Progressive loss of renal function is a chronic process that typically evolves over decades. It ranges from mild, asymptomatic loss of function associated with normal ageing, to progressive decline associated with high cardiovascular morbidity and mortality, eventually necessitating renal replacement therapy by dialysis or renal transplantation. Even after renal transplantation, the process of progressive loss of function associated with increased cardiovascular risk continues to dictate outcome. Therefore, effectively targeting chronic loss of renal function and its complications requires a multifactorial approach and a lifetime perspective in order to be able to account for the specific characteristics of each of the subsequent stage where each stage also carries the heritage of the preceding stages. This multifactorial approach should identify synergistic targets for treatment, including both pharmacological and non-pharmacological (lifestyle and nutrition) interventions.
Figure 1: Overall risk (renal and cardiovascular morbidity and mortality) in patients with progressive renal function loss over time, illustrating change in contribution of different types of risk factors over time. HD hemodialysis, PD peritoneal dialysis, Tx transplantation, BP blood pressure, DM diabetes mellitus.
An example of the multifactorial approach is the work on sodium handling and calcium/phosphate metabolism. In this research line calcification propensity and the interaction between vitamin D status, sodium intake and the renin angiotensin system is studied to design novel integrated renoprotective strategies in chronic kidney disease (CKD, PI M. de Borst).
Within this context, the main aims of the program are to:
- Identify the pathophysiological mechanisms of progressive loss of renal function and its complications
- Develop and improve strategies for prevention of progressive renal function loss and its complications with a focus on personalized medicine
To this end, the program covers the full range of investigative approaches, from basic science, via experimental and clinical intervention studies to clinical implementation, and dissemination in clinical care and society. The program includes:
1. Experimental studies aimed at dissecting underlying pathophysiological mechanisms in animal studies, in in vitro cell culture conditions and in the human experimental set-up.
2. Intervention studies including pharmacological intervention, lifestyle intervention and a combination of these. Intervention studies conducted within the GKC focus on interaction between lifestyle and pharmacological interventions such as DINAMO and VIRTUE as well as personalized medicine (IMPROVE trial). In addition to these mechanistic studies, researchers participating in the GKC have a leading role in coordination and execution of international landmark drug trials in nephrology including the VITAL, PLANET, TEMPO, REPRISE, BEACON, RADAR, SONAR, and CREDENCE trials.
3. Cohort studies to identify prognostic factors in the general population, populations at high risk for renal disease such as diabetes, and cardiac and/or renal patient populations, including native renal disease, transplant recipients and kidney donors. Including kidney donors allows us not only to analyze the effect of a reduction in renal capacity over time but also to study the role of specific aspects of the donor kidney for eventual transplant outcome. Finally, cohorts from routine care are also used to identify targets for improvement of clinical care.
Some specific research lines in GKC are:
- Albuminuria/Proteinuria. The research line within the GKC that helped define the program and through the PREVEND study has attracted international attention. The subsequent developments in this field led to the development of the new KDIGO CKD staging. R.T. Gansevoort / P.E. de Jong / D. de Zeeuw
- Deregulations in mineral metabolism. Within this line we focus on the central question of how deregulations in mineral metabolism translate into cardiorenal abnormalities and, eventually, clinical events. This question is primarily addressed in patients with chronic kidney disease and renal transplant recipients, however, we also aim to translate findings in this field to other populations such as those with heart failure. We have a strong focus on modifiable factors and aim to design intervention studies targeting deregulated mineral metabolism, with the ultimate goal of drastically reducing cardiovascular disease in patients with chronic kidney disease. M. de Borst / S.J. Bakker / G.J. Navis
- Cardiorenal and metabolic complications of CKD and renal replacement therapy (RRT). The effect of loss of renal function for the functioning of other organs such as the heart is studied here and the bi-directional interaction of the kidney with the heart has been designated as an area of focus. This collaboration has resulted in a number of publications in high-tier journals (e.g. thesis of S. Assa) and funding (e.g. RECONNECT consortium, CVON Groot 2015-2020). C. Fransen / G.J. Navis
- Polycystic kidney disease. This is an example of research that seeks to reduce disease progression and prevent end-stage renal disease through animal and human experimental studies and large scale intervention trials. The line was initiated in 2008 by R Gansevoort.
- Gasotransmitters. The work on gasotransmitters illustrates the elegant combination of biomarker research in clinical databases and the identification of novel targets for intervention which are proven effective in the experimental setting. H. van Goor / J.L. Hillebrands
- Personalized/Precision Medicine. Within this line the underlying mechanisms of the heterogeneity in drug response in patients with diabetic and non-diabetic nephropathy are investigated and strategies to overcome therapy resistance are explored. H.J. Lambers Heerspink / D. de Zeeuw