Therapeutic Potential of Ketogenic Interventions for Autosomal-Dominant Polycystic Kidney Disease: A Systematic Review

Abstract

Background: Recent findings have highlighted that abnormal energy metabolism is a key feature of autosomal-dominant polycystic kidney disease (ADPKD). Emerging evidence suggests that nutritional ketosis could offer therapeutic benefits, including potentially slowing or even reversing disease progression. This systematic review aims to synthesise the literature on ketogenic interventions to evaluate the impact in ADPKD.

Methods: A systematic search was conducted in Medline, Embase, and Scopus using relevant Medical Subject Headings (MeSH) and keywords. Studies assessing ketogenic interventions in the management of ADPKD in both human and animal models were selected for data extraction and analysis.

Results: Three animal reports and six human studies were identified. Ketogenic diets (KD) significantly slowed polycystic kidney disease (PKD) progression in rats with improved renal function and reduced cystic areas. There was reduced renal fibrosis and cell proliferation. The supplementation of beta-hydroxybutyrate (BHB) in rats also reduced PKD progression in a dose-dependent manner. Human studies (n = 129) on KD in ADPKD reported consistent body mass index (BMI) reduction across trials, with an average weight loss of ∼4 kg. Improvements in blood pressure were also noted. Ketosis was achieved in varying degrees. Effects on kidney function (eGFR) were beneficial. Results for kidney volume were mixed but most studies were underpowered for this outcome. Lipid profiles showed increases in total cholesterol (∼1 mmol/L) and LDL cholesterol (∼0.4 mmol/L) in most studies. Safety concerns such as "keto flu" symptoms, elevated uric acid levels, and occasional kidney stones were noted. Overall feasibility and adherence to the KD were rated positively by most participants.

Conclusions: Human studies are promising; however, they have been limited by small sample sizes and short durations. Larger, long-term trials are needed to assess the efficacy, adherence, and safety of ketogenic diets in people with ADPKD.

Keywords: autosomal-dominant polycystic kidney disease; ketogenic diet; ketogenic metabolic therapy; ketone bodies; ketosis; polycystic kidney disease.

Figure 1

Pathological mechanisms of cyst formation in ADPKD. Cystogenesis in ADPKD is driven by a complex interplay of dysregulated signalling pathways. Mutations in polycystin 1/2 reduce calcium influx, consequently increasing intracellular cAMP, NFAT, and PI3K-PKB, which stimulate cell proliferation in cystic cells. These effects are mediated through the activation of the MAPK-ERK pathway. Additionally, renal expression of JAK2 and STAT is abnormally elevated in ADPKD, promoting excessive growth of renal cells. Elevated EGF and EGFR activity further drive cystogenesis by stimulating phosphorylation of the MAPK-ERK pathway and upregulating mTOR signalling. In addition, phosphorylation of AMPK, a negative regulator of mTOR, is reduced in cells lacking polycystin 1, further contributing to mTOR activation. Collectively, these disruptions in signalling pathways lead to uncontrolled cyst growth and expansion in ADPKD. ADPKD: autosomal-dominant polycystic kidney disease; AMPK: AMP-activated protein kinase; cAMP: cyclic adenosine monophosphate; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; JAK2: Janus kinase 2; MAPK: mitogen-activated protein kinases; mTOR: mammalian target of rapamycin; NFAT: nuclear factor of activated T cells; PI3K: phosphoinositide 3-kinase; PKB: protein kinase B; STAT: signal transducer and activator of transcription.

Figure 2

PRISMA flow diagram of article selection for the systematic review.