Dinesh Khullar

BACKGROUND: Recent cardiovascular outcome trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. METHODS: DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2-4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin-angiotensin system inhibitor at enrolment. RESULTS: After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). CONCLUSION: DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.

BACKGROUND: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. METHODS: In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). RESULTS: Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). CONCLUSIONS: Participants with a wide range of underlying kidney diseases receiving renin-angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2-4 and increased albuminuria, with and without T2D.

The incidence of acute kidney injury (AKI) among acutely ill patients is reportedly very high and has vexing consequences on patient outcomes and health care systems. The risks and impact of AKI differ between developed and developing countries. Among developing countries, AKI occurs in young individuals with no or limited comorbidities, and is usually due to environmental causes, including infectious diseases. Although several risk factors have been identified for AKI in different settings, there is limited information on how risk assessment can be used at population and patient levels to improve care in patients with AKI, particularly in developing countries where significant health disparities may exist. The Acute Disease Quality Initiative consensus conference work group addressed the issue of identifying risk factors for AKI and provided recommendations for developing individualized risk stratification strategies to improve care. We proposed a 5-dimension, evidence-based categorization of AKI risk that allows clinicians and investigators to study, define, and implement individualized risk assessment tools for the region or country where they practice. These dimensions include environmental, socioeconomic and cultural factors, processes of care, exposures, and the inherent risks of AKI. We provide examples of these risks and describe approaches for risk assessments in the developing world. We anticipate that these recommendations will be useful for health care providers to plan and execute interventions to limit the impact of AKI on society and each individual patient. Using a modified Delphi process, this group reached consensus regarding several aspects of AKI risk stratification.

Background C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway.We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade.Methods APPEAR-C3G was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study of iptacopan versus placebo (both in addition to supportive care [renin-angiotensin-aldosterone system (RAAS) inhibitors] and immunosuppression).Adult participants (aged 18-60 years) with biopsy-confirmed C3 glomerulopathy were enrolled from 35 hospitals or medical centres in 18 countries.Inclusion criteria included reduced serum C3 concentration (ie, <77 mg/dL [defined as <085 lower limit of the central laboratory normal range]) at screening, urine proteincreatinine ratio (UPCR) of 10 g/g or higher at day -75 and day -15 before randomisation, estimated glomerular filtration rate (eGFR) of 30 mL/min per 173 m or higher at screening and day -15, and vaccination against Neisseria meningitidis and Streptococcus pneumoniae.All eligible participants were randomised 1:1 via interactive response technology to either the iptacopan or the placebo group, stratified by treatment with corticosteroids, mycophenolic acid, or both (yes or no).During the 6-month double-blind period, participants orally received either iptacopan 200 mg twice daily or placebo; this was followed by a 6-month open-label period in which all participants received iptacopan 200 mg twice daily.The primary endpoint was relative reduction in proteinuria (measured by logtransformed ratio to baseline in UPCR sampled from a 24-h urine collection) at 6 months.The primary analyses were done in the full analysis set (ie, all participants to whom study treatment was assigned by randomisation); all participants who received at least one dose of study treatment were included in the safety analysis.This trial was registered with ClinicalTrials.gov(NCT04817618) and the adult cohort has been completed.Findings Between July 28, 2021, and Feb 15, 2023, 132 participants were screened, of whom 58 did not complete the screening period and 74 (64% male; 69% White) were randomised 1:1 to receive either iptacopan (n=38) or placebo (n=36).One participant in the placebo group discontinued treatment during the open-label period.The 24-h UPCR percentage change relative to baseline at 6 months was -302% (95% CI -428 to -148) in the iptacopan group and 76% (-119 to 313) in the placebo group.In the iptacopan group, the geometric mean of 24-h UPCR was 333 g/g (95% CI 279 to 397) at baseline and 217 g/g (162 to 291) at 6 months; in the placebo group, this was 258 g/g (218 to 305) at baseline and 280 g/g (237 to 330) at 6 months.The primary endpoint was met with a relative reduction in 24-h UPCR at 6 months for iptacopan versus placebo of 351% (138 to 511; p=00014).30 (79%) of 38 participants in the iptacopan group had treatment-emergent adverse events, compared with 24 (67%) of 36 participants in the placebo group; most of these were of mild or moderate severity.There were no deaths, no treatment discontinuations due to treatment-emergent adverse events, and no meningococcal infections.Serious adverse events were reported in three (8%) participants in the iptacopan group and one (3%) participant in the placebo group.Interpretation Iptacopan showed a statistically significant, clinically meaningful proteinuria reduction in addition to RAAS inhibitors and immunosuppression at 6 months.Iptacopan was well tolerated with an acceptable safety profile in patients with C3 glomerulopathy.