Understanding the determinants of progression of chronic kidney disease (CKD) and how they are modified by treatment sodium-glucose co-transporter-2 (SGLT) inhibition [MRC PHRU]

BACKGROUND

Chronic kidney disease (CKD) is common and important. It is associated with an increased risk of cardiovascular disease and progresses over time such that some people with CKD develop kidney failure and require treatment with dialysis or kidney transplantation. PHRU’s 6609 participant EMPA-KIDNEY trial (www.empakidney.org) demonstrated that empagliflozin delays progression of CKD in a broad population of patients. This trial cohort had relevant clinical information collected at baseline and is now being phenotyped using clinical chemistry and targeted protein assays. These include urine markers of acute tubular injury, inflammation and fibrosis measured in 5500 participants at baseline and 2600 of these participants at 2 and 18 months of follow-up (data available by end Q2/2023). The biomarker data will enable a DPhil candidate to:

1. Characterise the EMPA-KIDNEY cohort of CKD patients in more detail and identify associations between novel measured biomarkers with risk of CKD progression;
2. Assess the effect of empagliflozin versus placebo on these biomarkers of acute kidney tubule function and dysfunction (the precise mechanisms for the remarkable renal benefits of SGLT2 inhibitors like empagliflozin are unknown); 
3. Assess whether the presence of such biomarkers modify the effect of empagliflozin versus placebo on the trial’s cardiorenal outcomes.

Funding for large-scale genotyping and proteomics is being sought, which would mean an even broader range of biomarker assessments would become possible for assessments 1-3 above. These data could also extend (or even change) the scope of a DPhil to assess the effects of other potential treatments for kidney disease theoretically using genomic and proteomic data to mimic the effects of a therapy. Potential applicants are encouraged to contact the supervisory team for updates on data availability and to develop a specific DPhil proposal.

RESEARCH EXPERIENCE, RESEARCH METHODS AND TRAINING

The project will provide a rich experience in its use of state-of-the-art phenotyping and biomarker measurements and an excellent grounding in both traditional and genetic epidemiological approaches to using such data. It is likely that this project will yield some important highly citable publications in the field of nephrology, but also lead to methodology publications.

FIELD WORK, SECONDMENTS, INDUSTRY PLACEMENTS AND TRAINING

There are no plans for fieldwork or industry placement as by the time that the project begins, all the necessary data should be available within the department. The student’s skills in such techniques will be enhanced and training on new methods will be provided (either by mentorship, or internal or external courses).

PROSPECTIVE STUDENT

The ideal candidate will have a Masters degree in a relevant area (e.g. statistics or epidemiology) or an equivalent level of experience and training. The candidate needs to be well-organised and inquisitive, with either a knowledge or willingness to learn the relevant clinical background to this project. Some background knowledge of renal disease is desirable but not essential.