bims-bicyki 2022-07-03 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022‒07‒03
fourteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

Crosstalk between lysine methyltransferase Smyd2 and TGF-β-Smad3 signaling promotes renal fibrosis in autosomal dominant polycystic kidney disease.
Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction.
Prevalence of cardiac valvar abnormalities in children and young people with autosomal dominant polycystic kidney disease.
A Deep Learning Approach for Automated Segmentation of Kidneys and Exophytic Cysts in Individuals with Autosomal Dominant Polycystic Kidney Disease.
PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan.
Structural Biology of Cilia and Intraflagellar Transport.
Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis.
Role of Primary Cilia in Skeletal Disorders.
TRPP2 ion channels: The roles in various subcellular locations.
Expression of active B-Raf proto-oncogene in kidney collecting ducts induces cyst formation in normal mice and accelerates cyst growth in mice with polycystic kidney disease.
Testimonials from PKD patients in the context of COVID-19.
The genetic landscape of cardiovascular left-right patterning defects.
Inhibition of U-II/UT signaling ameliorates cystitis-associated bladder hyperactivity by targeting the RhoA/Rho-kinase pathway.
Longitudinal nitric oxide levels and infections by ultrastructure and genotype in primary ciliary dyskinesia.

Am J Physiol Renal Physiol. 2022 Jun 27.

Crosstalk between lysine methyltransferase Smyd2 and TGF-β-Smad3 signaling promotes renal fibrosis in autosomal dominant polycystic kidney disease.

Linda Xiaoyan Li, Ewud Agborbesong, Lu Zhang, Xiaoqin Zhang, Julie Xia Zhou, Xiaogang Li.

  Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder, which is caused by mutations of PKD1 or PKD2 gene and is characterized by renal fluid-filled cyst formation and interstitial fibrosis. PKD1 gene mutation results in the upregulation of SET and MYND domain-containing lysine methyltransferase 2 (SMYD2) in Pkd1 mutant mouse and ADPKD patient kidneys. However, the role and mechanism of Smyd2 in the regulation of renal fibrosis in ADPKD remains elusive. In this study, we show that: 1) the expression of Smyd2 can be regulated by TGF-β-Smad3 in normal rat kidney 49F (NRK-49F) cells and mouse fibroblast NIH3T3 cells; 2) knockdown of Smyd2 and inhibition of Smyd2 with its specific inhibitor, AZ505, decreases TGF-β-induced expression of α-smooth muscle actin (α-SMA), fibronectin, collagens 1 and 3 and plasminogen activator inhibitor-1( PAI1) in NRK-49F cells; 3) Smyd2 regulates the transcription of fibrotic marker genes through binding on the promoters of those genes or through methylating histone H3 to indirectly regulate the expression of those genes; and 4) knockout and inhibition of Smyd2 significantly decreases renal fibrosis in Pkd1 knockout mice, supporting that targeting Smyd2 can not only delay cyst growth but also attenuate renal fibrosis in ADPKD. This study identifies a crosstalk between TGF-β signaling and Smyd2 in the regulation of fibrotic gene transcription and the activation of fibroblasts in cystic kidneys, suggesting that targeting Smyd2 with AZ505 is a potential therapeutic strategy for ADPKD treatment.

Keywords:  ADPKD; Smyd2; renal fibrosis

DOI:  https://doi.org/10.1152/ajprenal.00452.2021
Clin Kidney J. 2022 Jul;15(7): 1275-1283

Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction.

Baris Afsar, Rengin Elsurer Afsar, Atalay Demiray, Sevval Altay, Hakan Korkmaz, Abdulmecit Yildiz, Adrian Covic, Alberto Ortiz, Mehmet Kanbay.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease. Recent evidence suggests that the pathogenesis of ADPKD is a complex web of abnormal cellular processes including altered cell signaling, disordered cell metabolism, impaired autophagy, increased apoptosis, mitochondrial dysfunction and chronic inflammation. Sodium-glucose cotransporter (SGLT) inhibitors (SGLTi) reduce body weight, blood pressure and blood glucose levels, have kidney and cardiovascular protective activity, and have been reported to decrease inflammation, increase autophagy and improve mitochondrial dysfunction. We now review results from preclinical studies on SGLTi for ADPKD identified through a systematic search of the MEDLINE, Cochrane Library, Embase and PubMed databases. Potential underlying mechanisms for the conflicting results reported as well as implications for clinical translation are discussed, as ADPKD patients were excluded from clinical trials exploring kidney protection by SGLT2 inhibitors (SGLT2i). However, they were not excluded from cardiovascular safety trials or trials for cardiovascular conditions. A post-hoc analysis of the kidney function trajectories and safety of SGLT2i in ADPKD patients enrolled in such trials may provide additional information. In conclusion, SGLT2i are cardio- and nephroprotective in diverse clinical situations. Currently, it is unclear whether ADPKD patients may benefit from SGLT2i in terms of kidney function preservation, and their safety in this population remains unexplored. We propose a roadmap to address this unmet clinical need.

Keywords:  SGLT inhibitors; apoptosis; autophagy; canagliflozin; dapagliflozin; polycystic kidney disease

DOI:  https://doi.org/10.1093/ckj/sfac029
Pediatr Nephrol. 2022 Jun 28.

Prevalence of cardiac valvar abnormalities in children and young people with autosomal dominant polycystic kidney disease.

Alexandra Savis, John M Simpson, Saleha Kabir, Kelly Peacock, Hayley Beardsley, Manish D Sinha.

  BACKGROUND: Valvar abnormalities in children and adults with autosomal dominant polycystic kidney disease (ADPKD) have previously been reported as a frequent occurrence. Mitral valve prolapse (MVP), in particular, has been reported in almost one-third of adult patients and nearly 12% of children with ADPKD. Our objective in this study was to establish the prevalence of valvar abnormalities in a large, contemporary series of children and young people (CYP) with ADPKD.METHODS: A retrospective, single centre, cross-sectional analysis of the echocardiograms performed on all consecutive children seen in a dedicated paediatric ADPKD clinic. Full anatomical and functional echocardiograms were performed and analysed for valvar abnormalities.
RESULTS: The echocardiograms of 102 CYP with ADPKD (range 0.25-18 years, mean age 10.3 years, SD ± 5.3 years) were analysed. One (0.98%), 3-year-old boy, had MVP. There was no associated mitral regurgitation. Evaluating variations in normal valvar anatomy, 9 (8.8%) patients, aged 7.1 to 18 years, had minor bowing ± visual elongation of either the anterior or posterior leaflet of the mitral valve, none of which fell within the criteria of true MVP. Three (1.9%) patients, 2 boys and 1 girl aged between 7 and 14 years, had trivial or mild aortic regurgitation. No patients had echocardiographic evidence of tricuspid valve prolapse (TVP).
CONCLUSION: In this contemporary cohort of CYP with ADPKD, the incidence of MVP and other valvar lesions is significantly lower than previously reported. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords:  Autosomal dominant kidney disease; Cardiovascular disease; Mitral regurgitation; Mitral valve prolapse; Valvar regurgitation

DOI:  https://doi.org/10.1007/s00467-022-05500-w
J Am Soc Nephrol. 2022 Jun 29. pii: ASN.2021111400. [Epub ahead of print]

A Deep Learning Approach for Automated Segmentation of Kidneys and Exophytic Cysts in Individuals with Autosomal Dominant Polycystic Kidney Disease.

Youngwoo Kim, Cheng Tao, Hyungchan Kim, Geum-Yoon Oh, Jeongbeom Ko, Kyongtae T Bae.

  BACKGROUND: Total kidney volume (TKV) is an important imaging biomarker in autosomal dominant polycystic kidney disease (ADPKD). Manual computation of TKV, particularly with the exclusion of exophytic cysts, is laborious and time consuming.METHODS: We developed a fully automated segmentation method for TKV using a deep learning network to selectively segment kidney regions while excluding exophytic cysts. We used abdominal T2 -weighted magnetic resonance images from 210 individuals with ADPKD who were divided into two groups: one group of 157 to train the network and a second group of 53 to test it. With a 3D U-Net architecture using dataset fingerprints, the network was trained by K-fold cross-validation, in that 80% of 157 cases were for training and the remaining 20% were for validation. We used Dice similarity coefficient, intraclass correlation coefficient, and Bland-Altman analysis to assess the performance of the automated segmentation method compared with the manual method.
RESULTS: The automated and manual reference methods exhibited excellent geometric concordance (Dice similarity coefficient: mean±SD, 0.962±0.018) on the test datasets, with kidney volumes ranging from 178.9 to 2776.0 ml (mean±SD, 1058.5±706.8 ml) and exophytic cysts ranging from 113.4 to 2497.6 ml (mean±SD, 549.0±559.1 ml). The intraclass correlation coefficient was 0.9994 (95% confidence interval, 0.9991 to 0.9996; P<0.001) with a minimum bias of -2.424 ml (95% limits of agreement, -49.80 to 44.95).
CONCLUSIONS: We developed a fully automated segmentation method to measure TKV that excludes exophytic cysts and has an accuracy similar to that of a human expert. This technique may be useful in clinical studies that require automated computation of TKV to evaluate progression of ADPKD and response to treatment.

Keywords:  ADPKD; chronic kidney disease; chronic kidney failure; cystic kidney; deep learning; exophytic cyst; image segmentation; kidney volume; risk factors

DOI:  https://doi.org/10.1681/ASN.2021111400
NPJ Genom Med. 2022 Jul 01. 7(1): 40

PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan.

Taiwan PKD Consortium

Autosomal Dominant polycystic kidney disease (ADPKD) is the most common inherited adult kidney disease. Although ADPKD is primarily caused by PKD1 and PKD2, the identification of several novel causative genes in recent years has revealed more complex genetic heterogeneity than previously thought. To study the disease-causing mutations of ADPKD, a total of 920 families were collected and their diagnoses were established via clinical and image studies by Taiwan PKD Consortium investigators. Amplicon-based library preparation with next-generation sequencing, variant calling, and bioinformatic analysis was used to identify disease-causing mutations in the cohort. Microsatellite analysis along with genotyping and haplotype analysis was performed in the PKD2 p.Arg803* family members. The age of mutation was calculated to estimate the time at which the mutation occurred or the founder arrived in Taiwan. Disease-causing mutations were identified in 634 families (68.9%) by detection of 364 PKD1, 239 PKD2, 18 PKHD1, 7 GANAB, and 6 ALG8 pathogenic variants. 162 families (17.6%) had likely causative but non-diagnostic variants of unknown significance (VUS). A single PKD2 p.Arg803* mutation was found in 17.8% (164/920) of the cohort in Taiwan. Microsatellite and array analysis showed that 80% of the PKD2 p.Arg803* families shared the same haplotype in a 250 kb region, indicating those families may originate from a common ancestor 300 years ago. Our findings provide a mutation landscape as well as evidence that a founder effect exists and has contributed to a major percentage of the ADPKD population in Taiwan.

DOI: https://doi.org/10.1038/s41525-022-00309-w
Annu Rev Cell Dev Biol. 2022 Jun 29.

Structural Biology of Cilia and Intraflagellar Transport.

Nikolai Klena, Gaia Pigino.

Cilia are ubiquitous microtubule-based eukaryotic organelles that project from the cell to generate motility or function in cellular signaling. Motile cilia or flagella contain axonemal dynein motors and other complexes to achieve beating. Primary cilia are immotile and act as signaling hubs, with receptors shuttling between the cytoplasm and ciliary compartment. In both cilia types, an intraflagellar transport (IFT) system powered by unique kinesin and dynein motors functions to deliver the molecules required to build cilia and maintain their functions. Cryo-electron tomography has helped to reveal the organization of protein complex arrangement along the axoneme and the structure of anterograde IFT trains as well as the structure of primary cilia. Only recently, single-particle analysis (SPA) cryo-electron microscopy has provided molecular details of the protein organization of ciliary components, helping us to understand how they bind to microtubule doublets and how mechanical force propagated by dynein conformational changes is converted into ciliary beating. Here we highlight recent structural advances that are leading to greater knowledge of ciliary function. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-cellbio-120219-034238
Front Endocrinol (Lausanne). 2022 ;13 886534

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis.

Lei Wei, Jianjian Shi.

  Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

Keywords:  ROCK; ROCK isoform-selective; beige adipogenesis; energy expenditure; obesity

DOI:  https://doi.org/10.3389/fendo.2022.886534
Stem Cells Int. 2022 ;2022 6063423

Role of Primary Cilia in Skeletal Disorders.

Xinhua Li, Song Guo, Yang Su, Jiawei Lu, Donghua Hang, Shao Cao, Qiang Fu, Ziqing Li.

Primary cilia are highly conserved microtubule-based organelles that project from the cell surface into the extracellular environment and play important roles in mechanosensation, mechanotransduction, polarity maintenance, and cell behaviors during organ development and pathological changes. Intraflagellar transport (IFT) proteins are essential for cilium formation and function. The skeletal system consists of bones and connective tissue, including cartilage, tendons, and ligaments, providing support, stability, and movement to the body. Great progress has been achieved in primary cilia and skeletal disorders in recent decades. Increasing evidence suggests that cells with cilium defects in the skeletal system can cause numerous human diseases. Moreover, specific deletion of ciliary proteins in skeletal tissues with different Cre mice resulted in diverse malformations, suggesting that primary cilia are involved in the development of skeletal diseases. In addition, the intact of primary cilium is essential to osteogenic/chondrogenic induction of mesenchymal stem cells, regarded as a promising target for clinical intervention for skeletal disorders. In this review, we summarized the role of primary cilia and ciliary proteins in the pathogenesis of skeletal diseases, including osteoporosis, bone/cartilage tumor, osteoarthritis, intervertebral disc degeneration, spine scoliosis, and other cilium-related skeletal diseases, and highlighted their promising treatment methods, including using mesenchymal stem cells. Our review tries to present evidence for primary cilium as a promising target for clinical intervention for skeletal diseases.

DOI: https://doi.org/10.1155/2022/6063423
Biochimie. 2022 Jun 24. pii: S0300-9084(22)00172-9. [Epub ahead of print]

TRPP2 ion channels: The roles in various subcellular locations.

Peng-Fei Tian, Meng-Meng Sun, Xian-Yu Hu, Juan Du, Wei He.

  TRPP2 (PC2, PKD2 or Polycytin-2), encoded by PKD2 gene, belongs to the nonselective cation channel TRP family. Recently, the three-dimensional structure of TRPP2 was constructed. TRPP2 mainly functions in three subcellular compartments: endoplasmic reticulum, plasma membrane and primary cilia. TRPP2 can act as a calcium-activated intracellular calcium release channel on the endoplasmic reticulum. TRPP2 also interacts with other Ca2+ release channels to regulate calcium release, like IP3R and RyR2. TRPP2 acts as an ion channel regulated by epidermal growth factor through activation of downstream factors in the plasma membrane. TRPP2 binding to TRPC1 in the plasma membrane or endoplasmic reticulum is associated with mechanosensitivity. In cilium, TRPP2 was found to combine with PKD1 and TRPV4 to form a complex related to mechanosensitivity. Because TRPP2 is involved in regulating intracellular ion concentration, TRPP2 mutations often lead to autosomal dominant polycystic kidney disease, which may also be associated with cardiovascular disease. In this paper, we review the molecular structure of TRPP2, the subcellular localization of TRPP2, the related functions and mechanisms of TRPP2 at different sites, and the diseases related to TRPP2.

Keywords:  ADPKD; Ca(2+) ion channel; TRP channel; TRPP2

DOI:  https://doi.org/10.1016/j.biochi.2022.06.010
Kidney Int. 2022 Jun 24. pii: S0085-2538(22)00466-5. [Epub ahead of print]

Expression of active B-Raf proto-oncogene in kidney collecting ducts induces cyst formation in normal mice and accelerates cyst growth in mice with polycystic kidney disease.

Stephen C Parnell, Archana Raman, Yan Zhang, Emily A Daniel, Yuqiao Dai, Aditi Khanna, Gail A Reif, Jay L Vivian, Timothy A Fields, Darren P Wallace.

  Polycystic kidney disease (PKD) is characterized by the formation and progressive enlargement of fluid-filled cysts due to abnormal cell proliferation. Cyclic AMP agonists, including arginine vasopressin, stimulate ERK-dependent proliferation of cystic cells, but not normal kidney cells. Previously, B-Raf proto-oncogene (BRAF), a MAPK kinase kinase that activates MEK-ERK signaling, was shown to be a central intermediate in the cAMP mitogenic response. However, the role of BRAF on cyst formation and enlargement in vivo had not been demonstrated. To determine if active BRAF induces kidney cyst formation, we generated transgenic mice that conditionally express BRAFV600E, a common activating mutation, and bred them with Pkhd1-Cre mice to express active BRAF in the collecting ducts, a predominant site for cyst formation. Collecting duct expression of BRAFV600E (BRafCD) caused kidney cyst formation as early as three weeks of age. There were increased levels of phosphorylated ERK (p-ERK) and proliferating cell nuclear antigen, a marker for cell proliferation. BRafCD mice developed extensive kidney fibrosis and elevated blood urea nitrogen, indicating a decline in kidney function, by ten weeks of age. BRAFV600E transgenic mice were also bred to Pkd1RC/RC and pcy/pcy mice, well-characterized slowly progressive PKD models. Collecting duct expression of active BRAF markedly increased kidney weight/ body weight, cyst number and size, and total cystic area. There were increased p-ERK levels and proliferating cells, immune cell infiltration, interstitial fibrosis, and a decline in kidney function in both these models. Thus, our findings demonstrate that active BRAF is sufficient to induce kidney cyst formation in normal mice and accelerate cystic disease in PKD mice.

Keywords:  ADPKD; ERK; MAPK; cell proliferation; mitogen activated protein kinase; polycystic kidney disease

DOI:  https://doi.org/10.1016/j.kint.2022.05.028
Ethics Med Public Health. 2022 Oct;24 100787

Testimonials from PKD patients in the context of COVID-19.

Association Polykystose France



Keywords:  COVID-19; Kidney; Liver; Polycystic kidney disease; Transplant

DOI:  https://doi.org/10.1016/j.jemep.2022.100787
Curr Opin Genet Dev. 2022 Jun 28. pii: S0959-437X(22)00046-6. [Epub ahead of print]75 101937

The genetic landscape of cardiovascular left-right patterning defects.

John R Wells, Maria B Padua, Stephanie M Ware.

  Heterotaxy is a disorder with complex congenital heart defects and diverse left-right (LR) patterning defects in other organ systems. Despite evidence suggesting a strong genetic component in heterotaxy, the majority of molecular causes remain unknown. Established genes often involve a ciliated, embryonic structure known as the left-right organizer (LRO). Herein, we focus on genetic discoveries in heterotaxy in the past two years. These include complex genetic architecture, novel mechanisms regulating cilia formation, and evidence for conservation of LR patterning between distant species. We feature new insights regarding established LR signaling pathways, bring attention to heterotaxy candidate genes in novel pathways, and provide an extensive overview of genes previously associated with laterality phenotypes in humans.

Keywords:  cilia; congenital heart defect; heterotaxy; laterality; mitochondria

DOI:  https://doi.org/10.1016/j.gde.2022.101937
Kaohsiung J Med Sci. 2022 Jun 29.

Inhibition of U-II/UT signaling ameliorates cystitis-associated bladder hyperactivity by targeting the RhoA/Rho-kinase pathway.

Qian Liu, Qu-Dong Lu, Bi-Shao Sun, Jiang Zhao, Fan He, Jing-Zhen Zhu.

  Urotensin II (U-II) and its receptor (UT) are involved in the pathogenesis of various diseases; however, their association with the development of cystitis has not been elucidated. The present study was designed to investigate the functional role of U-II/UT signaling in cyclophosphamide (CYP)-induced cystitis. A total of 60 female rats were randomly divided into the control and CYP-treated groups. Intraperitoneal injection of CYP successfully induced cystitis in rats of the CYP-treated group. The protein and mRNA expression levels of U-II and UT were significantly enhanced in rat bladder tissues of the CYP-treated group. Furthermore, the results of the immunofluorescence staining analysis demonstrated that CYP treatment apparently increased the expression levels of UT in the urothelium layer, detrusor smooth muscle, and bladder interstitial Cajal-like cells. The selective antagonist of UT, SB657510 (10 μm), significantly suppressed the CYP-induced increase in the spontaneous contractions of muscle strips and ameliorated the bladder hyperactivity of CYP-treated rats. Moreover, CYP treatment significantly increased the protein expression levels of Ras homolog family member (Rho) A and Rho-associated protein kinase 2 in rat bladder tissues. Following pretreatment with the Rho-kinase inhibitor Y-27632 (10 μm), the inhibitory effects of SB657510 (10 μm) on the spontaneous contractions of muscle strips were eliminated. In conclusion, the results of the present study suggested that activation of U-II/UT signaling promoted the development of cystitis-associated-bladder hyperactivity by targeting the RhoA/Rho-kinase pathway, indicating that the U-II/UT signaling could serve as a novel target for the treatment of interstitial cystitis/bladder pain syndrome.

Keywords:  RhoA/Rho-kinase pathway; UT; bladder hyperactivity; cystitis; urotensin II

DOI:  https://doi.org/10.1002/kjm2.12569
Chest. 2022 Jun 28. pii: S0012-3692(22)01189-8. [Epub ahead of print]

Longitudinal nitric oxide levels and infections by ultrastructure and genotype in primary ciliary dyskinesia.

Massimo Pifferi, Attilio L Boner, Serena Gracci, Rossella Fonnesu, Debora Maj, Gabriele Donzelli, Angela Michelucci, Angela Cangiotti, Veronica Bertini, Angelo Valetto, Maria Adelaide Caligo, Mario Miccoli, Diego Peroni, Andrew Bush.

  BACKGROUND: We hypothesized that differences in nasal and fractional exhaled nitric oxide (nNO and FeNO respectively) relate to prognosis in primary ciliary dyskinesia (PCD).RESEARCH QUESTION: What is the relationship between baseline values and longitudinal evolution of nNO and FeNO and ultrastructure, genotype and respiratory infections in PCD?
STUDY DESIGN AND METHODS: Prospective, longitudinal, single-center study in adults and children evaluated biannually for up to 10 years. We compared cross-sectional and longitudinal values of nNO and FeNO in ultrastructural (IDA/MTD) and genetic (CCDC39/CCDC40) groups, known to have worse pulmonary function with patients within the ultrastructural and genetic groups with a better prognosis. Linear mixed effects models were used to evaluate longitudinal associations.
MEASUREMENTS AND MAIN RESULTS: 141 PCD patients had 1014 visits. At enrollment, in children there were no differences in nNO or FeNO between the IDA/MTD and the other ultrastructural groups. In adults nNO (p=0.038) and FeNO (p=0.032) were significantly lower in IDA/MTD than in all other combined ultrastructural groups. FeNO values were significantly lower in CCDC39/CCDC40 than DNAH5 and DNAH11 combined genotypes (p=0.033), and all other genotypes (p=0.032). IDA/MTD had a significant decline in nNO with age (p<0.01) compared with other ultrastructural groups who had stable levels. CCDC39/CCDC40 had the steepest decline in nNO over time (p<0.01) compared with all other genotypes. A higher nNO was associated with lower likelihood of any positive bacterial isolate from the lower respiratory tract (p=0.008). Changes in FeNO over time did not differ between structural groups or genotypes.
INTERPRETATION: Lower nNO in PCD patients with genetic and ultrastructural changes associated with greater lung function decline may be related to worse prognosis, but whether a low nNO is causal needs further study. If lower nNO directly results in a poorer prognosis, strategies augmenting upper airway NO production may be worth evaluating.

Keywords:  ciliary ultrastructure; genotype; lower airway nitric oxide; nasal nitric oxide; primary ciliary dyskinesia; pseudomonas aeruginosa; respiratory infections

DOI:  https://doi.org/10.1016/j.chest.2022.06.019