Aldosterone Antagonists in Monotherapy Are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats

Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers

Vascular access for lipid apheresis: a challenge in young children with homozygous familial hypercholesterolemia

Background: Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disorder leading to extremely increased LDL-cholesterol (LDL-C), resulting in high cardiovascular risk in early childhood. Lipid apheresis (LA) is an effective treatment and should be started as early as possible to prevent premature cardiovascular events. As peripheral punctures in children can be challenging due to small vessels and anxiety, this study aimed to evaluate feasibility and safety of central venous catheters (CVCs) as vascular access for LA in young children with hoFH. Methods: Retrospective analysis (2016-2019) on four children with hoFH aged 3-5 years, performing weekly or biweekly LA with a CVC. Results: LDL-C decreased by> 60%. In three children, the use of a permanent CVC for 698, 595, and 411 days, respectively, avoided difficult peripheral access, without the occurrence of occlusion or thrombosis. Unfortunately, one child had recurrent CVC-related infections and needed an arteriovenous fistula from the age of 5.Although the mean dwell time per catheter was 212 days, there were, as expected, severe side effects of early catheter infections with sepsis and accidental self-removal. Starting LA at an early age improved or stabilized carotid intima-media thickness (IMT) in three children. However, IMT did increase in one child caused by intolerance to peripheral punctures and LA interruption. Conclusions: Permanent CVCs are a viable temporary access choice for LA in young children with hoFH until peripheral venipuncture is practicable. The risk of CVC-related infections needs to be taken into account

Western blot analysis of Na/K ATPase (NKA).

<p>Aldosterone antagonists were the most effective in decreasing diabetes and hyperglycemia induced elevation of tubular NKA protein level. Top panel: Representative examples of Western blot analysis. Lower panels: <i>A</i>: Densitometric analysis of NKA protein levels in kidney homogenates of control, diabetic and treated diabetic rats. <i>B</i>: Densitometric analysis of NKA protein levels in HK-2 tubular cells. Bar graph represents densitometric analysis from multiple experiments. Data represent means ± SD; *p<0.05 <i>vs</i> Control; §p<0.05 <i>vs</i> Diabetes, respectively; (bars show means±SD; n = 8–10/group). IOD – integrated optical density.</p

Metabolic and renal parameters of control, diabetic and treated diabetic rats.

<p>Data are means ± SD, n = 8–10/group, ^*p<0.05 vs. C; ^§p<0.05 vs. D, ^**p<0.01 vs. C; ^§§p<0.01 vs. D, ^***p<0.001 vs. C; ^§§§p<0.001 vs. D; respectively. UD–undetectable.</p

Confocal images of control, diabetic and treated diabetic rats.

<p>Aldosterone inhibitors prevented the mislocation of NKA induced by diabetes in proximal tubules. Representative pictures of immunofluorescence staining of kidney sections for Na/K ATPase (NKA, green) in control (A), streptozotocin-diabetic (B) and diabetic, Enalapril (C), Losartan (D), Spironolactone (E) and Eplerenone (F) treated rats (63x magnification; scale bar–10 μm). Nuclei are stained blue with Hoechst. PT-proximal tubule, DT-distal tubule, Bm-basal membrane, Lu – apical membrane at the lumen and Nucl – nuclei. Fluorescent signal intensity of NKA (green) generated from a line shown as red arrow in the merged image are shown on the bottom right of each panel.</p

Assessing the efficacy, safety and utility of closed-loop insulin delivery compared with sensor-augmented pump therapy in very young children with type 1 diabetes (KidsAP02 study): an open-label, multicentre, multinational, randomised cross-over study protocol

Introduction Diabetes management in very young children remains challenging. Glycaemic targets are achieved at the expense of high parental diabetes management burden and frequent hypoglycaemia, impacting quality of life for the whole family. Our objective is to assess whether automated insulin delivery can improve glycaemic control and alleviate the burden of diabetes management in this particular age group.Methods and analysis The study adopts an open-label, multinational, multicentre, randomised, crossover design and aims to randomise 72 children aged 1–7 years with type 1 diabetes on insulin pump therapy. Following screening, participants will receive training on study insulin pump and study continuous glucose monitoring devices. Participants will be randomised to 16-week use of the hybrid closed-loop system (intervention period) or to 16-week use of sensor-augmented pump therapy (control period) with 1–4 weeks washout period before crossing over to the other arm. The order of the two study periods will be random. The primary endpoint is the between-group difference in time spent in the target glucose range from 3.9 to 10.0 mmol/L based on sensor glucose readings during the 16-week study periods. Analyses will be conducted on an intention-to-treat basis. Key secondary endpoints are between group differences in time spent above and below target glucose range, glycated haemoglobin and average sensor glucose. Participants’ and caregivers’ experiences will be evaluated using questionnaires and qualitative interviews, and sleep quality will be assessed. A health economic analysis will be performed.Ethics and dissemination Ethics approval has been obtained from Cambridge East Research Ethics Committee (UK), Ethics Committees of the University of Innsbruck, the University of Vienna and the University of Graz (Austria), Ethics Committee of the Medical Faculty of the University of Leipzig (Germany) and Comité National d’Ethique de Recherche (Luxembourg). The results will be disseminated by peer-reviewed publications and conference presentations.Trial registration number NCT03784027