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The heart and the vascular tree undergo major structural and functional changes when kidney function declines and renal replacement therapy is required. The many cardiovascular risk factors and adaptive changes the heart undergoes include left ventricular hypertrophy and dilatation with concomitant systolic and diastolic dysfunction. Myocardial fibrosis is the consequence of impaired angio-adaptation, reduced capillary angiogenesis, myocyte-capillary mismatch, and myocardial micro-arteriopathy. The vascular tree can be affected by both atherosclerosis and arteriosclerosis with both lipid rich plaques and abundant media calcification. Development of cardiac and vascular disease is rapid, especially in young patients, and the phenotype resembles all aspects of an accelerated ageing process and latent cardiac failure. The major cause of left ventricular hypertrophy and failure and the most common problem directly affecting myocardial function is fluid overload and, usually, hypertension. In situations of stress, such as intradialytic hypotension and hypoxaemia, the hearts of these patients are more vulnerable to developing cardiac arrest, especially when such episodes occur frequently. As a result, cardiac and vascular mortality are several times higher in dialysis patients than in the general population. Trials investigating one pharmacological intervention (eg, statins) have shown limitations. Pragmatic designs for large trials on cardio-active interventions are mandatory for adequate cardioprotective renal replacement therapy.

There is increasing evidence that sodium glucose cotransporter 2 (SGLT2) inhibitors have renoprotective effects, as demonstrated by the renal analyses from clinical trials including Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME), CANagliflozin Treatment And Trial Analysis versus SUlphonylurea (CANTATA-SU), and the dapagliflozin renal study. The potential mechanisms responsible are likely multifactorial, and direct renovascular and hemodynamic effects are postulated to play a central role. This report reviews the renal outcomes data from key SGLT2 inhibitor clinical trials, discusses the hypotheses for SGLT2 inhibitor-associated renoprotection, and considers the main renal safety issues associated with SGLT2 inhibitor treatment.

The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed clinical practice guidelines on lipid management for all adults and children with chronic kidney disease (CKD). Thirteen recommendations were obtained from the available evidence outlining a three-step management including assessment in all, treatment in many, and follow-up measurements in few. A key element is the recommendation of statin or statin/ezetimibe treatment in adults aged ≥50 years with estimated glomerular filtration rate (eGFR) <60ml/min per 1.73m2 but not treated with chronic dialysis or kidney transplantation. In dialysis patients, the magnitude of any relative reduction in risk appears to be substantially smaller than in earlier stages of CKD and initiation of statin treatment is not recommended for most prevalent hemodialysis patients. In the past, clinical practice guidelines suggested the use of targets for LDL cholesterol, which require repeated measurements. Treatment escalation with higher doses of statin would be a consequence when LDL cholesterol targets are not met. The KDIGO Work Group did not recommend this strategy because higher doses of statins have not been proven to be safe in the setting of CKD. Since LDL cholesterol levels do not necessarily suggest the need to increase statin doses, follow-up measurement of lipid levels is not recommended.

Individuals with diabetes mellitus exhibit an increased propensity to develop cardiovascular disorders such as coronary artery disease, stroke and heart failure. Over recent decades, numerous cardiovascular outcome trials in individuals with type 2 diabetes have been published, with data showing a reduction of cardiovascular morbidity and mortality by sodium–glucose cotransporter 2 (SGLT2) inhibitors. These results not only provide novel therapeutic options for this high-risk population but also advance our current understanding of cardiovascular risk reduction in diabetes. The current overview article summarises these aspects and discusses future treatment strategies with SGLT2 inhibitors in diabetic and non-diabetic individuals with chronic kidney disease, liver disease and heart failure.

Among patients with type 2 diabetes at high cardiovascular risk, the rates of progression of kidney disease and clinically relevant renal events were lower among patients receiving empagliflozin, a sodium–glucose cotransporter 2 inhibitor, than among those receiving placebo. Type 2 diabetes is a major risk factor for macrovascular and microvascular disease. 1 Kidney disease develops in approximately 35% of patients with type 2 diabetes 2 and is associated with increased mortality. 3 Intensive glucose-lowering strategies have been shown to reduce surrogate markers of renal complications in patients with type 2 diabetes; however, evidence for improvement in advanced renal complications is limited. 4 – 8 Thus, despite optimized glucose control and the use of single-agent blockade of the renin–angiotensin–aldosterone system (RAAS), patients with type 2 diabetes remain at increased risk for death and complications from cardiorenal causes. 9 , 10 Empagliflozin, a selective sodium–glucose cotransporter 2 . . .

Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda — kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality.Addressing the burden of non-communicable diseases is a global public health priority. In this joint Consensus Statement, the American Society of Nephrology, the European Renal Association and the International Society of Nephrology highlight the need to recognize kidney disease as a key driver of premature mortality, in addition to other non-communicable diseases already prioritized by the World Health Organization.

Among patients with heart failure and a reduced ejection fraction, those who received the SGLT2 inhibitor empagliflozin had a significantly lower incidence of cardiovascular death or hospitalization for heart failure than those who received placebo.

Globally, the prevalence of chronic kidney disease is estimated to be approximately 850 million cases, with approximately 4 million individuals needing kidney replacement therapy for kidney failure. By 2050, chronic kidney disease is projected to become the fifth leading underlying cause of death worldwide. Despite its numerous causes, chronic kidney disease can be screened for, diagnosed, and staged with simple laboratory tests. Individuals with chronic kidney disease are at increased risk of kidney failure and many other health implications. Risk of premature cardiovascular disease is particularly noteworthy, as most patients with chronic kidney disease develop a disability or die from cardiovascular disease before ever progressing to kidney failure. Since 2019, large randomised trials have identified several effective treatments that both slow progressive kidney function decline and reduce cardiovascular risk, greatly expanding available treatments for chronic kidney disease. The wide range of complications associated with chronic kidney disease means that patients encounter many different specialties. Active engagement in chronic kidney disease identification and timely initiation of cost-effective interventions by all clinicians could now substantially reduce the global burden of complications of chronic kidney disease and kidney failure.

Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes. We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618. We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [>99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37–85 mL/min per 1·73 m2). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0·63, 95% CI 0·58–0·69) with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23% (0·77, 0·70–0·84) and the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77, 0·74–0·81), again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death (0·86, 0·81–0·92) but did not significantly reduce the risk of non-cardiovascular death (0·94, 0·88–1·02). For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation. In addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function. UK Medical Research Council and Kidney Research UK.

This trial compared the oral HIF-PHI daprodustat with conventional erythropoiesis-stimulating agents for the treatment of anemia in patients with chronic kidney disease receiving dialysis. Daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes.