Polycystic liver disease is the most prevalent extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Non-obstructive asymptomatic common bile duct (CBD) dilatation has been observed anecdotally on CT scans, but CT is not optimal for biliary visualization. Here, we measured CBD diameter on T2-weighted MRI in ADPKD subjects to determine if CBD dilatation is associated with ADPKD. CBD diameter was measured retrospectively on ADPKD subjects (n = 254) and on age- and sex-matched controls without ADPKD (n = 254) who underwent abdominal MRI. CBD diameter in these groups was compared and correlated with clinical, laboratory and magnetic resonance imaging (MRI) features, including organ volumes and cyst burden. CBD median diameter [interquartile range, IQR, 25

Polycystic kidney disease (PKD) is a genetic disorder caused by mutations in the PKD1 or PKD2 genes, leading to autosomal dominant PKD (ADPKD), the most common inherited kidney disease. The disease is characterized by the formation of large, fluid-filled cysts in the kidneys, which often progresses to renal failure. Analyzing the composition of the cystic fluids (CF) could provide valuable insights into mechanisms underlying cyst development and disease progression. In this study, we utilized samples from the MUSC Kidney Translational Research Center (KTRC) and the Weill Cornell Medicine serum and CF library. The samples were obtained from male and female patients diagnosed with ADPKD, and benign cystic fluids were obtained from healthy discarded transplant kidneys (CF vs. benign; n ≥ 6 patients per sex for ADPKD, and n = 4 patients for benign groups). Metabolomic profiling revealed 72 significantly altered metabolites in CF compared to benign fluid: 47 metabolites were upregulated and 14 were downregulated, including purine cycle metabolites inosine, hypoxanthine, and histamine. Serum metabolomics of ADPKD patients highlighted an increase in amino acid (AA) profiles compared to benign cyst patients, with marked upregulation of taurine, glutamine, cysteine, ornithine, and citrulline. Additionally, the purine salvage pathway was strongly activated in ADPKD, as evidenced by elevated inosine, adenosine monophosphate, and xanthosine levels. While no significant differences in plasma metabolites were observed between male and female ADPKD patients, CF metabolomic profiles were influenced by biological sex. In a separate cohort of CF samples from ADPKD patients (n = 6 per sex), we measured taurine concentrations, osmolality, and Na + , K + , and phosphate (Pi) levels. Following classical ADPKD studies, cysts were classified as proximal (non-gradient, high Na + /low K + ) or distal (gradient, low Na + /high K + ). We had 9 proximal (5F, 4M) and 3 distal cysts (1F, 2M). Distal cysts K + concentrations were 24.1, 26.8, and 34 mM, Na + concentrations were 5.9, 11.9, and 2.5 mM, and Pi concentrations were 21.4, 8.2, and 9.27 mM). The average proximal cysts concentrations were 2.7±0.3 mM K + , 165±3.9 mM Na + , and 1.56±0.05 mM Pi. No sex-specific differences were observed in ion concentrations or osmolality (average: 310 ± 2.8 mOsms). Taurine concentrations averaged 3.3 ± 0.6 ng/mL in proximal cysts and ranged from 3.15 to 7.61 ng/mL in distal cysts. These findings provide a foundational characterization of CF metabolism in PKD, highlighting dysregulated pathways associated with disease pathogenesis. This work may inform dietary recommendations and identify therapeutic targets, particularly within purinergic and amino acid signaling pathways. R00HL153686, R01DK126720, U24DK126110 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

BACKGROUND AND PURPOSE:Patients with autosomal dominant polycystic kidney disease (ADPKD) develop cysts in the kidneys, liver, spleen, pancreas, prostate, and arachnoid spaces. In addition, spinal meningeal diverticula have been reported. To determine whether spinal meningeal diverticula are associated with ADPKD, we compared their prevalence in subjects with ADPKD with a control cohort without ADPKD. MATERIALS AND METHODS:Subjects with ADPKD and age- and sex-matched controls without ADPKD undergoing abdominal MRI from the midthorax to the pelvis from 2003 to 2023 were retrospectively evaluated for spinal meningeal diverticula by 4 blinded observers. The prevalence of spinal meningeal diverticula in ADPKD was compared with that in control subjects, using t tests and correlated with clinical and laboratory data and MR imaging features, including cyst volumes and cyst counts. RESULTS:Identification of spinal meningeal diverticula in ADPKD (n = 285, median age, 47; interquartile range [IQR], 37-56 years; 54% female) and control (n = 285, median age, 47; IQR, 37-57 years; 54% female) subjects had high interobserver agreement (pairwise Cohen κ = 0.74). Spinal meningeal diverticula were observed in 145 of 285 (51%) subjects with ADPKD compared with 66 of 285 (23%) control subjects without ADPKD (P < .001). Spinal meningeal diverticula in ADPKD were more prevalent in women (98 of 153 [64%]) than men (47 of 132 [36%], P < .001). The mean number of spinal meningeal diverticula per affected subject with ADPKD was 3.6 ± 2.9 compared with 2.4 ± 1.9 in controls with cysts (P < .001). The median volume (IQR, 25%-75%) of spinal meningeal diverticula was 400 (IQR, 210-740) mm3 in those with ADPKD compared with 250 (IQR, 180-440) mm3 in controls (P < .001). The mean spinal meningeal diverticulum diameter was greater in the sacrum (7.3 [SD, 4.1] mm) compared with thoracic (5.4 [SD, 1.8] mm) and lumbar spine (5.8 [SD, 2.0] mm), (P < .001), suggesting that hydrostatic pressure contributed to enlargement. CONCLUSIONS:ADPKD has a high prevalence of spinal meningeal diverticula, particularly in women.

IDH1 and IDH2 mutational status is a critical biomarker with diagnostic, prognostic, and treatment implications in glioma. Although IDH1 p.R132H-specific immunohistochemistry is available, it is unable to identify other mutations in IDH1/2. Next-generation sequencing can accurately determine IDH1/2 mutational status but suffers from long turnaround time when urgent treatment planning and initiation is medically necessary. The Idylla assay can detect IDH1/2 mutational status from unstained formalin-fixed paraffin-embedded (FFPE) slides in as little as a few hours. In a clinical validation, we demonstrate clinical accuracy of 97% compared to next-generation sequencing. Sensitivity studies demonstrated a limit of detection of 2.5-5% variant allele frequency, even at DNA inputs below the manufacturer's recommended threshold. Overall, the assay is an effective and accurate method for rapid determination of IDH1/2 mutational status.

Background and purpose The objective is to demonstrate feasibility of quantitative susceptibility mapping (QSM) in autosomal dominant polycystic kidney disease (ADPKD) patients and to compare imaging findings with traditional T1/T2w magnetic resonance imaging (MRI). Methods Thirty-three consecutive patients (11 male, 22 female) diagnosed with ADPKD were initially selected. QSM images were reconstructed from the multiecho gradient echo data and compared to co-registered T2w, T1w and CT images. Complex cysts were identified and classified into distinct subclasses based on their imaging features. Prevalence of each subclass was estimated. Results QSM visualized two renal calcifications measuring 9 and 10 mm, and three pelvic phleboliths measuring 2 mm but missed 24 calcifications measuring 1mm or less and 1 larger calcification at the edge of the field of view. A total of 121 complex T1 hyperintense/T2 hypointense renal cysts were detected. 52 (43%) cysts appeared hyperintense on QSM consistent with hemorrhage; 60 (49%) cysts were isointense with respect to simple cysts and normal kidney parenchyma, while the remaining 9 (7%) were hypointense. The presentation of the latter two complex cyst subtypes is likely indicative of proteinaceous composition without hemorrhage. Conclusions Our results indicate that QSM of ADPKD kidneys is possible and uniquely suited to detect large renal calculi without ionizing radiation, and able to identify properties of complex cysts unattainable with traditional approaches.

Abstract Mayo Imaging Classification (MIC) for predicting future kidney growth in autosomal dominant polycystic kidney disease (ADPKD) patients is calculated from a single MRI/CT scan assuming exponential kidney volume growth and height-adjusted total kidney volume at birth to be 150 mL/m. However, when multiple scans are available, how this information should be combined to improve prediction accuracy is unclear. Herein, we studied ADPKD subjects ( $$n = 36$$ n = 36 ) with 8+ years imaging follow-up (mean = 11 years) to establish ground truth kidney growth trajectory. MIC annual kidney growth rate predictions were compared to ground truth as well as 1- and 2-parameter least squares fitting. The annualized mean absolute error in MIC for predicting total kidney volume growth rate was $$2.1\% \pm 2\%$$ 2.1 % ± 2 % compared to $$1.1\% \pm 1\%$$ 1.1 % ± 1 % ( $$p = 0.002$$ p = 0.002 ) for a 2-parameter fit to the same exponential growth curve used for MIC when 4 measurements were available or $$1.4\% \pm 1\%$$ 1.4 % ± 1 % ( $$p = 0.01$$ p = 0.01 ) with 3 measurements averaging together with MIC. On univariate analysis, male sex ( $$p = 0.05$$ p = 0.05 ) and PKD2 mutation ( $$p = 0.04$$ p = 0.04 ) were associated with poorer MIC performance. In ADPKD patients with 3 or more CT/MRI scans, 2-parameter least squares fitting predicted kidney volume growth rate better than MIC, especially in males and with PKD2 mutations where MIC was less accurate.

Autosomal dominant polycystic kidney disease (ADPKD) has been associated with cardiac abnormalities including mitral valve prolapse and aneurysmal dilatation of the aortic root. Herein, we investigated the potential association of pericardial effusion with ADPKD. Subjects with ADPKD (n = 117) and control subjects without ADPKD matched for age, gender and renal function (n = 117) undergoing MRI including ECG-gated cine MRI of the aorta and heart were evaluated for pericardial effusion independently by three observers measuring the maximum pericardial effusion thickness in diastole using electronic calipers. Pericardial effusion thickness was larger in ADPKD subjects compared to matched controls (Mann–Whitney p = 0.001) with pericardial effusion thickness >5 mm observed in 24 of 117 (21%) ADPKD subjects compared to 4 of 117 (3%) controls (p = 0.00006). Pericardial effusion thickness in ADPKD was associated with female gender patients (1.2 mm greater than in males, p = 0.03) and pleural effusion thickness (p < 0.001) in multivariate analyses. No subjects exhibited symptoms related to pericardial effusion or required pericardiocentesis. In conclusion, pericardial effusion appears to be more prevalent in ADPKD compared to controls. Although in this retrospective cross-sectional study we did not identify clinical significance, future investigations of pericardial effusion in ADPKD subjects may help to more fully understand its role in this disease.

An epidemic caused by an outbreak of mpox (formerly monkeypox) in May 2022 rapidly spread inter-nationally, requiring an urgent response from the clinical diagnostics community. A detailed description of the clinical validation and implementation of a laboratory-developed real-time PCR test for detecting nonvariola Orthopoxvirus-specific DNA based on the newly designed RealStar Zoonotic Orthopoxvirus assay is presented. The validation was performed using an accuracy panel (n Z 97) comprising skin lesion swabs in universal transport media and from mpox virus genomic DNA spiked into pooled mpox virus-negative remnant universal transport media of lesion specimens submitted for routine clinical testing in the NewYork-Presbyterian Hospital clinical laboratory system. Accuracy testing demonstrated excellent assay agreement between expected and observed results and comparable diagnostic performance to three different reference tests. Analytical sensitivity with 95% detection probability was 126 copies/mL, and analytical specificity, clinical sensitivity, and clinical specificity were 100%. In summary, the RealStar Zoonotic Orthopoxvirus assay provides a sensitive and reliable method for routine diagnosis of mpox infections. (J Mol Diagn 2023, 25: 740-747; https://doi.org/10.1016/j.jmoldx.2023.06.010)

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 and PKD2 (PKD1/2), has unexplained phenotypic variability likely affected by environmental and other genetic factors. Approximately 10% of individuals with ADPKD phenotype have no causal mutation detected, possibly due to unrecognized risk variants of PKD1/2. This study was designed to identify risk variants of PKD genes through population genetic analyses. We used Wright's F-statistics (Fst) to evaluate common single nucleotide variants (SNVs) potentially favored by positive natural selection in PKD1 from 1000 Genomes Project (1KG) and genotyped 388 subjects from the Rogosin Institute ADPKD Data Repository. The variants with >90th percentile Fst scores underwent further investigation by in silico analysis and molecular genetics analyses. We identified a deep intronic SNV, rs3874648G> A, located in a conserved binding site of the splicing regulator Tra2-β in PKD1 intron 30. Reverse-transcription PCR (RT-PCR) of peripheral blood leukocytes (PBL) from an ADPKD patient homozygous for rs3874648-A identified an atypical PKD1 splice form. Functional analyses demonstrated that rs3874648-A allele increased Tra2-β binding affinity and activated a cryptic acceptor splice-site, causing a frameshift that introduced a premature stop codon in mRNA, thereby decreasing PKD1 full-length transcript level. PKD1 transcript levels were lower in PBL from rs3874648-G/A carriers than in rs3874648-G/G homozygotes in a small cohort of normal individuals and patients with PKD2 inactivating mutations. Our findings indicate that rs3874648G > A is a PKD1 expression modifier attenuating PKD1 expression through Tra2-β, while the derived G allele advantageously maintains PKD1 expression and is predominant in all subpopulations.

We evaluated the performance of SARS-CoV-2 TaqMan real-time reverse-transcription PCR (RT-qPCR) assays (ThermoFisher) for detecting 2 nonsynonymous spike protein mutations, E484K and N501Y. Assay accuracy was evaluated by whole genome sequencing (WGS). Residual nasopharyngeal SARS-CoV-2 positive samples (N = 510) from a diverse patient population in New York City submitted for routine SARS-CoV-2 testing during January-April 2020 were used. We detected 91 (18%) N501Y and 101 (20%) E484K variants. Four samples (0.8%) were positive for both variants. The assay had nearly perfect concordance with WGS in the validation subset, detecting B.1.1.7 and B.1.526 variants among others. Sensitivity and specificity ranged from 0.95 to 1.00. Positive and negative predictive values were 0.98-1.00. TaqMan genotyping successfully predicted the presence of B.1.1.7, but had significantly lower sensitivity, 62% (95% CI, 0.53, 0.71), for predicting B.1.526 sub-lineages lacking E484K. This approach is rapid and accurate for detecting SARS-CoV-2 variants and can be rapidly implemented in routine clinical setting.

This study develops, validates, and deploys deep learning for automated total kidney volume (TKV) measurement (a marker of disease severity) on T2-weighted MRI studies of autosomal dominant polycystic kidney disease (ADPKD). The model was based on the U-Net architecture with an EfficientNet encoder, developed using 213 abdominal MRI studies in 129 patients with ADPKD. Patients were randomly divided into 70% training, 15% validation, and 15% test sets for model development. Model performance was assessed using Dice similarity coefficient (DSC) and Bland-Altman analysis. External validation in 20 patients from outside institutions demonstrated a DSC of 0.98 (IQR, 0.97-0.99) and a Bland-Altman difference of 2.6% (95% CI: 1.0%, 4.1%). Prospective validation in 53 patients demonstrated a DSC of 0.97 (IQR, 0.94-0.98) and a Bland-Altman difference of 3.6% (95% CI: 2.0%, 5.2%). Last, the efficiency of model-assisted annotation was evaluated on the first 50% of prospective cases (n = 28), with a 51% mean reduction in contouring time (P < .001), from 1724 seconds (95% CI: 1373, 2075) to 723 seconds (95% CI: 555, 892). In conclusion, our deployed artificial intelligence pipeline accurately performs automated segmentation for TKV estimation of polycystic kidneys and reduces expert contouring time. Keywords: Convolutional Neural Network (CNN), Segmentation, Kidney ClinicalTrials.gov identification no.: NCT00792155 Supplemental material is available for this article. © RSNA, 2022.

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.

The incidence of adenovirus viremia and the role of screening in preventing adenovirus disease in adult transplant recipients are not well defined. Between January 2017 and May 2020, 262 allogeneic transplants were performed using in vivo T-cell depletion. Adenovirus viremia was found in 59 patients for a cumulative incidence of 10% by one hundred days and 23% (95% CI 20-26%) by one year. There was a higher incidence of viremia associated with cord blood transplant (p = .04). No other patient, donor or transplant characteristics were identified that predicted for viremia. In 47 patients (80%), viremia remained well below 200,000 copies/mL and resolved. Twelve patients developed high level viremia. Treatment with antivirals and in some cases adoptive cell therapy, was often ineffective and only two survived. Low lymphocyte count at initial detection of adenovirus viremia was the best predictor of uncontrolled disease.

Significance Statement Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 ( PKD1/2 ) in renal tubular epithelium. PKD1/2 somatic mutations were previously implicated in cyst formation, but studies of this second-hit model in ADPKD had significant technical limitations. Comprehensive analysis of renal cyst epithelium by whole-genome sequencing identified pathogenic inactivating somatic mutations of PKD1/2 in all 24 patients and in 93% of their 90 cysts. Short variant mutations occurred in 77% of cysts, and another 18% acquired chromosomal loss of heterozygosity encompassing PKD1/2, frequently at chromosomal fragile sites or in regions comprising chromosome microdeletion diseases/syndromes. These findings support a cellular recessive mechanism for renal cystogenesis in ADPKD caused by inactivating germline and somatic variants of PKD1/2 . Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). Methods To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. Results Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic “second hit” alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2 ; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 17% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another 18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14% of these cysts harbored copy number neutral LOH events, while the other 3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic “second hit” alterations occurred at the same germline mutated PKD1/2 gene. Conclusions These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.