Nephrology

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Internal Medicine / Nephrology.

Description

The scientific research of the department of Internal Medicine – division Nephrology is concentrated around the pathophysiology and treatment of renal disorders, renal replacement therapy, transplantation in diabetes and regenerative strategies. It spans a broad area, ranging from prevention of renal diseases, slowing down progression, optimally applying dialysis and transplantation and regenerative solutions.

These subjects are strictly aligned with the ‘Top Referral Function’ (TRF) of the division. More specifically this concerns the TRF expertise in vascular access problems, thrombotic microangiopathy and complement-related kidney problems, systemic diseases with renal involvement, polycystic kidney disease, and kidney and islet transplantation. Furthermore our TRF function for primary glomerular disease, kidney disease related to pregnancy and cardiovascular disease, complex diabetes mellitus, and plasma exchange and immunoadsorption. In addition, our program also complements the recognition as a Rare disease Expertise Center for Complement-mediated renal diseases and for Maturity-Onset Diabetes of the Young (MODY).

All subjects studied fall in the LUMC medical research profile of Vascular and Regenerative Medicine, which fits well with Regenerative Medicine being one of the three healthcare-related topics that are part of the Dutch National Research Agenda. The overarching goal of our research, innovation in disease monitoring and therapy is built on strong pillars of basic science programs and ‘state of the art technologies’ in regenerative and stem cell biology, vascular biology, immunology, molecular biology and imaging.

Aim and focus

Research in the division is multidisciplinary and covers clinical, translational and basic areas with the aim to improve patient care. The division is organized in different subgroups that focus on the following subjects:
  • Glomerulonephritis
  • Dialysis and vascular access
  • Kidney transplantation
  • Pancreas and islet transplantation
  • Islet biology and neogenesis
  • Glomerular endothelial glycobiology
  • Kidney regeneration and the bioengineered kidney
  • Pericyte biology and microvascular stabilisation

Position in international context

At the international level our lead scientist coordinated or are actively involved in several EU-sponsored projects including consortia (STELLAR, FP7) on the use of kidney derived stromal cells for therapeutic use in kidney failure, RECORD-KID with Murdoch Children's Research Institute (MCRI, Melbourne, Australia) in the re-cellularization of kidney scaffolds and with international partners of RegMed XB on the use of iPS-derived kidney organoids in regenerative medicine. In addition our researchers display international leadership by serving on international scientific boards including that of Eurotransplant, the working group on vascular tissue engineering at TERMIS (Tissue Engineering International & Regenerative Medicine Society) and the Immuno-nephrology Working Group ERA/EDTA. Finally, Dr. F. Lebrin directs the strategic alliance with INSERM (Paris) to develop ultrafast Doppler for intravital imaging.
At the national level, researchers of the division are actively involved in several consortia for example subsidised by the Dutch Kidney Foundation, the Dutch Heart Foundation as well as ZonMw (The Netherlands Organisation for Health Research and Development). Prof dr Ton Rabelink is the assigned NFU (The Netherlands Federation of University Medical Centres) figure head for the Regenerative Medicine route of the Dutch Science Agenda. Recently the public-private partnership Regenerative Medicine Crossing borders (RegMed XB) has started involving several health foundations, companies, several universities and the Topsector Life Sciences & Health. 

Content / highlights / achievements

  • A successful Phase 2a trial using combination of belumimab and rituximab in severe refractory SLE (SynBioSe) showing a pathophysiological connection between autoantibodies and NETosis (Autoimm Rev 2016).
  • Recognition as a an expertise center for C3 glomerulopathy and complement-mediated renal diseases and development of tools to monitor complement activation in experimental models and clinical conditions (COMBAT consortium).
  • Development and evaluation of in vivo tissue engineered blood vessels in a porcine model (Biomaterials 2016)
  • A multicenter, double-blinded, placebo-controlled randomized controlled trial on the effect of liposomal prednisolone on fistula maturation (LIPMAT study, J Vasc Access 2017)
  • A phase I trial of safely applying MSC in kidney transplantation (Stem Cell TM 2013), followed by a phase 2 trial (TRITON study) aimed at applying allogenic MSC to allow calcineurin withdrawal, combined with state of the art immune monitoring (TAS fund 2017).
  • Demonstrating the pivotal role of innate immunity and complement in ischemia reperfusion injury (Am J Transpl 2012) and develop a biomarker platform (urine, serum and tissue), combining hypothesis-driven injury markers as well as unbiased methods such as proteomics and metabolomics which can be applied in transplantation and polycystic kidney disease (DIPAK consortium)
  • Improvement of human islet isolation and preservation protocols combined with peri-transplant strategies and novel immunosuppressive regimen in clinical transplantation (Am J Transpl 2016)
  • Mechanisms of endocrine cell conversion and beta-cell plasticity (Diabetes 2013), combined with the identification and exploration of alternative sources of beta cells (RegMed XB). 
  • First demonstration of the essential role of the glycocalyx on glomerular endothelial cells in the prevention of albuminuria (Nat Rev Nephrol 2012, 2015), and innovative approaches to counteract loss of this glycocalyx under hyperglycemic conditions (Diabetes 2016).
  • Characterize the biochemical components of the human kidney scaffold and the role of the extracellular matrix in morphology, migration, proliferation, differentiation and cell survival of different renal cells including endothelial and epithelial cells and kidney cells derived from human induced pluripotent stem cells (hiPSCs).
  • Generation of kidney organoids using human induced pluripotent stem cells (hiPSC) that contain complete nephrons (collaboration with Dr. Little Melbourne), and investigate improvements of maturation and vascularization of the kidney organoids using advanced imaging technologies (2-photon, scanning and transmission electron microscopy)(RegMed XB)
  • Novel circulating (post-transcriptional) markers for microvascular injury in diabetic nephropathy and kidney transplant rejection (J Am Soc Nephrol 2014, Kidney Int 2016)
  • Identification of post-transcriptional networks in vascular injury and repair and the role of the role RNA-binding protein Quaking (Circ Res 2013, Sci Reports 2016, Nat Com 2016) (Irvine H. Page award 2016).

Future themes

Strategy for the coming years involves continuation of the current research lines within the Einthoven Laboratory for Vascular and Regenerative Medicine (www.einthovenlaboratory.com). Regenerative research lines will be further developed aiming both at intrinsic regeneration of the kidney as well as on long term goals to expand and mature kidney organoids for renal replacement therapy (RegMed XB). A novel theme involves the progressive use of advanced microfluidics-based organ- and microvessel-on-a-chip platforms that may in part replace animal models and allow the study of human tissues. To that we actively participate in the human organ and Disease Model Technology (hDMT) platform (van Zonneveld), an initiative aimed to promote collaboration and funding opportunities for in vitro organ models.
Our clinical and translational studies will focus on innovative cell- and immune-therapy in both the transplantation setting and in glomerulonephritis, in combination with state of the art immune-monitoring tools.

Cohesion within LUMC

Research of the Nephrology division is performed in the context of the Einthoven laboratory for Vascular and Regenerative Medicine as part of the department of Internal Medicine, which includes divisions of Endocrinology and Thrombosis Haemostasis. In addition, there is a close collaboration with several departments within the LUMC, including departments of Rheumatology, Surgery, Molecular Cell Biology, Immunohematology and Blood Transfusion, Clinical Chemistry and Epidemiology, as well as with the Technology Focus Areas of the Center for Proteomics and Metabolomics, the Center for Light and electron microscopy and the LUMC Flow cytometry Core Facility (FCF). All transplantation-related research is aligned with the developing research lines within the newly established (april 2017) LUMC Transplant Center.
Although this program is part of the biomedical research profile ‘Vascular and Regenerative Medicine’, there is a lot of interaction with research form the research profile ‘Infection, Immunity and Tolerance’. The research is part of the generic LUMC research profile ‘biomedical imaging’.