Research

Chronic kidney disease (CKD) is an important problem for patients, doctors and health administrators. An estimated 10% of the global population suffer from CKD and over 2 million people with an advanced stage of CKD currently receive renal replacement therapy (RRT). However, delivering RRT requires a multidisciplinary approach with adequate intellectual, infrastructural and financial resources and is therefore only limitedly available, i.e. predominantly in the more economically developed countries. Unfortunately, for many patients in the rest of the world, the proper care for severe renal failure is still lacking. In addition, the number of people with CKD worldwide is rapidly rising and this is considered a global health crisis.
Dialysis and kidney transplantation are the only two treatments available for chronic end-stage renal disease (ESRD). At the end of 2015, 2.8 million patients worldwide were on dialysis. Dialysis is an expensive treatment with an annual cost of € 15 billion for EU health systems, consuming 2% of health care budget of Europe. 
The goal of organ transplantation is to restore autonomous organ function by transferring a healthy organ from a donor to a patient. In practice, this entails the risk of recognition and rejection of the “non-self ” tissue by the recipient’s immune system and therefore the need to permanently suppress the immune system in order to establish a form of tolerance for the donor organ. Calcineurin inhibitors (CNIs) are a class of immunosuppressive that have revolutionized the field of solid-organ transplantation through their capacity to reduce rejection episodes and improve long-term outcome after solid organ transplantation. No other class of immunosuppressive medication has proven this successful and currently, tacrolimus, (a CNI that is associated with less rejection episodes and clinical tolerability than its “predecessor” cyclosporine) is considered the standard of care in transplantation medicine (both kidney and other solid organs). Despite its success in the prevention of rejection, the long-term use of CNIs by patients with a kidney transplant is accompanied with a gradual decline in renal function, accompanied by the development of a combination of histological abnormalities including arteriolar hyalinosis and interstitial fibrosis. However, this phenomenon is not exclusive for the field of renal transplantation, where different pathophysiological mechanisms have been described to result in similar histological findings. It is also reported in “non-renal” types of solid organ transplantation and other groups of patients on long-term CNI treatment such as: bone marrow transplantation, inflammatory bowel disease, different manifestations of auto-immune diseases (e.g. auto-immune hepatitis, systemic lupus erythematosus, nephrotic syndrome). The underlying pathophysiology of CNI-associated nephrotoxicity is still not known. There is no clear relationship with blood CNI concentrations and there appears to be inter-individual differences in the susceptibility for developing this complication. 
Since we currently still lack good alternative treatment strategies for this broad range of patients, we should put more effort in the better understanding of the detrimental effect of long-term treatment with tacrolimus on the kidney. We should focus on the identification of risk factors and the possibilities for prevention of CNI-associated nephrotoxicity.
The renal metabolism of CNI predominantly occurs in the proximal tubule cells (PTC) through the interplay of CYP3A5 and the P-glycoprotein (P-gp) efflux pump. We have generated for the first time, different PTC cell lines with the functional expression of the most common variants of CYP3A5 and P-gp in human population. We aim to unravel the mechanisms of CNI-induced toxicity in our cell model to: personalize the immunosuppressive therapy based on the susceptibility of kidneys to CNI toxicity and discover a new biomarker to predict the initiation and progress of CNI-induced renal fibrosis.
Using this model, we investigate these mechanisms by various cell and molecular biology techniques such as deep sequencing, transcriptome and protein analyses, real-time imaging and so forth.

Cystinosis is a rare autosomal recessive lysosomal storage disorder, characterized by cystine accumulation and crystal formation in all tissues. Various endocrine organs are affected, and in a substantial proportion of male cystinosis patients, primary hypogonadism is present. Azoospermia has been documented in all male cystinosis patients despite a normal hypothalamic-pituitary axis, early cysteamine treatment and normal renal function.
We aim to unravel the origin of azoospermia in male cystinosis patents. Moreover, based on the studies in animal models, we aim to examine the potential toxicity of cysteamine treatment on male fertility using a mouse model. Our ultimate objective is to generate knowledge and technology to create the possibility of pregnancy induction by male cystinosis patients.