MO016: Feasibility and Effectiveness of Short-Term Ketogenic Interventions in Autosomal Dominant Polycystic Kidney Disease (ADPKD): Results from the Reset-Pkd Study
Authors: Oehm Simon , Steinke Konstantin , Arjune Sita , Todorova Polina , Lindemann Christoph , Woestmann Fabian , Meyer Franziska , Siedek Florian , Weimbs Thomas , Grundmann Franziska , Mueller Roman-Ulrich 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Over the last years, there has been increasing evidence that defects in the energy metabolism of polycystic kidney disease (PKD) cyst lining cells, especially increased glucose dependency and defects in fatty acid oxidation, may underlie the pathogenesis of ADPKD, Rowe et al. (Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 2013; 19(4): 488–493). Based on these data, ketogenic dietary interventions have effectively been used in PKD animal models, Kipp et al. (A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am J Physiol Renal Physiol 2016;310(8):F726-F31), Torres et al. (Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab 2019;30(6):1007–23 e5) and Warner et al. (Food restriction ameliorates the development of polycystic kidney disease. J Am Soc Nephrol 2016;27(5):1437–1447). As a first-in-human pilot study, the RESET-PKD study now strives to translate these promising results in the clinical setting.

METHOD
The present study enrolled 10 ADPKD patients with rapid disease progression. After a screening visit (V1), patients followed their usual carbohydrate-rich diet for up to 4 weeks. In a second visit (V2), patients chose to either perform a 3-day water fast (WF) or a 14-day ketogenic diet (KD) until a third study visit (V3), after which they returned to their normal high-carbohydrate diet for 3–6 weeks until a final visit (V4). At all visits, total kidney volume (TKV) and total liver volume (TLV) were monitored using MRI; anthropometric parameters, body composition and biochemical parameters (i.e. serum creatinine, complete blood cell count, glucose, β-hydroxybutyrate in fingerstick blood and acetone in breath) were measured. Ketone bodies were evaluated at all visits and in between. Feasibility was examined using respective questionnaires. Undesirable effects such as feelings of hunger and discomfort were documented in a study diary.

RESULTS
All participants (KD: n = 5, WF: n = 5; age: 39.8 ± 11.6 years; eGFR: 82 ± 23.5 mL/min; TKV: 2224 ± 1156 mL) were classified as Mayo Class 1C to 1E. Serum creatinine values were not altered by the ketogenic dietary interventions (V2: 1.17 ± 0.33 mg/dL versus V3: 1.20 ± 0.35 mg/dL, P = 0.826), but serum glucose levels decreased significantly (V2: 84 ± 3 mg/dL, V3: 70 ± 13 mg/dL, P = 0.004). BHB blood levels as well as acetone levels in breath increased in both study arms (V1 to V2 average acetone: 2.6 ± 1.18 ppm, V2 to V3: 22.8 ± 11.9 ppm, P &lt; 0.0001; V1 to V2 average BHB: 0.22 ± 0.08 mmol/L, V2 to V3: 1.89 ± 0.92 mmol/L, P &lt; 0.0001). Nine out of 10 patients reached a ketogenic state during the intervention and 90% evaluated ketogenic interventions as being feasible while 80% of patients both reached the metabolic endpoint and rated ketogenic dietary interventions as feasible. TKV changes during KD and WF did not show any significant differences compared to the period on carbohydrate-rich diet (ΔTKV V1 to V2: 0.75 ± 0.54%, ΔTKV V2 to V3: −1.06 ± 1.16%).

CONCLUSION
The RESET-PKD study demonstrates feasibility of short-term ketogenic interventions both regarding reliable attainment of ketosis and patient-reported feasibility of this intervention in everyday life. In this proof of principle study, short-term ketogenic interventions could not show a significant reduction in TKV. However, this endpoint is likely to require long-term exposure to ketogenesis. Future large-scale clinical trials examining such long-term dietary interventions—e.g. the KETO-ADPKD study—will be of great importance to further evaluate long-term feasibility and the therapeutic potential of ketogenic diets in ADPKD.