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Background: Short bowel syndrome (SBS) is a malabsorptive condition that develops as a result of massive resection of the small intestine and causes morbidities such as chronic diarrhea, dehydration attacks, parenteral nutrition (PN) dependence, and recurrent infections. Kidney transplantation in this patient group may be complicated by aforementioned morbidities, as well as the absorption problems of immunosuppressive drugs. Methods: We report the first pediatric patient (18‐month‐old male) with SBS secondary to volvulus who underwent a successful living related kidney transplantation with a primary diagnosis of autosomal recessive polycystic kidney disease and had a successful 4‐year follow‐up without intestinal transplantation. Results: Tacrolimus, mycophenolate mofetil (MMF), and prednisolone were administered for maintenance of immunosuppression after transplantation. The patient reached therapeutic trough levels of tacrolimus with usual doses. The 4‐year renal survival was excellent without a clinical evidence of rejection, despite long‐term necessity of PN and intravenous fluids. Conclusions: Kidney transplantation should not be avoided in patients with SBS solely because of concerns about the effectiveness of immunosuppressive therapy. Prednisolone, tacrolimus, and MMF combination was effective in our case, and these drugs can be considered as first‐line agents in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Autosomal recessive polycystic kidney disease (ARPKD) ranks among the most severe chronic kidney diseases (CKD). Its primary cause is variants in the Polycystic Kidney and Hepatic Disease 1 gene (PKHD1). The clinical spectrum of ARPKD varies widely, ranging from mild late‐onset symptoms to severe perinatal mortality. However, achieving an early genetic diagnosis in ARPKD patients before clinical symptoms appear proves challenging. Case Presentation: This case is a 4‐year‐old boy who experienced a convulsion characterized by a generalized tonic attack lasting approximately 3‐5 minutes and later sought treatment to our hospital. However, routine abdominal ultrasound examination accidentally detected that he had diffuse liver lesions, splenomegaly, and bilateral renal enlargement with renal pelvis dilation. Given the uncertainty regarding the underlying cause of the patient's structural abnormalities and convulsions, karyotyping, whole exome sequencing (WES), structural variant analysis (SV analysis) of whole genome sequencing (WGS) were recommended. The result of SV analysis revealed that he has an RBT impacting PKHD1 and the precise location of breakpoints was confirmed through Long‐Range Polymerase Chain Reaction (LR‐PCR). However, WES did not screen out pathogenic variants initially, the WES data was reviewed subsequently based on SV analysis results. Conclusion: We identified an infrequent variant combination, c.2507T>C (p.V836A) in PKHD1 and an RBT with broken PKHD1, which extends the genetic spectrum of ARPKD, and provide a basis for further genetic counselling to the family. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The PKHD1 (Polycystic Kidney and Hepatic Disease 1) gene is essential for producing fibrocystin or polyductin, which is crucial in various cellular functions. Mutations in PKHD1 have been found to be involved in the development and progression of colorectal cancer (CRC). Along with APC, TP53, and KRAS, PKHD1 is one of the most frequently mutated genes in CRC. PKHD1 expression is governed by the Wnt/PCP pathway, often dysregulated in CRC. Targeting this pathway, crucial for CRC progression, could unveil potential therapeutic strategies for colon cancer treatment. Methods: This study examined an in-house dataset of 3702 colon cancer samples, analyzing mutation landscapes, clinical features, tumor mutational burden (TMB), microsatellite instability (MSI), and chromosomal instability (CIN) score. For the survival analysis of PKHD1 patients, survival data of 436 colon adenocarcinoma samples were obtained from TCGA dataset. Additionally, 433 samples from TCGA with RNA-seq data were used for the assessment of immune cell infiltration and gene set enrichment analysis. Results: Polycystic Kidney and Hepatic Disease 1 mutation was detected in 424 colon cancer patients from our in-house cohort and was associated with increased TMB, higher MSI, and lower CIN score. Importantly, within the TCGA dataset, PKHD1 mutations were identified as an independent prognostic factor, not merely correlated with established prognostic biomarkers, and were associated with poorer overall survival outcomes. In terms of immune response, these mutations correlated with increased enrichment scores for 12 immune cell types, including B cell plasma, macrophages, and naive CD4+ T cells. Additionally, interferon alpha and interferon-gamma gene sets were significantly down-regulated in patients with PKHD1 mutations (FDA q-value<0.1). Conclusions: Overall, these findings suggest that PKHD1 may be a potential biomarker for the prognosis of colon cancer and provide some insight for personalized immunotherapy. [ABSTRACT FROM AUTHOR]

Metformin (MET) has the potential to activate p‐AMPK and block mTORC1‐induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate. MET 150 mg/kg resulted in a therapeutic serum metformin level but had no effect on kidney weight, cyst indices, kidney function, or mTOR and autophagy proteins. In summary, a standard dose of MET was ineffective in reducing PKD, did not activate p‐AMPK or suppress mTOR and the higher dose resulted in increased lactate levels and nephrotoxicity. In conclusion, the study dampens enthusiasm for human studies of MET in PKD. Doubling the metformin dose resulted in a 10‐fold increase in mean blood levels and toxicity suggesting that the dosage range between therapeutic and toxic is narrow. [ABSTRACT FROM AUTHOR]

Objectives: To compile a list of instant diagnoses of major fetal anomalies, and to present their sonographic descriptors and test them in a retrospective series of fetuses with congenital anomalies managed at our center. Methods: The first step was to identify major anomalies that meet the following criteria: (1) can be diagnosed directly and unequivocally on the basis of a set of descriptors evident on a single sonographic view; (2) are among those more commonly diagnosed in utero; (3) represent major lethal or life‐threatening malformations or anomalies for which no or only palliative surgery can be performed. For each of these anomalies, a sonographic descriptor was produced. The second step was to test the descriptors of the instant diagnoses in all cases with these anomalies evaluated since January 2000 in our Fetal Medicine Unit, retrieved from our electronic database. For each congenital anomaly–sonographic descriptor pair we then evaluated the presence vs absence of an unequivocal relationship between anomaly and descriptor, assessing: whether a particular descriptor in a set reference plane identified unequivocally the anomaly, i.e. the same descriptor could not be found in any other malformation; and whether a particular anomaly presented the corresponding descriptor in all cases. Finally, we evaluated whether the sonographic descriptors could be applied in all trimesters or only selectively, considering the natural history of the 20 instant diagnoses. Results: Of the 20 instant diagnoses, five involved the central/peripheral nervous system (exencephaly/anencephaly, alobar/semilobar holoprosencephaly, cephalocele, open spinal dysraphism, complete agenesis of corpus callosum), five involved the heart (hypoplastic left heart syndrome, complete atrioventricular septal defect, severe Ebstein's anomaly, critical aortic stenosis, transposition of the great arteries), five involved the abdominal wall (left‐sided congenital diaphragmatic hernia, exomphalos, gastroschisis, body‐stalk anomaly) or gastrointestinal tract (duodenal atresia), and five involved the remaining systems (three urinary (autosomal recessive polycystic kidney disease, multicystic dysplastic kidney, lower urinary tract obstruction), two skeletal (transverse limb defect, radial ray defect)). All of the descriptors were found to identify unequivocally the related malformations, whereas four of the malformations were not associated with their reference descriptors in every case. For example, congenital diaphragmatic hernia (left‐sided) presented without the stomach in the thorax in 42/93 (45.2%) cases. Due to the natural history of the condition, not all signs were recognizable in the first trimester, some becoming evident only from the second trimester onwards. Conclusion: We have defined sonographic descriptors that enable an unequivocal instant diagnosis for a list of 20 major congenital anomalies: the 'INDIAMAN‐20' (INstant DIAgnosis of Major ANomalies) protocol. We believe that using this approach may facilitate focused training of less experienced operators and that it may be incorporated into artificial intelligence and deep learning protocols, further boosting the instant prenatal recognition of these lethal or life‐threatening malformations. © 2022 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This article, published in the journal Ultrasound in Obstetrics & Gynecology, discusses two cases of prenatal diagnosis of Bardet-Biedl Syndrome (BBS), a rare genetic disorder. The main finding in both cases was large, echogenic kidneys on prenatal imaging. BBS is characterized by renal dystrophy and malformations, polydactyly, intellectual disability, central obesity, and hypogonadism. Genetic testing confirmed BBS in both cases, with different mutated copies of the BBS10 and BBS1 genes. The article provides valuable information for researchers and healthcare professionals studying genetic abnormalities and prenatal diagnoses. [Extracted from the article]

Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+]i homeostasis and flow‐sensitive [Ca2+]i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP‐dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+]i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K+) and KB/C (5% K+ with bicarbonate/citrate) diets significantly increased TRPV4 levels when compared to control (0.9% K+). High KCl diet caused an increased TRPV4‐dependent Ca2+ influx, and partial restoration of mechanosensitivity in freshly isolated monolayers of cystic cells. Unexpectedly, high KB/C diet induced an opposite effect by reducing TRPV4 activity and worsening [Ca2+]i homeostasis. Importantly, high KCl diet decreased cAMP, whereas high KB/C diet further increased cAMP levels in cystic cells (assessed as AQP2 distribution). At the systemic level, high KCl diet fed PCK453 rats had significantly lower kidney‐to‐bodyweight ratio and reduced cystic area. These beneficial effects were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight, accelerated cystogenesis, and augmented renal injury. High KB/C diet also exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression. [ABSTRACT FROM AUTHOR]

We present a fetus with bilaterally enlarged and echogenic kidneys. Prenatal testing detected compound heterozygosity for a 0.676 Mb de novo deletion and an inherited pathogenic variant in PKHD1. This is the first case of autosomal recessive polycystic kidney disease (ARPKD) with a prenatally detected disease‐causing PKHD1 deletion. [ABSTRACT FROM AUTHOR]

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 (P2X4R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X4R allosteric modulator) and 5‐BDBD (P2X4R antagonist) on the development of ARPKD in PCK/CrljCrl‐Pkhd1pck/CRL (PCK) rats. Our data indicated that activation of ATP‐mediated P2X4R 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 5 mg/L, 6 weeks) or the inhibition of P2X4R 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 5 mg/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 P2X4R 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. [ABSTRACT FROM AUTHOR]

5/77 (6%) patients had their IS lowered based on the biopsy results: 3 patients decrease current IS dose and 2 patients stopped one of there is agents. The diagnosis leading to transplantation was primary hyperoxaluria type 1 (PH1) in 64 patients, in 70 patients autosomal recessive polycystic kidney disease (ARPKD), and in 25 patients various other diagnoses. Because young age and EBV seronegative recipients (R-) are known risk factors for EBV complications, living-donor LT may have a higher risk due to the combination of young recipients and adult donors, which often result in EBV mismatch. B Results b : A total of 21 (75%) patients were classified as PRETEXT IV, 4 (14.3%) patients as PRETEXT III and 3 (10.7%) patients were rescue LT. [Extracted from the article]

Renal cysts can be focal or diffuse and unilateral or bilateral. In childhood, most renal cysts are due to hereditary diseases rather than simple cysts or acquired cystic diseases, unlike adults. Inherited cystic diseases can be ciliopathies due to a primary ciliary defect (as in polycystic kidney diseases and nephronophthisis). Acquired causes include obstructive cystic dysplasia, dyselectrolytemia, and acquired cysts in renal replacement therapy. The final diagnosis requires a multispecialty approach, including radiology, pathology, and genetics. Imaging is a very important component in treating patients with cystic renal diseases. This article discusses the ultrasound findings of cystic renal diseases in children, along with a brief discussion of other imaging modalities and a suggested ultrasound reporting format. [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) is mainly caused by variants in the PKHD1 gene, encoding fibrocystin (FC), a large transmembrane protein of incompletely understood cellular function. Here, we show that a C‐terminal fragment of human FC can suppress a signalling module of the kinase SRC and signal transducer and activator of transcription 3 (STAT3). Consistently, we identified truncating genetic variants specifically affecting the cytoplasmic tail in ARPKD patients, found SRC and the cytoplasmic tail of fibrocystin in a joint dynamic protein complex and observed increased activation of both SRC and STAT3 in cyst‐lining renal epithelial cells of ARPKD patients. [ABSTRACT FROM AUTHOR]

B Background: b Patients with chronic kidney disease (CKD) requiring kidney replacement therapy in rural communities are at higher risk of mortality compared with patients in urban areas, and encounter many barriers in accessing care. Changes in plasma metabolites in individuals with diabetes associated chronic kidney disease:... A Lecamwasam 1,2,3, T Mansell 1,4, E I Ekinci 2,5, R Saffery 1,4, K M Dwyer 3 1 Murdoch Children's Research Institute, Epigenetics Research, 2 Austin Health, Department of... B Aim: b We investigated a cross-sectional metabolomic analysis of plasma and urine of patients with early or late diabetes associated chronic kidney disease (CKD), inclusive of stages 1-5 CKD, to identify potential metabolomic profiles between the two groups. Effect of lanthanum carbonate on endogenous calciprotein particles in CKD patients - Results fr... M Tiong 1,2, E R Smith 1,2, N M Lioufas 1,2,3, E Pedagogos 3, E M Pascoe 4, C M Hawley 4... 1 Department of Nephrology, The Royal Melbourne Hospital, 2 Department of Medicine (RMH), Uni... B Aim: b To examine the effect of lanthanum carbonate compared to placebo on calciprotein particles (CPPs) in patients with chronic kidney disease (CKD). Feasibility and acceptability of electronic patient reported outcome measures (e-PROMs) data... E Duncanson 1, P N Bennett 2, A K Viecelli 3, K Dansie 1, L M Greenham 1, A Tong 4, S J... 1 Australia and New Zealand Dialysis and Transplant Registry and SA Health and Medical Resear... B Aim: b To describe the perspectives and experiences of nephrologists, nurses, and patients receiving haemodialysis, about acceptability and feasibility of electronic patient-reported outcome measures (e-PROMs) collection with feedback to clinicians. [Extracted from the article]

Basic Science and Instrumentation A 15-Year Review of the Imaging Performance of Diagnostic Ultrasound Scanners Using the Edinb... I Scheduled Presenter: Carmel Moran, PhD - University of Edinburgh i I Author: Scott Inglis, PhD - NHS i I Author: Karne McBride, MSc - NHS i I Author: Christopher McLeod - NHS i I Author: Stephen Pye, PhD - NHS i B Objectives: b There is a strong clinical need for objective and quantitative assessment of ultrasound B-mode imaging performance: firstly in the hardware and software development cycle of ultrasound scanners; secondly to underpin decision making in the procurement and replacement of equipment; thirdly to ensure scanners are fit for purpose; and fourthly to assess new imaging modalities. Integrated Vascular Age for Cardiovascular/Stroke Risk Stratification: A Multicenter Retrospe... I Scheduled Presenter: Jasjit Suri - AtheroPoint™, Roseville, i I Author: Ankush Jamthikar - Visvesvaraya National Institute of Technology Nagpur i I Author: Elisa Cuadrado-Godia - Department of Neurology, Imim - Hospital del Mar, Barcelona, Spain i I Author: Vijay Viswanathan - MV Hospital for Diabetes and Professor M Viswanathan Diabetes Research Centre, Chennai, India i I Author: Harman Suri - Brown University, Providence, Rhode Island, USA i I Author: Andrew Nicolaides - Vascular Screening and Diagnostic Centre London, and Department of Biological Sciences University of Cyprus, Nicosia, Cyprus i I Author: Anudeep Puvvula - Annu's Hospitals for Skin and Diabetes, Nellore, Andra Pradesh, India i I Author: Deep Gupta - Visvesvaraya National Institute of Technology Nagpur i I Author: Narendra Khanna - Department of Cardiology, Indraprastha Apollo Hospitals, New Delhi, India i I Author: Luca Saba - Azienda Ospedaliero Universitaria (A.O.U.) di Cagliari Polo di Monserrato; Università di Cagliari, s.s. [Extracted from the article]

Congenital hepatic fibrosis (CHF) often accompanies autosomal recessive polycystic kidney disease (ARPKD), which stems from a PKHD1 gene mutation. The aim of this study was to clarify the prognosis of children with CHF who received living donor liver transplantation (LDLT) from donors who might be heterozygous carriers of a hepatorenal fibrocystic disease. Fourteen children with CHF who underwent LDLT at our center were enrolled. Eight and two patients had ARPKD and nephronophthisis, respectively. Eight of the donors were the recipients' fathers, and six donors were their mothers. We examined the histological and radiological findings of the donor livers and complications in the recipients following the liver transplantation. Seven of the donor livers presented morphological abnormalities of the bile ducts. Abdominal computed tomography revealed liver cysts in eight donors. One recipient underwent re‐LT for graft failure due to rejection. Three patients presented with rejection, and one presented with sepsis. The overall survival rate was 100% and the original graft survival rate was 93%. In conclusion, the prognosis of recipients who received a LDLT from their parents for CHF was excellent. However, the morphology of half the donor livers was abnormal. Careful follow‐up is needed to ensure long‐term graft survival. [ABSTRACT FROM AUTHOR]

Management of children with autosomal recessive polycystic kidney disease (ARPKD) who develop end‐stage renal disease (ESRD) remains challenging because of concomitant liver disease. Patients with recurrent cholangitis are candidates for liver‐kidney transplantation, while the treatment for patients with splenomegaly and pancytopenia due to portal hypertension is controversial. Herein, we report 7 children who were treated using an individualized treatment strategy stratified by liver disease. Two patients with recurrent cholangitis underwent sequential liver‐kidney transplantation, while 4 patients with splenomegaly and pancytopenia but without recurrent cholangitis underwent splenectomy followed by isolated kidney transplantation. The remaining patient, who did not have cholangitis and pancytopenia, underwent isolated kidney transplantation. Blood cell counts were normalized after splenectomy was performed at the median age of 8.7 (range, 7.4‐11.7) years. Kidney transplantation was performed at the median age of 8.8 (range, 1.9‐14.7) years in all patients. Overwhelming post‐splenectomy infections and cholangitis did not occur during the median follow‐up period of 6.3 (range, 1.0‐13.2) years. The estimated glomerular filtration rate at the last follow‐up was 53 (range, 35‐107) mL/min/1.73 m2. No graft loss occurred. Our individualized treatment strategy stratified by recurrent cholangitis and pancytopenia can be a feasible strategy for children with ARPKD who develop ESRD and warrants further evaluation. [ABSTRACT FROM AUTHOR]

On the cover: The cover image is based on the Review Article The molecular structure and function of fibrocystin, the key gene product implicated in autosomal recessive polycystic kidney disease (ARPKD) by Travis A K Bannell et al., https://doi.org/10.1111/ahg.12535.. [Extracted from the article]

Background & Aims: Wilson's disease (WD) is an autosomal recessive disorder associated with disease‐causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes. Methods: A total of 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform. Results: ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurological phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset. Conclusions: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype. [ABSTRACT FROM AUTHOR]

Caroli's syndrome (CS; also known as Grumbach's disease) is characterized by non-obstructive intrahepatic bile ductal ectasia and dilatation, classified as mono- or multilobar, and it is associated with congenital hepatic fibrosis[1]. Signs of CD may not be visible during the early stages of pregnancy, and MRI may be helpful to detect liver biliary tree dilatation. [Extracted from the article]

A novel autosomal recessive disorder characterized by pre‐ and postnatal growth restriction with microcephaly, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, early mortality, hydrocephalus, and genital hypoplasia was observed in 4 children from 3 families of New Mexican Hispanic heritage. Three of the children died before 3 years of age from uremia and/or sepsis. Exome sequencing of the surviving individual identified a homozygous c.587T>C (p.Ile196Thr) mutation in ZPR1 Zinc Finger (ZPR1) that segregated appropriately in her family. In a second family, the identical variant was shown to be heterozygous in the affected individual's parents and not homozygous in any of her unaffected siblings. ZPR1 is a ubiquitously expressed, highly conserved protein postulated to transmit proliferative signals from the cell membrane to the nucleus. Structural modeling reveals that p.Ile196Thr disrupts the hydrophobic core of ZPR1. Patient fibroblast cells showed no detectable levels of ZPR1 and the cells showed a defect in cell cycle progression where a significant number of cells remained arrested in the G1 phase. We provide genetic and molecular evidence that a homozygous missense mutation in ZPR1 is associated with a rare and recognizable multisystem syndrome. [ABSTRACT FROM AUTHOR]

ABSTRACT: Aim: Type IV collagen nephropathies include Alport Syndrome and thin basement membrane nephropathy (TBMN), which are caused by mutations in COL4A3/A4/A5 genes. Recently, reports of patients with heterozygous mutations in COL4A3/A4 have been increasing. The clinical course of these patients has a wide variety, and they are diagnosed as TBMN, autosomal dominant Alport syndrome (ADAS), or familial focal segmental glomerular sclerosis. However, diagnosis, frequency and clinicopathological manifestation of them remains unclear. We tested COL4A3/A4/A5 genes in patients with hereditary nephritis that was difficult to diagnose clinicopathologically, and investigated who should undergo such testing. Methods: We performed immunostaining for α5 chain of type IV collagen [α5 (IV)] in 27 patients from 21 families who fitted the following criteria: (i) haematuria and proteinuria (± renal dysfunction); (ii) family history of haematuria, proteinuria, and/or renal dysfunction (autosomal dominant inheritance); (iii) no specific glomerulonephritis; and (iv) thinning, splitting, or lamellation of the glomerular basement membrane (GBM) on electron microscopy. Then we performed genetic testing in 19 patients from 16 families who showed normal α5 (IV) patterns. We conducted a retrospective analysis of their clinicopathological findings. Results: Among 16 families, 69% were detected heterozygous mutations in COL4A3/A4, suggesting the diagnosis of TBMN/ADAS. Twenty‐one percent of patients developed end stage renal disease. All patients showed thinning of GBM, which was accompanied by splitting or lamellation in seven patients. Conclusion: A considerable fraction of patients with hereditary nephritis that is difficult to diagnose clinicopathologically have TBMN/ADAS. It is important to recognize TBMN/ADAS and perform genetic testing in appropriate patients. [ABSTRACT FROM AUTHOR]

Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic variants in NKX6‐2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole‐exome or whole‐genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6‐2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype‐phenotype correlation. [ABSTRACT FROM AUTHOR]

Abstract: We present a case of a 2‐year‐old child who underwent a combined en bloc liver and pancreas transplant following complications of WRS. WRS is characterized clinically through infantile insulin‐dependent diabetes mellitus, neutropenia, recurrent infections, propensity for liver failure following viral infections, bone dysplasia, and developmental delay. Usually, death occurs from fulminant liver and concomitant kidney failure. Few cases with WRS are reported in the literature, mostly from consanguineous parents. To the best of our knowledge, combined en bloc liver and pancreas transplant has not been performed in small children. [ABSTRACT FROM AUTHOR]

Abstract: Background: Gout is a clinical syndrome that occurs as an inflammatory response to increased concentration of uric acid and monosodium urate crystals. Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease with autosomal recessive inheritance. The Mediterranean fever (MEFV) gene is responsible for FMF and encodes pyrin that suppresses the inflammatory response. Most of the FMF‐related mutations have been identified in exon 2 (e.g., E148Q and R202Q) and exon 10 (M680I, M694V, M694I and V726A) of the MEFV gene, and each missense mutation is known to increase production of interleukin‐1, a proinflammatory cytokine. Our aim was to investigate effects of MEFV variant alleles on the manifestations of gout. Methods: Seventy‐one patients diagnosed with gout (age: 61.73 ± 11.73 years, F/M: 14/57) and 50 healthy subjects (age: 61.48 ± 11.97, F/M: 10/40) as controls were included in this study. Results: MEFV variant alleles were found in 24 (33.8%) of the gout patients and in 13 (26%) of the control subjects; the difference was not statistically significant. In the gout patients with a MEFV variant allele, the interval between the first two attacks was shorter (P = 0.014), and the platelet count was higher (P = 0.026), compared to the patients without a variant allele. In addition, the patients with a MEFV variant allele showed the higher incidence of tophus (8.5% vs. 1.4%) (P = 0.005) and the higher number of attacks per year (P = 0.001). Conclusion: We propose that a variant allele of the MEFV gene may be responsible for the severity of gout. [ABSTRACT FROM AUTHOR]

(C) Axial HASTE MRI image shows enlarged hyperintense bilateral kidneys with few cysts largest in left kidney. The fetal MRI findings were suggestive of Caroli's syndrome with ARPKD and bilateral pulmonary hypoplasia. Another case report by Castro et al.4 suggested the diagnosis of Caroli's syndrome based on the finding of biliary duct dilatation with visible "central dot sign" on 1.5T MRI. [Extracted from the article]

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot. [ABSTRACT FROM AUTHOR]

Schöpf-Schulz-Passarge syndrome (SSPS) is thought to be a rare autosomal recessive condition similar to many other ectodermal dysplasias. Diagnosis is difficult, with many possible differential diagnoses; however, eyelid cysts are a commonly seen feature. This clinical report aims to highlight this and describe the dental features and management of this syndrome, which existing literature has not previously described. [ABSTRACT FROM AUTHOR]

Methylmalonic acidemia (MMA) is an autosomal recessive disorder that can be classified into two types: (1) vitamin B12-responsive and (2) vitamin B12-non-responsive. In MMA cases with long-term survival, renal failure is often a problem, and timing for kidney transplantation for MMA is controversial. We encountered a vitamin B12-non-responsive MMA case for which regular hemodialysis for renal failure was initiated; the patient was 16 years old when she first received regular hemodialysis and 35 years old when she developed pulmonary artery hypertension (PAH). PAH can complicate regular hemodialysis; however, PAH in this case was considered to be a complication of MMA because it was responsive to medical treatment and reversible. In this report, we discuss the role of regular hemodialysis in MMA and the causal relationship between MMA and regular hemodialysis for PAH. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study regarding the missense variant of PNPLA1 gene that can cause autosomal recessive congenital ichthyosis (ARCI).

The article discusses a study related to use of micro computed tomography for ex-vivo imaging of human fetal kidney disease with comparative histology. It mentions that micro-CT was performed on three human fetal kidneys which included a structurally normal kidney, one with autosomal recessive polycystic kidney disease and another with multicystic dysplastic kidney disease. It also mentions vusualization of elongated cysts in case of polycystic disease.

Objective Non-syndromic sensorineural hearing impairment is inherited in an autosomal recessive fashion in 75-85% of cases. To date, 61 genes with this type of inheritance have been identified as related to hearing impairment, and the genetic heterogeneity is accompanied by a large variety of clinical characteristics. Adequate counselling on a patient's hearing prognosis and rehabilitation is part of the diagnosis on the genetic cause of hearing impairment and, in addition, is important for the psychological well-being of the patient. Type of review Traditional literature review. Data source All articles describing clinical characteristics of the audiovestibular phenotypes of identified genes and related loci have been reviewed. Conclusion This review aims to serve as a summary and a reference for counselling purposes when a causative gene has been identified in a patient with a non-syndromic autosomal recessively inherited sensorineural hearing impairment. [ABSTRACT FROM AUTHOR]

Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with infantile onset, has a more severe phenotype characterized by coarse facial features, hepatomegaly, dysostosis multiplex, and developmental delay while patients with the late and milder type, known as 'cherry red spot-myoclonus syndrome' develop myoclonic epilepsy, visual impairment and ataxia in the second or third decade of life. The diagnosis is usually suggested by increased urinary bound sialic acid excretion. We recently described genetically diagnosed patients with a specially mild phenotype, no retinal abnormalities and normal urinary sialic acid. This observation suggests that genetic analysis or the demonstration of the neuraminidase enzyme deficiency in cultured fibroblasts are needed to detect and diagnose mildest phenotypes. [ABSTRACT FROM AUTHOR]

Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array- CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive ( n = 50) or autosomal dominant ( n = 50) patterns of inheritance. Rare copy number variants ( CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss ( POU4F3, EYA4, USH2A, and BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness. In six cases, segregation of the CNVs in pedigrees excluded them as causative. In one case, segregation could not be investigated, while in another case, a point mutation likely explains the phenotype. These findings show that the presumptive patterns of inheritance were incorrect in at least two cases, thereby impacting genetic counselling. In addition, we report the first duplication reciprocal to the rare ABCD1, BCAP31, and SLC6A8 contiguous deletion syndrome; as with most microduplication syndromes, the associated phenotype is much milder than the respective microdeletion and, in this case, was restricted to hearing impairment. [ABSTRACT FROM AUTHOR]

Liver transplantation ( LT) represents an uncommon indication for Caroli's disease ( CD) or syndrome ( CS). Excellent results of LT have been reported as shown by recent multicentric European and American registry reports. Clear therapeutic flowcharts to adopt in these diseases are still lacking. This review aims at analyzing highlighting recent transplant experiences in this field and also at focusing on the role of LT in case-specific comorbidities such as development of cholangiocellular cancer or renal failure are present. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report the second known family affected by deafness‐dystonia syndrome associated with loss of function of FITM2. Our patient is compound heterozygous for pathogenic FITM2 variants, while affected siblings in the first report were homozygous. This case provides evidence that this novel genetic disorder is associated with autosomal recessive inheritance. [ABSTRACT FROM AUTHOR]

Primary hyperoxaluria (PH) is a rare, autosomal recessive disorder characterized by overproduction of oxalate caused by a deficiency in a hepatic enzyme. The excess oxalate combines with calcium in the kidneys to form deposits of calcium oxalate, which can lead to nephrocalcinosis and renal failure. PH type 1 (PH1), the most common form of this disease, is caused by a deficiency of the liver-specific enzyme alanine/glyoxylate aminotransferase (AGT). Liver transplantation is performed as a definitive therapy for PH to correct the enzyme defect. Usually, liver depositions are limited and liver function is normal without fibrosis. Here, we report an adult case of liver cirrhosis caused by PH1. A 28-year-old woman was admitted to our hospital under suspicion of PH1 and the presence of nephrocalcinosis. The patient had suffered from kidney stone recurrences from 17 years of age, and was initiated on hemodialysis due to renal failure at the age of 27 years. The serum level of oxalic acid was high, whereas the AGT level in the liver tissue was decreased. Thus, the patient was definitively diagnosed with PH1. Although she had normal liver function, surface nodularity and splenomegaly were detected by computed tomography, suggesting liver cirrhosis. The native liver showed micronodular cirrhosis and portal fibrosis. Several arterioles were filled with rhomboid and polyhedral refractile oxalate crystals and various portal tracts showed these crystals. Our case suggests that long-term oxalosis can lead to liver cirrhosis; thus, PH should be considered one of the causes of liver cirrhosis. [ABSTRACT FROM AUTHOR]

Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency ( MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease ( PKD) is transmitted as either an autosomal dominant or recessive trait and is a major cause of renal failure and liver fibrosis. The cpk mouse model of autosomal recessive PKD ( ARPKD) has been extensively characterized using standard histopathological techniques after euthanasia. In the current study, we sought to validate magnetic resonance microscopy ( MRM) as a robust tool for assessing the ARPKD phenotype. We used MRM to evaluate the liver and kidney of wild-type and cpk animals at resolutions <100 μm and generated three-dimensional (3D) renderings for pathological evaluation. Our study demonstrates that MRM is an excellent method for evaluating the complex, 3D structural defects in this ARPKD mouse model. We found that MRM was equivalent to water displacement in assessing kidney volume. Additionally, using MRM we demonstrated for the first time that the cpk liver exhibits less extensive ductal arborization, that it was reduced in volume, and that the ductal volume was disproportionately smaller. Histopathology indicates that this is a consequence of bile duct malformation. With its reduced processing time, volumetric information, and 3D capabilities, MRM will be a useful tool for future in vivo and longitudinal studies of disease progression in ARPKD. In addition, MRM will provide a unique tool to determine whether the human disease shares the newly appreciated features of the murine biliary phenotype. [ABSTRACT FROM AUTHOR]

MYH9-related disease ( MYH9- RD) is a rare autosomal dominant disease caused by mutation of MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA ( NMMHC-IIA). MYH9- RD patients have macrothrombocytopenia and granulocyte inclusions (pathognomonic sign of the disease) containing wild-type and mutant NMMHC-IIA. During life they might develop sensorineural hearing loss, cataract, glomerulonephritis, and elevation of liver enzymes. One of the MYH9 mutations, p. R705H, was previously reported to be associated with DFNA17, an autosomal dominant non-syndromic sensorineural hearing loss without any other features associated. We identified the same mutation in two unrelated families, whose four affected individuals had not only hearing impairment but also thrombocytopenia, giant platelets, leukocyte inclusions, as well as mild to moderate elevation of some liver enzymes. Our data suggest that DFNA17 should not be a separate genetic entity but part of the wide phenotypic spectrum of MYH9- RD characterized by congenital hematological manifestations and variable penetrance and expressivity of the extra-hematological features. [ABSTRACT FROM AUTHOR]

Defects in WDR72 ( WD repeat-containing protein 72) cause autosomal recessive hypomaturation amelogenesis imperfecta. We generated and characterized Wdr72-knockout/ lacZ-knockin mice to investigate the role of WDR72 in enamel formation. In all analyses, enamel formed by Wdr72 heterozygous mice was indistinguishable from wild-type enamel. Without WDR72, enamel mineral density increased early during the maturation stage but soon arrested. The null enamel layer was only a tenth as hard as wild-type enamel and underwent rapid attrition following eruption. Despite the failure to further mineralize enamel deposited during the secretory stage, ectopic mineral formed on the enamel surface and penetrated into the overlying soft tissue. While the proteins in the enamel matrix were successfully degraded, the digestion products remained inside the enamel. Interactome analysis of WDR72 protein revealed potential interactions with clathrin-associated proteins and involvement in ameloblastic endocytosis. The maturation stage mandibular incisor enamel did not stain with methyl red, indicating that the enamel did not acidify beneath ruffle-ended ameloblasts. Attachment of maturation ameloblasts to the enamel layer was weakened, and SLC24A4, a critical ameloblast calcium transporter, did not localize appropriately along the ameloblast distal membrane. Fewer blood vessels were observed in the papillary layer supporting ameloblasts. Specific WDR72 expression by maturation stage ameloblasts explained the observation that enamel thickness and rod decussation (established during the secretory stage) are normal in the Wdr72 null mice. We conclude that WDR72 serves critical functions specifically during the maturation stage of amelogenesis and is required for both protein removal and enamel mineralization. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder that results from functional and ultrastructural abnormalities of motile cilia. Patients with PCD have diverse clinical phenotypes that include chronic upper and lower respiratory tract infections, situs inversus, heterotaxy with or without congenital heart disease, and male infertility, among others. In this report, the carrier frequencies for eleven mutations in eight PCD-associated genes (DNAI1, DNAI2, DNAH5, DNAH11, CCDC114, CCDC40, CCDC65, and C21orf59) that had been found in individuals of Ashkenazi Jewish descent were investigated in order to advise on including them in existing clinical mutation panels for this population. Results showed relatively high carrier frequencies for the DNAH5 c.7502G>C mutation (0.58%), the DNAI2 c.1304G>A mutation (0.50%), and the C21orf59 c.735C>G mutation (0.48%), as well as lower frequencies for mutations in DNAI1, CCDC65, CCDC114, and DNAH11 (0.10- 0.29%). These results suggest that several of these genes should be considered for inclusion in carrier screening panels in the Ashkenazi Jewish population. [ABSTRACT FROM AUTHOR]

Background and purpose Spastic paraplegia type 5 ( SPG5) is an autosomal recessive ( AR) hereditary spastic paraplegia ( HSP) associated with pure or complicated phenotypes. This study aimed to screen SPG5 in Taiwanese HSP patients. Methods Sequencing of the SPG5 gene, CYP7B1, was performed in a cohort of 25 ethnic Han Taiwanese patients with AR or sporadic HSP. Clinical information and magnetic resonance imaging ( MRI) were analyzed in confirmed SPG5 patients. Results One (33%) AR kindred and four (18%) sporadic cases had CYP7B1 mutations. All of the SPG5 cases carried the mutation c.334 C>T (R112X). Haplotype analysis suggested a 'founder effect' in ethnic Hans for this mutation. The phenotype was either pure or complicated by cerebellar ataxia. For the primary HSP phenotype, there were profound dorsal column sensory deficits in all patients. Spine MRI showed thoraco-lumbar cord atrophy in some patients. Conclusions Spastic paraplegia type 5 is a common cause of AR and sporadic HSPs that has a higher frequency in Taiwanese than in other ethnic groups. It is associated with a CYP7B1 founder mutation and its phenotype is characterized by pronounced dorsal column sensory loss, with cerebellar ataxia in some patients. [ABSTRACT FROM AUTHOR]

Mutations in MYH7 cause autosomal dominant Laing distal myopathy. We present a family with a previously reported deletion (c.5186_5188del AGA, p.K1729del). Muscle pathology in one family member was characterized by an inflammatory myopathy with rimmed vacuoles, increased MHC Class I expression, and perivascular and endomysial muscle inflammation comprising CD3+, CD4+, CD8+, and CD68+ inflammatory cells. Interestingly, this biopsy specimen contained TDP-43, p62, and SMI-31-positive protein aggregates typical of inclusion body myositis. These findings should alert physicians to the possibility that patients with MYH7 mutations may have muscle biopsies showing pathologic findings similar to inclusion body myositis. [ABSTRACT FROM AUTHOR]

The natural history and survival of children with fibrocystic liver-kidney disease undergoing solid organ transplantation have infrequently been described. We report outcomes in a cohort of US children with fibrocystic liver-kidney disease receiving solid organ transplants over 20 yr. Retrospective cohort study of pediatric transplant recipients with diagnoses of fibrocystic liver-kidney disease from 1/1990 to 3/2010, using data from the SRTR. Subjects were categorized by the first transplanted organ: LT, KT, or SLK. Primary outcomes were death, re-transplant, transplant of the alternate organ, or initiation of dialysis. Seven hundred and sixteen subjects were transplanted in this period. Median age at first transplant was 9.7 yr. Of the LT, 14 (19%) required a second liver transplant at median of 0.2 yr, and five (7%) required kidney transplant or dialysis at a median of 9.0 yr. Of the KT, 188 (31%) required a second kidney transplant or dialysis at a median of 5.9 yr. Twenty-nine (5%) subsequently received liver transplant at a median of 6.0 yr. Among patients in this registry, far more children underwent kidney than liver transplants. The risk of subsequently needing transplantation of an alternate organ was low. [ABSTRACT FROM AUTHOR]

NODAT is increasingly prevalent. Compared with adult recipients, NODAT is less prevalent in pediatric renal transplant recipients; however, some risk factors for its development in young patients have been defined. We report four pediatric renal transplant recipients with ARPKD who developed NODAT. We review the current pediatric NODAT literature and hypothesize that ARPKD may be an additional risk factor for NODAT. [ABSTRACT FROM AUTHOR]

Aim To investigate whether endothelial nitric oxide synthase (eNOS) gene associate with the progression of autosomal dominant polycystic kidney disease (ADPKD). Methods Databases of EMBASE, Pubmed, ISI, Ovid Database, Cochrane library and China National Knowledge Infrastructure were all searched. Associated studies about eNOS polymorphisms and ADPKD were analyzed by meta-analysis. Results A total of 11 studies with Glu298Asp and 4b/a polymorphisms were included. A allele of the 4b/a polymorphism increased the risk of end stage renal disease ( ESRD) in ADPKD (odds ratio ( OR) = 1.85, 95% confidence interval ( CI) 1.17-2.94, P = 0.009). However, GG phenotype of Glu298Asp polymorphism neither decreased the ESRD risk ( OR = 0.77, 95% CI 0.55-1.08, P = 0.13) nor affected the hypertension risk ( OR = 1.04, 95% CI 0.66-1.66, P = 0.86). The GG phenotype carriers had later ESRD age compared with the T allele of Glu298Asp polymorphism ( WMD = 2.39; 95% CI 1.32-3.46; P < 0.0001). Significant association was also found in Caucasians ( WMD = 2.41; 95% CI 1.18-3.64; P = 0.0001). Subgroup analysis by gender indicated GG genotype carriers had older age of ESRD than T allele carriers in males ( WMD = 4.51; 95% CI 3.95-5.08; P = 0.00001), but not in females. Conclusions GG genotype of the Glu298Asp variant slowed the ESRD progression in ADPKD, while a allele carriers of the 4b/a variant increased the risk of ESRD. Variants of eNOS gene might play different roles in the ESRD progression in ADPKD. [ABSTRACT FROM AUTHOR]