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Background: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. Methods: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. Outcomes: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. Conclusion: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Lay Summary Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to kidney failure. However, ADPKD not only affects the kidney, but also involves other organ systems, including the vasculature. The pathogenesis of vascular disease is not well understood. Here we examined changes in the inner-most layer of blood vessels in ADPKD patients and found significant alterations of the endothelial surface layer (ESL). Considering the importance of the ESL in the integrity of vascular function, this finding is of great interest for ADPKD research. Background Vascular abnormalities and endothelial dysfunction are part of the spectrum of autosomal dominant polycystic kidney disease (ADPKD). The mechanisms behind these manifestations, including potential effects on the endothelial surface layer (ESL) and glycocalyx integrity, remain unknown. Methods Forty-five ambulatory adult patients with ADPKD were enrolled in this prospective, observational, cross-sectional, single-centre study. Fifty-one healthy volunteers served as a control group. All participants underwent real-time microvascular perfusion measurements of the sublingual microcirculation using sidestream dark field imaging. After image acquisition, the perfused boundary region (PBR), an inverse parameter for red blood cell (RBC) penetration into the ESL, was automatically calculated. Microvascular perfusion was assessed by RBC filling and capillary density. Concentrations of circulating glycocalyx components were determined by enzyme-linked immunosorbent assay. Results ADPKD patients showed a significantly larger PBR compared with healthy controls (2.09 +/- 0.23 mu m versus 1.79 +/- 0.25 mu m; P < .001). This was accompanied by significantly lower RBC filling (70.4 +/- 5.0% versus 77.9 +/- 5.4%; P < .001) as well as a higher valid capillary density {318/mm(2) [interquartile range (IQR) 269-380] versus 273/mm(2) [230-327]; P = .007}. Significantly higher plasma concentrations of

ADPKD ist die häufigste genetische Nierenerkrankung, die zur Dialysepflichtigkeit führt. Tolvaptan als ein V2-Rezeptor-Antagonist ist das erste Medikament mit krankheitsmodifizierender Wirkung und nachgewiesener Verzögerung des Nierenfunktionsverlustes. Da die Therapie möglichst lange bis zum Beginn der Dialysepflichtigkeit erfolgt, ist die Therapieadhärenz über Jahre essenziell. Ein relativ hoher Anteil der Patient:innen (10 %) bricht jedoch insbesondere wegen der aquaretischen Nebenwirkungen wie Polyurie und Nykturie ab. Ziel dieser Arbeit war es daher das Ausmaß der Polyurie im klinischen Alltag zu charakterisieren und mögliche modifizierbare und nicht- modifizierbare Faktoren zu identifizieren, die das gesteigerte Urinvolumen als Hauptnebenwirkung von Tolvaptan beeinflussen. Es zeigte sich ein signifikanter Anstieg des Urinvolumens direkt nach Beginn der Therapie mit Tolvaptan, wobei es bei weiterer Dosissteigerung zu keiner wesentlichen Zunahme des Urinvolumens kam. Jüngere Patient:innen und Patient:innen mit einer erhaltenen Nierenfunktion verzeichneten einen stärkeren Anstieg des Urinvolumens. Als modifizierbare Faktoren blieben die Kochsalz-und Osmolytaufnahme pro Tag nach Einleitung der Therapie konstant, zeigten jedoch eine klare Korrelation mit der Urinmenge. Hieraus ergab sich die Empfehlung, dass Patient:innen bei Auftreten von Tolvaptan-assoziierten Nebenwirkungen zunächst die Reduktion des Kochsalzkonsums zur Milderung der Beschwerden erwägen. Die Sorge vor einer weiteren massiven Steigerung des Urinvolumens als Folge der Dosissteigerung kann auf der Grundlage der Daten im Regelfall genommen werden. Zur Objektivierung der Nebenwirkungen und Verlaufskontrolle können in zukünftigen Studien Analysen zur Lebensqualität mittels standardisierter Fragebögen eingesetzt werden. In dieser Arbeit führte Tolvaptan effektiv zu einer Absenkung der Urinosmolalität, um jedoch den Abfall der Urinosmolalität im morgendlichen Spontanurin als Surrogatparameter des Therap

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 m(2); 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 (Delta TLV 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.