Research project update from Kathrine Parker, Highly specialist renal pharmacist- NIHR clinical doctoral fellow

We are really pleased to share this report from Kathrine Parker who received a research grant from Kidneys for Life in 2015.

Kidneys for life- Grant report

Does High Dose Haemodiafiltration alter drug kinetics compared to conventional dialysis therapy? A pilot study.

On 29th October 2015 I was awarded a grant of £9700 to undertake some pilot work, looking at four commonly used drugs in kidney patients on haemodialysis. Each patient was already taking these drugs as part of their clinical care. These drugs included: the antibiotics meropenem and flucloxacillin, and the painkiller oxycodone and pregabalin. We wanted to assess whether there was any difference with the newer methods of dialysis (haemodiafiltration) compared to more conventional therapy (high-flux haemodialysis) in terms of drug removal. Each patient underwent a session of both types of dialysis, and blood samples were taken at varying time points whilst on the dialysis machine to enable drug level measurements.

Unfortunately, there have been a few delays to the project. I received Preston NW NHS REC approval in November 2015 but at this point I was 38 weeks pregnant. I took a year of maternity leave and when I returned in January 2017 the ethics review process had changed, and the project required HRA approval. This was a new process with a backlog and the study was not approved to restart until late 2017.

A further delay related to a new collaboration with a Professor of Biochemistry at University hospitals South Manchester. Professor Keevil was able to set up columns and source materials, allowing us to undertake drug sample analysis locally rather than sending samples to Bristol and Wales. With the samples having complexities associated with their storage, for example antibiotic levels required minus 80degree storage, this has meant costs associated with transport were massively reduced. Delays resulted from the raw materials required for the column set up which came from Canada and were delivered to the wrong department before being returned back to Canada. It took a further 12 months, late 2018, for everything to be set up and calibrated for sample analysis.

Recruitment started in 2018 and this was completed by April 2019. We had difficulties recruiting to one of the antibiotics, flucloxacillin. This was because by the time we had given patients time to consider the study and gain consent they had completed the antibiotic course or switched to oral therapy. Although we had set up methods to analyse this drug it had to be excluded and the difficulties will be discussed in the final write-up. The cost for setting up drug analysis columns and for running the samples was £4297 which was significantly lower than the £7500 budgeted. It also brought about a fantastic local collaboration and highlighted potential opportunities for future work. The cost of transport of samples were approximately £300 and again were significantly reduced due to the locality.

I received some great support from people working in the Kidneys for Life labs at Manchester Royal who have helped me to spin the blood samples after collection, and found space for me to store them in the minus 80 and minus 20 degree Celcius freezers. I am also extremely grateful to the renal dialysis nurses who were able to collect the samples for me. They were happy to do this as were extremely interested in this study and what the findings would be. I was able to support them with setting up bottles, the plan for taking samples and ensuring appropriate storage so no renal research nurse time was required.

The analysis of samples were undertaken in 2019 whilst I was on a second maternity leave until 2020. When I returned to work the COVID-19 pandemic had taken hold. This has slowed down the publication of this work.

During the project the pharmacokinetic modeller from the University of Manchester moved to a University in Sweden. Experts in this field are very scarce but he is keen to finish this project and has decided to do this without cost.

We have been able to use the drug levels to predict the properties of meropenem, oxycodone and pregabalin during the various dialysis methods. A model was also created for meropenem to identify whether there was a difference in its removal between the two types of dialysis. No significant differences have been noted of removal of the drugs between the different types of dialysis. We note significant removal of all three drugs during any dialysis session. What was an important finding was that antibiotic levels (meropenem) were low in some patients prior to initiation of dialysis. This raises a potential concern with current dosing of meropenem in dialysis patients, as low levels before dialysis may predispose to inadequate treatment and antibiotic resistance.

We are in the final process of writing this research up which we feel could be relevant for practice, particularly in the way we dose antibiotics. This pilot study highlights the potential need to monitor certain drug levels, but easier ways of doing this are required to be able for this to be undertaken in routine practice. Issues include storage requirements (minus 80 degrees C) due to instability of samples and access to assays to allow analysis of drug samples.

The findings of subtherapeutic antibiotic dosing has direct impact on clinical practice and this will form part of the conclusion in the paper. It will also potentially alert clinicians in Manchester to dose Meropenem, a commonly used antibiotic, adequately in our patients which might help speedier recovery from sepsis and minimise drug resistance.

I am extremely grateful to Kidneys for Life for providing me with this grant. Not only has it given me the opportunity to experience managing a research project it has produced some interesting findings which will be of interest to the wider renal community. As this was only a pilot study we can’t draw conclusions on drugs that weren’t studied and I hope this project highlights that this work needs to be done for other key drugs.

Many thanks

Kathrine Parker MPharm MFRPSII MSc(dist) NMP

Highly specialist renal pharmacist- NIHR clinical doctoral fellow