Title: Uremic retention molecules and CKD-MBD: living apart together?
Other Titles: Uremic retention molecules and CKD-MBD: living apart together?
Authors: Viaene, Liesbeth
Issue Date: 21-Nov-2013
Abstract: Accumulating data suggest that in CKD patients, in addition to traditional well-known risk factors, a disrupted FGF23/Klotho and vitamin D axis and retention of protein-bound URMs contribute to the severely increased cardiovascular risk. The present research project aimed to unravel the cross talk between URMs (with focus on p-cresyl sulfate and indoxyl sulfate), bone and mineral metabolism and cardiovascular disease. In the present manuscript, we pointed to the existence of a cross talk between disturbances of the FGF23-Klotho axis and retention of p-cresyl sulfate, contributing in concert and by being separate culprits to the increased vascular (aortic) calcification of CKD. Our epidemiological data showed that p-cresyl sulfate may further impair renal and soluble Klotho generation, supported by increasing experimental data (Chapter 4.1). p-Cresyl sulfate associated with aortic calcification in a cohort of 264 CKD 1-5D patients (Chapter 4.2). Although direct toxic effects of p-cresyl sulfate on endothelial cells were previously shown, our data suggested that these deleterious effects may also be mediated by Klotho deficiency. Indeed, the association between p-cresyl sulfate and aortic calcification was lost after adjustment for FGF23. The interaction between p-cresyl sulfate levels, FGF23 and vascular calcification might be explained by Klotho deficiency. Klotho has been shown to preserve and protect vascular integrity through multiple independent mechanisms. Clinical data in 81 end-stage renal disease patients do not support direct toxic effect of indoxyl sulfate on renal osteodystrophy. In addition, using monocytes as in vitro model for extrarenal vitamin D metabolism, we identified for the first time FGF23, and not the protein-bound URMs, as inhibitor of local, monocytic vitamin D production, pointing to a second ‘non-classicalÂ’ effect of FGF23. Altogether, these observations indicate that the protein-bound URMs enhance the risk for cardiovascular complications, by acting in concert with FGF23/Klotho disturbances. These findings spur hope for interventions to improve outcome. Blood clearances of protein-bound URMs by current dialysis techniques are limited, mainly due to tight protein-binding. Strategies to lower p-cresyl sulfate levels include dietary measures and gastrointestinal adsorbents. The improved knowledge on determinants of p-cresyl sulfate and indoxyl sulfate (chapter 2), contributing to the high intra- and inter-individual variations, is crucial before targeting p-cresyl sulfate and indoxyl sulfate serum levels. Dietary manipulation of serum URMs will be the next logical step. Studies performed in animal models, as well as prospective follow-up studies, will be instrumental in determining the efficacy of, e.g. dietary manipulation, in lowering serum URMs concentrations and changing outcomes in CKD.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Nephrology

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