Assessment of biological organ age using molecular pathology in pre-transplant kidney biopsies.

Organ shortage is a major challenge in kidney transplantation but the use of older donors, often with co-morbidities, is hampered by inconsistent outcomes. Methods of accurately stratifying marginal donor organs by clinical and histological assessment are lacking. To better understand organ variability, we profiled the transcriptomes of 271 kidneys from deceased donors at retrieval. Following correction for biopsy composition, we assessed molecular pathways that associated with delayed, and sub-optimal one-year graft function. Analysis of cortical biopsies identified an adaptive immune gene-rich module that significantly associated with increasing age and worse outcomes. Cellular deconvolution using human kidney reference single cell transcriptomes confirmed an increase in kidney-specific B and T cell signatures, as well as kidney macrophage, myofibroblast and fibroblast gene sets in this module. Surprisingly, innate immune pathway and neutrophil gene signature enrichment was associated with better outcomes. Thus, our work uncovers cellular molecular features of pathological organ ageing, identifiable at kidney retrieval, with translational potential.

Left Bundle Branch Pacing: A Paradigm Shift in Physiological Pacing for Patients With Atrioventricular Block and Preserved Left Ventricular Systolic Function, A Systematic Review and Meta-analysis.

His-Purkinje conduction system pacing (HPCSP) via His bundle pacing (HBP) and Left Bundle Branch Pacing (LBBP) offer a physiological approach to pacing by restoring normal ventricular activation. This meta-analysis compares the feasibility, outcomes, and success rates of HBP and LBBP in patients with atrioventricular block (AVB) and preserved left ventricular function. A systematic search identified studies comparing LBBP with HBP in AVB patients with preserved systolic function. Primary outcomes included QRS duration, success rates, pacing threshold, and improvement in R-wave amplitudes. Secondary outcomes were procedure time and fluoroscopy time. Random-effects models calculated odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI). Methodological quality was assessed using the Newcastle-Ottawa scale. Among 382 screened articles, seven observational studies involving 1035 patients were analyzed. The mean age was 69.9 years, the mean LVEF was 59.3%, and the average follow-up duration was 8.7 months. LBBP showed higher R-wave amplitudes (MD 7.88, 95% CI 7.26 to 8.50, P < 0.0001) and lower pacing thresholds (MD -0.64, 95% CI -0.81 to -0.47, P < 0.0001) compared to HBP. LBBP had shorter procedure time (MD -17.81, 95% CI -30.44 to -5.18, P = 0.006) and reduced fluoroscopy time (MD -5.39, 95% CI -8.81 to -1.97, P = 0.002). No significant differences were observed in QRS duration or success rates. LBBP offers advantages over HBP, including improved electrical activation, lower pacing thresholds, and shorter procedure and fluoroscopy times. Success rates and QRS duration reductions were comparable between LBBP and HBP. These findings support LBBP as a feasible and effective alternative to HBP in AVB patients with preserved systolic function.

The vicious cycle of BRASH syndrome: A case report.

First described in 2016, BRASH syndrome is an underreported clinical entity characterized by bradycardia, renal dysfunction, atrioventricular nodal blockade (AVNB), shock, and hyperkalemia. The recognition of BRASH syndrome as a clinical entity is crucial for early and effective management. Patients with BRASH syndrome present with symptomatic bradycardia that is resistant to treatment with standard agents such as atropine. In this report, we present the case of a 67-year-old male patient who presented with symptomatic bradycardia with an ultimate diagnosis of BRASH syndrome. We also shed light on predisposing factors and challenges encountered during the management of affected patients.

Loss of Right Atrial Pacing Lead Capture Due to Myocardial Infarction Obscuring Diagnosis on Electrocardiogram.

Right coronary artery occlusion can lead to failure to capture from the right atrial pacing lead. In this case, acute infarction resulted in failure of the right atrial lead to capture and thus increased right ventricular pacing. The new ventricular pacing masked the diagnosis of acute myocardial infarction. (Level of Difficulty: Intermediate.).

The HIF complex recruits the histone methyltransferase SET1B to activate specific hypoxia-inducible genes.

Hypoxia-inducible transcription factors (HIFs) are fundamental to cellular adaptation to low oxygen levels, but it is unclear how they interact with chromatin and activate their target genes. Here, we use genome-wide mutagenesis to identify genes involved in HIF transcriptional activity, and define a requirement for the histone H3 lysine 4 (H3K4) methyltransferase SET1B. SET1B loss leads to a selective reduction in transcriptional activation of HIF target genes, resulting in impaired cell growth, angiogenesis and tumor establishment in SET1B-deficient xenografts. Mechanistically, we show that SET1B accumulates on chromatin in hypoxia, and is recruited to HIF target genes by the HIF complex. The selective induction of H3K4 trimethylation at HIF target loci is both HIF- and SET1B-dependent and, when impaired, correlates with decreased promoter acetylation and gene expression. Together, these findings show SET1B as a determinant of site-specific histone methylation and provide insight into how HIF target genes are differentially regulated.

CMV, EBV, JCV and BKV infection and outcome following kidney transplantation in children initiated on a corticosteroid-minimisation immunosuppressive regimen.

BACKGROUND: Modern immunosuppressive regimens in paediatric kidney transplant recipients have contributed to improved long-term allograft survival, but at the expense of an increased incidence of viral infections. Here, we describe, for the first time, the incidence, risk factors and clinical outcome of CMV, EBV, BKV and JCV viraemia in a cohort of paediatric allograft recipients treated with a corticosteroid-minimisation immunosuppressive regimen (CMR). METHODS: We retrospectively analysed 98 children treated with a CMR (basiliximab induction, corticosteroids until day 4, long-term tacrolimus and mycophenolate mofetil), who received a kidney transplant in our centre between 2009 and 2019. RESULTS: Over the first 4 years post-transplant, the incidences of viraemia were as follows: CMV, 25.5%; EBV, 52.0%; JCV, 16.3%; BKV, 26.5%. Younger children at time of transplant were more likely to develop EBV and BKV viraemia. EBV viraemia was also associated with a regimen involving corticosteroids, but lacking MMF. Recipient CMV serology predicted the development of EBV, BKV and CMV viraemia. Fifty-six percent of CMV viraemia episodes in high-risk patients occurred whilst the graft recipients were still receiving anti-viral prophylaxis or within 3 months of cessation. There was no difference in graft function at latest follow-up between those with and without viraemia. CONCLUSIONS: Judicious monitoring of viraemia, coupled with timely clinical intervention, can result in similar long-term outcomes for graft recipients compared to controls. The high incidence of CMV viraemia observed within a short period of cessation of anti-viral prophylaxis supports an extension of the length of prophylactic treatment in high-risk allograft recipients.

Acute rejection and growth outcomes in paediatric kidney allograft recipients treated with a corticosteroid minimisation immunosuppressive protocol.

BACKGROUND: Corticosteroid minimisation immunosuppressive protocols (CMP) for children are an approach to safely reduce unwanted medication side effects associated with long-term exposure following kidney transplantation. Here, we provide data regarding the incidence of acute rejection and growth over an extended follow-up in children receiving the CMP used in our centre. METHODS: We retrospectively analysed all children treated with a CMP who received a kidney transplant and had follow-up care in our centre between 2009 and 2019. Data were compared to 5 control groups from recent studies. RESULTS: Ninety-nine kidney allograft recipients were included in the study (mean follow-up 4.4 years). There was no difference in the cumulative frequency of acute rejection in CMP-treated graft recipients compared to controls. Graft function at latest follow-up was significantly lower in graft recipients experiencing acute rejection compared to those without acute rejection (53.7 mL/min/1.73 m2 vs. 66.8 mL/min/1.73 m2, p = 0.021). Children experiencing >1 acute rejection episode had a greatly elevated risk of graft failure (p = 0.0009, OR 68.25). At latest follow-up, 64/90 (71.1%) graft recipients had a normal height, and younger graft recipients demonstrated greater catch up growth than older children. CMP-treated graft recipients showed a reduced rate of height deficit (28.9% vs. 55.1%, p = 0.0025), less obesity (12.2% vs. 23.9%, p = 0.031), and reduced rates of hypertension (35.4% vs. 68.2%, p< 0.0001). CONCLUSIONS: Children treated with a CMP show greater height attainment, lower frequency of obesity, and reduced rates of hypertension, without an increased risk of acute rejection. Graphical abstract.

BK virus infection and outcome following kidney transplantation in childhood.

BK virus associated nephropathy (BKN) is an important cause of kidney allograft failure. In a cohort of paediatric kidney transplant recipients, we aimed to understand the incidence and clinical outcome associated with BKN, as well as identify risk factors for BKN and BK viraemia development. We retrospectively analysed all patients who received a kidney transplant and received follow up care in our centre between 2009-2019. Among 106 patients included in the study (mean follow up 4.5 years), 32/106 (30.2%) patients experienced BK viraemia. The incidence of BKN was 7/106 (6.6%). The median time of BK viraemia development post-transplant was 279.5 days compared to 90.0 days for BKN. Development of BKN was associated with younger age at transplantation (p = 0.013). Development of BK viraemia was associated with negative recipient serology for cytomegalovirus (CMV) at time of transplantation (p = 0.012) and a higher net level of immunosuppression (p = 0.039). There was no difference in graft function at latest follow up between those who experienced BKN and those without BKN. This study demonstrates that BK virus infection is associated with younger age at transplantation, CMV negative recipient serostatus and higher levels of immunosuppression. Judicious monitoring of BK viraemia in paediatric transplant recipients, coupled with timely clinical intervention can result in similar long-term outcomes for BKN patients compared to controls.

Outcomes of Standard Permanent Active Fixation Leads for Temporary Pacing.

OBJECTIVES: This study investigated the performance of Temporary Pacing via an Externalized Active-Fixation (TPEAF) lead. BACKGROUND: The incidence of cardiac implantable electronic device infections is increasing, which necessitates the need for transvenous lead extraction (TLE). Pacemaker-dependent patients require temporary pacing during the guideline-recommended waiting period before reimplantation. Data regarding safety and efficacy of TPEAF leads are very limited. METHODS: We evaluated patients implanted with TPEAF leads post-TLE at our center between April 2004 and December 2017. RESULTS: TPEAF leads were placed in 158 patients. The mean age was 74 ± 11 years. The median duration of the temporary lead was 6 days (range 1 to 29). There were 4 procedural complications (2.5% incidence): 1 patient had cardiac arrest from hyperkalemia, 2 developed cardiac tamponade, and 1 had profuse bleeding from the entry point of the leads. There were 13 complications post-implantation (8.2% incidence): 8 lead dislodgments, 1 elevated pacing threshold, 2 vegetations on the temporary lead, 1 pneumothorax, and 1 loss of capture due to the generator "safety switch." All dislodgements occurred within 24 h, except 1 on day 3. Sixteen patients died during the hospital stay: 10 due to septic shock, 2 due to hyperkalemic cardiac arrest, 3 due to ventricular tachycardia, and 1 due to a massive cerebrovascular accident. CONCLUSIONS: The use of TPEAF leads is safe and efficacious in pacemaker-dependent patients post-TLE. Dislodgement can occur within the first 24 h. The presence of persistent fever and positive blood cultures should raise concern for vegetation on the temporary lead.

Cardiovascular Disease Risk Factors and Myocardial Infarction in the Transgender Population.

BACKGROUND: As of 2016, ≈1.4 million people in the United States identify as transgender. Despite their growing number and increasing specific medical needs, there has been a lack of research on cardiovascular disease (CVD) and CVD risk factors in this population. Recent studies have reported that the transgender population had a significantly higher rate of CVD risk factors without a significant increase in overall CVD morbidity and mortality. These studies are limited by their small sample sizes and their predominant focus on younger transgender populations. With a larger sample size and inclusion of broader age range, our study aims to provide insight into the association between being transgender and cardiovascular risk factors, as well as myocardial infarction. METHODS AND RESULTS: The Behavioral Risk Factor Surveillance System data from 2014 to 2017 were used to evaluate the cross-sectional association between being transgender and the reported history of myocardial infarction and CVD risk factors. A logistic regression model was constructed to study the association between being transgender and myocardial infarction after adjusting for CVD risk factors including age, diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease, smoking, and exercise. Multivariable analysis revealed that transgender men had a >2-fold and 4-fold increase in the rate of myocardial infarction compared with cisgender men (odds ratio, 2.53; 95% CI, 1.14-5.63; P=0.02) and cisgender women (odds ratio, 4.90; 95% CI, 2.21-10.90; P<0.01), respectively. Conversely, transgender women had >2-fold increase in the rate of myocardial infarction compared with cisgender women (odds ratio, 2.56; 95% CI, 1.78-3.68; P<0.01) but did not have a significant increase in the rate of myocardial infarction compared with cisgender men. CONCLUSIONS: The transgender population had a higher reported history of myocardial infarction in comparison to the cisgender population, except for transgender women compared with cisgender men, even after adjusting for cardiovascular risk factors.

Outcomes of Acute Conduction Abnormalities Following Transcatheter Aortic Valve Implantation With a Balloon Expandable Valve and Predictors of Delayed Conduction System Abnormalities in Follow-up.

Transcatheter aortic valve implantation (TAVI) is an acceptable treatment for severe aortic stenosis in high or intermediate risk patients. Conduction abnormalities are a known complication of TAVI. Most abnormalities occur perioperatively but can develop later. The predictors of delayed conduction abnormalities are unknown. Patients who underwent TAVI at our institution were reviewed. Patients with a pre-existing pacemaker were excluded. Baseline, in-hospital, and 30-day follow-up ECGs were reviewed. Patient and procedural characteristics were analyzed to look for predictors of acute and delayed abnormalities. Ninety-eight patients were included. All valves implanted were balloon expandable, most commonly SAPIEN S3 (78%). Thirty-seven (37.7%) patients developed abnormalities before discharge. Of these patients, 20 (57.1%) had complete resolution at 30-day follow-up. No patients with new conduction abnormalities during hospitalization had additional abnormalities at 30-day follow-up. Five (5.1%) patients developed new conduction abnormalities following discharge. Overall, 22 (22.4%) patients had conduction abnormalities at 30-day follow-up which were not present at baseline. Predilatation (p = 0.003), higher ratios of balloon (p = 0.03) or valve (p = 0.05) size to left ventricular outflow tract, and previous myocardial infarction (p = 0.034) were predictive of acute conduction abnormalities. Baseline right bundle branch block (p = 0.002), longer baseline (p <0.001) and discharge (p = 0.004) QRS duration, moderate, or severe aortic insufficiency (p = 0.002) and atrial fibrillation (p = 0.031) were predictors of new conduction abnormalities after discharge. In conclusion, most new in-hospital conduction abnormalities resolve by 30-day follow-up. In-hospital conduction abnormalities are related to technical aspects of TAVI while delayed conduction abnormalities are related to baseline conduction system disease.

Rate Versus Rhythm Control in Patients with Normal to Mild Left Atrial Enlargement: Insights from the AFFIRM Trial.

BACKGROUND: Atrial fibrillation is the most commonly encountered sustained arrhythmia and is associated with significant morbidity and mortality. Several trials have demonstrated that no mortality benefit exists when choosing a rhythm-control strategy over a rate-control strategy, with some trials suggesting an increase in mortality. Using the AFFIRM trial database we sought to determine the effect of rhythm control strategy in patients with normal or mild atrial enlargement. METHODS: AFFIRM Trial database was used to evaluate the effect of rhythm-control strategy compared to rate-control strategy in a subgroup of patients with normal to mild left atrial (LA) enlargement. The primary outcome measures of this study were all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, and hospitalization/ED visit. RESULTS: We identified a subgroup of subjects from the AFFIRM trial with normal or mild LA enlargement (n=2022 of 4060 total subjects). Subjects in the rhythm-control group(n= 1022) had an increased risk of all-cause mortality by 34% (RR 1.34, 95% CI 1.08-1.67; P=0.007) and hospitalization/ED visits by 10% (RR 1.10, 95% CI 1.05-2.16; P=<0.001) compared to rate control group(n= 1000). CONCLUSION: This study demonstrated that rhythm-control strategy increases the risk of mortality and hospitalization in a subgroup of patients with normal to mild atrial enlargement compared to rate-control strategy. Amiodarone use in this subgroup of patients likely drove these findings.

Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1.

Nephrotic syndrome (NS) occurs when the glomerular filtration barrier becomes excessively permeable leading to massive proteinuria. In childhood NS, immune system dysregulation has been implicated and increasing evidence points to the central role of podocytes in the pathogenesis. Children with NS are typically treated with an empiric course of glucocorticoid (Gc) therapy; a class of steroids that are activating ligands for the glucocorticoid receptor (GR) transcription factor. Although Gc-therapy has been the cornerstone of NS management for decades, the mechanism of action, and target cell, remain poorly understood. We tested the hypothesis that Gc acts directly on the podocyte to produce clinically useful effects without involvement of the immune system. In human podocytes, we demonstrated that the basic GR-signalling mechanism is intact and that Gc induced an increase in podocyte barrier function. Defining the GR-cistrome identified Gc regulation of motility genes. These findings were functionally validated with live-cell imaging. We demonstrated that treatment with Gc reduced the activity of the pro-migratory small GTPase regulator Rac1. Furthermore, Rac1 inhibition had a direct, protective effect on podocyte barrier function. Our studies reveal a new mechanism for Gc action directly on the podocyte, with translational relevance to designing new selective synthetic Gc molecules.

Simultaneous binaural bithermal caloric testing: Clinical value.

The aim of this retrospective review was to determine the clinical value of simultaneous binaural bithermal caloric testing (SBT) versus alternate binaural bithermal caloric testing (ABB) in the setting of a tertiary care neurotology clinic. Charts of 131 adults who had presented with otologic complaints and had undergone both SBT and ABB examinations were included in the study. The main outcome measure was the identification of peripheral hypofunction. One hundred two patients had a normal ABB caloric examination; 86 of those 102 patients (84.3%) had normal ABB examinations but abnormal SBT results. We conclude that SBT is a more sensitive measure of peripheral pathology than the traditional ABB examination. If peripheral pathology is suspected but not confirmed by ABB, SBT appears useful for detecting mildly reduced vestibular response.

Recent developments in the detection and management of acute kidney injury.

Acute kidney injury (AKI) is a common condition in children admitted to hospital and existing serum and urine biomarkers are insensitive. There have been significant developments in stratifying the risk of AKI in children and also in the identification of new AKI biomarkers. Risk stratification coupled with a panel of AKI biomarkers will improve future detection of AKI, however, paediatric validation studies in mixed patient cohorts are required. The principles of effective management rely on treating the underlying cause and preventing secondary AKI by the appropriate use of fluids and medication. Further therapeutic innovation will depend on improving our understanding of the basic mechanisms underlying AKI in children.

The Effects of Extensive Glomerular Filtration of Thin Graphene Oxide Sheets on Kidney Physiology.

Understanding how two-dimensional (2D) nanomaterials interact with the biological milieu is fundamental for their development toward biomedical applications. When thin, individualized graphene oxide (GO) sheets were administered intravenously in mice, extensive urinary excretion was observed, indicating rapid transit across the glomerular filtration barrier (GFB). A detailed analysis of kidney function, histopathology, and ultrastructure was performed, along with the in vitro responses of two highly specialized GFB cells (glomerular endothelial cells and podocytes) following exposure to GO. We investigated whether these cells preserved their unique barrier function at doses 100 times greater than the dose expected to reach the GFB in vivo. Both serum and urine analyses revealed that there was no impairment of kidney function up to 1 month after injection of GO at escalating doses. Histological examination suggested no damage to the glomerular and tubular regions of the kidneys. Ultrastructural analysis by transmission electron microscopy showed absence of damage, with no change in the size of podocyte slits, endothelial cell fenestra, or the glomerular basement membrane width. The endothelial and podocyte cell cultures regained their full barrier function after >48 h of GO exposure, and cellular uptake was significant in both cell types after 24 h. This study provided a previously unreported understanding of the interaction between thin GO sheets with different components of the GFB in vitro and in vivo to highlight that the glomerular excretion of significant amounts of GO did not induce any signs of acute nephrotoxicity or glomerular barrier dysfunction.

The non-immunosuppressive management of childhood nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) is one of the most common renal diseases found in the paediatric population and is associated with significant complications, including infection and thrombosis. A high proportion of children enter sustained remission before adulthood, and therapy must therefore mitigate the childhood complications, while minimising the long-term risk to health. Here we address the main complications of INS and summarise the available evidence and guidance to aid the clinician in determining the appropriate treatment for children with INS under their care. Additionally, we highlight areas where no consensus regarding appropriate management has been reached. In this review, we detail the reasons why routine prophylactic antimicrobial and antithrombotic therapy are not warranted in INS and emphasise the conservative management of oedema. When pharmacological intervention is required for the treatment of oedema, we provide guidance to aid the clinician in determining the appropriate therapy. Additionally, we discuss obesity and growth, fracture risk, dyslipidaemia and thyroid dysfunction associated with INS. Where appropriate, we describe how recent developments in research have identified potential novel therapeutic targets.

Towards a biomarker panel for the assessment of AKI in children receiving intensive care.

BACKGROUND: Critically ill children and neonates are at high risk of developing acute kidney injury (AKI). AKI is associated with short- and long-term renal impairment and increased mortality. Current methods of diagnosing AKI rely on measurements of serum creatinine, which is a late and insensitive marker. Few studies to date have assessed AKI biomarkers in a heterogeneous patient cohort. METHODS: We conducted a prospective feasibility study in a paediatric intensive care setting over a 6-month period to describe the relationship between AKI (defined according to pRIFLE criteria) and new AKI biomarkers. RESULTS: In total, 49 patients between the ages of 16 days and 15 years were recruited for measurement of plasma cystatin C (Cys-C) and neutrophil gelatinase-associated lipocalin (pNGAL) concentrations, as well as for urinary kidney injury molecule-1 (KIM-1) and urinary NGAL (uNGAL) concentrations. Almost one-half (49 %) of the patient cohort experienced an AKI episode, and Cys-C and pNGAL were the strongest candidates for the detection of AKI. Our data suggest that the widely used estimated baseline creatinine clearance value of 120 mL/min/1.73 m(2) underestimates actual baseline function in patients admitted to paediatric intensive care units. CONCLUSIONS: This investigation demonstrates the feasibility of new AKI biomarker testing in a mixed patient cohort and provides novel biomarker profiling for further evaluation.