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

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

• MeSH
• chronická renální insuficience * etiologie   farmakoterapie   MeSH
• cílená molekulární terapie MeSH
• diabetické nefropatie farmakoterapie   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• lidé MeSH
• polycystické ledviny autozomálně dominantní epidemiologie   farmakoterapie   genetika   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• tolvaptan farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

• MeSH
• genetické testování MeSH
• lidé MeSH
• mucin 1 genetika   MeSH
• mutace MeSH
• polycystické ledviny autozomálně dominantní * diagnóza   genetika   MeSH
• uromodulin genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND & AIMS: Polycystic liver disease (PLD) occurs in two genetic disorders, autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant polycystic liver disease (ADPLD). The aim of this study is to compare disease severity between ADPKD and ADPLD by determining the association between diagnosis and height-adjusted total liver volume (hTLV). METHODS: We performed a cross-sectional analysis with hTLV as endpoint. Patients were identified from the International PLD Registry (>10 liver cysts) and included in our analysis when PLD diagnosis was made prior to September 2017, hTLV was available before volume-reducing therapy (measured on computed tomography or magnetic resonance imaging) and when patients were tertiary referred. Data from the registry were retrieved for age, diagnosis (ADPKD or ADPLD), gender, height and hTLV. RESULTS: A total of 360 patients (ADPKD n = 241; ADPLD n = 119) met our inclusion criteria. Female ADPKD patients had larger hTLV compared with ADPLD (P = 0.008). In a multivariate regression analysis, ADPKD and lower age at index CT were independently associated with larger hTLV in females, whereas in males a higher age was associated with larger hTLV. Young females (≤51 years) had larger liver volumes compared with older females (>51 years) in ADPKD. CONCLUSION: Aetiology is presented as a new risk factor associated with PLD severity. Young females with ADPKD represent a subgroup of PLD patients with the most severe phenotype expressed in hTLV.

• MeSH
• cysty diagnostické zobrazování   epidemiologie   genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• hodnocení rizik MeSH
• játra diagnostické zobrazování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• nemoci jater diagnostické zobrazování   epidemiologie   genetika   MeSH
• počítačová rentgenová tomografie * MeSH
• polycystické ledviny autozomálně dominantní diagnostické zobrazování   epidemiologie   genetika   MeSH
• prediktivní hodnota testů MeSH
• průřezové studie MeSH
• registrace MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• sexuální faktory MeSH
• stupeň závažnosti nemoci MeSH
• věkové faktory MeSH
• velikost orgánu MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Belgie MeSH
• Nizozemsko MeSH

Mucin 1 kidney disease, previously referred to as medullary cystic kidney disease type 1, is a rare hereditary kidney disease. It is one of several diseases now termed autosomal dominant tubulointerstitial kidney disease, as proposed by a KDIGO (Kidney Disease: Improving Global Outcomes) consensus report in 2014. Autosomal dominant tubulointerstitial kidney diseases share common clinical findings, such as autosomal dominant inheritance, bland urinary sediment, absent to mild proteinuria, and progressive loss of kidney function. Although the pathophysiology of mucin 1 kidney disease is still under investigation, genetic testing has been developed to detect the most well-known mutation, a single cytosine insertion into a string of 7 cytosines in the variable-number tandem repeat (VNTR) region of the MUC-1 gene. With this diagnostic tool, nephrologists can offer genetic counseling to affected families and monitor closely for progression of disease. We report a Hispanic patient with a strong family history of chronic kidney disease who tested positive for the MUC1 mutation.

• MeSH
• biopsie MeSH
• DNA genetika   MeSH
• dospělí MeSH
• ledviny patologie   MeSH
• lidé MeSH
• mucin 1 genetika   metabolismus   MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• polycystické ledviny autozomálně dominantní diagnóza   genetika   metabolismus   MeSH
• ultrasonografie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by mutations in the UMOD gene (ADTKD-UMOD) is considered rare and often remains unrecognised. We aimed to establish the prevalence of genetic kidney diseases, ADTKD and ADTKD-UMOD in adult chronic kidney disease (CKD) patients, and to investigate characteristic features. METHODS: We sent questionnaires on family history to all patients with CKD stages 3-5 in our tertiary renal centre to identify patients with inherited renal disease. Details on clinical and family history were obtained from patient interviews and clinical records. Sanger sequencing of the UMOD gene was performed from blood or saliva samples. RESULTS: 2027 of 3770 sent questionnaires were returned. 459 patients reported a family history, which was consistent with inherited kidney disease in 217 patients. 182 non-responders with inherited kidney diseases were identified through a database search. Of these 399 individuals, 252 had autosomal dominant polycystic kidney disease (ADPKD), 28 had ADTKD, 25 had Alports, and 44 were unknown, resulting in 11% of CKD 3-5 patients and 19% of end-stage renal disease patients with genetic kidney diseases. Of the unknown, 40 were genotyped, of whom 31 had findings consistent with ADTKD. 30% of unknowns and 39% of unknowns with ADTKD had UMOD mutations. Altogether, 35 individuals from 18 families were found to have ten distinct UMOD mutations (three novel), making up 1% of patients with CKD 3-5, 2% of patients with end-stage renal disease, 9% of inherited kidney diseases and 56% with ADTKD. ADTKD-UMOD was the most common genetic kidney disease after ADPKD with a population prevalence of 9 per million. Less proteinuria and haematuria, but not hyperuricaemia or gout were predictive of ADTKD-UMOD. The main limitations of the study are the single-centre design and a predominantly Caucasian population. CONCLUSIONS: The prevalence of genetic kidney diseases and ADTKD-UMOD is significantly higher than previously described. Clinical features poorly predicted ADTKD-UMOD, highlighting the need for genetic testing guided by family history alone.

• MeSH
• chronická renální insuficience diagnóza   epidemiologie   genetika   MeSH
• genetické testování metody   MeSH
• intersticiální nefritida diagnóza   epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polycystické ledviny autozomálně dominantní diagnóza   epidemiologie   genetika   MeSH
• průzkumy a dotazníky * MeSH
• senioři MeSH
• uromodulin genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, leading to end stage renal failure and kidney transplantation in its most serious form. The severity of the disease's manifestation depends on the genetic determination of ADPKD. The huge variability of different phenotypes (even within a single family) is not only modulated by the two main ADPKD genes (PKD1 and PKD2) but also by modifier genes and the whole genetic background. CASE PRESENTATION: This is a report of an ADPKD family with co-inheritance of PKD1 and PKD2 pathogenic variants. The proband, with an extremely serious manifestation of ADPKD (the man was diagnosed in early childhood, and with end stage renal disease aged 23), underwent genetic analysis of PKD1 and PKD2, which revealed the presence of pathogenic mutations in both of these genes. The missense PKD2 mutation p.Arg420Gly came from the proband's father, with a mild ADPKD phenotype. The same mutation of the PKD2 gene and similar mild disease presentation were found in the proband's aunt (father's sister) and her son. The nonsense mutation p.Gln2196* within the PKD1 gene was probably inherited from the proband's mother, who died at the age of 45. It was only discovered post mortem, that the real cause of her death was kidney failure as a consequence of untreated ADPKD. Unfortunately, neither the DNA of the proband's mother nor the DNA of any other family members from this side of the pedigree were available for further examination. The proband underwent successful cadaveric kidney transplantation at the age of 24, and this replacement therapy lasted for the next 15 years. CONCLUSIONS: Here, we present a first case of bilineal ADPKD inheritance in the Czech Republic. This report highlights the significant role of modifier genes in genetic determination of ADPKD, especially in connection with seriously deteriorated disease phenotypes. In our case, the modifying role is probably mediated by the PKD2 gene.

• MeSH
• dospělí MeSH
• genetická variace genetika   MeSH
• kationtové kanály TRPP genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• polycystické ledviny autozomálně dominantní diagnóza   genetika   MeSH
• rodokmen MeSH
• senioři nad 80 let MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. METHODS: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. RESULTS: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. CONCLUSIONS: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.

• MeSH
• genetická predispozice k nemoci epidemiologie   MeSH
• hodnocení rizik MeSH
• imunohistochemie MeSH
• incidence MeSH
• jehlová biopsie MeSH
• lidé MeSH
• mucin 1 genetika   MeSH
• mutace genetika   MeSH
• polycystické ledviny autozomálně dominantní genetika   mortalita   patologie   MeSH
• prognóza MeSH
• registrace MeSH
• retrospektivní studie MeSH
• rodokmen MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH