Abstract Background and Aims Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disease leading to kidney failure. Tolvaptan, the only approved targeted treatment strategy, comes with adverse events such as hepatotoxicity and massive polyuria, limiting its use. Novel treatment strategies are urgently needed. Cyst-lining epithelial cells are glucose-dependent and metabolically inflexible. Evidence from polycystic kidney disease (PKD) animal models show that ketogenic dietary interventions (KDI) can ameliorate cyst growth and loss of kidney function. To enable clinical translation of these findings, our group set up a series of trials—from small cohorts and proof of principle studies to our most recent trial KETO-ADPKD, showing that KDIs are feasible and can work as a treatment for ADPKD [1]. This has received a lot of attention. With this post-hoc analyses, we aim to share further in-depth analyses of the factors moderating the effects we see on ADPKD. Method KETO-ADPKD is an exploratory randomized and controlled clinical trial (NCT04680780). Sixty-six patients were randomized to 3 months dietary intervention (ketogenic diet [KD] or water fasting [WF]) or the control group. Here, we explore correlations between biochemical readout parameters of ketosis and markers of disease progression. Results The KD group shows a promising, yet statistically not significant decline in height-adjusted total kidney volume (htTKV). Patients reaching high biochemical thresholds of ketosis however significantly reduced their htTKV in comparison with the control group (KD −16.3 ml/m, CG + 14.8 ml/m, p-value 0.049). This becomes even clearer when higher thresholds for adherence are administered: In a smaller group requiring not only beta-hydroxybutyrate (BHB) levels ≥0.5 mmol/l but breath acetone ≥5 ppm on 75% of daily measurements, htTKV could be reduced by −17.6 ml/m (KD) vs +14.8 ml/m (CG), p-value 0.026. The significant reduction of liver volume upon KD is not influenced by the level of ketosis. Beneficial effects on estimated glomerular filtration rate (eGFR) can be equally observed in all subsets. Weight loss ≥5% was nor associated with a more significant loss of kidney nor liver volume. Conclusion Subgroup analyses of the KETO-ADPKD trial show stronger impact of the dietary intervention with higher ketone body levels. In particular, ketogenesis as a marker of metabolic reprogramming strongly moderates the effects we see on kidney volume. The assessment of renal cyst fractions could further enlighten the effects on cyst burden. This is in line with preclinical data showing that ketosis rather than caloric intake is responsible for the amelioration of disease progression [2].

BACKGROUND:Ketogenic dietary interventions (KDI) have been shown to be effective in animal models of polycystic kidney disease (PKD), but data from clinical trials are lacking. METHODS:Ten autosomal dominant PKD (ADPKD) patients with rapid disease progression were enrolled at visit V1 and initially maintained a carbohydrate-rich diet. At V2, patients entered one of the two KDI arms: a 3-day water fast (WF) or a 14-day ketogenic diet (KD). At V3, they resumed their normal diet for 3-6 weeks until V4. At each visit, magnetic resonance imaging kidney and liver volumetry was performed. Ketone bodies were evaluated to assess metabolic efficacy and questionnaires were used to determine feasibility. RESULTS:All participants [KD n = 5, WF n = 5; age 39.8 ± 11.6 years; estimated glomerular filtration rate 82 ± 23.5 mL/min/1.73 m2; total kidney volume (TKV) 2224 ± 1156 mL] were classified as Mayo Class 1C-1E. Acetone levels in breath and beta-hydroxybutyrate (BHB) blood levels increased in both study arms (V1 to V2 average acetone: 2.7 ± 1.2 p.p.m., V2 to V3: 22.8 ± 11.9 p.p.m., P = .0006; V1 to V2 average BHB: 0.22 ± 0.08 mmol/L, V2 to V3: 1.88 ± 0.93 mmol/L, P = .0008). Nine of 10 patients reached a ketogenic state and 9/10 evaluated KDIs as feasible. TKV did not change during this trial. However, we found a significant impact on total liver volume (ΔTLV V2 to V3: -7.7%, P = .01), mediated by changes in its non-cystic fraction. CONCLUSIONS:RESET-PKD demonstrates that short-term KDIs potently induce ketogenesis and are feasible for ADPKD patients in daily life. While TLV quickly changed upon the onset of ketogenesis, changes in TKV may require longer-term interventions.

Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.

Background Our laboratory published the first evidence that nutritional ketosis, induced by a ketogenic diet (KD) or time-restricted diet (TRD), ameliorates disease progression in polycystic kidney disease (PKD) animal models. We reasoned that, due to their frequent use for numerous health benefits, some autosomal dominant PKD (ADPKD) patients may already have had experience with ketogenic dietary interventions (KDIs). This retrospective case series study is designed to collect the first real-life observations of ADPKD patients about safety, feasibility and possible benefits of KDIs in ADPKD as part of a translational project pipeline. Methods Patients with ADPKD who had already used KDIs were recruited to retrospectively collect observational and medical data about beneficial or adverse effects and the feasibility and safety of KDIs in questionnaire-based interviews. Results A total of 131 ADPKD patients took part in this study. About 74 executed a KD and 52 a TRD for 6 months on average. A total of 86% of participants reported that KDIs had improved their overall health, 67% described improvements in ADPKD-associated health issues, 90% observed significant weight loss, 64% of participants with hypertension reported improvements in blood pressure, 66% noticed adverse effects that are frequently observed with KDIs, 22 participants reported safety concerns like hyperlipidemia, 45 participants reported slight improvements in estimated glomerular filtration rate and 92% experienced KDIs as feasible while 53% reported breaks during their diet. Conclusions Our preliminary data indicate that KDIs may be safe, feasible and potentially beneficial for ADPKD patients, highlighting that prospective clinical trials are warranted to confirm these results in a controlled setting and elucidate the impact of KDIs specifically on kidney function and cyst progression.

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 < 0.0001; V1 to V2 average BHB: 0.22 ± 0.08 mmol/L, V2 to V3: 1.89 ± 0.92 mmol/L, P < 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.

Key Points We developed a model for automated kidney and liver volumetry in ADPKD to provide assistance with time-consuming volumetry. The model works in both coronal and axial planes and was tested in the real-life setting using large multicentric cohorts. The trained model is published along with the code to allow for further joint development and integration into commercial software packages. Visual Abstract Background Imaging-based total kidney volume (TKV) and total liver volume (TLV) are major prognostic factors in autosomal dominant polycystic kidney disease (ADPKD) and end points for clinical trials. However, volumetry is time consuming and reader dependent in clinical practice. Our aim was to develop a fully automated method for joint kidney and liver segmentation in magnetic resonance imaging (MRI) and to evaluate its performance in a multisequence, multicenter setting. Methods The convolutional neural network was trained on a large multicenter dataset consisting of 992 MRI scans of 327 patients. Manual segmentation delivered ground-truth labels. The model’s performance was evaluated in a separate test dataset of 93 patients (350 MRI scans) as well as a heterogeneous external dataset of 831 MRI scans from 323 patients. Results The segmentation model yielded excellent performance, achieving a median per study Dice coefficient of 0.92–0.97 for the kidneys and 0.96 for the liver. Automatically computed TKV correlated highly with manual measurements (intraclass correlation coefficient [ICC]: 0.996–0.999) with low bias and high precision (−0.2%±4% for axial images and 0.5%±4% for coronal images). TLV estimation showed an ICC of 0.999 and bias/precision of −0.5%±3%. For the external dataset, the automated TKV demonstrated bias and precision of −1%±7%. Conclusions Our deep learning model enabled accurate segmentation of kidneys and liver and objective assessment of TKV and TLV. Importantly, this approach was validated with axial and coronal MRI scans from 40 different scanners, making implementation in clinical routine care feasible. Clinical Trial registry name and registration number: The German ADPKD Tolvaptan Treatment Registry (AD[H]PKD), NCT02497521

Background There is strong evidence that portal vein tumor thrombosis (PVTT) is associated with poor survival in patients with hepatocellular carcinoma (HCC). However, data regarding the clinical significance of hepatic vein tumor thrombosis (HVTT) is rare, particularly in Western patients. Objective To determine the HVTT prevalence in a Western patient population and its impact on survival. Methods We included 1310 patients with HCC treated in our tertiary referral center between January 2005 and December 2016. HVTT and PVTT were diagnosed with contrast-enhanced cross-sectional imaging. Overall survival (OS) was calculated starting from the initial HCC diagnosis, and in a second step, starting from the first appearance of vascular invasion. Results We observed macrovascular invasion (MVI) in 519 patients who suffered from either isolated HVTT (n = 40), isolated PVTT (n = 352), or both combined (HVTT + PVTT) (n = 127). Calculated from the initial HCC diagnosis, the median OS for patients with isolated HVTT was significantly shorter than that of patients without MVI (13.3 vs. 32.5 months, p < 0.001). Calculated from the first appearance of MVI, the median OS was similar among patients with isolated HVTT (6.5 months), isolated PVTT (5 months), and HVTT + PVTT (5 months). Multivariate analysis confirmed HVTT as an independent risk factor for poor survival. Conclusions HVTT may be more common than typically reported. In most patients, it was accompanied by PVTT. Isolated HVTT occurred less frequently and later than isolated PVTT; however, once developed, it had the same deleterious impact on survival. Therefore, patients with HVTT should be classified as advanced stage of HCC.