Background and Aims Age and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in hemodialysis are elderly. This study aimed to investigate the impact of COVID-19 in this population and to determine risk factors associated with mortality. Method Data was obtained from the Spanish COVID-19 CKD Working Group Registry, that included patients in renal replacement therapy (dialysis and kidney transplantation) infected by COVID-19. From March 18, 2020, to August 27, 2020, 1165 patients on hemodialysis affected by COVID-19 were included in the Registry. A total of 328 patients were under 65 years-old and 837 were 65 years old or older (elderly group). Results Mortality was 18.6% higher (95% confidence interval (CI): 13.8%-23.4%) in the elderly hemodialysis patients compared to the non-elderly group (see figure). Death from COVID-19 infection was increased 5.5-fold in hemodialysis patients compared to mortality in the general population for a similar period, and there was an age-associated mortality increase in both populations (see figure 1). In multivariate Cox regression analysis, age (hazard ratio (HR) 1.58, 95% CI: 1.31-1.92), dyspnea at presentation (HR 1.61, 95% CI: 1.20-2.16), pneumonia (HR 1.76, 95% CI: 1.12-2.75) and admission to hospital (HR 4.13, 95% CI: 1.92-8.88) were identified as independent mortality risk factors in the elderly hemodialysis population. Treatment with glucocorticoids reduced the risk of death (HR 0.71, 95% CI: 0.51-0.98) in aged patients on hemodialysis. Conclusion Mortality is dramatically increased in elderly hemodialysis patients affected by COVID-19. Age, dyspnea at presentation, pneumonia or hospitalization are factors associated with a worse prognosis, after adjusting dialysis population to other confounding factors. Treatment with glucocorticoids could be a therapeutic option for this specific population.
BACKGROUND AND AIMS sodium-glucose 2 cotransporter inhibitors (SGLT2i) prevent cardiovascular events in diabetic patients. Moreover, their diuretic effect could attenuate the adverse events of endothelin receptor antagonists (ERA), which have also shown kidney protective effects in diabetes. The present study aimed to evaluate the beneficial cardiorenal impact of the combination of SGLT2i, ERA and ramipril versus treatment with ramipril alone in experimental diabetes. METHOD Twelve-week-old db/db mice were treated for 8 weeks with different combinations of an SGLT2i (empagliflozin, 10 mg/Kg/day), an ERA (atrasentan, 7 mg/Kg/day) and an RAS blocker (ramipril, 8 mg/Kg/day). Vehicle-treated diabetic and nondiabetic mice were included as controls. During the experiment, blood pressure (BP), glomerular filtration rate (GFR) and echocardiographic parameters were measured. Kidney and heart were collected at the end for histological studies. RESULTS The triple therapy with empagliflozin, atrasentan and ramipril was superior to ramipril alone in reducing BP (mean BP 61.0 mmHg versus 67.10 mmHg in the ramipril group), preventing diabetic hyperfiltration (214.3 μL/100 g/min GFR decrease versus 34.7 μL/100 g/min decrease in the ramipril group) (Figure 1), and improving echocardiographic parameters of diastolic dysfunction, including left atrium diameter and isovolumetric relaxation time. Moreover, the combined therapy offered protection against diabetic injury in kidney and heart by a reduction of mesangial matrix expansion (46.0% of glomerular mesangial matrix versus 46.9% in the ramipril group), as well as left ventricle cardiomyocyte hypertrophy (mean cardiomyocyte area 125 μm2 versus 131 μm2 in the ramipril group) and heart collagen deposition (Figure 1). CONCLUSION In experimental diabetes, combined therapy of ramipril, empagliflozin and atrasentan promotes both heart and kidney protective effects that outweigh the beneficial effects of ramipril alone.
Background and Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors have proven to delay diabetic nephropathy (DN) progression on top of renin-angiotensin system (RAS) blockade. This protection is mainly attributed to improvement in renal hemodynamics, although direct effects on the kidney cannot be ruled out. The present study aimed to identify renal proteins differentially expressed between vehicle-treated diabetic mice and mice treated with empagliflozin, ramipril, or their combination, that could help explain the protective mechanisms of the drugs. Method Twelve weeks old diabetic db/db mice were given empagliflozin (10 mg/Kg/day), ramipril (8 mg/Kg/day), or the combination of both drugs during 8 weeks. Vehicle-treated db/db and db/m mice were used as controls. Serum glucose, blood pressure, GFR, and albuminuria were measured at baseline and at the end of the study. After 8 weeks, mice were euthanized, and the kidneys and serum were saved. A differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labelling) was performed in kidney cortex. Results Vehicle-treated db/db mice showed increased glycemia during the whole experiment, and empagliflozin reduced blood glucose. Ramipril treatment decreased blood pressure. Vehicle-treated diabetic mice also showed incipient DN with increased mesangial matrix and albuminuria compared to their non-diabetic littermates. All the treatments reduced mesangial matrix expansion and albuminuria. Only 13 proteins were differentially expressed (false discovery rate <5% and Log2FC ≥1 or ≤ −1) when comparing treated mice vs vehicle-treated db/db mice. The differentially expressed proteins were only identified between the mice treated with the combination of empagliflozin and ramipril and the vehicle-treated diabetic mice. Ramipril or empagliflozin alone did not produce significant changes in renal proteins. Kidney renin was evidently increased by the combination therapy with empagliflozin and ramipril, along with the tubular transporter scaffolding protein MAP17. The results were further validated through renin staining and renal renin concentration measurement. Renal renin concentration was increased by ramipril and further increased by the combination therapy with empagliflozin and ramipril when compared to vehicle-treated db/db mice (55 pg/μg (IQR:49–64), 94 pg/μg (IQR:71–102), and 112 pg/μg (IQR 104–116) in the groups treated with vehicle, ramipril and the combination of empagliflozin and ramipril respectively). However, renin serum concentration was similar between mice treated with ramipril and mice treated with the combination. Conclusion The combined therapy of empagliflozin with ramipril upregulated renin in the kidney of a diabetic mouse model. The increase in kidney renin suggests that other mechanisms different from RAS act in the regulation of glomerular hemodynamics and arteriolar tone. Moreover, the increased sodium delivery to the macula densa does not inhibit renal renin secretion.
Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and endothelin A receptor (ETA) antagonist have shown nephroprotective effects in diabetic kidney disease (DKD) through blood pressure and urinary albumin loss reduction. The protective impact and the pathways through which they exert this protection have not yet been elucidated. This study aimed to investigate the effects of the add-on therapy of SGLT2i and ETA antagonists on a type 2 diabetes murine model. Method 12 weeks-old db/db mice were treated for 8 weeks with different combinations of empagliflozin 10 mg/Kg/day (SGLT2i), atrasentan 7 mg/Kg/day (ETA antagonist) or ramipril 8 mg/Kg/day. A group of non-diabetic mice (db/m) was included as negative control. In vivo variables were recorded during treatment, including transdermal measured glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). After treatment kidneys were preserved for histopathological studies. Results After 8 weeks of treatment empagliflozin decreased fasting blood glucose alone or in combination with atrasentan or ramipril (234.2 mg/dL mean reduction in three treated groups when compared to db/db). Ramipril decreased blood pressure (BP) in monotherapy or in add-on therapy. Empagliflozin or atrasentan alone did not have any effect on blood pressure, but combination of atrasentan and ramipril had a synergistic effect and reduced both systolic (9.0 mmHg, CI 95%: -16.3 to -1.1; P=0.028) and diastolic BP (11.9 mmHg, CI 95%: -17.7 to -3.1; P=0.005) when compared to ramipril alone. The combination of atrasentan and ramipril significantly reduced UACR (1002 ug/mg, CI 95%: -2312.0 to -32.4; P=0.043). Empagliflozin treatment alone or in combination also reduced UACR (686.0 ug/mg mean reduction in three treated groups), although this reduction was not statistically significant. In the kidney, empagliflozin in monotherapy or combination reduced glomerular mesangial matrix expansion (4.85% mean mesangial reduction in three treated groups). Treatments with atrasentan and ramipril also reduced measangial matrix expansion. Conclusion Both empagliflozin and atrasentan demonstrated possible beneficial effects in DKD by reducing BP, UACR, and mesangial matrix expansion. The add-on therapy did not show greater protective effects in the analysed variables. Further studies are needed to characterize these protective effects and pathways involved.
Background and Aims Angiotensin converting enzyme 2 (ACE2) is one of the components of the renin-angiotensin system (RAS) that mainly degrades angiotensin II to angiotensin-(1-7). ACE2 is predominantly expressed in the kidney and the heart, but it has been evidenced in type 2 alveolar lung cells, where it acts as a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this context, a controversy arose as to whether the use of RAS blockers could increase ACE2 lung expression and the risk infection by COVID-19. This study aimed to investigate the effect of an ACE inhibitor (Ramipril) on ACE2 expression in experimental diabetes. Method 12 weeks old diabetic db/db mice (n=7) were given ramipril (8 mg/Kg/day) during 8 weeks or the respective vehicle. db/m (n=7) vehicle-treated non-diabetic mice were included as controls. ACE2 mRNA expression and enzymatic activity were studied in kidney, heart and lung samples of these animals to identify if the diabetic condition or treatment with ramipril modulated ACE2 expression. Results In vehicle-treated diabetic db/db animals, ACE2 mRNA expression was significantly increased in the kidney (p<0.001) and ramipril treatment reversed this effect (p=0.026). In the heart, ACE2 expression decreased in db/db when compared to db/m littermates (p=0.035) and ramipril had no effect. We found no differences in ACE2 gene expression in the lung. Besides, ACE2 enzymatic activity was increased in the kidney (29%) and also in the lung (16%) of db/db mice when compared to controls. Ramipril treatment decreased ACE2 activity a 19% in the lung and had no effect in the kidney when compared to untreated db/db (see figure). In the heart, ACE2 activity tended to decrease in db/db mice (29%) when compared to db/m and ramipril increased ACE2 activity (18%) but did not exceed the cardiac ACE2 activity of the db/m. Conclusion ACE2 is increased in the kidney and the lung, and decreased in the heart of diabetic mice. Ramipril treatment restores ACE2 levels. The results suggest that ACE inhibitors do not increase ACE2 expression and the activity decrease exerted in the lung may be protective against COVID-19 infection.
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