Immunopathology of vascular and renal diseases, and of organ and cell transplantation (Pathology 1)

Aim and focus

Research of our group focusses on the immunopathology of vascular and kidney disease. The vascular system has the ability to repair injury inflicted by hemodynamic, metabolic, inflammatory or genetic alterations. However, in a large number of patients with kidney diseases, the natural capacity of the vasculature and the renal tissue to repair and to remodel its original architecture is impaired or has been lost. Independent of the underlying aetiology of kidney disease, glomerular injury will eventually progress as “final common pathway” to glomerulosclerosis and degeneration of the tubular system. Sclerosis in the kidney is characterized by excessive accumulation of extracellular matrix components. This is accompanied by loss of cells via apoptosis and progressive scarring of renal tissue.

We have established a number of research lines in which we aim to elucidate the underlying mechanisms of defective vascular and epithelial repair in different types of kidney disease (diabetic nephropathy, lupus nephritis, ANCA-associated vasculitis, polycystic kidney disease, IgA nephropathy, focal segmental glomerulosclerosis, preeclampsia, and renal allograft rejection).

Our aims are: 

• to investigate the immunopathology of kidney disease
• to unravel underlying genetic alterations and to functionally characterize their impact on the development of renal injury 
• to analyse cellular processes involved in the development of fibrotic, sclerotic and necrotic lesions. The goal is to implement our findings in clinical medicine and to develop new strategies for treatment.

Position in international context

Our group is renowned for their contribution to the understanding of the pathogenesis of diabetic nephropathy (VEGF function, carnosine metabolism) and preeclampsia (underlying mechanisms, role of the complement system). This has resulted in a significant number of high impact publications and review articles. As result, members of our group are regularly invited as speakers on international meetings on kidney disease. Results obtained within the European KP6 consortium “Predictions” ( www.rzuser.uni-heidelberg.de/~jb5/) have led to the formation of a European carnosine consortium (http://users.unimi.it/carnosine_co/). In this consortium, researchers are collaborating on answering carnosine-related questions regarding functional genetics, sports physiology, neurology, food supplement industry and cell biology. Possible applications of carnosine treatment in renal disease are investigated together with the group of Prof. Benito Yard (Mannheim, Germany) and Prof Wim Derave (Gent, Belgium). We also aim at identifying new players involved in the development of kidney disease. This is performed in close collaboration with Prof. Reinhold Kreutz (Berlin, Germany).

In a longstanding fruitful collaboration with the group of Prof. Dorien Peters (Dept. Human genetics), we investigate the pathogenic mechanisms of polycystic kidney disease. These joint efforts have resulted in the establishment of the Dutch consortium (‘DIPAK’) funded by the Dutch Kidney Foundation. Members of the consortium perform cutting edge experimental research and have also set up a national clinical trial for patients with autosomal dominant polycystic kidney disease.

Results of our research also contributed significantly to classification, diagnosis and treatment of renal diseases worldwide. We have co-authored International Society of Nephrology/Renal Pathology Society (ISN/RPS) classifications of focal segmental glomerulosclerosis and lupus nephritis. In addition, we have actively participated in an international panel of experts leading to a novel classification for IgA nephropathy (the Oxford classification). Moreover, we have initiated and chaired two international consortia for the development of new classification systems for diabetic nephropathy (under the auspices of the Renal Pathology Society) and ANCA-associated glomerulonephritis (in collaboration with EUVAS, the European Vasculitis Study Group). These classifications are now international standards for clinical and pathological evaluation of these complex diseases. Recently, we joined an international workgroup that will establish pathologic criteria for C3 glomerulopathy, and we were part of the 2015 KDIGO Conference for C3 glomerulopathy.

Numerous joint publications in high impact journals are the result of ongoing international collaborations.

Content / highlights / achievements

Major findings:

• Identification of the TGF-b co-receptor endoglin as major regulator of the inflammatory status of the vasculature and of fibroblast-to-myofibroblast differentiation in diabetic nephropathy in this way providing a novel target for intervention.
• Establishing the podocyte slit pore protein nephrin as biomarker to predict remission and long-term renal outcome in patients with minimal change disease.
• Identification of a novel podocyte expressed candidate gene (Tmem63c) in the development of albuminuria.
• Carnosine Attenuates the Development of both Type 2 Diabetes and Diabetic Nephropathy in BTBR ob/ob Mice
• The VEGF-A inhibitor sFlt-1 improves renal function by reducing endothelial activation and inflammation in type 1 diabetes
• Stability and Species Specificity of Renal VEGF-A Splicing Patterns in Kidney Disease
• Identification of novel candidate genes predictive for / involved in the development of progressive renal or vascular disease. Functional analysis of these genes using zebrafish embryos as in vivo screening system.
• Anti-plasminogen antibodies compromise fibrinolysis and are associated with glomerular lesions in ANCA-associated vasculitis.
• Glomerular deposition of C4d, a split product of the complement cascade, is an indicator for thrombotic microangiopathy in lupus nephritis.
• Presence of C4d in the transplanted pancreas and anti-donor antibodies correlate with a worse prognosis.
• Transplanted kidneys show an increase in the number of lymphatic vessels, which is positively correlated with transplant survival.
• Tissue microchimerism is increased during pregnancy
• Activation of Smads is increased in experimental models and patients with polycystic kidney disease. This was not accomplished by activating TGF-β signalling, but by activation of the Hippo pathway downstream of the Activin receptor.
• Sclerotic class ANCA-Associated GN increases the instantaneous risk of renal relapse
• Rituximab treatment in ANCA-associated vasculitis is not associated with an increased malignancy risk compared to the general population
• Recurrence of ANCA-associated GN in the renal allograft contributes to graft loss
• Diabetic nephropathy is underdiagnosed in patients with diabetes as it may develop before the onset of clinical findings
• Complement Factor C4d is a common denominator in thrombotic microangiopathy
• Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis.

Future themes

Within the medical research profile ‘Vascular and Regenerative Medicine’, our main focus will be to:

• exploit the potential of anti-endoglin therapy to reduce vascular activation and fibrosis in diabetic nephropathy.
• functionally characterize further novel candidate genes that potentially play a role in the development of albuminuria, but may also be involved in promoting endothelial damage in kidney disease.
• investigate endothelial-podocyte crosstalk in focal segmental glomerulosclerosis in order to get a better understanding of the underlying pathogenesis and to identify novel treatment targets.
• elucidate the role of the complement system in different types of kidney disease.
• study the therapeutic potential of sFlt-1 in diabetic nephropathy and other immune mediated renal diseases.
• investigate carnosine metabolism and effects of carnosine supplementation on diabetic nephropathy. This will be accomplished within a European research consortium.
• unravel the underlying mechanisms of kidney disease in preeclampsia.

Within the medical research profile ‘Innovation in Health Strategy and Quality of Care’, we will:

• analyse the implementation of clinical-pathological classification systems for various renal diseases. This will be executed in close collaboration with the Renal Pathology Society (RPS).

Cohesion within LUMC

This research is conducted in extensive collaborations with the Departments of Nephrology (133 papers and 12 PhD theses together with the Dept. Nephrology), Endocrinology, Human Genetics, Epidemiology, Rheumatology, Obstetrics, and Immunohematology. The immunopathology group is also well-embedded in the medical research profiles ‘Vascular and Regenerative Medicine’ and ‘Innovation in Health Strategy and Quality of Care’ and in several ‘Centres of Excellence’, namely for Rare Autoinflammatory Diseases and for Complement Mediated Renal Disease, and ‘Translational Research Funds’ (C3/MPGN; Hereditary Kidney Diseases) and TRFs (Niertransplantatie, NPSLE, Diabetes Mellitus).