Reducing the risk of denosumab-induced hypocalcemia in patients with advanced chronic kidney disease: a quality improvement initiative.

Denosumab can improve bone health in advanced kidney disease (CKD) but is associated with hypocalcemia. We created a clinical care pathway focused on the safe provision of denosumab in advanced CKD that reduced the risk of hypocalcemia by 37% at our hospital. Similar pathways could be adopted and tested in other centers. PURPOSE: There is an increased risk of hypocalcemia with denosumab in advanced chronic kidney disease (CKD). We aimed to reduce the proportion of patients with advanced CKD who experienced denosumab-induced hypocalcemia at our center. METHODS: We conducted a quality improvement (QI) project of patients with CKD stage 3b or less (i.e., estimated glomerular filtration rate <45 mL/min/1.73m2 including dialysis) who were part of the Osteoporosis and Bone Disease Program at St. Joseph's Health Care London (Canada) between December 2020 and January 2023. Our intervention was a clinical care pathway which optimized CKD mineral and bone disorder (CKD-MBD) and 25-hydroxyvitamin levels; provided calcium and vitamin D prophylaxis; promoted multidisciplinary communication between bone and kidney specialists; and carefully monitored calcium post-denosumab injection. Our primary outcome measure was the proportion of patients with hypocalcemia (defined by albumin-corrected serum calcium <1.9mmol/L) at 60 days. Process measures included the appropriate provision of calcium and vitamin D prophylaxis. Balance measures included the development of hypercalcemia and hyperphosphatemia following prophylaxis. We used plan-do-see-act cycles to study four tests of change and presented results using descriptive statistics and run charts. RESULTS: There were 6 patients with advanced CKD treated with denosumab prior to the implementation of our care pathway (March 2015-October 2020; 83% receiving dialysis). At the time of their denosumab injection, 83% were using 500-1000 mg of calcium, and 83% used 1000-2000 IU of vitamin D3. Fifty percent developed denosumab-induced hypocalcemia. Following the implementation of our care pathway, 15 patients (40% receiving dialysis) were treated with denosumab. Ninety-three percent received calcium at a daily dose of 350 to 2250 mg and 87% received 1000-2000 IU of vitamin D3. Thirteen percent developed denosumab-induced hypocalcemia. There was no hypercalcemia or hyperphosphatemia. CONCLUSIONS: A clinical care pathway focused on the safe provision of denosumab in advanced CKD reduced the risk of hypocalcemia in patients treated in our hospital. Similar pathways could be adopted and tested in other centers.

Isolated Hodgkin lymphoma of the intracranial dura: A case report and review of the literature.

Primary dural Hodgkin lymphoma (PDHL) is an extremely rare subset of Hodgkin lymphoma (HL). Its existence is controversial, as Hodgkin lymphoma is not traditionally thought to arise from the central nervous system (CNS) or its meninges and only 0.02% of patients with Hodgkin lymphoma have any CNS involvement. We report a case of a 71-year-old Caucasian man who presented with progressive fatigue and sudden onset slurred speech, disorientation, and memory loss. Brain imaging identified a large extra-axial right frontal mass, and he underwent urgent subtotal resection. Pathology and subsequent workup revealed Stage IAE classical Hodgkin lymphoma of the right frontal dura, with no extra-cranial disease or leptomeningeal spread detected. The patient was subsequently treated with ABVD chemotherapy (completed 2.5 of 4 planned cycles) and 36 Gy in 20 fractions of consolidative involved-site radiotherapy (ISRT). He has been followed for 5 years with no clinical or radiological signs of recurrence. This is the second confirmed case of intracranial PDHL reported in the literature, with the longest follow-up for any case of PDHL.

Burden of opioid toxicity death in the fentanyl-dominant era for people who experience incarceration in Ontario, Canada, 2015-2020: a whole population retrospective cohort study.

OBJECTIVES: To describe mortality due to opioid toxicity among people who experienced incarceration in Ontario between 2015 and 2020, during the fentanyl-dominant era. DESIGN: In this retrospective cohort study, we linked Ontario coronial data on opioid toxicity deaths between 2015 and 2020 with correctional data for adults incarcerated in Ontario provincial correctional facilities. SETTING: Ontario, Canada. PARTICIPANTS: Whole population data. MAIN OUTCOMES AND MEASURES: The primary outcome was opioid toxicity death and the exposure was any incarceration in a provincial correctional facility between 2015 and 2020. We calculated crude death rates and age-standardised mortality ratios (SMR). RESULTS: Between 2015 and 2020, 8460 people died from opioid toxicity in Ontario. Of those, 2207 (26.1%) were exposed to incarceration during the study period. Among those exposed to incarceration during the study period (n=1 29 152), 1.7% died from opioid toxicity during this period. Crude opioid toxicity death rates per 10 000 persons years were 43.6 (95% CI=41.8 to 45.5) for those exposed to incarceration and 0.95 (95% CI=0.93 to 0.97) for those not exposed. Compared with those not exposed, the SMR for people exposed to incarceration was 31.2 (95% CI=29.8 to 32.6), and differed by sex, at 28.1 (95% CI=26.7 to 29.5) for males and 77.7 (95% CI=69.6 to 85.9) for females. For those exposed to incarceration who died from opioid toxicity, 10.6% died within 14 days of release and the risk was highest between days 4 and 7 postrelease, at 288.1 per 10 000 person years (95% CI=227.8 to 348.1). CONCLUSIONS: The risk of opioid toxicity death is many times higher for people who experience incarceration compared with others in Ontario. Risk is markedly elevated in the week after release, and women who experience incarceration have a substantially higher SMR than men who experience incarceration. Initiatives to prevent deaths should consider programmes and policies in correctional facilities to address high risk on release.

Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The health impacts of the COVID-19 pandemic on adults who experience imprisonment globally: A mixed methods systematic review.

BACKGROUND: The prison setting and health status of people who experience imprisonment increase the risks of COVID-19 infection and sequelae, and other health impacts of the COVID-19 pandemic. OBJECTIVES: To conduct a mixed methods systematic review on the impacts of the COVID-19 pandemic on the health of people who experience imprisonment. DATA SOURCES: We searched Medline, PsycINFO, Embase, the Cochrane Library, Social Sciences Abstracts, CINAHL, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Sociology Database, Coronavirus Research Database, ERIC, Proquest Dissertations and Theses, Web of Science, and Scopus in October 2021. We reviewed reference lists for included studies. STUDY ELIGIBILITY CRITERIA: Original research conducted in or after December 2019 on health impacts of the COVID-19 pandemic on adults in prisons or within three months of release. STUDY APPRAISAL AND SYNTHESIS METHODS: We used the Joanna Briggs Institute's Critical Appraisal Checklist for Qualitative Research for qualitative studies and the Joanna Briggs Institute's Critical Appraisal Checklist for Studies Reporting Prevalence Data for quantitative studies. We qualitized quantitative data and extracted qualitative data, coded data, and collated similar data into categories. RESULTS: We identified 62 studies. People in prisons had disproportionately high rates of COVID-19 infection and COVID-19 mortality. During the pandemic, all-cause mortality worsened, access to health care and other services worsened, and there were major impacts on mental wellbeing and on relationships with family and staff. There was limited evidence regarding key primary and secondary prevention strategies. LIMITATIONS: Our search was limited to databases. As the COVID-19 pandemic is ongoing, more evidence will emerge. CONCLUSIONS: Prisons and people who experience imprisonment should be prioritized for COVID-19 response and recovery efforts, and an explicit focus on prisons is needed for ongoing public health work including emergency preparedness. PROSPERO REGISTRATION NUMBER: 239324.

Denosumab in chronic kidney disease: a narrative review of treatment efficacy and safety.

People with chronic kidney disease (CKD) are at high risk of bone fractures. In this review, we summarize the complexity of fracture prevention in CKD, describe the usefulness of a medication called denosumab, and review its safety in this population. Our article will help doctors manage brittle bones in CKD and encourage researchers to conduct more studies to improve bone health in CKD. PURPOSE: Patients with CKD are at increased risk of fragility fractures and associated consequences. We discuss the complexity of fracture prevention in CKD, summarize the efficacy and safety of denosumab, and provide an approach to denosumab-induced hypocalcemia. METHODS: Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for studies on fracture prevention in CKD and the efficacy and safety of denosumab. We included observational studies, randomized controlled trials (RCTs), meta-analyses, evidence-based reviews, and clinical practice guidelines. RESULTS: The diagnosis of osteoporosis and prevention of related fragility fractures is complex in CKD, particularly in those with advanced and end-staged kidney disease (ESKD). Prior to initiating denosumab, it is important to assess for and optimize CKD-mineral and bone disorders (CKD-MBD). In observational studies and small RCTs, denosumab has been shown to improve bone mineral density and reduce bone turnover in CKD, but there have been no studies focused upon its fracture efficacy. Denosumab-induced hypocalcemia has also been reported, which disproportionately impacts those with ESKD. Risk factors for hypocalcemia with denosumab use in CKD include lower baseline serum calcium and 25 hydroxyvitamin D and both low and high bone turnover. Choosing the "right patient" for denosumab, supplementing with calcium and vitamin D, adjusting calcium dialysate, and close clinical monitoring are essential if considering this drug. CONCLUSION: With optimization of CKD-MBD, calcium and vitamin D supplementation, and close monitoring, denosumab can be considered in CKD. There are however opportunities to better understand its fracture efficacy and safety in an RCT setting.

Lipid effects of sodium-glucose cotransporter 2 inhibitors.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antihyperglycemic drugs that show remarkable cardiorenal protective effects in patients with or without type 2 diabetes. Furthermore, they are effective among patients across a wide range of baseline renal and cardiac function. Numerous mechanisms have been evaluated to understand these remarkable clinical benefits. From an early stage, these agents were noted to affect the plasma lipid profile. Here we review lipid profile alterations attributable to SGLT2 inhibitors and also some mechanisms explored in model systems and human studies. RECENT FINDINGS: SGLT2 inhibitors given to patients with diabetes as monotherapy shift substrate utilization from carbohydrates to lipids, and have mild effects on the lipid profile. Increased LDL cholesterol appears to be associated with increased hepatic production and decreased catabolism. Increased HDL cholesterol and decreased triglycerides appear to be associated with improved insulin sensitivity and increased lipolysis. Lipid effects of SGLT2 inhibitors are further modulated by background therapy with other diabetes medications and statins. SUMMARY: The minor lipid profile alterations observed in patients treated with SGLT2 inhibitors are offset by the staggering range of beneficial pleiotropic mechanisms that likely explain the marked cardiorenal benefits of these agents.

Liver Injury Associated With Ezetimibe Monotherapy.

Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.

L'intolérance aux statines, se manifestant principalement par une myalgie, n'est pas rare chez les patients traités pour des taux élevés de cholestérol à lipoprotéines à basse densité (LDL). Des médicaments n'appartenant pas à la classe des statines, comme l'ézétimibe, permettent d'éviter l'exposition aux statines chez les patients, tout en réduisant le taux le cholestérol LDL. L'ézétimibe est généralement bien toléré, bien que des symptômes gastro-intestinaux et musculosquelettiques aient été signalés à l'occasion. Nous décrivons un cas extrêmement rare de lésion hépatique associée à l'ézétimibe ayant nécessité un traitement prolongé par la prednisone et l'azathioprine. Il faut soupçonner une lésion hépatique liée à l'ézétimibe lors de la survenue d'anomalies hépatiques pendant le traitement par l'ézétimibe en l'absence d'autres facteurs déclencheurs.

Comparative efficacy of glucocorticoid receptor agonists on Th2 cell function and attenuation by progesterone.

BACKGROUND: Corticosteroids (CS)s suppress cytokine production and induce apoptosis of inflammatory cells. Prednisone and dexamethasone are oral CSs prescribed for treating asthma exacerbations. While prednisone is more commonly prescribed, dexamethasone is long acting and a more potent glucocorticoid receptor (GR) agonist. It can be administered as a one or two dose regime, unlike the five to seven days required for prednisone, a feature that increases compliance. We compared the relative ability of these two oral CSs to suppress type 2 inflammation. Since progesterone has affinity for the GR and women are more likely to relapse following an asthma exacerbation, we assessed its influence on CS action. RESULTS: Dexamethasone suppressed the level of IL-5 and IL-13 mRNA within Th2 cells with ~ 10-fold higher potency than prednisolone (the active form of prednisone). Dexamethasone induced a higher proportion of apoptotic and dying cells than prednisolone, at all concentrations examined. Addition of progesterone reduced the capacity of both CS to drive cell death, though dexamethasone maintained significantly more killing activity. Progesterone blunted dexamethasone-induction of FKBP5 mRNA, indicating that the mechanism of action was by interference of the CS:GR complex. CONCLUSIONS: Dexamethasone is both more potent and effective than prednisolone in suppressing type 2 cytokine levels and mediating apoptosis. Progesterone attenuated these anti-inflammatory effects, indicating its potential influence on CS responses in vivo. Collectively, our data suggest that when oral CS is required, dexamethasone may be better able to control type 2 inflammation, eliminate Th2 cells and ultimately lead to improved long-term outcomes. Further research in asthmatics is needed.

Browning of white adipose tissue after a burn injury promotes hepatic steatosis and dysfunction.

Burn patients experiencing hypermetabolism develop hepatic steatosis, which is associated with liver failure and poor outcomes after the injury. These same patients also undergo white adipose tissue (WAT) browning, which has been implicated in mediating post-burn cachexia and sustained hypermetabolism. Despite the clinical presentation of hepatic steatosis and WAT browning in burns, whether or not these two pathological responses are linked remains poorly understood. Here, we show that the burn-induced WAT browning and its associated increased lipolysis leads to the accelerated development of hepatic steatosis in mice. Deletion of interleukin 6 (IL-6) and the uncoupling protein 1 (UCP1), regulators of burn-induced WAT browning completely protected mice from hepatic steatosis after the injury. Treatment of post-burn mice with propranolol or IL-6 receptor blocker attenuated burn-induced WAT browning and its associated hepatic steatosis pathology. Lipidomic profiling in the plasma of post-burn mice and burn patients revealed elevated levels of damage-inducing lipids (palmitic and stearic acids), which induced hepatic endoplasmic reticulum (ER) stress and compromised hepatic fat oxidation. Mechanistically, we show that hepatic ER stress after a burn injury leads to a greater ER-mitochondria interaction, hepatocyte apoptosis, oxidative stress, and impaired fat oxidation. Collectively, our findings uncover an adverse "cross-talk" between the adipose and liver tissue in the context of burn injury, which is critically mediated by WAT browning.

IL-2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

BACKGROUND: Glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine expression and induce apoptosis. Asthma severity is associated with type 2 inflammation, circulating Th2 cells and higher GC requirements. OBJECTIVE: The aim of this study was to assess whether ex vivo production of interleukin 2 (IL-2), a T-cell survival factor, associated with clinical features of asthma severity, the proportion of blood Th2 cells and Th2 cell responses to GC. METHODS: Peripheral blood from asthma patients (n = 18) was obtained and the proportion of Th2 cells determined by flow cytometry. Peripheral blood cells were activated with mitogen (24 hours) and supernatant levels of IL-2 and IL-13 measured by enzyme-linked immunosorbent assay. In vitro differentiated Th2 cells were treated with dexamethasone (DEX) and IL-2 and assessed for apoptosis by flow cytometry (annexin V). Level of messenger RNA (mRNA) for antiapoptotic (BCL-2) and proapoptotic (BIM) genes, IL-13, GC receptor (GR) and FKBP5 were determined by quantitative real-time polymerase chain reaction. GR binding was assessed by chromatin immunoprecipitation. RESULTS: IL-2 produced by activated peripheral blood cells correlated negatively with lung function and positively with a daily dose of inhaled GC. When patients were stratified based on IL-2 level, high IL-2 producers made more IL-13 and had a higher proportion of circulating Th2 cells. In vitro, increasing the level of IL-2 in the culture media was associated with resistance to DEX-induced apoptosis, with more BCL-2/less BIM mRNA. Th2 cells cultured in high IL-2 had more IL-13, less GR mRNA, showed reduced binding of the GR to FKBP5, a known GC-induced gene, and required higher concentrations of DEX for cytokine suppression. CONCLUSIONS AND CLINICAL RELEVANCE: IL-2 downregulates Th2 cell responses to GC, supporting both their survival and pro-inflammatory capacity. These results suggest that a patient's potential to produce IL-2 may be a determinant in asthma severity.

Multiparameter functional diversity of human C2H2 zinc finger proteins.

C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2-ZF arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. In addition, little is known about whether or how these proteins regulate transcription. Most of the ∼700 human C2H2-ZF proteins also contain at least one KRAB, SCAN, BTB, or SET domain, suggesting that they may have common interacting partners and/or effector functions. Here, we report a multifaceted functional analysis of 131 human C2H2-ZF proteins, encompassing DNA binding sites, interacting proteins, and transcriptional response to genetic perturbation. We confirm the expected diversity in DNA binding motifs and genomic binding sites, and provide motif models for 78 previously uncharacterized C2H2-ZF proteins, most of which are unique. Surprisingly, the diversity in protein-protein interactions is nearly as high as diversity in DNA binding motifs: Most C2H2-ZF proteins interact with a unique spectrum of co-activators and co-repressors. Thus, multiparameter diversification likely underlies the evolutionary success of this large class of human proteins.