Dosing of Erythropoiesis-Stimulating Agents Can Be Reduced by a New Administration Regimen

Background/Aims:At our hemodialysis (HD) unit, we noted a drop in the treatment dose of erythropoietin-stimulating agents (ESAs) when the frequency of dose adjustment was reduced from weekly, where doses were withheld if hemoglobin was >130 g/l, to monthly, where doses were not withheld. The aim of this study was to find an explanation for this reduction in ESA requirement. Methods: This is a retrospective study on 18 stable HD patients. Comparable follow-up periods of 6 months with the two different ESA adjustment regimens were established and data on ESA dose, hemoglobin and known predictors of ESA response were collected. Results: With the new ESA administration regimen, a 22.5% drop in the total ESA dose was noted. The corresponding fall in the erythropoietin resistance index was 20.0%. Simultaneously, the dialysis dose and transferrin saturation increased significantly. However, in a multivariate linear regression model, changes in these factors did not significantly predict changes in ESA requirement. No relevant changes were noted in other erythropoiesis-modulating factors. Conclusion: Frequent dose adjustments and the current ESA administration practice of withholding ESA doses does not seem to reduce ESA demand. On the contrary, such practice is likely to increase ESA requirement over time

Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease:a prespecified analysis from the DAPA-CKD trial

BACKGROUND: Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause. METHODS: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1·73m2 were randomly assigned (1:1) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. Secondary efficacy outcomes were a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality. In this study, we conducted a prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by aetiology of chronic kidney disease. DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150. FINDINGS: The study took place between Feb 2, 2017, and June 12, 2020. 4304 participants were randomly assigned (2152 to dapagliflozin and 2152 to placebo) and were followed up for a median of 2·4 years (IQR 2·0-2·7). Overall, 2906 (68%) participants had a diagnosis of type 2 diabetes, of whom 396 (14%) had chronic kidney disease ascribed to causes other than diabetic nephropathy. The relative risk reduction for the primary composite outcome with dapagliflozin was consistent in participants with type 2 diabetes (hazard ratio [HR] 0·64, 95% CI 0·52-0·79) and those without diabetes (0·50, 0·35-0·72; pinteraction=0·24). Similar findings were seen for the secondary outcomes: kidney-specific composite outcome (0·57 [0·45-0·73] vs 0·51 [0·34-0·75]; Pinteraction=0·57), cardiovascular death or hospital admission for heart failure (0·70 [0·53-0·92] vs 0·79 [0·40-1·55]; Pinteraction=0·78), and all-cause mortality (0·74 [0·56-0·98] vs 0·52 [0·29-0·93]; Pinteraction=0·25). The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51-0·78), glomerulonephritides (n=695; 0·43, 0·26-0·71), ischaemic or hypertensive chronic kidney disease (n=687; 0·75, 0·44-1·26), and chronic kidney disease of other or unknown cause (n=412; 0·58, 0·29-1·19; Pinteraction=0·53), with similar consistency seen across the secondary outcomes. The proportions of participants in the dapagliflozin and placebo groups who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes. INTERPRETATION: Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease. FUNDING: AstraZeneca

Dapagliflozin in patients with chronic kidney disease

Background: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known. Methods: We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Results: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed. Conclusions: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo

The Kidney Protective Effects of the Sodium–Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists

Introduction: Mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of kidney failure in chronic kidney disease (CKD). We performed an analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial by baseline conventional MRA (spironolactone and eplerenone) prescription. Methods: Participants with CKD (estimated glomerular filtration rate [eGFR] 25-75 ml/min per 1.73 m2; urinary albumin-to-creatinine ratio 200-500 mg/g), with or without type 2 diabetes, were randomized 1:1 to dapagliflozin 10 mg or placebo, once daily. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or kidney or cardiovascular (CV) death. A prespecified kidney-specific secondary outcome was as the primary outcome but without CV death. Hyperkalemia (serum potassium ≥6.0 mmol/l) was an exploratory end point. Time-to-event analyses (proportional hazards [Cox] regression) assessed dapagliflozin versus placebo in patient subgroups defined by baseline conventional MRA use. Results: A total of 229 of 4304 DAPA-CKD participants (5.3%) were receiving conventional MRAs at baseline (dapagliflozin n = 109, placebo n = 120). The effect of dapagliflozin on the primary outcome was consistent in participants prescribed (hazard ratio [HR] 0.76, 95% CI 0.40-1.47) and not prescribed (HR 0.60, 95% CI 0.50-0.72, P-interaction = 0.59) MRAs. This consistency was maintained for the kidney-specific outcome. The effect of dapagliflozin on hyperkalemia (HR 0.87, 95% CI 0.70-1.09) was consistent among those prescribed (HR 0.94, 95% CI 0.41-2.20) and not prescribed (HR 0.87, 95% CI 0.69-1.10, P-interaction = 0.96) MRAs. Adverse events (AEs) leading to discontinuation and serious AEs were similar between treatment groups, regardless of baseline MRA prescription. Conclusion: Dapagliflozin was similarly safe and efficacious in reducing major adverse kidney outcomes in participants with CKD who were or were not prescribed MRAs at baseline

Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure

OBJECTIVES: The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF). BACKGROUND: Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline. METHODS: A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified. RESULTS: HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF. CONCLUSIONS: Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150)

Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease

Background: Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and kidney events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease. Methods: In the DAPA-CKD trial (Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomized to dapagliflozin 10 mg once daily or placebo. The primary endpoint was a composite of sustained decline in estimated GFR ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary endpoints were a kidney composite outcome (primary endpoint, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease. Results: Secondary prevention patients (n=1610; 37.4%) were older, more often male, had a higher blood pressure and body-mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio was similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (HR, 0.61 [95% CI, 0.48-0.78]) and secondary (0.61, 0.47-0.79) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67, 0.40-1.13 versus 0.70, 0.52-0.94, respectively, P-interaction=0.88), and all-cause (0.63, 0.41-0.98 versus 0.70, 0.51-0.95, respectively, P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease. Conclusions: Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival, in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03036150

A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high risk patients based on having chronic kidney disease (CKD) and severe albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m ) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function

Imaging the mantle beneath Iceland using integrated seismological techniques

Using a combination of body wave and surface wave data sets to reveal the mantle plume and plume head, this study presents a tomographic image of the mantle structure beneath Iceland to 400 km depth. Data comes primarily from the PASSCAL-HOTSPOT deployment of 30 broadband instruments over a period of 2 years, and is supplemented by data from the SIL and ICEMELT networks. Three sets of relative teleseismic body wave arrival times are generated through cross correlation: S and SKS arrivals at 0.03–0.1 Hz, and P and PKIKP arrivals at 0.03–0.1 and 0.8–2.0 Hz. Prior to inversion the crustal portion of the travel time anomalies is removed using the crustal model ICECRTb. This step has a significant effect on the mantle velocity variations imaged down to a depth of ∼250 km. Inversion of relative arrival times only provides information on lateral velocity variations. Surface waves are therefore used to provide absolute velocity information for the uppermost mantle beneath Iceland. The average wave number for the Love wave fundamental mode at 0.020 and 0.024 Hz is measured and used to invert for the average S velocity. Combination of the body wave and surface wave information reveals a predominantly horizontal low-velocity anomaly extending from the Moho down to ∼250 km depth, interpreted as a plume head. Below the plume head a near-cylindrical low-velocity anomaly with a radius of ∼100 km and peak VP and VS anomalies of −2% and −4%, respectively, extends down to the maximum depth of resolution at 400 km. Within the plume head, in the uppermost mantle above the core of the plume, there is a relatively high velocity with a maximum VP and VS anomaly of +2%. This high-velocity anomaly may be the result of the extreme degree of melt extraction necessary to generate the thick (46 km) crust in central Iceland. Comparison of the plume volumetric flux implied by our images, the crustal generation rate, and the degree of melting suggested by rare earth element inversions, suggests that (1) mantle material must be flowing horizontally away from the plume core faster than the overlying lithosphere and (2) the bulk of the plume material does not participate in melting beneath Iceland

Studies on treatment of renal anemia in patients on chronic hemodialysis

In patients with chronic kidney disease, treatment with erythropoiesis-stimulating agents (ESA) effectively corrects anemia. Most of these patients also need supplementation with regular iron injections to secure iron availability for proper erythropoiesis. Following intravenous iron injection, non-transferrin bound iron (NTBI) can appear in the circulation, capable of inducing harmful oxidative reactions. Direct measurement of free iron with the robust technique electron spin resonance (ESR) has not been used to investigate this issue in humans. The main purposes of this thesis were to use ESR to study the levels of NTBI and oxidative stress after intravenous (IV) iron injection and to compare two commercially available IV iron formulations, low-molecular weight iron-dextran (ID) and iron-sucrose (IS), regarding this topic. In addition, the impact of two different hemodialysis modalities on iron homeostasis and the effect of modifying the ESA administration praxis on ESA requirement, were studied. Sixty-four patients on chronic hemodialysis treatment participated in these studies. To investigate the appearance of NTBI and induction of oxidative stress, blood samples were collected before and after IV iron injections. To compare two different hemodialysis modalities, a prospective, randomized, patient-blinded study, with conventional hemodialysis (HD) and on-line hemodiafiltration (HDF), in a 2x2 months design, was conducted. Finally, a retrospective register study was performed on 18 patients, comparing periods with two different erythropoietin administration routines. After injection of IS, a parallel increase in oxidative stress and NTBI was noted, while no induction of oxidative stress was seen following injection of ID. After treatment with HDF, the levels of the iron-regulating peptide, 25-hepcidin, were in all cases within the reference interval. A change in ESA administration regimen, to less frequent dose-adjustments and no withheld doses, could be an explanation for the observed approximately 20 % reduction in ESA requirement. In conclusion, IS injection, but not ID injection, “leaks” catalytically active iron into the blood stream, which then initiates a burst of intravascular oxidative reactions. The increased clearance of 25-hepcidin by HDF could be of benefit for the dialysis patient, bringing the pathological iron homeostasis found in this population toward a more normal state. An erythropoietin regimen with optimal frequency of dose adjustments can reduce ESA demand and thereby decrease health care cost