Development Of Renal Cysts Research Articles

Matching clinical and genetic data in pediatric patients at risk of developing cystic kidney disease.

Cystic kidney disease is a heterogeneous group of hereditary and non-hereditary pathologic conditions, associated with the development of renal cysts. These conditions may be present both in children and adults. Cysts can even be observed already during the prenatal age, and pediatric patients with cysts need to be clinically monitored. An early clinical and genetic diagnosis is therefore mandatory for optimal patient management. The aim of this study was to perform genetic analyses in patients with echographic evidence of kidney cysts to provide an early molecular diagnosis. A cohort of 70 pediatric patients was enrolled and clinically studied at the time of first recruitment and at follow-up. Genetic testing by clinical exome sequencing was performed and a panel of genes responsible for "cystic kidneys" was analyzed to identify causative variants. Sanger validation and segregation studies were exploited for the final classification of the variants and accurate genetic counseling. Data showed that 53/70 of pediatric patients referred with a clinical suspicion of cystic kidney disease presented a causative genetic variant. In a significant proportion of the cohort (24/70), evidence of hyper-echogenic/cystic kidneys was already present in the prenatal period, even in the absence of a positive family history. This study suggests that cystic kidney disease may develop since the very early stages of life and that screening programs based on ultrasound scans and genetic testing play a critical role in diagnosis, allowing for better clinical management and tailored genetic counseling to the family.

Association Between Metabolic Syndrome and the Size of Renal Cysts: A Cross-Sectional Study.

Metabolic syndrome (MetS) is associated with the development of several diseases. However, the correlation between MetS and size of renal cysts remains unclear. This research aims to explore the potential connection between them, offering theoretical guidance for clinical prevention and treatment of renal cysts. A total of 467 patients diagnosed with renal cysts and admitted to Sir Run Run Hospital, Nanjing Medical University from September 2019 to September 2020 were eventually included in this study. They were divided into the small cyst group (cyst volume≤1.5cm³) and the large cyst group (cyst volume>1.5cm³) based on the median value of cyst volume. Multivariate logistic regression analysis was used to evaluate the association between MetS and size of renal cysts. Our results indicated that MetS (OR 1.941, 95% CI 1.286-2.927, P=0.002) was positively associated with the size of renal cysts. Additionally, multiple renal cysts (OR 2.259, 95% CI 1.402-3.640, P=0.001) and serum globulin (OR 0.945, 95% CI 0.905-0.987, P=0.011) were positively and negatively related to size of renal cysts, respectively. Our study reveals the association between MetS and the size of renal cysts. Patients with MetS are more likely to have larger renal cysts. The administration of MetS may help limit the development of renal cysts. Further prospective studies are needed to explore the causal relationship between MetS and renal cysts.

Unilateral Renal Cystic Disease

Background: Unilateral renal cystic disease of kidney is a non familial and non progressive disorder, characterized by replacement of the renal parenchyma by a cluster of multiple cysts with a normal contralateral kidney. Case: A 2-day-old newborn baby came to the Urology Department of the Perinatology Department of Andalas University Hospital. The baby with prenatal ultrasound results showed unilateral hydronephrosis and multicystic kidneys. From the postnatal ultrasound, it was found: The right kidney was normal in shape and size; clear differentiation of the cortex and medulla; the pelvic calyx system was not dilated; No stones were seen; There were multiple cystic lesions with regular borders in the renal cortex, the largest cyst size was 5.5x4 cm. The left kidney was normal in shape and size; clear differentiation of the cortex and medulla; The pelvic calyx system was not dilated; No stones or sludge were seen. The impression of multiple renal cysts. The patient was followed up for renal function and cyst development. Conclusion : This case highlights the importance of early diagnosis and follow-up in infants with unilateral renal cystic lesions. Differentiating URCD from other cystic renal diseases is essential for appropriate management and counseling. Further studies are needed to elucidate the pathogenesis and long-term outcomes of URCD.

#2662 Octreotide-LAR in ADPKD patients with very low kidney function: a monocentric real-life experience

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, characterized by development of fluid-filled renal cysts leading to progressive expansion of kidney volume, with decline in kidney function up to end-stage renal disease (ESRD). Octreotide long-acting release (OCT-LAR) is a synthetic somatostatin analogue, which has been shown to reduce kidney and cysts growth and to slow the progression of kidney function decline in ADPKD patients. Although the evidence of the literature supporting the protective effect of the OCT-LAR against progression of the disease in ADPKD patients with both early and later-stages, to date no data are available in ADPKD patients treated with this somatostatin analogue in a real-world clinical setting. In August 2018 OCT-LAR was approved only in Italy for the treatment of ADPKD adult patients with eGFR ranging from 30 to 15 mL/min/1.73 m2 at elevated risk of progression towards ESRD. The present study is aimed to report for the first time the effects on renal function of OCT-LAR in ADPKD patients with severe renal insufficiency (stage 4 CKD) receiving this somatostatin analogue for therapeutic indication in a real-world clinical setting. Method We conducted a retrospective, ADPKD-population-based cohort study using healthcare data from the medical records of patients with ADPKD referred to the Department of Nephrology of University “Federico II” of Naples from November 2018 to April 2023 aimed to analyse within-patient clinical outcomes, including eGFR decline, before and after treatment with OCT-LAR. We include adult ADPKD patients (≥18 years) with GFR (eGFR) between 30 and 15 mL/min/1.73 m2, stably treated from at least 1 years with the regular dose of OCTR-LAR. The primary endpoint was the assessment of eGFR decline from 1 year before the start of the treatment (T-1) to baseline (T0), and after 1 year of therapy with OCT-LAR (T1) in the overall population and in two subgroups of patients with eGFR ≥ or < 25 ml/min/1.73 m2. Results 31 ADPKD patients were analysed (18 with eGFR ≥ 25 and 13 with eGFR < 25). Compared to pre-treatment period, eGFR decline significantly slowed during therapy with OCT-LAR in both eGFR groups (Table 1), while no difference was found between eGFR groups. After the first year of observation, 7 patients required dialysis (all with eGFR <25). Conclusion This is the first study reporting the effects of OCT-LAR on eGFR of ADPKD patients with advanced chronic kidney disease (CKD) in a real-world clinical setting. Our results suggest that, compared the last year of follow-up pre-treatment, OCT-LAR slows eGFR decline after 1 year.

Netrin-1 increases epithelial cell proliferation and promotes renal cyst formation by activating Rac2 in collecting duct cells

Despite recent advances in our understanding of the pathogenesis of polycystic kidney disease (PKD), the underlying molecular mechanisms involved in cystogenesis are not fully understood. Common features of PKD are excessive epithelial cell proliferation and fluid-filled cyst formation in the kidney, leading to loss of kidney function. We recently demonstrated that netrin-1 is upregulated in primary human PKD cystic cells and in the kidneys of rodent models of PKD. Moreover, overexpression of netrin-1 in tubular epithelium increases cell proliferation (p<0.01) and induces renal cyst development (p<0.0001), while decreasing netrin-1 reduces cyst growth (p<0.01) and improves kidney function (p<0.05). However, the underlying mechanism by which netrin-1 induces cystic cell proliferation is unknown. We hypothesize that netrin-1 increases cystic epithelial cell proliferation by activating Ras-Related C3 Botulinum Toxin Substrate 2 (Rac2) in collecting duct (CD). 4-week-old male tubular overexpressed netrin-1 transgenic mice (NTN-1 Tg6) and 8-week old Pkd1RC/RC mice were randomized to receive vehicle or the specific Rac2 inhibitor EHT 1864 (20 mg/kg/48hr i. p; n=4-5/group) for 4 weeks. Blood and kidneys were collected for biochemical, histological, and Western blot analysis. Renal co-localization of Rac2 with CD specific marker Auaphorin-2 in kidney of human and mouse PKD was assessed by immunofluorescence staining and protein expression was measured by Western blot analysis. Renal Rac2 activity was measured using Rac2 activation kit. Cystic index were measured using H&E staining. Cell proliferation was measured using MTT assay and renal function was measured using BUN assay kit. Rac2 is upregulated in the CD of both human PKD and Pkd1RC/RC mice (p<0.01) compared to controls. Moreover, overexpression of netrin-1 activates Rac2 in the cystic kidney (p<0.001) and in human cystic cells (p<0.05). Overexpression of Rac2 increases cell proliferation and phosphorylation of ERK in CD cells (p<0.01). Inhibition of Rac2 reduces netrin-1-induced CD cell proliferation (p<0.01) and cyst growth (p<0.01) in both netrin-1 transgenic (NTN-1 Tg6) and Pkd1RC/RC mice. Our results demonstrate that overexpression of netrin-1 increases cystic epithelial cell proliferation via activating Rac2 in CD cells and contributes to cyst growth. Future studies will be carried out to dissect the downstream signaling mechanism of netrin-1/Rac2 mediated cell proliferation cyst formation in PKD. This work is supported by Intramural grant award (IGPP00043) from Augusta University to R. Mohamed; National Institute of Health (1P01HL134604-01) to J.C. Sullivan. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Notch3 as a novel therapeutic target for the treatment of ADPKD by regulating cell proliferation and renal cyst development

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic kidney disease. Emerging research indicates that the Notch signaling pathway plays an indispensable role in the pathogenesis of numerous kidney diseases, including ADPKD. Herein, we identified that Notch3 but not other Notch receptors was overexpressed in renal tissues from mice with ADPKD and ADPKD patients. Inhibiting Notch3 with γ-secretase inhibitors, which block a proteolytic cleavage required for Notch3 activation, or shRNA knockdown of Notch3 significantly delayed renal cyst growth in vitro and in vivo. Subsequent mechanistic study elucidated that the cleaved intracellular domain of Notch3 (N3ICD) and Hes1 could bind to the PTEN promoter, leading to transcriptional inhibition of PTEN. This further activated the downstream PI3K-AKT-mTOR pathway and promoted renal epithelial cell proliferation. Overall, Notch3 was identified as a novel contributor to renal epithelial cell proliferation and cystogenesis in ADPKD. We envision that Notch3 represents a promising target for ADPKD treatment.

Genotype-phenotype of autosomal dominant polycystic kidney disease in Malta

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple renal cysts causing kidney enlargement and end-stage renal disease (ESRD) in half the patients by 60 years of age. The aim of the study was to determine the genetic aetiology in Maltese patients clinically diagnosed with ADPKD and correlate the clinical features. MethodsA total of 60 patients over 18 years of age clinically diagnosed with ADPKD were studied using a customized panel of genes that had sufficient evidence of disease diagnosis using next generation sequencing (NGS). The genes studied were PKD1, PKD2, GANAB, DNAJB11, PKHD1 and DZIP1L. Selected variants were confirmed by bidirectional Sanger sequencing with specifically designed primers. Cases where no clinically significant variant was identified by the customized gene panel were then studied by Whole Exome Sequencing (WES). Microsatellite analysis was performed to determine the origin of an identified recurrent variant in the PKD2 gene. Clinical features were studied for statistical correlation with genetic results. ResultsGenetic diagnosis was reached in 49 (82%) of cases studied. Pathogenic/likely pathogenic variants PKD1 and PKD2 gene were found in 25 and in 23 cases respectively. The relative proportion of genetically diagnosed PKD1:PKD2 cases was 42:38. A pathogenic variant in the GANAB gene was identified in 1 (2%) case. A potentially significant heterozygous likely pathogenic variant was identified in PKHD1 in 1 (2%) case. Potentially significant variants of uncertain significance were seen in 4 (7%) cases of the study cohort. No variants in DNAJB11 and DZIP1L were observed. Whole exome sequencing (WES) added the diagnostic yield by 10% over the gene panel analysis. Overall no clinically significant variant was detected in 6 (10%) cases of the study population by a customized gene panel and WES. One recurrent variant the PKD2 c.709+1G > A was observed in 19 (32%) cases. Microsatellite analysis showed that all variant cases shared the same haplotype indicating that their families may have originated from a common ancestor and confirmed it to be a founder variant in the Maltese population.The rate of decline in eGFR was steeper and progression to ESRD was earlier in cases with PKD1 variants when compared to cases with PKD2 variants. Cases segregating truncating variants in PKD1 showed a significantly earlier onset of ESRD and this was significantly worse in cases with frameshift variants. Overall extrarenal manifestations were commoner in cases segregating truncating variants in PKD1. ConclusionsThis study helps to show that a customized gene panel is the first-line method of choice for studying patients with ADPKD followed by WES which increased the detection of variants present in the PKD1 pseudogene region. A founder variant in the PKD2 gene was identified in our Maltese cohort with ADPKD. Phenotype of patients with ADPKD is significantly related to the genotype confirming the important role of molecular investigations in the diagnosis and prognosis of polycystic kidney disease. Moreover, the findings also highlight the variability in the clinical phenotype and indicate that other factors including epigenetic and environmental maybe be important determinants in Autosomal Dominant Polycystic Kidney Disease.

The Cyst Epithelium in Polycystic Kidney Disease Patients Displays Normal Apical-Basolateral Cell Polarity.

The main characteristic of polycystic kidney disease is the development of multiple fluid-filled renal cysts. The discovery of mislocalized sodium-potassium pump (Na,K-ATPase) in the apical membrane of cyst-lining epithelia alluded to reversal of polarity as a possible explanation for the fluid secretion. The topic of apical Na,K-ATPase in cysts remains controversial. We investigated the localization of the Na,K-ATPase and assessed the apical-basolateral polarization of cyst-lining epithelia by means of immunohistochemistry in kidney tissue from six polycystic kidney disease patients undergoing nephrectomy. The Na,K-ATPase α1 subunit was conventionally situated in the basolateral membrane of all immunoreactive cysts. Proteins of the Crumbs and partitioning defective (Par) complexes were localized to the apical membrane domain in cyst epithelial cells. The apical targeting protein Syntaxin-3 also immunolocalized to the apical domain of cyst-lining epithelial cells. Proteins of the basolateral Scribble complex immunolocalized to the basolateral domain of cysts. Thus, no deviations from the typical epithelial distribution of basic cell polarity proteins were observed in the cysts from the six patients. Furthermore, we confirmed that cysts can originate from virtually any tubular segment with preserved polarity. In conclusion, we find no evidence of a reversal in apical-basolateral polarity in cyst-lining epithelia in polycystic kidney disease.

Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice

Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA’s role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT.

A long-read sequencing and SNP haplotype-based novel preimplantation genetic testing method for female ADPKD patient with de novo PKD1 mutation

The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history. Here we reported the application of long-read sequencing for direct haplotyping in a female patient with de novo PKD1 c.11,526 G > C mutation and successfully established the high-risk haplotype. Together with targeted short-read sequencing of SNPs for the couple and embryos, the carrier status for embryos was identified. A healthy baby was born without the PKD1 pathogenic mutation. Our PGT-M strategy based on long-read sequencing for direct haplotyping combined with targeted SNP haplotype can be widely applied to other monogenic disease carriers with de novo mutation.

#3812 ARE KIDNEY CYSTS MORE COMMON IN PEOPLE WITH COL4A3/COL4A4 PATHOGENIC VARIANTS?

Abstract Background and Aims Individuals with pathogenic heterozygous variants in the COL4A3/COL4A4 genes are usually asymptomatic or present only with microhaematuria, although some may develop proteinuria and chronic kidney disease (CKD). Simple renal cysts are common in healthy individuals, with an increasing incidence with age and CKD grade. A possible association between pathogenic variants of collagen type IV and renal cysts has been described. This study investigates the presence of renal cysts in a large cohort of individuals with heterozygous pathogenic variants in COL4A3/COL4A4. Method We evaluated the presence of kidney cysts, kidney size and lithiasis by ultrasound in 162 individuals with pathogenic variants in COL4A3/COL4A4 without kidney replacement therapy. The correlation between kidney cysts and age, proteinuria, eGFR, causing gene and type of variant, was analysed. Genetic testing had been performed in index cases by next generation sequencing (NGS) of a kidney-disease gene panel containing more than 400 genes including COL4A3, COL4A4 and COL4A5 genes. Results 153 patients with a heterozygous disease-causing variant in COL4A3 or COL4A4 and 9 patients with digenic/complex inheritance were included. The mean age at renal ultrasound was 46.19 years (SD 14.93) and the mean eGFR was 75 ml/min/1.73 m2 (SD 35 ml/min/1.73 m2). Renal cysts were present in 50% of patients (81/162) and were bilateral in 30.25%. The mean age of patients with renal cysts was 53.26 years vs. 39.12 years for those without, and the mean eGFR was 60ml/min/1.73 m2 vs. 89ml/min/1.73 m2 for patients with and without renal cysts. Only 2.5% (4/162) of patients had renal lithiasis. The mean kidney size was 104.05 mm (SD 13.86 mm) for the right kidney and 104.98 mm (SD 13.94 mm) for the left kidney. Cystic nephromegaly was observed in 3.7% (6/162). No correlation was found between renal cysts and gender (p = 0.632). Age and CKD stage had a positive correlation with the development of renal cysts (p = <0.001) (Tables 1 and 2). Proteinuria was more common in individuals with renal cysts 61% vs 39% (p = 0.012), but was related to age and CKD stage. The presence of a kidney cyst did not correlate with the mutated gene or the type of variant. Conclusion Individuals with COL4A3/COL4A4 pathogenic variants develop kidney cysts at a higher rate than age-matched healthy individuals, and their presence is also related to ageing, as in the general population. Gender is not relevant for the development of renal cysts, in contrast to the general population cohorts. Proteinuria and CKD grade correlate with the development of renal cysts but nephromegaly is rare. Renal cysts in heterozygous carriers of COL43 or COL4A4 pathogenic variants are common but have no clinical consequences.

#5496 EVALUATION OF THE PREDICTIVE ABILITY AND CONCORDANCE OF PROGNOSTIC SCORES FOR RAPID PROGRESSION IN ADPKD: A MULTICENTER COHORT

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of end-stage kidney disease (ESKD). It is characterized by the progressive development of bilateral renal cysts, resulting in enlargement of the kidney volume, hypertension (HBP), and ESKD. Recently, a position statement of the ERK-NET was published to assess indications for Tolvaptan according to 3 algorithmic criteria: total kidney volume (HtTKV) and Mayo Clinic Imaging Class (MCIC), rate of decline in eGFR, and the Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score, combining clinical and genetic variables. In this scenario, these scores (MCIC and PROPKD) are alternatively used to define rapid progressor patients. In this retrospective multicentric cohort, the primary outcome was to evaluate and improve the concordance of sensitivity and specificity of MCIC and PROPKD predictive abilities for rapid disease progression. Method Data from adult ADPKD patients were obtained from 3 different renal centers (Bologna, Dublin, Berlin/Leipzig). We defined rapid disease progression as individuals with eGFR slope ≥3 mL/min/1.73m2/ yearly over 4 years (Clinical Score), or MCIC classes 1C-D-E (Imaging Score), or high-risk PROPKD score (7 to 9 points). Descriptive statistics were used to summarize clinical parameters. The concordance between MCIC and PROPKD was assessed using Kappa statistics. In individuals with PKD1 missense variants, the REVEL score was obtained and treated as a continuous variable; score greater than 0.65 were considered ‘pathogenic’ and regarded as PKD1-truncating variants for PROPKD score calculation. Results We evaluated 298 ADPKD patients, demographic and clinical data are summarized in Table 1. After 4 yr of follow-up, MCIC (p 0,041), HBP (p 0,031), and urological events (p <0.001) result were statistically significant on multivariate analysis (Table 1). Assessment of rapid disease progression using PROPKD and MCIC scores yielded Kappa Cohen of 0,149; 47.9% (n = 143) were concordant, 49,32% (n = 148) patients identified as rapid progressor (RP) for MCIC were non- RP for PROPKD, while 2.3% (n = 7) of PROPKD score considered RP using PROPKD score were considered non-RP using MCIC classes. Following the reclassification of PKD1 missense variants by REVEL score, K of Cohen improved to 0.174, and PROPKD becomes predictive of fast progression also at multivariate (p 0.010). Conclusion Concordance between scores results low (K of Cohen 0,149). The PROPKD is more selective compared to the Mayo. Nevertheless, PROPKD allows the identification of some rapid progressor patients excluded from using the Mayo score only. The combined use of scoring may increase the ability to identify progressive patients. REVEL score could improve the agreement.

#4485 CLINICAL CASE OF MOSAICISM IN ADPKD PATIENT

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) it's mainly characterized by renal involvement with progressive bilateral development of renal cysts and volumetric increase of the kidneys, responsible for the progressive loss of renal function that leads to chronic kidney disease (CKD) and the need of renal replacement therapy. There are some cases (doubtful, uncertain) in which it is necessary to perform genetic testing to achieve a definitive diagnosis. It looks like in ADPKD patients, mosaicism could modulate the clinical course of the disease. Mosaicism is characterized by few cell populations with different genomes. In these special cases the diagnosis is very difficult and the genetic analysis could be an important and helpful tool. With this report, we want to highlight the importance of the use of several diagnostic methods in those ‘atypical’ cases where otherwise the analysis would have been negative from a first molecular approach. Method A 47 years old woman came to our attention with typical picture of ADPKD, arterial hypertension and chronic kidney disease CKD (3b). She had no ADPKD family history, but since she had a son, genetic testing was performed. According to our workflow, first level analysis includes Next Generation Sequencing (NGS). Second level analysis, performed to investigate other genes and large rearrangement, was based on Multiplex Ligation-dependent Probe Amplification (MLPA) analysis of PKD1 and PKD2 genes, using Salsa MLPA ProbeMix P352 PKD1PKD2 kit and ProbeMix P351 PKD1 kit ©MRC Holland. Results NGS did not detect the presence of any genomic variants. Therefore, second-level genetic analysis (several approaches), showed a large deletion in heterozygosis of the portion comprising the 3-33 exons of PKD1 gene in mosaic in percentage close to the resolution limits of the used technique (25-30%). The same analysis was confirmed in another laboratory. Conclusion We concluded that the identified large deletion, without establishing the real borders due to MLPA technical restrictions, was present as mosaicism. The variant is not reported, but due to the type of mutation and the clinical picture of the patient, it is to be considered as likely pathogenic. A stepwise genetic approach might be useful in those cases where standard methods do not allow to reach a definitive diagnosis.

Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1.

Polycystic kidney disease is a disorder of renal epithelial growth and differentiation. Transcription factor EB (TFEB), a master regulator of lysosome biogenesis and function, was studied for a potential role in this disorder. Nuclear translocation and functional responses to TFEB activation were studied in three murine models of renal cystic disease, including knockouts of folliculin, folliculin interacting proteins 1 and 2, and polycystin-1 (Pkd1) as well as in mouse embryonic fibroblasts lacking Pkd1 and three-dimensional cultures of Madin-Darby canine kidney cells. Nuclear translocation of Tfeb characterized cystic but not noncystic renal tubular epithelia in all three murine models as both an early and sustained response to cyst formation. Epithelia expressed elevated levels of Tfeb-dependent gene products, including cathepsin B and glycoprotein nonmetastatic melanoma protein B. Nuclear Tfeb translocation was observed in mouse embryonic fibroblasts lacking Pkd1 but not wild-type fibroblasts. Pkd1 knockout fibroblasts were characterized by increased Tfeb-dependent transcripts, lysosomal biogenesis and repositioning, and increased autophagy. The growth of Madin-Darby canine kidney cell cysts was markedly increased following exposure to the TFEB agonist compound C1, and nuclear Tfeb translocation was observed in response to both forskolin and compound C1 treatment. Nuclear TFEB also characterized cystic epithelia but not noncystic tubular epithelia in human patients with autosomal dominant polycystic kidney disease. Noncanonical activation of TFEB is characteristic of cystic epithelia in multiple models of renal cystic disease including those associated with loss of Pkd1. Nuclear TFEB translocation is functionally active in these models and may be a component of a general pathway contributing to cystogenesis and growth.NEW & NOTEWORTHY Changes in epithelial cell metabolism are important in renal cyst development. The role of TFEB, a transcriptional regulator of lysosomal function, was explored in several models of renal cystic disease and human ADPKD tissue sections. Nuclear TFEB translocation was uniformly observed in cystic epithelia in each model of renal cystic disease examined. TFEB translocation was functionally active and associated with lysosomal biogenesis and perinuclear repositioning, increased TFEB-associated protein expression, and activation of autophagic flux. Compound C1, a TFEB agonist, promoted cyst growth in 3-D cultures of MDCK cells. Nuclear TFEB translocation is an underappreciated signaling pathway for cystogenesis that may represent a new paradigm for cystic kidney disease.

Plant-derived compounds for treating autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic hereditary kidney disease, is the fourth leading cause of end-stage kidney disease worldwide. In recent years, significant progress has been made in delaying ADPKD progression with different kinds of chemical drugs, such as tolvaptan, rapamycin, and somatostatin. Meanwhile, numerous plant-derived compounds have been investigated for their beneficial effects on slowing ADPKD progression. Among them, saikosaponin-d, Ganoderma triterpenes, curcumin, ginkgolide B, steviol, resveratrol, Sparganum stoloniferum Buch.-Ham, Cordyceps sinensis, triptolide, quercitrin, naringin, cardamonin, gambogic acid, and olive leaf extract have been found to retard renal cyst development by inhibiting cell proliferation or promoting cell apoptosis in renal cyst-lining epithelial cells. Metformin, a synthesized compound derived fromFrench lilacor goat's rue (Galega officinalis), has been proven to retard the progression of ADPKD. This review focuses on the roles and mechanisms of plant-derived compounds in treating ADPKD, which may constitute promising new therapeutics in the future.

The Electrogenic Chloride Exchanger ClC5 as a Novel Player in Renal Cysts in Tuberous Sclerosis

Renal cystic diseases are complex and multifaceted disorders that can have genetic or nongenetic bases. The etiology of these disorders is not unique but may be associated with other systemic diseases, acquired or inherited. With significant progress in genetics, several mutated genes have been associated with renal cyst development. Different abnormal protein functions, causing different renal cystic diseases, imply that several molecular mechanisms may lead to the formation of cysts. Cysts can be generated from any tract of the nephron; they usually generate in the distal nephron and in the collecting ducts.

Discovery of Novel N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound 3 with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors' potency and selectivity. The representative compound B2 potently inhibited CDK7 with an IC50 value of 4 nM and showed high selectivity over CDKs. Compound B2 showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an in vitro Madin-Darby canine kidney cyst model. In addition, compound B2 was also highly efficacious in suppressing renal cyst development in an ex vivo embryonic kidney cyst model and in vivo ADPKD mouse model. These results indicate that compound B2 represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.

Utility of ultrasonography for predicting indications for tolvaptan in patients with autosomal dominant polycystic kidney disease

PurposeTolvaptan is the first approved treatment for autosomal dominant polycystic kidney disease (ADPKD) that targets a mechanism directly contributing to the development and growth of renal cysts. We investigated the ability of ultrasonography to predict total kidney volume (TKV) of 750 mL or more, which is an indication for tolvaptan therapy in patients with ADPKD.MethodsA total of 46 patients with ADPKD were evaluated. The most statistically appropriate measurement based on ultrasonography for predicting TKV determined by computed tomography (CT) was assessed.ResultsTKV determined by CT was 796.8 (508.8–1,560.3) mL. The median length, anteroposterior distance, and mediolateral distance determined using ultrasonography were 15.7 cm, 7.6 cm, and 7.6 cm in the left kidney, and 13.4 cm, 6.9 cm, and 7.2 cm in the right kidney, respectively. Multivariate regression analysis showed that total kidney length (left and right) [variance inflation factor (VIF), 9.349] and total mediolateral distance (left and right) (VIF, 3.988) were independently associated with TKV. The correlation (r) between the logarithm of TKV determined by CT and total mediolateral distance determined using ultrasonography was 0.915 (p < 0.001). The linear regression equation was log (total kidney volume) = 1.833 + 0.075 × total mediolateral distance (left and right) based on ultrasonography. The area under the receiver operating characteristic curve for total mediolateral distance determined using ultrasonography to predict TKV of 750 mL or more was 0.989. Using the total mediolateral distance cut-off value of 14.2 cm, the sensitivity and specificity were 96.0% and 100.0%, respectively.ConclusionTotal mediolateral distance determined using ultrasonography can predict TKV in patients with ADPKD.

Prevalence and associated risk factors of simple renal cysts in primary hyperparathyroidism.

Previous studies have pointed to the role of parathormone (PTH) in the development of simple renal cysts. However, there is insufficient evidence related to simple renal cysts in primary hyperparathyroidism (PHPT). Therefore, this study aimed to evaluate the prevalence and risk factors associated with renal cysts in PHPT patients. In this retrospective study, we included 235 patients treated surgically for PHPT and 147 control subjects. The clinical and physical examination findings, laboratory test results, and neck and urinary system ultrasonography examination findings were evaluated. Postoperative parathyroid adenoma volume and weight were also recorded. Simple renal cysts were found in 53 PHPT patients (22.6%) and in 15 control subjects (10.2%) (p = 0.002). Kidney stones were found in 33 PHPT patients (14%) and in only seven control subjects (4.8%) (p = 0.004). The presence of PHPT and high PTH levels independently supported the development of a simple renal cyst. Advanced age was determined as a risk factor for the development of simple renal cysts, and the presence of kidney stones was an independent predictor of simple renal cysts in PHPT patients. There was no relationship between the presence of simple renal cysts and the volume and weight of parathyroid adenoma. A diagnosis of PHPT, high PTH levels, advanced age, and kidney stones are independent risk factors for simple renal cysts in PHPT patients. These patients should be evaluated regularly for complications of renal cysts and nephrolithiasis.

Changes in Tubule Flow During Renal Cyst Development

Changes in Tubule Flow During Renal Cyst Development