Citations

Abstract Renovascular hypertension (RVH) affects up to 7% of individuals over 65 years of age. We have previously demonstrated that induction of oxidative stress is an early event in the development of RVH that leads to development of inflammation and renal atrophy. NLRP3 is one of the most well-known sensors of oxidative stress. However, the role of NLRP3 in the development of RVH and subsequent end-organ damage is not well understood. We therefore sought to test the hypothesis that inhibition of NLRP3 activation protects the heart and the kidneys of mice subjected to RVH. In accordance with our previous observations, wild type (WT) mice subjected to RVH developed 26±6% of renal atrophy within 1 week following cuff placement that progressed to almost 100% by 4 weeks. In contrast, although NLRP3-/- mice (KO) subjected to RVH developed similar degree of atrophy to their age-matched WT in the first week (29 ± 17 vs. 39 ± 20), the atrophy did not progress when evaluated at 4 weeks (29 ± 13 vs. 78 ± 10, p=0.013). Histologic evaluation of renal cortex of KO mice showed no significant interstitial infiltration with CD3+ T cells or F4/80+ macrophages. In addition, KO mice developed no cardiac hypertrophy, no cardiac fibrosis, or aortic lesion despite similar elevation in systolic blood pressure to the WT mice. We propose that NLRP3 activation plays a critical role in the development of renal atrophy in mice subjected to RVH and represent a potential therapeutic target.

Abstract Renal artery stenosis is a common finding in patients with cardiovascular disease. Recent studies have provided evidence that innate immunity plays a critical role in the development of chronic renal disease in renovascular hypertension. We have previously demonstrated that interstitial infiltration of lymphocytes is an early event in the development of renal atrophy in the 2K1C model of renovascular hypertension. We therefore sought to test the hypothesis that lymphocytes play a role in the development of progressive atrophy/fibrosis in this model. We subjected mice to renal artery stenosis through placement of a polytetrafluoroethylene cuff on the right renal artery. In accordance with our previous observations, wild type mice subjected to RAS developed renal atrophy within 2 weeks following placement of the cuff (70.5 +/- 11.9%). Chemokine expression in renal cortex of the stenotic kidney reflected predominantly a Th1 response (STAT1, STAT4, TBX21); CCL2, CCL17, CCL12, and TNF mRNA expression were also upregulated, but not IL-6 and IL-10. In striking contrast to wild type mice, Rag1 mice developed significantly less atrophy (23.1 +/- 10.4, p<0.0037 vs wild type). Unlike wild type mice, histologic evaluation of renal cortex of Rag1 mice showed no significant interstitial infiltration with CD3+ T cells or F4/80+ macrophages. We propose that T cell-mediated inflammation plays a critical role in the development of renal atrophy in 2K1C mice.

AbstractBackgroundMore than 300 variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes have been reported to cause Dominantly Inherited Alzheimer Disease (DIAD). However, most of these reports come from non‐Hispanic whites and the full extent of DIAD remains understudied in Latin American (LatAm) countries. Here we describe five AD affected families from LatAm carrying novel DIAD variants.MethodsFive novel variants in the presenilin1 (PSEN1) gene were identified in Brazilian (p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se and p.Ala275Thr) and Mexican families (p.Ile414Thr). To assign the likelihood of pathogenicity among these variants of unknown significance, we report pedigree information, frequency in control populations, in silico predictions, and cell‐based models.ResultThe mean age at onset in newly identified families was 43.5 years (range 36‐54). The novel variants were absent from gnomAD genome and exome databases. Two PSEN1 variants (p.Val103_Ser104delinsGly and p.Lys395Ile) showed segregation with the disease status; segregation studies were not possible in the other three families. Additionally, PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr produced Aβ profiles consistent with known AD pathogenic mutations (i.e. increased extracellular Aβ42/40); thus, we consider them as likely pathogenic. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation; therefore, PSEN1 p.Ile414Thr likely represents an AD risk factor or benign polymorphism.ConclusionOur study provides further insights into the genetics of AD in LatAm by identifying novel DIAD pathogenic variants in Brazil and Mexico, two countries with distinct genetic admixtures. Expanding the families eligible to participate in observational and clinical trials of DIAD enhances the generalizability of diagnosis and treatment approaches.

AbstractBackgroundHistory and physical examination are key features to narrow the differential diagnosis of central versus peripheral causes in patients presenting with acute vertigo. We conducted a systematic review and meta‐analysis of the diagnostic test accuracy of physical examination findings.MethodsThis study involved a patient–intervention–control–outcome (PICO) question: (P) adult ED patients with vertigo/dizziness; (I) presence/absence of specific physical examination findings; and (O) central (ischemic stroke, hemorrhage, others) versus peripheral etiology. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was assessed.ResultsFrom 6309 titles, 460 articles were retrieved, and 43 met the inclusion criteria: general neurologic examination—five studies, 869 patients, pooled sensitivity 46.8% (95% confidence interval [CI] 32.3%–61.9%, moderate certainty) and specificity 92.8% (95% CI 75.7%–98.1%, low certainty); limb weakness/hemiparesis—four studies, 893 patients, sensitivity 11.4% (95% CI 5.1%–23.6%, high) and specificity 98.5% (95% CI 97.1%–99.2%, high); truncal/gait ataxia—10 studies, 1810 patients (increasing severity of truncal ataxia had an increasing sensitivity for central etiology, sensitivity 69.7% [43.3%–87.9%, low] and specificity 83.7% [95% CI 52.1%–96.0%, low]); dysmetria signs—four studies, 1135 patients, sensitivity 24.6% (95% CI 15.6%–36.5%, high) and specificity 97.8% (94.4%–99.2%, high); head impulse test (HIT)—17 studies, 1366 patients, sensitivity 76.8% (64.4%–85.8%, low) and specificity 89.1% (95% CI 75.8%–95.6%, moderate); spontaneous nystagmus—six studies, 621 patients, sensitivity 52.3% (29.8%–74.0%, moderate) and specificity 42.0% (95% CI 15.5%–74.1%, moderate); nystagmus type—16 studies, 1366 patients (bidirectional, vertical, direction changing, or pure torsional nystagmus are consistent with a central cause of vertigo, sensitivity 50.7% [95% CI 41.1%–60.2%, moderate] and specificity 98.5% [95% CI 91.7%–99.7%, moderate]); test of skew—15 studies, 1150 patients (skew deviation is abnormal and consistent with central etiology, sensitivity was 23.7% [95% CI 15%–35.4%, moderate] and specificity 97.6% [95% CI 96%–98.6%, moderate]); HINTS (head impulse, nystagmus, test of skew)—14 studies, 1781 patients, sensitivity 92.9% (95% CI 79.1%–97.9%, high) and specificity 83.4% (95% CI 69.6%–91.7%, moderate); and HINTS+ (HINTS with hearing component)—five studies, 342 patients, sensitivity 99.0% (95% CI 73.6%–100%, high) and specificity 84.8% (95% CI 70.1%–93.0%, high).ConclusionsMost neurologic examination findings have low sensitivity and high specificity for a central cause in patients with acute vertigo or dizziness. In acute vestibular syndrome (monophasic, continuous, persistent dizziness), HINTS and HINTS+ have high sensitivity when performed by trained clinicians.

Tandem mass spectrometry (MS/MS) is the most universal platform currently available for the analysis of enzymatic activities and biomarkers in dried blood spots (DBS) for applications in newborn screening (NBS). Among the MS/MS applications in NBS, the most common is flow-injection analysis (FIA-) MS/MS, where the sample is introduced as a bolus injection into the mass spectrometer without the prior fractionation of analytes. Liquid chromatography combined with MS/MS (LC-MS/MS) has been employed for second-tier tests to reduce the false-positive rate associated with several nonspecific screening markers, beginning two decades ago. More recently, LC-MS/MS has been applied to primary screening for new conditions for which FIA-MS/MS or other methods, including genomic screening, are not yet adequate. In addition to providing a list of the currently used LC-MS/MS-based assays for NBS, the authors share their experience regarding the maintenance requirements of LC-MS/MS vs. FIA-MS/MS systems. The consensus is that the maintenance of LC-MS/MS and FIA-MS/MS instrumentation is similar, and LC-MS/MS has the advantage of allowing for a larger number of diseases to be screened for in a multiplex, cost-effective fashion with a high throughput and an adequate turnaround time.

Significance Statement Glomerular volume, ischemic glomeruli, and global glomerulosclerosis are not consistently assessed on kidney transplant biopsies. The authors evaluated morphometric measures of glomerular volume, the percentage of global glomerulosclerosis, and the percentage of ischemic glomeruli and assessed changes in these measures over time to determine whether such changes predict late allograft failure. All three features increased from transplant to five-year biopsy. Kidneys with smaller glomeruli at 5 years had more global glomerulosclerosis and a higher percentage of ischemic-appearing glomeruli. Smaller glomeruli and increasing percentages of global glomerulosclerosis and ischemic glomeruli at 5 years predicted allograft failure. Only increased percentage of ischemic glomeruli predicted allograft failure at 5 years independent of all Banff scores. Glomerular changes reflect pathologic processes that predicted allograft loss; measuring them quantitatively might enhance the current Banff system and provide biomarkers for intervention trials. Background Histology can provide insight into the biology of renal allograft loss. However, studies are lacking that use quantitative morphometry to simultaneously assess changes in mean glomerular volume and in the percentages of globally sclerosed glomeruli (GSG) and ischemic-appearing glomeruli in surveillance biopsies over time to determine whether such changes are correlated with late graft failure. Methods We used digital scans of surveillance biopsies (at implantation and at 1 and 5 years after transplantation) to morphometrically quantify glomerular volume and the percentages of GSG and ischemic-appearing glomeruli in a cohort of 835 kidney transplants. Cox proportional hazards models assessed the risk of allograft failure with these three glomerular features. Results From implantation to 5 years, mean glomerular volume increased by nearly 30% (from 2.8×10 6 to 3.6×10 6 µm 3 ), mean percentage of GSG increased from 3.2% to 13.2%, and mean percentage of ischemic-appearing glomeruli increased from 0.8% to 9.5%. Higher percentages of GSG and ischemic-appearing glomeruli at 5-year biopsy predicted allograft loss. The three glomerular features at 5-year biopsy were related; the percentage of GSG and the percentage of ischemic glomeruli were positively correlated, and both were inversely correlated to glomerular volume. At 5 years, only 5.3% of biopsies had ≥40% ischemic glomeruli, but 45% of these grafts failed (versus 11.6% for <40% ischemic glomeruli). Higher Banff scores were more common with increasing percentages of GSG and ischemia, but at 5 years, only the percentage of ischemic glomeruli added to predictive models adjusted for Banff scores. Conclusions Glomerular changes reflect important pathologic processes that predict graft loss. Measuring glomerular changes quantitatively on surveillance biopsies, especially the proportion of ischemic-appearing glomeruli, may enhance the current Banff system and be a useful surrogate end point for clinical intervention trials. Podcast This article contains a podcast at

AbstractBackgroundComputer‐assisted scoring is gaining prominence in the evaluation of renal histology; however, much of the focus has been on identifying larger objects such as glomeruli. Total inflammation impacts graft outcome, and its quantification requires tools to identify objects at the cellular level or smaller. The goal of the current study was to use CD45 stained slides coupled with image analysis tools to quantify the amount of non‐glomerular inflammation within the cortex.MethodsSixty renal transplant whole slide images were used for digital image analysis. Multiple thresholding methods using pixel intensity and object size were used to identify inflammation in the cortex. Additionally, convolutional neural networks were used to separate glomeruli from other objects in the cortex. This combined measure of inflammation was then correlated with rescored Banff total inflammation classification and outcomes.ResultsIdentification of glomeruli on biopsies had high fidelity (mean pixelwise dice coefficient of .858). Continuous total inflammation scores correlated well with Banff rescoring (maximum Pearson correlation .824). A separate set of thresholds resulted in a significant correlation with alloimmune graft loss.ConclusionsAutomated scoring of inflammation showed a high correlation with Banff scoring. Digital image analysis provides a powerful tool for analysis of renal pathology, not only because it is reproducible and can be automated, but also because it provides much more granular data for studies.

Abstract Background The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. Purpose To ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. Methods In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV(+)), 25 with AM and negative gene testing (DGV(−)), and 36 AM patients without genetics (w/o genetics). All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance imaging (CMRI). In 86 patients CMRI changes in function and structure were re-assessed at follow-up. Results In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular (LV) ejection fraction was 56% on CMRI (p=NS vs. the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared to DGV(−) and w/o genetics patients (62.3% vs. 17.5% vs. 5.3% at 5 years respectively; p&lt;0.0001), driven by myocarditis recurrence and ventricular arrhythmias (Figure 1A, B). At follow-up CMRI, a higher number of late-gadolinium enhanced segments was found in DGV(+) AM. Conclusions Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with AM patients without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health

Background: Hybrid debranching repair of pararenal and thoracoabdominal aortic aneurysms was initially designed as a better alternative to standard open repair, addressing the limitations of endovascular repair involving the visceral aorta. We reviewed the collective outcomes of hybrid debranching repairs using extra-anatomic, open surgical debranching of the renal-mesenteric arteries, followed by endovascular aortic stenting. Methods: Data from patients who underwent hybrid repair in 14 North American institutions during 10 years were retrospectively reviewed. Society of Vascular Surgery scores were used to assess comorbidity risk. Early and late outcomes, including mortality, morbidity, reintervention, and patency were analyzed. Results: A total of 208 patients (118 male; mean age, 71±8 years old) were treated by hybrid repair with extraanatomic reconstruction of 657 renal and mesenteric arteries (mean 3.2 vessels/patient). Mean aneurysm diameter was 6.6±1.3 cm. Thoracoabdominal aortic aneurysms were identified in 163 (78%) patients and pararenal aneurysms in 45 (22%). A single-stage repair was performed in 92 (44%) patients. The iliac arteries were the most common source of inflow (n=132; 63%), and most (n=150; 72%) had 3 or more bypasses. There were 30 (14%) early deaths, ranging widely across sites (0%–21%). A Society of Vascular Surgery comorbidity score >15 was the primary predictor of early mortality ( P <0.01), whereas mortality was 3% in a score ≤9. Early complications occurred in 140 (73%) patients and included respiratory complications in 45 patients (22%) and spinal cord ischemia in 22 (11%), of whom 10 (45%) fully recovered. At 5 years, survival was 61±5%, primary graft patency was 90±2%, and secondary patency was 93±2%. The most significant predictor of late mortality was renal insufficiency ( P <0.0001). Conclusions: Mortality after hybrid repair and visceral debranching is highly variable by center, but strongly affected by preoperative comorbidities and the centers’ experience with the technique. With excellent graft patency at 5 years, the outcomes of hybrid repair done at centers of excellence and in carefully selected patients may be comparable (or better) than traditional open or even totally endovascular approaches. However, in patients already considered as high-risk for surgery, it may not offer better outcomes.

ObjectiveTo describe people with gout who were diagnosed with coronavirus disease 2019 (COVID‐19) and hospitalized and to characterize their outcomes.MethodsData on patients with gout hospitalized for COVID‐19 between March 12, 2020, and October 25, 2021, were extracted from the COVID‐19 Global Rheumatology Alliance registry. Descriptive statistics were used to describe the demographics, comorbidities, medication exposures, and COVID‐19 outcomes including oxygenation or ventilation support and death.ResultsOne hundred sixty‐three patients with gout who developed COVID‐19 and were hospitalized were included. The mean age was 63 years, and 85% were male. The majority of the group lived in the Western Pacific Region (35%) and North America (18%). Nearly half (46%) had two or more comorbidities, with hypertension (56%), cardiovascular disease (28%), diabetes mellitus (26%), chronic kidney disease (25%), and obesity (23%) being the most common. Glucocorticoids and colchicine were used pre‐COVID‐19 in 11% and 12% of the cohort, respectively. Over two thirds (68%) of the cohort required supplemental oxygen or ventilatory support during hospitalization. COVID‐19‐related death was reported in 16% of the overall cohort, with 73% of deaths documented in people with two or more comorbidities.ConclusionThis cohort of people with gout and COVID‐19 who were hospitalized had high frequencies of ventilatory support and death. This suggests that patients with gout who were hospitalized for COVID‐19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.