Search

Background The identification of new biomarkers in autosomal-dominant polycystic kidney disease (ADPKD) is crucial to improve and simplify prognostic assessment as a basis for patient selection for targeted therapies. Post-Hoc-Analyses of the TEMPO 3:4 study indicated that copeptin could be one of those biomarkers. Methods Copeptin was tested in serum samples from patients of the AD(H)PKD study. Serum copeptin levels were measured using a time-resolved amplified cryptate emission (TRACE) based assay. In total, we collected 711 values from 389 patients without tolvaptan treatment and a total of 243 values (of which 64 were pre-tolvaptan) from 94 patients on tolvaptan. These were associated to rapid progression and disease-causing gene variants and their predictive capacity tested and compared to the Mayo Classification. Results As expected, copeptin levels showed a significant negative correlation with eGFR. Measurements on tolvaptan showed significantly higher copeptin levels (9.871 pmol/l vs. 23.90 pmol/l at 90/30 mg; p Conclusion Copeptin levels are associated with kidney function and independently explained future eGFR slopes. As expected, treatment with tolvaptan strongly increases copeptin levels.

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.

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.

BACKGROUND Prediction of disease progression is one of the main challenges in the treatment of Autosomal-Dominant Polycystic Kidney Disease (ADPKD). In addition to already established biomarkers such as total kidney volume (TKV), further biomarkers that are feasible and easy to collect would be important to allow conclusions on prognosis as well as, in the best case, on long-term treatment response. Post-hoc analyses of the TEMPO 3:4 study showed that copeptin could serve as such a biomarker [1, 2]. In this study, we investigated copeptin over a multi-year course in participants of the AD(H)PKD study. METHOD Copeptin was measure from serum samples of 486 patients in the AD(H)PKD study at both initial and follow-up presentations. A total of 95 patients were on tolvaptan therapy at least at one of the measurement time points. We examined the measured values with respect to their distribution in different patient groups (e.g. age, Mayo class) and their changes on tolvaptan administration. Baseline eGFR values were developed using historic creatinine measurements up to 8000 days prior and 1500 days after copeptin measurements. For each patient with at least 5 creatinine measurements an eGFR slope was calculated. The models were developed using a robust linear modelling approach. Slopes were extracted to be the parameter associated to date and multiplied by 365 to retrieve an annual eGFR slope. eGFRs predicted for the specific dates at which copeptin has been measured were then calculated and used in subsequent modelling approaches. To develop a model predictive of eGFR, we used a stepwise regression approach, removing insignificant coefficients at each step. RESULTS As expected, copeptin was significantly lower in 391 tolvaptan naive patients than in 95 patients on therapy (9.95 pmol/L versus 19.78 pmol/L; P CONCLUSION Our data obtained from the real-life setting should again be reconciled with the results from the TEMPO 3:4 cohort. Our findings show that copeptin levels are both associated with kidney function and with future eGFR loss. Adding copeptin to the model of the Mayo Classification indeed improves the prediction of future eGFR. However, it is not clear yet whether this mild effect will have an impact in routine clinical care. Copeptin has the potential to facilitate prognostic assessment as a biomarker and thus could be helpful in deciding on therapy initiation and possibly more patient-specific dosing. Future analyses of outcome in relation to copeptin will provide further data and might enable implementation in clinical practice.

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 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.