Prenatal sonographic patterns in autosomal dominant polycystic kidney disease: a multicenter study.

OBJECTIVE: To determine whether a specific prenatal sonographic pattern can be identified for autosomal dominant polycystic kidney disease (ADPKD) and if so whether it would be helpful in orienting complementary analysis, properly counseling parents and adapting pregnancy management. METHODS: A retrospective multicenter study was conducted in four prenatal diagnostic centers. The records of fetuses with a prenatal ultrasound examination revealing abnormal kidneys and with a final diagnosis of ADPKD were analyzed. Ultrasound analysis included: amount of amniotic fluid, bladder size, renal length, presence or absence of renal cysts and size of renal pelves, and was focused on parenchyma echogenicity and status of corticomedullary differentiation. Postnatal follow-up was reviewed. RESULTS: Of the 27 patients included in the study, 25 had hyperechogenic renal cortex and 20 had hypoechogenic medulla resulting in increased corticomedullary differentiation (CMD). In six cases, the medulla was hyperechogenic leading to absent or decreased CMD. One patient had normal cortical echogenicity and CMD. Renal cysts were present during the prenatal period in four patients (at 22 weeks in one case and after 30 weeks in three cases). In 12 patients, the cysts appeared after birth (within the first 6 months of postnatal life in 10 cases and by the age of 1 year in two cases). Elevated blood pressure was observed in only two cases and moderate chronic renal failure in one case. CONCLUSION: We have described the sonographic presentation in fetuses with ADPKD: moderately enlarged hyperechogenic kidneys with increased CMD. Although not specific to ADPKD, these findings should prompt familial screening. Other prenatal sonographic features (absent or decreased CMD and cortical cysts) are less frequent.     

Molecular diagnosis of autosomal dominant polycystic kidney disease

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that accounts for 5–10% of end-stage renal disease in developed countries. Mutations in PKD1 and PKD2 account for a majority of cases. Mutation screening of PKD1 is technically challenging largely due to the complexity resulting from duplication of its first 33 exons in six highly homologous pseudogenes (i.e. PKD1P1-P6). Protocol using locus-specific long-range and nested PCR has enabled comprehensive PKD1 mutation screening but is labor-intensive and costly. Here, the authors review how recent advances in Next Generation Sequencing are poised to transform and extend molecular diagnosis of ADPKD.

Areas covered: Key original research articles and reviews of the topic published in English identified through PubMed from 1957–2017.

Expert commentary: The authors review current and evolving approaches using targeted resequencing or whole genome sequencing for screening typical as well as challenging cases (e.g. cases with no detectable PKD1 and PKD2 mutations which may be due to somatic mosaicism or other cystic disease; and complex genetics such as bilineal disease).     

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.     

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.     

Hepatic cysts in autosomal dominant polycystic kidney disease

Hepatic cysts are one of several extrarenal manifestations of the ADPKD gene. Several factors, including age, gender, pregnancy, the degree of renal cystic disease, and the extent of renal functional impairment, may modify the expression of hepatic cystic disease. With advances in medical care, such as improvement in the management of end-stage renal disease, hemodialysis, and renal transplantation, patients with ADPKD will experience an increased life expectancy. As a result, complications associated with hepatic cysts may become more common, and physicians may encounter an increasing number of patients with ADPKD who have infected hepatic cysts. Several issues in the management of this complication remain unresolved, but the article by Telenti and associates in this issue of the Proceedings addresses some of the critical issues that physicians who are responsible for the care of these patients will certainly confront in future years.     

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.     

Hepatic cyst infection in autosomal dominant polycystic kidney disease

To characterize the syndrome of hepatic cyst infection in autosomal dominant polycystic kidney disease (ADPKD) and to review its diagnosis and management, we retrospectively studied five such cases in patients from our institution and nine detailed case reports from the literature. The clinical manifestations were an acute (58%) or subacute (42%) febrile illness, typically associated with tenderness in the right upper quadrant, leukocytosis, a very high erythrocyte sedimentation rate, but minor abnormalities of liver function tests. Bacteremia was present in 7 of 11 patients. Enterobacteriaceae grew in pure culture from the cyst fluid in 9 of 12 patients. Complex cysts were observed by ultrasonography (in four of eight patients), computed tomography (in six of nine), and magnetic resonance imaging (in two of two). 111In leukocyte scans were positive in all four patients in whom they were done, and 67Ga scans were positive in only one of three patients. An unfavorable outcome was observed in six of seven patients treated with only antibiotics, in contrast with one of seven patients who received antibiotics and early drainage. In two patients, ciprofloxacin cyst levels were 2.3 and 4.8 times higher than the level in serum; in a third patient, cyst levels remained in therapeutic range 30 hours after the last dose of ciprofloxacin, at which time serum levels were undetectable. Clinical and laboratory features and the use of modern scanning techniques facilitate a prompt diagnosis of infection in hepatic cysts in ADPKD. The treatment of choice is a combination of percutaneous drainage and antimicrobial therapy.     

CAPD in patients with autosomal dominant polycystic kidney disease.

OBJECTIVE: To investigate whether there are specific complications to continuous ambulatory peritoneal dialysis (CAPD) in patients with autosomal dominant polycystic kidney disease (ADPKD) due to defects in various wall structures--causing hernia and diverticulitis--and to enlarged kidneys. DESIGN: The clinical experience of CAPD in 26 patients with ADPKD, treated for 11+/-6 months, was studied in retrospect and compared with that of 26 contemporary controls. Medical records were reviewed with respect to survival in this treatment form and any complication. Peritoneal dialysis capacity (PDC), as measured in 21 ADPKD patients and 20 controls, was also evaluated. SETTING: University Hospital. RESULTS: Before initiation of CAPD, enlarged kidneys necessitated nephrectomy in 2 of 26 ADPKD patients; both cases were registered as preparation for transplantation, not for CAPD. Survival in CAPD was similar in ADPKD patients and controls. Hernia was present in 4 ADPKD patients and 2 controls, and required transfer to hemodialysis in 1 patient from each group, temporarily. The incidence of peritonitis was 1 per 20 months in ADPKD patients versus 1 in 27 months in the controls, not significantly different. Peritonitis was caused by colonic bacteria in similar numbers. Residual renal function was 1.9 2.1 mL/min per 1.73 m2 in ADPKD patients versus 1.9+/-1.4 mL/min per 1.73 m2 in the controls. No difference was detected in any of the variables measured by PDC. CONCLUSION: There were no specific problems related to ADPKD.     

Cardiovascular manifestations of autosomal dominant polycystic kidney disease in young adults

PURPOSE: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disorder. In addition to renal structure and function abnormalities, the cardiovascular changes (extra renal manifestations) are the frequent findings observed in these subjects. This pilot study describes the viscoelastic properties of the aorta, a predisposing factor for the genesis of hypertension and left ventricular hypertrophy in young adults diagnosed with ADPKD. METHODS: Twenty new patients with ADPKD, all the off springs of previously diagnosed patients with ADPKD were recruited to participate in the study. Each patient underwent the measurement of 24-hour creatinine clearance (Ccr), 24-hour Ambulatory Blood Pressure Monitoring (ABPM), and ultrasonographic determination of the aortic dimensions and left ventricular measurements by M-mode echocardiogram and 12-lead electrocardiogram (ECG) in the echo laboratory. RESULTS: The mean age of our ADPKD subjects was 29.9 +/- 6.5 yr. Five patients had impaired renal functions (Ccr < 1.48 ml/sec). Fourteen patients had hypertension and nine were considered Non-dippers on ABPM. The median value of LVMI and AOD was 84.9 g/m2 and 28.5 x 10(-3)/kPa respectively. Forty five percent of these subjects had non-dipping circadian pattern with smaller nocturnal BP reduction. No relationship between AOD, LVMI and 24-hr ABPM was observed; however, a positive trend towards Ccr and AOD was evident. CONCLUSION: The majority of our ADPKD subjects have an unfavourable cardiovascular risk profile: hypertension and a non-dipping circadian BP rhythm. Subjects with evidence of renal function impairment had reduced aortic distensibility, placing them at an increased risk for cardiovascular morbidity and mortality.     

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.     

Hypertension and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

Hypertension is a common problem in patients with autosomal dominant polycystic kidney disease affecting both renal and patient survival. Activation of the renin-angiotensin-aldosterone system due to cyst expansion and local renal ischemia has been proposed to play an important role in the development of hypertension in autosomal dominant polycystic kidney disease. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with autosomal dominant polycystic kidney disease. Both hypertension and the activation of the renin-angiotensin-aldosterone system play a role in the development of left ventricular hypertrophy in these patients. Prospective randomized results indicate that aggressive control of blood pressure is important for the optimal reversal of left ventricular hypertrophy, thereby diminishing a major risk factor for cardiovascular morbidity and mortality of patients with autosomal dominant polycystic kidney disease. There is also substantial epidemiological support for aggressive control of blood pressure in slowing renal disease progression in autosomal dominant polycystic kidney disease patients. Blockade of the renin-angiotensin-aldosterone system should be the initial approach in the treatment of hypertension in these patients.     

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1^+/null mice are normal, Pkd1^RC/null mice have rapidly progressive disease, and Pkd1^RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero–onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.     

Hypertension and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

Hypertension is a common problem in patients with autosomal dominant polycystic kidney disease affecting both renal and patient survival. Activation of the renin–angiotensin–aldosterone system due to cyst expansion and local renal ischemia has been proposed to play an important role in the development of hypertension in autosomal dominant polycystic kidney disease. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with autosomal dominant polycystic kidney disease. Both hypertension and the activation of the renin–angiotensin–aldosterone system play a role in the development of left ventricular hypertrophy in these patients. Prospective randomized results indicate that aggressive control of blood pressure is important for the optimal reversal of left ventricular hypertrophy, thereby diminishing a major risk factor for cardiovascular morbidity and mortality of patients with autosomal dominant polycystic kidney disease. There is also substantial epidemiological support for aggressive control of blood pressure in slowing renal disease progression in autosomal dominant polycystic kidney disease patients. Blockade of the renin–angiotensin–aldosterone system should be the initial approach in the treatment of hypertension in these patients.     

Mutation analysis of autosomal dominant polycystic kidney disease genes in Han Chinese

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2. The complexity of these genes, particularly PKD1, has complicated genetic screening, though recent advances have provided new opportunities for amplifying these genes. In the Han Chinese population, no complete mutational analysis has previously been conducted across the entire span of PKD1 and PKD2. Here, we used single-strand conformation polymorphism (SSCP) analysis to screen the entire coding sequence of PKD1 and PKD2 in 85 healthy controls and 72 Han Chinese from 24 ADPKD pedigrees. In addition to 11 normal variants, we identified 17 mutations (12 in PKD1 and 5 in PKD2), 15 of which were novel ones (11 for PKD1 and 4 for PKD2). We did not identify any seeming mutational hot spots in PKD1 and PKD2. Notably, we found several disease-associated C-T or G-A mutations that led to charge or hydrophobicity changes in the corresponding amino acids. This suggests that the mutations cause conformational alterations in the PKD1 and PKD2 protein products that may impact the normal protein functions. Our study is the first report of screenable mutations in the full-length PKD1 and PKD2 genes of the Han Chinese, and also offers a benchmark for comparisons between Caucasian and Han ADPKD pedigrees and patients.     

Sonographic diagnosis of seminal vesicle cysts in autosomal dominant polycystic kidney disease

Multiple, bilateral seminal vesicle cysts were found in a young man by transabdominal sonography. Examination of the kidneys disclosed previously unknown autosomal dominant polycystic kidney disease. This case report draws attention to the rare association between these 2 conditions. © 1998 John Wiley & Sons, Inc. J Clin Ultrasound 26:221–222, 1998.     

Wnt信号通路与常染色体显性多囊肾病发病关系的研究进展

Wnt信号通路是一条保守的信号途径,其生物学效应非常广泛,对细胞的黏附、迁移、增殖和凋亡具有调控作用,与多种疾病的发生发展均有关系。近年研究发现,在常染色体显性多囊肾病的发病过程中,Wnt信号通路扮演着非常重要的角色。本文就Wnt信号通路与常染色体显性多囊肾病发病的研究进展做一综述。     

后腹腔镜去顶减压术治疗成人型多囊肾

目的 探讨后腹腔镜去顶减压术治疗成人型多囊肾的临床价值.方法 2001年1月～2004年10月,应用后腹腔镜去顶减压术治疗成人型多囊肾患者25例.结果 所有手术均获成功.平均手术时间150min,手术失血量30～150mL,术后肠道功能恢复时间12～24 h,下床活动时间24～48 h,术后平均住院时间6.5 d.随访10～54个月,20例腰痛患者中腰痛减轻13例;19例血压升高者中15例平均血压下降超过10 mmHg,其中11例血压下降至正常范围;血清Cr下降10μmol/L以上者6例,血清Cr一过性升高10μmol/L以上者2例.未发生严重并发症.结论 后腹腔镜去顶减压术治疗成人型多囊肾疗效确切,创伤小,恢复快,值得在临床上推广应用.     

去顶减压加内引流治疗成人型多囊肾

目的　探讨治疗成人型多囊肾 (ADPKD)的疗效。方法　去顶减压加内引流术治疗 15例成人型多囊肾 ,观察比较术前术后的主观症状、肾功能变化及有关影像学改变。结果　 15例术后随访 ,主观症状明显减轻 ,血压下降 ,内生肌酐清除率由 (5 0 .6± 6 .2 5 )ml/min升至 (81.2± 8.36 )ml/min ,ECT肾动态峰值缩短1～ 10分钟 ,肾小球滤过率由 (6 1.5± 5 .4 )ml/min升至 (78.3± 6 .2 )ml/min ,提示肾功能有明显改善。结论　此方法是治疗成人型多囊肾的一种较好术式。