Polycystic Kidney Disease at Howard University Hospital

Adult polycystic kidney disease treatment at Howard University Hospital is summarized. The cases are taken from autopsies performed between January 1955 and November 1975 and from the Hospital''s dialysis population. Polycystic kidney disease was identified in six adults and four infants. Only two dialysis patients were clinically thought to have the disease. A review of the major clinical features of the disease is presented.     

Genetics and Pathogenesis of Autosomal Dominant Polycystic Kidney Disease: 20 Years On

Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is characterized by the progressive development and expansion of bilateral fluid‐filled cysts derived from the renal tubule epithelial cells. Although typically leading to end‐stage renal disease in late middle age, ADPKD represents a continuum, from neonates with hugely enlarged cystic kidneys to cases with adequate kidney function into old age. Since the identification of the first causative gene (i.e., PKD1, encoding polycystin 1) 20 years ago, genetic studies have uncovered a large part of the key factors that underlie the phenotype variability. Here, we provide a comprehensive review of these significant advances as well as those related to disease pathogenesis models, including mutation analysis of PKD1 and PKD2 (encoding polycystin 2), current mutation detection rate, allelic heterogeneity, genotype and phenotype relationships (in terms of three different inheritance patterns: classical autosomal dominant inheritance, complex inheritance, and somatic and germline mosaicism), modifier genes, the role of second somatic mutation hit in renal cystogenesis, and findings from mouse models of polycystic kidney disease. Based upon a combined consideration of the current knowledge, we attempted to propose a unifying framework for explaining the phenotype variability in ADPKD.     

Autosomal dominant Polycystic Kidney Disease: A linkage evaluation of heterogeneity in Italy

A survey of 29 families with Adult Polycystic Kidney Disease (ADPKD) was performed to evaluate the genetic heterogeneity of the disease in Italy. The approach was through the linkage between the disease and 2 polymorphic DNA fragments as detected by the probes 3′HVR and 24.1. Linkage between the polymorphic markers and the disease was confirmed, with the following lod scores: between 3′HVR and ADPKD1 = 12.974 at θ = 0.02; between 24.1 and ADPKD = 1.716 at θ = 0.07; between 3′HVR and 24.1 = 2.738 at θ = 0.09. No evidence of significant genetic heterogeneity in the examined Italian regions was detected.     

后腹腔镜肾囊肿去顶减压术治疗成人型多囊肾的疗效观察

目的评价后腹腔镜肾囊肿去顶减压术治疗多囊肾的临床疗效。方法2005年1月至2009年12月期间,行后腹腔镜肾囊肿去顶减压术的ADPKD患者17例,于术后1月、6月进行随访,观察患者的腰腹部胀痛情况、血压、血清肌酐、GFR的变化。结果腰腹部胀痛、血压明显低于术前,但随着时间推移,效果有所减弱;血清肌酐、GFR无变化。结论对于单侧症状明显的多囊肾患者,行后腹腔镜肾囊肿去顶减压术能改善腰腹部胀痛及血压。     

Successful Pregnancy in a Patient with Autosomal Dominant Polycystic Kidney Disease on Long-Term Hemodialysis

Recent advances in dialysis and a multidisciplinary approach to pregnant patients with advanced chronic kidney disease provide a better outcome. A 38-yr-old female with autosomal dominant polycystic kidney disease (ADPKD) became pregnant. She was undergoing hemodialysis (HD) and her kidneys were massively enlarged, posing a risk of intrauterine fetal growth restriction. By means of intensive HD and optimal management of anemia, pregnancy was successfully maintained until vaginal delivery at 34.5 weeks of gestation. We discuss the special considerations involved in managing our patient with regard to the underlying ADPKD and its influence on pregnancy.

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腹腔镜下多囊肾去顶减压术的应用分析

目的 探究腹腔镜下多囊肾去定减压术的应用效果,为今后临床治疗提供可靠的经验。方法 选取佳木斯市中心医院泌尿外科2015年2月~2017年2月收治的44例多囊肾患者,随机分为观察组和对照组,每组22例。观察组接受腹腔镜下去顶减压术治疗,对照组采用传统开腹手术方案。观察两组患者术前术后血压,血清尿素氮,肌酐水平等,对治疗结果进行分析。结果 20例术前患有高血压的患者,均口服降压药物治疗,其中12例患者联合服用降压药物,8例单一服用降压药物,术后20例服用高血压药物的患者用药剂量均下降,12例联合服用降压药物的患者,4例改为单一用药,8例维持原来用药种类,但剂量减少。8例单一服药的患者2例停药,6例减少剂量;两组患者术后血压、腰腹疼痛评分、血清尿素氮水平、肌酐均较术前明显降低,差异有统计学意义（P＜0.05）;组间比较上,观察组的术后血压、腰腹疼痛评分、血清尿素氮水平、肌酐均低于对照组,差异有统计学意义（P＜0.05）。结论 腹腔镜多囊肾去顶减压术治疗的效果显著,疼痛轻,术后康复快,值得在临床上推广使用。     

Tubular Obstruction Leads to Progressive Proximal Tubular Injury and Atubular Glomeruli in Polycystic Kidney Disease

In polycystic kidney disease (PKD), renal parenchyma is destroyed by cysts, hypothesized to obstruct nephrons. A signature of unilateral ureteral obstruction, proximal tubular atrophy leads to formation of atubular glomeruli. To determine whether this process occurs in PKD, kidneys from pcy mice (moderately progressive PKD), kidneys from cpk mice (rapidly progressive PKD), and human autosomal dominant PKD were examined in early and late stages. Integrity of the glomerulotubular junction and proximal tubular mass were determined in sections stained with Lotus tetragonolobus lectin. Development of proximal tubular atrophy and atubular glomeruli was determined in serial sections of individual glomeruli. In pcy mice, most glomerulotubular junctions were normal at 20 weeks, but by 30 weeks, 56% were atrophic and 25% of glomeruli were atubular; glomerulotubular junction integrity decreased with increasing cyst area (r = 0.83, P < 0.05). In cpk mice, all glomerulotubular junctions were normal at 10 days, but by 19 days, 26% had become abnormal. In early-stage autosomal dominant PKD kidneys, 50% of glomeruli were atubular or attached to atrophic tubules; in advanced disease, 100% were abnormal. Thus, proximal tubular injury in cystic kidneys closely parallels that observed with ureteral obstruction. These findings support the hypothesis that, in renal cystic disorders, cyst-dependent obstruction of medullary and cortical tubules initiates a process culminating in widespread destruction of proximal convoluted tubules at the glomerulotubular junction.Polycystic kidney disease (PKD) is the leading monogenetic cause of chronic kidney disease.¹ Autosomal dominant PKD (ADPKD) is usually slowly progressive and diagnosed in adults, but can present in childhood.² Autosomal recessive PKD (ARPKD) is usually diagnosed by fetal ultrasonography or by the discovery of renomegaly at birth, and progresses rapidly.² Follow-up of patients with ADPKD suggests that total kidney volume, a surrogate indicator for aggregate renal cyst size, can predict the rate of progression to renal insufficiency.³ The increase in cyst size over time appears to be exponential.⁴As total cyst volume increases with age, the volume of functioning cortex parenchyma, composed primarily of proximal tubules, declines and ultimately disappears in a sea of expanding cysts. Cysts develop in only a few nephrons, and the mechanisms by which so few cysts destroy renal function and eventually cause organ failure are poorly understood. The most economical explanation is that cysts squeeze out other nephrons, but, to our knowledge, that scenario has never been directly examined. In this regard, information from studies unrelated to PKD has suggested a new way to view the factors underlying the pernicious decline in glomerular filtration rate (GFR) that is a feature of most heritable renal cystic disorders.⁵Unilateral ureteral obstruction (UUO) in the mouse currently serves as the most widely used model of chronic kidney disease.⁵ The renal response to UUO has uncovered a rich array of anatomical and biochemical changes that result from stopping the flow of urine by surgical ureteral obstruction.⁶ These cellular responses likely represent ineffective reparative responses to urinary obstruction. Morphometric studies of renal injury in the UUO model reveal that oxidative stress and cell death and remodeling at the glomerulotubular junction (GTJ) lead to the complete separation of the glomerulus from the proximal tubule (atubular glomeruli).^7,8 Although similarities in the biochemical features of UUO and PKD were pointed out in 2000,⁵ it was not until the disappearance of proximal tubule mass secondary to cell death was clearly defined that the potential connection was appreciated more widely by those working in the PKD field. The current study applies the methods developed in the murine UUO model to renal cystic disorders to determine whether progressive tubule obstruction could contribute to the loss of renal function.Atubular glomeruli have been reported in the Cy rat, a model of ADPKD in which cysts develop in proximal tubules⁹; however, atubular glomeruli have not been described in human ADPKD or other genetic causes of PKD. To determine whether GTJ atrophy and the formation of atubular glomeruli are a common feature of cystic kidneys and follow a course similar to UUO, two murine PKD models were investigated: the pcy mouse, which develops moderately progressive, late-onset disease (analogous to human ADPKD); and the cpk mouse, which develops rapidly progressive, early-onset disease (analogous to human ARPKD). In addition, relatively early- and late-stage human ADPKD kidneys were examined for evidence of atrophy in the proximal convoluted tubules, GTJ abnormalities, and the presence of atubular glomeruli.     

多囊肾肾动脉血液动力学改变与血压变化的研究

目的 探讨多囊肾患者的血液动力学改变与血压变化的相关性和敏感性.方法 用超声多普勒法(包括频谱多普勒和彩色多普勒)分别测定44例多囊肾患者(多囊肾组)和15例正常人、15例非多囊肾1级高血压患者、15例非多囊肾2级高血压患者、15例非多囊肾3级高血压患者(对照组)的肾主动脉(MRA)、肾段动脉(sRA)、肾叶间动脉(IRA)的收缩期峰值流速(Vman)、最小流速(Vmin)、搏动指数(PI)、阻力指数(R I),并测量血压水平,对其资料进行分析.结果 血压正常的多囊肾组三级肾动脉的Vmax、vrnjn均低于血压正常对照组(P＜0.01),PI、RI明显高于对照组(P＜0.01);1级高血压的多囊肾组Vmax、Vmin显著低于1级非多囊肾1级高血压对照组(P＜0.01),PI、R I显著高于对照组(P＜0.01);2级高血压的多囊肾组Vmax、Vmin显著低于2级非多囊肾1级高血压对照组(P＜0.01),PI、RI显著高于对照组(P＜0.01、P＜0.05).结论 ①多囊肾患者的血液动力学改变早于血压变化:②Vmax、Vmin的下降和PI、RI的增高与血压水平呈正相关.     

PKDB: Polycystic Kidney Disease Mutation Database--a gene variant database for autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) arises from mutations in the PKD1 and PKD2 genes. The Polycystic Kidney Disease Mutation Database (PKDB) is an internet-accessible relational database containing comprehensive information about germline and somatic disease-causing variants within these two genes, as well as polymorphisms and variants of indeterminate pathogenicity. The PKDB database structure incorporates an interface between these gene variant data and any associated patient clinical data. An initiative of the Polycystic Kidney Disease Foundation, PKDB is a publicly accessible database that aims to streamline the evaluation of PKD1 and PKD2 gene variants detected in samples from those with ADPKD, as well as to assist ongoing clinical and molecular research in the field. As the accurate reporting of nucleotide variants is essential for ensuring the quality of data within PKDB, a mutation checker has been mounted on the PKDB server allowing contributors to assess the accuracy of their PKD1 and PKD2 variant reports. Researchers and clinicians may submit their PKD1/PKD2 gene variants and any associated deidentified clinical data via standardized downloadable data entry forms accessible through the PKDB site. PKDB has been launched with the full details of PKD1 and PKD2 gene variant reports published in 73 peer-reviewed articles. Through a series of user-friendly advanced search facilities, users are able to query the database as required. The PKDB server is accessible at http://pkdb.mayo.edu.     

Therapeutic Potential of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitors in Polycystic Kidney Disease

In the common genetic disorder autosomal dominant polycystic kidney disease (ADPKD), kidney function is disrupted by multiple fluid-filled epithelial cysts. Cyst growth in ADPKD involves fluid accumulation within the cyst lumen driven by cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial Cl^? secretion. This suggests that inhibitors of the CFTR Cl^? channel might retard cyst growth. This review considers how knowledge of CFTR structure and function and its role in transepithelial salt and water movements provides insight into the mechanism of action of CFTR inhibitors. Some small molecules, termed open-channel blockers, inhibit directly the CFTR Cl^? channel by physically obstructing the CFTR pore and preventing Cl^? flow. By contrast, other small molecules, termed allosteric inhibitors, bind to CFTR at a site remote from the channel pore and interfere with conformational changes that open the pore. The application of high-throughput screening to CFTR drug discovery has led to the identification of new inhibitors of the CFTR Cl^? channel including the thiazolidinone CFTR_inh-172 and the glycine hydrazide GlyH-101. The demonstration that CFTR inhibitors retard cyst expansion and kidney enlargement in mouse models of ADPKD provides proof of concept for the use of small-molecule CFTR inhibitors in the treatment of ADPKD.     

Generalized Vascular Dissection on Pathological Examination in a Patient With Polycystic Kidney Disease and Acute Aortic Dissection

Polycystic kidney disease (PKD) is a multiple cystic disease involving both the kidneys. Some studies have reported cases of patients with PKD and concurrent aortic dissection; however, autopsy has been performed in only few of these cases. Here, we present the case of a 62-year-old male patient with PKD who showed generalized vascular degeneration, including aortic dissection. The patient had a family history of autosomal dominant PKD and was brought to our hospital because of cardiopulmonary arrest. He was diagnosed with Stanford type A aortic dissection and died on the same day, despite being under cardiopulmonary resuscitation. Autopsy detected multiple cysts in the kidneys, liver, pancreas, and testes. Moreover, multiple tears in the vascular wall of the splenic artery and superior mesenteric artery, including the aorta, were observed. The case findings indicate that patients with PKD may develop associated generalized vascular disease; however, development of cerebral aneurysms and aortic dissections with PKD is particularly serious. Therefore, suitable screening tests must be developed for the early diagnosis and disease characterization, thus, ensuring that the appropriate treatment is administered to the patients.     

Autosomal dominant polycystic kidney disease: a linkage evaluation of heterogeneity in Italy. Italian Collaborative Group on Polycystic Kidney Disease

A survey of 29 families with Adult Polycystic Kidney Disease (ADPKD) was performed to evaluate the genetic heterogeneity of the disease in Italy. The approach was through the linkage between the disease and 2 polymorphic DNA fragments as detected by the probes 3'HVR and 24.1. Linkage between the polymorphic markers and the disease was confirmed, with the following lod scores: between 3'HVR and ADPKD1 = 12.974 at theta = 0.02; between 24.1 and ADPKD = 1.716 at theta = 0.07; between 3'HVR and 24.1 = 2.738 at theta = 0.09. No evidence of significant genetic heterogeneity in the examined Italian regions was detected.