Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population

Effects of canagliflozin on hyperkalaemia and serum potassium in people with diabetes and chronic kidney disease: insights from the CREDENCE trial

Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin aldosterone system (RAAS), particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. We sought to assess the effect of canagliflozin on hyperkalaemia and other potassium-related outcomes in people with T2DM and CKD by conducting a post-hoc analysis of the CREDENCE trial. The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post-hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin angiotensin system blockade. Canagliflozin reduced the risk of investigator-reported hyperkalaemia or initiation of potassium binders (HR 0.78, 95% CI 0.64–0.95, p=0.014; Figure 1). The incidence of laboratory-determined hyperkalaemia was similarly reduced (HR 0.77, 95% CI 0.61–0.98, p=0.031; Figure 2); the risk of hypokalaemia (HR 0.92, 95% CI 0.71–1.20, p=0.53) was not increased. Mean serum potassium over time with canagliflozin was similar to that of placebo. Among patients treated with RAAS inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia

Reduced risk of myocardial infarct and revascularization following coronary artery bypass grafting compared with percutaneous coronary intervention in patients with chronic kidney disease

Coronary atherosclerotic disease is highly prevalent in chronic kidney disease (CKD). Although revascularization improves outcomes, procedural risks are increased in CKD and unbiased data comparing bypass surgery (CABG) and percutaneous intervention (PCI) in CKD are sparse. To compare outcomes of CABG and PCI in stage 3-5 CKD, we identified randomized trials comparing these procedures. Investigators were contacted to obtain individual, patient-level data. Ten of 27 trials meeting inclusion criteria provided data. These trials enrolled 3993 patients encompassing 526 patients with stage 3-5 CKD of which 137 were stage 3b-5 CKD. Among individuals with stage 3-5 CKD survival through 5-years was not different following CABG compared with PCI (hazard ratio 0.99, 95% confidence interval: 0.67, 1.46) or stage 3b-5 CKD (1.29: 0.68, 2.46). However, CKD modified the impact on survival free from myocardial infarction: it was not different between CABG and PCI for individuals with preserved kidney function (0.97: 0.80, 1.17), but was significantly lower following CABG in stage 3-5 CKD (0.49: 0.29, 0.82) and stage 3b-5 CKD (0.23: 0.09, 0.58). Repeat revascularization was reduced following CABG compared with PCI regardless of baseline kidney function. Results were limited by unavailability of data from several trials and paucity of enrolled patients with stage 4-5 CKD. Thus, our patient-level meta-analysis of individuals with CKD randomized to CABG versus PCI suggests that CABG significantly reduces the risk of subsequent myocardial infarction and revascularization without impacting survival in these patients

Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering

Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. Research design and methods We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. Results HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m 2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. Conclusions The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.2

Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease: Insights from the CREDENCE trial

Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) experience a high burden of hypertension but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population is uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP lowering therapy is also unknown. Methods: The CREDENCE trial randomized people with T2DM and CKD to canagliflozin or placebo. Post-hoc, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mmHg while receiving ≥3 classes of BP lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4,401 participants of whom 3,361 (76.4%) had baseline systolic BP ≥130 mmHg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50mmHg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP lowering therapy subgroups (all P-interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP lowering agents during the trial (HR 0.68, 95% CI 0.61-0.75). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease (HR 0.70, 95% CI 0.59-0.82) was consistent across BP and BP lowering therapy subgroups (all P-interaction ≥0.35), as were effects on other key kidney, cardiovascular and safety outcomes. Conclusions: In people with T2DM and CKD, canagliflozin lowers systolic BP across all BP defined subgroups and reduces the need for additional BP lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP lowering therapy in people with CKD. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT02065791

Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop

Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Chronic Kidney Disease According to Baseline HbA1c, Including Those with HbA1c <7%: Results From the CREDENCE Trial

Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.1 Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).2-3 Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.1 We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%

Canagliflozin Reduces Kidney-Related Adverse Events in Type 2 Diabetes and CKD:Findings From the Randomized CREDENCE Trial

RATIONALE AND OBJECTIVE: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). STUDY DESIGN: A randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING AND PARTICIPANTS: 4,401 trial participants with T2DM, CKD, and urinary albumin:creatinine ratio >300-5000mg/g. INTERVENTIONS: Participants were randomly assigned to receive canagliflozin 100mg/day or placebo. OUTCOMES: Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73m2). RESULTS: Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR]: 0.71 [95% confidence interval (CI): 0.61, 0.82]; P<0.001), with consistent results for serious kidney-related AEs (HR: 0.72 [95% CI: 0.51, 1.00]; P=0.05) and acute kidney injury (AKI; HR: 0.85 [95% CI: 0.64, 1.13]; P=0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73m2, respectively; P-interaction=0.3), with similar results for AKI (P-interaction=0.9). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio: 2.2 [95% CI: 1.0, 4.7]; P=0.04). LIMITATIONS: Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured and creatinine data after an AKI event were not available for all participants. CONCLUSION: Canagliflozin compared to placebo was associated with a reduced incidence of serious and non-serious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney disease events

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups: Results from the Randomized CREDENCE Trial

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction &gt;0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791

Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes:A Post Hoc Analysis from the CREDENCE Trial

Background The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition. Methods TheCanagliflozin and Renal Events inDiabeteswith EstablishedNephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR].300 mg/g). This post hoc analysis assessed canagliflozin's effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death. Results Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR ( odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P,0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P,0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P,0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm. Conclusions In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes