Autosomal Recessive Polycystic Kidney Research Articles

Protocol for the nationwide registry of patients with polycystic kidney disease: japanese national registry of PKD (JRP).

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP). The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10years every 6months and 12months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice.

Variable Clinical Presentations and Renal Outcome in Neonates With Autosomal Recessive Polycystic Kidney Disease

Variable Clinical Presentations and Renal Outcome in Neonates With Autosomal Recessive Polycystic Kidney Disease

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE ABOUT A NEW CASE REPORT

We present the case of a 25-year-old woman gravida 2, para 01 who presented for childbirth at 40 weeks of gestation. Which Fetal Anatomy Ultrasound showed enlarged, hyperechoic fetal kidneys and a normal amniotic fluid index. Karyotyping was done on umbilical cord blood to look for mutations in the PKHD1 gene for the presumptive diagnosis of autosomal recessive polycystic kidney disease (ARPKD). In our patient, a previously reported pathogenic missense mutation in the PKHD1 gene, c.10444C>T, was found to be maternally inherited. A second previously unknown de novo mutation, c.5909-2delA, was discovered. This mutation is likely pathogenic because it affects the canonical splice site. Our case emphasizes PKHD1 allelic heterogeneity and the importance of prenatal genetic testing in a setting where many other genetic etiologies can phenocopy ARPKD.

Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were 2 aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight and cyst index. Mechanisms of increased cyst growth that were investigated were pro-inflammatory cytokines, the inflammasome and crystal deposition in the kidney. Oxonic acid resulted in an increase in pro-inflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.

The ARPKD Protein DZIP1L Regulates Ciliary Protein Entry by Modulating the Architecture and Function of Ciliary Transition Fibers.

Serving as the cell's sensory antennae, primary cilia are linked to numerous human genetic diseases when they malfunction. DZIP1L, identified as one of the genetic causes of human autosomal recessive polycystic kidney disease (ARPKD), is an evolutionarily conserved ciliary basal body protein. Although it has been reported that DZIP1L is involved in the ciliary entry of PKD proteins, the underlying mechanism remains elusive. Here, an uncharacterized role of DZIP1L is reported in modulating the architecture and function of transition fibers (TFs), striking ciliary base structures essential for selective cilia gating. Using C. elegans as a model, C01G5.7 (hereafter termed DZIP-1) is identified as the sole homolog of DZIP1L, which specifically localizes to TFs. While DZIP-1 or ANKR-26 (the ortholog of ANKRD26) deficiency shows subtle impact on TFs, co-depletion of DZIP-1 and ANKR-26 disrupts TF assembly and cilia gating for soluble and membrane proteins, including the ortholog of ADPKD protein polycystin-2. Notably, the synergistic role for DZIP1L and ANKRD26 in the formation and function of TFs is highly conserved in mammalian cilia. Hence, the findings illuminate an evolutionarily conserved role of DZIP1L in TFs architecture and function, highlighting TFs as a vital part of the ciliary gate implicated in ciliopathies ARPKD.

Renal Pathology of Ciliopathies.

Renal ciliopathies are a group of genetic disorders that affect the function of the primary cilium in the kidney, as well as other organs. Since primary cilia are important for regulation of cell signaling pathways, ciliary dysfunction results in a range of clinical manifestations, including renal failure, cyst formation, and hypertension. We summarize the current understanding of the pathophysiological and pathological features of renal ciliopathies in childhood, including autosomal dominant and recessive polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, as well as skeletal dysplasia associated renal ciliopathies. The genetic basis of these disorders is now well-established in many cases, with mutations in a large number of cilia-related genes such as PKD1, PKD2, BBS, MKS, and NPHP being responsible for the majority of cases. Renal ciliopathies are broadly characterized by development of interstitial fibrosis and formation of multiple renal cysts which gradually enlarge and replace normal renal tissue, with each condition demonstrating subtle differences in the degree, location, and age-related development of cysts and fibrosis. Presentation varies from prenatal diagnosis of congenital multisystem syndromes to an asymptomatic childhood with development of complications in later adulthood and therefore clinicopathological correlation is important, including increasing use of targeted genetic testing or whole genome sequencing, allowing greater understanding of genetic pathophysiological mechanisms.

Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review.

Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes. A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period. Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes. During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation. This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

A280 HEPATOBILIARY DISEASE IN INDIVIDUALS LIVING WITH FRAGILE X SYNDROME: A CASE SERIES

Abstract Background Fragile X syndrome is a genetic disorder known to cause intellectual disability through decreased or absent FMR protein (FMRP). Basic science studies have identified potential associations with hepatobiliary inflammation. Clinical reports of liver disease in Fragile X syndrome are however infrequent. Aims We describe 3 individuals living with Fragile X syndrome and chronic liver disease. Methods A case series and literature review were performed. Results The 1st person is a woman with concurrent Fragile X and autosomal recessive polycystic kidney disease, initially seen by Hepatology at 18 y.o. with evidence of hepatic fibrosis on abdominal ultrasound with normal liver enzymes (Table 1). She subsequently developed liver cirrhosis and portal hypertension, as well as biliary duct dilatation seen on MRI. Her overall presentation was thought to be in keeping with Caroli syndrome and congenital hepatic fibrosis, and she is currently pending genetic screening for hepatorenal ciliopathy. The 2nd person is a woman with Fragile X syndrome and ulcerative colitis, who initially presented to Hepatology at 24 y.o. with mixed liver enzyme abnormalities. Lab tests over time revealed immunology suggestive of autoimmune hepatitis (AIH) (Table 1). Subsequent investigations demonstrated primary sclerosing cholangitis (PSC) with cirrhosis. Her disease is currently managed as AIH/PSC overlap syndrome with ursodeoxycholic acid (UDCA), tacrolimus, mycophenolate, and budesonide. The 3rd person is a man with Fragile X syndrome who initially presented to Hepatology at 17 y.o. with acute hepatitis with AIH immunology (Table 1). Liver biopsy at the time demonstrated findings suggestive of early PSC as well as possible AIH. He continued to have progressive cirrhosis as well as overt PSC on subsequent abdominal imaging and is currently managed as AIH/PSC overlap syndrome with UDCA, azathioprine, and budesonide. A review of literature revealed that asides from known intellectual, behavioral, and physical effects of Fragile X syndrome, there are minimal reports of other associated medical complications including liver problems or autoimmune conditions including IBD. There are however reports of autoimmunity in those with altered FMR1 (Fragile X Mental Retardation 1) gene mutations. Conclusions These 3 cases of liver disease in Fragile X highlight young age of presentation for chronic liver disease with both biliary and immune-mediated characteristics, along with progression to cirrhosis. Additional review for liver manifestations in people living with Fragile X would help understand if this association is incidental or causal. Investigations of individuals with Fragile X syndrome and liver disease Funding Agencies None

Survival of Infants With Severe Congenital Kidney Disease After ECMO and Kidney Support Therapy.

Congenital kidney failure not only affects the homeostatic functions of the kidney, but also affects neonatal respiratory integrity. Until recently, extracorporeal membrane oxygenation (ECMO) support was not used in this population because the need for ECMO clearly established nonviability. Since 2016, 31 neonates have been admitted to the NICU at Children's of Alabama with congenital kidney failure. Five patients were placed on ECMO for severe respiratory distress unresponsive to conventional interventions. We evaluated neonates with congenital kidney failure and pulmonary hypoplasia/hypertension refractory to conventional therapies who received ECMO support within the first 9 postnatal days. We describe the pre and postnatal diagnoses, ECMO course details, dialysis modalities, complications, procedures, and long-term outcomes of these patients. All 5 patients received kidney support therapy by postnatal day 7. Diagnoses included posterior urethral valves, bilateral renal dysplasia, and autosomal recessive polycystic kidney disease. Gestational age ranged from 35.6 to 37.1 weeks. Birth weight ranged from 2740 to 3140 g. Days on ECMO ranged from 4 to 23. Four survived and are living today. Pulmonary hypertension resolved in surviving patients. Three surviving patients require no oxygen support, and 1 patient requires nocturnal oxygen. Three survivors received a kidney transplant, and 1 awaits transplant evaluation. Patients with congenital kidney failure with severe pulmonary hypoplasia/pulmonary hypertension no longer warrant a reflexive assignment of nonviability. Meticulous ECMO, respiratory, nutritional, and kidney support therapies may achieve a favorable long-term outcome. Further investigation of strategies for optimal outcome is needed.

Fetal hyperechoic kidneys: Diagnostic considerations and genetic testing strategies.

Isolated bilateral hyperechoic kidneys (HEK) on prenatal ultrasound presents diagnostic, prognostic, and counseling challenges. Prognosis ranges from normal outcome to lethal postnatally. Presence/absence of extra-renal malformations, gestational age at presentation, amniotic fluid volume, and renal size may distinguish underlying etiologies and thereby prognosis, as prognosis is highly dependent upon underlying etiology. An underlying genetic diagnosis, clearly impactful, is determined in only 55%-60% of cases. We conducted a literature review of chromosomal (aneuploidies, copy number variants [CNVs]) single genes and other etiologies of fetal bilateral HEK, summarized how this information informs prognosis and recurrence risk, and critically assessed laboratory testing strategies. The most commonly identified etiologies are autosomal recessive and autosomal dominant polycystic kidney disease and microdeletions at 17q12 involving HNF1b. With rapid gene discovery, alongside advances in prenatal imaging and fetal phenotyping, the growing list of single gene diagnoses includes ciliopathies, overgrowth syndromes, and renal tubular dysgenesis. At present, microarray and gene panels or whole exome sequencing (WES) are first line tests employed for diagnostic evaluation. Whole genome sequencing (WGS), with the ability to detect both single nucleotide variants (SNVs) and CNVs, would be expected to provide the highest diagnostic yield.

Epidemiology and outcomes of pediatric autosomal recessive polycystic kidney disease in the Middle East and North Africa.

The incidence of rare diseases is expected to be comparatively higher in the Middle East and North Africa (MENA) region than in other parts of the world, attributed to the high prevalence of consanguinity. Most MENA countries share social and economic statuses, cultural relativism, religious beliefs, and healthcare policies. Polycystic kidney diseases (PKDs) are the most common genetic causes of kidney failure, accounting for nearly 8.0% of dialysis cases. The development of PKDs is linked to variants in several genes, including PKD1, PKD2, PKHD1, DZIP1L, and CYS1. Autosomal recessive PKD (ARPKD) is the less common yet aggressive form of PKD. ARPKD has an estimated incidence between 1:10,000 and 1:40,000. Most patients with ARPKD require kidney replacement therapy earlier than patients with autosomal dominant polycystic kidney disease (ADPKD), often in their early years of life. This review gathered data from published research studies and reviews of ARPKD, highlighting the epidemiology, phenotypic presentation, investigations, genetic analysis, outcomes, and management. Although limited data are available, the published literature suggests that the incidence of ARPKD may be higher in the MENA region due to consanguineous marriages. Patients with ARPKD from the MENA region usually present at a later disease stage and have a relatively short time to progress to kidney failure. Limited data are available regarding the management practice in the region, which warrants further investigations.

An “Adult” with Autosomal Recessive Polycystic Kidney Disease: A Roller Coaster Ride to a Clinical Diagnosis

We present a young male being treated as an idiopathic chronic kidney disease on dialysis for 10 years with splenomegaly. Further workup and retrospective historical details confirmed the diagnosis of autosomal recessive polycystic kidney disease and coexisting Caroli’s syndrome. The case is being presented for its rarity and glitches encountered during its workup.

Combined liver-kidney transplantation in pediatric patients.

Combined liver-kidney transplantation (CLKT) is a surgical procedure that involves transplanting both liver and kidney organs. There are two types of CLKT: simultaneous liver-kidney transplantation (smLKT) and sequential LKT (sqLKT). CLKT accounts for a small percentage of liver transplantations (LTs), particularly in pediatric cases. Nevertheless, the procedure has demonstrated excellent outcomes, with high survival rates and lower rejection rates. The main indications for CLKT in pediatric patients differ somewhat from that in adults, in which end-stage kidney disease after LT is the major indication. In children, congenital diseases are common reason for performing CLKT; the examples of such diseases include autosomal recessive polycystic kidney disease with congenital hepatic fibrosis which equally affects both organs, and primary hyperoxaluria type 1, a primary liver disease leading kidney failure. The decision between smLKT or sqLKT depends on the dominant organ failure, the specific pathophysiology, and available organ sources. However, there remain significant surgical and societal challenges surrounding CLKT. Innovations in pharmacology and genetic engineering have decreased the necessity for CLKT in early-diagnosed cases without portal hypertension or kidney replacement therapy. Nonetheless, these advancements are not universally accessible. Therefore, decision-making algorithms should be crafted, considering region-specific organ allocation systems and prevailing medical environments.

A Comprehensive Investigation into the Underlying Etiology of Massive Splenomegaly

Background: Massive Splenomegaly is commonly encountered in routine hematology practice. However, a comprehensive analysis of the underlying pathologies driving splenomegaly is lacking and few studies have investigated the epidemiology of this finding. In many cases, splenomegaly is detected incidentally in asymptomatic patients. The numerous potential causes of massive splenomegaly can pose a challenge when evaluating a patient. This study aims to identify the most prevalent etiologies among patients who initially exhibited massive splenomegaly. The objective is to determine outcomes and provide insights to guide clinical decision-making. Methods: We undertook a retrospective cohort study at the Oregon Health & Science University in Portland OR, including adults between ages of 18-89 years who had documented splenomegaly on their medical problem list or imaging within the last 10 years (January 2012-June 2023). Massive splenomegaly was defined as spleen measuring greater than 20 cm in its largest dimension. The presence of massive splenomegaly was confirmed by direct review of the medical record and available imaging modalities including ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI). Splenic pathology results and splenectomy outcomes were obtained if available. Results: We identified 224 patients with massive splenomegaly with a mean age of 52.6 years. Of the 224 patients, 113 (50.4%) were ultimately found to have a hematological diagnosis underlying the splenomegaly, while 93 (41.5%) ultimately had a diagnosis related to liver dysfunction. 18 (8%) were idiopathic or representative of a rare disease. Among those with hematologic diagnosis, myeloproliferative neoplasms accounted for 40.7% followed by Leukemia (23%) and lymphoma (21.2%). Among those ultimately diagnosed with some form of liver pathology driving their presentation, cirrhosis was the most common etiology, encompassing 79.6% while the remaining 20.4% had non-cirrhotic pathology including non-alcoholic fatty liver disease without overt cirrhosis (NAFLD), Primary sclerosing cholangitis (PSC), Autoimmune hepatitis or others. Chronic Hepatitis C related cirrhosis (32.3%) followed by Non-alcoholic Steatohepatitis (NASH) related cirrhosis (19.4%) were the most common forms of cirrhosis. Of the 18 cases not specifically related to hematologic or liver disease, 5 (2.2%) were of an unknown etiology, 6 (2.7%) were due to solid organ cancers or metastases and 3 (1.3%) appeared to be related to sequalae of Cystic Fibrosis. The remaining 4 cases were attributed to singular cases of Type 2 Glycogen Storage Disease causing cirrhosis, Autosomal Recessive Polycystic Kidney Disease, Felty Syndrome, and sequelae of motor vehicle accident, respectively. Conclusion: This large cohort of patients with massive splenomegaly offers many insights into the epidemiology of the underlying differential diagnosis. We found that approximately half of cases involved a hematologic disorder with myeloproliferative neoplasms being the most common etiology. Liver pathology was also a common driver, accounting for approximately 40% of cases. These findings underscore the necessity for appropriate diagnostic workup to better address the diverse etiologies contributing to massive splenomegaly.

Differential regulation of MYC expression by PKHD1/Pkhd1 in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is a severe, hereditary, hepato-renal fibrocystic disorder that leads to early childhood morbidity and mortality. Typical forms of ARPKD are caused by pathogenic variants in the PKHD1 gene, which encodes the fibrocystin/polyductin (FPC) protein. MYC overexpression has been proposed as a driver of renal cystogenesis, but little is known about MYC expression in recessive PKD. In the current study, we provide the first evidence that MYC is overexpressed in kidneys from ARPKD patients and confirm that MYC is upregulated in cystic kidneys from cpk mutant mice. In contrast, renal MYC expression levels were not altered in several Pkhd1 mutant mice that lack a significant cystic kidney phenotype. We leveraged previous observations that the carboxy-terminus of mouse FPC (FPC-CTD) is proteolytically cleaved through Notch-like processing, translocates to the nucleus, and binds to double stranded DNA, to examine whether the FPC-CTD plays a role in regulating MYC/Myc transcription. Using immunofluorescence, reporter gene assays, and ChIP, we demonstrate that both human and mouse FPC-CTD can localize to the nucleus, bind to the MYC/Myc P1 promoter, and activate MYC/Myc expression. Interestingly, we observed species-specific differences in FPC-CTD intracellular trafficking. Furthermore, our informatic analyses revealed limited sequence identity of FPC-CTD across vertebrate phyla and database queries identified temporal differences in PKHD1/Pkhd1 and CYS1/Cys1 expression patterns in mouse and human kidneys. Given that cystin, the Cys1 gene product, is a negative regulator of Myc transcription, these temporal differences in gene expression could contribute to the relative renoprotection from cystogenesis in Pkhd1-deficient mice. Taken together, our findings provide new mechanistic insights into differential mFPC-CTD and hFPC-CTD regulation of MYC expression in renal epithelial cells, which may illuminate the basis for the phenotypic disparities between human patients with PKHD1 pathogenic variants and Pkhd1-mutant mice.

Assessing the potential of DZIP1L gene in autosomal recessive polycystic kidney disease gene therapy

Assessing the potential of <i>DZIP1L</i> gene in autosomal recessive polycystic kidney disease gene therapy

The molecular structure and function of fibrocystin, the key gene product implicated in autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease is an early onset inherited hepatorenal disorder affecting around 1 in 20,000 births with no approved specific therapies. The disease is almost always caused by variations in the polycystic kidney and hepatic disease 1 gene, which encodes fibrocystin (FC), a very large, single-pass transmembrane glycoprotein found in primary cilia, urine and urinary exosomes. By comparison to proteins involved in autosomal dominant PKD, our structural and molecular understanding of FC has lagged far behind such that there are no published experimentally determined structures of any part of the protein. Bioinformatics analyses predict that the ectodomain contains a long chain of immunoglobulin-like plexin-transcription factor domains, a protective antigen 14 domain, a tandem G8-TMEM2 homology region and a sperm protein, enterokinase and agrin domain. Here we review current knowledge on the molecular function of the protein from a structural perspective.

State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies.

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

Complications and prognosis of patients diagnosed with autosomal recessive polycystic kidney disease in neonatal period.

There are no clinical guidelines for performing nephrectomy in patients with autosomal recessive polycystic kidney disease (ARPKD). Few reports have described the clinical course of ARPKD diagnosed in the neonatal period in detail. Here, we report seven patients diagnosed with ARPKD and treated at our center during the neonatal period. Two died within 48h of life due to pulmonary hypoplasia. Of the remaining five patients, three had anuria and required for kidney replacement therapy (KRT) within one week after birth, whereas two with a milder phenotype survived without KRT. All three patients who received KRT underwent unilateral nephrectomy and peritoneal dialysis (PD) catheter placement. To prevent fluid leakage, PD was initiated 7-14days after catheter placement. However, peritoneal leakage occurred in two patients, resulting in peritonitis and discontinuation of PD; one who required long-term hemodialysis contracted a catheter-related bloodstream infection as well as developed subdural and epidural hematomas. Meanwhile, two patients underwent a second nephrectomy within 6weeks after birth; one developed severe persistent hypotension and neurological complications, while the other died of bacteremia that may have resulted from cholangitis diagnosed on day 67 of life. A severe clinical course, life-threatening adverse events, and severe neurological sequalae may occur in patients with ARPKD who receive KRT in neonatal period.

Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis

Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.