Autosomal Recessive Polycystic Kidney Research Articles

Autosomal recessive polycystic kidney disease (ARPKD) in fetus: Autopsy based approach

Polycystic kidney disease is a rare developmental anomaly inherited as Autosomal dominant or recessive. Autosomal recessive polycystic kidney disease (ARPKD) is an intractable cystic renal disease that results in chronic renal failure. It has a profound effect on growing fetus and result in serious implications if pregnancy is continued in the long run after being detected on sonography. Although prenatal imaging studies and clinical findings are suggestive of ARPKD it can be accurately diagnosed by histopathology if an autopsy is performed in cases of infant death. In this article we here in present the features of ARPKD diagnosed antenatally by USG in a 22 yr female, and was confirmed further by fetal autopsy.

Ultrasound Diagnosis of the Perinatal Form of Autosomal Recessive Polycystic Kidney Disease at 29 Weeks of Gestation

Ultrasound Diagnosis of the Perinatal Form of Autosomal Recessive Polycystic Kidney Disease at 29 Weeks of Gestation

Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD.

Treatment of Autosomal Recessive Polycystic Kidney Disease With CFTR Modulators

Treatment of Autosomal Recessive Polycystic Kidney Disease With CFTR Modulators

Disruption of Cystin Myristoylation Causes Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Disruption of Cystin Myristoylation Causes Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Modulation of P2X4 receptor activity by ivermectin and 5-BDBD has no effect on the development of ARPKD in PCK rats.

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited pathology caused mainly by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene, which usually leads to end-stage renal disease. Previous studies suggested that the P2X purinoreceptor 4 (P2X4 R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X4 R allosteric modulator) and 5-BDBD (P2X4 R antagonist) on the development of ARPKD in PCK/CrljCrl-Pkhd1pck/CRL (PCK) rats. Our data indicated that activation of ATP-mediated P2X4 R signaling with ivermectin for 6 weeks in high dose (50 mg/L; water supplementation) decreased the total body weight of PCK rats while the heart and kidney weight remained unaffected. Smaller doses of ivermectin (0.5 or 5mg/L, 6 weeks) or the inhibition of P2X4 R signaling with 5-BDBD (18 mg/kg/day, food supplement for 8 weeks) showed no effect on electrolyte balance or the basic physiological parameters. Furthermore, cystic index analysis for kidneys and liver revealed no effect of smaller doses of ivermectin (0.5 or 5mg/L) and 5-BDBD on the cyst development of PCK rats. We observed a slight increase in the cystic liver index on high ivermectin dose, possibly due to the cytotoxicity of the drug. In conclusion, this study revealed that pharmacological modulation of P2X4 R by ivermectin or 5-BDBD does not affect the development of ARPKD in PCK rats, which may provide insights for future studies on investigating the therapeutic potential of adenosine triphosphate (ATP)-P2 signaling in PKD diseases.

Clinical characteristics and genetic analysis of a child with autosomal recessive polycystic kidney disease

To explore the clinical characteristics and molecular pathogenesis of a child with autosomal dominant polycystic kidney disease (ARPKD). Prenatal ultrasound, clinical feature and family history of the child were analyzed. Whole exome sequencing was carried out for the child. Candidate variants were verified by Sanger sequencing. The child has featured premature birth with very low weight, neonatal respiratory distress, metabolic acidosis, and congenital nephrotic syndrome. Gene sequencing revealed that he has harbored compound heterozygous variants of the PKHD1 gene (NM_138694), including c.3885T>A (p.Tyr1295*) in exon 32 and c.7812_7816dupTGATA (p.Thr2606Metfs*63) in exon 49, which were respectively inherited from his mother and father. The compound heterozygous variants of the PKHD1 gene probably underlay the disease in this child.

Drug Development for Cystic Kidney Diseases.

Inherited cystic diseases include a spectrum of disorders, such as autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant polycystic liver disease, and an expanding group of recessively inherited diseases collectively termed hepatorenal fibrocystic disorders. ADPKD is the most common monogenic disorder that can lead to kidney failure, with a prevalence of 600,000 people in the United States (1). ARPKD is associated with significant kidney- and liver-related morbidity and mortality in children, with >50% of affected individuals progressing to kidney failure within the first decade of life (2). Although one therapy (tolvaptan) has been approved in the United States and other regions for the treatment of ADPKD, the development of clear regulatory pathways and viable end points would be critical for further development in the area of polycystic kidney and liver disorders. On May 19–20, 2021, representatives from academia, industry, regulatory agencies (US Food and Drug Administration and European Medicines Agency), and the patient community came together to discuss the unmet needs in ADPKD and ARPKD drug and regulatory development as part of the 2021 PKD Regulatory Summit. The conference was organized by the PKD Outcomes Consortium from Critical Path Institute in partnership with the PKD Foundation. The issues discussed covered a broad range of topics, including obstacles to drug development for early ADPKD and ARPKD, clinical trial design in ADPKD, development of novel biomarkers for disease progression, development of clinical outcome assessment tools, and disease progression modeling. The following series of Perspective articles summarize the salient points from the three sessions of the Summit, including drug development for ARPKD, early ADPKD, and clinical trial design for ADPKD. The conclusions drawn from these Perspective articles emphasize: (1) The importance of international collaborations and large observational studies, which are critical for shedding light on the different risk patterns in ARPKD (given its multiple temporal disease manifestations), thus paving the way for future interventional trials. The criticality of stringent patient selection, clinical descriptions, and biosampling as part of the trial process will be essential for progress (3). (2) The need to define the best timing for interventions and identifying novel targets that are relevant in the early ADPKD disease stage. Challenges to this include the identification and validation of indicators, both measuring and predicting disease progression from childhood, and distinguishing slow from rapid progressors in the early-stage ADPKD population (4). (3) The importance of standardization of the key elements of an ADPKD pivotal trial template that can serve to derisk and potentially accelerate the development of therapies. As well as the importance of designing trials that are accessible to patients to enter and remain across the ≥2 year study duration that ADPKD trials would require (5). Much unmet need remains in polycystic kidney disease, both on the regulatory and therapeutic sides. Continued collaboration and data-sharing efforts in the field among relevant stakeholders are needed to achieve enhanced prognostic and therapeutic biomarkers, end points, and a feasible regulatory pathway (for all forms of PKD including ARPKD), which will hopefully lead to more therapies becoming available for affected individuals. Disclosures S. Fedeles reports being employed by the Critical Path Institute and is an author on the WO2015057894A1 patent (published in April 2015) “Methods for treating polycystic kidney disease and polycystic liver disease.” R.D. Perrone reports having consultancy agreements with Caraway, Navitor, Otsuka, Palladiobio, Reata, and Sanofi-Genzyme; having other interests in, or relationships with, Critical Path Institute, PKD Foundation, and UpToDate; serving on a speakers bureau for Haymarket Media; receiving research funding from Kadmon, Palladiobio, Reata, and Sanofi; serving in an advisory or leadership role for Otsuka, PalladioBio, and Sanofi-Genzyme; and receiving honoraria from Otsuka, Reata, and Sanofi-Genzyme. Funding This work was supported by Otsuka Pharmaceutical and PKD Foundation.

Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hepatorenal fibrocystic disease that often presents prenatally or in the first year of life and remains a major cause of morbidity and mortality in pediatric nephrology. Here, we summarize key aspects discussed in a session on drug

S3073 Liver Involvement in Autosomal Recessive Polycystic Kidney Disease

S3073 Liver Involvement in Autosomal Recessive Polycystic Kidney Disease

A Rare Cause of Liver Fibrosis in an Adolescent Woman

A Rare Cause of Liver Fibrosis in an Adolescent Woman

Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery.

Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration–approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.

EP27.15: Findings and evolution of a patient diagnosed with autosomal recessive polycystic kidney disease in childhood during prenatal period

EP27.15: Findings and evolution of a patient diagnosed with autosomal recessive polycystic kidney disease in childhood during prenatal period

Targeted Next Generation Sequencing Revealed Novel Variants in the PKD1 and PKD2 Genes of Iranian Patients with Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD), one of the common inherited disorders in humans, is characterized by the development and enlargement of renal cysts, often leading to end-stage renal disease (ESRD). In this study, Iranian ADPKD families were subjected to high-throughput DNA sequencing to find potential causative variants facilitating the way toward risk assessment and targeted therapy. Our protocol was based on the targeted next generation sequencing (NGS) panel previously developed in our center comprising 12 genes involved in PKD. This panel has been applied to investigate the genetic causes of 32 patients with a clinical suspicion of ADPKD. We identified a total of 31 variants for 32 individuals, two of which were each detected in two individuals. Twenty-seven out of 31 detected variants were interpreted as pathogenic/likely pathogenic and the remaining 4 of uncertain significance with a molecular diagnostic success rate of 87.5%. Among these variants, 25 PKD1/2 pathogenic/likely pathogenic variants were detected in 32 index patients (78.1%), and variants of uncertain significance in four individuals (12.5% in PKD1/2). The majority of variants was identified in PKD1 (74.2%). Autosomal recessive PKD was identified in one patient, indicating the similarities between recessive and dominant PKD. In concordance with earlier studies, this biallelic PKD1 variant, p.Arg3277Cys, leads to rapidly progressive and severe disease with very early-onset ADPKD. Our findings suggest that targeted gene panel sequencing is expected to be the method of choice to improve diagnostic and prognostic accuracy in PKD patients with heterogeneity in genetic background.

Evaluation of galectin-3 and intestinal fatty acid binding protein as serum biomarkers in autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) causes fibrocystic kidney disease, congenital hepatic fibrosis, and portal hypertension. Serum galectin-3 (Gal-3) and intestinal fatty acid binding protein (I-FABP) are potential biomarkers of kidney fibrosis and portal hypertension, respectively. We examined whether serum Gal-3 associates with kidney disease severity and serum I-FABP associates with liver disease severity in ARPKD. Cross-sectional study of 29 participants with ARPKD (0.2-21years old) and presence of native kidneys (Gal-3 analyses, n = 18) and/or native livers (I-FABP analyses, n = 21). Serum Gal-3 and I-FABP were analyzed using enzyme linked immunosorbent assay. Kidney disease severity variables included estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV). Liver disease severity was characterized using ultrasound elastography to measure liver fibrosis, and spleen length and platelet count as markers of portal hypertension. Simple and multivariable linear regression examined associations between Gal-3 and kidney disease severity (adjusted for liver disease severity) and between I-FABP and liver disease severity (adjusted for eGFR). Serum Gal-3 was negatively associated with eGFR; 1 standard deviation (SD) lower eGFR was associated with 0.795 SD higher Gal-3 level (95% CI -1.116, -0.473; p < 0.001). This association remained significant when adjusted for liver disease severity. Serum Gal-3 was not associated with htTKV in adjusted analyses. Overall I-FABP levels were elevated, but there were no linear associations between I-FABP and liver disease severity in unadjusted or adjusted models. Serum Gal-3 is associated with eGFR in ARPKD, suggesting its value as a possible novel biomarker of kidney disease severity. We found no associations between serum I-FABP and ARPKD liver disease severity despite overall elevated I-FABP levels.

First Author Spotlight

AnnouncementFirst Author SpotlightPublished Online:07 Jun 2022https://doi.org/10.1152/ajprenal.2022.322.6.AUMoreSectionsPDF (247 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat MADELINE GAUTHIERDepartment of Physiology, University of Arizona Health Sciences Center, Tucson, ArizonaFigure 1.Madeline GauthierDownload figureDownload PowerPointMadeline Gauthier is an MD student and PhD candidate, conducting a PhD while on a leave of absence from medical school at Loyola University Chicago. She is currently completing her PhD in the Physiological Sciences Graduate Interdisciplinary Program at the University of Arizona [Photo: Fig. 1].https://doi.org/10.1152/ajprenal.00009.2022OLHA KRAVTSOVADepartment of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FloridaFigure 2.Olha KravtsovaDownload figureDownload PowerPointOlha Kravtsova is a postdoctoral fellow in Dr. Alexander Staruschenko’s laboratory at the University of South Florida in the Department of Molecular Pharmacology and Physiology. She earned her PhD degree at the Institute of Hydrobiology, Kyiv, Ukraine. Her current research focuses on renal transporters, specifically in the proximal tubule. Outside of work, she enjoys workouts, traveling, and hiking [Photo: Fig. 2].https://doi.org/10.1152/ajprenal.00053.2022This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformation Collections Related ArticlesSGLT2 inhibition effect on salt-induced hypertension, RAAS, and Na+ transport in Dahl SS rats 16 May 2022American Journal of Physiology-Renal PhysiologyContributions of afferent and sympathetic renal nerves to cystogenesis and arterial pressure regulation in a preclinical model of autosomal recessive polycystic kidney disease 16 May 2022American Journal of Physiology-Renal Physiology More from this issue > Volume 322Issue 6June 2022Pages i-i Crossmark Copyright & PermissionsCopyright © 2022 the American Physiological Society.https://doi.org/10.1152/ajprenal.2022.322.6.AUHistory Received 2 November 2021 Accepted 30 March 2022 Published online 7 June 2022 Published in print 1 June 2022 Metrics

Genetics, pathobiology and therapeutic opportunities of polycystic liver disease.

Polycystic liver diseases (PLDs) are inherited genetic disorders characterized by progressive development of intrahepatic, fluid-filled biliary cysts (more than ten), which constitute the main cause of morbidity and markedly affect the quality of life. Liver cysts arise in patients with autosomal dominant PLD (ADPLD) or in co-occurrence with renal cysts in patients with autosomal dominant or autosomal recessive polycystic kidney disease (ADPKD and ARPKD, respectively). Hepatic cystogenesis is a heterogeneous process, with several risk factors increasing the odds of developing larger cysts. Depending on the causative gene, PLDs can arise exclusively in the liver or in parallel with renal cysts. Current therapeutic strategies, mainly based on surgical procedures and/or chronic administration of somatostatin analogues, show modest benefits, with liver transplantation as the only potentially curative option. Increasing research has shed light on the genetic landscape of PLDs and consequent cholangiocyte abnormalities, which can pave the way for discovering new targets for therapy and the design of novel potential treatments for patients. Herein, we provide a critical and comprehensive overview of the latest advances in the field of PLDs, mainly focusing on genetics, pathobiology, risk factors and next-generation therapeutic strategies, highlighting future directions in basic, translational and clinical research.

Phenotypic Variability in Siblings With Autosomal Recessive Polycystic Kidney Disease

IntroductionAutosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disorder characterized by early onset fibrocystic hepatorenal changes. Previous reports have documented pronounced phenotypic variability even among siblings in terms of patient survival. The underlying causes for this clinical variability are incompletely understood.MethodsWe present the longitudinal clinical courses of 35 sibling pairs included in the ARPKD registry study ARegPKD, encompassing data on primary manifestation, prenatal and perinatal findings, genetic testing, and family history, including kidney function, liver involvement, and radiological findings.ResultsWe identified 70 siblings from 35 families with a median age of 0.7 (interquartile range 0.1–6.0) years at initial diagnosis and a median follow-up time of 3.5 (0.2–6.2) years. Data on PKHD1 variants were available for 37 patients from 21 families. There were 8 patients from 7 families who required kidney replacement therapy (KRT) during follow-up. For 44 patients from 26 families, antihypertensive therapy was documented. Furthermore, 37 patients from 24 families had signs of portal hypertension with 9 patients from 6 families having substantial hepatic complications. Interestingly, pronounced variability in the clinical course of functional kidney disease was documented in only 3 sibling pairs. In 17 of 20 families of our cohort of neonatal survivors, siblings had only minor differences of kidney function at a comparable age.ConclusionIn patients surviving the neonatal period, our longitudinal follow-up of 70 ARPKD siblings from 35 families revealed comparable clinical courses of kidney and liver diseases in most families. The data suggest a strong impact of the underlying genotype.

Patient Selection for Renal Denervation in Hypertensive Patients: What Makes a Good Candidate?

Renal denervation (RDN) as a therapeutic intervention in patients with hypertension has been intensively studied for over a decade, yet a critical question remains unanswered: what kind of patients are the ideal target population for RDN to achieve its maximum clinical benefit? We herein provide a review of current literature to answer questions related to patient selection to identify populations that will benefit most from RDN, drawing first from human studies but also important clues derived from preclinical animal models. Different aspects that may influence the selection of patients such as the cause of hypertension, the severity of hypertension, concurrent pharmaceutical treatment, renal function, and renal artery anatomy are discussed. Based on current evidence, patients who have severe primary hypertension, regardless of medication or degree of renal dysfunction, who have an accessible accessory renal artery, can achieve a desirable response if a thorough ablation is achieved. In preclinical models, as in humans, RDN shows variable impact, with evidence indicating it does not work in specific conditions such as reduced renal mass, salt-sensitive hypertension, and autosomal recessive polycystic kidney disease. The thresholds, however, for indicators are such that it is still not possible to reliably predict which patients could benefit from the technique. Confirmation of predictive factors and identification of biomarkers are needed before RDN can be integrated in clinical practice on clear and reliable grounds.

Afferent Renal Nerve Activity is Proportionately Increased with Cystic Progression in a Preclinical Model of Autosomal Recessive Polycystic Kidney Disease

Polycystic kidney disease (PKD) is the most common genetic cause of kidney failure, though the mechanisms underlying cyst formation and disease progression remain unclear. Innervation of the kidney contributes to the pathology of other cardiorenal dysfunction, including hypertension and chronic kidney disease ‐ frequent complications of PKD. In previous studies, we demonstrated renal denervation (RDNX), either total or afferent‐targeted (sensory) nerve ablation, reduced cystogenesis in a rat model of autosomal recessive PKD, thus highlighting a role for renal afferent nerves in PKD renal cystogenesis. To further elucidate this novel relationship, we aimed to quantify the renal afferent nerve activity (ARNA) in the adult PCK rat compared to non‐cystic controls. We hypothesized that ARNA would be elevated in the PCK rat compared to controls, and ARNA would directly correlate with renal cystic severity.To address our hypothesis, we conducted direct afferent renal nerve recordings in 10‐week‐old PCK (n=15; 11M/4F) and age‐matched Sprague‐Dawley controls (SD; n=14; 6M/8F). Multiunit nerve recording was performed under isoflurane anesthesia by isolating and placing a renal nerve bundle on an iridium bipolar electrode, which was then encased in silicone. The nerve bundle was severed proximal to the electrode to isolate afferent renal nerve activity (ARNA). Following a 10‐minute stabilization period, resting ARNA was recorded for 10 minutes. To permit comparison between animals, resting ARNA was normalized to a maximal stimulus, achieved by renal pelvic perfusion of 50 µM capsaicin. Finally, electrical noise was isolated by sectioning the distal end of the nerve bundle. Recordings were rectified and integrated over 50 ms. ARNA was expressed as a percentage of maximal ARNA. Following nerve recording, kidneys were collected, formalin fixed, and embedded in paraffin for histologic analysis of renal cystic index (CI). Kidneys were stained with Masson’s Trichrome and analyzed using ImageJ, and CI was quantified by normalizing cystic area to the total kidney area. Data presented as mean ±SEM.Resting ARNA was higher in PCK (22.7±4.2%) rats compared to non‐cystic SD controls (7.4±1.3%; Figure 1). Overall, PCK rats had an average CI of 8.7±0.7%. No sex differences in ARNA between male and female PCK rats were detected; however, CI was higher in male PCK rats (9.5±2.3%) compared to female PCK (6.3±1.9%). Further analysis of ARNA versus cystic index revealed a direct correlation between ARNA and renal cystic severity (F=5.9; R=0.61; p&lt;0.05; Figure 2).These findings support our hypothesis that ARNA is elevated in the PCK rat. Importantly, ARNA is directly correlated with cystic progression in this model. To our knowledge, this study is the first to directly measure ARNA in this model of ARPKD, as well as to compare ARNA to cyst severity. These findings, combined with our previous studies, lead us to conclude that increased ARNA may directly contribute to the progression of PKD in this model. Presently, these data are limited to single endpoint observations. We are currently conducting additional studies to further dissect the temporal relationship between ARNA and renal cyst development. Our future studies will investigate the stimuli amplifying ARNA in a continued effort to parse the role of this novel neural‐renal axis in the pathogenesis of PKD.