Renal disorders About themeThe mission of the renal disorders theme is to deliver excellent, efficient and innovative clinical care to our patients at the Radboudumc and beyond, and to be leading in the field of kidney disease research. The primary aim of the renal disorders theme is to understand the molecular mechanisms, physiology and pathogenesis of glomerular diseases and tubular transport disorders, including acquired and inherited forms of kidney diseases. To achieve this aim, we will increase knowledge of the molecular and immunological basis of glomerular and tubular disorders; develop biomarkers for optimal prediction of disease prognosis; and apply strategies for preventing and improving renal replacement therapy. The research projects are carried out at genetic, molecular, cellular and integrative levels, as well as on human subjects.
- We will increase knowledge of the molecular and immunological basis of glomerular and tubular disorders and of graft performance.
- We will combine genetic and functional cutting-edge methodology to diagnose and identify novel renal diseases.
- We will identify novel therapeutic targets for renal disorders and kidney transplant survival.
- We aim to develop biomarkers for optimal diagnosis, prevention and prognosis of renal diseases, kidney injury and transplant survival.
- We aim to optimize treatment strategies for patients with renal diseases, focusing on patient-tailored treatment.
- We will apply strategies for preventing and improving renal replacement therapy.
Lines of research
Glomerular diseasesThe glomerulus plays an essential role in the filtration of blood and the formation of urine. Knowledge of the structure and function of the glomerulus aids in understanding the clinical manifestations of glomerular diseases. Within the renal disorders theme, research on glomerular diseases is aimed at unraveling the molecular mechanisms underlying proteinuria, glomerular inflammation and sclerosis.
Research lines focus on the role of heparan sulfate at the structure-functional level and the glomerular endothelial glycocalyx. The development of anti-chromatin autoantibodies and lupus nephritis is another key interest, and focuses on the effects of apoptotic blebs and apoptosis-induced chromatin modifications on dendritic cells. In addition, the role of podocyte injury in proteinuric glomerular diseases is studied, with special emphasis on the TRPC6 calcium channel and its role in focal segmental glomerulosclerosis.
Renal replacement therapy
Alternatively, we focus on the identification of biomarkers for nephrotoxic kidney injury. Also, the role of drug transporters in renal regeneration is investigated, with an emphasis on the role of stem cells in kidney tissue repair. When kidneys are damaged and renal function is lost, patients depend on haemodialysis to remove waste products from their blood. This procedure, however, causes an accumulation of certain waste products, leading to severe health complaints.
The research lines within the renal disorders theme focus on both clinical and experimental research topics concerning renal transplantation. Various aspects of immune regulation are studied, such as the generation and characterization of tolerogenic dendritic cells, and the role of chemokines and heparan sulfate. As part of the BioKid consortium, researchers from the renal disorders theme aim to develop living membranes for an intradialytic biological kidney support device, which will be capable of effective clearance of toxins ex vivo, improving haemodialysis.
Tubular disordersIn the kidney, prourine is concentrated along the nephron, where water and valuable electrolytes are reabsorbed to prevent excess losses via the urine. Over the last decades, a large number of patients were studied that suffer from hereditary defects leading to rare tubular disorders. These studies have led to the identification of a number of proteins and hormones that are involved in water and electrolyte homeostasis.
Within the renal disorders theme, research lines focus on tubular transport of calcium, magnesium, sodium, iron and water. Studies mainly focus on the function and (hormonal) regulation of the transport proteins and channels that are responsible for the reabsorption of electrolytes and water in the kidney. In addition, the role of other organs, such as intestine, blood and bone, are studied, as they are essential to maintain homeostasis.
News and agenda
A novel hypokalemic-alkalotic salt-losing tubulopathy in patients with CLDN10 mutations. read more
The discovery of a new rare kidney disorder
Societal relevance:Clinical expertise regarding rare kidney disorders, especially renal tubular disorders, is sparse. Hypokalemic alkalosis is often due to increased water and sodium delivery to the collecting duct with concomitant enhanced aldosterone action due to volume contraction. Frequently, secondary electrolyte disorders due to reduced or enhanced renal tubular reabsorption occur. After the exclusion of acquired and/or drug-induced causes of hypokalemic alkalosis, the differential diagnosis includes several rare (genetic) renal tubular disorders. We show how a collaborative approach including in-depth clinical phenotyping, specialized renal tubular function testing and genetic analyses excluded all known genetic hypokalemic-alkalotic renal tubular disorders in these patients, and eventually led to the discovery of a new disorder for which the pathogenesis could be elucidated by further clinical, genetic and in vitro analyses.
Discovery:We identified and characterized mutations in CLDN10, the gene encoding the tight junction protein Claudin-10, in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants. Mice lacking distal tubular expression of claudin-10 show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remained previously undetermined. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype.
This was the first publication of pathogenic CLDN10 mutations affecting TAL paracellular ion transport and causing a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.
Restrictive eculizumab regimen in patients with atypical hemolytic uremic syndrome is safe and effective. read more
Evaluation restrictive use of eculizumab
Societal relevanceAtypical hemolytic uremic syndrome (aHUS) is a rare and severe disease, characterized by micro thrombi in the renal vasculature. Without therapy, the outcome is dismal with most of the patients in need of renal replacement therapy. With the introduction of the complement C5-inhibitor eculizumab, a new era was entered in the treatment of patients with aHUS. Eculizumab therapy improved mortality and morbidity significantly. However, initial guidelines recommended lifelong treatment together with prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. There is no evidence to support lifelong therapy duration and treatment is not without risks. Furthermore, one has to consider the social impact of eculizumab therapy with costs up to €500,000 per patient per year.
DiscoveryAt Radboudumc we performed two pilot studies to evaluate restrictive use of eculizumab. In the first study eculizumab therapy was tapered and/or discontinued in all 20 aHUS patients, after which only 5 (20%) experienced a relapse. Moreover, with rapid reinitiating of eculizumab no chronic sequelae were detected and therapy was tapered again in these patients.
In the second pilot study, 17 patients with a history of aHUS and end stage renal disease received a kidney transplantation following a specific in-house drafted protocol, without the use of prophylactic eculizumab infusions. Recurrence of aHUS was only observed in 1 of these 17 patients and no chronic sequelae were detected after rapid initiation of eculizumab. With this approach a cost reduction of €20 million was achieved.
These pilot studies paved the way toward a new Dutch guideline for the treatment of aHUS. This guideline was written by the national aHUS working group led by N. van de Kar and J. Wetzels. The guideline advocates the use of a restrictive treatment protocol of eculizumab. Meanwhile the Radboudumc has set up a nationwide, prospective, observational, study (CUREiHUS study) to monitor all aHUS patients treated with this new guideline. Blood is drawn to study potential biomarkers to predict among others recurrence, and to evaluate therapeutic drug monitoring with the potential to individualize therapy. Furthermore, cost-effectiveness analysis and budget impact analysis will be conducted.
Our studies and initiatives, all in close collaboration with the Dutch Kidney patient association, have helped approval of eculizumab treatment by the national healthcare institute. They decided to reimburse eculizumab for 4 years, with the restriction that all patients need to be treated according to new guideline and (when possible and after informed consent) need to be included in the CUREiHUS study so all patients will be monitored closely.
Proton pump inhibitors are the first line of treatment for stomach acid-related diseases and are used by approximately 3 million people in the Netherlands. read more
Site effects of proton pump inhibitorsProton pump inhibitors (PPIs, e.g. omeprazole) are the first line of treatment for stomach acid-related diseases and are used by approximately 3 million people in the Netherlands.
We have previously demonstrated that 13% of the PPI-users develop hypomagnesemia (serum magnesium (Mg2+) < 0.7 mmol/L), which causes severe health problems. We aimed to translate the experimental results about the molecular mechanism of PPI-induced hypomagnesemia into novel treatment strategies for patients.
This resulted in the prebiotic intervention trial (PRIVET), were we targeted the gut microbiome by dietary inulin fibers and significantly restore serum Mg2+ levels in these patients.
“The ins and outs of the kidney: From physiomics to transplantation”. read more
Radboud Summer SchoolThe renal theme participated in August 2017 for the first time with a new course “The ins and outs of kidneys: From physiomics to transplantation” in the Radboud Summer School.
We welcomed 23 participants from 11 countries. Enthusiastic researchers and clinicians from several groups within the renal theme contributed to a highly successful week of lectures, demonstrations, hands-on activities, interactive sessions, and workshops. The participants were challenged to prepared a presentation about one of the four topics involved: Glomerular diseases, Tubular disorders, Ciliopathies or Replacement therapies.
During the summer of 2018, from August 6 – 11, the second edition of the course will be organized. We hope for a similar success in number of participants, enthusiasm and teachers to achieve an effective outreach by the renal theme. The summer school course is promoted within our national and international networks.
European Reference NetworkERKNet is the European Reference Network for Rare Kidney Diseases, a consortium of 38 expert pediatric and adult nephrology centers in 12 European countries providing healthcare to more than 40,000 patients with rare disorders of the kidneys.
The ERKNet partners offer top quality multidisciplinary healthcare for a wide range of rare kidney disorders. They uniformly apply clinical guidelines and pathways according to latest medical knowledge and strictly monitor the quality and outcomes of therapy across the Network.
Supported by the EU, ERKNet offers virtual consultation services to physicians throughout Europe who need advice for challenging cases with a rare kidney disease.
ERKNet is dedicated to improve knowledge about rare kidney diseases among patients and healthcare professionals. We disseminate disease information via this website and by multiple education and training activities.
ERKNet actively supports clinical research to improve diagnosis and risk prediction and advance the development of new therapies for patients with rare kidney disorders.
Centers of clinical expertise
Information is only available in Dutch.
Affiliated institutes and centers
Radboudumc Technology Center Microscopic Imaging Center
The Microscopic Imaging Center offers access to both standard and innovative advanced microscopy infrastructure and applications including technical operator-assistance and in-depth microscopic imaging knowledge.read more