Publications by authors named "David C Wheeler"

261 Publications

Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.

Lancet Diabetes Endocrinol 2021 Nov 4;9(11):743-754. Epub 2021 Oct 4.

Study Design and Biostatistics Center, University of Utah Health Sciences, Salt Lake City, UT, USA.

Background: Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)-ie, the eGFR slope.

Methods: DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73m. Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete.

Findings: Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8-2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m per year [0·73 to 1·85]; p=0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m per year (-0·10 to 1·03; p=0·040). The total eGFR slope was steeper in patients with higher baseline HbA and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA and UACR.

Interpretation: Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA, and higher UACR.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S2213-8587(21)00242-4DOI Listing
November 2021

Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.

Lancet Diabetes Endocrinol 2021 Nov 4;9(11):755-766. Epub 2021 Oct 4.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands; The George Institute for Global Health, Sydney, NSW, Australia. Electronic address:

Background: Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial.

Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m and 75 mL/min per 1·73 m and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150.

Findings: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (p<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056).

Interpretation: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S2213-8587(21)00243-6DOI Listing
November 2021

Using a GPS Watch to Characterize Life-Space Mobility in Dementia: A Dyadic Case Study.

J Gerontol Nurs 2021 Oct 1;47(10):15-22. Epub 2021 Oct 1.

Persons with dementia (PWD) often experience difficulty navigating their environments and performing out-of-home activities. Life-space mobility (LSM) is an effective way of assessing functional levels and independence. We present a dyadic case study to explore the feasibility of using a global positioning system (GPS) watch to measure LSM of a Latino PWD. Methods included travel diary, LSM questionnaire, and qualitative interviews in addition to the GPS-based mobility characterization. GPS data indicated that the PWD made outdoor trips regularly and was active socially, with day-to-day variations. Caregiver and PWD interviews revealed contextual information about mobility patterns captured by other methods. The dyad had positive perceptions of the GPS watch for tracking health and activities. This study demonstrated a use for wearable location tracking technology to support accurate LSM assessment in dementia that can inform nursing practice, policy, and research to promote well-being and delay functional deterioration in PWD. [(10), 15-22.].
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http://dx.doi.org/10.3928/00989134-20210908-03DOI Listing
October 2021

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.

Kidney Int 2021 Sep 22. Epub 2021 Sep 22.

The George Institute for Global Health, Sydney, Australia; Department of Renal Medicine, University College London, London, UK.

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 substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that 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.
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http://dx.doi.org/10.1016/j.kint.2021.09.005DOI Listing
September 2021

Modeling annual elevated blood lead levels among children in Maryland in relation to neighborhood deprivation.

Sci Total Environ 2021 Sep 15;805:150333. Epub 2021 Sep 15.

Department of Public Health, College of Life Sciences, Brigham Young University, Provo, UT, United States of America.

Estimating environmental lead exposure using ecologic risk models is an inexpensive strategy to inform public health departments and to develop location-based intervention strategies such as targeted screening and mitigation. Importantly, studies in this area have not assessed temporal and spatio-temporal lead exposure risk trends. Due to lead abatement efforts and targeted screening efforts, it is anticipated that lead exposure risk has decreased over time. However, it is unknown if decreases have occurred, and if the decreases are evenly distributed across neighborhoods. Thus, the purpose of this study was to examine the association between neighborhood deprivation and risk of elevated blood lead levels (EBLLs) in both temporal and spatio-temporal contexts within the US state of Maryland in 2005-2015. To consider the temporal dimension of lead risk, we used a novel extension of Bayesian index models to estimate time-varying neighborhood deprivation indices along with time-varying index effects. The results showed that overall EBLL proportion decreased over time, from a high of 0.11 in 2006 to a low of 0.02 in 2015. The association between neighborhood deprivation and EBLL risk was positive and significant annually, but generally diminished over time. The most important variables in the neighborhood deprivation index were percent of houses built before 1940 and median household income. In summary, using Bayesian index models that can account for both temporal and spatio-temporal contexts is a promising approach to inform public health efforts to remediate lead and focus testing efforts and may be useful in studies in other geographic areas and times.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150333DOI Listing
September 2021

Standardised Outcomes in Nephrology - Chronic Kidney Disease (SONG-CKD): a protocol for establishing a core outcome set for adults with chronic kidney disease who do not require kidney replacement therapy.

Trials 2021 Sep 9;22(1):612. Epub 2021 Sep 9.

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Background: Globally, over 1.2 million people die from chronic kidney disease (CKD) every year. Patients with CKD are up to 10 times more likely to die prematurely than progress to kidney failure requiring kidney replacement therapy. The burden of symptoms and impaired quality of life in CKD may be compounded by comorbidities and treatment side effects. However, patient-important outcomes remain inconsistently and infrequently reported in trials in patients with CKD, which can limit evidence-informed decision-making. The Standardised Outcomes in Nephrology - Chronic Kidney Disease (SONG-CKD) aims to establish a consensus-based core outcome set for trials in patients with CKD not yet requiring kidney replacement therapy to ensure outcomes of relevance to patients, caregivers and health professionals are consistently reported in trials.

Methods: SONG-CKD involves four phases: a systematic review to identify outcomes (domains and measures) that have been reported in randomised controlled trials involving adults with CKD who do not require kidney replacement therapy; stakeholder key informant interviews with health professionals involved in the care of adults with CKD to ascertain their views on establishing core outcomes in CKD; an international two-round online Delphi survey with patients, caregivers, clinicians, researchers, policy makers and industry representatives to obtain consensus on critically important outcome domains; and stakeholder consensus workshops to review and finalise the set of core outcome domains for trials in CKD.

Discussion: Establishing a core outcome set to be reported in trials in patients with CKD will enhance the relevance, transparency and impact of research to improve the lives of people with CKD.

Trial Registration: Not applicable. This study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) database: http://www.comet-initiative.org/Studies/Details/1653 .
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http://dx.doi.org/10.1186/s13063-021-05574-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427149PMC
September 2021

Effects of Spironolactone and Chlorthalidone on Cardiovascular Structure and Function in Chronic Kidney Disease: A Randomized, Open-Label Trial.

Clin J Am Soc Nephrol 2021 Oct 30;16(10):1491-1501. Epub 2021 Aug 30.

Institute of Cardiovascular Sciences, University of Birmingham, United Kingdom.

Background And Objectives: In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone.

Design, Setting, Participants, & Measurements: A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg).

Results: There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g, =0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s, =0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, =0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, =0.07).

Conclusions: Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.
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http://dx.doi.org/10.2215/CJN.01930221DOI Listing
October 2021

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

JACC Heart Fail 2021 Aug 5. Epub 2021 Aug 5.

The George Institute for Global Health, Sydney, Australia; Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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).
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http://dx.doi.org/10.1016/j.jchf.2021.06.017DOI Listing
August 2021

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

Eur Heart J 2021 Aug 23. Epub 2021 Aug 23.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 AD Groningen, the Netherlands.

Aims: 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, 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.

Methods And Results: 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. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo.

Conclusion: Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.
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http://dx.doi.org/10.1093/eurheartj/ehab497DOI Listing
August 2021

Randomized Trial-PrEscription of intraDialytic exercise to improve quAlity of Life in Patients Receiving Hemodialysis.

Kidney Int Rep 2021 Aug 30;6(8):2159-2170. Epub 2021 May 30.

School of Health Sciences, Queen Margaret University, Edinburgh, UK.

Introduction: Whether clinically implementable exercise interventions in people receiving hemodialysis (HD) therapy improve health-related quality of life (HRQoL) remains unknown. The PrEscription of intraDialytic exercise to improve quAlity of Life PEDAL) study evaluated the clinical benefit and cost-effectiveness of a 6-month intradialytic exercise program.

Methods: In a multicenter, single-blinded, randomized, controlled trial, people receiving HD were randomly assigned to (i) intradialytic exercise training (exercise intervention group [EX]) and (ii) usual care (control group [CON]). Primary outcome was change in Kidney Disease Quality of Life Short-Form Physical Component Summary (KDQOL-SF 1.3 PCS) from baseline to 6 months. Cost-effectiveness was determined using health economic analysis; physiological impairment was evaluated by peak oxygen uptake; and harms were recorded.

Results: We randomized 379 participants; 335 and 243 patients (EX  = 127; CON  = 116) completed baseline and 6-month assessments, respectively. Mean difference in change PCS from baseline to 6 months between EX and CON was 2.4 (95% confidence interval [CI]: -0.1 to 4.8) arbitrary units ( = 0.055); no improvements were observed in peak oxygen uptake or secondary outcome measures. Participants in the intervention group had poor compliance (47%) and poor adherence (18%) to the exercise prescription. Cost of delivering intervention ranged from US$598 to US$1092 per participant per year. The number of participants with harms was similar between EX ( = 69) and CON ( = 56). A primary limitation was the lack of an attention CON. Many patients also withdrew from the study or were too unwell to complete all physiological outcome assessments.

Conclusions: A 6-month intradialytic aerobic exercise program was not clinically beneficial in improving HRQoL as delivered to this cohort of deconditioned patients on HD.
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http://dx.doi.org/10.1016/j.ekir.2021.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343798PMC
August 2021

The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure.

J Card Fail 2021 Jul 18. Epub 2021 Jul 18.

Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands. Electronic address:

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor's natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage.
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http://dx.doi.org/10.1016/j.cardfail.2021.07.003DOI Listing
July 2021

Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease.

J Am Soc Nephrol 2021 Sep 16;32(9):2352-2361. Epub 2021 Jul 16.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Background: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.

Methods: Adults with eGFR of 25-75 ml/min per 1.73 m and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.

Results: A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m per year in the dapagliflozin and placebo groups, respectively (=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.

Conclusions: Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.
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http://dx.doi.org/10.1681/ASN.2021020167DOI Listing
September 2021

Evaluation of neighborhood deprivation and store characteristics in relation to tobacco retail outlet sales violations.

PLoS One 2021 16;16(7):e0254443. Epub 2021 Jul 16.

Department of Health Behavior & Policy, Virginia Commonwealth University, Richmond, VA, United States of America.

Introduction: Regulations of the sale of tobacco products to minors have been effective at reducing adolescent tobacco use overall. However, these efforts may not be uniformly enforced in all areas, creating uneven protection against adolescent smoking. Knowledge regarding factors associated with tobacco retail outlet (TRO) violations could help inform better enforcement strategies.

Methods: In this study, we used Bayesian index regression models to determine if tobacco sales to minors violations across Virginia (2012-2021) were related to store characteristics and neighborhood deprivation and identify geographic areas at significantly elevated risk for violations after adjusting for these factors.

Results: Results show that there were multiple factors associated with a higher likelihood of tobacco sales violations. Store type was an important factor, as grocery stores and pharmacies had significantly lowered likelihood of violations compared with convenience stores. Being located near another TRO was significantly associated with increased risk of sales to a minor. Neighborhood deprivation was also positively associated with TRO sales violations. Further, there were statistically higher likelihood of sales violations occurring in specific areas (e.g., southwest and southeast) of the state that were not explained by neighborhood deprivation and store attributes.

Conclusions: Together, results highlight the need to better understand where and why TRO sales violations are occurring in order to improve efforts aimed at monitoring and remediating TRO sales violations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254443PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284798PMC
July 2021

Data from a pooled post hoc analysis of 14 placebo-controlled, dapagliflozin treatment studies in patients with type 2 diabetes with and without anemia at baseline.

Data Brief 2021 Aug 21;37:107237. Epub 2021 Jun 21.

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

Dapagliflozin is a highly selective sodium-glucose cotransporter 2 inhibitor associated with stabilization of estimated glomerular filtration rate (eGFR); reductions in glycated hemoglobin (HbA1c), systolic blood pressure, body weight, and albuminuria; and a small and consistent increase in hematocrit [1], [2], [3], [4]. This data set is based on the associated article [5] analyzing data from 5325 patients with type 2 diabetes from 14 placebo-controlled, phase 3 (one phase 2/3), double-blind dapagliflozin treatment studies of 24-104 weeks' duration. Data on dapagliflozin's effects (vs. placebo) on hemoglobin (Hb), hematocrit, serum albumin, serum total protein concentrations, urine albumin/creatinine ratio, eGFR, heart rate, blood pressure, body weight, and safety in patients with type 2 diabetes with and without anemia were pooled and analyzed. Patients were divided into two groups according to baseline Hb levels: anemia (Hb <13 g/dL in men and <12 g/dL in women) and no anemia. Some biomarkers associated with erythropoiesis and the presence of anemia, such as iron, transferrin, ferritin, reticulocytes, and hepcidin, were not included in the original studies and therefore data for these biomarkers were not available. Descriptive statistics were used for baseline characteristics and safety data and a longitudinal repeated-measures mixed model for efficacy data. Changes in Hb concentrations were evaluated, and the proportion of patients with baseline anemia who were no longer anemic at week 24 was determined, as was the occurrence of polycythemia (Hb >16.5 g/dL in men and >16.0 g/dL in women). Because anemia commonly occurs in patients with diabetes and chronic kidney disease [6], the data can be of value to further analyze trends in relevant physiological and pathophysiological parameters.
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http://dx.doi.org/10.1016/j.dib.2021.107237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255174PMC
August 2021

Methods and rationale of the DISCOVER CKD global observational study.

Clin Kidney J 2021 Jun 11;14(6):1570-1578. Epub 2021 Apr 11.

Department of Renal Medicine, University College London, London, UK.

Background: Real-world data for patients with chronic kidney disease (CKD), specifically pertaining to clinical management, metabolic control, treatment patterns, quality of life (QoL) and dietary patterns, are limited. Understanding these gaps using real-world, routine care data will improve our understanding of the challenges and consequences faced by patients with CKD, and will facilitate the long-term goal of improving their management and prognosis.

Methods: DISCOVER CKD follows an enriched hybrid study design, with both retrospective and prospective patient cohorts, integrating primary and secondary data from patients with CKD from China, Italy, Japan, Sweden, the UK and the USA. Data will be prospectively captured over a 3-year period from >1000 patients with CKD who will be followed up for at least 1 year via electronic case report form entry during routine clinical visits and also via a mobile/tablet-based application, enabling the capture of patient-reported outcomes (PROs). In-depth interviews will be conducted in a subset of ∼100 patients. Separately, secondary data will be retrospectively captured from >2 000 000 patients with CKD, extracted from existing datasets and registries.

Results: The DISCOVER CKD program captures and will report on patient demographics, biomarker and laboratory measurements, medical histories, clinical outcomes, healthcare resource utilization, medications, dietary patterns, physical activity and PROs (including QoL and qualitative interviews).

Conclusions: The DISCOVER CKD program will provide contemporary real-world insight to inform clinical practice and improve our understanding of the epidemiology and clinical and economic burden of CKD, as well as determinants of clinical outcomes and PROs from a range of geographical regions in a real-world CKD setting.
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http://dx.doi.org/10.1093/ckj/sfab046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264307PMC
June 2021

Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial.

Diabetes Care 2021 08 28;44(8):1894-1897. Epub 2021 Jun 28.

Department of Renal Medicine, University College London, London, U.K.

Objective: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.

Research Design And Methods: We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m, and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.

Results: Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent ( for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.

Conclusions: Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.
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http://dx.doi.org/10.2337/dc21-0300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385469PMC
August 2021

Identifying Area-Level Disparities in Human Papillomavirus Vaccination Coverage Using Geospatial Analysis.

Cancer Epidemiol Biomarkers Prev 2021 Sep 25;30(9):1689-1696. Epub 2021 Jun 25.

Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.

Background: Human papillomavirus (HPV) is the most common sexually transmitted infection within the United States (US). Despite clinical agreement on the effectiveness and widespread availability of the prophylactic HPV vaccine, vaccination coverage in the US is suboptimal and varies by geographic region and area-level variables. The goals of this article were to model the variation in vaccination rates among boys and girls within ZIP Codes in Virginia, determine whether neighborhood sociodemographic variables explain variation in HPV vaccination, and identify areas with significantly depressed vaccination coverage.

Methods: We used Bayesian hierarchical spatial regression models with statewide immunization registry data to consider the correlation in vaccination among boys and girls, as well as the spatial correlation in vaccination for each sex.

Results: The results showed low vaccination coverage in our birth cohort (28.9% in girls and 23.8% in boys) relative to the national level (56.8% and 51.8%, respectively). Several area-level variables were significantly and positively associated with vaccination coverage, including population density, percentage of Hispanic population, and average number of vehicles. In addition, there were several areas of significantly lowered vaccination coverage, including predominantly rural ones, and overall large geographic disparities in HPV vaccination.

Conclusions: Determining the geospatial patterning and area-level factors associated with HPV vaccination within a prescribed geographic area helps to inform future planning efforts.

Impact: The results of this study will help inform future planning efforts for geographically targeted interventions and policies, as well as drive new research to implement clinical and community strategies to increase HPV vaccination.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419078PMC
September 2021

Exercise programme to improve quality of life for patients with end-stage kidney disease receiving haemodialysis: the PEDAL RCT.

Health Technol Assess 2021 06;25(40):1-52

School of Health Sciences, Queen Margaret University, Edinburgh, UK.

Background: Whether or not clinically implementable exercise interventions in haemodialysis patients improve quality of life remains unknown.

Objectives: The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial evaluated the clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on quality of life compared with usual care for haemodialysis patients.

Design: We conducted a prospective, multicentre randomised controlled trial of haemodialysis patients from five haemodialysis centres in the UK and randomly assigned them (1 : 1) using a web-based system to (1) intradialytic exercise training plus usual-care maintenance haemodialysis or (2) usual-care maintenance haemodialysis.

Setting: The setting was five dialysis units across the UK from 2015 to 2019.

Participants: The participants were adult patients with end-stage kidney disease who had been receiving haemodialysis therapy for > 1 year.

Interventions: Participants were randomised to receive usual-care maintenance haemodialysis or usual-care maintenance haemodialysis plus intradialytic exercise training.

Main Outcome Measures: The primary outcome of the study was change in Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score (from baseline to 6 months). Cost-effectiveness was determined using health economic analysis and the EuroQol-5 Dimensions, five-level version. Additional secondary outcomes included quality of life (Kidney Disease Quality of Life Short Form, version 1.3, generic multi-item and burden of kidney disease scales), functional capacity (sit-to-stand 60 and 10-metre Timed Up and Go tests), physiological measures (peak oxygen uptake and arterial stiffness), habitual physical activity levels (measured by the International Physical Activity Questionnaire and Duke Activity Status Index), fear of falling (measured by the Tinetti Falls Efficacy Scale), anthropometric measures (body mass index and waist circumference), clinical measures (including medication use, resting blood pressure, routine biochemistry, hospitalisations) and harms associated with intervention. A nested qualitative study was conducted.

Results: We randomised 379 participants; 335 patients completed baseline assessments and 243 patients (intervention,  = 127; control,  = 116) completed 6-month assessments. The mean difference in change in physical component summary score from baseline to 6 months between the intervention group and control group was 2.4 arbitrary units (95% confidence interval -0.1 to 4.8 arbitrary units;  = 0.055). Participants in the intervention group had poor compliance (49%) and very poor adherence (18%) to the exercise prescription. The cost of delivering the intervention ranged from £463 to £848 per participant per year. The number of participants with harms was similar in the intervention ( = 69) and control ( = 56) groups.

Limitations: Participants could not be blinded to the intervention; however, outcome assessors were blinded to group allocation.

Conclusions: On trial completion the primary outcome (Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score) was not statistically improved compared with usual care. The findings suggest that implementation of an intradialytic cycling programme is not an effective intervention to enhance health-related quality of life, as delivered to this cohort of deconditioned patients receiving haemodialysis.

Future Work: The benefits of longer interventions, including progressive resistance training, should be confirmed even if extradialytic delivery is required. Future studies also need to evaluate whether or not there are subgroups of patients who may benefit from this type of intervention, and whether or not there is scope to optimise the exercise intervention to improve compliance and clinical effectiveness.

Trial Registration: Current Controlled Trials ISRCTN83508514.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256322PMC
June 2021

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

JACC Heart Fail 2021 Jul 9;9(7):518-527. Epub 2021 Jun 9.

Department of Renal Medicine, King's College Hospital, London, United Kingdom.

Objectives: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients.

Background: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat.

Methods: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial.

Results: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event.

Conclusions: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).
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http://dx.doi.org/10.1016/j.jchf.2021.04.005DOI Listing
July 2021

Estimated IQ points and lifetime earnings lost to early childhood blood lead levels in the United States.

Sci Total Environ 2021 Jul 9;778:146307. Epub 2021 Mar 9.

Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23284, USA. Electronic address:

There is no safe detectable level of lead (Pb) in the blood of children. Blood lead levels (BLLs) at ages 6-24 months ≥2 μg/dL result in lost grade school intelligence quotient (IQ) points at ages 5-10 years. Black children continue to have the highest BLLs in the United States. Therefore, we examined currently undetermined racial/ethnic disparities in anticipated IQ points and associated lifetime earnings lost to early childhood blood lead. We conducted secondary analysis of infants with blood lead (in μg/dL) measured at ages 12-24 months by the cross-sectional National Health and Nutrition Examination Survey (NHANES) during 1999 to 2010. Nationally-representative estimates were produced using weighted simulation model. A total of 1241 infants were included from the NHANES sample (52% male; mean [SD] age, 18.5 [3.5] months; 25% Black [non-Hispanic], 42% Hispanic [any race], 5% Other/Multiracial, and 29% White [non-Hispanic]) after excluding 811 without BLL determinations. For national outcomes, Black infants experienced approximately 46-55% greater average estimated loss of grade school IQ points from blood lead than Hispanic or White infants (-1.78 IQ points vs. -1.15 and -1.21 respectively) with similar disparities in costs to expected lifetime earnings (-$47,116 USD vs. -$30,393 and -$32,356 respectively). Our estimated nationwide costs of IQ points lost to BLLs during this 12-year period totaled $554 billion ($46.2 billion/year), in which blood lead <5 μg/dL accounted for 74% of this total burden. We report two aspects of the substantial national costs attributable to lead exposure in just the second year of life alone, which disproportionately impact predominately African-American Black infants from continuing legacies of environmental racism in lead exposure. Our findings underscore the remarkably high costs from recognized hazards of blood lead even at the lowest levels and the importance of primary prevention regarding childhood lead exposure.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146307DOI Listing
July 2021

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

Am J Kidney Dis 2021 May 23. Epub 2021 May 23.

The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Concord Repatriation General Hospital, Sydney, Australia.

Rationale & 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 (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) 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 & Participants: 4,401 trial participants with T2DM, CKD, and urinary albumin-creatinine ratio >300-5,000 mg/g.

Interventions: Participants were randomly assigned to receive canagliflozin 100 mg/d 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/1.73 m).

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% 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/1.73 m, respectively; P = 0.3 for interaction), with similar results for AKI (P = 0.9 for interaction). 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.

Conclusions: Compared with placebo, canagliflozin was associated with a reduced incidence of serious and nonserious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney-related AEs.

Funding: The CREDENCE trial and this analysis were funded by Janssen Research & Development, LLC, and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical.

Trial Registration: The CREDENCE trial was registered at ClinicalTrials.gov with identifier number NCT02065791.
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http://dx.doi.org/10.1053/j.ajkd.2021.05.005DOI Listing
May 2021

The PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease trial: study design and baseline data for a multicentre randomized controlled trial.

Clin Kidney J 2021 May 10;14(5):1345-1355. Epub 2020 Sep 10.

School of Health Sciences, Centre for Health, Activity and Rehabilitation Research, Queen Margaret University, Edinburgh, UK.

Background: Exercise interventions designed to improve physical function and reduce sedentary behaviour in haemodialysis (HD) patients might improve exercise capacity, reduce fatigue and lead to improved quality of life (QOL). The PrEscription of intraDialytic exercise to improve quAlity of Life study aimed to evaluate the effectiveness of a 6-month intradialytic exercise programme on QOL and physical function, compared with usual care for patients on HD in the UK.

Methods: We conducted a prospective, pragmatic multicentre randomized controlled trial in 335 HD patients and randomly (1:1) assigned them to either (i) intradialytic exercise training plus usual care maintenance HD or (ii) usual care maintenance HD. The primary outcome of the study was the change in Kidney Disease Quality of Life Short Form (KDQOL-SF 1.3) Physical Component Score between baseline and 6 months. Additional secondary outcomes included changes in peak aerobic capacity, physical fitness, habitual physical activity levels and falls (International Physical Activity Questionnaire, Duke's Activity Status Index and Tinetti Falls Efficacy Scale), QOL and symptom burden assessments (EQ5D), arterial stiffness (pulse wave velocity), anthropometric measures, resting blood pressure, clinical chemistry, safety and harms associated with the intervention, hospitalizations and cost-effectiveness. A nested qualitative study investigated the experience and acceptability of the intervention for both participants and members of the renal health care team.

Results: At baseline assessment, 62.4% of the randomized cohort were male, the median age was 59.3 years and 50.4% were white. Prior cerebrovascular events and myocardial infarction were present in 8 and 12% of the cohort, respectively, 77.9% of patients had hypertension and 39.4% had diabetes. Baseline clinical characteristics and laboratory data for the randomized cohort were generally concordant with data from the UK Renal Registry.

Conclusion: The results from this study will address a significant knowledge gap in the prescription of exercise interventions for patients receiving maintenance HD therapy and inform the development of intradialytic exercise programmes both nationally and internationally.

Trial Registration: ISRCTN N83508514; registered on 17 December 2014.
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http://dx.doi.org/10.1093/ckj/sfaa107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087141PMC
May 2021

Understanding and Overcoming the Challenges Related to Cardiovascular Trials Involving Patients with Kidney Disease.

Clin J Am Soc Nephrol 2021 09 23;16(9):1435-1444. Epub 2021 Apr 23.

Department of Medicine, Division of Cardiology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota

Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%-60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.
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http://dx.doi.org/10.2215/CJN.17561120DOI Listing
September 2021

A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy.

Kidney Int 2021 07 18;100(1):215-224. Epub 2021 Apr 18.

Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.
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http://dx.doi.org/10.1016/j.kint.2021.03.033DOI Listing
July 2021

Bayesian Group Index Regression for Modeling Chemical Mixtures and Cancer Risk.

Int J Environ Res Public Health 2021 03 27;18(7). Epub 2021 Mar 27.

UC Berkeley School of Public Health, University of California, Berkeley, CA 94704-7394, USA.

There has been a growing interest in the literature on multiple environmental risk factors for diseases and an increasing emphasis on assessing multiple environmental exposures simultaneously in epidemiologic studies of cancer. One method used to analyze exposure to multiple chemical exposures is weighted quantile sum (WQS) regression. While WQS regression has been demonstrated to have good sensitivity and specificity when identifying important exposures, it has limitations including a two-step model fitting process that decreases power and model stability and a requirement that all exposures in the weighted index have associations in the same direction with the outcome, which is not realistic when chemicals in different classes have different directions and magnitude of association with a health outcome. Grouped WQS (GWQS) was proposed to allow for multiple groups of chemicals in the model where different magnitude and direction of associations are possible for each group. However, GWQS shares the limitation of WQS of a two-step estimation process and splitting of data into training and validation sets. In this paper, we propose a Bayesian group index model to avoid the estimation limitation of GWQS while having multiple exposure indices in the model. To evaluate the performance of the Bayesian group index model, we conducted a simulation study with several different exposure scenarios. We also applied the Bayesian group index method to analyze childhood leukemia risk in the California Childhood Leukemia Study (CCLS). The results showed that the Bayesian group index model had slightly better power for exposure effects and specificity and sensitivity in identifying important chemical exposure components compared with the existing frequentist method, particularly for small sample sizes. In the application to the CCLS, we found a significant negative association for insecticides, with the most important chemical being carbaryl. In addition, for children who were born and raised in the home where dust samples were taken, there was a significant positive association for herbicides with dacthal being the most important exposure. In conclusion, our approach of the Bayesian group index model appears able to make a substantial contribution to the field of environmental epidemiology.
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http://dx.doi.org/10.3390/ijerph18073486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037139PMC
March 2021

Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial.

Eur Heart J 2021 03;42(13):1216-1227

The George Institute for Global Health, Level 5, 1 King Street, Newtown, Sydney, NSW 2042, Australia.

Aims: Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.

Methods And Results: DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.

Conclusion: In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
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http://dx.doi.org/10.1093/eurheartj/ehab094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244648PMC
March 2021

Study design and baseline characteristics of patients on dialysis in the ASCEND-D trial.

Nephrol Dial Transplant 2021 Mar 21. Epub 2021 Mar 21.

Medical University of Silesia, Katowice, Poland.

Background: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Dialysis (ASCEND-D) trial will test the hypothesis that daprodustat is non-inferior to comparator epoetin alfa or darbepoetin alfa for two co-primary endpoints: haemoglobin efficacy and cardiovascular safety.

Methods: We report the trial design, key demographic, clinical, and laboratory findings, and baseline therapies of 2964 patients randomised in the open-label (sponsor-blinded) active-controlled, parallel-group, randomised ASCEND-D clinical trial. We also compare baseline characteristics of ASCEND-D patients with patients who are on dialysis (CKD G5D) enrolled in other large cardiovascular outcome trials (CVOTs) and in the most relevant registries.

Results: The median age of patients was 58 years, 43% were female; 67% were white and 16% were black. The median haemoglobin at baseline was 10.4 g/dL. Among randomised patients, 89% were receiving haemodialysis and 11% peritoneal dialysis. Among key co-morbidities, 42% reported a history of diabetes mellitus, and 45% a history of cardiovascular disease. Median blood pressure was 134/74 mmHg. The median weekly dose of epoetin was 5751 units. Intravenous and oral iron use was noted in 64% and 11% of patients, respectively. Baseline demographics were similar to patients with CKD G5D enrolled in other CVOTs and renal patient registries.

Conclusion: ASCEND-D will evaluate the efficacy and safety of daprodustat compared with epoetin alfa or darbepoetin alfa in the treatment of patients with anaemia with CKD G5D.
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March 2021

An examination of social and environmental determinants of secondhand smoke exposure among non-smoking adolescents.

Tob Prev Cessat 2021 12;7:20. Epub 2021 Mar 12.

Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, United States.

Introduction: Adolescents are at increased risk of secondhand smoke exposure (SHS) due to the limited control that they have over social and physical environments. Yet, knowledge regarding determinants of SHS among non-smoking adolescents is limited. This study identifies social and environmental factors associated with SHS among non-smoking adolescents.

Methods: To be included, parents and adolescents (aged 11-17 years) of the Adolescents, Place, and Behavior Study had to have completed surveys between March 2019 and May 2020. Adolescents had to have not reported smoking within the past 30 days and provided a saliva sample assayed for cotinine (≤3 ng/mL). A series of stepwise linear regression models were fit to the data to identify social and environmental determinants of SHS, using log-transformed salivary cotinine.

Results: Of the 105 adolescent and parent dyads included, 90.3% were African American, 26.9% of parents reported smoking, 33.3% resided in multi-unit housing, and 67.7% lived in homes where smoking was not permitted. Significant associations were found between parent tobacco use (β=2.56, SE=0.98, p=0.0082) and residing in multi-unit housing (β=1.72, SE=0.86, p=0.0460) with increased log-transformed cotinine levels among non-smoking adolescents. Adolescent age, gender, and race/ ethnicity, parental education, peer tobacco use, the number of adults and children in the home, average number of days of self-reported SHS within public spaces outside of the home, and home smoking policies were not significantly associated with cotinine.

Conclusions: Results emphasize the importance of reducing secondhand smoke exposure by reducing parental smoking and altering exposures within social and home environments. Parental tobacco use and residential setting should be considered when developing interventions to reduce secondhand smoke exposure among non-smoking adolescents.
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http://dx.doi.org/10.18332/tpc/131875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954078PMC
March 2021

Survival on four compared with three times per week haemodialysis in high ultrafiltration patients: an observational study.

Clin Kidney J 2021 Feb 28;14(2):665-672. Epub 2020 Dec 28.

Department of Renal Medicine, University College London, UK.

Background: The harm caused by the long interdialytic interval in three-times-per-week haemodialysis regimens (3×WHD) may relate to fluid accumulation and associated high ultrafiltration rate (UFR). Four-times-per-week haemodialysis (4×WHD) may offer a solution, but its impact on mortality, hospitalization and vascular access complications is unknown.

Methods: From the AROii cohort of incident in-centre haemodialysis patients, 3×WHD patients with a UFR >10 mL/kg/h were identified. The hazard for the outcomes of mortality, hospitalization and vascular access complications in those who switched to 4×WHD compared with staying on 3×WHD was estimated using a marginal structural Cox proportional hazards model. Adjustment included baseline patient and treatment characteristics with inverse probability weighting used to adjust for time-varying UFR and cardiovascular comorbidities.

Results: From 10 637 European 3×WHD patients, 3842 (36%) exceeded a UFR >10 mL/kg/h. Of these, 288 (7.5%) started 4×WHD and at baseline were more comorbid. Event rates while receiving 4×WHD compared with 3×WHD were 12.6 compared with 10.8 per 100 patient years for mortality, 0.96 compared with 0.65 per year for hospitalization and 14.7 compared with 8.0 per 100 patient years for vascular access complications. Compared with 3×WHD, the unadjusted hazard ratio (HR) for mortality on 4×WHD was 1.05 [95% confidence interval (CI) 0.78-1.42]. Following adjustment for baseline demographics, time-varying treatment probability and censoring risks, this HR was 0.73 (95% CI 0.50-1.05; P = 0.095). Despite these adjustments on 4×WHD, the HR for hospitalization remained elevated and vascular access complications were similar to 3×WHD.

Conclusions: This observational study was not able to demonstrate a mortality benefit in patients switched to 4×WHD. To demonstrate the true benefits of 4×WHD requires a large, well-designed clinical trial. Our data may help in the design of such a study.
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http://dx.doi.org/10.1093/ckj/sfaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886573PMC
February 2021

Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis.

Clin J Am Soc Nephrol 2021 03 22;16(3):384-395. Epub 2021 Feb 22.

The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia.

Background And Objectives: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial.

Design, Setting, Participants, & Measurements: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (=2348), >1000 to <3000 mg/g (=1547), and ≥3000 mg/g (=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP.

Results: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup ( =0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years ( =0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories.

Conclusions: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g.

Clinical Trial Registry Name And Registration Number: ClinicalTrials.gov: CREDENCE, NCT02065791.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.
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http://dx.doi.org/10.2215/CJN.15260920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011002PMC
March 2021
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