mTOR inhibitors after lung transplantation: a real-life experience.

Background: The mammalian target of rapamycin (mTOR) inhibitors in combination with calcineurin inhibitors (CNIs), antimetabolites and corticosteroids for immunosuppression after lung transplantation (TPL) have gained importance in patients with chronic kidney disease (CKD). The goal of this study was to characterize lung transplant recipients (LTR) treated with mTOR inhibitors, with a special focus on kidney function. Methods: LTR transplanted at the University Hospital Zurich between December 1992 and April 2022 were analyzed. Demographics, estimated glomerular filtration rate (eGFR) before and after mTOR initiation, TPL circumstances, immunosuppressive regimens, and allograft function were recorded. We used linear regression to calculate the Mitch curves and a linear mixed-effects model to compare the eGFR. Results: Of all LTR, 70/593 (12%) received mTOR inhibitors. Intolerance or adverse events of antimetabolites were the most common indications for mTOR inhibitor introduction. Discontinuation in 34/70 (49%) was often related to planned or urgent surgery to prevent impaired wound healing. The majority of patients had a preserved baseline eGFR at mTOR inhibitor introduction with CKD Kidney Disease Improving Global Outcomes (KDIGO) stage G1 or 2. The mean annual eGFR decline changed significantly from -16.19 mL/min/1.73 m2/year [95% confidence interval (CI): -22.27 to -10.11] 12 months before to -6.16 mL/min/1.73 m2/year (95% CI: -13.37 to 1.05) 12 months after mTOR initiation (P=0.009) showing better outcomes with earlier mTOR inhibitor initiation after lung TPL. Conclusions: This retrospective study suggests stabilization of kidney function after mTOR inhibitor initiation in LTR documented by a slower eGFR decline after mTOR inhibitor introduction with better outcomes early after lung TPL. Intolerance or adverse events of antimetabolites are important indications for the introduction of mTOR inhibitors. A relatively high discontinuation rate (49%) can be explained by planned discontinuation of mTOR inhibitors prior to surgery to avoid impaired wound healing.

Too Much of a Good Thing: Severe Hypercalcemia Presenting with Lethargy and Kidney Failure.

INTRODUCTION: We present a case of a 58-year-old man with a history of laryngo-pharyngectomy including bilateral thyroidectomy due to hypopharyngeal cancer presenting with lethargy, acute kidney failure, and hypercalcemia. Milk alkali syndrome was diagnosed given the history of high-dose calcium / vitamin D supplementation after ruling out other causes of hypercalcemia. After initial treatment with normal saline, furosemide and denosumab, the patient developed severe symptomatic hypocalcemia as a rare adverse effect of denosumab.

A narrative review of the socioeconomic burden associated with generalised pustular psoriasis.

Generalised pustular psoriasis (GPP) is a rare, chronic and life-threatening inflammatory skin disease characterised by widespread eruption of sterile pustules. With the approval of a GPP flare treatment in several countries occurring only recently, the socioeconomic burden associated with GPP is not well established. To highlight current evidence for patient burden, healthcare resource utilization (HCRU) and costs associated with GPP. Patient burden results from serious complications including sepsis and cardiorespiratory failure causing hospitalization and death. HCRU is driven by high hospitalization rates and treatment costs. The mean duration of a GPP hospital stay ranges from 10 to 16 days. A quarter of patients require intensive care, and the mean intensive care stay is 18 days. In comparison to patients with plaque psoriasis (PsO), patients with GPP have: a 64% higher score on the Charlson Comorbidity Index; higher hospitalization rates (≤36.3% vs. ≤23.3%); lower overall quality of life, and higher symptom scores for pain, itch, fatigue, anxiety and depression; direct costs associated with treatment 1.3- to 4.5-fold higher; higher rates of disabled work status (20.0% vs. 7.6%); and increased presenteeism (i.e. worse impairment at work), impaired daily activities, and medically related absenteeism. Current medical management and drug treatment utilising non-GPP-specific therapies impose a significant patient and direct economic burden. GPP also imposes an indirect economic burden by increasing work productivity impairment and medically related absenteeism. This high level of socioeconomic burden reinforces the need for new therapies with proven efficacy in the treatment of GPP.

Mammalian Target of Rapamycin Inhibitors and Kidney Function After Thoracic Transplantation: A Systematic Review and Recommendations for Management of Lung Transplant Recipients.

BACKGROUND: Chronic kidney disease (CKD) after lung transplantation is common and limits the survival of transplant recipients. The calcineurin inhibitors (CNI), cyclosporine A, and tacrolimus being the cornerstone of immunosuppression are key mediators of nephrotoxicity. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used in combination with reduced CNI dosage after lung transplantation. METHODS: This systematic review examined the efficacy and safety of mTOR inhibitors after lung transplantation and explored their effect on kidney function. RESULTS: mTOR inhibitors are often introduced to preserve kidney function. Several clinical trials have demonstrated improved kidney function and efficacy of mTOR inhibitors. The potential for kidney function improvement and preservation increases with early initiation of mTOR inhibitors and low target levels for both mTOR inhibitors and CNI. No defined stage of CKD for mTOR inhibitor initiation exists, nor does severe CKD preclude the improvement of kidney function under mTOR inhibitors. Baseline proteinuria may negatively predict the preservation and improvement of kidney function. Discontinuation rates of mTOR inhibitors due to adverse effects increase with higher target levels. CONCLUSIONS: More evidence is needed to define the optimal immunosuppressive regimen incorporating mTOR inhibitors after lung transplantation. Not only the indication criteria for the introduction of mTOR inhibitors are needed, but also the best timing, target levels, and possibly discontinuation criteria must be defined more clearly. Current evidence supports the notion of nephroprotective potential under certain conditions.

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease.

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.

Granulomatous lung disease and immune reconstitution inflammatory syndrome in Whipple's disease.

We present the case of a 70-year-old woman with a history of seronegative arthritis, recurrent pleural effusion and weight loss. A prior lung biopsy had revealed non-caseating epithelioid cell granulomas without evidence for microbial organisms on special stains. Intestinal biopsy findings where suspicious for Whipple's disease, which was confirmed by PCR testing, both on the intestinal and retrospectively on the lung tissue. Treatment with ceftriaxone resulted in clinical deterioration with fever, arthritis and recurrent pleuritis consistent with immune reconstitution inflammatory syndrome. Dose increase of glucocorticoids and therapy rotation to doxycycline and hydroxychloroquine resulted in rapid clinical improvement.

Hyperregenerative macrocytic anaemia: the role of copper and zinc.

In a patient with a history of bariatric surgery, severe copper deficiency presenting with macrocytic hyperregenerative anaemia was diagnosed. Besides the impaired intestinal absorption due to a short bowel syndrome, the enteral zinc supplementation competitively decreased the intestinal copper uptake. Once the zinc supplementation was stopped, enteral copper replacement ensued and normalised haemoglobin levels with decreasing median corpuscular volume were observed during follow-up visits.

Coronavirus disease (COVID-19): observations and lessons from primary medical care at a German community hospital.

The pandemic outbreak of COVID-19 challenges medical care systems all around the world. We here describe our experiences during the treatment of COVID-19 patients (n = 42) treated from 2 March 2020 to 16 April 2020 at a German district hospital. Forty-two COVID-19 patients were hospitalized and five patients developed a severe disease, requiring intensive care. Overall, 11 out of 42 hospitalized patients died. COVID-19 caused lymphocytopenia, as well as increased d-dimer, c-reactive protein and creatine kinase, and lactate dehydrogenase levels. These changes were mostly pronounced in patients that developed a severe disease course. Radiologic findings included ground-glass opacity, bilateral/multilobular involvement, consolidation, and posterior involvement. We compared COVID-19 patients to an average population of 'non-COVID' patients. Interestingly, no laboratory or radiologic finding was specific for COVID-19 when standing alone, as comorbidities of 'non-COVID' patients certainly can mimic similar results. In common praxis, the diagnosis of COVID-19 is based on a positive PCR result. However, a false-negative result causes problems for the workflow of an entire hospital. In our clinic, the consequences of a false assumption of SARS-CoV-2 negativity in four cases had dramatic consequences, as contact persons had to be quarantined. To avoid this, a comprehensive view of lab-results, radiology, clinical symptoms and comorbidities is necessary for the correct diagnosis or exclusion of COVID-19.

Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

Long non-coding RNA LASSIE regulates shear stress sensing and endothelial barrier function.

Blood vessels are constantly exposed to shear stress, a biomechanical force generated by blood flow. Normal shear stress sensing and barrier function are crucial for vascular homeostasis and are controlled by adherens junctions (AJs). Here we show that AJs are stabilized by the shear stress-induced long non-coding RNA LASSIE (linc00520). Silencing of LASSIE in endothelial cells impairs cell survival, cell-cell contacts and cell alignment in the direction of flow. LASSIE associates with junction proteins (e.g. PECAM-1) and the intermediate filament protein nestin, as identified by RNA affinity purification. The AJs component VE-cadherin showed decreased stabilization, due to reduced interaction with nestin and the microtubule cytoskeleton in the absence of LASSIE. This study identifies LASSIE as link between nestin and VE-cadherin, and describes nestin as crucial component in the endothelial response to shear stress. Furthermore, this study indicates that LASSIE regulates barrier function by connecting AJs to the cytoskeleton.

Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction.

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition.

Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under proinflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT-promoting, proinflammatory, and hypoxic conditions. Silencing of JMJD2B reduced TGF-ß2-induced expression of mesenchymal genes, prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-ß signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and Sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting, proinflammatory, and hypoxic conditions, and supports the acquirement of a mesenchymal phenotype.

Interfacial Stability of Phosphate-NASICON Solid Electrolytes in Ni-Rich NCM Cathode-Based Solid-State Batteries.

A nondegrading, low-impedance interface between a solid electrolyte and cathode active materials remains a key challenge for the development of functional all-solid-state batteries (ASSBs). The widely employed thiophosphate-based solid electrolytes are not stable toward oxidation and suffer from growing interface resistance and thus rapid fading of capacity in a solid-state battery. In contrast, NASICON-type phosphates such as Li1+ xAl xTi2- x(PO4)3 and Li1+ xAl xGe2- x(PO4)3 are stable at high potentials, but their mechanical rigidity and high grain boundary resistance are thought to impede their application in bulk-type solid-state batteries. In this work, we present a comparative study of a LiNi0.8Co0.1Mn0.1O2 (NCM-811) cathode composite employing either ß-Li3PS4 (LPS) or Li1.5Al0.5Ti1.5(PO4)3 (LATP) as a solid electrolyte. LPS is employed as a separator in both cases to assemble a functional ASSB. To avoid high-temperature processing of LATP, along with subsequent detrimental interfacial reactions with NCM materials, the ASSBs are constructed and operated in a hot-press setup at 150 °C. The cathode interfaces are investigated using in situ electrochemical impedance spectroscopy and X-ray photoelectron spectroscopy, which reveals that the interface resistance is strongly suppressed and the chemical state of the composite is unchanged during cycling when employed with LATP. The cell using LATP is reversibly charged and discharged for multiple cycles and outperforms a comparable cell using a thiophosphate composite electrode. The results indicate that LATP in the cathode composite represents an excellent candidate to overcome interfacial challenges in bulk-type solid-state batteries.

Tobacco Use After Lung Transplantation: A Retrospective Analysis of Patient Characteristics, Smoking Cessation Interventions, and Cessation Success Rates.

BACKGROUND: Smoking remains the leading cause of preventable disease and death in the developed world that kills half of all long-term users. Tobacco use after solid organ transplantation is associated with allograft dysfunction, cancer, and reduced overall survival. METHODS: In this single-center, retrospective study, we describe the frequency of tobacco use after lung transplantation (LTx), pretransplant patient characteristics associated with tobacco use, and the safety, efficacy, and outcomes of posttransplant tobacco cessation interventions. RESULTS: Four percent of our LTx cohort resumed tobacco use posttransplant. Chronic obstructive pulmonary disease (P = 0.043), the cessation duration before LTx (P < 0.001), and the packyear-cessation index (PCI) (P < 0.001) were found to be significantly associated with tobacco use posttransplant. A PCI cutoff value of 0.32 had 100% sensitivity and 45% specificity for tobacco use resumption. Thirty-five percent of the posttransplant tobacco users successfully quit tobacco consumption. CONCLUSIONS: Patients with chronic obstructive pulmonary disease and a short duration of smoking cessation before LTx were at greatest risk of tobacco use after LTx. The PCI may be a useful predictor of tobacco use resumption. Pharmacological tobacco cessation interventions were found to have a comparable safety and efficacy profile compared to nontransplant patients.

Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling.

Aims: Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19. Methods and results: H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation. Conclusion: These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.

Smoking resumption after heart or lung transplantation: a systematic review and suggestions for screening and management.

Smoking remains the leading cause of preventable disease and death in the developed world and kills half of all long-term users. Smoking resumption after heart or lung transplantation is associated with allograft dysfunction, higher incidence of cancer, and reduced overall survival. Although self-reporting is considered an unreliable method for tobacco use detection, implementing systematic cotinine-based screening has proven challenging. This review examines the prevalence of smoking resumption in thoracic transplant patients, explores the risk factors associated with a post-transplant smoking resumption and discusses the currently available smoking cessation interventions for transplant patients.

Stiffness-Induced Endothelial DLC-1 Expression Forces Leukocyte Spreading through Stabilization of the ICAM-1 Adhesome.

Leukocytes follow the well-defined steps of rolling, spreading, and crawling prior to diapedesis through endothelial cells (ECs). We found increased expression of DLC-1 in stiffness-associated diseases like atherosclerosis and pulmonary arterial hypertension. Depletion of DLC-1 in ECs cultured on stiff substrates drastically reduced cell stiffness and mimicked leukocyte transmigration kinetics observed for ECs cultured on soft substrates. Mechanistic studies revealed that DLC-1-depleted ECs or ECs cultured on soft substrates failed to recruit the actin-adaptor proteins filamin B, α-actinin-4, and cortactin to clustered ICAM-1, thereby preventing the ICAM-1 adhesome formation and impairing leukocyte spreading. This was rescued by overexpressing DLC-1, resulting in ICAM-1 adhesome stabilization and leukocyte spreading. Our results reveal an essential role for substrate stiffness-regulated endothelial DLC-1, independent of its GAP domain, in locally stabilizing the ICAM-1 adhesome to promote leukocyte spreading, essential for efficient leukocyte transendothelial migration.

H19 Induces Abdominal Aortic Aneurysm Development and Progression.

BACKGROUND: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. METHODS: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient ( ApoE-/-) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. RESULTS: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region. CONCLUSIONS: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.