ABSTRACTAutosomal Dominant Polycystic Kidney Disease Research Articles

Deep venous thrombosis in autosomal dominant polycystic kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic cystic condition that results in progressive loss of renal function. The disease is associated with various complications, including compression of adjacent structures like the inferior vena cava (IVC), which can lead to deep vein thrombosis (DVT) and ultimately, pulmonary embolism. This report details a case of a 41-year-old patient with ADPKD who presented with left leg DVT. Imaging revealed IVC compression due to enlarged kidneys, and blood tests indicated low levels of coagulation proteins C and S. The patient is hypertensive and has advanced renal failure (glomerular filtration rate [GFR] 12.6 mL/min) but has not yet initiated dialysis. The patient was initiated on treatment with the novel oral anticoagulant, apixaban, and exhibited favorable outcomes. His DVT is believed to be the result of multiple factors acting in concert. IVC compression, a significant precipitant doctor of DVT, is frequently observed in ADPKD patients, with rates as high as 15% in severe cases and 15% in mild cases, according to a study by Yin et al. The incidence of venous thromboembolism (VTE) in patients with chronic kidney disease increases as GFR decreases, with rates 2.5–5.5-fold higher in moderate-to-severe end-stage renal disease than in the general population. VTE is a multifactorial disease with both acquired and inherited thrombophilia factors. This particular case presents a unique event within our medical practice, as it is relatively uncommon to witness such a correlation between DVT and polycystic kidney disease. It serves as an exemplification of a case that necessitates diligent monitoring due to the heightened risk of recurrent DVT.

P289 HEART FAILURE DUE TO HIGH OUTPUT ARTERIOVENOUS FISTULA IN A DIALYSIS PATIENT AFFECTED BY AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Autosomal dominant polycystic kidney disease (ADPKD) can determine end stage renal disease (ESRD) which require haemodialysis. Surgical creation of arteriovenous fistula (AVF) has been associated with development of left ventricular (LV) dilatation and high output heart failure (HF) and right ventricle (RV) dysfunction at long term follow–up. Databases show an association between ADPKD and idiopathic dilated cardiomyopathy, suggesting that PKD mutations contribute to development of heart failure. 36 ys old female patient affected by ADPKD who required in 2018 bilateral nephrectomy, due to a relapse of severe urinary tract bleeding, and then put in thrice–weekly hemodialysis. Before the procedure in 2016 an echocardiogram showed normal biventricular function, with valvular defects. An AVF, between left humeral artery and the perforator vein of the elbow, was employed as vascular access. 6 months later she was referred to our center for atypical chest pain and palpitations. A transthoracic echocardiogram showed a diffuse hypokinesia with severe left ventricular dysfunction and dilation (EF 25%, VTDi 90ml/mq), a cardiac output of 6,5 l/min, moderate mitral insufficiency, hypokinetic RV, pulmonary artery systolic pressure (PASP) of 56mmHg, severe biatrial dilatation. No signs of congestion. She was admitted to our service. The coronary angiogram was normal, ruling out an underlying ischemic cardiomyopathy. Therapy with b–blocker and ACE–I was started. Doppler ultrasonography of the AVF was performed and showed an high output fistula. Two weeks later at Hospital discharge with medical therapy only, EF improved to 43%. Five months later, the AVF was ligated, after the creation of another more distal one. Echocardiographic re–evaluation one month after the intervention showed a normalization of left ventricular function and volumes ( EF 55%, VDTi 54ml/mq)and of PASP. In 2020 she underwent renaltransplant without complications. The patient is nowadays stable only on beta–blocker for some PVCs, with ongoing annual follow–up. Even if dilated cardiomyopathy and HF in patients affected by APDKD can be caused by genetic predisposition, in our case the main factor was a high output AVF, as showed by complete reversion of left ventricular dysfunction after its ligation.

P221 ASSOCIATION BETWEEN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE AND A SEVERE DILATED CARDIOMYOPATHY: A CASE REPORT

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 genes, encoding polycystin 1 and 2. We report the case of a 51–year–old woman with arterial hypertension and stage V chronic kidney disease from polycystic kidney disease, without a significant family health history. She was admitted to our Cardiology Ward for worsening dyspnea, dependent oedemas and a 3/6 systolic heart murmur detected. Blood tests showed mild anemia and hyperkalemia, severe renal failure (creatinine 6 mg/dl) and normal both liver and thyroid function. The ECG showed sinus rhythm with normal atrioventricular conduction, low voltage in precordial leads and non–specific repolarization disturbances. Hemodialysis and intravenous decongestion therapy were started. A transthoracic two–dimensional echocardiography was performed and a dilated left ventricle with severe global systolic dysfunction (EF 25%) was documented, with severe secondary mitral regurgitation (MR) with a central jet (EROA 0,5 cm2). A possible bicuspid aortic valve was suggested with moderate aortic regurgitation. CT scans showed small pleural and pericardial effusions, polycystosis affecting both kidneys and liver. Coronary CT showed a subcritical interventricular artery stenosis and confirmed a bicuspid aortic valve. Magnetic resonance angiography was negative for intracranial aneurysms. Finally, genetic testing revealed a heterozygous pathogenic mutation of PKD1 gene (c.9622del G p.Ala3208Hisfs*108 exone 28). Maximum tolerated heart failure therapy was prescribed after discharge, resulting in symptoms reduction but only mild echocardiographic improvement (EF 30% with severe MR). An edge–to–edge transcatheter mitral valve repair was proposed. In literature we learn that PKD1 mutations are linked to various cardiomyopathies: hypertrophic, dilated, left ventricular non compaction. We report the association of ADPKD with a complex dilated cardiomyopathy with severe secondary MR, an aortic congenital defect and an associated subcritical coronary artery stenosis. Further investigations are needed to study the genetic aspect of the ADPKD when associated with different cardiac anomalies.

Transcription factor FoxM1 promotes cyst growth in PKD1 mutant ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood. Here, we show that FoxM1 is an important regulator of cyst growth in ADPKD. FoxM1 is upregulated in cyst-lining epithelial cells in Pkd1 mutant mouse kidneys and human ADPKD kidneys. FoxM1 promotes cystic renal epithelial cell proliferation by increasing the expression of Akt and Stat3 and the activation of ERK and Rb. FoxM1 also regulates cystic renal epithelial cell apoptosis through NF-κB signaling pathways. In addition, FoxM1 regulates the recruitment and retention of macrophages in Pkd1 mutant mouse kidneys, a process that is associated with FoxM1-mediated upregulation of monocyte chemotactic protein 1. Targeting FoxM1 with its specific inhibitor, FDI-6, delays cyst growth in rapidly progressing and slowly progressing Pkd1 mutant mouse kidneys. This study suggests that FoxM1 is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for targeting FoxM1 as a therapeutic strategy for ADPKD treatment.

CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of fluid-filled cysts, causing nephron loss and a decline in renal function. Mammalian target of rapamycin (mTOR) is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement; however, the mechanism for mTOR stimulation remains unclear. We discovered that calcium/calmodulin (CaM) dependent kinase IV (CaMK4), a multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and PKD mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited cell proliferation and in vitro cyst formation of ADPKD cells. Moreover, inhibition of calcium/CaM-dependent protein kinase kinase-β and CaM, two key upstream regulators of CaMK4, also decreased mTOR signaling. The effects of KN-93 were independent of the liver kinase B1-adenosine monophosphate-activated protein kinase (AMPK) pathway, and the combination of KN-93 and metformin, an AMPK activator, had additive inhibitory effects on mTOR signaling and in vitro cyst growth. Our data suggest that increased CaMK4 expression and activity contribute to mTOR signaling and the proliferation of cystic cells of ADPKD kidneys.

PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan

Autosomal Dominant polycystic kidney disease (ADPKD) is the most common inherited adult kidney disease. Although ADPKD is primarily caused by PKD1 and PKD2, the identification of several novel causative genes in recent years has revealed more complex genetic heterogeneity than previously thought. To study the disease-causing mutations of ADPKD, a total of 920 families were collected and their diagnoses were established via clinical and image studies by Taiwan PKD Consortium investigators. Amplicon-based library preparation with next-generation sequencing, variant calling, and bioinformatic analysis was used to identify disease-causing mutations in the cohort. Microsatellite analysis along with genotyping and haplotype analysis was performed in the PKD2 p.Arg803* family members. The age of mutation was calculated to estimate the time at which the mutation occurred or the founder arrived in Taiwan. Disease-causing mutations were identified in 634 families (68.9%) by detection of 364 PKD1, 239 PKD2, 18 PKHD1, 7 GANAB, and 6 ALG8 pathogenic variants. 162 families (17.6%) had likely causative but non-diagnostic variants of unknown significance (VUS). A single PKD2 p.Arg803* mutation was found in 17.8% (164/920) of the cohort in Taiwan. Microsatellite and array analysis showed that 80% of the PKD2 p.Arg803* families shared the same haplotype in a 250 kb region, indicating those families may originate from a common ancestor 300 years ago. Our findings provide a mutation landscape as well as evidence that a founder effect exists and has contributed to a major percentage of the ADPKD population in Taiwan.

Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction.

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease. Recent evidence suggests that the pathogenesis of ADPKD is a complex web of abnormal cellular processes including altered cell signaling, disordered cell metabolism, impaired autophagy, increased apoptosis, mitochondrial dysfunction and chronic inflammation. Sodium–glucose cotransporter (SGLT) inhibitors (SGLTi) reduce body weight, blood pressure and blood glucose levels, have kidney and cardiovascular protective activity, and have been reported to decrease inflammation, increase autophagy and improve mitochondrial dysfunction. We now review results from preclinical studies on SGLTi for ADPKD identified through a systematic search of the MEDLINE, Cochrane Library, Embase and PubMed databases. Potential underlying mechanisms for the conflicting results reported as well as implications for clinical translation are discussed, as ADPKD patients were excluded from clinical trials exploring kidney protection by SGLT2 inhibitors (SGLT2i). However, they were not excluded from cardiovascular safety trials or trials for cardiovascular conditions. A post-hoc analysis of the kidney function trajectories and safety of SGLT2i in ADPKD patients enrolled in such trials may provide additional information. In conclusion, SGLT2i are cardio- and nephroprotective in diverse clinical situations. Currently, it is unclear whether ADPKD patients may benefit from SGLT2i in terms of kidney function preservation, and their safety in this population remains unexplored. We propose a roadmap to address this unmet clinical need.

Massive liver involvement in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with an estimated prevalence of between 1/400 and 1/1000 [1]. The PKD1 genetic mutation, encoding polycystin-1, is found in 80% of cases, while 20% of patients carry the PKD2 mutation, encoding polycystin-2. Liver involvement is the most common extrarenal manifestation, occurring in over 50% of cases of hepato-renal polycystosis the most frequent extrarenal manifestation in autosomal-dominant polycystic kidney disease (ADPKD). Liver cysts are responsible for most hepatic complications. A 40-year-old female presented on 13st April 2013 to the Nephrology Unit of Fundeni Clinical Institute with abdominal distension and renal dysfunction. ADPKD had been diagnosed 5 years previously and had progressed to end-stage renal disease, treated by hemodialysis, in May 2014. Her medical history included well controlled hypertension and hyperlipidemia. The family history included ADPKD affected relatives. Conclusion. Because early complications and mortality after either procedure remain frequent, the hazards of surgery have to be balanced against benefits; therefore, selection of the optimum therapy still remains a challenge.

Examining the Role of HIPPO/YAP and AMOT Dysregulation and Imbalance in Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder, most commonly caused by mutations in Polycystin-1 and Polycystin-2 (PC1 and PC2), in which many large lumenal cysts develop in the kidney epithelium. The disease is progressive and ultimately leads to renal dialysis and/or kidney transplant given the lack of efficacious therapeutic intervention. Current research has implicated HIPPO/YAP pathway dysregulation and AMOT imbalance following defects in cell-cell adhesion and contact inhibition as the molecular basis for ADPKD. To test this hypothesis as to the minimum cellular changes necessary to produce cystogenesis, the Bacallao lab microinjected normal human kidney epithelial (HK2) cells in order to drive ectopic expression of Cadherin-8 (CAD-8). Our Imaging with confocal microscopy and subsequent image analysis indicates CAD-8, a cadherin abnormally expressed in renal epithelial cells of ADPKD patients, is sufficient to cause formation of cysts albeit with uncharacteristically small lumens compared to typical ADPKD cysts. However, these cells exhibit significantly larger cyst expansion when they are transduced for coexpression of CAD-8 and constitutively active YAP5SA. Cells modified for heterozygosity with respect to a defective PC1 gene (PKD) also exhibited significantly larger lumen cysts when transduced with YAP5SA reinforcing the role of Yap in lumen size control. Finally, PKD cells transduced with AMOTL1 exhibited significantly smaller lumen sizes. AMOTL1 belongs to a family of adapter proteins which bind and inhibit Yap activity thus showing conclusively that positive and negative modulation of Yap activity correlates with cyst lumen size expansion and reduction respectively.
 “This project was funded, in part, with support from the O’Brien Center for Advanced Renal Microscopic Analysis funded, in part by P30 DK079312 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”

Synergistic Antiproliferative Effects of All-Trans Retinoic Acid and Paclitaxel on Autosomal Dominant Polycystic Kidney Disease Epithelial Cells.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by uncontrollable epithelial cell growth, cyst formation, and kidney malfunction. In the present study, we investigated the antiproliferative effects of the treatment with the combination of paclitaxel (PAC) and all-trans retinoic acid (ATRA) on ADPKD epithelial cells. Our results show that the combined treatment with 1 nM PAC and 10 nM ATRA significantly suppressed ADPKD cell proliferation (20%), while the treatment with ATRA or PAC alone had no such effect. Treatment with PAC and ATRA induced cell cycle arrest at the G2/M phase and apoptosis by upregulating p53 and caspase-8 expression and increased the intracellular calcium (Ca2+) level possibly by enhancing Ca2+ uptake via plasma membrane channels. In addition, this treatment suppressed extracellular signal-regulated kinase signaling possibly through mitogen-activated protein kinase phosphatase-1 activation. Thus, the combination of PAC and ATRA can be explored as a potential treatment regimen for ADPKD.

Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited renal disorder, characterized by renal cyst development leading to end-stage renal disease. Although the appropriate choice of suitable reference is critical for quantitative RNA analysis, no comparison of frequently used “housekeeping” genes is available. Here, we determined the validity of 7 candidate housekeeping genes (Actb, Actg1, B2m, Gapdh, Hprt, Pgam1 and Ppia) in kidney tissues from mouse models orthologous to ADPKD, including a cystic mice (CY) 10–12 weeks old (Pkd1flox/flox:Nestincre/Pkd1flox/−:Nestincre, n = 10) and non-cystic (NC) controls (Pkd1flox/flox/Pkd1flox/-, n = 10), Pkd1-haploinsufficient (HT) mice (Pkd1+/−, n = 6) and wild-type (WT) controls (Pkd1+/+, n = 6) and a severely cystic (SC) mice 15 days old (Pkd1V/V, n = 7) and their controls (CO, n = 5). Gene expression data were analyzed using six distinct statistical softwares. The estimation of the ideal number of genes suggested the use of Ppia alone as sufficient, although not ideal, to analyze groups altogether. Actb, Hprt and Ppia expression profiles were correlated in all samples. Ppia was identified as the most stable housekeeping gene, while Gapdh was the least stable for all kidney samples. Stat3 expression level was consistent with upregulation in SC compared to CO when normalized by Ppia expression. In conclusion, present findings identified Ppia as the best housekeeping gene for CY + NC and SC + CO groups, while Hprt was the best for the HT + WT group.

NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics, and zebrafish and mouse models.

Autosomal‐dominant polycystic kidney disease (ADPKD) is characterized by uncontrolled renal cyst formation, and few treatment options are available. There are many parallels between ADPKD and clear‐cell renal cell carcinoma (ccRCC); however, few studies have addressed the mechanisms linking them. In this study, we aimed to investigate their convergences and divergences based on bioinformatics and explore the potential of compounds commonly used in cancer research to be repurposed for ADPKD. We analysed gene expression datasets of ADPKD and ccRCC to identify the common and disease‐specific differentially expressed genes (DEGs). We then mapped them to the Connectivity Map database to identify small molecular compounds with therapeutic potential. A total of 117 significant DEGs were identified, and enrichment analyses results revealed that they are mainly enriched in arachidonic acid metabolism, p53 signalling pathway and metabolic pathways. In addition, 127 ccRCC‐specific up‐regulated genes were identified as related to the survival of patients with cancer. We focused on the compound NS398 as it targeted DEGs and found that it inhibited the proliferation of Pkd1 −/− and 786‐0 cells. Furthermore, its administration curbed cystogenesis in Pkd2 zebrafish and early‐onset Pkd1‐deficient mouse models. In conclusion, NS398 is a potential therapeutic agent for ADPKD.

Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia

Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Here we performed transcriptomic analyses of Pkd1- and Pkd2-deficient mIMCD3 kidney epithelial cells followed by a meta-analysis to integrate all published ADPKD transcriptomic data sets. Based on the hypothesis that Pkd1 and Pkd2 operate in a common pathway, we first determined transcripts that are differentially regulated by both genes. RNA sequencing of genome-edited ADPKD kidney epithelial cells identified 178 genes that are concordantly regulated by Pkd1 and Pkd2. Subsequent integration of existing transcriptomic studies confirmed 31 previously described genes and identified 61 novel genes regulated by Pkd1 and Pkd2. Cluster analyses then linked Pkd1 and Pkd2 to mRNA splicing, specific factors of epithelial mesenchymal transition, post-translational protein modification and epithelial cell differentiation, including CD34, CDH2, CSF2RA, DLX5, HOXC9, PIK3R1, PLCB1 and TLR6. Taken together, this model-based integrative analysis of transcriptomic alterations in ADPKD annotated a conserved core transcriptomic profile and identified novel candidate genes for further experimental studies.

Evaluation of sirtuin 1 (SIRT1) levels in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and the majority of patients have a PKD-1 or PKD-2 mutation. Sirtuin 1 (SIRT1) has roles in cellular aging, antioxidant activity, cellular proliferation. In an experimental study, inhibition of SIRT1 was found to delay renal cyst development in ADPKD. The purpose of this study is to determine the SIRT1 levels in ADPKD patients. To our knowledge, this is the first study that investigating blood and urine SIRT1 levels in ADPKD patients. Sixty-seven patients with ADPKD and 34 control cases with normal renal functions and without renal cysts were included in this study. Serum and urine SIRT1 concentrations were determined by human enzyme-linked immunosorbent assay (ELISA) kit. 24-h urine samples were used for urine SIRT1 measurements. The urine SIRT1 levels were statistically significantly lower in ADPKD patients group (p < 0.001). Although blood SIRT1 levels of ADPKD patients were higher than control cases but there were no statistically significant difference between the groups in terms of blood SIRT1 levels. Urine SIRT1 levels (β = 2.452, CI 95% 1.419-4.239, p = 0.001) were found an independent factor in multivariate regression analysis for ADPKD. Urine SIRT1 levels were lower in ADPKD patients than control group. The low urinary SIRT1 levels despite the similar blood SIRT1 levels might be due to the impaired metabolism of SIRT1 in ADPKD patients; this state might has a role in cyst development.

Drug repurposing in autosomal dominant polycystic kidney disease: back to the future with pioglitazone

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney failure. At present, only one drug, tolvaptan, has been approved for use to slow disease progression, but its use is limited by reduced tolerability and idiosyncratic liver toxicity. Thiazolidinediones were first developed as insulin-sensitizers but also regulate gene transcription in multiple tissues, leading to systemic effects on metabolism, inflammation and vascular reactivity. In this issue, Blazer-Yost et al. report the results of a single-centre Phase 1b double-blind placebo-controlled crossover study of the peroxisome proliferator-activated receptor γ (PPAR-γ) agonist pioglitazone in 18 ADPKD patients. Encouragingly, there were no major safety signals, although evidence of efficacy could not be demonstrated due to the small sample size. We review the preclinical evidence for the use of PPAR-γ agonists in ADPKD and speculate on the likely beneficial and adverse clinical effects of this interesting class of compounds in a future trial.

A practical guide for the management of acute abdominal pain with fever in patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of numerous renal cysts leading to kidney enlargement and chronic kidney disease. Extra-renal manifestations, including polycystic liver disease and connective tissue defects, are frequently observed in ADPKD. Acute cyst complications, i.e. hemorrhage and infection, represent rare but severe conditions of ADPKD. The distinction between cystic versus non-cystic abdominal complications is often problematic. Here, we propose a practical guide for the diagnostic and therapeutic management of an "acute abdominal pain with fever" in patients with ADPKD.

Cystic renal-epithelial derived induced pluripotent stem cells from polycystic kidney disease patients.

Autosomal‐dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient‐specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore, iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole‐genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney‐specific DNA methylation memory. In addition, comparison of PKD1+/− and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular.

Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferator-activator receptor gamma (PPARγ) agonist pioglitazone slows disease progression in the PCK rat model for PKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. Other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow PKD progression. The ongoing phase II clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADPKD treatment.

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2\u2212/\u2212 phenotype

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α−androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Pharmacokinetics and Implications for Practice

Autosomal dominant polycystic kidney disease (ADPKD) is incurable and occurs once in every 1,000 births. Confirmation of AKPKD is made through imaging and a positive family history. Symptoms typically appear in mid-life and include kidney, side, and/or back pain related to the rupture of kidney cysts, renal stones, infection, pressure of cysts against other organs, and stretching of the renal capsule. In addition to end stage renal disease, cerebral aneurysm may also be a threat to individuals with this diagnosis. Recent clinical trials have shown that tolvaptan, a vasopressin-2 receptor antagonist, produced a moderate to significant reduction in total kidney volume and improved function, leading to its recent approval by the U.S. Federal Drug Administration for treatment of patients with ADPKD. This article provides a comprehensive look at the pathophysiology of ADPKD, pharmacokinetics and pharmacodynamics of tolvaptan, and tolvaptan's clinical implications, effects, and contraindications. In addition, we present a case study discussing tolvaptan's clinical usefulness and address patient concerns in an adult presenting with rapidly progressing ADPKD.