Sodium-glucose linked transporter-2 inhibitor renal outcome modification in type 2 diabetes : Evidence from studies in patients with high or low renal risk

Abstract Data from three completed cardiovascular outcome trials (CVOTs), EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58, add to the evidence supporting the potential renoprotective effects of sodium-glucose linked transporter-2 (SGLT2) inhibitors in patients with type-2 diabetes (T2D). Despite recommendations in recent guidelines, it is difficult to support a view that definitive evidence for renoprotection exists from these SGLT2 inhibitor CVOT results. To date, the only dedicated trial to report definitive data on the renal impact of SGLT2 inhibition is CREDENCE. Notably, the total number of patient relevant renal endpoint events (dialysis, transplant or renal death) observed in CREDENCE was significantly higher than the total for all three CVOTs collectively (183 events/4,401 patients vs. 69 events/34,322 patients, respectively), which demonstrates the increased statistical power of CREDENCE for these renal endpoints. Treatment with canagliflozin was associated with a 30% relative risk reduction (RRR) in the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes and a 34% RRR for the renal-specific elements of this primary endpoint (PPeer reviewe

Randomized trial comparing proactive, high-dose versus reactive, low-dose intravenous iron supplementation in hemodialysis (PIVOTAL) : Study design and baseline data

Background: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. Methods: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin 700 μg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 μg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. Results: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. Conclusions: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. Trial Registration: EudraCT number: 2013-002267-25.Peer reviewedFinal Published versio

The Association of Echocardiographic Peak Systolic Strain Rate with Cardiovascular Outcomes in Haemodialysis Patients

Background/Aims: Echocardiographic abnormalities of systolic function can be detected earlier with advancing echocardiographic technologies. Given the high prevalence of left ventricular hypertrophy in dialysis patients, we hypothesised that one such marker of strain, peak systolic strain rate (SR) would demonstrate association with cardiovascular outcome in a haemodialysis cohort. Methods: Recruited prevalent haemodialysis patients underwent standard transthoracic echocardiography as part of a detailed cardiovascular assessment on a non-dialysis day during a short inter-dialytic midweek break. Patients were followed up to mortality and cardiovascular end points. Multivariate Cox proportional hazard models were built to determine the association of above versus below median SR in a model adjusted for confounding factors. Results: 183 patients were enrolled and followed up for a median 925 days. Median age was 64.9 years, prevalence of LVH 55%, and median SR -0.86 (-1.00 to -0.72). An SR greater than -0.86 S-1 (less negative) had a hazard ratio (HR) of 2.32 (1.36 to 3.95) in association with all-cause mortality after adjustment for EF, age, smoking history, MI, previous transplant, albumin and systolic blood pressure. For cardiovascular mortality, the HR was 2.343 (0.99 to 5.553) p =0.046. The only echocardiographic parameter independently associated with MACE was above median E/e (HR 2.09 [1.03 to 4.24], p=0.04). No echocardiographic parameter was associated with heart failure episodes. Conclusion: SR demonstrates association with outcome in this population and highlights the consideration that such sub-clinical cardiac changes should be routinely sought when referring haemodialysis patients for cardiac assessments

Characterising the burden of chronic kidney disease among people with type 2 diabetes in England: a cohort study using the Clinical Practice Research Datalink.

OBJECTIVES: To describe prevalence of chronic kidney disease (CKD), demographic and clinical characteristics, treatment patterns and rates of cardiovascular and renal complications for patients with type 2 diabetes (T2D) treated in routine clinical care. DESIGN: Repeat cross-sectional study (6 monthly cross-sections) and cohort study from 1 January 2017 to 31 December 2019. SETTING: Primary care data from English practices contributing to the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. PARTICIPANTS: Patients with T2D aged >18 years, at least one year of registration data. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was prevalence of CKD defined as chronic kidney disease epidemiology collaboration (CKD-EPI) estimated glomerular filtration rate <60 mL/min/1.73 m2, and/or urinary albumin creatinine ratio ≥3 mg/mmol in the past 24 months. Secondary outcomes were prescriptions of medications of interest and clinical and demographic characteristics in the past 3 months.In the cohort study rates of renal and cardiovascular complications, all-cause mortality and hospitalisations over the study period were compared among those with and without CKD. RESULTS: There were 574 190 eligible patients with T2D as of 1 January 2017 and 664 296 as of 31 December 2019. Estimated prevalence of CKD across the study period was stable at approximately 30%. Medication use was stable over time in people with CKD and T2D, with low use of steroidal mineralocorticoid receptor antagonists (approximately 4.5% across all time points) and a low use but steady increase in use of sodium-glucose co-transporter-2 inhibitors (from 2.6% to 6.2%). Rates of all complications were higher in those with CKD at the start of the study period, with increasing rates, with increased severity of CKD, heart failure and albuminuria. CONCLUSIONS: The burden of CKD in patients with T2D is high and associated with substantially increased rates of complications particularly in those with comorbid heart failure

Kidney volume to GFR ratio predicts functional improvement after revascularization in atheromatous renal artery stenosis

Background: Randomized controlled trials (RCT) have shown no overall benefit of renal revascularization in atherosclerotic renovascular disease (ARVD). However, 25% of patients demonstrate improvement in renal function. We used the ratio of magnetic resonance parenchymal volume (PV) to isotopic single kidney glomerular filtration rate (isoSKGFR) ratio as our method to prospectively identify "improvers" before revascularization. Methods: Patients with renal artery stenosis who were due revascularization were recruited alongside non-ARVD hypertensive CKD controls. Using the controls, 95% CI were calculated for expected PV:isoSK-GFR at given renal volumes. For ARVD patients, “improvers” were defined as having both >15% and >1ml/min increase in isoSK-GFR at 4 months after revascularization. Sensitivity and specificity of PV:isoSK-GFR for predicting improvers was calculated. Results: 30 patients (mean age 68 ±8 years), underwent revascularization, of whom 10 patients had intervention for bilateral RAS. Stented kidneys which manifested >15% improvement in function had larger PV:isoSK-GFR compared to controls (19±16 vs. 6±4ml/ml/min, p = 0.002). The sensitivity and specificity of this equation in predicting a positive renal functional outcome were 64% and 88% respectively. Use of PV:isoSK-GFR increased prediction of functional improvement (area under curve 0.93). Of note, non-RAS contralateral kidneys which improved (n = 5) also demonstrated larger PV:isoSK-GFR (15.2±16.2 ml/ml/min, p = 0.006). Conclusion: This study offers early indicators that the ratio of PV:isoSK-GFR may help identify patients with kidneys suitable for renal revascularization which could improve patient selection for a procedure associated with risks. Calculation of the PV:isoSK-GFR ratio is easy, does not require MRI contrast agent

The role of iron in calciphylaxis—a current review

Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare and often fatal condition, frequently diagnosed in end-stage renal disease (ESRD) patients. Although exact pathogenesis remains unclear, iron supplementation is suggested as a potential risk factor. Iron and erythropoietin are the main stay of treatment for anaemia in ESRD patients. Few observational studies support the role of iron in the pathogenesis of calciphylaxis although data from the pivotal trial was not strongly supportive of this argument, i.e., no difference in incidence of calciphylaxis between the low-dose and high-dose iron treatment arms. Elevated levels of vascular cell adhesion molecules in association with iron excess were postulated to the pathogenesis of CUA by causing inflammation and calcification within the microvasculature. In-addition, oxidative stress generated because of iron deposition in cases of systemic inflammation, such as those seen in ESRD, may play a role in vascular calcification. Despite these arguments, a direct correlation between cumulative iron exposure with CUA incidence is not clearly demonstrated in the literature. Consequently, we do not have evidence to recommend iron reduction or cessation in ESRD patients that develop CUA

Short Paper: Blockcheck the Typechain

Recent efforts have sought to design new smart contract programming languages that make writing blockchain programs safer. But programs on the blockchain are beholden only to the safety properties enforced by the blockchain itself: even the strictest language-only properties can be rendered moot on a language-oblivious blockchain due to inter-contract interactions. Consequently, while safer languages are a necessity, fully realizing their benefits necessitates a language-aware redesign of the blockchain itself. To this end, we propose that the blockchain be viewed as a typechain: a chain of typed programs-not arbitrary blocks-that are included iff they typecheck against the existing chain. Reaching consensus, or blockchecking, validates typechecking in a byzantine fault-tolerant manner. Safety properties traditionally enforced by a runtime are instead enforced by a type system with the aim of statically capturing smart contract correctness. To provide a robust level of safety, we contend that a typechain must minimally guarantee (1) asset linearity and liveness, (2) physical resource availability, including CPU and memory, (3) exceptionless execution, or no early termination, (4) protocol conformance, or adherence to some state machine, and (5) inter-contract safety, including reentrancy safety. Despite their exacting nature, typechains are extensible, allowing for rich libraries that extend the set of verified properties. We expand on typechain properties and present examples of real-world bugs they prevent

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN):an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos.</p

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN):an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos.</p