For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

/pdf/the-nox-family-of-ros-generating-nadph-oxidases-physiology-zjc88zvh59.pdf

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-related risk, and to guide management. The auscultatory technique with a trained observer and mercury sphygmomanometer continues to be the method of choice for measurement in the office, using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended. They have the advantage of being able to take multiple measurements. Proper training of observers, positioning of the patient, and selection of cuff size are all essential. It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a failure of blood pressure to fall during the night may be associated with increased risk. In obese patients and children, the use of an appropriate cuff size is of paramount importance.

/pdf/recommendations-for-blood-pressure-measurement-in-humans-and-19z5w6eq69.pdf

Recommendations for Blood Pressure Measurement in Humans and Experimental Animals Part 1: Blood Pressure Measurement in Humans: A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

The ferritins: molecular properties, iron storage function and cellular regulation☆

Chronic kidney disease can arise from the misappropriation of processes that normally promote tissue homeostasis in health. Such is the case when certain Ig light chains use megalin-cubilin receptors to enter proximal tubular epithelial cells. These receptors, apically located on the proximal tubule, form complexes with any one of a number of plasma proteins that escape into the urinary space.1 After endocytosis, the receptors disengage from the complexes and cycle back to the apical surface, whereas the ligands are processed and catabolized by lysosomes. In health, the function of such receptor-mediated endocytosis in the kidney is truly substantial: This endocytotic process restrains urinary loss of proteins, reclaims amino acids and nutrients derived from protein catabolism, recovers filtered vitamins, and influences the fate of hormones by either degrading them or activating their precursors.1

The incorporation and catabolism of Ig light chains by the proximal tubule would seem, at first glance, a beneficial renal response in myeloma and light-chain proteinuria. Clearance of light chains by the proximal tubule would reduce their downstream delivery and their interaction with Tamm-Horsfall protein, thereby decreasing the risk for cast nephropathy; however, as made clear by a number of studies,2–5 the uptake of light chains by the proximal tubule triggers a vigorous inflammatory response. The studies of Basnayake et al.6 in this issue of JASN examine the basis for this inflammatory behavior by exposing human proximal tubular epithelial cells to pathophysiologically relevant concentrations of light chains derived from patients with myeloma and kidney disease. Their findings demonstrate that light-chain uptake by megalin-cubilin receptors increases cellular generation of hydrogen peroxide, the latter activating c-Src, which in turn induces the chemokine monocyte chemoattractant protein 1 (MCP-1).

The activation of c-Src by nephrotoxic light chains is a significant observation, because c-Src, a nonreceptor tyrosine kinase family member, is a critical hub in cell signaling networks.7 Not only is c-Src activated upon receptor binding of certain growth factors, but also c-Src itself can facilitate the transactivation of growth factor receptors; c-Src recruits such signaling species as mitogen-activated protein kinase members, Akt, Stat3, and PGC-1α. c-Src can also activate transcription factors such as NF-κB and AP-1. In view of these broad effects of c-Src on cell signaling, it is not surprising that c-Src is increasingly implicated in renal processes, including those that are physiologic (e.g., acid-base homeostasis,8 renal hypertrophy9) and those that are pathophysiologic (e.g., podocyte proliferation and dedifferentiation,10 cystic kidney disease,11 albumin-induced cytokine expression12). The findings of Basnayake et al.6 are important for several reasons: First, they identify another disease instigated by the activation of c-Src; second, they provide an explanation for the recruitment of mitogen-activated protein kinase–dependent signaling and activation of NF-κB described in previous studies of light-chain–exposed renal epithelial cells2,3; and third, they direct attention to c-Src as an inducer of MCP-1, a chemokine strongly upregulated and broadly implicated in kidney injury.

Previous studies by Sanders' laboratory demonstrated that Ig light chains, quite remarkably, generate substantial amounts of hydrogen peroxide (H2O2) in cell-free solutions.4 In the study by Basnayake et al.,6 the addition of catalase, a scavenger of H2O2, to the light-chain–containing medium did not reduce the cellular production of MCP-1. These findings led to the plausible conclusion that H2O2, accounting for the induction of MCP-1, originates in the intracellular, not the extracellular, compartment.6 It would be of interest to determine the specific intracellular site and biochemical mechanism accounting for increased production of H2O2, because such oxidant generation links cellular uptake of light chains and activation of c-Src. The role of the hydroxyl radical and labile cellular iron would also be of interest: DMTU, used as a trap for H2O2 in the study by Basnayake et al.,6 is also a hydroxyl radical scavenger, and H2O2 can generate the hydroxyl radical in the presence of iron.13 Defining the role of labile cellular iron is clinically relevant, because such involvement can be blocked by iron chelators. Finally, the failure of extracellular catalase to reduce cellular production of MCP-1 suggests that extracellular catalase did not scavenge intracellular H2O2, an oxidant that diffuses across cell membranes. This raises the intriguing possibility that in the extracellular medium, nephrotoxic light chains, either directly or in concert with the H2O2 they generate therein, denature catalase; if so, then this would indicate that light chains impose oxidative stress not only by generating oxidants but also by disabling mechanisms that scavenge them.

Further exploration of the elegant in vitro analyses of Basnayake et al.6 would be facilitated by the availability of a relevant in vivo model of light-chain–induced kidney disease; however, the absence of such a model is a challenging issue in this field. Approximately 20 years ago, it was shown that administration of certain Bence Jones proteins to mice induced renal lesions resembling those observed in patients from whom these Bence Jones proteins were obtained.14 More recently, systemic infusion of nephrotoxic light chains over 3 days to rats increased renal production of TNF-α, but it is uncertain whether structural and functional effects accompany such TNF-α production.15 Although a transgenic light-chain–overexpressing mouse has been described, the renal lesions that develop are those of crystalline light-chain deposits in tubules.16 Nonetheless, the observations of Basnayake et al.6 can be readily pursued by translational analyses in patients with monoclonal gammopathies. For example, expression of oxidant stress markers, c-Src, and MCP-1 can be assessed in kidney biopsies. Urine normally contains micromolar amounts of H2O2,17 and it would be of interest to determine whether increased urinary excretion of H2O2 and MCP-1 antedates the appearance of paraproteinemic kidney disease, or a decrease in such excretory rates predicts the remission of such kidney disease. Urinary content of H2O2 and MCP-1 thus may serve as biomarkers for light-chain–induced kidney disease.

By defining the concatenation of steps that culminate in Ig light-chain–induced renal production of MCP-1 and the particular role of c-Src activation in this process, the findings of Basnayake et al.6 are of therapeutic significance. There is a substantial need for new therapies for kidney disease caused by monoclonal gammopathies,18 and germane to the findings of Basnayake et al.6 is that inhibitors of c-Src are under considerable investigation as a therapy for cancer.7 Such targeting of c-Src may mitigate Ig light-chain–induced kidney disease and thus offers a novel therapeutic approach in this disorder.

Receptor-mediated endocytosis is a Trojan horse in light-chain nephrotoxicity.

The COVID-19 Pandemic and Mayo Clinic Proceedings.

Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-β/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.

/pdf/klf11-deficiency-enhances-chemokine-generation-and-fibrosis-174ccui4.pdf

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

Progression of chronic kidney disease (CKD) involves the recruitment and engagement of cellular processes originating in specific compartments of the kidney on the one hand and biochemical pathways of cell injury that contribute to these processes on the other hand. Many of these processes possess the capacity to ramify broadly beyond the compartment where they initially arose. It is this essential consideration that contributes so fundamentally to the increasing loss of functional nephrons and the progression of CKD. A number of different biochemical pathways contribute to CKD progression: angiotensin II induces TGF-β1 and the consequent elaboration of extracellular matrix; angiotensin II also induces oxidative stress which itself can upregulate TGF-β1 in vicinal cells and thus the propagation of a fibrosing response. This lack of containment of compartmental processes, and this versatility of injurious biochemical pathways, not only underlies the pathogenesis of CKD but also holds substantial therapeutic significance. Namely, the best hope for retarding or preventing the progression of CKD resides in a combined, multipronged therapeutic approach that interrupts these processes and pathways at separate and several steps.

Karl A. Nath

Papers

Receptor-mediated endocytosis is a Trojan horse in light-chain nephrotoxicity.

The COVID-19 Pandemic and Mayo Clinic Proceedings.

KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction

Pathophysiology of Chronic Kidney Disease Progression: Organ and Cellular Considerations

Disease Progression and End-Stage Renal Disease in Diverse Glomerulopathies.