BACKGROUND: Impaired kidney concentration capacity is present in half of the patients with autosomal dominant polycystic kidney disease (ADPKD). The kidney concentrating capacity was further impaired within the animal model of autosomal recessive polycystic kidney disease (ARPKD). To date, only one small study has investigated it in children having ARPKD. Therefore, we aimed to study the kidney concentrating ability in a larger cohort of children with ARPKD. METHODS: Eighteen children (median age 8.5 years, range 1.3-16.8) were retrospectively investigated. A standardized kidney concentrating capacity test was performed after the application of a nasal drop of desmopressin (urine osmolality > 900 mOsmol/kg). The glomerular filtration rate was estimated using the Schwartz formula (eGFR) and blood pressure (BP) was measured as office BP. RESULTS: Kidney concentrating capacity was decreased (urine osmolality < 900 mOsmol/kg) in 100% of children with ARPKD. The median urine osmolality after desmopressin application was 389 (range 235-601) mOsmol/kg. Sixteen patients (89%) were defined as hypertensive based on their actual BP level or their use of antihypertensive drugs. The maximum amounts of urinary concentration correlated significantly with eGFR (r = 0.72, p < 0.0001) and hypertensive scores (r = 0.50, p < 0.05), but not with kidney size. Twelve patients (67%) were defined as having CKD stages 2-4. The median concentrating capacity was significantly lower in children within this group, when compared to children with CKD stage 1 possessing a normal eGFR (544 mOsmol/kg, range 413-600 mOsmol/kg vs. 327 mOsmol/kg, range 235-417 mOsmol/l, p < 0.001). CONCLUSIONS: Impaired kidney concentrating capacity is present in most children with ARPKD and is associated with decreased eGFR and hypertension. A higher resolution version of the Graphical abstract is available as Supplementary information.

• MeSH
• chronická renální insuficience * komplikace   MeSH
• desmopresin MeSH
• dítě MeSH
• hodnoty glomerulární filtrace MeSH
• hypertenze * MeSH
• ledviny MeSH
• lidé MeSH
• polycystické ledviny autozomálně dominantní * MeSH
• polycystické ledviny autozomálně recesivní * komplikace   MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.

• MeSH
• cilie patologie   MeSH
• kationtové kanály TRPP genetika   metabolismus   MeSH
• kinasy NEK genetika   metabolismus   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• myši MeSH
• novorozenec MeSH
• polycystická choroba ledvin * genetika   MeSH
• polycystické ledviny autozomálně dominantní * patologie   MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• serin genetika   metabolismus   MeSH
• transportní proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• novorozenec MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• hypoglykemika farmakologie   klasifikace   terapeutické užití   MeSH
• ledvinné látky aplikace a dávkování   farmakologie   klasifikace   MeSH
• lidé MeSH
• měření krevního tlaku MeSH
• polycystické ledviny autozomálně dominantní * farmakoterapie   patofyziologie   terapie   MeSH
• somatostatin analogy a deriváty   farmakologie   terapeutické užití   MeSH
• tolvaptan aplikace a dávkování   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy 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
• antagonisté antidiuretického hormonu škodlivé účinky   MeSH
• benzazepiny škodlivé účinky   MeSH
• dítě MeSH
• dospělí MeSH
• kvalita života MeSH
• ledviny MeSH
• lidé MeSH
• mladiství MeSH
• polycystické ledviny autozomálně dominantní * MeSH
• tolvaptan škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

Autozomálně dominantní polycystická choroba ledvin je geneticky podmíněné onemocnění, které u asi poloviny pacientů vede k chronickému renálnímu selhání. Jedná se o multisystémové onemocnění s predominancí postižení ledvin a výrazně zhoršující zdravotní stav nemocného. Kauzální terapie není známa. Mezi renální komplikace patří infekce močových cest, nefrolitiáza, hematurie, krvácení do cyst a další. Léčba ve fázi chronického renálního selhání zahrnuje náhradu funkce ledvin - hemodialýzu/peritoneální dialýzu a transplantaci ledviny. Kontroverzní otázkou je indikace, načasování a technika nefrektomie nativních polycystických ledvin. Vždy je třeba postupovat individuálně, žádný jednoznačný konsensus není. Rutinně se provádět nedoporučuje. Má také své chirurgické aspekty a implikace. K jejímu provedení se doporučují symptomatické ledviny, asymptomatické při potřebě získání místa k transplantaci ledviny a ledviny, kde je podezření na tumor. V tomto přehledu vyzdvihujeme důležité aspekty tohoto onemocnění v urologii.

Autosomal dominant polycystic kidney disease is a genetic disease that leads to chronic renal failure in about half of patients. It is a multisystem disease with a predominance of kidney affection and significantly worsening the patient's health. Causal therapy is not known. Renal complications include urinary tract infections, nephrolithiasis, hematuria, cyst bleeding and others. Treatment in chronic renal failure includes renal replacement therapy - hemodialysis/peritoneal dialysis and kidney transplantation. Indication, timing and technique of nephrectomy of native polycystic kidneys remains controversial. It is necessary to proceed individually, there is no clear consensus. It is not recommended to perform nephrectomy routinely. It also has its surgical aspects and implications. Native nephrectomy is recommended in symptomatic kidneys, in asymptomatic kidneys when it is necessary to obtain a place for kidney transplantation and in kidneys where a tumor is suspected. This review focuses on important aspects of ADPKD for urologists.

• MeSH
• diferenciální diagnóza MeSH
• lidé MeSH
• nefrektomie MeSH
• polycystické ledviny autozomálně dominantní * diagnóza   genetika   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Úvod: Autozomálně dominantní polycystická choroba ledvin je geneticky podmíněné onemocnění, které asi u poloviny pacientů vede k chronickému renálnímu selhání. Jedná se o multisystémové onemocnění s predominancí postižení ledvin a výrazně zhoršující zdravotní stav nemocného. Kontroverzní otázkou je indikace, načasování a technika nefrektomie nativních polycystických ledvin. Metody: Retrospektivní observační studie zaměřená na chirurgické aspekty pacientů s ADPKD, kteří podstoupili na našem pracovišti nativní nefrektomii. Do souboru byli zařazeni pacienti operovaní v období 1. 1. 2000 – 31. 12. 2020. Celkem bylo zařazeno 115 pacientů s ADPKD (14,7 % ze všech transplantovaných). V souboru jsme u pacientů zhodnotili základní demografická data, typ operačního výkonu, indikace, komplikace. Výsledky: U 68 pacientů z celkových 115 (59 %) byla provedena nativní nefrektomie. U 22 pacientů (32 %) z nich byla provedena unilaterálně, u 46 (68 %) bilaterálně. Nejčastější indikace byly infekce (42 pacientů, 36 %), bolesti (31 pacientů, 27 %), hematurie (14 pacientů, 12 %), gastrointestinální důvody (1 pacient, 1 %), respirační důvody (1 pacient, 1 %), získání místa pro transplantaci (17 pacientů, 15 %) a podezření na tumor (5 pacientů, 4 %). Závěr: K provedení nativní nefrektomie se doporučují symptomatické ledviny, asymptomatické při potřebě získání místa k transplantaci ledviny a ledviny, kde je podezření na tumor.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that leads to chronic renal failure in about half of patients. It is a multisystemic disease with a predominance of kidney involvement, which significantly worsens the patient’s health. Controversial issues include the indication and the timing and technique of nephrectomy of native polycystic kidneys. Methods: A retrospective observational study focused on the surgical aspects of patients with ADPKD who underwent native nephrectomy at our institution. The group included patients operated on in the period 1/1/2000–31/12/2020. A total of 115 patients with ADPKD were enrolled (14.7% of all transplant recipients). We evaluated the basic demographic data, type of surgery, indications and complications in this group. Results: Native nephrectomy was performed in 68 out of a total of 115 (59%) patients. Unilateral nephrectomy was done in 22 (32%) patients and bilateral in 46 (68%). The most common indications were infections (42 patients, 36%), pain (31 patients, 27%), hematuria (14 patients, 12%), gastrointestinal reasons (1 patient, 1%), respiratory reasons (1 patient, 1%), obtaining a site for transplantation (17 patients, 15%) and suspected tumor (5 patients, 4%). Conclusion: Native nephrectomy is recommended in symptomatic kidneys, or in asymptomatic kidneys when it is necessary to obtain a place for kidney transplantation, and in kidneys where a tumor is suspected.

• MeSH
• lidé MeSH
• nefrektomie metody   MeSH
• polycystické ledviny autozomálně dominantní * chirurgie   MeSH
• retrospektivní studie MeSH
• transplantace ledvin MeSH
• Check Tag
• lidé 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
• antagonisté antidiuretického hormonu škodlivé účinky   MeSH
• cysty * farmakoterapie   MeSH
• dítě MeSH
• ledviny MeSH
• lidé MeSH
• longitudinální studie MeSH
• novorozenec MeSH
• polycystické ledviny autozomálně dominantní * MeSH
• polycystické ledviny autozomálně recesivní * diagnostické zobrazování   farmakoterapie   MeSH
• tolvaptan terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem 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
• antagonisté antidiuretického hormonu farmakologie   terapeutické užití   MeSH
• ledviny MeSH
• lidé MeSH
• polycystické ledviny autozomálně dominantní * farmakoterapie   MeSH
• tolvaptan terapeutické užití   MeSH
• výběr pacientů MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie 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
• apoptóza genetika   MeSH
• cysty * MeSH
• fosfatidylinositol-3-kinasy MeSH
• lidé MeSH
• polycystické ledviny autozomálně dominantní * farmakoterapie   genetika   metabolismus   MeSH
• tolvaptan MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• antagonisté antidiuretického hormonu farmakologie   terapeutické užití   MeSH
• chronická renální insuficience terapie   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• pití MeSH
• polycystické ledviny autozomálně dominantní * farmakoterapie   genetika   komplikace   MeSH
• somatostatin analogy a deriváty   terapeutické užití   MeSH
• statiny terapeutické užití   MeSH
• tolvaptan farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH