Beta-adrenergic antagonist tolerance in amyloid cardiomyopathy

Background: Beta-adrenergic antagonists or blockers (BB) are a cornerstone of cardiac therapy for multiple indications. However, BB are considered relatively contraindicated in amyloid cardiomyopathy due to poor tolerance. This intolerance is hypothesized to be due to concomitant neuropathy and significant restrictive cardiomyopathy. This study analyzes the incidence and characteristics of BB tolerance in patients with amyloid cardiomyopathy. Methods: Through a single-center retrospective chart review, patients with amyloid cardiomyopathy, confirmed by endomyocardial biopsy or technetium-99 pyrophosphate scan, were identified and clinical data was collected. Statistical methods included Chi-square test and two sample Results: Of 135 cardiac amyloidosis patients, 27 patients (20.0%) had no BB use, 56 patients (41.5%) were current BB users, and 52 patients (38.5%) were prior BB users. The most frequent indications for BB use were heart failure, hypertension, coronary artery disease, and arrhythmia. The most common reason for stopping BB therapy was hypotension (62.8%) followed by fatigue, bradycardia, and orthostasis. Neurologic symptoms at the initial BB prescription or most recent evaluation were not significantly different between current and prior BB users. Their cardiovascular profiles were similar by ejection fraction, wall thickness, troponin I, and brain natriuretic peptide. There was no association for BB discontinuation based on amyloid subtype, sex, or race. Conclusion: The majority of patients with amyloid cardiomyopathy were prescribed BB, and over half of these patients still tolerated BB therapy. Current and prior BB users had similar profiles from a cardiovascular and neurologic perspective, with no association identified to predict BB discontinuation

Rethinking Lupus Nephritis Classification on a Molecular Level

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN. Renal compartmental mRNA abundance was measured in 54 biopsy specimens from LN patients and correlated to ISN/RPS classification and individual histologic lesions. A subset of transcripts was also evaluated in sequential biopsies of a separate longitudinal cohort of 36 patients with paired samples obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance did not demonstrate a relationship with the (ISN/RPS) classification, nor did univariate statistical analysis. Exploratory analyses suggested a correlation with individual histologic lesions. Glomerular FN1 (fibronectin), SPP1 (secreted phosphoprotein 1), and LGALS3 (galectin 3) abundance correlated with disease activity and changed following treatment. Exploratory analyses suggested relationships between specific transcripts and individual histologic lesions, with the important representation of interferon-regulated genes. Our findings suggested that the current LN classification could be refined by the inclusion of molecular descriptors. Combining molecular and pathologic kidney biopsy phenotypes may hold promise to better classify disease and identify actionable treatment targets and merits further exploration in larger cohorts

Network trip assignment and aggregation procedures in urban transportation planning and design

This study documents a performed research on transportation trip (traffic) assignment procedures as well as on techniques of aggregation applied to urban transportation networks. It should be seen as a contribution to the analysis and research on assignment and aggregation principles. It concludes with a procedure proposed in the hope of reaching a working and feasible transportation network level of aggregation. Two aggregate networks consisting of 47 zones (295 links) and 183 zones (1,292 links) were used to investigate trip assignment procedures using the BPR link performance function. This function uses the free flow travel time and the volume/capacity ratio raised to the fourth power in order to compute for congestion. The major concern is, first, to study the applicability of three transportation network assignment algorithms: (1) All-or-nothing incremental, tree-by-tree, and Volume/capacity restrained. (2) Stochastic multi-path incremental, using double-pass method. (3) User-equilibrium using the convex combination method. These algorithms simulate and assign traffic along (i) primary roads, and (ii) primary and secondary roads. Some effort was made to explain the underlying theories of the applied procedures and their equation structure. The second major concern was to study the applicability of two transportation network aggregation procedures: (1) Abstraction aggregation as presented by Chan 1976. (2) Extraction aggregation as presented by Haghani and Daskin 1983. The User Equilibrium is used to simulate and to assign traffic on the aggregate networks where it proved to better assign flows on links. Some underlying theories of aggregation in different fields were explained and a review of related literature provided. The effects of the level of aggregation on assignment outcomes were investigated. It was shown that Chan\u27s abstraction aggregation could not be applied to certain types of transportation network, while Haghani and Daskin\u27s extraction aggregation is not practical for large problems and has some deficiencies. The City of Eindhoven in the Province of Brabant in The Netherlands was used for this study. Actual street counts, trip tables, and a survey on travel times and trips were characteristically available. The used network consists primarily of 1,286 zones and 6,648 links with 29,287 inter-zonal and 143 intra-zonal hourly trips

Network trip assignment and aggregation procedures in urban transportation planning and design

This study documents a performed research on transportation trip (traffic) assignment procedures as well as on techniques of aggregation applied to urban transportation networks. It should be seen as a contribution to the analysis and research on assignment and aggregation principles. It concludes with a procedure proposed in the hope of reaching a working and feasible transportation network level of aggregation. Two aggregate networks consisting of 47 zones (295 links) and 183 zones (1,292 links) were used to investigate trip assignment procedures using the BPR link performance function. This function uses the free flow travel time and the volume/capacity ratio raised to the fourth power in order to compute for congestion. The major concern is, first, to study the applicability of three transportation network assignment algorithms: (1) All-or-nothing incremental, tree-by-tree, and Volume/capacity restrained. (2) Stochastic multi-path incremental, using double-pass method. (3) User-equilibrium using the convex combination method. These algorithms simulate and assign traffic along (i) primary roads, and (ii) primary and secondary roads. Some effort was made to explain the underlying theories of the applied procedures and their equation structure. The second major concern was to study the applicability of two transportation network aggregation procedures: (1) Abstraction aggregation as presented by Chan 1976. (2) Extraction aggregation as presented by Haghani and Daskin 1983. The User Equilibrium is used to simulate and to assign traffic on the aggregate networks where it proved to better assign flows on links. Some underlying theories of aggregation in different fields were explained and a review of related literature provided. The effects of the level of aggregation on assignment outcomes were investigated. It was shown that Chan\u27s abstraction aggregation could not be applied to certain types of transportation network, while Haghani and Daskin\u27s extraction aggregation is not practical for large problems and has some deficiencies. The City of Eindhoven in the Province of Brabant in The Netherlands was used for this study. Actual street counts, trip tables, and a survey on travel times and trips were characteristically available. The used network consists primarily of 1,286 zones and 6,648 links with 29,287 inter-zonal and 143 intra-zonal hourly trips

ANCA-Associated Vasculitis: An Update.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The two major antigens targeted by ANCAs are leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). AAV can be classified into 3 categories based on patterns of clinical involvement: namely, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA). Clinically, AAV involves many organ systems including the lungs, kidneys, skin, and nervous system. The prognosis of AAV has improved dramatically due to advances in the understanding of its pathogenesis and treatment modalities. This review will highlight some of the recent updates in our understanding of the pathogenesis, clinical manifestations, and treatment options in patients with AAV focusing on kidney involvement

ANCA-Associated Vasculitis: An Update.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The two major antigens targeted by ANCAs are leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). AAV can be classified into 3 categories based on patterns of clinical involvement: namely, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA). Clinically, AAV involves many organ systems including the lungs, kidneys, skin, and nervous system. The prognosis of AAV has improved dramatically due to advances in the understanding of its pathogenesis and treatment modalities. This review will highlight some of the recent updates in our understanding of the pathogenesis, clinical manifestations, and treatment options in patients with AAV focusing on kidney involvement

Functional Impairments of Amyloidosis Patients: Physical Therapy Assessment

Amyloidosis is a rare, systemic disease that can result in significant functional impairment. Specific guidelines for the rehabilitation assessment of amyloidosis patients have yet to be established. The purpose of this study was to identify functional deficits and assess differences based on disease type, organ involvement, age, and gender of patients with amyloidosis. Materials and Methods: The multidisciplinary Comprehensive Amyloidosis Clinic (CAC) at Ohio State University (OSU) has developed structured assessment guidelines for amyloidosis patients. A retrospective, single-institution review of patients assessed in CAC between December 2017 and April 2020 was performed. Outcome measure data from the Timed Up and Go (TUG), 30 s sit-to-stand, and physical function portion of the SF 36 were gathered by chart review. Comparisons were made between CAC patient scores and normative data. Kruskal–Wallis tests were used to compare scores across the disease types (light chain, transthyretin wild-type, and hereditary variant transthyretin) and the Mann–Whitney U test was used for pairwise comparisons within disease types and cardiac involvement. Linear regression models were used to assess associations between patient characteristics (including age, gender, disease type, and cardiac involvement) and performance scores. Results: Data from sixty-four patients was evaluated. On the 30-s sit-to-stand test, patients with light chain amyloidosis performed 3.32 fewer repetitions than patients with transthyretin wild-type, p = 0.03. Patients with cardiac involvement had 2.55 fewer repetitions than patients without cardiac involvement, p = 0.03. Older patients were found to have slower TUG performance, and a 10-year increase in age was associated with an 11% increase in TUG scores. Conclusions: Findings indicate patients with light chain amyloidosis and patients with cardiac involvement, when compared to other amyloidosis patients, present with more physical impairments

Creatinine Fluctuation in Patients With Lupus Nephritis: Considerations for Clinical Trial Endpoints.

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus (SLE) and a major driver of morbidity and mortality. Proliferative forms of LN are typically managed with immunosuppressive therapy, with the aim of attenuating renal inflammation and preserving kidney function.1 Unfortunately, despite several clinical trials of LN conducted over the past 30 to 40 years, none has translated into new Food and Drug Administration (FDA)−approved therapies. Multiple issues in clinical trial design likely contributed to these negative outcomes, such as confounding background medications (especially high-dose glucocorticoids), trial duration, and the choice of trial endpoints. Most trials incorporated composite endpoints to define clinical response based on proteinuria and kidney function. Kidney function was generally assessed as a change in estimated glomerular filtration rate or serum creatinine (sCr) as compared to the patients’ values at trial entry.2 Thresholds were then chosen to define the extent of the clinical response (complete, partial, or no response). However, evidence supporting these thresholds is not robust. For example, most studies used a proteinuria cutoff of <0.3 to 0.5 g/d to describe complete response; however, a post hoc analysis of 2 large LN trials demonstrated that proteinuria levels of <0.7 to 0.8 g/d after 1 year of treatment predicted favorable long-term kidney outcomes, suggesting that a less stringent proteinuria cutoff may be reasonable. Similarly, an sCr value <15% above baseline has often been required for complete response in LN trials.S1−S5 However, day-to-day variations in sCr measurements are routinely observed in clinical practice in patients with and without chronic kidney disease, even when measured within a 24-hour period.3 To determine a threshold of kidney function that accounts for expected day-to-day variations, we investigated the fluctuation of sCr in a cohort of patients with LN who were complete renal responders. [...

The Diagnostic Conundrum of Glomerular Crescents With IgA Deposits

Introduction: Glomerulonephritis (GN) with crescents and IgA deposits in kidney biopsy poses a frequent diagnostic and therapeutic dilemma because of multiple possibilities. Methods: Native kidney biopsies showing glomerular IgA deposition and crescents (excluding lupus nephritis) were identified from our biopsy archives between 2010 and 2021. Detailed clinicopathologic features were assessed. One-year clinical follow-up on a subset of cases was obtained. Results: A total of 285 cases were identified, and these clustered into IgA nephropathy (IgAN, n = 108), Staphylococcus or other infection-associated GN/infection-related GN (SAGN/IRGN, n = 43), and antineutrophil cytoplasmic antibody-associated GN (ANCA-GN, n = 26) based on a constellation of clinicopathologic features, but 101 cases (group X) could not be definitively differentiated. The reasons have been elucidated, most important being atypical combination of clinicopathologic features and lack of definitive evidence of active infection. Follow-up (on 72/101 cases) revealed that clinicians\u27 working diagnosis was IgAN in 43%, SAGN/IRGN in 22%, ANCA-GN in 28%, and others in 7% of the cases, but treatment approach varied from supportive or antibiotics to immunosuppression in each subgroup. Comparing these cases as received immunosuppression versus non-immunosuppression, only 2 features differed, namely C3-dominant staining, and possibility of recent infection (both higher in the no-immunosuppression group) (P \u3c 0.05). Renal loss was higher in the non-immunosuppression subgroup, but not statistically significant (P = 0.11). Conclusion: Diagnostic overlap may remain unresolved in a substantial number of kidney biopsies with glomerular crescents and IgA deposits. A case-by-case approach, appropriate antibiotics if infection is ongoing, and consideration for cautious immunosuppressive treatment for progressive renal dysfunction may be needed for best chance of renal recovery