Glucocorticoids in the Treatment of Glomerular Diseases

Ponticelli, Claudio; Locatelli, Francesco

doi:10.2215/cjn.12991117

Cited by 73 publications

(57 citation statements)

References 50 publications

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“…A large randomized controlled trial showed that dexamethasone reduced 28-day mortality in severely ill patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization, but not among those receiving no respiratory support 216 . These findings are encouraging since dexamethasone treatment is also highly beneficial in patients with pre-existing chronic kidney disease 217 , 218 .…”

Section: Therapeutic Considerationsmentioning

confidence: 78%

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

et al. 2020

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In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.

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Section: Therapeutic Considerationsmentioning

confidence: 78%

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

et al. 2020

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“…Glucocorticoids have been extensively used in the treatment of immune-related kidney diseases because of their anti-inflammatory and immunosuppressive effects 1 . However, the use of systemic glucocorticoids is associated with a range of adverse effects, including increased risks of osteoporosis and fracture 2 .…”

Section: Introductionmentioning

confidence: 99%

Risk of fracture according to glucocorticoid use after renal biopsy: a nationwide population-based study

Lee

Park

et al. 2020

Sci Rep

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Few data are available regarding fracture risk in patients treated with glucocorticoids, including patients with kidney disease. A population-based retrospective cohort study was performed using Health Insurance Review and Assessment Service database, a South Korean nationwide cohort set. This study identified 44,702 patients with diagnosis code of kidney diseases who received a renal biopsy between January 1, 2012 and December 31, 2017. A total of 8,624 patients met all study inclusion criteria. A total of 1,406 fractures of any site were observed in the study period. The glucocorticoid-exposed group had more fractures than the unexposed (14.4% vs 8.8%, P < 0.0001). Vertebral fractures were the most common, followed by upper limb, and lower limb fractures. The exposed group showed a remarkably higher hazard ratio of fracture risk (HR 6.0, 95% CI 5.01-7.23) than the unexposed group, indicating systemic glucocorticoid exposure was highly associated with fracture risk. Although HR increased at doses even less than 5 mg/day, it was independent of dose. Older age showed a significant effect on fracture risk (HR 1.2, 95% CI 1.05-1.44), even after adjusting for systemic glucocorticoid exposure. Glucocorticoids was associated with higher risk of fracture even at a low daily dose and short term exposure. Glucocorticoids have been extensively used in the treatment of immune-related kidney diseases because of their anti-inflammatory and immunosuppressive effects 1. However, the use of systemic glucocorticoids is associated with a range of adverse effects, including increased risks of osteoporosis and fracture 2. These agents can decrease the net absorption of calcium and inhibit bone formation 3. Glucocorticoid-induced osteoporosis and osteopenia have been reported in as many as 30-50% of patients receiving chronic glucocorticoid therapy 3,4. Many studies using population-based cohort of adults have documented increased fracture risk of rheumatoid arthritis (RA), pulmonary disease, and inflammatory bowel disease after glucocorticoid exposure 2,5. However, data on the risk of glucocorticoid-associated fractures in patients with kidney disease are lacking. Assessing the relation between glucocorticoid use and fracture risk is challenging because exposures are dynamic and difficult to measure. In addition, the association may be confounded by independent associations of fracture risk with underlying diseases, patient age, and sex. Despite the same use of glucocorticoid, kidney disease and other diseases differ in several underlying conditions. The dosage and the duration of the use of glucocorticoid for kidney disease are different from those for other diseases. They tend to be started with pulsating and finished with shorter or longer duration for kidney disease than for other chronic inflammatory diseases 6,7. The sex and age at which kidney disease occurs are also different from those of other diseases 8. Focusing on patients who received a kidney biopsy, the objective of this study was to determine potential independent e...

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“…Using the validated gene set for further analyses, a convergence of molecular mechanisms was identified including activation of inflammatory pathways and suppression or inhibition of differentiation related pathways. For the inflammatory-related pathways, evidence for their potential causal role in autoimmune or renal disease has been established, including TNF [28][29][30] , JAK-STAT 16 , NFκB 31 , proteasome signaling 32,33 , and reactivation of glucocorticoid signaling through the use of glucocorticoid agonists 34 . JAK-STAT pathway activation has already been implicated across other kidney diseases including diabetic kidney disease (DKD) [35][36][37][38] , and FSGS 13 .…”

Section: Discussionmentioning

confidence: 99%

Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

Eddy

Nair

Mariani

et al. 2018

Preprint

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249 words ABSTRACT Background: Glomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets. Methods: Renal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.Results: In the discovery cohort, 10-25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60-77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFRbased outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (p<0.001), a JAK-STAT biomarker, predictors of CKD progression, interstitial fibrosis (r=0.41, p<0.001), and urinary EGF (r=-0.51, p<0.001).Conclusion: AAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.

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Glucocorticoids in the Treatment of Glomerular Diseases

Cited by 73 publications

References 50 publications

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

Risk of fracture according to glucocorticoid use after renal biopsy: a nationwide population-based study

Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

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