Determinants of RAndall’s Plaque Outbreak and urolithiasis epidemic: a multidisciplinary approach. – DRAPO

Background and objectives: Urolithiasis (renal stones) affects more than 10 % of the population in western countries and its prevalence is currently increasing. Renal stones result in repeated hospitalizations, and sometimes in kidney infections, chronic kidney disease, and renal replacement therapies. We observed during the past years that a heterogeneous nucleation process due to the presence of calcifications named Randall’s plaques at the tip of renal papilla is responsible for a growing number of renal stones in young patients. Actually, morpho-constitutional analysis of expulsed stones reveals plaque fragments at stone surface, evidencing thereby the original nucleation site. Nevertheless, the process underlying the formation mechanisms and the dramatic outbreak of Randall’s plaques during the past years remains unknown. The aim of the project is to determine (i) the composition and the initial site of formation of Randall’s plaques, (ii) the relationships of Randall’s plaque with renal tissue and stones (iii) the intrinsic factors responsible for plaque formation in kidney, and (iv) the environmental factors which may explain why Randall’s plaque related stones increase exponentially.
Experimental approaches and hypotheses:
Identification of the composition and the initial location of Randall’s plaques
Our preliminary results obtained by infrared spectroscopy suggest that carbapatite is the main crystalline phase and that other compounds are frequent. The use of techniques such as electron microscopy, Synchrotron infra-red beamlines (SOLEIL), magnetic nuclear resonance/MACS technique or X-ray fluorescence will help us to characterize plaque composition. We will also study incipient intra-tissular plaques from healthy papillae in kidneys harvested for cancer. The examination of the initial site of formation of incipient plaques in papillae will be essential to identify the underlying pathophysiological mechanism responsible for plaque formation.
Relationships of Randall’s plaque with renal tissue and stones
Immunostainings around plaques in papilla will be analyzed to identify inflammatory cells and measurements of metalloprotease activity, as well as quantification of fibrosis will be performed to identify whether matrix remodeling participates to plaque extrusion at the tip of the papilla. Scanning electron microscopy will be used to analyze the stone/plaque interface.
Intrinsic factors responsible for plaque formation in kidneys
Pyrophosphate is an essential inhibitor of tissue mineralization. We will analyze in human and in original rat models whether proteins involved in pyrophosphate metabolism such as tissue non-specific alkaline phosphatase, plasma cell membrane glycoprotein-1 and especially progressive ankylosis protein, fetuin A and osteopontin are associated with Randall’s plaque formation.
Extrinsic factors responsible for plaque formation in kidneys
The epidemics of Randall’s plaques in young patients advocate for the implication of environmental factors. Some of our preliminary results suggest that two factors may be involved: high vitamin D/calcium intakes and fluoride supplementation during youth. We will perform experimental models of rats supplemented with fluor or calcium/vitamin D with the aim to create Randall’s plaque experimental models.
Discussion and Conclusion: The project will be performed in the UMR S 702 laboratory in Tenon hospital, a reference site for the management of renal stone formers. By taking advantage of a large collection of fully analyzed renal stones (n=70,000) and intra-tissular Randall’s plaque in humans and animal models as well, we plan to identify the determinants of the formation of these plaques which represent a major under-recognized and growing public health concern since Randall’s plaque-related stones will affect more than 4 percent of the population during the next decades. This proposal is an opportunity for the applicant to develop a new thematic of research.