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Background: In EMPEROR-Reduced, empagliflozin reduced cardiovascular death or HF hospitalization, total HF hospitalizations, and slowed the progressive decline in kidney function in patients with HF and a reduced ejection fraction (HFrEF), with and without diabetes. We aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function. Methods: In this pre-specified analysis, patients were categorized by the presence or absence of CKD at baseline (eGFR<60ml/min/1.73m 2 or UACR>300mg/g). The primary and key secondary outcomes were (1) a composite of cardiovascular death or HF hospitalization (primary outcome); (2) total HF hospitalizations, and (3) eGFR slope. The direct impact on kidney events was investigated by a prespecified composite kidney outcome (defined as a sustained profound decline in eGFR, chronic dialysis or transplant). The median follow-up was 16 months. Results: 3730 patients were randomized to empagliflozin or placebo, of whom 1978 (53%) had CKD. Empagliflozin reduced the primary outcome and total HF hospitalizations in patients with and without CKD: primary outcome HR=0.78 (95%CI=0.65-0.93) and HR=0.72 (95%CI=0.58-0.90), respectively; interaction P=0.63. Empagliflozin slowed the slope of eGFR decline by 1.11 (0.23-1.98) ml/min/1.73m 2 /year in patients with CKD and by 2.41 (1.49-3.32) ml/min/1.73m2/year in patients without CKD. The risk of the composite kidney outcome was reduced similarly in patients with and without CKD: HR=0.53 (95%CI=0.31-0.91) and HR=0.46 (95%CI=0.22-0.99), respectively. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across a broad range of baseline kidney function, measured by clinically relevant eGFR subgroups or by albuminuria, including patients with eGFR as low as 20 ml/min/1.73m 2 . Empagliflozin was well tolerated in CKD patients. Conclusions: In EMPEROR-reduced, empagliflozin had a beneficial effect on the key efficacy outcomes and slowed the rate of kidney function decline in patients with and without CKD and regardless of the severity of kidney impairment at baseline. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03057977

Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin–angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain. Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight. In the kidney, increased sodium delivery to the macula densa mediated by SGLT-2 inhibition has the potential to reduce intraglomerular pressure, which may explain why SGLT-2 inhibitors reduce albuminuria and appear to slow kidney function decline in people with diabetes. Importantly, in the trials completed to date, these benefits appeared to be maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and did not appear to be dependent on ambient hyperglycaemia. There is therefore a rationale for studying the cardio-renal effects of SGLT-2 inhibition in people at risk of CV disease and hyperfiltration (i.e. those with substantially reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes.

We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman’s capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multistakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The

Background The effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on renal and cardiovascular disease have not been tested in a dedicated population of people with chronic kidney disease (CKD). Methods The EMPA-KIDNEY trial is an international randomized, double-blind, placebo-controlled trial assessing whether empagliflozin 10 mg daily reduces risk of kidney disease progression or cardiovascular death in people with CKD. People with or without diabetes mellitus (DM) were eligible provided they had: (i) an estimated glomerular filtration rate (eGFR) ≥20, &lt;45 mL/min/1.73m2;  or (ii) an eGFR ≥ 45, &lt;90 mL/min/1.73m2 with a urinary albumin: creatinine ratio (uACR) ≥200 mg/g. The trial design is streamlined: extra work for collaborating sites is kept to a minimum, and only essential information is collected. Results Between 15 May 2019 and 16 April 2021, 6609 people from eight countries in Europe, North America and East Asia were randomized. Mean age at randomization was 63.8 (SD 13.9) years, 2192 (33%) were female, and 3570 (54%) had no prior history of DM. Mean eGFR was 37.5 (14.8) mL/min/1.73m2, including 5185 (78%) with an eGFR &lt; 45 mL/min/1.73m2. Median (Q1-Q3) uACR was 412 (94–1190) mg/g, with a uACR &lt; 300 mg/g in 3194 (48%). The causes of kidney disease included diabetic kidney disease (n = 2057 [31%]), glomerular disease (n = 1669 [25%]), hypertensive/renovascular disease (n = 1445 [22%]), other (n = 808 [12%]), and unknown causes (n = 630 [10%]). Conclusions EMPA-KIDNEY will evaluate the efficacy and safety of empagliflozin in a widely generalizable population of people with CKD at risk of kidney disease progression. Results are anticipated in 2022.

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