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Polycystic liver disease (PLD) is a group of genetic disorders characterized by progressive development of cholangiocyte-derived fluid-filled hepatic cysts. PLD is the most common manifestation of autosomal dominant and autosomal recessive polycystic kidney diseases and rarely occurs as autosomal dominant PLD. The mechanisms of PLD are a sequence of the primary (mutations in PLD-causative genes), secondary (initiation of cyst formation), and tertiary (progression of hepatic cystogenesis) interconnected molecular and cellular events in cholangiocytes. Nonsurgical, surgical, and limited pharmacological treatment options are currently available for clinical management of PLD. Substantial evidence suggests that pharmacological targeting of the signaling pathways and intracellular processes involved in the progression of hepatic cystogenesis is beneficial for PLD. Many of these targets have been evaluated in preclinical and clinical trials. In this review, we discuss the genetic, molecular, and cellular mechanisms of PLD and clinical and preclinical treatment strategies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Antecedentes: La poliquistosis renal es una enfermedad genética que afecta a más de 13 millones de personas a nivel mundial, siguiendo el patrón de herencia mendeliano al transmitirse de forma autosómica dominante o autosómica recesiva, por mutaciones en los genes PKD1, PKD2, PKHD1, donde los dos primeros genes mencionados codifican para las proteínas policistinas 1 y 2 y el tercer gen mencionado codifica para la proteína fibrocistina. Esta patología se caracteriza por la presencia de quistes renales unilaterales o bilaterales que van remplazando el parénquima renal, además de evolucionar hasta el punto de ocasionar una insuficiencia renal con requerimiento de terapia de remplazo renal, inclusive se estima que un 8% a un 10% de los pacientes que reciben diálisis es causa de la poliquistosis renal que avanzo hasta ocasionar una insuficiencia renal terminal, generando una gran carga al sistema de salud, así como un gran impacto en la calidad de vida de estos pacientes Objetivo: Por lo que esta revisión tiene como objeto de estudio Describir la influencia de las vías de señalización celular en la poliquistosis renal. Objetivos específicos: Identificar las mutaciones genéticas y su participación en la fisiopatología de la enfermedad poliquística renal, determinar los mecanismos moleculares implicados en el desarrollo de la enfermedad poliquística renal y describir las vías de señalización celular en las alteraciones en los cilios primarios que desencadenan la enfermedad. Métodos: Se realizó una búsqueda bibliográfica sobre la señalización celular de la poliquistosis renal, así como de otros apartados importantes para su mayor comprensión, en especial su base genética, dentro de la revisión de la literatura se utilizaron estudios publicados desde el 2010 al 2020, de los cuales fueron tomados en las bases de datos del sciencedirect, Clinical key, PUBMED, revistas virtuales y Scielo, con los siguientes términos enfermedad poliquística renal, poliquistosis renal autosómica domínate, poliquistosis renal autosómica recesiva. Resultados: De los artículos seleccionados, se escogieron los siguientes datos para su análisis: año de la publicación, características genéticas de las presentaciones de la enfermedad renal poliquística, fisiopatología y genes implicados, manifestaciones y diagnóstico. De este modo se examinaron 50 artículos de los cuales se tomaron 30 para esta revisión. Conclusiones: Al ser una enfermedad genética, donde se afectan genes como el PKD1, PKD2 y PKHD1, que en condiciones normales codifican las proteínas policistinas y fibrocistina, que están presentes en los cilios primarios, se va a desencadenar alteraciones en las vías moleculares y metabólicas que promueven a la poliquistosis renal, que de forma general lo que hacen es aumentar la liberación de calcio intracelular y los niveles de AMPc, habiendo un aumento de calcio intracelular que estimula la señalización por MAPK/ERK (Ras-Raf- MEK-ERK) para la proliferación celular en el epitelio renal, donde se evidencian los cambios. Background: Polycystic kidney disease is a genetic disease that affects more than 13 million people worldwide, following the Mendelian inheritance pattern by being transmitted in an autosomal dominant or autosomal recessive manner, due to mutations in the PKD1, PKD2, PKHD1 genes, where both the first mentioned genes code for the polycystin proteins 1 and 2 and the third mentioned gene codes for the fibrocystin protein. This pathology is characterized by the presence of unilateral or bilateral renal cysts that are replacing the renal parenchyma, in addition to evolving to the point of causing renal failure requiring renal replacement therapy, including an estimated 8% to 10% of patients receiving dialysis is the cause of polycystic kidney Disease that progressed to end-stage renal failure, generating a great burden on the health system, as well as a great impact on the quality of life of these patients. Objective: Therefore, the purpose of this review is to describe the influence of cell signaling pathways in polycystic kidney disease. Specific objectives: Identify genetic mutations and their participation in the pathophysiology of polycystic kidney disease, determine the molecular mechanisms involved in the development of polycystic kidney disease and describe the cellular signaling pathways in the alterations in the primary cilia that trigger the disease. Methods: A bibliographic search was carried out on the cellular signaling of polycystic kidney disease, as well as other important sections for its greater understanding, especially its genetic basis, within the literature review studies published from 2010 to 2020 were used, of the which were taken from the databases of sciencedirect, Clinical key, PUBMED, virtual magazines and Scielo, with the following terms polycystic kidney disease, autosomal polycystic kidney disease dominate, autosomal recessive polycystic kidney disease. Results: From the selected articles, the following data were chosen for analysis: year of publication, genetic characteristics of the presentations of polycystic kidney disease, pathophysiology and genes involved, manifestations and diagnosis. In this way, 50 articles were examined, of which 30 were taken for this review. Conclusions: Being a genetic disease, where genes such as PKD1, PKD2 and PKHD1 are affected, which in normal conditions encode the polycystin and fibrocystin proteins, which are present in the primary cilia, it will trigger alterations in the molecular and metabolic pathways that promote to polycystic kidney disease, which generally increases intracellular calcium release and cAMP levels, with an increase in intracellular calcium that stimulates MAPK / ERK (Ras-Raf-MEK-ERK) signaling for the cell proliferation in the renal epithelium, where the changes are evident.

Fibropolycystic liver disorders (FLD) arise from abnormal development of the ductal plate and are classified according to the size of the affected hepatobiliary duct. Congenital hepatic fibrosis (CHF) has small duct involvement characterized by a variable degree of periportal fibrosis and hyperplasia without affecting the liver’s architecture. Caroli’s disease (CD) is a rare autosomal recessive disorder with a prevalence of one case per 1,000,000 people and is characterized by cystic dilation of large intrahepatic ducts. When the disease presents with congenital hepatic fibrosis, it is referred to as Caroli’s syndrome (CS). Patients are usually diagnosed around the age of 20 with episodes of cholangitis, portal hypertension or hepatomegaly. We present the case of a two-year-old male with a previous history of autosomal recessive polycystic kidney disease (ARPKD) who presented to the emergency room with variceal bleeding secondary to portal hypertension. The physical examination showed an acutely ill-looking boy, with evident paleness and distended abdomen. Past medical history was negative for previous gastrointestinal bleeding or episodes of cholangitis. An upper gastrointestinal endoscopy was performed, showing esophageal varices secondary to portal hypertension. Imaging studies revealed hepatosplenomegaly, alterations in liver echogenicity, and dilated saccular bile ducts affecting both liver lobes without observing any apparent obstruction, highly suggestive of CD. A liver biopsy revealed nodular liver tissue with marked fibrosis between nodules, which confirmed the presence of CHF. Both kidneys were increased in size, hyperechoic and with loss of corticomedullary differentiation. FLD commonly present with coexisting hepatobiliary and renal alterations. Therefore, starting at the time of initial diagnosis, all patients with ARPKD should be evaluated to detect liver abnormalities due to the high association. Despite the rarity of CS, especially in early childhood, the association between ARPKD and FLD is well documented. So if this clinical presentation arises, CS should be suspected.

Introducción. La enfermedad renal poliquística (PKD, por su sigla en inglés) es una enfermedad genética frecuente en la que se desarrollan de forma progresiva lesiones quísticas que reemplazan el parénquima renal. Es una causa de insuficiencia renal terminal y una indicación común para diálisis y trasplante renal. Existen dos presentaciones de esta enfermedad que se distinguen por sus patrones de herencia: la enfermedad renal poliquística dominante (ADPKD, por su sigla en inglés) y la enfermedad renal poliquística recesiva (ARPKD, por su sigla en inglés).Objetivo. Resumir los aspectos más relevantes de la enfermedad renal: epidemiología, fisiopatología, diagnóstico, manifestaciones clínicas, tratamiento y pronóstico.Materiales y métodos. Revisión sistemática de la literatura en las bases de datos PubMed, Lilacs, UptoDate y Medline con los siguientes términos: enfermedades renales poliquísticas, riñón poliquístico autosómico dominante y riñón poliquístico autosómico recesivo.Resultados. Se encontraron 271 artículos y se escogieron 64 con base en su importancia.Conclusiones. Todo paciente con enfermedad renal poliquística en insuficiencia renal grado V debe ser estudiado para un trasplante renal; en la gran mayoría de los casos no se encontrará contraindicación para realizarlo. Introduction: Polycystic kidney disease (PKD) is a common genetic disease in which cystic lesions develop and progressively replace the renal parenchyma. This is a cause of end-stage kidney disease and a common indication for dialysis and kidney transplantation. These disease presents in two forms, which can be differentiated by their inheritance patterns: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).Objective: To present a brief account of the most relevant aspects of kidney disease: epidemiology, pathophysiology, diagnosis, clinical manifestations, treatment and prognosis.Materials and methods: Systematic literature review conducted in the PubMed, Lilacs, UptoDate and Medline databases with the following terms: polycystic kidney diseases, autosomal dominant polycystic kidney and autosomal recessive polycystic kidney.Results: 271 articles were found and 64 were chosen based on their relevance.Conclusions: All autosomal polycystic kidney disease patients with stage 5 chronic kidney disease should be considered for transplantation, since it is not contraindicated in most cases.

Item does not contain fulltext BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) shows a great phenotypic variability between patients, ranging from perinatal demise to mildly affected adults. Autosomal dominant polycystic liver disease (PCLD) does not manifest in childhood. CASE-DIAGNOSIS/TREATMENT: A boy was reported with the co-occurrence of ARPKD and PCLD. He presented at the age of 16 days with pyelonephritis and urosepsis. Subsequent investigations showed enlarged kidneys and hyperechogenic renal medulla and liver parenchyma. Genetic analysis revealed compound heterozygous mutations in the PKHD1 gene (p.Arg496X and p.Ser1862Leu). After his mother was diagnosed with PCLD, the finding of a liver cyst on ultrasound prompted analysis of the PRKCSH gene, revealing a missense mutation (p.Arg139His). At the most recent follow-up at 13 years of age, the patient's course and clinical examination was uneventful with normal renal and liver function without evidence of portal hypertension. CONCLUSIONS: The patient with ARPKD and PCLD has so far demonstrated a benign clinical outcome, consistent with the great phenotypic variability of ARPKD and, apart from the liver cyst, asymptomatic manifestation of PCLD in childhood. However, close long-term follow-up is mandatory. 01 juli 2012

INTRODUÇÃO: A Doença Renal Policística Autossômica Recessiva (DRPAR) é uma causa importante de morbidade e mortalidade pediátricas, com um espectro variável de manifestações clínicas. MÉTODOS: A apresentação e evolução clínica de 25 pacientes (Pts) foram analisadas através da revisão de prontuários, aplicando-se os formulários propostos por Guay-Woodford et al. As morbidades associadas à doença foram avaliadas quanto à frequência e à idade de manifestação. RESULTADOS: A idade média de diagnóstico foi de 61,45 meses (0 a 336,5 meses), com distribuição similar entre os sexos (52% dos pts do sexo feminino). Houve histórico familiar da doença em 20% dos casos (5/25), com dois casos de consanguinidade. Na análise inicial, diagnosticou-se hipertensão arterial (HAS) em 56% dos Pts (14/25); doença renal crônica estágio > 2 (DRC > 2) em 24% (6/25); infecções do trato urinário (ITU) em 40% (10/25) e hipertensão portal (HP) em 32% dos casos (8/25). Das ultrassonografias abdominais iniciais, 80% demonstraram rins ecogênicos com cistos grosseiros e 64% detectaram fígado e vias biliares normais. Inibidores da ECA foram utilizados em 36% dos Pts, betabloqueadores em 20%, bloqueadores de canais de cálcio em 28% e diuréticos em 36% dos casos. Na análise final, após um tempo de acompanhamento médio de 152,2 meses (29,8 a 274,9 meses), HAS foi diagnosticada em 76% dos Pts, DRC > 2 em 44%, ITU em 52% e HP em 68%. CONCLUSÃO: As altas morbidade e mortalidade associadas à DRPAR justificam a construção de um banco de dados internacional, visando ao estabelecimento de um tratamento de suporte precoce. INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD) is an important pediatric cause of morbidity and mortality, with a variable clinical spectrum. METHODS: The clinical presentation and evolution of 25 patients (Pts) were analyzed by clinical record review, according to the forms proposed by Guay-Woodford et al. Morbidities associated with the disease were evaluated with respect to their frequencies and age of onset. RESULTS: The median age at the diagnosis was 61.45 months (0 to 336.5 months), with similar gender distribution (52% of the patients were female). A family ARPKD history was found in 20% of the cases (5/25), two of them associated with consanguinity. On arrival, arterial hypertension (SAH) was diagnosed in 56% of the Pts (14/25); chronic kidney disease stage > 2 (CKD > 2) in 24% (6/25); urinary tract infection (UTI) in 40% (10/25); and portal hypertension (PH) in 32% of the cases (8/25). Eighty percent of the initial abdominal ultrasonograms detected echogenic kidneys with gross cysts and 64% demonstrated normal liver and biliary ducts. ACE inhibitors were used in 36% of the analyzed patients, beta-blockers in 20%, calcium channel blockers in 28%, and diuretics in 36% of them. In the final evaluation, after an average follow-up time of 152.2 months (29.8 to 274.9 months), SAH was detected in 76% of the cases, CKD > 2 in 44%, UTI in 52% and PH in 68%. CONCLUSION: The high morbidity and mortality associated with ARPKD justify the assembly of an international database, with the aim of establishing an early therapeutic support.