Codesigned online cognitive bias modification of interpretations for anxiety and depression in children: study protocol of a randomised controlled trial.

INTRODUCTION: Previous research has shown that cognitive bias modification of interpretations (CBM-I) may be a promising intervention for anxiety in youth; however, results are mixed. Given the high comorbidity between anxiety and depression in youth, it is surprising that no child studies have targeted biases associated with both. This study aims to evaluate the effectiveness and acceptability of an online CBM-I intervention (Mindmaster) for children with symptom scores of anxiety or depression above a borderline or clinical threshold. The intervention has been codesigned with children, parents and mental health professionals to promote user engagement. METHODS AND ANALYSIS: The study is a randomised controlled trial, with two parallel arms. Participants are 143 children aged 8-10 years with scores of anxiety and/or depressive symptoms above a borderline or clinical threshold. They will be allocated to either the intervention group or the waitlist control group. The intervention consists of 2 weeks of online CBM-I training, with four sessions (10-15 min) per week. Outcome assessments will be conducted at baseline, 4 weeks after baseline (post-training/post-waitlist) and 8 weeks after baseline (follow-up) for the intervention group only. The primary outcome is interpretation bias. Secondary outcomes are anxiety and depressive symptoms and life interference. Analyses will be conducted within an intention-to-treat framework using mixed models for repeated measures. ETHICS AND DISSEMINATION: The study was approved by the University of New South Wales Human Research Ethics Committee (HC220758). Findings will be reported to (1) participating families; (2) presented at scientific conferences and (3) disseminated to peer-review publications. Data will be available from the corresponding author on request. TRIAL REGISTRATION NUMBER: ACTRN12622001493730.

Collapsing glomerulopathy is likely a major contributing factor for worse allograft survival in patients receiving kidney transplants from black donors.

Although a few registry-based studies have shown associations between receiving kidney allografts from Black donors and shorter allograft survival, detailed, large, single-center studies accounting for common confounding factors are lacking. Furthermore, pathologic alterations underlying this potential disparity have not been systematically studied. We performed a retrospective clinical-pathological study of kidney transplant recipients who received kidney allografts from either Black (n = 407) or White (n = 1,494) donors at Columbia University Irving Medical Center from 2005 to 2018, with median follow-up of 4.5 years post-transplantation. Black donor race was independently associated with allograft failure (adjusted HR = 1.34, p = 0.02) and recipients of kidney allografts from Black donors had a higher incidence of collapsing glomerulopathy [7.4% vs. 1.9%, OR = 4.17, p < 0.001]. When causes of allograft failure were examined, only allograft failure following development of collapsing glomerulopathy was more frequent in recipients of allografts from Black donors [15% vs. 5%, OR = 3.16, p = 0.004]. Notably, when patients who developed collapsing glomerulopathy were excluded from analysis, receiving kidney allografts from Black donors was not independently associated with allograft failure (adjusted HR = 1.24, p = 0.10). These findings revealed that, compared with recipients of kidney allografts from White donors, recipients of kidneys from Black donors have modestly shorter allograft survival and a higher probability of developing collapsing glomerulopathy, which negatively impacts allograft outcome. Identification of collapsing glomerulopathy risk factors may help decrease this complication and improve allograft survival, which optimally may reduce racial disparities post-transplantation.

Cognitive bias modification of interpretations for anxiety and depression in children and adolescents: A meta-analysis.

Background: Evidence suggests that cognitive bias modification of interpretations (CBM-I) is effective in modifying interpretation biases and has a small effect on reducing anxiety in children and adolescents. However, most evidence to date is based on studies which report anxiety or general distress using ad-hoc Likert-type or Visual Analogue Scales, which are useful but do not reliably index symptoms of clinical importance. This meta-analysis aimed to establish the effects of CBM-I for children and adolescents on both anxiety and depression using psychometrically validated symptom measures, as well as state negative affect and negative and positive interpretation bias. Methods: We identified studies through a systematic search. To be eligible for inclusion, studies needed to target interpretation biases, not combine CBM-I with another intervention, randomly allocate participants to CBM-I or a control condition, assess a mental health outcome (i.e., anxiety or depression symptoms using validated measures or state measures of negative affect) and/or interpretation bias and have a mean age less than 18 years. Results: We identified 36 studies for inclusion in the meta-analysis. CBM-I had a small and non-significant unadjusted effect on anxiety symptoms (g = 0.16), no effect on depression symptoms (g = -0.03), and small and non-significant unadjusted effects on state negative affect both at post-training (g = 0.16) and following a stressor task (g = 0.23). In line with previous findings, CBM-I had moderate to large unadjusted effects on negative and positive interpretations (g = 0.78 and g = 0.52). No significant moderators were identified. Conclusions: CBM-I is effective at modifying interpretation bias, however there were no effects on mental health outcomes. The substantial variability across studies and paucity of studies using validated symptom measures highlight the need to establish randomized controlled trial protocols that evaluate CBM-I in clinical youth samples to determine its future as a clinical intervention.

A Rare Case of Varicella-Zoster Virus Encephalitis Presenting With Lost Ability to Play the Piano in an Immunocompetent Pediatric Patient.

Varicella-zoster virus (VZV) is a member of the alpha-herpesvirus family, which can occasionally cause severe neurological complications such as encephalitis. In this case report, we discuss a rare finding of VZV encephalitis in which an immunocompetent pediatric patient, vaccinated against varicella, presented with altered mental status and no vesicular rash. A 15-year-old male presented to the Emergency Department with progressively worsening altered mental status over the past three days. The patient's mother stated that he was exhibiting frequent memory lapses as well as the sudden loss of the ability to play the piano. After admission to the pediatric general floor, lumbar puncture was performed and cerebrospinal fluid analysis returned positive for VZV, confirmed by polymerase chain reaction. The patient was then started on intravenous (IV) acyclovir at a dose of 650 mg every 8 hours to treat VZV-induced encephalitis. While the patient continued to have intermittent episodes of confusion and headaches, his overall condition improved, and by day 4, he was able to resume playing the piano and ukulele. The patient was discharged on day 8 with no home medications, and a follow-up with this primary care physician was scheduled. This patient is one of only four recorded cases of VZV encephalitis in immunocompetent children. It is extremely rare to encounter pediatric patients with this diagnosis and, as such, can elude physicians when developing differential diagnoses. If VZV is suspected, a lumbar puncture should be performed promptly, and, if confirmed, IV acyclovir should be started. Furthermore, this case highlights the need for future research with regard to VZV and potential predisposing factors in immunocompetent patients.

Polycystic kidneys: interaction of notch and renin.

Polycystic kidney disease (PKD) is a developmental disorder, which either manifests in early childhood or later in life, depending on the genetic mutation one harbors. The mechanisms of cyst initiation are not well understood. Increasing literature is now suggesting that Notch signaling may play a critical role in PKD. Activation of Notch signaling is important during nephrogenesis and slows down after development. Deletion of various Notch molecules in the cap mesenchyme leads to formation of cysts and early death in mice. A new study by Belyea et al. has now found that cells of renin lineage may link Notch expression and cystic kidney disease. Here, we use our understanding of Notch signaling and PKD to speculate about the significance of these interactions.

Estimated Prevalence of Depressive Disorders in Children From 2004 to 2019: A Systematic Review and Meta-Analysis.

Importance: Depression during childhood (ie, age <13 years) poses a major health burden. Recent changes in environmental and lifestyle factors may increase children's risk of mental health problems. This has been reported for anxiety disorders, but it is unclear whether this occurs for depressive disorders. Objective: To provide prevalence estimates for the depressive disorders (ie, major depressive disorder [MDD], dysthymia, disruptive mood dysregulation disorder [DMDD], and overall) in children, and whether they have changed over time. Data Sources: The MEDLINE, PsycINFO, Embase, Scopus, and Web of Science databases were searched using terms related to depressive disorders, children, and prevalence. This was supplemented by a systematic gray literature search. Study Selection: Studies were required to provide population prevalence estimates of depressive disorder diagnoses (according to an established taxonomy and standardized interviews) for children younger than 13 years, information about participants' year of birth, and be published in English. Data Extraction and Synthesis: Data extraction was compliant with the Meta-Analysis of Observational Studies in Epidemiology guidelines. A total of 12 985 nonduplicate records were retrieved, and 154 full texts were reviewed. Data were analyzed from 2004 (the upper limit of a previous review) to May 27, 2023. Multiple proportional random-effects meta-analytic and mixed-effects meta-regression models were fit. Main Outcomes and Measures: Pooled prevalence rates of depressive disorders, prevalence rate differences between males vs females and high-income countries (HICs) vs low-and middle-income countries (LMICs), and moderating effects of time or birth cohort. Results: A total of 41 studies were found to meet the inclusion criteria. Pooled prevalence estimates were obtained for 1.07% (95% CI, 0.62%-1.63%) for depressive disorders overall, 0.71% (95% CI, 0.48%-0.99%) for MDD, 0.30% (95% CI, 0.08%-0.62%) for dysthymia, and 1.60% (95% CI, 0.28%-3.90%) for DMDD. The meta-regressions found no significant evidence of an association with birth cohort, and prevalence rates did not differ significantly between males and females or between HICs and LMICs. There was a low risk of bias overall, except for DMDD, which was hindered by a lack of studies. Conclusions and Relevance: In this systematic review and meta-analysis, depression in children was uncommon and did not increase substantially between 2004 and 2019. Future epidemiologic studies using standardized interviews will be necessary to determine whether this trend will continue into and beyond the COVID-19 pandemic.

Quality Improvement Increases Pediatric Community Hospital Smoking Cessation Interventions.

BACKGROUND: Tobacco use commonly starts during adolescence and is the leading cause of preventable disease, disability, and death in the United States. Secondhand smoke (SHS) exposure increases asthma and respiratory infection hospitalizations and contributes to sudden unexpected infant death. Few pediatric hospitalist-led smoking cessation studies are formal quality improvement (QI), with most at academic institutions and studying caregivers. OBJECTIVES: To increase SHS exposure/tobacco use screening, smoking cessation discharge instructions, and Smokers' Helpline referrals for community hospital pediatric patients/caregivers through QI. METHODS: All pediatric, newborn, and NICU admissions were eligible. The baseline period was December 2019 through November 2020 and intervention period December 2020 through June 2021. Interventions included hospitalist education, standardizing documentation, visual reminders, and Helpline wallet cards. The primary measure was monthly percentage of patients screened for SHS exposure/tobacco use. Secondary measures were percentage of patients/caregivers positive for SHS exposure/tobacco use who received (1) discharge instructions or (2) Helpline referral. Length of stay was a balancing measure. Primary and balancing measures were analyzed with statistical process control. Secondary measures were monitored on run charts. RESULTS: Average SHS exposure/tobacco use screening rates increased from 14% to 90%, meeting special cause variation beginning December 2020. Median discharge instructions increased from 0% to 56%. Helpline referrals increased from 0% to 17%. Length of stay remained approximately 2 days. CONCLUSIONS: Pediatrician-led QI can increase SHS exposure/tobacco use screening and interventions in the community hospital setting to encourage smoke exposure reduction and smoking cessation for patients and caregivers.

Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC).

TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50-60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.

Effects of Delayed Graft Function on Transplant Outcomes: A Meta-analysis.

Delayed graft function (DGF) is a frequent complication of kidney transplantation, but its impact on long- and short-term transplant outcomes is unclear. We conducted a systematic literature search for studies published from 2007 to 2020 investigating the association between DGF and posttransplant outcomes. Forest plots stratified between center studies and registry studies were created with pooled odds ratios. Posttransplant outcomes including graft failure, acute rejection, patient mortality, and kidney function were analyzed. Of the 3422 articles reviewed, 38 papers were included in this meta-analysis. In single-center studies, patients who experienced DGF had increased graft failure (odds ratio [OR] 3.38; 95% confidence interval [CI], 1.85-6.17; P < 0.01), acute allograft rejection (OR 1.84; 95% CI, 1.30-2.61; P < 0.01), and mortality (OR 2.32; 95% CI, 1.53-3.50; P < 0.01) at 1-y posttransplant. Registry studies showed increased graft failure (OR 3.66; 95% CI, 3.04-4.40; P < 0.01) and acute rejection (OR 3.24; 95% CI, 1.88-5.59; P < 0.01) but not mortality (OR 2.27; 95% CI, 0.97-5.34; P = 0.06) at 1-y posttransplant. DGF was associated with increased odds of graft failure, acute rejection, and mortality. These results in this meta-analysis could help inform the selection process, treatment, and monitoring of transplanted kidneys at high risk of DGF.

The pathologic spectrum of adenovirus nephritis in the kidney allograft.

Adenovirus nephritis (ADVN) is a rare and understudied complication of kidney transplantation. Unlike BK virus nephropathy (BKVN), our knowledge of clinicopathologic manifestations of ADVN remains rudimentary and essentially limited to case reports. To expand on this, we retrospectively studied 11 kidney transplant recipients with ADVN and compared their allograft biopsies to 33 kidney transplant recipients with BKVN using conventional microscopy and the 770 gene Nanostring Banff Human Organ Transplant Profiling Panel. Patients with ADVN had a median age of 44 years, were predominantly male, and developed ADVN at a median of 31 months post-transplantation. Eight patients presented with fever and ten had hematuria. The most common histologic manifestations included granulomas (82%), tubulocentric inflammation (73%), and tubular degenerative changes consistent with acute tubular necrosis (73%). During a median follow-up of 55 months after biopsy, three patients developed allograft failure from subsequent acute rejection. All seven patients with available follow-up PCR showed resolution of viremia at a median of 30 days after diagnosis. Compared to BKVN, ADVN demonstrated more granulomas and less tubulointerstitial scarring. On follow-up, patients with ADVN had more rapid clearance of viral DNA from plasma. Transcriptomic analyses showed that ADVN had increased expression of several pro-inflammatory transcriptomes, mainly related to innate immunity, was associated with increased expression of transcripts with inhibitory effects on inflammatory response and showed higher enrichment with neutrophils, which can cause aggressive but short-lasting damage. Thus, we demonstrate that, despite its association with aggressive neutrophil-rich inflammation, ADVN does not often lead to allograft failure. Hence, preventing subsequent acute rejection following resolution of ADVN may improve allograft survival.

"I miss seeing the kids!": Australian teachers' changing roles, preferences, and positive and negative experiences of remote teaching during the COVID-19 pandemic.

The COVID-19 pandemic has caused significant upheaval in schools in Australia and internationally. The aim of this study was to map Australian teachers' positive and negative experiences during remote and online learning. Our study took place during the first COVID-19 wave, in the early stages of lockdown. Using an online instrument, we asked 210 primary and secondary teachers about changes in their teaching roles due to COVID-19. Responses were coded for positive and negative themes using inductive thematic analysis. The majority of teachers reported negative themes (88.6%), while half also reported positive themes (44.8%). Participants reported missing their students and struggling with excessive workload demands. They also experienced difficulties tracking student progress and felt worried for student wellbeing. Interestingly, concerns about technology were less common. Indeed, 19.1% enjoyed learning new online skills and integrating IT in new ways. Implications for student-teacher relationships, mental health, and future teaching are discussed.

CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of fluid-filled cysts, causing nephron loss and a decline in renal function. Mammalian target of rapamycin (mTOR) is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement; however, the mechanism for mTOR stimulation remains unclear. We discovered that calcium/calmodulin (CaM) dependent kinase IV (CaMK4), a multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and PKD mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited cell proliferation and in vitro cyst formation of ADPKD cells. Moreover, inhibition of calcium/CaM-dependent protein kinase kinase-ß and CaM, two key upstream regulators of CaMK4, also decreased mTOR signaling. The effects of KN-93 were independent of the liver kinase B1-adenosine monophosphate-activated protein kinase (AMPK) pathway, and the combination of KN-93 and metformin, an AMPK activator, had additive inhibitory effects on mTOR signaling and in vitro cyst growth. Our data suggest that increased CaMK4 expression and activity contribute to mTOR signaling and the proliferation of cystic cells of ADPKD kidneys.

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.

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.

How Individuals With Low Back Pain Conceptualize Their Condition: A Collaborative Modeling Approach.

Low back pain (LBP) is complex. This study aimed to use collaborative modeling to evaluate conceptual models that individuals with LBP have of their condition, and to compare these models with those of researchers/clinicians. Twenty-eight individuals with LBP were facilitated to generate mental models, using "fuzzy cognitive maps," that represented conceptualization of their own LBP and LBP "in general." "Components" (ie, causes, outcomes and treatments) related to pain, disability and quality of life were proposed, along with the weighted "Connections" between Components. Components were classified into thematic categories. Weighting of Connections were summed for each Component to judge relative importance. Individual models were aggregated into a metamodel. When considering their own condition, participants' models included 19(SD = 6) Components and 43(18) Connections with greatest weight on "Biomechanical" components. When considering LBP in general, models changed slightly. Patient models contrasted the more complex models of researchers/clinicians (25(7) Components; 77(42) Connections), with most weight on "Psychological" components. This study provides unique insight into how individuals with LBP consider their condition, which is largely biomedical and narrower than clinician/researcher perspectives. Findings highlight challenges for changing public perception of LBP, and provide a method with potential utility to understand how individuals conceptualize their condition. PERSPECTIVE: Collaborative modeling was used to understand how individuals with low back pain conceptualize their own condition, the condition in general, and compare this with models of expert researchers/clinicians. Data revealed issues in how individuals with back pain conceptualize their condition, and the method's potential utility for clinical evaluation of patients.

Kidney allograft biopsy findings after COVID-19.

COVID-19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID-19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS-CoV-2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID-19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS-CoV-2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS-CoV-2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow-up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID-19, the most common being acute rejection with arteritis.

Quinomycin A reduces cyst progression in polycystic kidney disease.

Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer. Here, we show that Quinomycin A decreased cell proliferation and cyst growth of human ADPKD cyst epithelial cells cultured within a 3D collagen gel. Treatment with Quinomycin A reduced kidney weight to body weight ratio and decreased renal cystic area and fibrosis in Pkd1RC/RC ; Pkd2+/- mice, an orthologous PKD mouse model. This was accompanied by reduced expression of Notch pathway proteins, RBPjk and HeyL and cell proliferation in kidneys of PKD mice. Quinomycin A treatments also normalized cilia length of cyst epithelial cells derived from the collecting ducts. This is the first study to demonstrate that Quinomycin A effectively inhibits PKD progression and suggests that Quinomycin A has potential therapeutic value for PKD patients.

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy.

INTRODUCTION: A large proportion of patients with COVID-19 develop acute kidney injury (AKI). While the most severe of these cases require renal replacement therapy (RRT), little is known about their clinical course. METHODS: We describe the clinical characteristics of COVID-19 patients in the ICU with AKI requiring RRT at an academic medical center in New York City and followed patients for outcomes of death and renal recovery using time-to-event analyses. RESULTS: Our cohort of 115 patients represented 23% of all ICU admissions at our center, with a peak prevalence of 29%. Patients were followed for a median of 29 days (2542 total patient-RRT-days; median 54 days for survivors). Mechanical ventilation and vasopressor use were common (99% and 84%, respectively), and the median Sequential Organ Function Assessment (SOFA) score was 14. By the end of follow-up 51% died, 41% recovered kidney function (84% of survivors), and 8% still needed RRT (survival probability at 60 days: 0.46 [95% CI: 0.36-0.56])). In an adjusted Cox model, coronary artery disease and chronic obstructive pulmonary disease were associated with increased mortality (HRs: 3.99 [95% CI 1.46-10.90] and 3.10 [95% CI 1.25-7.66]) as were angiotensin-converting-enzyme inhibitors (HR 2.33 [95% CI 1.21-4.47]) and a SOFA score >15 (HR 3.46 [95% CI 1.65-7.25). CONCLUSIONS AND RELEVANCE: Our analysis demonstrates the high prevalence of AKI requiring RRT among critically ill patients with COVID-19 and is associated with a high mortality, however, the rate of renal recovery is high among survivors and should inform shared-decision making.

Overexpression of TGF-ß1 induces renal fibrosis and accelerates the decline in kidney function in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of numerous fluid-filled cysts, extensive fibrosis, and the progressive decline in kidney function. Transforming growth factor-ß1 (TGF-ß1), an important mediator for renal fibrosis and chronic kidney disease, is overexpressed by cystic cells compared with normal kidney cells; however, its role in PKD pathogenesis remains undefined. To investigate the effect of TGF-ß1 on cyst growth, fibrosis, and disease progression, we overexpressed active TGF-ß1 specifically in collecting ducts (CDs) of phenotypic normal (Pkd1RC/+) and Pkd1RC/RC mice. In normal mice, CD-specific TGF-ß1 overexpression caused tubule dilations by 5 wk of age that were accompanied by increased levels of phosphorylated SMAD3, α-smooth muscle actin, vimentin, and periostin; however, it did not induce overt cyst formation by 20 wk. In Pkd1RC/RC mice, CD overexpression of TGF-ß1 increased cyst epithelial cell proliferation. However, extensive fibrosis limited cyst enlargement and caused contraction of the kidneys, leading to a loss of renal function and a shortened lifespan of the mice. These data demonstrate that TGF-ß1-induced fibrosis constrains cyst growth and kidney enlargement and accelerates the decline of renal function, supporting the hypothesis that a combined therapy that inhibits renal cyst growth and fibrosis will be required to effectively treat ADPKD.

Dietary phosphate restriction attenuates polycystic kidney disease in mice.

Studies in rodents with reduced nephron mass have suggested a strong positive correlation between dietary phosphate consumption and CKD progression. Prior work by our group demonstrated that dietary phosphate restriction can prevent tubular injury and microcyst formation in rodents with glomerulonephritis. Tubular injury and cystic dilation of tubules are key contributors to kidney function decline in polycystic kidney disease (PKD). Here, we determined whether dietary phosphate restriction slows renal cyst growth and fibrosis in a mouse model of PKD. Pcy/pcy mice received a normal phosphate (0.54%) or a phosphate-restricted (0.02%) diet (n = 10/group) from 7 to 20 wk of age. All of the other major dietary constituents, including protein source and content, were comparable between the two diets. At 20 wk, body weight, kidney weight-to-body weight ratio (KW/BW), cystic area, cyst number, and kidney fibrosis were quantified. Pcy/pcy mice fed a phosphate-restricted diet had lower serum phosphate, fibroblast growth factor 23, and parathyroid hormone levels, along with elevated serum calcium levels and increased kidney Klotho gene expression compared with mice that consumed the control diet. Dietary phosphate restriction resulted in a 25% lower KW/BW ratio and reduced the cyst number, cystic index, and gene expression for the tubular injury markers neutrophil gelatinase-associated lipocalin and interleukin-18. Mice fed the phosphate-restricted diet exhibited lower kidney expression for pathways involved in collagen deposition and myofibroblast activation (collagen type I-α1, phosphorylated SMAD3, and α-smooth muscle actin); however, histological differences in kidney fibrosis were not appreciated. Dietary phosphate restriction slows cystogenesis and inhibits the activation of key pathways in the generation of kidney fibrosis in PKD mice.

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease.

In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells of PKD kidneys. Periostin binds αVß3-integrins and activates integrin-linked kinase (ILK), leading to Akt/mammalian target of rapamycin (mTOR)-mediated proliferation of human PKD cells. By contrast, periostin does not stimulate the proliferation of normal human kidney cells. This difference in the response to periostin is due to elevated expression of αVß3-integrins by cystic cells. To determine whether periostin accelerates cyst growth and fibrosis, we generated mice with conditional overexpression of periostin in the collecting ducts (CDs). Ectopic CD expression of periostin was not sufficient to induce cyst formation or fibrosis in wild-type mice. However, periostin overexpression in pcy/pcy ( pcy) kidneys significantly increased mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis; and accelerated the decline in renal function. Moreover, CD-specific overexpression of periostin caused a decrease in the survival of pcy mice. These pathological changes were accompanied by increased renal expression of vimentin, α-smooth muscle actin, and type I collagen. We also found that periostin increased gene expression of pathways involved in repair, including integrin and growth factor signaling and ECM production, and it stimulated focal adhesion kinase, Rho GTPase, cytoskeletal reorganization, and migration of PKD cells. These results suggest that periostin stimulates signaling pathways involved in an abnormal tissue repair process that contributes to cyst growth and fibrosis in PKD.