Polycystické onemocnění ledvin autosomálně dominantního typu je nejčastější dědičné onemocnění vedoucí k nezvratnému selhání ledvin. Mutace postihující nejčastěji geny pro polycystiny PKD1 a PKD2 podmiňují progresivní tvorbu a růst cyst a vedou k destrukci renálního parenchymu. Základem léčby je léčba podpůrná, zejména korekce hypertenze, a léčba specifická, zahrnující somatostatinová analoga a blokádu receptoru V2 pro vasopresin – tolvaptan. V současné době se řada studií zabývá dalšími terapeutickými modalitami.

Autosomal dominant polycystic kidney disease is the most frequent hereditary renal disease leading to irreversible renal failure. The most common mutations affect genes encoding polycystins PKD1 and PKD2 that leads to progressive cyst formation, growth and, subsequently, to destruction of renal parenchyma. Therapeutical approach is based on supportive treatment, especially on correction of hypertension, and on specific treatment involving somatostatin analogues and vasopressin receptor V2 blockade, tolvaptan. Currently, several trials are studying other therapeutic options.

• MeSH
• Drug Therapy classification   MeSH
• Conservative Treatment classification   methods   MeSH
• Humans MeSH
• Disease Management MeSH
• Metformin pharmacology   therapeutic use   MeSH
• MicroRNAs antagonists & inhibitors   pharmacology   MeSH
• Polycystic Kidney, Autosomal Dominant * diagnosis   drug therapy   genetics   MeSH
• Somatostatin analogs & derivatives   pharmacology   therapeutic use   MeSH
• Tolvaptan pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• MeSH
• Hypoglycemic Agents pharmacology   classification   therapeutic use   MeSH
• Renal Agents administration & dosage   pharmacology   classification   MeSH
• Humans MeSH
• Blood Pressure Determination MeSH
• Polycystic Kidney, Autosomal Dominant * drug therapy   physiopathology   therapy   MeSH
• Somatostatin analogs & derivatives   pharmacology   therapeutic use   MeSH
• Tolvaptan administration & dosage   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND: Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD. METHODS: This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc. RESULTS: Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable. CONCLUSIONS: Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.

• MeSH
• Antidiuretic Hormone Receptor Antagonists adverse effects   MeSH
• Benzazepines adverse effects   MeSH
• Child MeSH
• Adult MeSH
• Quality of Life MeSH
• Kidney MeSH
• Humans MeSH
• Adolescent MeSH
• Polycystic Kidney, Autosomal Dominant * MeSH
• Tolvaptan adverse effects   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

PURPOSE: Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition characterized by massive kidney enlargement and developmental liver defects. Potential consequences during childhood include the need for kidney replacement therapy (KRT). We report the design of 2 ongoing clinical trials (Study 204, Study 307) to evaluate safety, tolerability, and efficacy of tolvaptan in children with ARPKD. METHODS: Both trials are of multinational, multicenter, open-label design. Age range at enrollment is 28 days to < 12 weeks in Study 204 and 28 days to < 18 years in Study 307. Subjects in both studies must have a clinical diagnosis of ARPKD, and those in Study 204 must additionally have signs indicative of risk of rapid progression to KRT, namely, all of: nephromegaly, multiple kidney cysts or increased kidney echogenicity suggesting microcysts, and oligohydramnios or anhydramnios. Target enrollment is 20 subjects for Study 204 and ≥ 10 subjects for Study 307. RESULTS: Follow-up is 24 months in Study 204 (with optional additional treatment up to 36 months) and 18 months in Study 307. Outcomes include safety, tolerability, change in kidney function, and percentage of subjects requiring KRT relative to historical data. Regular safety assessments monitor for possible adverse effects of treatment on parameters such as liver function, kidney function, fluid balance, electrolyte levels, and growth trajectory, with increased frequency of monitoring following tolvaptan initiation or dose escalation. CONCLUSIONS: These trials will provide data on tolvaptan safety and efficacy in a population without disease-specific treatment options. TRIAL REGISTRATION: Study 204: EudraCT 2020-005991-36; Study 307: EudraCT 2020-005992-10.

• MeSH
• Antidiuretic Hormone Receptor Antagonists adverse effects   MeSH
• Cysts * drug therapy   MeSH
• Child MeSH
• Kidney MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Infant, Newborn MeSH
• Polycystic Kidney, Autosomal Dominant * MeSH
• Polycystic Kidney, Autosomal Recessive * diagnostic imaging   drug therapy   MeSH
• Tolvaptan therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Renal Insufficiency, Chronic * complications   physiopathology   therapy   MeSH
• Child MeSH
• Sodium-Glucose Transporter 2 Inhibitors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacology   therapeutic use   MeSH
• Polycystic Kidney Diseases drug therapy   MeSH
• Tolvaptan pharmacology   therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

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.

• MeSH
• Antidiuretic Hormone Receptor Antagonists pharmacology   therapeutic use   MeSH
• Kidney MeSH
• Humans MeSH
• Polycystic Kidney, Autosomal Dominant * drug therapy   MeSH
• Tolvaptan therapeutic use   MeSH
• Patient Selection MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. Another feature of cystic tissue is increased extracellular production and recruitment of inflammatory cells and abnormal connections among cells. Moreover, metabolic alterations in cystic cells including defective glucose metabolism, impaired beta-oxidation and abnormal mitochondrial activity were shown to be associated with cyst expansion. Although tolvaptan has been recently approved as a drug that slows ADPKD progression, some patients do not tolerate tolvaptan because of frequent aquaretic. The advances in the knowledge of multiple molecular pathways involved in cystogenesis led to the development of animal and cellular studies, followed by the development of several ongoing randomized controlled trials with promising drugs. Our review is aimed at pathophysiological mechanisms in cystogenesis in connection with the most promising drugs in animal and clinical studies.

• MeSH
• Apoptosis genetics   MeSH
• Cysts * MeSH
• Phosphatidylinositol 3-Kinases MeSH
• Humans MeSH
• Polycystic Kidney, Autosomal Dominant * drug therapy   genetics   metabolism   MeSH
• Tolvaptan MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• Antidiuretic Hormone Receptor Antagonists pharmacology   therapeutic use   MeSH
• Renal Insufficiency, Chronic therapy   MeSH
• Clinical Studies as Topic MeSH
• Humans MeSH
• Drinking MeSH
• Polycystic Kidney, Autosomal Dominant * drug therapy   genetics   complications   MeSH
• Somatostatin analogs & derivatives   therapeutic use   MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use   MeSH
• Tolvaptan pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

• MeSH
• Renal Insufficiency, Chronic * etiology   drug therapy   MeSH
• Molecular Targeted Therapy MeSH
• Diabetic Nephropathies drug therapy   MeSH
• Angiotensin-Converting Enzyme Inhibitors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Polycystic Kidney, Autosomal Dominant epidemiology   drug therapy   genetics   MeSH
• Rituximab pharmacology   therapeutic use   MeSH
• Tolvaptan pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH

Autozomálně dominantní polycystické onemocnění ledvin (ADPKD) je častou příčinou chronického selhání ledvin vyžadujícího náhradu funkce ledvin dialýzou. Důležitou roli v progresi onemocnění hraje vazopresin. Tolvaptan, inhibitor V2 receptoru pro vazopresin, zpomalil progresi chronického onemocnění ledvin u pacientů v časné i pozdní fázi ADPKD. Komentovaná evropská doporučení poskytují praktický návod, jak u pacientů s ADPKD a rychlou progresí onemocnění k léčbě tolvaptanem přistupovat.

Autosomal dominant polycystic kidney disease (ADPKD) is a frequent cause of chronic kidney failure requiring substitution of kidney function with dialysis. Vasopressin plays a vital role in the progression of the disease. Tolvaptan, a V2 vasopressin receptor inhibitor, slowed the progression of chronic kidney disease in patients in the early and late stages of ADPKD. Commented European recommendations offer a practical manual on approaching the treatment with tolvaptan in patients with ADPKD and quick progression of the disease.

• MeSH
• Glomerular Filtration Rate drug effects   MeSH
• Humans MeSH
• Drinking MeSH
• Polycystic Kidney, Autosomal Dominant * drug therapy   MeSH
• Polyuria therapy   MeSH
• Disease Progression MeSH
• Renal Insufficiency drug therapy   MeSH
• Tolvaptan * administration & dosage   adverse effects   therapeutic use   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Humans MeSH