Renal Medicine

Lesson of the week

Inhibition of the sodium glucose co-transporter SGLT2 is beneficial in diabetes, heart failure and chronic kidney disease. Data recently published from the EMPA-Kidney study, led by OKU colleagues Will Herrington, with Parminder Judge, Doreen Zhu and Richard Haynes, demonstrates a 28% risk reduction in the composite primary end point of cardiovascular death or kidney disease progression, and this benefit was evident down to an eGFR of 20. As a result, new NICE guidance recommends SGLT2i in CKD with eGFR 20-45 irrespective of proteinuria.

Citation: https://www.nejm.org/doi/full/10.1056/NEJMoa2204233 PMID: 36331190, and https://www.nice.org.uk/guidance/ta942

Clinical case
Presenter: Dr Ben Storey

Summary: Two cases of membranous nephropathy presented. The first case presented with pulmonary embolus in the distal right main pulmonary trunk. Subsequently he represented with breathlessness and lower limb oedema, albumin 19 and uPCR 1067mg/mmol. A presumptive diagnosis of primary membranous nephropathy was made, and subsequently confirmed by positive serum antibodies to PLA2R. Case 2 was a 44 year old of Pakistani heritage who presented with nephrotic syndrome, and was noted to have lighter facial skin compared to hands. Biopsy confirmed membranous nephropathy, and she admitted to use of skin lightening creams. High levels of mercury in the cream and the blood were confirmed. Hg levels and proteinuria slowly improved on cessation of the cream. Subsequently glomerular deposition of antibodies to NELL1 was confirmed.

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Teaching
Presenter: Dr Ben Storey

Summary: The pathophysiology of membranous nephropathy was reviewed. Venous thromboembolism risk is high (HR 10.8), especially if albumin <29. The majority of 'primary' cases of membranous are now recognised to be due to antibodies against glomerular proteins, most commonly PLA2R. A series of antibodies are now linked to membranous, NELL1 is recognised in tumour contexts and with exposure to indigenous medicines and mercury toxicity.

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Research
Presenter: Dr Matt Brook

Summary: Current immunosuppressive regimes for renal transplantation contribute to increased risk of malignancy and nephrotoxicity. There is experiment evidence for prevention of rejection and long term graft survival in animal models with infusions of expanded regulatory T cells. Data from the ONE study demonstrated safety of a Treg protocol in renal transplant recipients and Oxford is leading the ongoing Phase IIb TWO study. If you are interested in Treg therapy research for your specialty, get in touch with Matthew.brook@ouh.nhs.uk

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Presenter: Dr Katherine Bull
Summary: In order to improve renal disease classification and stratification, and to identify new therapeutic targets, we need new cellular approaches to renal pathology. These include single cell RNA profiling, spatial transcriptomics and proteomics, and tools to functionally validate candidate genes and pathways, including in vitro and in vivo disease models. This is illustrated by work in our group in a murine model of lupus nephritis. Renal single nuclei RNA sequencing identified mesangial de-differentiation into a more fibroblast like phenotype.

Gene editing in cultured human mesangial cells supports a functional role for a key mesangial protein in driving this phenotype. To translate these approaches to human tissue, we access samples through the Oxford based QUOD national kidney donor biobank, the Oxford Transplant Biobank, the Oxford Centre for Histopathology Research and the Oxford Kidney Pathology Atlas. The latter collects an additional core for research at the time of a clinically indicated renal biopsy. In human IgA nephropathy, with single nuclei sequencing, and glomerular transcriptomics, we can start to define cell type specific and early versus late disease signatures.

New technologies are allowing us to explore spatial RNA signatures at increasingly high resolution, revealing cell context and neighbour interactions. These new techniques present new methodological challenges to deconvolute and define cell boundaries in tissue. To address this, in collaboration with Heather Harrington in the Mathematics Institute, we have developed a topological analysis method to better harness the rich granular data in these new spatial platforms, with the ultimate goal of improving our understanding of renal disease pathology, in order to identify novel candidate therapeutic targets for glomerular kidney disease.

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Speciality Contacts

Dr Katherine Bull, Hon Consultant in Renal Medicine: katherine.bull@ndm.ox.ac.uk
Dr Ben Storey, Consultant in Renal Medicine: Ben.Storey@ouh.nhs.uk
Dr Matt Brook, Consultant in Renal Medicine: Matthew.Brook@ouh.nhs.uk