Eculizumab discontinuation in atypical haemolytic uraemic syndrome : TMA recurrence risk and renal outcomes

Eculizumab modifies the course of disease in patients with atypical haemolytic uraemic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated haematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analysed. The primary endpoint was the proportion of patients suffering from thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: estimated glomerular filtration rate changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. We analysed 151 patients with clinically diagnosed aHUS who had evidence of haematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; seven (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essentia

Projecting ocean acidification impacts for the Gulf of Maine to 2050: new tools and expectations

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Siedlecki, S. A., Salisbury, J., Gledhill, D. K., Bastidas, C., Meseck, S., McGarry, K., Hunt, C. W., Alexander, M., Lavoie, D., Wang, Z. A., Scott, J., Brady, D. C., Mlsna, I., Azetsu-Scott, K., Liberti, C. M., Melrose, D. C., White, M. M., Pershing, A., Vandemark, D., Townsend, D. W., Chen, C,. Mook, W., Morrison, R. Projecting ocean acidification impacts for the Gulf of Maine to 2050: new tools and expectations. Elementa: Science of the Anthropocene, 9(1), (2021): 00062, https://doi.org/10.1525/elementa.2020.00062.Ocean acidification (OA) is increasing predictably in the global ocean as rising levels of atmospheric carbon dioxide lead to higher oceanic concentrations of inorganic carbon. The Gulf of Maine (GOM) is a seasonally varying region of confluence for many processes that further affect the carbonate system including freshwater influences and high productivity, particularly near the coast where local processes impart a strong influence. Two main regions within the GOM currently experience carbonate conditions that are suboptimal for many organisms—the nearshore and subsurface deep shelf. OA trends over the past 15 years have been masked in the GOM by recent warming and changes to the regional circulation that locally supply more Gulf Stream waters. The region is home to many commercially important shellfish that are vulnerable to OA conditions, as well as to the human populations whose dependence on shellfish species in the fishery has continued to increase over the past decade. Through a review of the sensitivity of the regional marine ecosystem inhabitants, we identified a critical threshold of 1.5 for the aragonite saturation state (Ωa). A combination of regional high-resolution simulations that include coastal processes were used to project OA conditions for the GOM into 2050. By 2050, the Ωa declines everywhere in the GOM with most pronounced impacts near the coast, in subsurface waters, and associated with freshening. Under the RCP 8.5 projected climate scenario, the entire GOM will experience conditions below the critical Ωa threshold of 1.5 for most of the year by 2050. Despite these declines, the projected warming in the GOM imparts a partial compensatory effect to Ωa by elevating saturation states considerably above what would result from acidification alone and preserving some important fisheries locations, including much of Georges Bank, above the critical threshold.This research was financially supported by the Major Special Projects of the Ministry of Science and Technology of China (2016YFC020600), the Young Scholars Science Foundation of Lanzhou Jiaotong University (2018033), and the Talent Innovation and Entrepreneurship Projects of Lanzhou (2018-RC-84)

RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm

Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury blood flow was decreased in the inner cortex of wild type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) to secrete the macrophage chemoattractant, RANTES; a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared to transgenic and non-transgenic mice after the 10 minute injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation

Long-Term Retention of an Intraorbital Metallic Foreign Body Adjacent to the Optic Nerve

We report the case of an asymptomatic 47 year-old male patient who suffered a penetrating wound from a metallic foreign body that became embedded adjacent to the optic nerve for over thirty years, as well as the associated examination, imaging, and fundus photography. Intraorbital metallic foreign bodies can be well tolerated and may not require surgical intervention despite proximity to important structures

RGS4, a GTPase activator, improves renal function in ischemia–reperfusion injury

Acute kidney dysfunction after ischemia–reperfusion injury (IRI) may be a consequence of persistent intrarenal vasoconstriction. Regulators of G-protein signaling (RGSs) are GTPase activators of heterotrimeric G proteins that can regulate vascular tone. RGS4 is expressed in vascular smooth muscle cells in the kidney; however, its protein levels are low in many tissues due to N-end rule-mediated polyubiquitination and proteasomal degradation. Here, we define the role of RGS4 using a mouse model of IRI comparing wild-type (WT) with RGS4-knockout mice. These knockout mice were highly sensitized to the development of renal dysfunction following injury exhibiting reduced renal blood flow as measured by laser-Doppler flowmetry. The kidneys from knockout mice had increased renal vasoconstriction in response to endothelin-1 infusion ex vivo. The intrinsic renal activity of RGS4 was measured following syngeneic kidney transplantation, a model of cold renal IRI. The kidneys transplanted between knockout and WT mice had significantly reduced reperfusion blood flow and increased renal cell death. WT mice administered MG-132 (a proteasomal inhibitor of the N-end rule pathway) resulted in increased renal RGS4 protein and in an inhibition of renal dysfunction after IRI in WT but not in knockout mice. Thus, RGS4 antagonizes the development of renal dysfunction in response to IRI

Alternative Diagnostic Strategy for the Assessment and Treatment of Pulmonary Embolus: A Case Series

Introduction: Ferumoxytol-enhanced magnetic resonance angiography (FeMRA) can be used as an alternate and safe method to diagnose patients with compromised renal function who present with acute pulmonary embolus in the emergency department (ED) setting.Case Report: A 62-year old man with a history of renal transplant and lymphoproliferative disease described new onset of breathlessness. His clinical symptoms were suggestive of pulmonary embolus. He underwent FeMRA in the ED to avoid exposure to intravenous iodinated contrast. FeMRA demonstrated a left main pulmonary artery embolus, which extended to the left interlobar pulmonary artery. Afterward, the patient initiated anticoagulation therapy. With preserved renal function he was able to continue his outpatient chemotherapy regimen.Conclusion: This case highlights a safe imaging technique for emergency physicians to diagnose pulmonary embolus and subsequently guide anticoagulation therapy for patients in whom use of conventional contrast is contraindicated

Alternative Diagnostic Strategy for the Assessment and Treatment of Pulmonary Embolus: A Case Series

Introduction: Ferumoxytol-enhanced magnetic resonance angiography (FeMRA) can be used as an alternate and safe method to diagnose patients with compromised renal function who present with acute pulmonary embolus in the emergency department (ED) setting.Case Report: A 62-year old man with a history of renal transplant and lymphoproliferative disease described new onset of breathlessness. His clinical symptoms were suggestive of pulmonary embolus. He underwent FeMRA in the ED to avoid exposure to intravenous iodinated contrast. FeMRA demonstrated a left main pulmonary artery embolus, which extended to the left interlobar pulmonary artery. Afterward, the patient initiated anticoagulation therapy. With preserved renal function he was able to continue his outpatient chemotherapy regimen.Conclusion: This case highlights a safe imaging technique for emergency physicians to diagnose pulmonary embolus and subsequently guide anticoagulation therapy for patients in whom use of conventional contrast is contraindicated

Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease

Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3‐arm cross‐sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next‐generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced β‐actin (P<0.01), β‐tubulin (P<0.01), vimentin (P<0.05), and increased expression of vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways