Research team

Pathophysiology

Development of a cutting-edge service platform for in vivo preclinical testing of drug candidates able to treat chronic kidney disease and its associated co-morbidities. 01/09/2020 - 31/08/2021

Abstract

Disorders of mineral metabolism, specifically calcium and phosphorus homeostasis, are common in patients with chronic kidney disease (CKD), diabetes and osteoporosis. CKD is a world-wide recognized public health problem affecting 8-16% of the world population. Also the prevalence of diabetes and osteoporosis is high (12.3% for diabetes and 30% for osteoporosis of all postmenopausal women) and still increasing. Essentially, these three disorders of mineral metabolism typically share interconnected features including renal failure, vascular calcification and aberrant bone metabolism. CKD represents a progressive loss of renal function over a period of months or years ultimately leading to end-stage renal disease, which inevitably requires renal replacement therapy, i.e. dialysis and kidney transplantation. Vascular calcification in the medial layer of blood vessels is a major clinical problem and the most important cause of death in CKD patients. Structures similar to bone and cartilage are detected in the calcified arterial wall thereby mimicking bone formation. In addition, the disturbed mineral metabolism in CKD patients leads to the development of renal osteodystrophy which ultimately result in a reduced bone strength and increased incidence of bone fractures. The concomitant occurrence of a disturbed bone metabolism with a pathological calcification of the vessel wall in CDK patients is referred to as "the calcification paradox", which is also observed in diabetes and osteoporosis patients. The strong increase in the number of elderly boosts the prevalence of aging-related disorders such as CKD, diabetes and osteoporosis, and herewith the interest of pharmaceutical companies in clinical as well as preclinical research on these disorders. During the last decade, the Laboratory of Pathophysiology has developed unique animal models for the in vivo investigatation of different aspects of this interconnected triad (kidney, vessels and bone) in mineral metabolism disorders. These animal models besides investigation of fundamental mechanisms underlying these pathophysiological processes also allow to intervene in these processes by candidate therapeutics. This unique combination of animal models, substantiated by fundamental pathological knowledge, resulted in a cutting edge platform for preclinical (animal model) drug testing, which successfully attracted contract research with industrial partners resulting in an income of 500k€/year during the last decade. From our unique position at the interface between academics and industry, we note that industrial interest is shifting from symptomatic treatment (hypertension or hyperphosphatemia) towards a direct interference with CKD and vessel wall calcification. To anticipate this trend and level-up the valorization potential of our current platform of animal models, this IOF-service platforms project aims to expands its portfolio and setup novel innovative animal models to guarantee a further increase in industrial revenue.

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Quantitating nephrectomy induced renal epithelial repair. 01/04/2020 - 31/03/2021

Abstract

Acute kidney injury (AKI) is characterized by a temporary failure of renal function leading to a dysregulated body fluid homeostasis and accumulation of metabolites and waste products. Clinical studies of the last decade identified that AKI, which is considered reversible, actually is an important risk factor for the development of chronic kidney disease (CKD). The tubular epithelial cell plays a crucial role in this. Despite its high sensitivity to toxic and ischemic insults, this cell type has a significant regenerative capacity and contributes heavily in repair by replacing deathly injured cells through cell division. Repair, however, is not always successful and chronic kidney disease may develop. To date, there are no treatments that directly target the injured kidney, enhance its repair or prevent the subsequent progression towards CKD. The intriguing biological phenomenon of "nephrectomy-induced enhanced renal recovery" has the potential to adress these issues. This phenomenon comes down to the observation that an acutely injured kidney shows a remarkable degree of recovery when the healthy contralateral kidney is removed (i.e. nephrectomy) shortly after the insult. As a necessary first step to exploit this phenomenons full potential, we here, by lineage tracing analysis in transgenic mice, will quantitate to what extent nephrectomy is able to stimulate proliferation of tubular epithelial cells and tubular epithelial progenitor cells in the injured kidney.

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High-resolution slide scanner for digital histopathological phenotyping in health and disease. 01/01/2020 - 31/12/2021

Abstract

Digital pathology involves high-speed, high-resolution digital acquisition of images representing entire stained tissue sections from glass slides and allows them to be viewed directly in much the same way as standard microscopy. While this creates a permanent record of histological slide data and facilitates data sharing with collaborators, importantly, it allows analysis, quantification and objective pathological assessment of entire tissue samples, which is now current practice in pre-clinical and clinical research. We propose to acquire a high-resolution whole-slide scanner, notably absent at UA, not only to facilitate research at the promotors' groups, but virtually any research group performing basic, pre-clinical or clinical research at UA involving histopathology. We firmly believe that acquisition of such a digital scanner will help research groups at UA to stay competitive in biomedical research, facilitate and forge scientific and industrial collaborations at UA and beyond, and generate important industrial revenues.

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Toxin induced lysosomal storage disease: a new etiological, mechanistic, diagnostic and prognostic paradigm for the worldwide increasing prevalence of agrochemical-associated nephropathy. 01/01/2019 - 31/12/2022

Abstract

Chronische nierinsufficiëntie (CKD) is een klinische conditie gekenmerkt door the progressief verlies van functionele renale massa. Gedurende de laatste 20 jaar werd in een aantal agrarische gemeenschappen een continue stijging van patiënten met chronische nierinsufficiëntie waargenomen, die wereldwijd miljoenen menen treft. De ziekte werd Chronische Interstitiële Nefritis in Agrarische Culturen genoemd (CINAC). Daar waar chronische dehydratie door sommigen als de voornaamste oorzaak van de aandoening werd voorgesteld, is er momenteel meer en meer evidentie voor blootstelling aan agrochemicaliën als belangrijkste oorzaak. De oorzakelijke oorzaak en onderliggende mechanismen blijven echter nog steeds een onderwerp van discussie.

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The use of metformin in the battle against chronic kidney disease and its cardiovascular complications. 01/10/2017 - 30/09/2021

Abstract

Over the past decades metformin is the optimal first-line drug for type 2 diabetes mellitus (T2DM) with 70 million prescriptions in the United States in 2013. Only in the last few years, it has become clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on its anti-ageing and anti-cancer properties. Recent data from preclinical and clinical studies are additionally pointing towards a putative beneficial impact of metformin on the kidney and cardiovascular system. Chronic kidney disease (CKD) is a world-wide recognized public health problem affecting 8–16% of the world population and represents a progressive loss of renal function over a period of months or years ultimately leading to end stage renal disease (CKD stage 5) which inevitably requires renal replacement therapy, i.e. dialysis or kidney transplantation. CKD also confers a markedly increased risk of cardiovascular disease (mainly vascular calcification) which accounts for 50% of all deaths in this population. Current treatment strategies for bot CKD and vascular calcification mainly focus on controlling important risk factors, however to date, effective treatment directly targeting the kidney and/or the vessels is lacking. Therefore the current project aims to investigate the possibility to use metformin in the treatment/prevention of CKD and its most important complication vascular calcification. Hereto the following objectives are put forward: (1) to investigate whether metformin is able to slow down or arrest the progression of CKD in rats with mild to moderate CKD and (2) to investigate whether metformin can prevent calcification in the arteries in an established rat model of vascular calcification. For the whole project, we will study the effect of metformin at the functional, structural (histopathological) and mechanistic level of the kidney and the aorta. Therefore, we will use both conventional and novel, more challenging techniques. If this project manages to demonstrate that this agent is able to retard or effectively halt the progression of CKD and to prevent, slow down or even arrest the development of vascular calcification, one of the major comorbidities of CKD, a major step forward will be taken in the treatment of this expanding population in our ageing society. Undoubtedly, such a finding will have far-reaching clinical and social benefits for the patients as well as a significant financial relieve for health insurance systems, taken into account the low cost of this generic drug (few euros/month) versus the high financial impact of dialysis and transplantation.

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Functional and cell biological validation of a unique model of chronic kidney disease with a tunable degree of renal dysfunction 01/04/2017 - 31/03/2018

Abstract

Chronic kidney disease (CKD) is characterized by a progressive decline in renal function, clinically divided in 5 classes, each with an own set of physiological characteristics and putative therapeutic measures. Basic as well as therapeutic/interventional studies are particularly performed in animal models that pay little or no attention to the actual degree of renal dysfunction. Extrapolating findings of these studies to a class of CKD, often proves challenging, yet is indispensable. Moreover, pre-clinical compounds that show no effect in severe renal dysfunction (CKD 4-5) are likely to be dropped from further development, whereas they might have been beneficial in milder (i.e. earlier) CKD-conditions (CKD 2-3). To address this issue and facilitate translational renal research, we here propose a new animal model with a tunable pre-defined degree of renal dysfunction. The model combines unilateral renal ischemia/reperfusion with delayed contralateral nephrectomy, where the nephrectomy delay-time determines the degree of eventual CKD. In the current project, we particularly aim to validate this model both on the functional as well as cell biological level by state-of-the art transcutaneous renal function measurement on the one hand and tissue repair analysis on the other hand.

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Cell cycle control in proximal epithelial cells during progression of acute kidney injury to chronic kidney disease in vivo. 01/01/2013 - 31/12/2016

Abstract

The proposed project aims at getting profound molecular insight in cell cycle control of the proximal tubular epithelial cell in injured kidneys, an event recently recognized to play a critical role in the progression of acute kidney injury to chronic kidney disease.

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DNA methylome and RNA transcriptoom analysis in proximal tubular cells, blood and urine during development of chronic kidney disease in mice 01/01/2012 - 31/12/2012

Abstract

Chronic kidney disease encompasses all renal conditions which, irrespective of their cause, are characterized by histomorphological damage and/or a decreased glomerular filtration rate (<60 ml/min/1,73m2), either of which are present for at least 3 months. Up to now, end stage renal disease (i.e. the final stage of chronic kidney disease) can only be treated by dialysis or transplantation. DNA methylation is an epigenetic modification of DNA governed by DNA methyltransferases (Dnmts). DNA methylation generally suppresses transcription and plays an important role in the development of cancer. It also is an important etiological factor in other pathologies, such as renal fibrosis. Fibrosis is the cell biological process underlying chronic kidney disease. By losing control of the normal reparing fibrotic process, healthy tissue is affected and progressively replaced by non-functional fibrous tissue. Two renal cell types play a crucial role herein: (1) the proximal tubular epithelial cell, which produces pro-fibrotic cytokines (TGF-β, CTGF) in response to damage/stress, and (2) the fibroblast, which in a pro-fibrotic environment is activated to proliferate and produce extracellular matrix (ECM, fibrous deposition). If exposure of fibroblasts to this environment is sufficiently long, fibroblasts get terminally activated, resulting in chronic renal fibrosis. Up to now, the role of DNA methylation in the PTC is unknown. The goals of this project are: 1) identification of differentially methylated genes of PTCs associated with development of chronic kidney disease after acute kidney injury and 2) correlating DNA methylome and RNA-transcriptome analysis in PTC, urine and blood in order to progress towards diagnostic and therapeutic markers.

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Cellular and experimental research of causal factors in nephrolithiasis. 15/02/2004 - 30/09/2004

Abstract

Retention of crystals in renal tubuli leads to the formation of kidney stones. Multiple factors have been correlated with this initial phase of nephrolithiasis: renal injury/-regeneration, upregulation of osteopontin (OPN) and hyaluronan (HA) - known crystal binding molecules - and redistribution of their common receptor CD44. In this study we will try to elucidate the role of renal injury, OPN and HA in crystal retention by using animal models of nephrolithiasis on one hand and OPN knock-out mice, where both in vivo and in vitro experiments will be performed, on the other.

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