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Aim: To assess the association between urinary albumin‐to‐creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes. Materials and Methods: PubMed and Embase were systematically searched for real‐world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two‐category (UACR <10 mg/g vs. 10‐30 mg/g) and a three‐category division (UACR <5 mg/g vs. 5‐10 and 10‐30 mg/g). A random effects meta‐analysis was performed on studies eligible for the meta‐analysis. Results: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta‐analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all‐cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10‐30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all‐cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5‐10 mg/g) was also associated with a higher risk of all‐cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]. Conclusions: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria. [ABSTRACT FROM AUTHOR]

Background Chronic pain is prevalent but difficult to treat in patients undergoing hemodialysis (HD). Effective and safe analgesics are limited in this patient population. Our aim in this feasibility study was to evaluate the safety of sublingual oil based medical cannabis for pain management in patients undergoing HD. Methods In a prospective randomized, double-blind, cross-over design, patients undergoing HD with chronic pain were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained trans-delta-9-‏tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:6 ratio (1:6, THC:CBD). Patients were treated for 8 weeks, with subsequent 2-week wash out, followed by a cross-over to a different arm. The primary endpoint was safety. Results Eighteen patients were recruited and 15 were randomized. Three did not complete drug titration period due to adverse events (AEs) and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine receiving placebo. The most common AEs were sleepiness, which improved after dose reduction or patient adaptation. Most AEs were mild to moderate and resolved spontaneously. Serious AEs considered related to study drug included one episode of accidental overdose (WPE) leading to hallucinations. Liver enzymes were stable during cannabis treatment. Conclusions Short-term medical cannabis use in patients treated with HD was generally well tolerated. The safety data supports further studies to assess the overall risk–benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population. [ABSTRACT FROM AUTHOR]

Objective: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6.Research Design and Methods: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model.Results: The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively.Conclusions: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6-lowering therapy on CV, kidney, and safety outcomes remains to be tested. [ABSTRACT FROM AUTHOR]

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

a-Synuclein (a-Syn) is a protein implicated in the pathogenesis of Parkinson's disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for a-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of a-Syn in these mechanisms is currently unclear. Here we investigate the associations of a-Syn with the acidic phosphoinositides (PIPs), phosphatidylinositol 4,5-bisphosphate (PI(4,5) P2) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). Our results show that a-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor protein 2 (AP2) at clathrin-coated pits. Using endocytosis of transferrin as an indicator for clathrin-mediated endocytosis (CME), we find that a-Syn involvement in endocytosis is specifically mediated through PI(4,5)P2 levels on the plasma membrane. In accord with their effects on PI(4,5)P2 levels, the PD associated A30P, E46K, and A53T mutations in a-Syn further enhance CME in neuronal and nonneuronal cells. However, lysine to glutamic acid substitutions at the KTKEGV repeat domain of a-Syn, which interfere with phospholipid binding, are ineffective in enhancing CME. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by thea-Syn mutations and associates with their effects on PI(4,5)P2 levels, however, with the exception of the A30P mutation. This study provides evidence for a critical involvement of PIPs in a-Syn- mediated membrane trafficking. [ABSTRACT FROM AUTHOR]

Background: A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level., Methods: Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200-5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes., Results: Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211-0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33-0.76], 0.62 [0.45-0.85], and 0.64 [0.49--0.83], respectively; p-interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p-interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p-interaction = 0.63), and all-cause mortality (p-interaction p = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively)., Conclusions: The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Chronic pain is prevalent but difficult to treat in patients undergoing hemodialysis (HD). Effective and safe analgesics are limited in this patient population. Our aim in this feasibility study was to evaluate the safety of sublingual oil based medical cannabis for pain management in patients undergoing HD., Methods: In a prospective randomized, double-blind, cross-over design, patients undergoing HD with chronic pain were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained trans-delta-9-‏tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:6 ratio (1:6, THC:CBD). Patients were treated for 8 weeks, with subsequent 2-week wash out, followed by a cross-over to a different arm. The primary endpoint was safety., Results: Eighteen patients were recruited and 15 were randomized. Three did not complete drug titration period due to adverse events (AEs) and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine receiving placebo. The most common AEs were sleepiness, which improved after dose reduction or patient adaptation. Most AEs were mild to moderate and resolved spontaneously. Serious AEs considered related to study drug included one episode of accidental overdose (WPE) leading to hallucinations. Liver enzymes were stable during cannabis treatment., Conclusions: Short-term medical cannabis use in patients treated with HD was generally well tolerated. The safety data supports further studies to assess the overall risk-benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population., Competing Interests: N.A. is an employee of BOL Pharma Ltd. N.V. and B.H. are former employees of BOL Pharma Ltd. O.M. is a former employee of BOL; Advisory Board: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, AstraZeneca, Bayer, BOL Pharma; Research grant: Novo Nordisk, AstraZeneca; Speakers Bureau: Novo Nordisk, AstraZeneca, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Published in 2015, the EMPA-REG cardiovascular outcome trial (CVOT) investigated empagliflozin in patients with type 2 diabetes (T2D). This agent promotes glycosuria by inhibiting Sodium-Glucose Cotransporter-2 (SGLT2), that is expressed in the first segment of the renal proximal tubule. The study aimed to provide evidence for the drug's cardiovascular (CV) safety, as required by regulatory authorities for newly developed glucose lowering agents (GLA)s. Surprisingly, besides being safe, empagliflozin was effective in reducing CV morbidity and mortality as well as improving renal outcomes, compared with placebo. EMPA-REG was followed by subsequent CVOTs that demonstrated the value of additional SGLT2 inhibitors to improve CV and renal outcomes in different populations: patients with mostly normal kidney function (DECLARE-TIMI 58), with early stage chronic kidney disease (CKD) (EMPA-REG and CANVAS) and patients with advanced proteinuric CKD (CREDENCE). Intriguingly, recent reports demonstrated that SGLT2 inhibitors improve CV and renal outcomes in high-risk populations with and without T2D: patients with CKD (DAPA-CKD) or with heart failure and reduced ejection fraction (HFrEF; DAPA-HF and EMPEROR-Reduced). This review focuses on the renal aspect of the large trials investigating SGLT2 inhibitors. We will discuss the populations investigated, the defined renal outcomes and their hierarchy within the trials - all used as a framework to interpret the renal findings and their conclusions. Lastly, we will outline some of the suggested mechanisms underlying the renal protective effects of the inhibitors of SGLT2.