纤毛在多囊肾病发病中的作用

多囊肾病(polycystic kidney disease,PKD)是人类常见的单基因遗传疾病之一。上海地区统计数据显示,PKD所致的透析患者占整个透析人群的     

常染色体显性遗传性多囊肾的诊断与外科治疗

多囊肾病(polycystic kidney disease,PKD)指双侧肾脏发生多个囊肿且进行性增大而导致肾脏结构和功能损害的一种最常见的常染色体遗传性疾病.     

多囊肾病发病机制转化治疗策略

多囊肾病(polycystic kidney disease,PKD)是人类最常见的单基因遗传性肾脏疾病。欧美国家和我国上海地区的血液透析患者资料数据库均显示,多囊肾病是导致终末期肾病的第4位病因。多囊肾病患者中最多、危害最大的是常染色体显性多囊肾病     

常染色体显性多囊肾病的临床问题及其肾脏替代治疗的选择

常染色体显性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)是一种常见的单基因疾病,其遗传模式与其他慢性肾脏病(chronic kidney disease,CKD)不同,其特征是肾脏充满液体囊肿。ADPKD是多系统进行性障碍疾病,常伴有肝囊肿、疼痛、感染、出血、高血压、心脑血管疾病、肿瘤等许多特有的临床问题。典型病例在中年时会发展为终末期肾病(end stage renal disease,ESRD),有5%～10%需行肾替代治疗。在本篇文章中,我们回顾了这些临床问题及探讨了此类患者肾替代治疗方式如何选择。     

常染色体显性遗传性多囊肾病的基因诊断方法及其临床应用

常染色体显性遗传性多囊肾病（autosomal dominant polyeystic kidney disease，ADPKD）是一种常见的单基因遗传性疾病．发病率约为1／1000。ADPKD主要在中年以后发病，临床表现为肾脏皮、髓质可有多个液性囊肿形成和增大，约50％患者在60岁左右发展成终末期肾功能衰竭，需要反复透析治疗或肾脏移植。ADPKD可累及多个器官和系统，如发生肝囊肿、颅内动脉瘤、心脏瓣膜异常等。     

成人型多囊肾伴癌变1例报道

成人型多囊肾（adult polycystic kidney），又称常染色体显性多囊肾病（autosomal dominant polycystic kidney disease，ADPKD），是较常见的人类单基因遗传性疾病。主要特征是双侧肾形成多个液性囊泡，囊肿进行性增大，造成肾结构和功能的损害，最终可引起肾功能衰竭。本病是中年人尿毒症常见原因之一，也是遗传性肾病最多见的疾病之一。本文报告1例病理确诊为ADPKD癌变病例并结合临床病理资料进行分析，以期探讨其发病机制、组织形态学以及临床病理。     

成人多囊性肾病89例临床分析

多囊肾按遗传方式分为常染色体显性遗传多囊性肾病(autosmal dominant polycystic kidney disease,ADPKD)和常染色体隐性遗传多囊性肾病(autosmal recessive polystickidney disease,ARPKD),ARPKD主要见于小儿,是造成小儿肾衰竭的主要疾病,患儿多在幼儿时夭折[1].     

基于常染色体显性多囊肾病基因芯片数据的生物信息学分析

目的通过GEO数据库(Gene Expression Omnibus)下载常染色体显性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)患者基因芯片数据集进行分析,得出共同差异表达基因(differentially expressed genes,DEGs)并进行生物信息学分析,探索ADPKD发病机制中可能的信号通路和蛋白-蛋白相互作用机制。方法通过GEO数据库下载两组关于ADPKD患者肾囊肿组织及对照组织的基因芯片数据集GSE7869和GSE35831,对其进行DEGs筛选,使用DAVID数据库和Funrich软件分析生物学信息及信号通路,使用STRING数据库分析蛋白-蛋白相互作用机制。结果 GSE7869共有3970个DEGs,GSE35831共有147个DEGs。两组DEGs有28个相同的上调基因和24个相同的下调基因:上调DEGs的功能集中在离子通道相关通路,相关信号通路富集于自噬相关通路如m TOR和PI3K/Akt通路、生长因子和整合素相关通路;下调DEGs集中于能量代谢功能和相关信号通路。结论通过分析ADPKD得出的52个DEGs和相关富集信号通路,可为疾病研究提供潜在的生物标记物和方向;调控ADPKD肾细胞自噬、延缓囊肿进展将可能成为新的研究焦点。     

1例成人多囊肝围手术期的护理

成人多囊肝(adult polycystic liver disease,APLD)是临床少见的常染色体显性遗传病,通常合并多囊肾(polycystic kidney disease,PKD)[1].病人发病早期症状不明显,随着囊肿的体积不断增大和增多,病人出现压迫症状,有腹胀、上腹疼痛、乏力、食欲减退、平卧时呼吸困难、下肢肿胀、腹水等.多囊肝病人由于出现明显症状后需要进行反复的肝囊肿穿刺、引流,病程迁延多年,对病人的身心造成了严重的伤害.但伴随症状越来越重,囊肿数量和体积不断增多和增大,病人最终需要手术治疗.肝叶部分切除和开窗术现已成为治疗本病最常用的手术方法[2].笔者通过对1例多囊肝病人围手术期护理,现将体会报告如下.     

多囊肾病患者肾脏体积与临床表现关系的研究

目的:探讨常染色体显性遗传性多囊肾病(autosomaldominantpolycystickidneydisease,ADPKD)肾脏体积与临床症状及肾功能预后的关系,以期指导临床治疗和随访。方法:确诊的ADPKD患者65例,平均病程7.8年。对照组为正常健康人40名。采用B超,由专人测量患者双侧肾脏的长、宽、厚三径,计算肾脏体积。同时测血清肌酐,记录体重、血压,肉眼血尿以及腹部症状等。计算肾小球滤过率(GFR),分为GFR正常、轻度、中度、重度减低、肾衰竭5组。另按两侧肾脏长径均值>150mm分组。观察各组肾脏体积和临床症状,肾功能预后的关系。结果:患者肾脏平均体积较正常对照组明显增大[分别为(625576±48076)和(117496±1475)mm3,P<0.001]。患者各组肾脏体积与正常对照组相比均明显增大(P均<0.01)。ADPKD其他各组肾脏体积与GFR正常组相比,除GFR轻度减低组外均显著增加(P<0.05)。ADPKD肾功能明显损害病例大多出现在肾脏长径均值>150mm组。ADPKD肾脏体积大小与GFR呈负相关(r=-0.51,P<0.01)。随着肾脏体积增大,腹部压迫、疼痛及肉眼血尿等并发症明显增加。高血压与肾脏体积无相关关系(r=-0.01,P>0.05)。结论:ADPKD患者的肾脏体积越大肾功能预后越差,并发症明显增加。肾脏体积大小和增长率是疾病进展的指标。定期B超随访观察,有助早期综合治     

Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and treatment

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder affecting 1 in 1,000 people in the general population and accounts for up to 10% of all patients on renal replacement therapy. Numerous fluid-filled epithelial cysts arise from different nephron segments as spherical dilatations or small out-pouchings, enlarge progressively and eventually become disconnected from the rest of the renal tubule. The development of cysts is accompanied by destruction of the renal parenchyma, interstitial fibrosis, cellular infiltration and loss of functional nephrons. ADPKD is not only a kidney disease but also a systemic disorder associated with intracranial arterial aneurysms, cardiac valvular defects, colonic diverticulosis and cyst formation in other organs such as the liver, spleen and pancreas. The identification of PKD1 and PKD2 together with the drive to elucidate the functions of their encoded proteins, polycystin-1 (PC1) and polycystin-2 (PC2), has led to an explosion of clinical and scientific interest in this common disorder. The aim of this review is to highlight recent advances in our understanding of ADPKD pathogenesis which are leading to exciting new treatment strategies.     

Practical genetics for autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common mendelian disorder of the kidney and accounts for ~5% of end-stage renal disease in North America. It is characterized by focal development of renal cysts which increase in number and size with age. Mutations of PKD1 and PKD2 account for most cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with larger kidneys and earlier onset of end-stage renal disease. Furthermore, marked within-family renal disease variability is well documented in ADPKD and suggests a strong modifier effect from as yet unknown genetic and environmental factors. In turn, the significant inter- and intra-familial renal disease variability poses a challenge for diagnosis and genetic counseling. In general, renal ultrasonography is commonly used for the diagnosis, and age-dependent criteria have been defined for subjects at risk of PKD1. However, the utility of the PKD1 ultrasound criteria in the clinical setting is unclear since their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. Additionally, both DNA linkage and gene-based direct sequencing are available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, a negative or indeterminate family history, or in younger at-risk individuals being evaluated as potential living related kidney donor. This review will highlight the utility and limitations of clinical predictors of gene types, imaging- and molecular-based diagnostic tests, and present an integrated approach for evaluating individuals suspected to have ADPKD.     

Abdominal sonographic study of autosomal dominant polycystic kidney disease

PURPOSE: The purpose of this study was to determine whether kidney size in patients who have autosomal dominant polycystic kidney disease (ADPKD) is related to renal function, hypertension, or extrarenal manifestations of the disease and to sonographically evaluate the abdominal manifestations of ADPKD. METHODS: Between 1994 and 1998, 400 individuals from 85 families with a history of ADPKD were examined. There were 213 persons with ADPKD and 187 unaffected family members; there were 182 males and 218 females, 1-82 years old (mean, 39.3 years). We obtained a complete medical history, performed a physical examination, measured the arterial blood pressure and serum creatinine levels, and performed abdominal sonography on each subject. The sonographic features that were studied were renal length and the presence and number of cysts on the kidneys, liver, and pancreas. RESULTS: There was a relationship between kidney size and age (p < 0.05), kidney size and renal function (p < 0.001), and kidney size and hypertension (p < 0.001). The overall prevalence of hepatic cysts in patients with ADPKD was 67%, and the prevalence increased with age. The presence of hepatic cysts was related to the severity of renal disease. Females had more severe polycystic liver disease, and massive polycystic liver disease (ie, hepatomegaly with innumerable cysts) was seen only in females. The prevalence of pancreatic cysts in the 187 persons in whom the pancreas was well evaluated sonographically was 5%. CONCLUSIONS: Kidney size in patients with ADPKD is related to renal function, hypertension, and extrarenal involvement and can be used to predict the outcome of the disease. Hepatic cysts are very common in patients with ADPKD and are related to age and renal function; pancreatic cysts are infrequent in these patients.     

The pathogenesis of autosomal dominant polycystic kidney disease

In individuals with autosomal dominant polycystic kidney disease (ADPKD), renal function deteriorates as the kidneys become replaced by multitudes of fluid-filled cysts. Although the PKD genes were identified a decade ago, the pathway(s) leading from mutation to disease remain the subject of intense investigation. As a result of this work, it has become apparent that the polycystins are multifunctional proteins that, in the broadest sense, appear to be involved in the transduction of a number of environmental cues into appropriate cellular responses. It is likely that the central pathogenetic pathway for cystogenesis stems from de-differentiation of tubular epithelial cells. Available evidence indicates that loss of polycystin activity leads to subtle derangements of cell calcium regulation through several possible pathways. Abnormal cell calcium homeostasis might then lead to altered differentiation in affected cells. The study of the polycystins has revealed some entirely novel insights into fundamental cell biology but these have not yet been satisfactorily integrated into a verified pathogenetic pathway for the development of ADPKD.     

Polycystic liver and kidney diseases

There have been remarkable advances in research on polycystic liver and kidney diseases recently, covering cloning of new genes, refining disease classifications, and advances in understanding more about the molecular pathology of these diseases. Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary disease affecting kidneys. It affects 1/400 to 1/1000 live births and accounts for 5% of the end stage renal disease in the United States and Europe, and is caused by gene defects in the PKD1 or PKD2 genes. Compared to ADPKD, polycystic liver disease (PCLD) is a milder disease and does not lower life expectancy. Both diseases are usually adult-onset diseases. Defects in genes, which code the hepatocystin and SEC63 proteins, have just recently been found to cause PCLD. It now seems that ADPKD is caused by malfunction of the primary cilia, a cell organ sensing fluid movement, and that PCLD is a sequel from defects in protein processing. Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes. All ARPKD patients have a gene defect in a gene called PKHD1, the protein product of which localizes to primary cilia. We summarize the present clinical and molecular knowledge of these diseases in this review.     

Autosomic dominant polycystic kidney disease and metformin: Old knowledge and new insights on retarding progression of chronic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disorder, generally caused by mutations in the PKD1 and PKD2 genes, coding for polycystins 1 and 2. Its pathogenesis is accompanied by alterations of the cAMP, mTOR, MAPK/ERK, and JAK/STAT pathways. ADPKD is clinically characterized by the formation of many growing cysts with kidney enlargement and a progressive damage to the parenchyma, up to its complete loss of function, and the onset of end-stage renal disease (ESRD). The current aim of ADPKD therapy is the inhibition of cyst development and retardation of chronic kidney disease progression. Several drugs have been recently included as potential therapies for ADPKD including metformin, the drug of choice for the treatment of type 2 diabetes mellitus, according to its potential inhibitory effects on cystogenesis. In this review, we summarize preclinical and clinical evidence endorsing or rejecting metformin administration in ADPKD evolution and pathological mechanisms. We explored the biology of APDKD and the role of metformin in slowing down cystogenesis searching PubMed and Clinical Trials to identify relevant data from the database inception to December 2020. From our research analysis, evidence for metformin as emerging cure for ADPKD mainly arise from preclinical studies. In fact, clinical studies are still scanty and stronger evidence is awaited. Its effects are likely mediated by inhibition of the ERK pathway and increase of AMPK levels, which are both linked to ADPKD pathogenesis.     

Molecular genetics of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder, occurring in approximately 1 in 1000 births and accounting for 8% to 10% of cases of end-stage renal disease (ESRD). Mutations of 2 genes, PKD1 and PKD2, account for the disease in approximately 80% to 85% and 10% to 15% of families respectively. The gene products (polycystin 1 and 2) of PKD1 and PKD2 are plasma membrane proteins and components of a novel signalling pathway that regulates epithelial cell growth and differentiation. Significant inter- and intrafamilial renal disease variability in ADPKD has been well documented and is influenced by both germline and somatic genetic events. Specifically, genetic locus heterogeneity and 2 rare Mendelian syndromes have been shown to strongly influence the variability of interfamilial renal disease, and as-yet-unknown genetic and environmental factors likely modify both inter- and intrafamilial renal disease severity. Furthermore, individual cyst formation in ADPKD represents an aberration of monoclonal growth triggered by somatic PKD1 or PKD2 mutations within individual epithelial cells. Current studies are in progress to identify major genetic and environmental modifiers of renal disease variability. A thorough knowledge of these determinants will allow better patient risk assessment and development of mechanism-based therapy in ADPKD.     

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation

Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed to be a monoclonal proliferation of PKD-deficient (PKD(-/-)) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1(-/-) ES cells and Pkd1(+/+) morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both Pkd1(-/-) and Pkd1(+/+) renal tubular epithelial cells in the early stages of cystogenesis. Pkd1(-/-) cyst epithelial cells changed in shape from cuboidal to flat and replaced Pkd1(+/+) cyst epithelial cells lost by JNK-mediated apoptosis in intermediate stages. In late-stage cysts, Pkd1(-/-) cells continued immortalized proliferation with downregulation of p53. These results provide a novel understanding of the cystogenesis of ADPKD patients. Furthermore, immortalized proliferation without induction of p53 was frequently observed in 3T3-type culture of mouse embryonic fibroblasts from Pkd1(-/-) mice. Thus, Pkd1 plays a role in preventing immortalized proliferation of renal tubular epithelial cells through the induction of p53 and activation of JNK.     

Mechanism-based therapeutics for autosomal dominant polycystic kidney disease: recent progress and future prospects

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, accounting for up to 10% of patients on renal replacement therapy. There are presently no proven treatments for ADPKD and an effective disease-modifying drug would have significant implications for patients and their families. Since the identification of PKD1 and PKD2, there has been an explosion in knowledge identifying new disease mechanisms and testing new drugs. Currently, the three major treatment strategies are to: (1) reduce cAMP levels; (2) inhibit cell proliferation, and (3) reduce fluid secretion. Several compounds shown to be effective in preclinical models have already undergone clinical trials and more are planned. In addition, a whole raft of other compounds have been developed from preclinical studies. The purpose of this paper is to evaluate the results of recent published trials, review current trials and highlight the most promising compounds in the pipeline. There appears to be no shortage of potential candidates, but several key issues need to be addressed to facilitate clinical translation.     

Differential diagnosis of fetal hyperechogenic cystic kidneys unrelated to renal tract anomalies: A multicenter study.

OBJECTIVES: To identify important factors in the differential diagnosis of renal cysts associated with hyperechogenic kidneys. METHODS: This was a retrospective multicenter study. We identified 93 fetuses presenting between 1990 and 2002 with hyperechogenic kidneys and which had a diagnosis of nephropathy confirmed later. We analyzed retrospectively the prenatal ultrasound findings of those fetuses which were found sonographically to have renal cysts. RESULTS: Of the 93 fetuses presenting with hyperechogenic kidneys and with a later diagnosis of nephropathy, there were 28 with autosomal dominant polycystic kidney disease (ADPKD), 31 with autosomal recessive polycystic kidney disease (ARPKD), 11 with Bardet-Biedl syndrome, nine with Meckel-Gruber syndrome, six with Ivemark II syndrome, one with Jarcho-Levin syndrome, one with Beemer syndrome and one with Meckel-like syndrome. One third of the fetuses (30/93) had renal cysts. Cystic characteristics (size, location, number) were not very useful for diagnosis; more useful was diagnosis of an associated malformation. Three (11%) of the fetuses with ADPKD had cysts, as did nine (29%) of those with ARPKD, three (27%) of those with Bardet-Biedl syndrome, all (100%) of those with Meckel-Gruber syndrome, three (50%) of those with Ivemark II syndrome, and each of the three cases with other syndromes (Jarcho-Levin, Beemer and Meckel-like syndromes). None of the cases with trisomy 13 had cysts. There were no associated malformations in the 12 cases with renal cysts and polycystic kidney disease; the other 18 cases with renal cysts were associated with malformations that were often specific, such as polydactyly in Bardet-Biedl and Beemer syndromes, occipital defect and Dandy-Walker malformation in Meckel-Gruber or Meckel-Gruber-like syndromes, and thoracic and/or vertebral abnormalities in Jarcho-Levin and Beemer syndromes. CONCLUSION: Renal cysts associated with hyperechogenic kidneys are not rare. The clue to diagnosis is the demonstration of an associated malformation. If no malformation is found, the main diagnosis remains polycystic kidney disease, i.e. ARPKD or ADPKD.