Aim of KaroKidney
"The Karolinska Kidney Research Center KaroKidney" - aims to develop into a high level translational kidney research cluster where programs for synergistic collaborations between basic and clinical researchers lead to discoveries and better healthcare strategies that will improve outcomes of patients with kidney disease.
The mission of this network is to tackle the common - and extremely costly - kidney disease, the primary causes of which are largely not understood. Researchers try to elucidate the mechanisms of kidney disease, identify new drug targets and drug candidates and develop new tools for preventing and treating CKD, halt its progression to ESRD, and treat the devastating complications. For this purpose we, have mobilized all available resources in the Stockholm region and formed the Karolinska Kidney Research Center KaroKidney to create translational synergies between basic and clinical researchers in projects including existing large patient cohorts and representing all stages, etiologies and age categories of CKD patients.
Vision and goals
Our vision is for KaroKidney to result into a better understanding of factors causing CKD and its complications, leading to novel diagnostic, therapeutic and preventive measures. To accomplish this we are building a unique network of multidisciplinary basic molecular, laboratory and clinical researchers dedicated to this vision. A systematic research program joining research efforts (thus minimizing fragmentation) and enhancing further national and international partners in academia, healthcare and industry will help us to accomplish these goals.
Basic experimental models and human genetics will yield knowledge of genes, proteins and pathways that are involved in renal - and in particular glomerular - function, and pathophysiology. Protein product abnormalities as well as genetic and epigenetic variations will be identified and analyzed together with markers of renal disease initiation, rate of progression of CKD, outcome and responses to pharmacological and renal replacement therapies. We envision that KaroKidney - based on innovations in basic and clinical research - will lead to: (1) Identification of novel pathways leading to CKD and its complications, allowing the development of new treatments and preventive strategies; (2) Early identification of high risk subjects, and; (3) Better allocation of resources for prevention and treatment.
Since this project will utilize, in part, existing experimental models and large existing cohorts of CKD patients, KaroKidney can commence its program without delay. We anticipate the discovery of key biomarkers that allow us to identify individuals with high risk of progression. This may lead to new and/or improved therapeutic strategies to improve renal health. One of our focuses will contemplate the study of biomarkers and genotypes that in concert with environmental factors explain the high-risk complications of CKD patients, such as wasting, CVD, infections and bone disease. KaroKidney includes renowned experts in basic research, access to a wide network of researchers and entrepreneurs in industry, as well as invaluable participation of dedicated clinicians who can implement results in clinical practice. This is of importance as we strive for identification, development and testing of novel treatment and preventive strategies based on better use of todays tools and on results of trials of novel pharmaceuticals and nutraceutical substances, as well as new forms of dialysis and blood purification.
This project will create bridges among the clinics responsible for care of pediatric, adult and geriatric patients at various stages of CKD, and clinical and basic researchers with strong competence in areas including epidemiology, pharmacology genetics, epigenetics, pathology and molecular biology. We will promote dissemination of results as well as research education and training through a broad range of joint activities, such as seminars or graduate/post-graduate programs for basic and clinical researchers, which will result into a new breed of translational, multidisciplinary scientists with the common focus on renal disease. In addition, KaroKidney plan to develop programs for education of health care professionals to increase the general awareness of CKD as a public health problem.
Structure of KaroKidney
The team leaders of KaroKidney hold extensive networks of national and international collaborators. This enables KaroKidney to access cutting-edge expertise in different areas of basic research, such as glomerular filter structure, genomics and proteomics (Karl Tryggvason), epigenetics (Tomas Ekström), genomics (Martin Schalling), epidemiology (Anders Ekbom), renal pathology (Annika Wernerson), immunology (Joachim Lundahl), renal physiology (Anita Aperia), cardiology (Tomas Kahan) and pharmacology (Leif Bertilsson). Well-established clinical groups with access to large patients materials of adult (Peter Stenvinkel and Stefan Jacobson) and pediatric (Mikael Norman) CKD patients, as well as transplanted (Lars Wennberg) and diabetic (Kerstin Brismar) patients ensure high quality in the phenotyping and follow-up of patients. The participation of Baxter Novum (Bengt Lindholm) and its extensive international network (at present >50 centers around the world) ensures continuous inflow of post-docs for proposed collaborative projects within KaroKidney.
Leadership and management
The activities of KaroKidney will be integrated with the research, education and training strategies of Karolinska Institutet. Peter Stenvinkel and Karl Tryggvason will act as director and co-director, respectively. Together with team leaders, they are part of the scientific advisory board, which will coordinate research, allocation of research funding and decide on internal and external activities. The scientific advisory board will serve as a source for quality development of the research. A representative of the Stockholm Patient Kidney Organization will also be invited to take part in meetings of the scientific advisory board. To promote recruitment of young researchers and acknowledge the importance of the junior faculty at KaroKidney, two younger KaroKidney members (one basic and one clinical researcher) will serve as project coordinators. Together with the director and co-director they will be in charge of arranging educational activities and seminars that will communicate the results to KaroKidney and its partners as well as to health care professionals and society at large. Project development and monitoring of achievement of goals will be done through full-day seminars twice per year where partners of the KaroKidney will discuss results and advances, followed by discussions and planning of further collaborative research projects. An important task for KaroKidney is to be involved in lobbying for the interest of CKD patients and to apply for grants from national and international sources.
The first KaroKidney research seminar was organized in Sept 2009 at the Karolinska University Hospital at Huddinge. Subsequent meetings were organized Sept 2010 at Danderyd University Hospital and March 2011 at campus Karolinska Institutet.
Renal Medicine Danderyd Hospital Karolinska Institutet
Baxter Novum Karolinska Institutet
Examples of ongoing or planned research projects include:
- Translational epidemiological and genetic studies linked by biobanking of serum and DNA in all CKD patients within the greater Stockholm area.
- Systems biology and genomics approach to glomerular disease to understand disease mechanisms and develop new diagnostics and therapies to prevent CKD (Karl Tryggvason, Annika Wernersson, Jaakko Patrakka).
The top part of the Figure shows that the transcriptome, proteome and metabolome of uremic patients should be compared to healthy controls and integrated in databases to be correlated to genes and gene products. This approach may expand the biological knowledge of the impact of the toxic uremic milieu on premature vascular ageing. The lower part of the Figure shows that DNA sequence and the environment do not only determine the uremic phenotype, but also by the epigenome (which regulates the activity of genes in response to environmental factors).
- Initiation of interventional studies of novel treatment strategies to treat complications of chronic kidney disease (Peter Stenvinkel, Juan Jesus Carrero, Peter Barany, Olof Heimbürger).
- In renal-endocrinological projects the links between vitamin D, KLOTHO, and FGF-23 will be studied (Tobias Larsson).
- Renal epidemiology: Polypharmacy and drug dosages in people with reduced kidney function or chronic kidney disease in National registries (Juan Jesus Carrero, Marie Evans, Bjorn Wettermark, Peter Stenvinkel, Carl-Gustaf Elinder)
The figure gives a schematic presentation of causes of chronic kidney disease and its progression to end-stage renal disease and need of renal replacement therapy. Several different treatment options are available and include A) specific treatment of underlying renal disease, B) life style interventions, C) pharmacological treatment to arrest progression and prevent complications and D) potential new treatments strategies that should be tested in randomized controlled trials of patients with end-stage renal disease.
- Understanding the role of (epi)genetic variations, sex, inflammation, oxidative stress, uremic bone disease on the risk to develop premature vascular disease in CKD (Martin Schalling, Tomas Ekström, Peter Stenvinkel, Jonas Axelsson, Bengt Lindholm).
- Impact of sex and endocrine alterations on the risk of cardiovascular and nutritional complications in ESRD (Juan Jesus Carrero, Peter Stenvinkel).
- Studies on metabolic risk factors including uremic insulin resistance and fructose (Jonas Axelsson, Juan Jesus Carrero, Björn Anderstam, Bengt Lindholm, Annette Bruchfeld, Olof Heimbürger, Peter Barany, Peter Stenvinkel).
- Ex vivo studies on endothelial vascular function in uremia (Karolina Kublickiene, Juan Jesus Carrero and Peter Stenvinkel).
- A renal biopsy project to study structural, genetic and biological markers for diagnosis of kidney disease (Annika Wernersson, Jaakko Patrakka, Annette Bruchfeld, Peter Barany)
- Genetic studies of glomerulonephritis with special focus on IgA nephropathy and lupus nephritis (Stefan Jacobson, Leonid Padyukov, Iva Gunnarsson, Sigrid Lundberg).
- Leukocyte function in chronic kidney disease experimental and clinical studies (Joachim Lundahl, Stefan Jacobson).
- Studies of ANCA-associated vasculitides with a clinical, cellular, molecular and genetic focus (Annette Bruchfeld, Iva Gunnarsson).
- Mapping of cardiovascular risk factors in peritoneal dialysis patients (Britta Hylander, Olof Heimbürger, Bengt Lindholm, Peter Barany, Peter Stenvinkel)
- Ouabain protects renal cells against shigatoxin-triggered apoptosis (Evgeniya Burlaka, Diana Karpman, Anita Aperia, Xiaoli Liu)
- Ouabain attenuates the progression of chronic glomerular disease in rats with passive Heyman Nephritis (Evgeniya Burlaka, Xiaoli Liu, Agnes Fogo, Ulla Holtbäck, Anita Aperia)
- Transcriptome studies of embryonic kidney; effect of malnourishment and rescuing substances (Georgly Khodos, Alexander Bondar, Anita Aperia, Hjalmar Brismar).
- Reciprocity between angiotensin AT1 receptors and Dopamine D1 receptors; therapeutic consequences (Lena Scott, Fernando Ibarra, Anita Aperia).
- The Karolinska cardiorenal theme center (Stefan Jacobson, Tomas Jernberg, Jonas Spaak, Thomas Kahan, Pia Lundman, Anders Hamsten).
- Acute Kidney Injury following CABG and risk of death, myocardial infarction and end-stage renal disease
Affiliated senior researchers
Peter Barany, MD, PhD (renal medicine)
Olof Heimburger, MD, PhD (renal medicine)
Maarit Korkeila, MD, PhD (renal medicine)
Annette Bruchfeld, MD, PhD (renal medicine)
Fredrik Dunér, MD, PhD (renal medicine)
Astrid Seeberger, MD, PhD (renal medicine)
Karin Lindström, MD, PhD (renal medicine)
Jonas Axelsson, MD, PhD (renal medicine)
Britta Hylander MD, PhD (renal medicine)
Marie Evans, MD, PhD (renal medicine and epidemiology)
Carl-Gustaf Elinder, MD, PhD (epidemiology and renal medicine)
Tobias Larsson, MD, PhD (bone disease and renal medicine)
Kjell Hultenby, PhD (pathology)
Louise Nordfors, PhD (genetics)
Juan Jesus Carrero, PhD (gender research and epidemiology)
Leonid Padyukov, PhD (rheumatology)
Iva Gunnarsson, MD, PhD (rheumatology)
Karolina Kublickiene, MD, PhD (vascular and endothelial research)
Folke Hammarqvist, MD, PhD (nutrition, metabolism, surgery)
Gianni Celsi, MD, PhD (pediatric nephrology)
Stefan Arver, MD, PhD (andrology)
Tomas Jernberg, MD, PhD (cardiology)
Pia Lundman, MD, PhD (cardiology)
Martin Holzmann, MD, PhD (cardiology)
Harvest Gu, MD, PhD (endocrinology)
Jonas Spaak, MD, PhD (cardiology)
Tony Qureshi, MD, PhD (statistics/epidemiology)
Björn Anderstam, PhD (Lab)
Olle Ljungqvist, MD, PhD (nutrition, metabolism and surgery)
Anna Witasp, PhD (genetics)
Jaakko Patrakka, MD, PhD (renal medicine and pathology)
Håkan Wallén, MD, PhD (hemostasis, platelet function)
Xiaoli Liu, PhD (renal physiology)
Anita Aperia MD, PhD (pediatric nephrology, renal physiology)
Robert Frithiof MD, PhD (renal physiology)
Björn Wettermark PhD (pharmaceut)
Maria Herthelius MD, PhD (pediatric nephrology)
Sohier Beshara MD, PhD (clinical chemistry)
Dissertations within the group
Fredrik Duner: "Ultrastructural studies of the blood-urine barrier in proteinuric states"
Anna Witasp: "Expression of inflammatory and insulin signaling genes in acute and chronic stress"
Marie Evans: "Prognosis and Progression in Chronic Kidney Disease"
Josefin Paulsson: "The inflammatory response in extravasated leukocytes in patients with coronary artery disease"
Jenny Olsson: "Leukocyte dysfunction inflammatory markers in patients with chronic kidney disease and patients on dialysis"
Mai Tuyet Vuong: "Genetic studies of glomerulonephritis with special focus on IgA nephropathy and lupus nephritis"
Karolina Szummer: "Influence of renal dysfunction on therapy and prognosis in patients with myocardial infarction"
Masatoshi Nukui: "Glomerular expression profiling and novel proteins in normal mouse kidney and adriamycin-induced nephrosis"
Zhijie Xiao: "Identification, expression and functional analyses of novel renal glomerular proteins"