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Kinetic modelling to optimise dialysis

Mike Chappell - DialysisThrough the mathematical modelling of biomedical processes, outcomes for patients with multiple myeloma (a form of bone cancer that can lead to kidney failure, a major cause of morbidity) have been vastly improved, with the result that dialysis treatment may no longer be necessary alongside their myeloma treatment. Regaining kidney function for these patients improves their quality of life and results in significant cost savings for the NHS. Research into the modelling of the kinetics of whole antibodies produced by multiple myeloma patients (and others) has also had an impact on patient outcomes and clinical decisions. There have also been economic benefits for Gambro, a German company that sells products developed on the basis of the research results.

A long-established research collaboration exists between the Biomedical and Biological Systems Laboratory (Engineering, Warwick), The Binding Site Ltd and the Department of Immunology (Birmingham). This work has primarily involved the application of Warwick's research into mathematical modelling of biomedical processes to the use of monoclonal antibodies for targeting tumours, for both diagnostic and therapeutic purposes. Since 2002, Warwick's research has been extended to antibody synthesis and the modelling of the kinetics of antibodies and free light chains based upon assay data that can be obtained only from The Binding Site Ltd. The Binding Site is a global specialist protein company providing immunodiagnostic assays for the global laboratory market.

Chappell (Head of Warwick group), Evans and EPSRC PhD student Hattersley (Warwick 2007- 2009) performed engineering state space (compartmental) modelling in 2005-2006. This was based on multiple myeloma patients and used systems modelling and simulation techniques. These incorporated the effects of novel scheduling strategies and theoretically predicted that the use of alternative types of dialysis filter (High Cut Off/High Frequency (HCO/HF) filters) for longer initial dialysis sessions than were normally used would greatly increase the extraction of free light chains. The modelling performed was novel not only in terms of the generation of a mechanistic model of serum free light chain kinetics in humans, but also in being the first simulations to suggest that the use of alternative dialysis filters extracted excess serum-free light chains from myeloma sufferers.

Warwick modelled the prevalence of free light chains in patients with multiple myeloma, and the effect of these light chains on kidney function on the outcome of certain forms of chemotherapy. Patients with multiple myeloma and severely reduced kidney function or kidney failure can become dependent on dialysis, which is an additional burden on their quality of life as well as being costly from an economic perspective. In order to improve the quality of life of such patients, a key objective is to remove the greatly increased amounts of the free light chains produced, permitting recovery of kidney function and hence a release from dialysis dependence.

This modelling work prompted a series of local clinical trials which took place between April 2006 and May 2008, in which multiple myeloma patients with kidney failure were treated using larger filters than previously used and over extended dialysis sessions, being up to 12 hours daily for a few weeks compared to the previous treatment of 3-4 hours 3 times per week potentially indefinitely. The results of these trials were extremely encouraging, with 85% of patients recovering kidney function and no longer requiring dialysis treatment. The remaining 15% of patients had confounding symptoms with suggested clear reasons as to why they did not benefit from this optimised protocol.

The promising results obtained from these trials have now led to a Europe-wide series of clinical trials (EuLite, http://clinicaltrials.gov/ct2/show/NCT00700531), which are currently underway, with the results expected from January 2014 onwards. The modelling has also been applied to the treatment of other medical conditions such as rhabdomyolysis. A two compartment model has been developed by Warwick to treat rhabdomyolysis patients undergoing dialysis for the removal of myoglobin. The application of the modelling, using Gambro filters removes myoglobin more effectively without the removal of other larger essential molecules.

Publications

C.A. Hutchison, P. Cockwell, S. Reid, K. Chandler, G.P. Mead, J. Harrison, J. Hattersley, N.D. Evans, M.J. Chappell, M. Cook, H. Goehl, M. Storr and A.R. Bradwell "Efficient removal of immunoglobulin free light chains by haemodialysis for multiple myeloma: in-vitro and in-vivo studies.",Journal of the American Society of Nephrology, 18(3) 886 - 895. (2007) DOI: 10.1681/ASN.2006080821 JIF: 8.288, 5yr JIF: 7.960, ERA: B, Citations: 58

G. Pratt, G.P. Mead, K.R. Godfrey, Y.Hu, N.D. Evans, M.J. Chappell, R. Lovell and A.R. Bradwell. "The tumour kinetics of multiple myeloma following autologous stem cell transplantation as assessed by measuring serum free light chains". Leukemia and Lymphoma, 47(1) 21 - 28. (2006) DOI: 10.1080/10428190500254216 JIF: 2.492, 5 yr JIF: 2.089, ERA: B, Citations: 10

N.D. Evans, J. Hattersley, C. Hutchison, Y. Hu, K.R. Godfrey, A.R. Bradwell, G.P. Mead, and M.J. Chappell. "Modelling of haemodialysis in limiting serum free light chains in patients with renal failure", in: Proceedings of the 6th IFAC Symposium on Modelling and Control in Biomedical Systems 6(1) (D. Feng, O. Dubois, J. Zaytoon and E. Carson, eds), Reims, 20-22 September, 2006, Elsevier, Oxford, pp. 75-80) DOI: 10.3182/20060920-3-FR-2912.00018 (Full paper peer- reviewed international conference)

C.A Hutchison, A.R. Bradwell, M. Cook, K. Basnayake, S. Basu, S. Harding, J.G. Hattersley, N.D. Evans, M.J. Chappell, P. Sampson, L. Foggensteiner, D. Adu and P. Cockwell. "Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off haemodialysis", Clinical Journal of the American Society of Nephrology 2009, 4:745-754. DOI: 10.2215/CJN.04590908

R. Keir, N.D. Evans, C.A. Hutchison, M.R. Vigano, A. Stella, P. Fabbrini, M. Storr, M.J. Chappell. "Kinetic modelling of haemodialysis removal of myoglobin in rhabdomyolysis patients", Computer Methods and Programs in Biomedicine 2013 Aug 14. pii: S0169-2607(13)00252-6. DOI: 10.1016/j.cmpb.2013.07.017