RESUMO
Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (â¼78% and â¼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (â¼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.
Assuntos
Alelos , Proteínas de Transporte , Predisposição Genética para Doença , Mutação , Rim Policístico Autossômico Dominante/genética , Adulto , Idoso , Substituição de Aminoácidos , Bancos de Espécimes Biológicos , Cílios/patologia , Variações do Número de Cópias de DNA , Feminino , Estudos de Associação Genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Rim Policístico Autossômico Dominante/diagnóstico , Análise de Sequência de DNA , Reino Unido , Sequenciamento do ExomaRESUMO
BACKGROUND AND AIMS: Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). APPROACH AND RESULTS: A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06-61.87; P < 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24-7.36; P < 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16-0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21-0.41) and dCCA (OR, 0.06; CI, 0.03-0.14), all P < 0.0001. Moderate-intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34-0.67; P < 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29-0.97; P = 0.04). CONCLUSIONS: This case-control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.
Assuntos
Neoplasias dos Ductos Biliares/prevenção & controle , Colangiocarcinoma/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/etiologia , Neoplasias dos Ductos Biliares/mortalidade , Estudos de Casos e Controles , Colangiocarcinoma/etiologia , Colangiocarcinoma/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.
Assuntos
Rim Policístico Autossômico Dominante , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mosaicismo , Mutação , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genéticaAssuntos
Transtornos Mieloproliferativos/complicações , Circulação Esplâncnica , Trombose Venosa/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Síndrome de Budd-Chiari/etiologia , Comorbidade , Feminino , Seguimentos , Humanos , Janus Quinase 2/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/etiologia , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/epidemiologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Veia Porta/diagnóstico por imagem , Prognóstico , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Fatores de Risco , Esplenomegalia/etiologia , Falha de Tratamento , Trombose Venosa/tratamento farmacológico , Adulto JovemAssuntos
Janus Quinase 2/genética , Policitemia Vera/genética , Idoso , Contagem de Células Sanguíneas , Progressão da Doença , Éxons/genética , Feminino , Seguimentos , Hemoglobinas/análise , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Policitemia Vera/sangue , Policitemia Vera/mortalidade , Mielofibrose Primária/epidemiologia , Esplenomegalia/epidemiologia , Esplenomegalia/etiologia , Trombose/epidemiologia , Trombose/etiologiaAssuntos
Tamponamento Cardíaco/etiologia , Mielofibrose Primária/complicações , Idoso , Idoso de 80 Anos ou mais , Tamponamento Cardíaco/cirurgia , Feminino , Hematopoese Extramedular , Humanos , Hidroxiureia/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pericardiectomia , Pericardiocentese , Pericardite/complicações , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/radioterapia , Infecções Estafilocócicas/complicaçõesRESUMO
BACKGROUND: Primary sclerosing cholangitis (PSC) is a major risk factor for cholangiocarcinoma (CCA). We investigated biliary and fecal microbiota to determine whether specific microbes in the bile or stool are associated with PSC or CCA. METHODS: Bile was obtained from 32 patients with PSC, 23 with CCA with PSC, 26 with CCA without PSC, and 17 controls. Over 90% of bile samples were from patients with perihilar CCA. Stool was obtained from 31 patients with PSC (11 were matched to bile), 16 with CCA with PSC (10 matched to bile), and 11 with CCA without PSC (6 matched to bile). Microbiota composition was assessed using 16SrRNA-marker-based sequencing and was compared between groups. RESULTS: Bile has a unique microbiota distinguished from negative DNA controls and stool. Increased species richness and abundance of Fusobacteria correlated with duration of PSC and characterized the biliary microbiota in CCA. Stool microbiota composition showed no significant differences between groups. CONCLUSIONS: We identified a unique microbial signature in the bile of patients with increased duration of PSC or with CCA, suggesting a role for microbiota-driven inflammation in the pathogenesis and or progression to perihilar CCA. Further studies are needed to test this hypothesis.
RESUMO
INTRODUCTION: Cystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD. METHODS: This is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records. RESULTS: Differences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age (P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at <47, 47-61, or >61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients. CONCLUSION: HtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age.
RESUMO
BACKGROUNDA treatment option for autosomal dominant polycystic kidney disease (ADPKD) has highlighted the need to identify rapidly progressive patients. Kidney size/age and genotype have predictive power for renal outcomes, but their relative and additive value, plus associated trajectories of disease progression, are not well defined.METHODSThe value of genotypic and/or kidney imaging data (Mayo Imaging Class; MIC) to predict the time to functional (end-stage kidney disease [ESKD] or decline in estimated glomerular filtration rate [eGFR]) or structural (increase in height-adjusted total kidney volume [htTKV]) outcomes were evaluated in a Mayo Clinic PKD1/PKD2 population, and eGFR and htTKV trajectories from 20-65 years of age were modeled and independently validated in similarly defined CRISP and HALT PKD patients.RESULTSBoth genotypic and imaging groups strongly predicted ESKD and eGFR endpoints, with genotype improving the imaging predictions and vice versa; a multivariate model had strong discriminatory power (C-index = 0.845). However, imaging but not genotypic groups predicted htTKV growth, although more severe genotypic and imaging groups had larger kidneys at a young age. The trajectory of eGFR decline was linear from baseline in the most severe genotypic and imaging groups, but it was curvilinear in milder groups. Imaging class trajectories differentiated htTKV growth rates; severe classes had rapid early growth and large kidneys, but growth later slowed.CONCLUSIONThe value of imaging, genotypic, and combined data to identify rapidly progressive patients was demonstrated, and reference values for clinical trials were provided. Our data indicate that differences in kidney growth rates before adulthood significantly define patients with severe disease.FUNDINGNIDDK grants: Mayo DK058816 and DK090728; CRISP DK056943, DK056956, DK056957, and DK056961; and HALT PKD DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401.
Assuntos
Processamento de Imagem Assistida por Computador/métodos , Falência Renal Crônica/patologia , Rim/patologia , Mutação , Rim Policístico Autossômico Dominante/fisiopatologia , Canais de Cátion TRPP/genética , Adulto , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/diagnóstico por imagem , Rim Policístico Autossômico Dominante/genética , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The GALAD score is a serum biomarker-based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. METHODS: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. RESULTS: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93-97], which was higher than the AUC of ultrasound (0.82, P <0.01). At a cutoff of -0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88-0.96; cutoff -1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85-0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96-0.99; cutoff -0.18, sensitivity 95%, specificity 91%). CONCLUSIONS: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. IMPACT: The GALAD score was validated in the United States.