Autosomal Recessive Polycystic Kidney Research Articles

A risk score to predict kidney survival in patients with autosomal recessive polycystic kidney disease at the age of two months.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe hepatorenal fibrocystic disorder. Its rareness and the variability of disease courses have been major obstacles for the establishment of clinical trials on treatment of kidney disease in ARPKD. In this observational study we characterized kidney disease progression in a very large cohort of up to 658 patients with the clinical diagnosis of ARPKD and identified risk factors associated with rapid kidney disease progression. The estimated probability of kidney failure by the age of 20 years was 50.1% (95% confidence interval 42.2%‒57.0%), with earlier kidney failure in specific subgroups. Mean yearly estimated glomerular filtration rate decline after the first year of life was 1.3 ml/min per 1.73m2 during childhood and adolescence in the overall cohort, ranging from 0.5 to 2.2 ml/min per 1.73m2 in various subgroups. Furthermore, we developed prediction models for the relative risk of early kidney failure to be applied at the age of two months in daily clinical life. The finally chosen predictor set for a score based on a Cox model encompassed five factors: gestational age at oligo- or anhydramnios, gestational age at birth, functional genotype, serum creatinine (mg/dl) as well as documentation of arterial hypertension at the age of two months. The derived simple prognostic score showed good prediction performance, especially in the first three years of life. It reliably identified patients who are not at risk of early kidney failure and may be helpful to identify patients at risk of more rapid disease progression that could benefit from novel therapeutic interventions.

Elucidating the Molecular Landscape of Cystic Kidney Disease: Old Friends, New Friends and Some Surprises.

Cystic kidney diseases (CyKD) are a diverse group of disorders affecting more than 1 in 1000 individuals. Over 120 genes are implicated, primarily encoding components of the primary cilium, transcription factors, and morphogens. Prognosis varies greatly by molecular diagnosis. Causal variants are not identified in 10%-60% of individuals due to our limited understanding of CyKD. To elucidate the molecular landscape of CyKD, we queried the CAG Biobank using the ICD10 codes N28.1, Q61.1, Q61.11, Q61.19, Q61.2, Q61.3, and Q61.8 to identify individuals with CyKD. One hundred eight individuals met clinical criteria for CyKD and underwent proband-only exome sequencing. Causal variants were identified in 86/108 (80%) individuals. The most common molecular diagnoses were PKD1-related autosomal dominant polycystic kidney disease (32/108; 30%) and autosomal recessive polycystic kidney disease (21/108; 19%). Other common molecular diagnoses were ciliopathy syndromes (7/108; 6.5%) and Tuberous Sclerosis (6/108; 5.6%). Seven individuals had variants in genes not previously associated with CyKD (7/108; 6.5%). Candidate genes were identified in five individuals (5/108; 4.5%). Discordance between molecular and clinical diagnosis was present in two individuals. We demonstrate a high molecular diagnosis rate in individuals with CyKD that can result in diagnostic reclassification, supporting a role for genetic testing in CyKD.

Hepatopulmonary syndrome from liver disease associated with autosomal recessive polycystic kidney disease.

Hepatopulmonary syndrome (HPS) is a life-threatening complication of chronic liver disease (CLD) that currently can be managed only by liver transplant. Though uncommon, some children with kidney disease have coexistent CLD and hence are at risk of developing HPS. Paediatric cases of HPS are rarely described in the nephrology literature. We present a patient with autosomal recessive polycystic kidney disease (ARPKD) and persistent hypoxaemia diagnosed as HPS and successfully managed with a liver transplant. We suggest that nephrologists caring for children with kidney and concomitant CLD consider routine screening for HPS with pulse oximetry.

Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease.

Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated Hedgehog (Hh) signaling in ADPKD, with increased levels of Hh components in experimental ADPKD and reduced cystogenesis following pharmacological Hh inhibition. In contrast, the role of the Hh pathway in ARPKD is poorly understood. We hypothesized that Hh pathway activity would be elevated during ARPKD pathogenesis, and its modulation may slow disease progression. We utilized Cpk mice which phenocopy ARPKD and generated a PKHD1-mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector Gli3 were found in Cpk mice, a finding replicated in PKHD1-mutant spheroids. In Cpk mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased Gli3 levels via heterozygous genetic deletion in Cpk mice did not affect cyst formation. Additionally, lowering GLI3 transcripts to wildtype levels did not influence PKHD1-mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.

Gene therapy in polycystic kidney disease: A promising future.

Polycystic kidney disease (PKD) is a genetic disorder marked by numerous cysts in the kidneys, progressively impairing renal function. It is classified into autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), with ADPKD being more common. Current treatments mainly focus on symptom relief and slowing disease progression, without offering a cure. Recent advancements in gene editing technologies, such as CRISPR-Cas9, have introduced new therapeutic possibilities for PKD. These approaches include miR-17 antisense oligonucleotides, adenovirus-mediated gene knockdown, Pkd1 gene or polycystin -1 C-terminal tail enhancement therapy, and 3-UTR miR-17 binding element by CRISPR-Cas9, which have shown potential in animal models and early clinical trials. Specifically for ARPKD, strategies like antisense oligonucleotide therapy targeting c-myc and CRISPR/ Cas9 knockdown of the P2rx7 gene have shown promise. Despite facing challenges such as technological limitations, ethical and legal issues, and high costs, gene therapy presents unprecedented hope for PKD treatment. Future interdisciplinary collaboration and international cooperation are essential for developing more effective treatment strategies for PKD patients.

Autosomal recessive polycystic kidney disease: late-onset renal enlargement and proteinuria with rare PKHD1 mutation—a case report

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is a genetically inherited pediatric disorder. It is caused by a mutation in the PKHD1 gene located on chromosome 6. The predominant phenotype is characterized by early-onset bilateral enlarged kidneys, as well as fibrocystic changes in the kidney and liver. Fetuses or infants usually present with Potter syndrome, and they are more likely to develop severe renal insufficiency. Generally, patients die perinatally or in infancy. Liver involvement has been reported in adults with ARPKD who have survived the neonatal period and childhood. However, renal involvement is rarely expected in adulthood. The case is being presented for its clinical rarity, in addition to emphasize the critical role of NGS approaches in diagnosis.Case presentationWe hereby describe a 33-year-old female with adult-onset proteinuria and nephromegaly. She had a rare homozygous missense mutation of the PKHD1 gene with autosomal recessive inheritance. The proband has consanguineous heterozygote parents. The mutation was identified by whole-exome sequencing, and the results were confirmed by segregation analysis.ConclusionHere, we reported a thorough literature review of late-onset autosomal recessive polycystic kidney disease. Furthermore, we explored the importance of genetic work-up in families with genetic disorders and consanguineous marriages, particularly in underdeveloped countries.

Ciliopathy organoid models: a comprehensive review.

Cilia are membrane-bound organelles found on the surface of most mammalian cell types and play numerous roles in human physiology and development, including osmo- and mechanosensation, as well as signal transduction. Ciliopathies are a large group of, usually rare, genetic disorders resulting from abnormal ciliary structure or ciliary dysfunction that have a high collective prevalence. Autosomal dominant or recessive polycystic kidney disease (ADPKD/ARPKD), Bardet-Biedl-Syndrome, and primary ciliary dyskinesia (PCD) are the most frequent etiologies. Rodent and zebrafish models have improved the understanding of ciliopathy pathophysiology. Yet, the limitations of these genetically modified animal strains include the inability to fully replicate the phenotypic heterogeneity found in humans, including variable multiorgan involvement. Organoids, self-assembled three-dimensional cell-based models derived from human induced pluripotent stem cells (iPSCs) or primary tissues, can recapitulate certain aspects of the development, architecture, and function of the target organ "in the dish." The potential of organoids to model patient-specific genotype-phenotype correlations has increased their popularity in ciliopathy research and led to the first preclinical organoid-based ciliopathy drug screens. This review comprehensively summarizes and evaluates current ciliopathy organoid models, focusing on kidney, airway, liver, and retinal organoids, as well as the specific methodologies used for their cultivation and for interrogating ciliary dysfunction.

A rare cause of echogenic kidneys with oligohydramnios in the fetus: report of two different cases

BackgroundPrenatal ultrasound findings of fetal bilateral echogenic kidneys accompanied by oligohydramnios can be highly stressful for both pregnant women and physicians. The diversity of underlying causes makes it challenging to confirm a prenatal diagnosis, predict postnatal outcomes, and counsel regarding recurrence risks in future pregnancies.Case PresentationWe report two cases of abnormal fetal echogenic kidneys with oligohydramnios detected in the early third trimester. Autosomal recessive polycystic kidney disease (ARPKD), a rare genetic syndrome, was initially suspected in both cases. However, postnatal diagnoses differed: the first case was confirmed as glomerulocystic kidney disease (GCKD) through renal pathology, while the second case was diagnosed as ARPKD with a compound heterozygous likely pathogenic PKHD1 mutation.ConclusionPrenatal diagnosis of fetal echogenic kidneys with oligohydramnios should prioritize accurate diagnosis. Given the differences in the clinical spectrum, GCKD should be considered a differential diagnosis for this condition, particularly ARPKD. This study highlights the importance and benefits of molecular diagnosis and postnatal renal pathology for precise diagnosis and effective counseling.

Urinary Dickkopf-3 Reflects Disease Severity and Predicts Short-Term Kidney Function Decline in Renal Ciliopathies

Phenotypic heterogeneity and unpredictability of individual disease progression present enormous challenges in ultrarare renal ciliopathies. The tubular-derived glycoprotein, Dickkopf-related protein 3 (DKK3) is a promising biomarker for kidney fibrosis and prediction of kidney function decline. Here, we measured urinary DKK3 (uDKK3) levels in 195 pediatric patients with renal ciliopathy to assess its potential as a discriminative and prediction marker. uDKK3 concentration was measured in 357 spot urine samples from 247 individuals, including 52 healthy age-matched controls. Disease entities comprised nephronophthisis (NPH) (n= 37), autosomal recessive polycystic kidney disease (ARPKD) (n= 61), Bardet Biedl syndrome (BBS) (n= 57), and hepatocyte nuclear factor 1 beta (HNF1B)-nephropathy (n= 40). The results were correlated with chronic kidney disease (CKD) stage and annual estimated glomerular filtration rate (eGFR) decline. Median uDKK3-to-creatinine ratios (uDKK3/crea) in all disease entities were significantly higher compared with healthy controls (11pg/mg uDKK3/crea, P< 0.001): NPH, 1.219 pg/mg; HNF1B, 731 pg/mg; BBS, 541 pg/mg; and ARPKD, 437 pg/mg. A significant correlation of CKD stage with uDKK3 levels was observed for all disease entities (P< 0.0001) with no other clinical parameter having a relevant impact. In our cohort, uDKK3 values >4.700 pg/mg were associated with a significantly greater annual eGFR loss independently of diagnosis and eGFR (P= 0.0029). Although we observed a trend toward lower uDKK3 levels in glomerulopathies compared to renal ciliopathies, there was no discriminative difference between individual ciliopathy entities (P= 0.2637). In renal ciliopathies, uDKK3 is a marker to assess disease severity and estimate short-term kidney function decline.

Unveiling Kidney Disease Progression in Autosomal Recessive Polycystic Kidney Disease with Hypertension: Insights from the SS-PCK Rat Model

Unveiling Kidney Disease Progression in Autosomal Recessive Polycystic Kidney Disease with Hypertension: Insights from the SS-PCK Rat Model

Qualitative Analysis and Comparison of Externally Led, Patient-Focused Drug Development (EL-PFDD) Concepts for Autosomal Recessive Polycystic Kidney Disease (ARPKD) against Standardized Outcomes in Nephrology (SONG) Initiatives

Qualitative Analysis and Comparison of Externally Led, Patient-Focused Drug Development (EL-PFDD) Concepts for Autosomal Recessive Polycystic Kidney Disease (ARPKD) against Standardized Outcomes in Nephrology (SONG) Initiatives

Cerebral Aneurysm in an Adult with Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Cerebral Aneurysm in an Adult with Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Diseases of the primary cilia: a clinical characteristics review.

Ciliopathies encompass a broad spectrum of diseases stemming from dysfunction of the primary (non-motile) cilia, present on almost all cells in the human body. These disorders include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, and multisystem ciliopathies such as Joubert, Meckel, Bardet-Biedl, Alström, oral-facial-digital syndromes, and skeletal ciliopathies. The majority of these ciliopathies are associated with fibrocystic kidney disease resulting in progressive kidney dysfunction. In addition, many ciliopathies are associated with extra-renal manifestations including congenital hepatic fibrosis, retinal dystrophy, obesity, and brain and skeletal anomalies. The diagnoses may be challenging due to their overlapping clinical features and molecular heterogeneity. To date, over 190 genes encoding proteins that localize to the primary cilia have been identified as disease-causing. This review will discuss the clinical features of the most frequently encountered disorders of primary cilia.

Multimodal Magnetic Resonance Imaging Assessments of Kidney Disease Severity in Autosomal Recessive Polycystic Kidney Disease

Multimodal Magnetic Resonance Imaging Assessments of Kidney Disease Severity in Autosomal Recessive Polycystic Kidney Disease

Phenotype and genotype features of isolated cystic kidney diseases with autosomal recessive type of inheritance in children

The relevance of the problem of hereditary cystic kidney diseases (cystosis) is due to the wide variability of the renal phenotype and the genotype that determines the prognosis, the progression to renal failure as early as in childhood. Purpose. To present the results of the analysis of the correlation of genotype and phenotype, renal function in isolated cystic kidney diseases with an autosomal recessive type of inheritance in children. Material and methods. in 14 children (from 13 families) aged 9 months — 17 years, the features of the clinical phenotype of kidney cysts with autosomal recessive type of inheritance and gene mutation were evaluated according to the results of a molecular genetic study. Results. In 3 (23 %) of 13 families, the family history is burdened by kidney cysts. The characteristic of gene mutation in cystic kidney diseases with autosomal recessive type of inheritance in 13 patients is presented (in 2 tables). Of the 21 identified variants in the genes PKHD1, INVS, NPHP1, TMEM67, 15 (71 %) had known pathogenic significance, 6 (29 %) had previously undescribed variants in data-bases. Variants of the PKHD1 gene were identified in 11 children with the phenotype of polycystic kidney disease with autosomal recessive type of inheritance and liver fibrosis. In the study, variant C.107C&gt;T (Thr36Met) is the most common among children with identified variants of the PKHD1 gene in autosomal recessive polycystic kidney disease in 5 out of 21 (23.8 %), c.664A&gt;G (Ile222Val) in 1 (4.8 %), c.6992T&gt;A (Ile2331Lys) in 1 (4.8 %), c.10444C&gt;T (Arg3482Cys) at 1 (4.8 %). Infantile (n=1) and juvenile (n = 2) nephronophthysis were confirmed in 3 children with homozygous and compound heterozygous pathogenic variants in the INVS, NPHP1, TMEM67 genes. Conclusion. The features of the genotype and phenotype are presented in 14 children with autosomal recessive type of inheritance of isolated kidney cysts in autosomal recessive polycystic kidney disease (n = 11) and nephronophthysis (n = 3), of whom chronic kidney disease was established in 13 children aged 2–17 years: in 4 (30.8 %) C1, in 4 (30.8 %) C2, in 3 (23 %) C3, in 1 (7.7 %) C4, in 1 (7.7 %) C5.

Novel splice site and nonsense variants in PKHD1 cause autosomal recessive polycystic kidney disease in a Chinese Zhuang ethnic family.

This study aims to report the clinical characteristics of a child with autosomal recessive polycystic kidney disease (ARPKD) within a Chinese Zhuang ethnic family. We used whole exome sequencing (WES) in the family to examine the genetic cause of the disease. Candidate pathogenic variants were validated by Sanger sequencing. We identified previously unreported mutations in the PKHD1 gene of the proband with ARPKD through WES: a splice site mutation c.6809-2A > T, a nonsense mutation c.4192C > T(p.Gln1398Ter), and a missense mutation c.2181T > G(p.Asn727Lys). Her mother is a heterozygous carrier of c.2181T > G(p.Asn727Lys) mutation. Her father is a carrier of c.6809-2A > T mutation and c.4192C > T(p.Gln1398Ter) mutation. The identification of novel mutations in the PKHD1 gene through WES not only expands the spectrum of known variants but also potentially enhances genetic counseling and prenatal diagnostic approaches for families affected by ARPKD.

Unilateral multicystic dysplastic kidney complicated with urinary tract infection by E. coli in a premature newborn

Autosomal recessive polycystic kidney disease is a renal development anomaly characterized by cystic transformation in renal parenchyma. ARPKD is more common in children. We present the case of a premature newborn, female, 36-37 weeks gestation, small for gestational age (SGA) originating from a completely unmonitored pregnancy, diagnosed upon admission to the clinic with unilateral multicystic dysplastic kidney. The condition complicated by a urinary tract infection with E. coli. This newborn displayed no clinical symptoms, was carefully monitored during hospitalization, and received antibiotic treatment. Antenatal ultrasound screening can aid in the early diagnosis of congenital anomalies and determining the appropriate course of action.

Genetic landscape and clinical outcomes of autosomal recessive polycystic kidney disease in Kuwait

Autosomal recessive polycystic kidney disease (ARPKD), a rare genetic disorder characterized by kidney cysts, shows complex clinical and genetic heterogeneity. This study aimed to explore the genetic landscape of ARPKD in Kuwait and examine the intricate relationship between its genes and clinical presentation to enhance our understanding and contribute towards more efficient management strategies for ARPKD. This study recruited 60 individuals with suspected ARPKD from 44 different families in Kuwait. The participants were of different ethnicities and aged 0-70 years. Additionally, 33 were male, 15 were female, and 12 had indeterminant sex due to congenital anomalies. Comprehensive clinical data were collected. Mutations were identified by next-generation whole exome sequencing and confirmed using Sanger sequencing. Of the 60 suspected ARPKD cases, 20 (33.3%) died within hours of birth or by the end of the first month of life and one (1.7%) within 12 months of birth. The remaining 39 (65.0%) cases were alive, at the time of the study, and exhibited diverse clinical features related to ARPKD, including systematic hypertension (5.0%), pulmonary hypoplasia (11.7%), dysmorphic features (40.0%), cardiac problems (8.3%), cystic liver (5.0%), Potter syndrome (13.3%), developmental delay (8.3%), and enlarged cystic kidneys (100%). Twelve mutations, including novel truncating mutations, were identified in 31/60 cases (51.7%) from 17/44 families (38.6%). Additionally, 8/12 (66.7%) mutations were in the PKHD1 gene, with the remaining four in different genes: NPHP3, VPS13P, CC2D2A, and ZNF423. This study highlights the spectrum of clinical features and genetic mutations of patients with ARPKD in Kuwait. It highlights the necessity for personalized approaches to improve ARPKD diagnosis and treatment, offering crucial insights into managing ARPKD.

A case report of autosomal recessive polycystic kidney disease with noncompaction of ventricular myocardium: coincidence or different manifestations of ciliopathy?

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is a rare inherited cystic disease characterized by bilateral renal cyst formation and congenital liver fibrosis. Cardiovascular disorders such as noncompaction of ventricular myocardium (NVM) have not been reported with ARPKD.Case presentationA 5-month-old girl was examined after presenting with a fever and turbid urine for one day and was diagnosed as urinary tract infection. Urinary ultrasound showed multiple round, small cysts varying in size in both kidneys. Genetic testing revealed two heterozygous mutations and one exon deletion in the polycystic kidney and hepatic disease 1 gene, indicating a diagnosis of ARPKD. During hospitalization, she was found to have chronic heart failure after respiratory tract infection, with an ejection fraction of 29% and fraction shortening of 13%. When the patient was 15 months old, it was found that she had prominent trabeculations and deep intertrabecular recesses with the appearance of blood flow from the ventricular cavity into the intertrabecular recesses by echocardiography. The noncompaction myocardium was 0.716 cm and compaction myocardium was 0.221 cm (N/C = 3.27), indicating a diagnosis of NVM. Liver and kidney function remained normal during four-year follow-up.ConclusionsThis is the first report of NVM in a patient with ARPKD. It is unsure if the coexistence of NVM and ARPKD is a coincidence or they are different manifestations of ciliary dysfunction in the heart and kidneys.

Next generation sequencing identifies WNT signalling as a significant pathway in Autosomal Recessive Polycystic Kidney Disease (ARPKD) manifestation and may be linked to disease severity

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by sequence variants in PKHD1. ARPKD presents with considerable clinical variability relating to the type of PKHD1 sequence variant, but not its position. Animal models of Polycystic Kidney Disease (PKD) suggest a complex genetic landscape, with genetic modifiers as a potential cause of disease variability. To investigate in an unbiased manner the molecular mechanisms of ARPKD and identify potential indicators of disease severity, Whole Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) were employed on human ARPKD kidneys and age-matched healthy controls. WES confirmed the clinical diagnosis of ARPKD in our patient cohort consisting of ten ARPKD kidneys. Sequence variant type, nor position of PKHD1 sequence variants, was linked to disease severity. Sequence variants in genes associated with other ciliopathies were detected in the ARPKD cohort, but only PKD1 could be linked to disease severity. Transcriptomic analysis on a subset of four ARPKD kidneys representing severe and moderate ARPKD, identified a significant number of genes relating to WNT signalling, cellular metabolism and development. Increased expression of WNT signalling-related genes was validated by RT-qPCR in severe and moderate ARPKD kidneys. Two individuals in our cohort with the same PKHD1 sequence variants but different rates of kidney disease progression, with displayed transcriptomic differences in the expression of WNT signalling genes. ARPKD kidney transcriptomics highlights changes in WNT signalling as potentially significant in ARPKD manifestation and severity, providing indicators for slowing down the progression of ARPKD.