Department of Medical Sciences

Renal medicine

Docent Inga Soveri, MD, PhD, Prof. Bengt Fellström, MD, PhD, Docent Torbjörn Linde, MD, PhD, Dr Hans Furuland, MD, PhD

The overall objective of the research is to investigate means and methods for prevention of renal failure, and prevention and treatment of complications in renal failure. Our research program involves studies on cardio-vascular complications in chronic kidney disease and renal transplantation, studies on FGF-23 in renal failure, clinical studies on chronic kidney disease and haemodialysis as well as studies on new biomarkers for renal failure.

Inflammation and cardiovascular disease in renal failure is targeted in several of the different substudies, including inflammatory processes, oxidative stress, immunologic dysregulation and calcium-phosphate metabolic aberrations in uremia, addressed both in experimental and in clinical settings. Recently we have also finalized new approaches with regard to pathogenesis and treatment of IgA nephropathy, and commenced a new joint venture with the research group in Nanotechnology and Functional Surfaces. A substantial research grant has been approved for development of a new generation of dialysers and new devices for extracorporeal blood treatment. It is our firm belief that the outcome of this research will lead to an improved medical and social rehabilitation of patients with renal failure.

Projects - Renal medicine

Cardio Vascular Complications in Chronic Kidney Disease and Renal Transplantation

Bengt Fellström, Hans Furuland, Inga Soveri, Eva Carlsson, Hilde Kloster, Liina Vassil
Cardiovascular disease (CVD) is extremely common in patients with renal insufficiency, which includes dialysis and renal transplant patients. Our efforts are targeting the importance of e.g. endothelial dysfunction, oxidative stress, and inflammation as contributing factors to the high rate of CVD. An important part of our efforts is treatment studies, often initiated from our own unit. Such studies include the ALERT trial in renal transplant patients, the AURORA trial in haemodialysis patients, and the SHARP trial in preuremic and dialysis patients. In a new study we are investigating if a low-dose aldosterone blockade by Spironolactone may have a positive effect on cardiovascular morbidity and mortality in haemodialysis patients. We have also initiated a CV study in renal transplant patients studying CV biomarkers while switching from CNI based immunosuppression to a belatacept based regimen. Other trials involve e.g. studies in patients with IgA nephropathy using a corticosteroid compound acting primarily in the gut (budesonide) and results from a phase 2b trial demonstrated  reduction in proteinuria and stabilisation of renal function (GFR). In diabetic nephropathy, the benefit (and safety) of mineralocorticoid receptor antagonist is being investigated focusing on renal as well as cardiovascular endpoints (FIDELIO/FIGARO). Another study is focusing on effects on proteinuria and outcome in DM2 by use of of an endothelin receptor antagonist atrasentan ( SONAR ).

A new line of research in CVD in renal failure includes studies of complement activation, formation of microparticles  and screening of inflammatory markers using the multiplex  PLA technology. In addition we are also collecting samples such as plasma and vascular tissue for proteomics analysis in collaboration with Prof. J Bergqvist at SciLifeLab. Preliminary results are emerging and pointing at new potentially important pathways. In parallel vascular tissue from patients with ESRD and healthy controls(donors) are also captured for proteomics  studies  along the same lines. The dynamics of anti-PC levels in the course of dialysis is being studied as well as complement and contact systems to detect possible new players responsible for sustained inflammation in these patients.

In addition, the accuracy of GFR measurement has been looked into and the study on physiological variability of urinary biomarkers is ongoing.

Superb biobanks have been collected from the MIMICK, AURORA  and ALERT  trials, which we have used to analyze genomic aberrations in inflammation-related genes as well as telomere length in DNA material, and shown a striking relationship to the degree of inflammation, oxidative stress, fetuin levels and patient survival.. A regional biobank with follow-up in SNR (Swedish Renal Registry) is in a start-up phase and will be an important infrastructure in future biomarker research.

The role of FGF-23 in phosphate regulation and calcium/phosphate homeostasis in chronic kidney disease

Torbjörn Linde, PerAnton Westerberg
FGF-23 is a secreted growth factor that is produced in bone and circulates in the bloodstream to ultimately regulate phosphate handling and vitamin D production in the kidney. An important pathophysiological role of FGF23 has been implicated in several hereditary and acquired disorders.

Our studies, aiming to understand the molecular mechanisms and the endocrine action of FGF-23, are important for several reasons. Identification of FGF23 down-stream targets within the kidney proximal tubule as well as the parathyroid glands will be critical for understanding the molecular mechanisms of FGF-23 on Pi and vitamin D metabolism. Furthermore, it will provide opportunities to modify FGF-23 signalling and consequently to develop novel drug targets for disorders of calcium and Pi homeostasis.

Polycystic kidney disease (PKD)

Jan Melin, Hans Furuland, Inga Soveri, Bengt Fellström
A novel research path includes studies of biomarkers for progression of PKD , as well as initiation of a treatment study using Tolvaptan, which was just recently started. Patient recruitement has been going on and three patients in Uppsala have entered the study

A cardivascular risk calculator

Inga Sovieri, Bengt Fellström
A cardiovascular risk calculator for prevalent renal transplant recipients has been developed and externally validated. The calculator web-application can be accessed here.

References:
Sovieri I, Holme I, Holdaas H, Budde K, Jardine AG, Fellström B. A cardiovascular risk calculator for renal transplant recipients. Transplantation 2012, 15;94(1):57-62.

Sovieri I, Snyder J, Holdaas H, Holme I, Jardine AG, L'Italien GJ, Fellström B. The external validation of the cardivascular risk equation for renal transplant recipients: applications to BENEFIT and BENEFIT-EXT trials. Transplantation 2013, 15;95(1):142-7.