Kidney Research

In the kidney team at Department of Urology at Aarhus University Hospital our aim is to improve the outcome for patients with kidney diseases that are managed surgically. In our daily practice we cover all areas of diagnostic workup, surgical and ablative treatment of kidney tumors. Furthermore, we also manage patients with chronic renal failure who are in need of dialysis or a kidney transplantation.

Our research in the kidney team covers all the above aspects, with special focus on improving the outcome after kidney transplantation, kidney cancer and kidney fibrosis. Our research is carried out in clinical studies and in large experimental animal models in multidisciplinary collaborations with local and international groups within the area.

Projects

DCB-REN

Collection of blood and urine under the auspices of the Danish Cancer Biobank (DCB) for research into renal cancer.

The collection takes place in collaboration with the Department of Molecular Medicine MOMA

Primary responsibility: Professor, Consultant, DMSc Jørgen Bjerggaard Jensen

PRE-IMAGE: PREPAIR-1

PRE-IMAGE: PREPAIR-1: Physiology of Renal Ex vivo Perfusion for organ Assessment and Injury Repair – 1

The PRE-IMAGE project aims to determine the molecular mechanisms of ex vivo kidney perfusion prior to renal transplantation in order to develop breakthrough pre-transplant perfusion-based diagnostic markers that can indicate kidney transplant outcomes and to establish the added value of pre-transplant normothermic ex vivo kidney perfusion. (Pre-IMAGE.eu)

PREPAIR-1
Physiology of Renal Ex vivo Perfusion for organ Assessment and Injury Repair – 1 is carried out in Aarhus University Hospital. In PREPAIR-1, a preclinical model will be utilized to identify molecular biomarkers that define the effect of ex vivo normothermic perfusion on porcine kidneys and how ex vivo perfusion differs from a kidney perfused in vivo. First, both kidneys of each animal are imaged in vivo in an MRI scanner, while under general anesthesia. Next, both kidneys are surgically retrieved and perfused ex vivo. One kidney of each pair will be exposed to warm ischemic injury. From both kidneys, tissue biopsies and circulating perfusate / blood samples will be taken just prior to retrieval and, subsequently, each hour during ex vivo perfusion. Radiological data are obtained while the anesthetized pig and the ex vivo machine are placed in an MRI scanner. Molecular multi-omics and radiomics analyses will be performed. Ex vivo and in vivo findings will be longitudinally contrasted in order to characterize the typical effect that ex vivo perfusion has on an isolated kidney.

Collaboration
The project is a collaboration between Department of Organ Donation and Transplantation, University Medical Center Groningen, The Department of Urology, Aarhus University Hospital The department of nephrology, Aarhus University Hospital and The MR Research Center, Aarhus University,

Contact 
PhD student Tim Hamelink (t.l.hamelink@umcg.nl)
Anna Krarup Keller (anna.keller@clin.au.dk), Department of Urology

Precision-cut kidney slices: a translational model of renal fibrosis

Title
Precision-cut kidney slices: a translational model of renal fibrosis

Aim
Renal fibrosis, characterized by the excessive deposition of extracellular matrix proteins, is a driver of progressive chronic kidney diseases. During disease progression, fibrotic lesions replace functional tissue ultimately resulting in organ failure, necessitating the need for renal replacement therapy or renal transplantation. To date, anti-fibrotic therapeutics are hardly available, and drug development is impeded by the lack of appropriate cell and animal models to study human fibrosis. In vitro models lack cellular heterogeneity, which is a prerequisite to mimic the multicellular character of fibrosis, while animal models often do not recapitulate human pathophysiology. To overcome these issues, our lab uses human precision-cut kidney slices (PCKS) to study renal fibrosis and as drug-screening platform.     

Method/description
PCKS is a unique model that is more physiologically relevant as compared to most of the currently used in vitro systems. Each slice contains all cell types and acellular components of the whole organ in the original configuration, while preserving cell-cell and cell‐matrix interactions. In other words, PCKS are miniaturized organs that retain native tissue architecture and intact cellular environment, making it an extremely useful model to elucidate the process of fibrogenesis and to accelerate the search for effective anti-fibrotics. In our lab, PCKS are prepared from human renal tissue obtained from either 1) tumor nephrectomies – selecting for macroscopically healthy cortical tissue or 2) end-stage renal disease nephrectomies/transplantectomies. The first group is regarded as healthy and can be used to study the onset of renal fibrosis, while the second group is used to study established fibrosis. In short, PCKS is a useful and versatile translational tool to study renal (patho)physiology.

Collaboration
The project is a collaboration between Departments of Clinical Medicine, Biomedicine, iNANO, Aarhus University, and The Department of Urology, Aarhus University Hospital.

Contact
Associate Professor Rikke Nørregaard, RN@clin.au.dk
Assistant Professor Henricus A.M. Mutsaers, h.a.m.mutsaers@clin.au.dk, Department of Clinical Medicin
Mia Gebauer Madsen, miamadse@rm.dk or www.norregaardlab.com, Department of Clinical Medicine
Anna Krarup Keller, anna.keller@clin.au.dk, Department of Urology

Imaging immuno-fibrogenic kidney metabolism with hyperpolarized MRI

Title
Imaging immuno-fibrogenic kidney metabolism with hyperpolarized MRI

Aim
Kidney fibrosis is casually linked with the progression of kidney disease to end-stage disease. Early detection and continuous assessment are warranted for development, initiation, and follow-up of anti-fibrotic drugs. In this study, we aim to understand if a metabolic MRI technology, hyperpolarized MRI, can detect the early metabolic changes that follow development of fibrosis, ultimately allowing detection of the early stages of fibrosis. We will obtain tissue from nephrectomies for biochemical analysis of metabolism. The results will be compared to MRI scans and biopsies from animal models of kidney fibrosis. We expect the project to elucidate the translational potential of metabolic MRI in kidney fibrosis.

Collaboration
The project is a collaboration between The MR Research Center, Aarhus University, and The Department of Urology, Aarhus University Hospital.

Contact
The MR Research Center: Nikolaj Bøgh, nikolaj.boegh@clin.au.dk
Department of Urology: Anna Krarup Keller, anna.keller@clin.au.dk.

VITALIZE

Title
Donor kidney Vitality prediction and real-time therapy monitoring using nanoparticles applied during machine perfusion: Towards Zero organ waste (VITALIZE).

Aim
The VITALIZE project aims to develop an objective method to quantify pre-transplant kidney quality, to diminish organ waste and better utilize available kidneys. As of now expanded criteria donors and donation after circulatory death are increasingly being used. With the use of these marginal kidneys comes an added risk and with the lack of reliable and objective assessment tools it might lead to poor kidney transplants or potential kidney grafts being discarded. Moreover, normothermic machine perfusion makes it possible to have an active metabolizing kidney in an ex-vivo setup, hereby creating a unique opportunity to assess kidney vitality. To exploit that opportunity, we have a setup combining normothermic machine perfusion, nanoparticle-based biosensors, and near-infrared-fluorescence whole kidney imaging. Ultimately, we will investigate the diagnostic value of our method through comparison of damage and healthy porcine kidneys.

Collaboration
The project is a collaboration between Department of Organ Donation and Transplantation, University Medical Center Groningen, The Department of Urology, Aarhus University Hospital, The department of nephrology, and the interdisciplinary Nanoscience center (iNANO), Aarhus University.

Contact 
Research year student Jesper Staulund, Jesperstaulund@clin.au.dk
Anna Krarup Keller, anna.keller@clin.au.dk, Department of Urology
Marco Eijken, m.eijken@clin.au.dk, Department of Nephrology

Targeting the activin-signaling pathway during normothermic machine perfusion as a novel therapy in kidney transplantation

Titel: Targeted therapeutic intervention during normothermic machine perfusion as a novel therapy in kidney transplantation

Background
Following clinical implementation of hypothermic machine perfusion (HMP) prior to kidney transplantation, ex-vivo normothermic machine perfusion (NMP) has been intensely studied as a promising tool for assessment and reconditioning of kidney function. Additionally, NMP provides an opportunity for ex-vivo pharmacological intervention before transplantation. Ex-vivo pharmacological intervention targeted towards the inflammatory pathways associated with the initiation of acute kidney injury are therefore promising novel therapies in the prevention of ischemia-reperfusion injury.

Aim
The aim of this project is to evaluate the feasibility of different biological-based therapeutic interventions during ex-vivo NMP with the intention to prevent the signalling of different inflammatory pathways during NMP, hopefully leading to a better post-transplant outcome.

Methods
Paired porcine kidneys are exposed to a period of warm ischemia following overnight HMP and subsequent NMP using erythrocyte-based perfusate. During NMP, kidneys are randomized to therapeutic intervention or control. Samples from tissue, perfusate and urine are continuously collected to evaluate the effect(s) of intervention.

Perspectives
Providing a proof of concept of the feasibility and safety of ex-vivo pharmacological intervention during NMP could improve the clinical results of kidney. Follow-up studies will be able to combine ex-vivo treatment with an auto-transplantation model to investigate outcomes of intervention following transplantation.

Collaboration
Department of Renal Medicine, Aarhus University Hospital
Department of Urology, Aarhus University Hospital
Department of Organ Surgery and Transplantation, University Medical Center Groningen

Contact:
Thomas Weiss, Research year student
Department of Renal Medicine
Thowei@clin.au.dk
+45 50720944

Pernille Duedahl, Research year student
Department of Renal Medicine
perdue@post.au.dk
+45 25794406

PRE-TREAT: Post transplant fibrosis prevention through RNA treatment of donor kidneys

Background and aim 

Owing to organ shortage, new policies regarding donor criteria have been implemented such as extended criteria donors (ECD) and donors after circulatory death (DCD). These organs are more susceptible to the well-known ischemia reperfusion injury and therefore, more prone to develop, among others, post-transplant fibrosis. Fibrosis is the leading cause of reduction in graft function and graft survival after transplantation. Kidney ex vivo machine perfusion during organ preservation poses the perfect platform for targeted interventions to these marginal kidneys. Moreover, the combination of ex vivo machine perfusion with mRNA therapy has great potential to prevent fibrosis as mRNA has transient effect. mRNA is delivered to the cells and then translated to a therapeutic protein. Therefore, even though it is delivered during ex vivo machine perfusion its effects continue after transplantation.  

In a porcine model, The PRE-TREAT project aims to develop an mRNA-based treatment strategy to prevent post transplant fibrosis development for marginal donor kidneys combining mRNA therapy with ex vivo kidney machine perfusion.  

Collaboration 

This project is in collaboration with the interdisciplinary nanoscience institute (iNANO) at Aarhus University, the department of Urology, Nephrology and the Nørregard lab at Aarhus University Hospital.  

Contact

PhD student, Cristina Ballester Bergada (crisballester@clin.au.dk).  

Anna Krarup Keller (anna.keller@clin.au.dk), Department of Urology. 

Marco Eijken (m.eijken@clin.au.dk), Department of Clinical Medicine. (main supervisor) 

KIDNEY-PAGER - Analysis of circulating tumor DNA as a biomarker in renal cancer

Aim
The KIDNEY-PAGER project aims to investigate the potential of using circulating tumor DNA (ctDNA) as a prognostic marker in renal cell carcinoma (RCC). We will analyze ctDNA in plasma and urine samples before and after curatively intended nephrectomy, as well as longitudinally during follow-up. We hypothesize that ctDNA detected before surgery of the primary tumor can identify patients with a high risk of recurrence, that ctDNA detected after surgery can identify subclinical residual disease, and further that ctDNA will be applicable for more sensitive recurrence detection during surveillance when compared to CT scans. The study is an observational study initiated to confirm the prognostic role of ctDNA in RCC with blood and urine samples taken prospectively during surveillance until five years of follow-up. Ultimately, results will improve RCC management through initiation of future ctDNA-guided clinical trials. 

Collaboration
Department of Urology, Aarhus University Hospital
Department of Molecular Medicine, Aarhus University Hospital 

Contact
Anna Krarup Keller (anna.keller@clin.au.dk)
Iben Lyskjær Heimann (iben.lyskjar@clin.au.dk

Research Coordinator for kidney research projects

Anna Krarup Keller

Clinical Associate Professor

PhD students

Research Year Student

Frederik Deutch

Email: frederik.deutch@clin.au.dk

Other research contacts

Mia Gebauer Madsen
Overlæge
miamadse@rm.dk