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Aims/hypothesisHigher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS).MethodsBiomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression.ResultsIn total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes.Conclusions/interpretationCanagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.

Chronic kidney disease is a progressive disease with no cure and high morbidity and mortality that occurs commonly in the general adult population, especially in people with diabetes and hypertension. Preservation of kidney function can improve outcomes and can be achieved through non-pharmacological strategies (eg, dietary and lifestyle adjustments) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions. A plant-dominant, low-protein, and low-salt diet might help to mitigate glomerular hyperfiltration and preserve renal function for longer, possibly while also leading to favourable alterations in acid-base homoeostasis and in the gut microbiome. Pharmacotherapies that alter intrarenal haemodynamics (eg, renin–angiotensin–aldosterone pathway modulators and SGLT2 [SLC5A2] inhibitors) can preserve kidney function by reducing intraglomerular pressure independently of blood pressure and glucose control, whereas other novel agents (eg, non-steroidal mineralocorticoid receptor antagonists) might protect the kidney through anti-inflammatory or antifibrotic mechanisms. Some glomerular and cystic kidney diseases might benefit from disease-specific therapies. Managing chronic kidney disease-associated cardiovascular risk, minimising the risk of infection, and preventing acute kidney injury are crucial interventions for these patients, given the high burden of complications, associated morbidity and mortality, and the role of non-conventional risk factors in chronic kidney disease. When renal replacement therapy becomes inevitable, an incremental transition to dialysis can be considered and has been proposed to possibly preserve residual kidney function longer. There are similarities and distinctions between kidney-preserving care and supportive care. Additional studies of dietary and pharmacological interventions and development of innovative strategies are necessary to ensure optimal kidney-preserving care and to achieve greater longevity and better health-related quality of life for these patients.

In contemporary clinical practice, there are numerous glucose-lowering agents available for the treatment of type 2 diabetes mellitus (T2DM): from older drugs such as metformin and sulfonylureas to newer agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors. In the past decade, large-scale randomized controlled trials (RCTs) of glucose-lowering agents have shown varying benefits on cardiovascular and kidney outcomes among patients with T2DM. Sodium-glucose cotransporter-2 inhibitors act by blocking the paired reuptake of sodium and glucose in the proximal tubule, thereby promoting urinary glucose excretion; these agents have been shown to lower glycated hemoglobin by about 0.5%-0.7% in individuals with normal kidney function. Sodium-glucose cotransporter-2 inhibitors are a practicechanging development in the treatment of T2DM, and data to date from completed trials support their ability to provide cardiovascular and kidney protection in addition to current standard of care.

Background This post-hoc analysis of the DELIGHT trial assessed effects of the SGLT2 inhibitor dapagliflozin on iron metabolism and markers of inflammation. Methods Patients with type 2 diabetes and albuminuria were randomized to dapagliflozin, dapagliflozin and saxagliptin, or placebo. We measured hemoglobin, iron markers (serum iron, transferrin saturation, and ferritin), plasma erythropoietin, and inflammatory markers (urinary MCP-1 and urinary/serum IL-6) at baseline and week 24. Results 360/461 (78.1%) participants had available biosamples. Dapagliflozin and dapagliflozin-saxagliptin, compared to placebo, increased hemoglobin by 5.7 g/L (95%CI 4.0, 7.3; p < 0.001) and 4.4 g/L (2.7, 6.0; p < 0.001) and reduced ferritin by 18.6% (8.7, 27.5; p < 0.001) and 18.4% (8.7, 27.1; p < 0.001), respectively. Dapagliflozin reduced urinary MCP-1/Cr by 29.0% (14.6, 41.0; p < 0.001) and urinary IL-6/Cr by 26.6% (9.1, 40.7; p = 0.005) with no changes in other markers. Conclusions Dapagliflozin increased hemoglobin and reduced ferritin and urinary markers of inflammation, suggesting potentially important effects on iron metabolism and inflammation. Trial registration ClinicalTrials.gov NCT02547935.

ObjectivesGuideline-based strategies to prevent chronic kidney disease (CKD) progression and complications are available, yet their implementation in clinical practice is uncertain. We aimed to synthesise the available evidence on the concordance of CKD care with clinical guidelines to identify gaps and inform future CKD care.DesignSystematic review and meta-analysis.Data sources, participants, and outcomesWe systematically searched MEDLINE (OVID), EMBASE (OVID) and CINAHL (EBSCOhost) (to 18 July 2025) for observational studies of adults with CKD reporting data on the quality of CKD care. We assessed data on quality indicators of CKD care across domains that related to patient monitoring (glomerular filtration rate and albuminuria), medications use (ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), statins) and treatment targets (blood pressure (BP) and HbA1c). Pooled estimates (95% CI) of the percentage of patients who met the quality indicators for CKD care were estimated using random effects model.Results59 studies across 24 countries, including a total of 3 003 641 patients with CKD, were included. Across studies, 81.3% (95% CI: 75% to 87.6%) of patients received eGFR monitoring, 47.4% (95% CI: 40.0% to 54.7%) had albuminuria testing, and 90% (95% CI: 84.3% to 95.9%) had BP measured. ACEIs/ARBs were prescribed among 56.7% (95% CI: 51.5% to 62%), and statins among 56.6% (95% CI: 48.9% to 64.3%) of patients. BP (systolic BP ≤140/90 mm Hg) and HbA1c (<7%) targets were achieved in 56.5% (95% CI: 48.5% to 64.6%) and 43.5% (95% CI: 39.4% to 47.6%) of patients, respectively. Subgroup analysis indicated higher rates of proteinuria testing among patients with diabetes (52.2%) compared with those without (31.3%).ConclusionsCurrent evidence shows substantial variation in CKD care quality globally. Guideline-concordant care varied according to quality measures and across patient groups, with gaps in indicators like albuminuria testing. These findings underscore the need for effective quality improvement strategies to address gaps in CKD care, including increased albuminuria testing for risk stratification, together with systematic measures for monitoring care quality.PROSPERO registration numberCRD42023391749.

ObjectiveTo evaluate the patterns of abnormal estimated glomerular filtration rate (eGFR) and urine albumin–creatinine ratio (UACR) follow-up testing for the detection of chronic kidney disease (CKD) in Australian general practices.DesignRetrospective, population-based observational study.Setting and participants2 717 966 adults who visited a MedicineInsight participating general practice between 1 January 2012 and 31 December 2020, had ≥1 serum creatinine measurement (with or without a UACR measurement) and did not have CKD at baseline.Main outcome measure‘Guideline-concordant follow-up’ was defined as having a record of a repeat eGFR or UACR testing (assessed separately) within 6 months following the abnormal (eGFR<60 mL/min/1.73 m2; UACR≥2.5 mg/mmol in males, ≥3.5 mg/mmol in females) incident result. Multivariable logistic regression was used to identify patient factors associated with receiving appropriate follow-up testing.ResultsA total of 220 841 and 114 889 patients with an abnormal incident eGFR and UACR result, respectively, were identified. Nearly half (45.0%) of the patients with an abnormal eGFR result and over two-thirds (69.7%) of the patients with an abnormal UACR result did not have a follow-up test within 6 months. Patient factors associated with a higher likelihood of follow-up eGFR testing included indicators of poorer baseline health and greater CKD risk, such as comorbid diabetes (adjusted OR 1.36, 95% CI 1.32 to 1.40) or more severe incident eGFR (adjusted ORs for eGFR categories 30–44, 15–29 and <15 mL/min/1.73 m², respectively, vs eGFR 45–59 mL/min/1.73 m²: 1.51 (1.47 to 1.55), 1.85 (1.76 to 1.95) and 1.62 (1.47 to 1.78)). Higher incident UACR level was associated with greater follow-up UACR testing (adjusted OR for severely increased albuminuria vs moderately increased albuminuria (OR 1.42, 95% CI 1.37 to 1.48).ConclusionsIn this large, population-based study, we observed substantial gaps in the follow-up of abnormal eGFR and UACR for the detection of CKD in primary care settings. Effective strategies to optimise follow-up testing for CKD detection are needed.

Background Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have been proven to prevent decline in kidney function and failure. Whether SGLT2i affect the risk of contrast-associated acute kidney injury (CA-AKI) remains uncertain. Methods Use of SGLT2i was assessed in consecutive diabetics undergoing coronary angiography (CA) or percutaneous coronary intervention (PCI) from January 2020 to May 2023 at a tertiary hospital in Chongqing, China. Propensity-matched analysis was used to adjust for baseline variables. CA-AKI was defined by the Acute Kidney Injury Network (AKIN) as creatinine increase ≥ 0.3 mg/dl (26.4 μmol/l), or a percentage increase in the serum creatinine level of ≥ 50%. Results A total of 604 new users of SGLT2i, and 298 chronic users of SGLT2i were matched with non-users. New use of SGLT2i was not associated with an increased incidence of AKIN-defined CA-AKI (OR 1.60; 95% CI 0.97–2.63; p  = 0.065), in-hospital new-onset dialysis (OR 0.50; 95% CI 0.09–2.73; p  = 0.422), or death (OR 0.55; 95% CI 0.18–1.66; p  = 0.289). However, it was associated with a minor (> 25%) creatinine elevation (OR 1.55; 95% CI 1.04–2.30; p  = 0.030), a 0.3 mg/dl increase in creatinine (OR 1.66; 95% CI 1.01–2.75; p  = 0.048), and CMSC-defined CA-AKI (OR 1.51; 95% CI 1.02–2.24; p  = 0.039). By 90 days, there was no evidence creatinine elevation differed between the two groups ( p  = 0.590). Chronic use of SGLT2i was not associated with AKIN-defined CA-AKI (OR, 0.92; 95% CI 0.41–2.05; p  = 0.838). Conclusions New use of SGLT2i during CA or PCI was not associated with an AKIN-defined CA-AKI, and it did not translate into new-onset dialysis or death during hospital stay. Chronic usage of SGLT2i did not affect creatinine. Further randomized clinical trials are warranted to confirm this finding. Key learning points What was known: Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have a renal protective effect; however, they cause an acute increase in the creatinine level and dip in glomerular filtration rate (GFR) upon treatment initiation. This study adds: New use of SGLT2i during coronary angiography or percutaneous coronary intervention was associated with an acute increase in the creatinine level, but it did not translate into new-onset dialysis or death during hospital stay, causing a pseudo contrast-associated acute kidney injury, and the creatinine level seemed return to normal thereafter. Continuation of SGLT2i did not affect creatinine elevation. Potential impact: Usage of SGLT2i may be safe during coronary angiography or percutaneous coronary intervention. Randomized controlled trials and other observational studies are needed to validate our observation.

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min −1 per 1.73 m 2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R 2 ) = 0.97 (95% Bayesian credible interval (BCI) 0.82–1.00)) and moderately associated with those on chronic slope (R 2  = 0.55 (95% BCI 0.25–0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression. A meta-analysis of individual-level patient data from 66 clinical studies supports the utility of glomerular filtration rate as a surrogate endpoint in clinical trials for chronic kidney disease, with potential to enable detection of events earlier in the disease course.

Aims The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes. Methods and results The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed‐effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all Pdifference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54–0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93–1.36), Pheterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin‐to‐creatinine ratio, were similar between groups (all Pdifference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (−0.52% vs. −0.64%, Pheterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all Pheterogeneity > 0.07). Conclusions Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.

Purpose of ReviewSodium glucose transporter 2 inhibitors (SGLT2 inhibitors) are increasingly prescribed due to their considerable benefits on clinical outcomes in people with diabetes, heart failure, and chronic kidney disease (CKD). Hypertension is a common comorbidity in each of these disease states, increasing risk of cardiovascular morbidity and mortality. We herein review the effects of SGLT2 inhibitors on blood pressure in different populations, proposed mechanisms of action, and the contribution of blood pressure lowering to end-organ protection.Recent FindingsA recognised effect of SGLT2 inhibitors in recent clinical trials is blood pressure lowering, with multiple postulated mechanisms. This advantageous effect was first identified in populations with type 2 diabetes mellitus, prior to expansion of these trials to broader cohorts.SummaryOn our review, we identified that the blood pressure lowering effect of SGLT2 inhibitors appears to be a dose-independent class-effect, with a magnitude of effect comparable to that seen with a low dose hydrochlorothiazide. There is considerable evidence demonstrating that this effect is observed across populations including those with type 2 diabetes mellitus, chronic kidney disease, and resistant hypertension.