal Medicine, Newcastle University
2009 Raine Award- Renal Association Young Investigator Award
2011 Wellcome Intermediate Research Fellow
Royal Society Pairing Scheme
The Royal Society’s MP-Scientist pairing scheme aims to build bridges between parliamentarians and some of the best scientists in the UK. Dr Kavanagh was paired with Chi Onwurah MP for Newcastle Central and Shadow Minister for Innovation, Science and Digital Infrastructure. Dr Kavanagh gives a personal personal account of his experiences in a 'complement' to the Commons.
In a reciprocal visit, Chi joined the Renal Complement Group to gain first hand experience of Biomedical Research
Kidney Disease in The North East of England
Dan Ashby discusses awareness of kidney disease in the North East with Dr Kavanagh - click to watch
aHUS Screening forms
Understanding the structural and functional mechanisms underlying genetic renal disease
The inherited form of haemolytic uraemic syndrome (atypical HUS), a clinical condition in which patients develop a low platelet count and anaemia in the setting of severe, often irreversible, renal failure, is rare but important due to the high mortality and morbidity seen in affected patients. My work, and that of previous investigators in Professor Tim Goodship’s group, has identified mutations in the genes which code for proteins which participate in the alternative pathway of complement, a key defence system of the body which normally protects against infection. I have identified mutations in the complement regulatory protein factor I and demonstrated that the mutations located in the serine protease part of the protein are functionally significant, as they cause loss of an enzymatic activity, known as ‘cofactor activity’. This prevents appropriate down-regulation of complement activation, leading to damage to the tissues of the kidney. I have also mapped the structural and functional effects of mutations in the C-terminus of the Factor H protein (fH) and demonstrated that there is a detrimental effect on cell surface protection in the kidney which predisposes to aHUS. The C-terminal region is normally responsible for binding C3b and glycosaminoglycans. Using NMR, it can be shown that the mutations in the C-terminal region result in only very limited and localized effects on protein structure. Strikingly, binding studies demonstrated that affinities for C3b or glycosaminoglycans did not correlate with the extent to which all the mutants were found to be impaired in a more physiological assay that measured their ability to inhibit cell surface complement functions of full-length fH. This suggests that disruption of a complex fH-self surface recognition process, involving a balance of affinities for protein and physiological carbohydrate ligands, predisposes to aHUS. Future studies will investigate the cross-talk between the complement and coagulation systems and how this predisposes to aHUS.
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal dominant microvascular endotheliopathy. The disease manifestations begin in the fourth or fifth decade with central nervous system degeneration and progressive loss of visual acuity secondary to retinal vasculopathy. Mild-moderate liver and kidney impairment are also seen. We demonstrated that C-terminal truncating mutations in the 3’-5’ DNA exonuclease, TREX1, caused RVCL. We established that these truncated proteins retained exonuclease activity but lost normal perinuclear localization. Future studies will examine the incidence and prevalence of this condition in the U.K.
We also have ongoing research collaborations focusing on pre-eclampsia and age-related macular degeneration
Renal Complement Group
Dr Edwin Wong- MRC Clinical Training Fellow
Rachel Challis - PhD Student
KRUK Legacy meeting york 2012
- Hunt D, Kavanagh D, Drummond I, Weller B, Bellamy C, Overell J, Evans S, Jackson A, Chandran S. Thrombotic Microangiopathy Associated with Interferon Beta. New England Journal of Medicine 2014, 370(13), 1270-1271.
- Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, Goldstein JI, Triebwasser M, Anderson HE, Zerbib J, Kavanagh D, Souied E, Katsanis N, Daly MJ, Atkinson JP, Raychaudhuri S. Rare variants in CFI, C3 and C9 are associated with high risk of advancedage-related macular degeneration. Nature Genetics 2013, 45, 1366-1370.
- Richards A, van den Maagdenberg A, Jen J, Kavanagh D, Bertram P, Spitzer D, Liszewski K, Barilla-LaBarca M, Terwindt G, Kasai Y, McLellan M, Grand M, Vanmolkot K, de Vries B, Wan J, Kane M, Mamsa H, Schafer R, Stam A, Haan J, de Jong P, Storimans C, van Schooneveld M, Oosterhuis J, Gschwendter A, Dichgans M, Kotschet K, Hodgkinson S, Hardy T, Delatycki M, Hajj-Ali R, Kothari P, Nelson S, Frants R, Baloh R, Ferrari M, Atkinson JP. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nature Genetics 2007, 39(9), 1068-1070.
- Blaum BS, Hannan JP, Herbert AP, Kavanagh D, Uhrin D, Stehle T. Structural basis for sialic acid-mediated self-recognition by complement factor H. Nature Chemical Biology 2015, 11(1), 77-82.
- Challis RC, Araujo GSR, Wong EKS, Anderson HE, Awan A, Dorman AM, Waldron M, Wilson V, Brocklebank V, Strain L, Morgan BP, Harris CL, Marchbank KJ, Goodship THJ, Kavanagh D. A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H–Related 3 Gene in Atypical Hemolytic Uremic Syndrome. Journal of the American Society of Nephrology 2016, 27(6), 1617-1624.
- Wong EKS, Anderson HE, Herbert AP, Challis RC, Brown P, Reis GS, Tellez JO, Strain L, Fluck N, Humphrey A, Macleod A, Richards A, Ahlert D, Santibanez-Koref M, Barlow PN, Marchbank KJ, Harris CL, Goodship THJ, Kavanagh D. Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN. Journal of American Society of Nephrology 2014, 25(11), 2425-2433.
- Kavanagh D, Pappworth IY, Anderson H, Hayes CM, Moore I, Hunze EM, Bennaceur K, Roversi P, Lea S, Strain L, Ward R, Plant N, Nailescu C, Goodship TH, Marchbank KJ. Factor I Autoantibodies in Patients with Atypical Hemolytic Uremic Syndrome: Disease-Associated or an Epiphenomenon?. Clinical Journal of the American Society of Nephrology 2012, 7(3), 417-426.
- Morgan HP, Schmidt CO, Guariento M, Blaum BS, Gillespie D, Herbert AP, Kavanagh D, Mertens HD, Svergun DI, Johansson CM, Uhrin D, Barlow PN, Hannan JP. Structural basis for engagement by complement factor H of C3b on a self surface. Nature Structural and Molecular Biology 2011, 18(4), 463-470.
- Yu Y, Triebwasser MP, Wong EKS, Schramm EC, Thomas B, Reynolds R, Mardis ER, Atkinson JP, Daly M, Raychaudhuri S, Kavanagh D, Seddon JM. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Human Molecular Genetics 2014, 23(19), 5283-5293.
- Ferreira VP, Herbert AP, Cortés C, McKee KA, Blaum BS, Esswein ST, Uhrín D, Barlow PN, Pangburn MK, Kavanagh D. The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. Journal of Immunology 2009, 182(11), 7009-7018.
- Francis NJ, McNicholas B, Awan A, Waldron M, Reddan D, Sadlier D, Kavanagh D, Strain L, Marchbank KJ, Harris CL, Goodship THJ. A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome. Blood 2012, 119(2), 591-601.
- Phillips EH, Westwood JP, Brocklebank V, Wong EKS, Tellez JO, Marchbank KJ, McGuckin S, Gale DP, Connolly J, Goodship THJ, Kavanagh D, Scully MA. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. Journal of Thrombosis and Haemostasis 2016, 14(1), 175-185.
- Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006, 108(4), 1267-1279.
- Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship THJ. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. Journal of the American Society of Nephrology 2005, 16(7), 2150-2155.
- Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, Goodship T, Fremeaux-Bacchi V, Atkinson JP. Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort. PLoS Medicine 2011, 8(3), e1001013.
- Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship THJ, Marchbank KJ. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 2010, 115(2), 379-387.
- Hageman GS, Hancox LS, Taiber AJ, Gehrs KM, Anderson DH, Johnson LV, Radeke MJ, Kavanagh D, Richards A, Atkinson J, Meri S, Bergeron J, Zernant J, Merriam J, Gold B, Allikmets R, Dean M. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Annals of Medicine 2006, 38(8), 592-604.
- Kavanagh D, Smith-Jackson K. Eculizumab in children with hemolytic uremic syndrome. Kidney International 2016, 89(3), 537-538.
- Kavanagh D, Raman S, Sheerin NS. Management of hemolytic uremic syndrome. F1000 Prime Reports 2014, 6, 1-11.
- Wong E, Challis R, Sheerin N, Johnson S, Kavanagh D, Goodship TH. Patient stratification and therapy in atypical haemolytic uraemic syndrome (aHUS). Immunobiology 2015.
- Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Seminars in Nephrology 2013, 33(6), 508-530.
- Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrin D, Barlow PN. A New Map of Glycosaminoglycan and C3b Binding Sites on Factor H. Journal of Immunology 2008, 181(4), 2610-2619.
- Pechtl IC, Kavanagh D, McIntosh N, Harris CL, Barlow PN. Disease-associated N-terminal complement factor H mutations perturb cofactor and decay-accelerating activities. Journal of Biological Chemistry 2011, 286(13), 11082-11090.
- Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, Caudy A, Arzouk N, Cleper R, Francois M, Guest G, Pourrat J, Seligman R, Fridman WH, Loirat C, Atkinson JP. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. Journal of the American Society of Nephrology 2006, 17(7), 2017-2025.
- Wong EKS, Goodship THJ, Kavanagh D. Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Molecular Immunology 2013, 56(3), 199-212.
- Nester CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship THJ, Kavanagh D, Noris M, Pickering M, Sanchez-Corral P, Skerka C, Zipfel P, Smith RJH. Atypical aHUS: State of the art. Molecular Immunology 2015, 67(1), 31-42.
- Brocklebank V, Wong EKS, Fielding R, Goodship THJ, Kavanagh D. Atypical haemolytic uraemic syndrome associated with a CD46 mutation triggered by Shigella flexneri. Clinical Kidney Journal 2014, 7(3), 286-288.
- Holmes LV, Strain L, Staniforth SJ, Moore I, Marchbank K, Kavanagh D, Goodship JA, Cordell HJ, Goodship THJ. Determining the Population Frequency of the CFHR3/CFHR1 Deletion at 1q32. PLoS ONE 2013, 8(4), e60352.
- Goodship THJ, Pappworth IY, Toth T, Denton M, Houlberg K, McCormick F, Warland D, Moore I, Hunze EM, Staniforth SJ, Hayes C, Cavalcante DP, Kavanagh D, Strain L, Herbert AP, Schmidt CQ, Barlow PN, Harris CL, Marchbank KJ. Factor H autoantibodies in membranoproliferative glomerulonephritis. Molecular Immunology 2012, 52(3-4), 200-206.
- Kavanagh D, Holmes M, Appleton M, Bartlett K. Interference of urinary amino acid analysis by pregabalin. Clinica Chimica Acta 2012, 413(9-10), 953-954.
- Kavanagh D, Anderson HE. Interpretation of genetic variants of uncertain significance in atypical hemolytic uremic syndrome. Kidney International 2012, 81(1), 11-3.
- Herbert AP, Kavanagh D, Johansson C, Morgan HP, Blaum BS, Hannan JP, Barlow PN, Uhrin D. Structural and Functional Characterization of the Product of Disease-Related Factor H Gene Conversion. Biochemistry 2012, 51(9), 1874-1884.
- Kavanagh D, Goodship T. Haemolytic Uraemic Syndrome. Nephron Clinical Practice 2011, 118(1), C37-C42.
- Dhillon B, Wright AF, Tufail A, Pappworth I, Hayward C, Moore I, Strain L, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Armbrecht AM, Laude A, Deary IJ, Staniforth SJ, Holmes LV, Goodship THJ, Marchbank KJ. Complement Factor H Autoantibodies and Age-Related Macular Degeneration. Investigative Ophthalmology & Visual Science 2010, 51(11), 5858-5863.
- Kavanagh D, Goodship T. Genetics and complement in atypical HUS. Pediatric Nephrology 2010, 25(12), 2431-2442.
- Goodship THJ, Kavanagh D. Pulling the Trigger in Atypical Hemolytic Uremic Syndrome: The Role of Pregnancy. Journal of the American Society of Nephrology 2010, 21(5), 731-732.
- Kavanagh D, Richards A, Goodship T, Jalanko H. Transplantation in Atypical Hemolytic Uremic Syndrome. Seminars in Thrombosis and Hemostasis 2010, 36(6), 653-659.
- Bento D, Mapril J, Rocha C, Marchbank KJ, Kavanagh D, Barge D, Strain L, Goodship THJ, Meneses-Oliveira C. Triggering of atypical hemolytic uremic syndrome by influenza A (H1N1). Renal Failure 2010, 32(6), 753-756.
- Richards A, Kavanagh D. Pathogenesis of thrombotic microangiopathy: insights from animal models. Nephron Experimental Nephrology 2009, 113(4), e97-e103.
- Blom AM, Bergström F, Edey MMJ, Diaz-Torres M, Kavanagh DG, Lampe AK, Goodship JA, Strain L, Moghal N, McHugh M, Inward C, Tomson C, Frémeaux-Bacchi V, Villoutreix BO, Goodship THJ. A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity. Journal of Immunology 2008, 180(9), 6385-6391.
- Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. British Journal of Haematology 2008, 143(3), 336-348.
- Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski MK, Karpman D, Goodship JA, Fremeaux-Bacchi V, Remuzzi G, Goodship THJ, Atkinson JP. Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Molecular Immunology 2008, 45(1), 95-105.
- Kavanagh D, Richards A, Atkinson J. Complement regulatory genes and hemolytic uremic syndromes. Annual Review of Medicine 2008, 59(1), 293-309.
- Morgan HP, Jiang JZ, Herbert AP, Kavanagh D, Uhrin D, Barlow PN, Hannan JP. Crystallographic determination of the disease-associated T1184R variant of complement regulator factor H. Acta Crystallographica Section D: Biological Crystallography 2011, 67, 593-600.
- Kavanagh D, Spitzer D, Kothari PH, Shaikh A, Liszewski MK, Richards A, Atkinson JP. New roles for the major human 3′-5′ exonuclease TREX1 in human disease. Cell Cycle 2008, 7(12), 1718-1725.
- Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, Uhrin D, Barlow PN. Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations. Journal of Biological Chemistry 2008, 283(14), 9475-9487.
- Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship THJ, Atkinson JP. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Molecular Immunology 2007, 44(1-3), 111-122.
- Richards A, Kavanagh D, Atkinson JP. Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory statesthe examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration. Advances in Immunology 2007, 96, 141-177.
- Kavanagh D, Richards A, Fremeaux-Bacchi V, Noris M, Goodship T, Remuzzi G, Atkinson JP. Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clinical Journal of the American Society of Nephrology 2007, 2(3), 591-596.
- Kavanagh D, Burgess R, Spitzer D, Richards A, Diaz-Torres ML, Goodship JA, Hourcade DE, Atkinson JP, Goodship THJ. The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation. Molecular Immunology 2007, 44(12), 3162-3167.
- Kavanagh D, Goodship TH. Update on evaluating complement in hemolytic uremic syndrome. Current Opinion in Nephrology and Hypertension 2007, 16(6), 565-571.
- Kavanagh D, Goodship THJ, Richards A. Atypical haemolytic uraemic syndrome. British Medical Bulletin 2006, 77-78(1), 5-22.
- Kavanagh D, Kemp EJ, Richards A, Burgess RM, Mayland E, Goodship JA, Goodship THJ. Does complement factor B have a role in the pathogenesis of atypical HUS?. Molecular Immunology 2006, 43(7), 856-859.
- Kavanagh D, Goodship THJ. Membrane cofactor protein and factor I: Mutations and transplantation. Seminars in Thrombosis and Hemostasis 2006, 32(2), 155-159.
- Richards A, Ng Kam Chuen J, Taylor C, Jackson R, Toms G, Kavanagh D. Acute respiratory infection in a renal transplant recipient. Nephrology Dialysis Transplantation 2005, 20(12), 2848-2850.
- Atkinson JP, Liszewski MK, Richards A, Kavanagh D, Moulton EA. Hemolytic uremic syndrome: an example of insufficient complement regulation on self-tissue. Annals of The New York Academy of Sciences 2005, 1056(1), 144-152.
- Siddiqui S, Kavanagh D, Traynor J, Mak M, Deighan C, Geddes C. Risk factors for restless legs syndrome in dialysis patients. Nephron - Clinical Practice 2005, 101(3), C155-C160.
- Kavanagh D, Prescott GJ, Mactier RA. Peritoneal dialysis-associated peritonitis in Scotland (1999-2002). Nephrology, Dialysis, Transplantation 2004, 19(10), 2584-2591.
- Geddes C, Kavanagh D, Siddiqui S. Restless Legs bei Uramie. Nephrologie fur Klink and Praxis 2004, 20, 1-7.
- Kavanagh D, Siddiqui S, Geddes CC. Restless legs syndrome in patients on dialysis. American Journal of Kidney Diseases 2004, 43(5), 763-771.
- Woo YM, McLean D, Kavanagh D, Ward L, Aitken S, Miller GJ, Egan P, Hughes K, Clark L, Carswell K, Morris ST, Northridge DB, Rodger RS, Jardine AG. The influence of pre-operative electrocardiographic abnormalities and cardiovascular risk factors on patient and graft survival following renal transplantation. Journal of Nephrology 2002, 15(4), 380-386.
- Kavanagh D, Morris ST, Northridge DB, Rodger RS, Jardine AG. Electrocardiogram and Outcome following Renal Transplantation. Nephron 1999, 81(1), 109-110.
- Wagner E, Kavanagh D, Yu Y, Schramm E, Triebwasser M, Raychaudhuri S, Daly M, Atkinson J, Seddon JM. Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum Factor I level. In: 2015 ARVO Annual Meeting. 2015, Denver, CO, USA: Association for Research in Vision and Ophthalmology.