An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International

Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use

An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International

Approval of the vasopressin V2 receptor antagonist tolvaptan—based on the landmark TEMPO 3:4 trial—marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use

Autosomal dominant holycystic kidney disease (ADPKD) : from molecular genetics to the development of prognostic tools

La Polykystose Rénale Autosomique Dominante (PKRAD) est une des pathologies héréditaires les plus fréquentes et affecte environ un individu sur 1000. Elle se caractérise par une importante variabilité clinique, notamment dans l’âge de survenue de l’insuffisance rénale terminale. Deux gènes sont en cause : le gène PKD1 situé sur le chromosome 16 (85% des cas) et le gène PKD2 situé sur le chromosome 4 (15% des cas). Les progrès majeurs dans la compréhension des mécanismes moléculaires impliqués ont permis le développement de stratégies thérapeutiques spécifiques, et de nouvelles questions surgissent : quels patients traiter ? Quand débuter les traitements ? La cohorte Genkyst, qui vise à inclure tous les patients suivis pour PKRAD dans la région Grand Ouest, nous a d’abord permis de décrire la variabilité génétique rencontrée dans la PKRAD. Nous avons ensuite démontré l’existence de fortes corrélations génotype-phénotype, en rapportant l’influence sur l’âge de survenue de l’insuffisance rénale terminale non seulement du gène en cause, mais aussi du type de mutation pour le gène PKD1. Enfin, l’analyse des données cliniques et génétiques de 1341 patients nous a permis de développer un algorithme pronostique, baptisé le PROPKD score, permettant de stratifier le risque de progression vers l’insuffisance rénale terminale. Nous espérons que ces travaux participeront à l’individualisation de la prise en charge des patients atteints de PKRAD, ce qui est un enjeu crucial à l’arrivée des nouveaux traitements.Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most frequent Mendelian inherited disorders, and affects approximately one individual out of 1000. ADPKD is marked by a high clinical variability, especially regarding age at end-stage renal disease (ESRD). Two genes are identified: PKD1 located on the chromosome 16 (85% of the pedigrees) and PKD2 located on the chromosome 4 (15% of the pedigrees). Substantial progress in understanding the cellular mechanisms underlying ADPKD has triggered the development of targeted therapies, and new questions are arising: which patients should be treated? When should we begin these treatments? Thanks to Genkyst cohort, which aims to include all consenting ADPKD patients from the western part of France, we first described the important allelic variability encountered in ADPKD. Secondly, we demonstrated the important influence of not only the gene involved, but also of PKD1 mutation type. Last, the analysis of clinical and genetic characteristics of 1341 patients from the Genkyst cohort allowed us to develop a prognostic algorithm, named the PROPKD score for predicting renal outcome in ADPKD. Our hope is that these works will participate in the development of individualized medicine in ADPKD, which is crucial in the context of the emerging targeted therapies

[Autosomal dominant polycystic kidney disease: is the treatment for tomorrow?].

International audienceAutosomal dominant polycystic kidney disease (ADPKD) is the most frequent Mendelian inherited disorder. It covers 6.1% of incident ESRD patients in France in 2011. Long left untreated, this disease will soon benefit from targeted therapies currently under evaluation. Several molecules have already reached the stage of clinical trials: the evaluation of mTOR inhibitors yielded deceiving results and, more recently, 2 different molecules demonstrated a slight impact on the progression of total kidney volume (TKV): tolvaptan, vasopressin receptor-V2 inhibitor and somatostatin analogues; both of these molecules acting throughout the decrease of intracellular AMPc. The purpose of this review is to briefly describe the signaling pathways involved, then to present both the published and ongoing clinical trials and the promising molecules evaluated in murine models

Clinical trials in antineutrophil cytoplasmic antibody-associated vasculitis: what we have learnt so far, and what we still have to learn

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Polycystic kidney disease: Kidney volume--a crystal ball for ADPKD prognosis?

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Aspects génétiques de la polykystose rénale autosomique dominante dans une population de 409 patients bretons

La polykystose renale autosomique (PKAD) est une pathologie dont le phénotype clinique est extrêmement variable, notamment en termes d'âge d'insuffisance rénale terminale (IRT), et de survenue d'anevrysmes intracraniens (AIC). L'objectif de ce travail est d etudier l'influence de facteurs génétiques sur cette variabilité. Patients et méthodes : Nous avons inclus dans cette étude tous les patients du registre Genkyst chez qui le génotypage complet des gènes PKD1 et PKD2 était disponible. Ce génotypage est réalisé par séquencage direct après amplification du matériel génomique. Nous avons comparé les différents groupes de patients par l'analyse de l'âge median d'lRT et des courbes de suivie rénale par la méthode de Kaplan-Meier. Nous avons comparé les positions médianes de la mutation du gène PKD1 dans les familles chez lesquels un antécedent d'AIC et dans les 186 autres familles par un test de Wilcoxon et les répartitions des types de mutation par un test de Student. Résultats. Parmi les 409 patients de cette cohorte, 191 ont atteints le stade IRT, à l'age moyen de 54,3 ans, avec une survie rénale significativement meilleure chez les femmes. L'âge médian de l'IRT est de 57.4 ans quand une mutation du gène PKD1 est en cause et de 69.5 ans quand il s agit du gene PKD2. Au sein des mutations du gène PKD1, les mutations entrainant la synthèse d une protéine tronquée sont les plus sévères, avec un âge median d IRT de 7 ans plus précoce que pour les mutations non troncatives. Nous n'avons pas mis en évidence d'influence du type ou de la localisation des mutations du gène PKD1 sur la survenue d'anévrismes intracraniens. Conclusion. L'influence du type de mutation sur le phénotype de la PKAD est donc importante. A l'aube du développement de thérapies ciblées efficaces, il semble primordial de déterminer de tels facteurs pronostiques, afin de pouvoir reconnaitre les patients les plus à risque de maladie sévère.BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

[Autosomal dominant polycystic kidney disease: is the treatment for tomorrow?].

International audienceAutosomal dominant polycystic kidney disease (ADPKD) is the most frequent Mendelian inherited disorder. It covers 6.1% of incident ESRD patients in France in 2011. Long left untreated, this disease will soon benefit from targeted therapies currently under evaluation. Several molecules have already reached the stage of clinical trials: the evaluation of mTOR inhibitors yielded deceiving results and, more recently, 2 different molecules demonstrated a slight impact on the progression of total kidney volume (TKV): tolvaptan, vasopressin receptor-V2 inhibitor and somatostatin analogues; both of these molecules acting throughout the decrease of intracellular AMPc. The purpose of this review is to briefly describe the signaling pathways involved, then to present both the published and ongoing clinical trials and the promising molecules evaluated in murine models

Can ultrasound kidney length qualify as an early predictor of progression to renal insufficiency in autosomal dominant polycystic kidney disease?

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