#5187 GREASE II: A PHASE II RANDOMIZED, 24-MONTH, PARALLEL-GROUP, SUPERIORITY STUDY TO EVALUATE THE EFFICACY OF A KETOGENIC DIET IN ADPKD PATIENTS
Authors: Pezzuoli Carla , Testa Francesca , Giovanella Silvia , Ligabue Giulia , Marchiò Maddalena , Biagini Giuseppe , Magistroni Riccardo 
Published: June 2023

Abstract

Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD) is the 4th cause of end-stage renal disease in Western Countries, nevertheless still represents an illness with a significant unmet medical need. In recent years, deregulation in glucose metabolism in ADPKD has been identified. Data suggest that cystic cells shift their energy metabolism from oxidative phosphorylation to aerobic glycolysis. Preclinical experiences show beneficial effects in terms of cystic size reduction, interstitial fibrosis and disease progression, targeting these deregulated metabolic pathways by ketosis induction. A ketogenic diet treatment approach, such as a Modified Atkins Diet (MAD), to ADPKD represents an interesting therapeutic strategy, because of its low cost, tolerability and safety [1]. The Primary Endpoint of this study is the evaluation of the effect of the MAD protocol on the modification of the Total Kidney Volume (TKV), formally qualified, both by FDA and by EMA, as a prognostic enrichment biomarker for selecting patients at high risk for a progressive decline.

Method
the initial protocol [2] has been modified in a multicentric study that involves the Divisions of Nephrology of AOU Policlinico di Modena (Modena, Italy) and Policlinico di Sant'Orsola (Bologna, Italy). GREASE II is supported by the Italian Ministry of Health (Ricerca Finalizzata grant no. RF-2021-12374522). During the run-in period, 90 patients will follow a Balanced Normocaloric Diet (BND). In the week preceding the randomization, patients will perform a baseline MRI. Patients will be then randomized to MAD or BND according to a stratified 1:1 ratio. Patients will be followed for 12 months at scheduled clinical and dietetic visits. In the 12ve month, the patients on the MAD arm will be switched to BND and a second MRI will be performed after a month (± 7 days). After the MRI, the patients will be switched again to their original MAD. Patients will be followed for further 12 months at scheduled clinical and dietetic visits. At the 24th month, patients of the MAD arm will be switched once again to BND and after a month (± 7 days) a final visit will be performed (Fig. 1). As co-primary endpoint tolerability and safety will be assessed. Furthermore, as secondary outcomes, the study will evaluate renal function decline, total liver volume (TLV) and the impact of the diets on urinary and serum markers β2MG and MCP-1.

Results
we expect to obtain a reduction of the TKV in the group of patients treated by the MAD protocol. Safety and tolerability are coprimary endpoints of the study. As secondary exploratory outcomes, the study will evaluate the effect of the diet on the TLV and quality of life (ADPKD-IS and SF-12 questionnaires). This clinical trial will allow us to evaluate the proof of concept of the therapeutic efficacy of MAD in the ADPKD clinical setting.

Conclusion
GREASE II represents the first multicenter RCT evaluating the reduction of the TKV in ADPKD and renal function decline. The identification of a coordinated reduction of TKV and renal function decline in the patients randomized to the MAD compared to the BND will suggest a protective role of the ketogenic diet against disease progression of ADPKD.