AIMS/INTRODUCTION:While SGLT2 accounts for >90% of kidney glucose reabsorption, its pharmacological inhibition or genetic knockdown reduces glucose reabsorption by only 50%. MATERIALS AND METHODS:We postulated that the less than expected glucosuric response to SGLT2 inhibition might result from a compensatory increase in the length of the proximal tubule as seen in experimental diabetes where early tubular proliferation is followed by tubular lengthening. Taking advantage of their differing anatomical locations, stereological techniques were used to differentiate the SGLT1 expressing straight proximal tubule that lies within the outer stripe of the outer medulla (S3 segment) and that of the predominantly SGLT2 expressing early proximal convoluted tubule located within the kidney cortex (S1, S2 segments). RESULTS:The SGLT2 inhibitor, dapagliflozin, induced an early, transient hyperplastic response (3-fold increase of Ki67 labelling, P < 0.0001) in S3 proximal tubular cells followed by a 32% increase in its length (P < 0.0001). In contrast, the length of the SGLT2 expressing S1, S2 segments of the proximal tubule was unaffected. CONCLUSIONS:The finding that SGLT2 inhibition leads to expansion of the S3 segment of the proximal tubule, the site of SGLT1, is suggestive of a physiological response to diminish urinary glucose loss akin to that occurring in experimental diabetes. These findings provide a cogent explanation for the less-thanthan-expected effect of this drug class on glucose reabsorption.

AIMS:To compare preconception use of sodium-glucose cotransporter-2 (SGLT2i) and dipeptidyl peptidase-4 (DPP4i) inhibitors to sulfonylurea agents, and associated peri-conceptional A1c concentration, and risk of pregnancy loss and congenital anomalies. METHODS:This population-based cohort study used administrative datasets for all of Ontario, Canada, and included women eligible for free medication coverage and who achieved a recognized pregnancy from April 2007-November 2021. Exposure was a SGLT2i, DPP4i or sulfonylurea (referent) dispensed at least 90 days preconception. Study outcomes included differences in periconceptional A1c; miscarriage, induced abortion, or stillbirth; and any congenital anomaly - the latter two outcomes assessed using propensity score overlap weighting. RESULTS:The mean (SD) periconceptional A1c was 8.1 % (2.0) among those prescribed any sulfonylurea, compared with 8.3 % (2.0) with a DPP4i and 7.8 % (1.6) with any SGLT2i. The risk of pregnancy loss was lowest among those exclusively prescribed a SGLT2i (relative risk [RR] 0.51, 95 % CI 0.22 to 0.91). Risk of a congenital anomaly at birth did not differ significantly comparing DPP4i or SGLT2i to sulfonylurea agents. CONCLUSIONS:Neither SGLT2i nor DPP4i use before pregnancy was associated with a difference in A1c, or a higher risk of selective adverse outcomes, compared to sulfonylureas. Future larger studies are required, including assessment of medication use after conception, during the critical period of embryogenesis.

Background Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. Hypothesis We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. Methods Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. Results PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). Significance Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Introduction The integrative physiological response to anemia is complex and incompletely understood. We utilized data from studies of acute anemia in rodents to determine the relationship between changes in blood oxygen content (CaO2) and the heterogenous response of the kidney, heart and brain. We hypothesize that renal hypoxia sensing mechanisms contribute to adaptive physiological responses to maintain cerebral oxygen delivery (DO2) during acute anemia. Methods With animal care committee approval, we synthesized novel and published data from 5 previously published studies. Outcomes included: assessment of the relationship between CaO2 and microvascular renal and brain PO2 (phosphorescence quenching of oxyphor G4); cardiac output (CO) and renal and cerebral blood flow (ultrasound Doppler); hypoxia induced cellular responses (brain and kidney erythropoietin (EPO) mRNA and serum protein levels (ELISA)). Statistical analysis (SigmaPlot 14) was performed by ANOVA, Holm-Sidak and Mann-Whitney rank sum test when appropriate. Significance was assigned at p<0.05. Results In two models of anemia (hemodilution and RBC antibody mediated), acute reductions in blood CaO2 were associated with larger decreases in renal microvascular PO2, relative to brain microvascular PO2 (p<0.05). After acute hemodilution, there was a strong relationship between CaO2 and renal microvascular PO2 (r2=0.75). The magnitude of reduction in renal microvascular PO2 correlated with the degree of renal EPO mRNA expression and serum EPO protein levels. The magnitude of the increase in EPO mRNA was much larger in the kidney than in the brain (p<0.03). While no change in renal blood flow was observed in either model, a significant increase in common carotid and internal carotid blood flow was observed in both models (p<0.012). When DO2 was assessed, the kidney DO2 was reduced at all levels of anemia (p<0.01) whereas brain tissue DO2 was maintained in mild and moderate (Hb 90 and 70 g/L) (p=0.44) anemia but reduced in severe anemia (Hb 50 g/L) (p<0.02). The role of active cardiovascular increases in brain blood flow and maintained DO2 during anemia was impaired by systemic beta blockade, suggesting that active cardiovascular mechanisms are required to maintain optimal brain DO2 during anemia. Discussion Our analysis demonstrated: evidence of quantitative renal PO2 sensing of changes in CaO2; the clamping of renal blood flow (reduced DO2) during anemia may be a central mechanism allowing for sensing of changes in CaO2; reduced arterial CaO2 resulted in a local renal hypoxia response (increased serum EPO) and may have initiated the cardiovascular response to increase cerebral blood flow and maintain cerebral DO2. Inhibition of the adrenergic system impaired these responses and resulted in reduced brain DO2. Understanding the heterogeneous adaptive responses to acute anemia may inform clinical practice and optimize management of acutely anemia patients.

Background: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (PkO2), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on PkO2 in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary PkO2 were measured utilizing excitations with blue and red light wavelengths, respectively. Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in PkO2. By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in PkO2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.

Sensing changes in blood oxygen content ([Formula: see text]) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in [Formula: see text] are incompletely understood. Accurate measurements of kidney tissue oxygen tension ([Formula: see text]) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery. We hypothesized that hemodilution with starch colloid solutions would reduce [Formula: see text] to a more severe degree than other diluents. Anesthetized Sprague-Dawley rats ( n = 77) were randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (0.9% saline), or a sham procedure (control) ( n = 13–18 rats/group). Data were analyzed by ANOVA with significance assigned at P < 0.05. After hemodilution, mean arterial pressure (MAP) decreased marginally in all groups, while hemoglobin (Hb) and [Formula: see text] decreased in proportion to the degree of hemodilution. Cardiac output was maintained in all groups after hemodilution. [Formula: see text] decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb, and maintained arterial oxygen values, hemodilution with starch resulted in larger decreases in [Formula: see text] relative to animals hemodiluted with albumin or saline ( P < 0.008). Renal medullary erythropoietin (EPO) mRNA levels increased more prominently, relative to other hypoxia-regulated molecules (GLUT-1, GAPDH, and VEGF). Our data demonstrate that the kidney acts as a biosensor of reduced [Formula: see text] following hemodilution and that [Formula: see text] may provide a quantitative signal for renal cellular responsiveness to acute anemia. Evidence of a more severe reduction in [Formula: see text] following hemodilution with starch colloid solution suggests that tissue hypoxia may contribute to starch induced renal toxicity.

Abstract Background and aims Sodium–glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions. Methods Pressure–volume (P–V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later. Results The circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy. Conclusion Empagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.

Recent clinical trials have demonstrated significant reductions in heart failure hospitalization and cardiovascular death with sodium-glucose cotransport protein 2 inhibitors in patients with or without type 2 diabetes mellitus.1Zinman B. Wanner C. Lachin J.M. Fitchett D. Bluhmki E. Hantel S. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7198) Google Scholar, 2Neal B. Perkovic V. Mahaffey K.W. de Zeeuw D. Fulcher G. Erondu N. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2190) Google Scholar, 3McMurray J. Solomon S.D. Inzucchi S.E. Kober L. Kosiborod M.N. Martinez F.A. et al.Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (2828) Google Scholar The mechanism of cardiovascular benefit with sodium-glucose transport coprotein 2 inhibitors was investigated in the EMPA-HEART CardioLink-6 trial, a double-blind, placebo-controlled clinical trial that randomized patients with type 2 diabetes and stable coronary artery disease to empagliflozin 10 mg once daily (n = 49) or placebo (n = 48). The EMPA-HEART CardioLink-6 trial showed via cardiac magnetic resonance imaging that empagliflozin use was associated with a reduction in left ventricular mass index (LVMI) at 6 months, with an average decrease of −2.6 g/m2 compared with −0.01 g/m2 in the placebo group (adjusted difference, −3.35 g/m2; 95% CI, −5.9 to −0.81 g/m2; P = .0103).4Verma S. Mazer C.D. Yan A.T. Mason T. Garg V. Teoh H. et al.Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.Circulation. 2019; 140: 1693-1702Crossref PubMed Scopus (273) Google Scholar The goal of this prespecified substudy was to determine if structural changes identified on transthoracic echocardiography might provide further insight into the mechanism of empagliflozin-associated left ventricular (LV) reverse remodeling and the effect of empagliflozin on diastolic function. The study design and primary results have been published separately.4Verma S. Mazer C.D. Yan A.T. Mason T. Garg V. Teoh H. et al.Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.Circulation. 2019; 140: 1693-1702Crossref PubMed Scopus (273) Google Scholar Every participant underwent transthoracic echocardiography at baseline and at 6 months (±14 days) after randomization. Measurements were performed according to standard guidelines,5Mitchell C. Rahko P.S. Blauwet L.A. Canaday B. Finstuen J.A. Foster M.C. et al.Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American Society of Echocardiography.J Am Soc Echocardiogr. 2019; 32: 1-64Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar and sonographers and readers were blinded to the treatment assignment. The primary outcome of this substudy was the change in E/e′ ratio from baseline to the 6-month visit. Secondary outcomes of interest included changes in other LV diastolic parameters. The mean baseline E/e′ ratio, LVMI, and LV ejection fraction were normal in both the empagliflozin and placebo groups (Table 1). At 6 months, there was no significant difference in the change in average E/e′ ratio in the empagliflozin versus placebo group (0.15 vs −0.35, respectively; adjusted difference, −0.23; 95% CI, −1.29 to 0.82; P = .66). Similarly, there was no difference between the groups in change in medial E/e′ ratio, lateral E/e′ ratio, or left atrial volume index (Table 1).Table 1Changes in echocardiographic parameters in patients treated with empagliflozin versus placeboEchocardiographic parameterPlacebo (n = 48)Empagliflozin (n = 49)Adjusted difference between groups95% CIPBaseline6 moChangeBaseline6 moChangeLVEF (%)∗Measured using cardiac magnetic resonance imaging.55.5 ± 8.754.3 ± 8.9−1.0 ± 6.558.0 ± 7.559.1 ± 8.570.72 ± 5.12.2(−0.2 to 4.7).10LV chamber quantification LVISd (cm)3.2 ± 0.83.2 ± 0.7−0.02 ± 0.63.0 ± 0.63.0 ± 0.70.05 ± 0.6−0.03(−0.3 to 0.2).80 LVIDd (cm)4.6 ± 0.84.5 ± 0.7−0.08 ± 0.64.4 ± 0.54.3 ± 0.6−0.16 ± 0.5−0.14(−0.4 to 0.1).20 IVS (cm)1.0 ± 0.21.0 ± 0.20 ± 0.21.0 ± 0.21.0 ± 0.20.03 ± 0.20.01(−0.1 to 0.1).80 PWT (cm)0.9 ± 0.20.9 ± 0.20.01 ± 0.20.9 ± 0.20.9 ± 0.20.05 ± 0.20.03(−0.004 to 0.1).40Diastolic parameters Mitral DTIAverage E/e′ ratio10.1 ± 3.110.3 ± 2.50.2 ± 3.010.6 ± 3.010.5 ± 3.6−0.4 ± 2.5−0.2(−1.3 to 0.8).70Medial E/e′ ratio12.3 ± 3.912.5 ± 3.60.1 ± 3.712.6 ± 4.212.6 ± 5.2−0.3 ± 3.3−0.3(−1.7 to 1.1).70Lateral E/e′ ratio8.0 ± 2.88.2 ± 2.20.2 ± 2.78.7 ± 2.68.4 ± 2.5−0.4 ± 2.7−0.1(−1.0 to 0.8).80 Mitral E velocity (cm/sec)68.6 ± 15.270.6 ± 14.71.8 ± 15.474.4 ± 18.271.2 ± 16.8−3.2 ± 15.1−2.3(−7.9 to 3.3).40 Mitral A velocity (cm/sec)74.7 ± 17.977.9 ± 18.82.9 ± 15.976.2 ± 16.575.8 ± 14.5−1.4 ± 11.7−3.5(−8.9 to 1.9).20 Pulmonary vein S wave (cm/s)52.1 ± 10.549.0 ± 10.0−4.3 ± 13.850.0 ± 10.147.8 ± 8.3−4.6 ± 11.3−0.9(−6.1 to 4.4).70 Pulmonary vein D wave (cm/s)43.5 ± 7.640.8 ± 8.1−2.6 ± 8.341.2 ± 11.539.9 ± 9.4−2.6 ± 13.0−0.8(−5.8 to 4.2).70 Pulmonary vein S:D ratio1.2 ± 0.31.2 ± 0.30 ± 0.41.3 ± 0.31.2 ± 0.2−0.1 ± 0.30.0(−0.2 to 0.2).90 LA volume index (mL/m2)32.7 ± 7.930.8 ± 8.1−2.0 ± 6.730.2 ± 6.728.7 ± 5.5−1.8 ± 6.5−0.9(−3.4 to 1.6).50Blood pressure†As reported in Verma et al.4DTI, Doppler tissue imaging; IVS, interventricular septum; LA, left atrial; LVEF, LV ejection fraction; LVIDd, LV internal diastolic dimension; LVISd, LV internal systolic diameter; PWT, posterior wall thickness.Data are expressed as mean ± SD.∗ Measured using cardiac magnetic resonance imaging.† As reported in Verma et al.4Verma S. Mazer C.D. Yan A.T. Mason T. Garg V. Teoh H. et al.Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.Circulation. 2019; 140: 1693-1702Crossref PubMed Scopus (273) Google Scholar Open table in a new tab DTI, Doppler tissue imaging; IVS, interventricular septum; LA, left atrial; LVEF, LV ejection fraction; LVIDd, LV internal diastolic dimension; LVISd, LV internal systolic diameter; PWT, posterior wall thickness. Data are expressed as mean ± SD. Subgroup analyses showed no significant change in E/e′ ratio among patients with average baseline E/e′ ≥ 13 (n = 16): −1.3 ± 3.5 with empagliflozin versus −2.5 ± 4.6 with placebo (adjusted difference, 1.99; 95% CI, −2.3 to 6.2) or among patients with baseline LVMI ≥ 60 g/m2 (n = 37): 0.2 ± 2.7 with empagliflozin versus −0.06 ± 3.6 with placebo (adjusted difference, 0.88; 95% CI, −0.9 to 2.6). There was also no difference in those with baseline LV ejection fraction > 50% versus ≤50%. This echocardiographic substudy of the EMPA-HEART CardioLink-6 trial had some limitations. The sample size calculation was based on detecting changes in LVMI using cardiac magnetic resonance imaging, and thus the study may have been underpowered to detect changes in diastolic function on echocardiography. Second, the majority of patients demonstrated only grade 1 diastolic dysfunction, with mostly normal left atrial size. Future studies are warranted to determine the impact empagliflozin may have on individuals who have more advanced diastolic dysfunction. In conclusion, this prespecified echocardiographic study revealed no significant change in key LV diastolic parameters with empagliflozin treatment for 6 months. These findings suggest that in the EMPA-HEART CardioLink-6 population, changes in loading conditions (i.e., preload) did not mediate the observed reduction in LV mass.

Background While histopathologic changes correlate with functional impairment in cross-sectional studies of diabetic nephropathy (DN), whether these findings predict future rate of kidney function loss remains uncertain. We thus sought to examine the relationship between kidney histopathology, incidence of end-stage kidney disease (ESKD), and rate of estimated glomerular filtration rate (eGFR) loss in DN. Methods In this longitudinal cohort study, we studied 50 adults diagnosed with biopsy-proven DN. We analyzed the histopathologic parameters of each patient’s kidney biopsy, as defined by the Renal Pathology Society classification system for DN, and tracked all available eGFR measurements post-biopsy. We additionally collected baseline clinical parameters (at the time of biopsy), including eGFR, albumin-to-creatinine ratio (ACR), and hemoglobin A 1c . Multivariable linear regression was used to assess the relationship between histologic and clinical parameters at the time of the biopsy and eGFR slope. Kaplan-Meier curves and Cox regression were used to evaluate the association between histologic and clinical parameters and ESKD incidence. Results Progression to ESKD was associated with worsening interstitial fibrosis score ( p = 0 . 05), lower baseline eGFR ( p = 0 . 02), higher ACR ( p = 0 . 001), and faster eGFR decline ( p < 0.001). The rate of eGFR decline did not associate with any histologic parameter. Baseline ACR was the only studied variable correlating with eGFR slope (rho = − 0 . 41). Conclusions Renal histology predicts ultimate progression to ESKD, but not the rate of progression. Future work is required to identify novel predictors of rapid functional decline in patients with diabetic nephropathy.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.

ObjectivesDiabetes is associated with adverse outcomes, including death, after coronavirus disease 19 (COVID-19) infection. Beyond the lungs, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, can infect a range of other tissues, including the kidney, potentially contributing to acute kidney injury in those with severe disease. We hypothesized that the renal abundance of angiotensin-converting enzyme (ACE) 2, the cell surface receptor for SARS-CoV-2, may be modulated by diabetes and agents that block the renin-angiotensin-aldosterone system (RAAS).MethodsThe expression of ACE 2 was examined in 49 archival kidney biopsies from patients with diabetic kidney disease and from 12 healthy, potential living allograft donors using next-generation sequencing technology (RNA Seq).ResultsMean ACE 2 messenger RNA was increased approximately 2-fold in diabetes when compared with healthy control subjects (mean ± SD, 13.2±7.9 vs 7.7±3.6 reads per million reads, respectively; p=0.001). No difference in transcript abundance was noted between recipients and nonrecipients of agents that block the RAAS (12.2±6.7 vs 16.2±10.7 reads per million reads, respectively; p=0.25).ConclusionsIncreased ACE 2 messenger RNA in the diabetic kidney may increase the risk and/or severity of kidney infection with SARS-CoV-2 in the setting of COVID-19 disease. Further studies are needed to ascertain whether this diabetes-related overexpression is generalizable to other tissues, most notably the lungs.

Aim The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting. Methods We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX. Results While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria. Conclusion These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes including hospitalization for heart failure, renal function and mortality. Previou...

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD+ -dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age-related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1Y/Y ) mice had lower GFRs and fewer glomeruli than their wild-type (Sirt1+/+ ) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.

Recent studies send an unambiguous signal that the class of agents known as sodium-glucose-linked co-transporter-2 inhibitors (SGLT2i) prevent heart failure hospitalization in patients with type 2 diabetes. However, the mechanisms remain unclear. Herein the authors utilize a rodent model of heart failure with preserved ejection fraction (HFpEF), and demonstrate that treatment with the SGLT2i empagliflozin, reduces left ventricular mass, improving both wall stress and diastolic function. These findings extend the observation that the main mechanism of action of empagliflozin involves improved hemodynamics (i.e., reduction in preload and afterload) and provide a rationale for upcoming trials in patients with HFpEF irrespective of glycemic status.