SAT-093 THE STRANGE CASE OF RENAL FUNCTION AFTER RADICAL NEPHRECTOMY: A FOGGY FORECAST

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Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19

Hospital admissions and mortality from the Coronavirus disease 2019 (COVID-19) pandemic are spreading throughout the world, and second and third waves are thought to be likely. Risk factors for severe COVID-19 include diabetes, chronic kidney disease and cardiovascular disease. Currently, there is no vaccine and no approved therapy. Therapeutic approaches are aimed at preventing viral replication and spread, limiting the impact of the inflammatory overdrive (cytokine storm), preventing thromboembolic complications and replacing or supporting organ function. However, despite organ support, mortality is currently 65% for those receiving advanced respiratory support and 78% for those requiring renal replacement therapies. Thus, efforts should be made to provide adjuvant organ protection therapy. This may imply novel therapies in clinical development (e.g., the Fas ligand trap asunercept), but uptake of repurposed drugs already in clinical use may be faster. In this regard, sodium glucose co-transporter-2 (SGLT2) inhibitors were recently shown to protect the heart and kidney both within and outside of a diabetic milieu context. Further, preclinical data support a beneficial effect for the lung. We now discuss the potential benefits and risks of SGLT2 inhibitors in COVID-19 and an ongoing clinical trial testing the impact of dapagliflozin on outcomes in COVID-19 patients with respiratory failure

SAT-092 THE DUEL OF DAVID AND GOLIATH: HOW SHOULD MGFR BEAT THE ESTIMATED GFR?

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Glucose homeostasis changes and pancreatic β-cell proliferation after switching to cyclosporin in tacrolimus-induced diabetes mellitus

AbstractBackgroundSwitching to cyclosporin A may result in a reversion of tacrolimus-induced diabetes mellitus. However, mechanisms underlying such a reversion are still unknown.MethodsObese Zucker rats were used as a model for tacrolimus-induced diabetes mellitus. A cohort of 44 obese Zucker rats received tacrolimus for 11 days (0.3mg/kg/day) until diabetes development; then, (a) 22 rats were euthanized at day 12 and were used as a reference group (tacrolimus-day 12), and (b) 22 rats on tacrolimus were shifted to cyclosporin (2.5mg/kg/day) for 5 days (tacrolimus-cyclosporin). An additional cohort of 22 obese Zucker rats received the vehicle for 17 days and was used as a control group. All animals underwent an intraperitoneal glucose tolerance test at the end of the study.Resultsβ-Cell proliferation, apoptosis and Ins2 gene expression were evaluated. Compared to rats in tacrolimus-day 12 group, those in tacrolimus-cyclosporin group showed a significant improvement in blood glucose levels in all assessment points in intraperitoneal glucose tolerance test. Diabetes decreased from 100% in tacrolimus-day-12 group to 50% in tacrolimus-cyclosporin group. Compared to tacrolimus-day-12 group, rats in tacrolimus-cyclosporin group showed an increased β-cell proliferation, but such an increase was lower than in rats receiving the vehicle. Ins2 gene expressions in rats receiving tacrolimus-cyclosporin and rats receiving the vehicle were comparable.ConclusionAn early switch from tacrolimus to cyclosporin in tacrolimus-induced diabetes mellitus resulted in an increased β-cell proliferation and reversion of diabetes in 50% of cases

Morphometric and genetic characterization as tools for selection of Apis mellifera (Hymenoptera: Apidae) stocks in an area of natural hybridization in Argentina

Beekeepers around the world select bees’ characteristics that facilitate and favor production. In regions where hybridization among lineages is taking place, this selection is a challenge, given that these regions are “natural laboratories”, where the action of evolutionary processes of a population or species occurs in real time. A natural honeybee (Apis mellifera) hybrid zone exists in Argentina between 28° and 35° South, where Africanized (AHB) and European (EHB) populations converge. In this zone, beekeepers use selected genetic resources of European origin mostly, since the local Africanized bees show a higher defensive behavior, which is not desirable for management. Although EHB colonies have many advantages for honey production, they are not fully adapted to the subtropical climate and are susceptible to certain parasitosis such as varroosis. In addition, both AHB and EHB mate in drone congregation areas (DCAs), where males and virgin queens fly to meet, resulting in variability in the desired characteristics. In this study, we explored the degree of hybridization within a DCA and its reference apiary, located in the province of Entre Ríos, by applying two complementary techniques. First, morphotypes with different degrees of hybridization between European and African subspecies were observed in the reference apiary, indicating a high sensitivity of this morphometric approach to detect hybridization in these populations. Second, a genetic analysis revealed haplotypes of both origins for drones in DCAs, with a higher prevalence of European haplotypes, while all the colonies from the reference apiary exhibited European haplotypes. Overall, our results are in line with the strong impact that commercial beekeeping has on the genetics of DCAs. We show how wing morphometry may be used to monitor hybridization between European and African subspecies, a tool that may be evaluated in other regions of the world where hybridization occurs.Instituto de GenéticaFil: Litvinoff, Leonardo. Reinas del Litoral SRL; ArgentinaFil: Menescardi, Francisco. Reinas del Litoral SRL; ArgentinaFil: Porrini, Leonardo. Instituto de Investigaciones en Producción, Sanidad y Ambiente (CONICET-UNSAM). Centro de Investigación en Abejas Sociales; ArgentinaFil: Porrini, Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Russo, Romina Maria. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Genética; ArgentinaFil: Russo, Romina Maria. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Russo, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Liendo, María Clara. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Genética; ArgentinaFil: Liendo, María Clara. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Liendo, María Clara. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Nucci, Alejandro. Instituto de Investigaciones en Producción, Sanidad y Ambiente (CONICET-UNSAM). Centro de Investigación en Abejas Sociales; ArgentinaFil: Nucci, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lusarreta, Esteban. Instituto de Investigaciones en Producción, Sanidad y Ambiente (CONICET-UNSAM). Centro de Investigación en Abejas Sociales; ArgentinaFil: Lusarreta, Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ventura, Rocio. Instituto de Investigaciones en Producción, Sanidad y Ambiente (CONICET-UNSAM). Centro de Investigación en Abejas Sociales; ArgentinaFil: Ventura, Rocio. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Espasadin, Luna. Fundación Miguel Lillo. Instituto de Entomología; ArgentinaFil: Monmany-Garzia, A. Carolina. Universidad Nacional de Tucumán. Instituto de Ecología Regional; ArgentinaFil: Monmany-Garzia, A. Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Scannapieco, Alejandra Carla. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Genética; ArgentinaFil: Scannapieco, Alejandra Carla. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Scannapieco, Alejandra Carla. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Galindo Cardona, Alberto. Fundación Miguel Lillo. Instituto de Entomología; ArgentinaFil: Galindo Cardona, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation and Study of Diabetic Nephropathy with Atrasentan: what was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan?

Albuminuria; Atrasentan; CanagliflozinAlbuminuria; Atrasentan; CanagliflozinaAlbuminúria; Atrasentan; CanagliflozinaIn April 2019, two major Phase 3 randomized clinical trials were published that assessed primary renal outcomes in diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) tested an already available antidiabetic drug, canagliflozin, and the Study of Diabetic Nephropathy with Atrasentan (SONAR) tested a novel molecule, the endothelin-1 receptor blocker atrasentan, both on top of renin-angiotensin system blockade. Both trials demonstrated significant nephroprotection in patients with overt DKD (albuminuria >300 mg/g urinary creatinine) for combined primary endpoints of end-stage kidney disease (ESKD), doubling of serum creatinine or death from renal or cardiovascular causes in CREDENCE {hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.59-0.82]} and ESKD and doubling of serum creatinine in SONAR [HR 0.65 (95% CI 0.49-0.88)]. Canagliflozin also decreased the secondary renal endpoint ESKD, doubling of serum creatinine or renal death [HR 0.66 (95% CI 0.53-0.81)], which was similar in nature and impact to the primary endpoint in SONAR. In addition, canagliflozin decreased a secondary endpoint of cardiovascular death or hospitalization for heart failure [HR 0.69 (95% CI 0.57-0.83)], whereas atrasentan had no significant impact on a secondary cardiovascular composite endpoint or on hospital admissions for heart failure and, despite restrictive exclusion criteria, there was a non-significant trend towards more frequent episodes of heart failure. Based on these results, canagliflozin will likely be approved for the indication of treating DKD in T2DM and the estimated glomerular filtration rate threshold for prescribing it will be lifted, whereas the future and place of atrasentan in the treatment of DKD remain unclear.Funded by FIS/Fondos FEDER (PI16/02057, PI16/01814. PI17/00257, ISCIII-RETIC REDinREN RD016/0009), Sociedad Espanola de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. E.P. is a researcher in the Ramón y Cajal Program

Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation and Study of Diabetic Nephropathy with Atrasentan : what was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan?

In April 2019, two major Phase 3 randomized clinical trials were published that assessed primary renal outcomes in diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) tested an already available antidiabetic drug, canagliflozin, and the Study of Diabetic Nephropathy with Atrasentan (SONAR) tested a novel molecule, the endothelin-1 receptor blocker atrasentan, both on top of renin-angiotensin system blockade. Both trials demonstrated significant nephroprotection in patients with overt DKD (albuminuria >300 mg/g urinary creatinine) for combined primary endpoints of end-stage kidney disease (ESKD), doubling of serum creatinine or death from renal or cardiovascular causes in CREDENCE {hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.59-0.82]} and ESKD and doubling of serum creatinine in SONAR [HR 0.65 (95% CI 0.49-0.88)]. Canagliflozin also decreased the secondary renal endpoint ESKD, doubling of serum creatinine or renal death [HR 0.66 (95% CI 0.53-0.81)], which was similar in nature and impact to the primary endpoint in SONAR. In addition, canagliflozin decreased a secondary endpoint of cardiovascular death or hospitalization for heart failure [HR 0.69 (95% CI 0.57-0.83)], whereas atrasentan had no significant impact on a secondary cardiovascular composite endpoint or on hospital admissions for heart failure and, despite restrictive exclusion criteria, there was a non-significant trend towards more frequent episodes of heart failure. Based on these results, canagliflozin will likely be approved for the indication of treating DKD in T2DM and the estimated glomerular filtration rate threshold for prescribing it will be lifted, whereas the future and place of atrasentan in the treatment of DKD remain unclear

Obesity and Metabolic Traits after High-Fat Diet in Iberian Pigs with Low Birth Weight of Placental Origin

Intrauterine growth restriction (IUGR) and later obesity and metabolic disorders have classically been associated with maternal malnutrition, but most cases of IUGR are related to placental insufficiency. The current study, using a swine model for IUGR and obesity, aimed to determine the interaction of birth weight (categorized as low birth weight [LBW] or normal birth-weight [NBW]) and postnatal diet (categorized as maintenance diet [MD] or fattening diet [FD]) on body weight, adiposity and metabolic traits. FD induced higher body weight and adiposity (both p < 0.0001), with higher fructosamine levels (p < 0.005) and a trend toward higher HOMA-β index (p = 0.05). NBW pigs remained heavier than LBW pigs during the early juvenile period (p < 0.005), but there were no differences at later stages. There were no differences in metabolic traits during juvenile development, but there were differences in adulthood, when LBW pigs showed higher glucose and lower insulin levels than NBW pigs (both p < 0.05). These results suggest that (a) FD allows LBW offspring to achieve similar obesity in adulthood as NBW offspring, and (b) glucose metabolism is more compromised in obese LBW than obese NBW pigs. The comparison of our data with previous studies highlights significant differences between offspring with LBW induced by maternal malnutrition or placental insufficiency, which should be considered when studying the condition

Integrated miRNA–mRNA Analysis Reveals Critical miRNAs and Targets in Diet-Induced Obesity-Related Glomerulopathy

This study aimed to investigate obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: 15 rats were fed with a standard diet (SD-rats), and 15 rats were fed with a high-fat diet (HFD-rats). After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD-rats gained significantly more weight (55.8% vs. 29.2%; p < 0.001) and albuminuria (10,384.04 ng/mL vs. 5845.45 ng/mL; p < 0.001) compared to SD-rats. HFD-rats exhibited early stages of ORG, with predominant mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that miR-205, which was DE in both the kidneys and urine of HFD-rats, negatively regulated the PTEN gene, promoting lipid endocytosis in podocytes. The downregulation of PTEN was proved through a higher PTEN/nephrin ratio in the SD-rats and the presence of lipid vacuoles in HFD-podocytes. This study has found a specific targetome of miRNAs and gene expression in early stages of ORG. Also, it emphasizes the potential value of miR-205 as a urinary biomarker for detecting podocyte injury in ORG, offering a tool for early diagnosis, and opening new avenues for future therapeutic research of obesity-related glomerulopathy