Extended monitoring of re-coiled cerebral aneurysms after initial postcoiling recanalization: Safety and durability of repeat coil embolization.

PURPOSE: In the endovascular era, postcoiling recanalization of cerebral aneurysms is occurring with greater frequency. Repeat coiling is usually done to prevent rebleeding, although long-term outcomes of re-embolization have yet to be adequately investigated. The present study was undertaken to assess clinical and radiographic outcomes of re-embolization in recanalized aneurysms, focusing on procedural safety, efficacy, and durability. METHOD: In this retrospective review, we examined 308 patients with 310 recurrent aneurysms. All lesions were re-coiled, once major recanalization (after initial coil embolization) was established. Medical records and radiologic data amassed during extended follow-up were then subject to review. Cox proportional hazards regression analysis was undertaken to identify risk factors for subsequent recurrence. RESULT: During a lengthy follow-up (mean, 40.2 ± 33.0 months), major recanalization developed again in 87 aneurysms (28.1%). Multivariable Cox regression analysis linked re-recanalization to initial saccular neck width (p=.003) and autosomal dominant polycystic kidney disease (ADPKD; p<.001). Stent implantation (p=.038) and successful occlusion at second coiling (p=.012) were protective against later recanalization in this setting. The more recent the second embolization was performed, the lower the risk of further recurrence (p=.023). Procedure-related complications included asymptomatic thromboembolism (n = 9), transient ischemic neurologic deficits (n = 2), procedural bleeding (n = 1), and coil migration (n = 1), but there were no residual effects or deaths. CONCLUSION: Repeat coil embolization is a safe therapeutic option for recanalized cerebral aneurysms. Wide-necked status and ADPKD emerged as risks for subsequent recanalization, whereas successful occlusion and stent implantation seemed to reduce the likelihood of recurrence after re-embolization procedures.

ß3 adrenergic receptor as potential therapeutic target in ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) disrupts renal parenchyma through progressive expansion of fluid-filled cysts. The only approved pharmacotherapy for ADKPD involves the blockade of the vasopressin type 2 receptor (V2R). V2R is a GPCR expressed by a subset of renal tubular cells and whose activation stimulates cyclic AMP (cAMP) accumulation, which is a major driver of cyst growth. The ß3-adrenergic receptor (ß3-AR) is a GPCR expressed in most segments of the murine nephron, where it modulates cAMP production. Since sympathetic nerve activity, which leads to activation of the ß3-AR, is elevated in patients affected by ADPKD, we hypothesize that ß3-AR might constitute a novel therapeutic target. We find that administration of the selective ß3-AR antagonist SR59230A to an ADPKD mouse model (Pkd1fl/fl ;Pax8rtTA ;TetO-Cre) decreases cAMP levels, producing a significant reduction in kidney/body weight ratio and a partial improvement in kidney function. Furthermore, cystic mice show significantly higher ß3-AR levels than healthy controls, suggesting a correlation between receptor expression and disease development. Finally, ß3-AR is expressed in human renal tissue and localizes to cyst-lining epithelial cells in patients. Thus, ß3-AR is a potentially interesting target for the development of new treatments for ADPKD.

Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1-Deficient Polycystic Kidney Disease in Animal Model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways. METHODS: We established the forskolin (FSK)-induced three-dimensional (3D) Madin-Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate-stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst-lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein-tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct-specific Pkd1 knockout mouse models. RESULTS: FAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways. CONCLUSIONS: Our study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA-regulated proliferation.

The effects of intrinsic apoptosis on cystogenesis in PKD1-deficient ADPKD pig model.

BACKGROUND: Apoptosis is a form of cell death that plays a critical role in the maintenance of tissue homeostasis involving the development and elimination of unwanted cells. Dysregulation of apoptosis appears to be associated in the pathogenesis of many human diseases. Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease and is mainly caused by mutations in PKD1. Previous studies proved that increased cell death occurred in ADPKD patients and animal models. However, the role of apoptosis in kidney cystogenesis is not clear. METHODS: In current study, due to the high similarities between human and pig, PKD1-deficient (PKD1+/-) pigs and PKD1-knockdown (PKD1KD) pig kidney epithelial cells were used to investigate the mechanisms of apoptosis in driving cystogenesis. RESULTS: In PKD1+/- pigs, increased intrinsic and extrinsic apoptosis were found at ages of 1 month and 3 months, whereas the autophagy and pyroptosis were not altered. Meanwhile, the intrinsic apoptosis was activated along with untouched extrinsic apoptosis in PKD1KD pig kidney cells. Thus, the intrinsic apoptosis played important roles in cystogenesis. CONCLUSIONS: This work provides detail analysis of the roles of different cell death types during cystogenesis in ADPKD pig model. The results suggested a potential new strategy for the diagnosis and treatment of ADPKD by targeting intrinsic apoptosis.

Overweight and Obesity and Progression of ADPKD.

BACKGROUND AND OBJECTIVES: On the basis of earlier observations, we evaluated the association between overweight and obesity and rapid progression of autosomal dominant polycystic kidney disease in participants in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial. More importantly, we also determined whether efficacy of tolvaptan was attenuated in individuals with baseline overweight or obesity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 1312 study participants with relatively early-stage autosomal dominant polycystic kidney disease (mean eGFR 78±22 ml/min per 1.73 m2) who were at high risk of rapid progression were categorized by body mass index (BMI; calculated using nonkidney weight) as normal weight (18.5-24.9 kg/m2; n=670), overweight (25.0-29.9 kg/m2; n=429), or obese (≥30 kg/m2; n=213). Linear and multinomial logistic regression models were used to determine the association of baseline overweight and obesity with change in total kidney volume (TKV) over the 3-year study period. RESULTS: In fully adjusted models, higher BMI was associated with greater annual percent change in TKV (difference of 1.20 [95% confidence interval (95% CI), 0.85 to 1.55] per five-unit higher BMI). Overweight and obesity were associated with higher odds of annual percent change in TKV of ≥7% versus <5% (overweight: odds ratio, 2.04 [95% CI, 1.45 to 2.87]; obese: odds ratio, 4.31 [95% CI, 2.83 to 6.57] versus normal weight). eGFR decline did not differ according to BMI (fully adjusted difference in decline of -0.95 [95% CI, -2.32 to 0.40] ml/min per 1.73 m2 per year per five-unit higher BMI). The three-way interaction (treatment×time×BMI group) was not statistically significant in linear mixed models with an outcome of TKV (log-transformed estimated coefficient comparing the treatment effect for overweight versus normal weight: 0.56% [95% CI, -0.70% to 1.84%] per year; P=0.38; obese versus normal weight: 0.07% [95% CI, -1.47% to 1.63%] per year; P=0.93) or eGFR (estimated coefficient comparing overweight versus normal weight: -0.07 [95% CI, -0.95 to 0.82] ml/min per 1.73 m2 per year; P=0.88; obese versus normal weight: 0.22 [95% CI, -0.93 to 1.36] ml/min per 1.73 m2 per year; P=0.71). CONCLUSIONS: Overweight and particularly obesity are strongly and independently associated with kidney growth, but not eGFR slope, in the TEMPO 3:4 trial, and tolvaptan efficacy is irrespective of BMI categorization. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4, NCT00428948.

A Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies.

Autosomal dominant tubulointerstitial kidney diseases (ADTKDs) are a group of rare genetic diseases that lead to kidney failure. Mutations in the MUC1 gene cause ADTKD-MUC1 (MUC1 kidney disease, MKD), a disorder with no available therapies. Recent studies have identified the molecular and cellular mechanisms that drive MKD disease pathogenesis. Armed with patient-derived cell lines and pluripotent stem cell (iPSC)-derived kidney organoids, it was found that MKD is a toxic proteinopathy caused by the intracellular accumulation of misfolded MUC1 protein in the early secretory pathway. We discuss the advantages of studying rare monogenic kidney diseases, describe effective patient-derived model systems, and highlight recent mechanistic insights into protein quality control that have implications for additional proteinopathies beyond rare kidney diseases.

Nueva mutación asociada a poliquistosis renal autosómica dominante con efecto fundador localizada en la Alpujarra de Granada / New mutation associated with autosomal dominant polycystic kidney disease with founder effect located in the alpujarra region of granada

OBJETIVO: Demostrar que la variante no descrita en el gen PKD1 c.7292T>A, identificada en cuatro familias de la comarca de la Alpujarra de Granada, es la causante de la poliquistosis renal autosómica dominante (PQRAD). Esta variante consiste en una sustitución transversión de timina (T) por adenina (A) que a nivel de la proteína policistina 1 produce un cambio de leucina (Leu/L) por glutamina (Gln/Q) en la posición 2431 (p.Leu2431Gln). MÉTODO: Registramos variables sociodemográficas y clínicas a través de la realización de historias clínicas, árboles genealógicos, ecografías y estudios genéticos a individuos afectos y sanos pertenecientes a estas familias en el contexto del estudio de segregación. RESULTADOS: Todos los individuos afectados portaban en heterocigosis la variante c.7292T>A, mientras que los individuos sanos no la portaron. En las familias estudiadas, el 62,9% eran mujeres. El diagnóstico de PQRAD se realizó a los 29,3 ± 15,82 años de edad, después de haber tenido el primer hijo en el 64,8%. Los motivos principales de diagnóstico de la enfermedad fueron antecedentes familiares y episodios de hematuria. El inicio de tratamiento renal sustitutivo (TRS) se produjo a la edad de 55,8 ± 7,62 años (rango 44-67), y el éxitus a los 63 ± 92,2 años (rango 48-76), siendo la causa desconocida, cardiovascular e insuficiencia renal las más frecuentes; la mediana de supervivencia renal se estableció a los 58,5 ± 0,77 años y la mediana de supervivencia del paciente a los 67 ± 3,54 años. No observamos diferencias en la supervivencia del riñón y del paciente según el sexo. De los pacientes fallecidos, el 52,2% necesitaron TRS y el 94,4% tenían algún grado de insuficiencia renal (IR). CONCLUSIONES: La variante c.7292T>A en el gen PKD1 es responsable de la enfermedad y su distribución en la comarca de la Alpujarra de Granada sugiere un efecto fundador. En la PQRAD es necesario realizar estudios de segregación que ayuden a reclasificar variantes genéticas, en este caso de indeterminada a patogénica

OBJECTIVE: To demonstrate that the variant not described in PKD1 gene c.7292T> A, identified in four families from the Alpujarra in Granada, is the cause of autosomal dominant polycystic kidney disease (ADPKD). This variant consists of a transversion of thymine (T) by adenine (A) that at the level of the Polycystin 1 protein produces a change of leucine (Leu / L) by Glutamine (Gln / Q) in position 2431 (p.Leu2431Gln). METHOD: Sociodemographic and clinical variables were registered using clinical histories, genealogical trees, ultrasounds and genetic analysis to ADPKD and healthy individuals belonging to these families in the context of segregation study. RESULTS: All PKD individuals carried the c.7292T>A variant in heterozygosis, whereas healthy ones did not. Among all ADPKD patients, 62.9% were women. ADPKD diagnosis was made at 29.3 ± 15.82 years, after having the first child in 64.8%. The main reasons for diagnosis were family history and hematuria episodes. The onset of renal replacement therapy (RRT) occurred at 55.8 ± 7.62 years (range 44-67), and death at 63 ± 92.2 years (range 48-76), being the cause unknown, cardiovascular and insufficiency kidney the most frequent; the median of renal survival was established at 58.5 ± 0.77 years and the median survival of patients at 67.2 ± 3.54 years. No differences in kidney and patient survivals were observed according to sex. Among deceased patients, 52.2% required RRT and 94.4% suffered from renal failure. CONCLUSIONS: The variant c.7292T>A in PKD1 gene is responsible for the disease, and its distribution in the Alpujarra region of Granada suggests a founder effect. In ADPKD it is necessary to perform segregation studies that help us to reclassify genetic variants, in this case from indeterminate to pathogenic

An Overview of In Vivo and In Vitro Models for Autosomal Dominant Polycystic Kidney Disease: A Journey from 3D-Cysts to Mini-Pigs.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety of cellular and animal models have been developed to decipher the pathophysiological mechanisms and related pathways underlying the disease. As none of these models perfectly recapitulates the complexity of the human disease, the aim of this review is to give an overview of the main tools currently available to ADPKD researchers, as well as their main advantages and limitations.

Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2-Mediated Blood Pressure Reduction Independent of Cystogenesis.

BACKGROUND: Hypertension often occurs before renal function deteriorates in autosomal dominant polycystic kidney disease (ADPKD). It is unknown whether the Pkd1 gene product polycystin-1-the predominant causal factor in ADPKD-itself contributes to ADPKD hypertension independent of cystogenesis. METHODS: We induced nephron-specific disruption of the Pkd1 gene in 3-month-old mice and examined them at 4-5 months of age. RESULTS: Kidneys from the Pkd1 knockout mice showed no apparent renal cysts, tubule dilation, or increased cell proliferation. Compared with control mice, Pkd1 knockout mice exhibited reduced arterial pressure during high salt intake; this associated with an increased natriuretic, diuretic, and kaliuretic response during the first 2-3 days of salt loading. The lower arterial pressure and enhanced natriuresis during high salt loading in Pkd1 knockout mice were associated with lower urinary nitrite/nitrate excretion and markedly increased urinary PGE2 excretion, whereas GFR, plasma renin concentration, and urinary endothelin-1 excretion were similar between knockout and control mice. Kidney cyclooxygenase-2 protein levels were increased in Pkd1 knockout mice during high salt intake; administration of NS-398, a selective cyclooxygenase-2 inhibitor, abolished the arterial pressure difference between the knockout and control mice during high salt intake. Total kidney Na+/K+/2Cl- cotransporter isoform 2 (NKCC2) levels were greatly reduced in Pkd1 knockout mice fed a high salt diet compared with controls. CONCLUSIONS: These studies suggest that nephron polycystin-1 deficiency does not itself contribute to ADPKD hypertension and that it may, in fact, exert a relative salt-wasting effect. The work seems to comprise the first in vivo studies to describe a potential physiologic role for nephron polycystin-1 in the absence of cysts, tubule dilation, or enhanced cell proliferation.

Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease (ESRD). Genetic information is of the utmost importance in understanding pathogenesis of ADPKD. Therefore, this study aimed to demonstrate the genetic characteristics of ADPKD and their effects on renal function in 749 Korean ADPKD subjects from 524 unrelated families. Genetic studies of PKD1/2 were performed using targeted exome sequencing combined with Sanger sequencing in exon 1 of the PKD1 gene and a multiple ligation probe assay. The mutation detection rate was 80.7% (423/524 families, 331 mutations) and 70.7% was novel. PKD1 protein-truncating (PKD1-PT) genotype was associated with younger age at diagnosis, larger kidney volume, lower renal function compared to PKD1 non-truncating and PKD2 genotypes. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (64.9 vs. 72.9 years old, P < 0.001). In frailty model controlled for age, gender, and familial clustering effect, PKD2 genotype had 0.2 times lower risk for reaching ESRD than PKD1-PT genotype (p = 0.037). In conclusion, our results suggest that genotyping can contribute to selecting rapid progressors for new emerging therapeutic interventions among Koreans.

Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: PKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known. METHODS: To examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity. RESULTS: We found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD. CONCLUSIONS: These data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

In vitro cyst formation of ADPKD cells.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the relentless growth of numerous fluid-filled cysts in the kidneys. Mutations in PKD1 and PKD2, genes that encode polycystin 1 and 2, respectively, are responsible for most cases of ADPKD. Currently, the cellular mechanisms responsible for cyst formation remain poorly understood. In vitro models have been used by researchers to investigate cellular processes for cyst formation in carefully controlled experimental conditions. Madin-Darby canine kidney (MDCK) cells, a distal tubule epithelial cell line, were first used to form 3-dimensional (3-D) cysts within a hydrated collagen gel. This method was applied to epithelial cells cultured from cysts of human ADPKD kidneys, allowing investigators to study cellular mechanisms for cyst growth using cells that harbor the genetic mutations responsible for ADPKD in humans. Studies using ADPKD in vitro cysts have provided insight into cellular processes regulating cell proliferation, fluid secretion, and cell polarity. These assays were used to demonstrate the central role of cAMP agonists, such as arginine vasopressin, on cyst growth; and to test the effectiveness of potential therapeutic agents, including tolvaptan. Results obtained from in vitro cyst experiments demonstrate the translational value of cell model systems for investigating the mechanisms for cyst formation in human ADPKD. In this chapter, we describe protocols for growing ADPKD cells in a 3-D in vitro cyst assay and measuring total cyst volume by microscopy and image analysis.

ALG9 Mutation Carriers Develop Kidney and Liver Cysts.

BACKGROUND: Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). METHODS: We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. RESULTS: Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. CONCLUSIONS: ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.

ADPKD-what the radiologist should know.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal genetic disorder and a leading cause of end stage renal failure (ESRF) affecting over 12 million people worldwide. Whilst the mainstay of diagnosis has historically favoured the imaging domain, the progression of disease was until very recently thought to be best monitored via biochemical analysis, i.e. measurement of estimated glomerular filtration rate. Imaging modalities such as sonography, CT and MRI have more recently proven to be key in monitoring disease progression. As much as half of the renal parenchyma can be lost with no real derangement in renal function. Tolvaptan, a vasopressin antagonist has been shown to slow disease progression and preserve renal function. Here we discuss at length the pathogenesis of ADPKD, the various diagnostic challenges surrounding its evaluation, new treatment options and monitoring of disease progression via serial imaging. We also propose monitoring of the efficacy of Tolvaptan at slowing the rate of deterioration in renal function in patients with ADPKD through MRI guided volumetric analysis of the kidneys.

Renal cyst evolution in childhood: a contemporary observational study.

INTRODUCTION: Children with renal cysts often undergo ultrasound (US) monitoring to identify malignant transformation or polycystic kidney disease (PKD). However, the utility of ongoing surveillance is uncertain. OBJECTIVE: The objective of this study was to assess the natural history of simple or minimally complex cysts and the proportion of progression to autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), or malignancy. STUDY DESIGN: The institutional review board approved retrospective chart review at one institution between 2004 and 2014. Eligible patients had ≤3 simple or minimally complex cyst(s) discovered on US without an initial diagnosis of multicystic dysplastic kidney, genitourinary malignancy, ADPKD, or ARPKD. Patient demographics and cyst details were recorded at identification and follow-up visits. Logistic regression was used to examine univariate association between diagnosis of ADPKD/ARPKD and each recorded variable. RESULTS: Eighty-seven eligible patients were identified. Twenty-two patients were identified antenatally or in the first year of life; the remaining 65 were identified at >1 year of age, median 7.6 years (interquartile range [IQR]: 4.2, 10.6). Most (60/87, 69%) had a solitary cyst at initial US. The median length of follow-up was 4.1 years (IQR: 1.9, 6.8) with median 3 follow-up US (IQR: 2, 5). Eleven patients (12.6%) were diagnosed with ADPKD. One patient (1.2%) was diagnosed with ARPKD. A median 2 follow-up US (IQR: 1, 4) procedures were performed over a median of 2.2 years (IQR: 1.0, 3.9) to obtain diagnoses of ADPKD or ARPKD. No patients developed malignancy. DISCUSSION: This study's results reveal that children identified to have a small number of simple or minimally complex renal cysts on initial US are unlikely to require additional treatment for these cysts as transformation to PKD or malignant condition is rare. Supporting this are results from literature that although simple cysts in childhood may evolve over time, most do not require any surgical or invasive treatment in the long term. Limitations include retrospective design and single institution. CONCLUSIONS: Autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease diagnosis occurs early in follow-up evaluation in children with simple or minimally complex cysts. Malignant transformation did not occur in any patients in this study. PATIENT SUMMARY: This study examines the natural history of renal cysts in childhood. Following up simple renal cysts routinely beyond 2-3 years after initial detection may not be optimal due to the use of limited medical resources.

Endothelin-1 Level in Patients with Simple Renal Cyst.

INTRODUCTION: Endothelin-1 (ET-1) is potent vasoconstrictive peptide and elevated ET-1 levels are associated with hypertension, endothelial dysfunction and atherosclerosis. Research on (ET-1) has demonstrated that elevated ET-1 levels in autosomal dominant polycystic kidney disease leads to systemic hypertension. The prevalence of simple renal cysts increases with age and the association with simple renal cyst and hypertension is not clear. The aim of this study was to investigate the ET-1 levels in patients with simple renal cyst and compare them with those in healthy adults. MATERIALS AND METHODS: The study included patients that underwent laparoscopic renal cyst decortication in the Department of Urology and healthy controls. Serum and urinary ET-1 levels were measured before surgery and one month after it in the patients with simple renal cyst. Serum ET-1 levels were measured in healthy adult patients. Ambulatory blood pressure was measured in all patients. Glomerular filtration rate was measured according to the chronic kidney disease epidemiology collaboration formula. RESULTS: Thirty-two patients were included in the present study. Of these, 16 patients with simple renal cyst were allocated into group 1 and 16 healthy patients - in group 2. There was no significant difference between systolic and diastolic blood pressure between the groups (. CONCLUSIONS: The present study demonstrated that serum EL-1 level in patients with simple renal cyst was lower than that in healthy people. Further studies are needed to investigate the EL-1 levels in simple renal cyst patients.

HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor. HIF-1α expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1α co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1α expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1α does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.

Genetic Mechanisms of ADPKD.

Autosomal dominant polycystic kidney disease is caused by mutation of PKD1 (polycystic kidney disease-1) or PKD2 (polycystic kidney disease-2). PKD1 and PKD2 encode PC1 (polycystin-1) and PC2 (polycystin-2), respectively. In addition, the mutation of cilia-associated proteins is also a recognized major factor of pathogenesis, since PC1 and PC2 are located in primary cilium. Abnormalities of PC1 or PC2 lead to aberrant signaling through downstream pathways, such as the negative growth regulation, G protein activation, and canonical and non-canonical Wnt pathways. According to the "second hit" model, an additional somatic mutation results in the expansion of cyst growth. In this chapter we discuss the genetic mechanisms and signaling pathways involved in ADPKD.

Variable Cyst Development in Autosomal Dominant Polycystic Kidney Disease: The Biologic Context.

Patients with autosomal dominant polycystic kidney disease (ADPKD) typically carry a mutation in either the PKD1 or PKD2 gene, which leads to massive cyst formation in both kidneys. However, the large intrafamilial variation in the progression rate of ADPKD suggests involvement of additional factors other than the type of mutation. The identification of these factors will increase our understanding of ADPKD and could ultimately help in the development of a clinically relevant therapy. Our review addresses the mechanisms by which various biologic processes influence cyst formation and cyst growth, thereby explaining an important part of the inter- and intrafamilial variability in ADPKD. Numerous studies from many laboratories provide compelling evidence for the influence on cyst formation by spatiotemporal gene inactivation, the genetic context, the metabolic status, the presence of existing cysts, and whether the kidneys were challenged by renal injury. Collectively, a solid basis is provided for the concept that the probability of cyst formation is determined by functional PKD protein levels and the biologic context. We model these findings in a graphic representation called the cystic probability landscape, providing a robust conceptual understanding of why cells sometimes do or do not form cysts.