Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors

2021 ◽  
pp. annrheumdis-2021-221474
Author(s):  
Marcus Säemann ◽  
Andreas Kronbichler
Keyword(s):  
Lupus Nephritis ◽  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Kidney Injury ◽  
Renal Outcome ◽  
Diabetic Patients ◽  
Clinical Effects ◽  
Cardiovascular Outcome Trials ◽  
Anca Associated Vasculitis ◽  
Risk Patients

Sodium–glucose cotransporter- 2 inhibitors (SGLT- 2i) have recently been demonstrated to exert profound cardio- and nephroprotection in large cardiovascular outcome trials. They reduce progression of chronic kidney disease (CKD) including albuminuria and improve outcomes in heart failure patients with and without type 2 diabetes on top of angiotensin-blocking agents. These benefits translate into improved mortality in cardiorenal risk patients. While the detailed molecular mechanisms underlying these surprising clinical outcomes are not fully understood, their antidiabetic properties are not causative. Rather reduction of glomerular hyperfiltration and tubuloprotection are involved as root cause mechanisms of their clinical effects. Finally, their side effect profile is advantageous especially in non-diabetic patients also reducing the risk of acute kidney injury. Among the independent risk factors for excess mortality, CKD is still one of the strongest predictors of a poor prognosis in patients with both ANCA- associated vasculitis (AAV) and lupus nephritis (LN). Since patients with autoimmune disease were excluded from all recent large renal outcome trials with SGLT-2i and given their strong nephroprotective potential, we herein advocate to study this unique class of disease-modifying therapies when it comes to kidney and cardiovascular health in patients with AAV and LN.

scholarly journals Clinico-pathological considerations in a 48-years-old female with acute kidney injury: is it lupus nephritis, ANCA-associated vasculitis or something else?

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Marie Lemerle ◽  
Anne-Sophie Garnier ◽  
Anne Croue ◽  
Alain Chevailler ◽  
Jean-Paul Saint-André ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Lupus Nephritis ◽  
Kidney Injury ◽  
Anca Associated Vasculitis

scholarly journals Prevention of contrast-induced nephropathy by limb ischemic preconditioning: underlying mechanisms and clinical effects

2018 ◽  
Vol 314 (3) ◽  
pp. F319-F328 ◽  
Author(s):  
George J. Dugbartey ◽  
Andrew N. Redington
Keyword(s):  
Ischemic Preconditioning ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Coronary Intervention ◽  
Experimental Models ◽  
Clinical Effects ◽  
Renal Protection ◽  
Contrast Induced Nephropathy ◽  
Iodinated Contrast

Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemia-reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN.

Acute kidney injury in Chinese patients with lupus nephritis: a large cohort study from a single center

Lupus ◽  
2011 ◽  
Vol 20 (14) ◽  
pp. 1557-1565 ◽  
Author(s):  
D Zhu ◽  
Z Qu ◽  
Y Tan ◽  
F Yu ◽  
M-h Zhao
Keyword(s):  
Acute Kidney Injury ◽  
Risk Factor ◽  
Lupus Nephritis ◽  
Independent Risk Factor ◽  
Kidney Injury ◽  
Large Cohort ◽  
Chinese Patients ◽  
Renal Outcome ◽  
Male Predominance ◽  
The Impact

Objective In this study we assess clinicopathologic characteristics, treatment and prognosis of acute kidney injury (AKI) in a large cohort of Chinese patients with lupus nephritis. Methods The clinical, laboratory, renal histopathology, treatment and outcome data were retrospectively collected and compared between lupus nephritis patients with and without AKI. The impact of AKI on renal outcome was evaluated. Results Among 322 patients with renal biopsy-proven lupus nephritis, 66 (20.5%) were identified as AKI. Male predominance was observed in patients with AKI ( p < 0.001). In comparison with the non-AKI group, patients with AKI had significantly higher proportions of serositis ( p < 0.001), neurologic disorder ( p = 0.026), anemia ( p < 0.001), thrombocytopenia ( p = 0.013) and nephrotic syndrome ( p = 0.011), but significant lower serum C3 ( p < 0.001). The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, renal pathological activity indices and chronicity indices were significantly higher in the AKI group ( p < 0.001 in all cases). Regarding outcome, the AKI group had a significantly poorer renal outcome compared with non-AKI group ( p < 0.001). In the AKI group, patients with crescentic glomerulonephritis and thrombotic microangiopathy had the worst renal outcome. AKI was an independent risk factor for renal outcome (hazard ratio [HR] = 5.819, 95% confidence interval 2.411–14.044 , p < 0.001). Conclusions AKI is common in lupus nephritis and is an independent risk factor for renal outcome.

scholarly journals Inflammation and Kidney Injury in Diabetic African American Men

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Lei Cao ◽  
Ava Boston ◽  
Olugbemiga Jegede ◽  
Heather A. Newman ◽  
Scott H. Harrison ◽  
...  
Keyword(s):  
African American ◽  
Kidney Disease ◽  
Molecular Mechanisms ◽  
African American Men ◽  
Kidney Injury ◽  
Diabetic Patients ◽  
Tnf Receptor ◽  
Urinary Levels ◽  
Signaling Axis ◽  
Multiple Biomarkers

African Americans are disproportionately burdened by diabetic kidney disease (DKD). However, little is known about the cellular and molecular mechanisms underlying the onset and progression of DKD in this population. The goal of the current study was to determine the association between specific inflammation markers and kidney injury in diabetic African American men. To this end, we recruited diabetic patients either with (n=20) or without (n=87) diagnosed kidney disease along with age-matched nondiabetic controls (n=81). Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFR) were used for biochemical assessment of kidney function. We then measured plasma and urinary levels of seven inflammatory markers, including adiponectin, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), interleukin-6 (IL-6), and intercellular cell adhesion molecule-1 (ICAM-1). Plasma levels of TNF-α, TNFR1, and TNFR2 were significantly higher in diabetics with macroalbuminuria compared to nondiabetic controls and diabetics with normoalbuminuria or microalbuminuria. Likewise, urinary levels of ICAM-1 were higher in diabetics with macroalbuminuria compared to the other groups. Indeed, urinary ICAM-1, plasma TNF-α, and adiponectin had moderate positive correlations with UACR while plasma TNFR1 and TNFR2 levels were strongly correlated with kidney injury, indicated by multiple biomarkers of kidney injury. In contrast, though plasma CRP was elevated in diabetic subjects relative to nondiabetic controls, its levels did not correlate with kidney injury. Together, these data suggest that inflammation, particularly that mediated by the TNF-α/NF-κB signaling axis, may play a role in the pathogenesis of DKD in African American men.

scholarly journals Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

2021 ◽  
Vol 11 (1) ◽  
pp. 137
Author(s):  
Jing Xu ◽  
Taro Hirai ◽  
Daisuke Koya ◽  
Munehiro Kitada
Keyword(s):  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Sglt2 Inhibitors ◽  
Major Adverse Cardiovascular Events ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Cardiovascular Outcome Trials ◽  
Sodium Glucose Cotransporter ◽  
Reduce Blood Glucose

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

scholarly journals Mouse Models and Techniques for the Isolation of the Diabetic Endothelium

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
April L. Darrow ◽  
J. Gregory Maresh ◽  
Ralph V. Shohet
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Transcriptional Analysis ◽  
Diabetic Patients ◽  
Endothelial Response ◽  
Elevated Glucose

Understanding the molecular mechanisms underlying diabetic endothelial dysfunction is necessary in order to improve the cardiovascular health of diabetic patients. Previously, we described an in vivo, murine model of insulin resistance induced by feeding a high-fat diet (HFD) whereby the endothelium may be isolated by fluorescence-activated cell sorting (FACS) based on Tie2-GFP expression and cell-surface staining. Here, we apply this model to two new strains of mice, ScN/Tie2-GFP and ApoE(−/−)/Tie2-GFP, and describe their metabolic responses and endothelial isolation. ScN/Tie2-GFP mice, which lack a functional toll-like receptor 4 (TLR4), display lower fasting glucose and insulin levels and improved glucose tolerance compared to Tie2-GFP mice, suggesting that TLR4 deficiency decreases susceptibility to the development of insulin resistance. ApoE(−/−)/Tie2-GFP mice display elevated glucose and cholesterol levels versus Tie2-GFP mice. Endothelial isolation by FACS achieves a pure population of endothelial cells that retain GFP fluorescence and endothelial functions. Transcriptional analysis of the aortic and muscle endothelium isolated from ApoE(−/−)/Tie2-GFP mice reveals a reduced endothelial response to HFD compared to Tie2-GFP mice, perhaps resulting from preexisting endothelial dysfunction in the hypercholesterolemic state. These mouse models and endothelial isolation techniques are valuable for assessing diabetic endothelial dysfunction and vascular responses in vivo.

Management of the Asymptomatic Diabetic Patient with Evidence of Ischaemia

2010 ◽  
Vol 6 (1) ◽  
pp. 62
Author(s):  
Dimitrios Bliagos ◽  
Ajay J Kirtane ◽  
Jeffrey W Moses ◽  
◽  
◽  
...  
Keyword(s):  
Coronary Artery ◽  
Medical Therapy ◽  
Artery Bypass ◽  
Coronary Intervention ◽  
Diabetic Patients ◽  
Ageing Population ◽  
Patients With Diabetes ◽  
Risk Patients ◽  
Asymptomatic Diabetic Patient ◽  
Artery Disease

In the US, a total of 23.6 million people have diabetes, representing 7.8% of the population, and the prevalence of diabetes is on the rise due to an increasingly sedentary lifestyle, increasing obesity and an ageing population. Coronary artery disease is the leading cause of death in patients with diabetes, despite a reduction in cardiovascular events over the last 50 years, due in part to better medical therapy. Asymptomatic diabetic patients with evidence of ischaemia on stress testing have higher cardiac mortality; increasing amounts of ischaemia are associated with higher mortality rates. Revascularisation of high-risk patients, or those with significant ischaemia, has the potential to improve outcomes in this patient population. The choice of which revascularisation strategy to choose – either percutaneous coronary intervention (PCI) or coronary artery bypass grafting – should be carefully individualised, and must always be implemented against the background of optimal medical therapy.

Neuroblastoma: An Updated Review on Biology and Treatment

2020 ◽  
Vol 20 (13) ◽  
pp. 1014-1022 ◽  
Author(s):  
Suresh Mallepalli ◽  
Manoj Kumar Gupta ◽  
Ramakrishna Vadde
Keyword(s):  
Survival Rate ◽  
High Risk ◽  
Molecular Mechanisms ◽  
Definitive Treatment ◽  
Therapeutic Drug ◽  
Mycn Amplification ◽  
Dependent Manner ◽  
High Risk Patients ◽  
Treatment And Prevention ◽  
Risk Patients

Background: Neuroblastoma (NB) is the second leading extracranial solid tumors of early childhood and clinically characterized by the presence of round, small, monomorphic cells with excess nuclear pigmentation (hyperchromasia).Owing to a lack of definitive treatment against NB and less survival rate in high-risk patients, there is an urgent requirement to understand molecular mechanisms associated with NB in a better way, which in turn can be utilized for developing drugs towards the treatment of NB in human. Objectives: In this review, an approach was adopted to understand major risk factors, pathophysiology, the molecular mechanism associated with NB, and various therapeutic agents that can serve as drugs towards the treatment of NB in humans. Conclusions: Numerous genetic (e.g., MYCN amplification), perinatal, and gestational factors are responsible for developing NB. However, no definite environmental or parental exposures responsible for causing NB have been confirmed to date. Though intensive multimodal treatment approaches, namely, chemotherapy, surgery &radiation, may help in improving the survival rate in children, these approaches have several side effects and do not work efficiently in high-risk patients. However, recent studies suggested that numerous phytochemicals, namely, vincristine, and matrine have a minimal side effect in the human body and may serve as a therapeutic drug during the treatment of NB. Most of these phytochemicals work in a dose-dependent manner and hence must be prescribed very cautiously. The information discussed in the present review will be useful in the drug discovery process as well as treatment and prevention on NB in humans.

scholarly journals SAT0211 RENAL INJURY IN SYSTEMIC LUPUS ERYTHEMATOSUS CHARACTERIZED BY THROMBOTIC MICROANGIOPATHY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1048.1-1048
Author(s):  
W. Hu
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Renal Biopsy ◽  
Lupus Erythematosus ◽  
Thrombotic Microangiopathy ◽  
Renal Injury ◽  
Renal Outcome ◽  
Pathological Examination ◽  
Systemic Lupus ◽  
Tubulointerstitial Lesions

Background:Classical lupus nephritis (LN) is characterized by glomerular immune complex(IC) deposition with glomerular proliferation, basement membrane destruction and cell infiltration. Non-IC mediated renal injury with thrombotic microangiopathy (TMA) was also reported in patients with systemic lupus erythematosus (SLE-renal TMA), but most studies were reported in patients with both LN and renal TMA.Objectives:In this study, clinical features and outcomes of SLE-renal TMA in absence of obvious IC in SLE patients were analyzed.Methods:Patients with glomerular TMA and/or vascular TMA in the absence of obvious subendothelial or epithelial immune deposits were screened out from 2332 biopsied in SLE patients who underwent first renal biopsy from January 2005 to August 2016. Their clinical, histological features and outcomes were retrospectively analyzed.Results:In 2332 renal biopsies obtained from SLE patients, 257 (11.0%) showed renal TMA, of which 237 showed both renal TMA and LN, and 20 biopsies had only renal TMA (SLE-renal TMA). There were 2 males and 18 females with an average age of (25 ± 10) years. The median course of SLE and LN were 3.0(1.0, 6.0) and 0.8(0.5, 1.9) months. All 20 patients deserved acute kidney injury, of which 11 (55%) needed renal replacement therapy (RRT) and 12 (60%) were nephrotic syndrome. Blood system involvement was found in all cases, including 13 cases (65.0%) with TMA triad (microvascular hemolytic anemia, thrombocytopenia and elevated lactate dehydrogenase).Pathological examination showed that 17 cases (85.0%) had both glomerular TMA and vascular TMA. Immunofluorescence and electron microscopy showed that 8 cases (40%) had no IC deposition in glomerulus and 12 cases (60%) had only IC deposition in mesangium. Acute tubulointerstitial lesions in patients requiring RRT were more serious than those no needing for RRT((43.6±24.9) %vs(21.7±20.1) %,P=0.047). The fusion range of foot process was positively correlated with proteinuria (r2= 0.347,P=0.006).All patients received high-dose methylprednisolone pulse therapy. Four patients received plasma exchange and three patients received gamma globulin, respectively. Eleven patients requiring RRT all stop RRT in a median time of 16.0 (9.0, 30.0) days. During a median follow-up of 58.0 (36.0, 92.3) months, complete remission (CR) was obtained in 15 cases, partial remission in 4 cases and no remission in 1 case. Six cases (30%) relapsed. No case died or progressed to end stage renal disease.Conclusion:Renal injury characterized by TMA is not uncommon in SLE renal biopsy cases. The clinical manifestation is special and the renal injury is serious. The renal outcome is good by intensive immunosuppressive therapy. It should be considered as a unique type of renal injury in SLE.References:[1]Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002. 347(8): 589-600.[2]Anders HJ, Weening JJ. Kidney disease in lupus is not always ‘lupus nephritis’. Arthritis Res Ther. 2013. 15(2): 108.[3]Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther. 2013. 15(1): R12.[4]Hu WX, Liu ZZ, Chen HP, Zhang HT, Li LS, Liu ZH. Clinical characteristics and prognosis of diffuse proliferative lupus nephritis with thrombotic microangiopathy. Lupus. 2010. 19(14): 1591-8.[5]Tomov S, Lazarchick J, Self SE, Bruner ET, Budisavljevic MN. Kidney-limited thrombotic microangiopathy in patients with SLE treated with romiplostim. Lupus. 2013. 22(5): 504-9.[6]Li C, Yap D, Chan G, et al. Clinical Outcomes and Clinico-pathological Correlations in Lupus Nephritis with Kidney Biopsy Showing Thrombotic Microangiopathy. J Rheumatol. 2019 .[7]Chen MH, Chen MH, Chen WS, et al. Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan. Rheumatology (Oxford). 2011. 50(4): 768-75.[8]Park MH, AUID- Oho, Caselman N, Ulmer S, Weitz IC, AUID- Oho. Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Adv. 2018. 2(16): 2090-2094.Disclosure of Interests:None declared

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