PracticeUpdate Conference Series ISN WCN 2019

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

INTERNATIONAL SOCIETY OF NEPHROLOGY WORLD CONGRESS OF NEPHROLOGY 12–15 APRIL 2019 • MELBOURNE, AUSTRALIA

THE BEST OF WCN 2019 CREDENCE Shows Safety and Efficacy of Canagliflozin for Renal Endpoints in Type 2 Diabetes • Hemodiafiltration Offers Benefits Over Hemodialysis in Pediatric Setting • Global Kidney Health Atlas Reveals Worldwide Gaps in Care • High BMI May Not Be Barrier to Successful Kidney Transplantation

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FABRY DISEASE CAN BE FOUND IN APPROXIMATELY 1 IN 200 PATIENTS WITH UNEXPLAINED END-STAGE RENAL DISEASE CASES 1,2

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References: 1. van der Tol L, et al. J Med Genet 2014; 51: 1-9. 2. Tanaka M, et al. Clin Nephrol 2005; 64: 281-87.

© 2017–2019 ISN WCD 2019 All rights reserved.

CONTENTS WCN 2019 • 12–15 April 2019 • Melbourne, Australia BY THE PRACTICEUPDATE EDITORIAL TEAM

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3 Weight Gain and Obesity Post-Kidney Transplant Alarmingly High in Pediatric Population 4 CREDENCE Shows Safety and Efficacy of Canagliflozin for Renal Endpoints in Type 2 Diabetes 6 Cardiorenal Benefits of Empagliflozin Demonstrated in Proteinuric Diabetic Kidney Disease 7 Lower Dose Tacrolimus Remains Effective Immunosuppressive Strategy Following Kidney Transplant

8 Australian Study Demonstrates Benefits of Home Dialysis 9 ACTIVE Study Finds Extended Time on Dialysis Does Not Improve Survival 10 SONAR Study Reveals Potential for Atrasentan to Slow Kidney Disease Progression in Well-Selected Patients 12 Hemodiafiltration Offers Benefits Over Hemodialysis in Pediatric Setting 13 SGLT2 Inhibitors Benefit Patients With Diabetes and Chronic Kidney Disease 14 Global Kidney Health Atlas Reveals Worldwide Gaps in Care

16 Follow-Up Telehealth Service Saves Significant Money, Time for Kidney Transplant Patients 17 Kidney Disease Screening and Awareness Program Effectively Identifies Undetected Proteinuria 18 Undetected Community-Acquired Acute Kidney Injury Common in Low- Resource Settings 19 High BMI May Not Be Barrier to Successful Kidney Transplantation 20 Effects of Vitamin D Uncertain in Patients with Chronic Kidney Disease

The production of this publication is sponsored by Sanofi Genzyme. The provision of this information is not intended to advocate any use not covered by the Product Information. Please check that the product is approved for use and always consult the Product Information before prescribing.

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WCN 2019 • PRACTICEUPDATE CONFERENCE SERIES

PRACTICEUPDATE PRIMARY CARE BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise.

Editor-in-Chief

David Rakel MD, FAAFP Professor and Chair, Department of Family & Community Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico

PracticeUpdate ® is a registered trademark of Elsevier Inc. ©2019 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’smission istohelpmedicalprofessionals navigatethevastarrayofavailable literatureand focuson themostcritical informationfortheirpatientsandpractice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medicalprofessionals.The ideasandopinionsexpressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.Pleaseconsult the fullcurrentProduct Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this publication is sponsored by Sanofi Genzyme. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. Content was produced by Elsevier with no involvement by Sanofi Genzyme. All content printed in this publication can be found on PracticeUpdate.com SALES Matthew Buttsworth m.buttsworth@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Cover: Blood supply of the kidneys/gettyimages.com ISSN 2208-150X (Print) • ISSN 2208-1518 (Online) contributors. DISCLAIMER

Associate Editors

Tricia C. Elliott MD, FAAFP Vice President, Academic Affairs, Chief Academic Officer, Designated Institutional Official, John Peter Smith Health Network; Adjunct Professor, Family Medicine, University of Texas Medical Branch, Texas

Peter Lin MD, CCFP Director, Primary Care Initiatives, Canadian Heart Research Centre; Medical Director, LinCorp Medical Inc, Ontario, Canada

Advisory Board

Robert Bonakdar MD, FAAFP, FACN Director of Pain Management, Scripps Center for Integrative Medicine, La Jolla, California

Dennis J. Butler PhD Professor Emeritus of Family Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin

Irene Mace Hamrick MD, FAAFP, AGSF Associate Professor, Clinical Health Sciences, Department of Family Medicine, University of Wisconsin; Director of Geriatrics Services, Department of Family Medicine, University of Wisconsin, Madison, Wisconsin

Dipesh Navsaria MPH, MSLIS, MD Associate Professor of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Jonathan Temte MD, PhD Professor, University of Wisconsin School of Medicine and Public Health, Department of Family Medicine and Community Health, Madison, Wisconsin

Editorial Contributors

Michael Allen MD Chief Resident – Family Medicine, Jennie Sealy Hospital, UTMB Health John Sealy Hospital, Galveston, Texas

Andrea Dotson MD, MSPH NRSA Primary Care Research Fellow, University of North Carolina, Department of Family Medicine, Cecil G. Sheps Center for Health Services Research, Chapel Hill, North Carolina

ELSEVIER AUSTRALIA ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 Printed in Australia. EMCS051901

Weight Gain and Obesity Post-Kidney Transplant Alarmingly High in Pediatric Population Strategies to prevent excessive weight gain are sorely needed in this population.

A s many as half of children who undergo kidney transplantation are overweight or obese 1 year later, according to an analysis presented at WCN 2019. Independent predictors of weight gain were found to be body mass index (BMI) at the time of transplantation and during time on dialysis. The data were presented by Sean Kennedy, MD, of Sydney Children's Hospital in Randwick, New South Wales. Dr. Kennedy and his colleagues per- formed a single-center, retrospective analysis of 55 kidney transplants per- formed in 53 recipients between January 2000 and July 2017. All recipients were 18 years of age or younger, and their median age at the time of transplantation was 10 years (interquartile range 7.06–15.13). The primary outcome was the change in BMI Z-score at 12 months, with a secondary outcome at 24 months. Weight and height data were recorded at transplantation, monthly until 6 months, every 3 months thereafter until 12 months, and then every 6 months until 24 months. The prevalence of overweight and obesity increased from 24% and 9% at transplanta- tion to 26% and 24% at 12months, and 32% and 26% at 24 months, respectively. The mean change in BMI Z-score rose signifi- cantly from 0.60 (95% confidence interval 0.27–0.93) at transplantation to 1.29 (95% CI 0.98–1.60) at 12 months and 1.49 (95% CI 1.14–1.83) at 24 months. Multivariate analysis revealed that BMI-Z at transplant (P < .001) as well as >12 months spent on dialysis (P = .006) were " It is striking that this many patients became obese. It is greater than that seen in the adult population. "

both significant predictors of change in BMI Z-score at 12 months and 24 months post-transplantion (P < .001 and P = .034, respectively). No other patient- or treat- ment-related variables, including age, gender, ethnicity, primary disease etiology, gastrostomy prevalence, supplementary feeding, or cumulative prednisolone dose between time of transplantation and 3 months afterwards, were found to significantly predict weight gain in an independent fashion. In a comment on the study for Elsevier’s PracticeUpdate , session moderator Toby Coates, MD, of the University of Adelaide, South Australia, noted that the

high proportion of patients who were overweight and obese in this population is “alarming.” Such substantial weight gain places these patients at higher risk of type 2 diabetes which, in turn, places additional strain on the kidneys. “Obesity is bad on many fronts,” Dr. Coates said. “It is striking that this many patients became obese. It is greater than that seen in the adult population.” There is an important unanswered ques- tion, he added: “What strategies can be developed to prevent weight gain, includ- ing non-drug strategies?”

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CREDENCE Shows Safety and Efficacy of Canagliflozin for Renal Endpoints in Type 2 Diabetes Benefits in cardiovascular outcomes were also demonstrated.

T he SGLT2 inhibitor canagliflozin effectively reduces the risk of renal and cardiovascular events in patients with type 2 diabetes and chronic kidney disease, even those with con- siderably poor renal function, according to the CREDENCE trial. The background, study design, findings and clinical implications of CREDENCE were each presented by different members of the study’s steering committee. “There has been a huge increase in those going on to end-stage kidney disease (ESKD), espe- cially since the 1990s, but that trend started back in the 1980s,” said George Bakris, MD, from the University of Chicago, during his presentation on the background of CREDENCE. “… If you project out to 2030, there is going to be a doubling of renal replacement therapy around the world that is going to be needed. This is particularly important to certain regions of the world, such as Asia and North America. “This is a problem that is not going away,” he added. “It is getting worse, and we really need some inroads on it. Diabetes is by far the leading cause of people requiring renal replacement therapy,

and this problem is also headed for much bigger numbers, so this is a huge epidemic with major consequences.” SGLT2s, he continued “… reduce intraglomerular pressure, they affect atrial natriuretic peptide, they reduce albuminuria, … [they reduce] oxidant stress within the diabetic kidney, and [they produce] dramatic blunting of angiotensinogen within the diabetic kidney. And they have other mechanisms dealing with anti-fibrotic and anti-inflammatory effects.” While previous trials of SGLT2 inhibitors have shown promise with regard to their effects on the kidney, these trials were not primarily designed to evaluate renal effect, so few patients were included who had substantial nephropathy. The primary goal of CREDENCE, however, was to “assess the effects of the SGLT2 inhibitor canagli- flozin on clinically important outcomes in people with type 2 diabetes and established chronic kid- ney disease,” said Dr. Bakris. For the trial, which was sponsored by Janssen, manufacturers of canagliflozin, 4401 patients from 34 countries with type 2 diabetes and an estimated

Dr. George Bakris

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canagliflozin therapy was 0.72 (95% CI 0.54–0.97). These effects were consistent regardless of baseline eGFR or UACR, as well as other baseline characteristics. While eGFR dropped more in the treat- ment than the placebo group during the first weeks after randomization, this rapidly attenuated. By 42 months, eGFR had dropped by a mean of –1.85 mg/mL/ min/1.73 m 2 per year in the canagliflozin group and a mean of –4.59 mg/mL/ min/1.73 m 2 per year in the placebo group, which translated to a 60% reduction in eGFR slope decline. Cardiovascular and safety outcomes were similarly promising. Comparing active therapy with placebo yielded superior outcomes with respect to the compositive of cardiovascular death or hospitaliza- tion from heart failure (HR 0.69; 95% CI 0.57–0.83; P < .001), cardiovascular death, myocardial infarction or stroke (HR 0.80; 95% CI 0.67–0.95; P = .01), hospitalization for heart failure (HR 0.61; 95% CI 0.47– 0.80; P < .001), and cardiovascular death (HR 0.78; 95% CI 0.61–1.00; P = .0502). No differences were found between the two groups of patients with respect to risk of fracture or amputation. The safety profile of canagliflozin was consistent with other studies of this drug. In his presentation on the clinical impli- cations of CREDENCE, David C. Wheeler, MD, of University College London in the United Kingdom, pointed out that, among patients with an eGFR of 30 to 45 mL/ min/1.73 m 2 , only 16 patients would need to be treated for 2.5 years to prevent a clinical outcome. “Canagliflozin safely reduced the risk of kidney failure and pre- vented cardiovascular events in people with type 2 diabetes and chronic kidney disease,” he concluded. bigger numbers, so this is a huge epidemic with major consequences. " the leading cause of people requiring renal replacement therapy, and this problem is also headed for much " Diabetes is by far

glomerular filtration rate (eGFR) of 30 to 90 mL/min/1.73 m 2 as well as a urinary albumin-to-creatinine ratio (UACR) of 3000 to 5000 mg/g were randomized to canagliflozin 100 mg once daily or placebo. Patients were followed up at week 3, 13 and 26, then every 13 weeks thereafter. Prior to randomization, all patients were receiving standard of care therapy, includ- ing a maximum tolerated dose of an ACE inhibitor or angiotensin II receptor blocker. Patients were maintained on treatment regardless of eGFR decline or devel- opment of an eGFR <30 mL/min/1.73 m 2 , unless they received chronic dialysis or received a kidney transplant. The patients’ mean age was 63 years, and 34% were female. The mean duration of diabetes was 16 years. Overall, 97% of par- ticipants had hypertension, 15% had heart failure (New York Heart Association class I to III), 50% had cardiovascular disease, and 5% had received a prior amputation. These and other characteristics, including

background therapy and renal character- istics, were well-balanced between the treatment and placebo groups. In July 2018, after a planned interim anal- ysis, the CREDENCE trial was stopped prematurely for efficacy reasons. The primary endpoint was the compos- ite of ESKD (defined as chronic dialysis for ≥30 days, kidney transplantation or eGFR <15 mg/mL/min/1.73m 2 for ≥30 days), doubling of serum creatinine, or renal or cardiovascular death. This occurred in 245 patients on active therapy and 340 patients on placebo (hazard ratio 0.70; 95% confidence interval 0.59–0.82; P = .00001). Looking at the renal composite endpoint of ESKD, doubling of serum creatinine, or renal death yielded a hazard ratio of 0.66 (95% CI 0.53–0.81; P < .001) with canagliflozin, compared with placebo. The hazard ratio for ESKD alone was 0.68 (95% CI 0.54–0.86; P = .002). For the composite of dialysis, kidney transplanta- tion or renal death, the hazard ratio with

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Cardiorenal Benefits of Empagliflozin Demonstrated in Proteinuric Diabetic Kidney Disease EMPA-RENAL will further elucidate benefits in a broader population.

T he beneficial effects of the SGLT2 inhibitor empagliflozin on the primary cardiorenal outcome measure used in the EMPA-REG OUTCOME trial are evident even among those with proteinuric diabetic kidney disease, as defined in the CREDENCE trial. The findings were presented in a poster at WCN 2019. Because of these pos- itive findings, the EMPA-KIDNEY study, which will evaluate the effects of empagliflozin on primary cardiorenal outcomes in a broader diabetic kidney disease population, will move forward. “So far, we have encouraging results from second- ary endpoints of large cardiovascular outcome trials with empagliflozin, canagliflozin and dapag- liflozin with respect to kidney outcomes,” presenter Christoph Wanner, MD, from the University Hospital of Würzburg in Germany told Elsevier’s PracticeUpdate . What remains to be seen is how SGLT2 inhibitors fare when kidney outcomes com- prise the primary endpoint. “With the present study,” he explained, “we evalu- ated the CREDENCE kidney primary endpoint in the EMPA-REG OUTCOME study in order to see whether a secondary endpoint will match the pri- mary endpoint when made equal.” The CREDENCE trial, which compared the effect of canagliflozin with placebo on renal and cardiovascular outcomes in the setting of proteinuric diabetic kidney disease was stopped early because of efficacy. For the EMPA-REG OUTCOME trial, 7020 adults from 42 countries with type 2 diabetes, a glycated hemoglobin (HbA1c) 7.0% to 9.0% if they were

Dr. Christoph Wanner

drug-naive and 7.0% to 10.0% if they were on stable glucose-lowering therapy, established car- diovascular disease, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 were ran- domized in a 1:1:1 fashion to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo once daily, in addition to standard of care. Glucose-lowering therapy remained unchanged for the first 12 weeks, although glycemic rescue medication was permit- ted if the patient had a confirmed fasting glucose >240 mg/dL. Subsequently, investigators were encouraged to adjust the glucose-lowering therapy to achieve optimal glycemic control, according to local guidelines. Overall, 4.3% of patients treated with empagliflozin and 7.3% on placebo achieved the post-hoc cardio- renal outcome of end-stage kidney disease (ESKD), defined as initiation of maintenance renal replace- ment therapy or sustained eGFR <15 mL/min/1.73 m 2 , sustained doubling of serum creatinine, and renal or cardiovascular death, which translated to a 43% reduction in relative risk (hazard ratio 0.57; 95% CI 0.46–0.70). Dr. Wanner and his colleagues analyzed the outcomes based on patients’ eligibility for the CREDENCE trial, which included an eGFR ≥30 to <90mL/min/1.73m 2 and a urine albumin-to-creatinine

" SGLT2 inhibitors are effective in lower ranges of kidney function, a range which is not covered by current labels in most parts of the world. "

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Lower Dose Tacrolimus Remains Effective Immunosuppressive Strategy Following Kidney Transplant Acute rejection rates did not increase with the lower dose. P atients given a lower-than-standard dose of tacrolimus as part of an immunosuppressive regimen following kidney transplantation were less likely to have supratherapeutic levels of the drug in the days following transplant surgery and did not have an increased risk of organ rejection, according to a single center experience. “The SYMPHONY study established low-dose tacrolimus, mycophenolate, prednisolone, and IL-2 receptor antagonist induction as standard of care for immunosuppression in kidney transplant recipients,” the authors wrote in their abstract. The study was led by Justin Chua, MD, of Austin Health in Melbourne. The study investigators reduced the starting tacrolimus dose from 0.075mg/ kg twice daily to 0.05 mg/kg twice daily among their kidney transplant patients, in an effort to minimize supratherapeutic tacrolimus levels in the early post-transplant period. Dr. Chua and his colleagues conducted a retrospective study of 127 kidney transplant recipients who were treated at their institution while they were still using higher dose tacrolimus (n=64; Nov 1, 2015 to October 31, 2016) as well as after they switched to the lower dose (n=63; December 1, 2016 to November 30, 2017). Multiorgan transplant recipients were excluded. The standard immunosuppression regimen used throughout was tacrolimus, mycophenolate mofetil, prednisolone and basiliximab. The two groups of patients were well-matched for age (mean 52.1 ± 12.1 years), gender (63% male) and pre-transplant diabetes mellitus (18.9%). Compared with those who received the higher dose of tacrolimus, those who received the lower dose had significantly lower mean tacrolimus levels during day 1 to 3 (10.8 ± 4.6 vs 15.3 ± 6.4 mcg/L; P < .001), day 4 to 7 (7.5 ± 2.4 vs 9.5 ± 3.4 mcg/L; P < .001) and day 8 to 14 (7.3 ± 1.4 vs 8.4 ± 2.2 mcg/L; P = .002), but not at day 21 or day 28. A higher proportion of patients on the lower dose of tacrolimus achieved therapeutic levels, defined as 6 to 10 mcg/L, during day 1 to 3 (36.1% vs 18.8%; P = .0022), day 4 to 7 (50.8% vs 40.6%; P = .0011), and day 8 to 14 (83.6% vs 71.7%; P = .025). In addition, those on the higher dose were more likely to have supratherapeutic levels, defined as levels >10 mcg/L, during day 1 to 3 (54.1% vs 79.7%, P = .0022). There were no significant differences between the two treatment groups with respect to rates of treated acute rejection at 6 months (26.4% vs 25.4%), delayed graft function (47.6% vs 46.8%), or post-transplant diabetes mellitus (38.2% vs 39.0%). In a comment on the study, session moderator Toby Coates, MD, of the University of Adelaide, told Elsevier’s PracticeUpdate that, “Tacrolimus is associated with transplant kidney nephrotoxicity. Therefore, a lower dose, if it could be achieved [without compromising efficacy], would reduce the damage of the drug to the kidney,” which in turn could help improve the graft outcome. Dr. Coates called these findings “very promising” but noted that they will need to be confirmed in a larger, more diverse population before any recommended changes to standard care can be made.

ratio (UACR) >300 mg/g. This was the trial’s defini- tion of proteinuric diabetic kidney disease. Of the 7020 EMPA-REG OUTCOME participants, 643 (9.2%) met CREDENCE criteria for proteinuric diabetic kidney disease. As with the overall cohort, the use of empagliflozin versus placebo showed consistent treatment effects, with a hazard ratio of 0.46 (95% CI 0.31–0.68) for the cardiorenal outcome. Outcomes in the subgroup of patients who met CREDENCE criteria were similar to the overall cohort with respect to the positive effects of empagliflozin on cardiovascular death and the composite of cardiovascular death and hospital- ization for heart failure. Similar to the overall population, there was no increased risk with empagliflozin versus placebo in events consistent with acute renal failure (12.6% vs 16.7%) or hyperkalemia (3.6% vs 7.2%). Based on these findings and those from the CREDENCE study also presented at the WCN conference, Dr. Wanner concluded that, “SGLT2 inhibitors are effective in lower ranges of kidney function, a range which is not covered by current labels in most parts of the world.”

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Australian Study Demonstrates Benefits of Home Dialysis Findings suggest access to home dialysis should be improved. D emonstrated benefits of home dialysis for patients with end-stage kidney failure (ESKD) suggest that

calcium, phosphate and parathyroid hormone), proportion of patients in each group with a hemoglobin below 100 g/L and phosphate above 1.8mmol/L, and whether transplanted patients were alive 6 months after their transplant. In all, there were 542 patients included in the analysis, with a cumulative 2135 per- son-years of data. The incidence rate of death was 6 per 100 person-years. There were no significant differences between groups in average age, gender, race, smoking status, late referral, or cause of ESKD. Body mass index (BMI) was signif- icantly higher in home dialysis patients: 30.2 kg/m 2 compared with 27.3 kg/m 2 (P < .0001). There was also a significantly higher prevalence of cerebrovascular disease at baseline in the satellite group, as compared with home dialysis patients (P = .001), but no differences were found in the prevalence of lung disease, coro- nary artery disease, peripheral vascular disease, cancer, diabetes or hepatitis C. Home dialysis patients had a significantly reduced risk of death (hazard ratio 0.28; 95% CI 0.17–0.47; P < .001). Transplant rates were also higher in home dialysis patients (61.8%) compared with satellite dialysis patients (51.6%, P = .03). The sur- vival rate at 6 months post-transplantation was very high in both groups, 99.5% in satellite dialysis patients and 100% in home dialysis patients. The proportion of patients with low hemo- globin, which was defined as <100 g/L, was not significantly different between groups (P = .35). High phosphate levels, defined as >1.80 mmol/L, were found in 46.6% of in satellite dialysis patients compared with 35.8% of home patients (P < .05). The study authors conclude in their abstract that home dialysis, “is associated with reduced risk of mortality, increased rates of transplantation, and improved phosphate control in an Australian dialy- sis population. With only 9.6% of dialysis patients in Australia dialysing at home, it would be worthwhile working to improve access to home [dialysis] for Australians with ESKD.”

The need for travel is removed with home dialysis, and the number of hours on dialysis increases from 5 to 8 hours on alternate days. Because most home dialysis patients do the procedure overnight, this results in less interference with their other daily activities of living. The intent of the current study was to assess whether there were significant dif- ferences in outcomes between home and satellite dialysis patients in an Australian centre. Emily Yeung, MBBS, of the Monash Medical Centre in Clayton, Victoria, pre- sented the findings. Home dialysis patients from a tertiary care centre were included in the study start- ing in 2008, and incident patients were added up until June 2017. Three satellite dialysis patients served as controls and were matched to each home dialysis patient on three criteria: age, gender, and cause of ESKD. The primary outcomes were all-cause mortality (censored for transplantation) and transplantation. Secondary outcomes were average bio- chemical levels (hemoglobin, corrected

increasing access to this service is worth- while, according to research presented at WCN 2019. Earlier research has shown that home dialysis has been associated with improve- ments in both clinical and non-clinical outcomes. Improvements in biochemical parameters and intradialytic blood pres- sure control have been reported along with a reduction in recovery time after dialysis, fewer adverse events (including hospitalization), and an overall improved quality of life and survival. At the end of 2017 in Australia, there was a total of 1023 patients on home dialy- sis, slightly less than 10% of all dialysis patients in the country. Satellite dialysis, on the other hand, accounts for 51.4% of all hemodialysis patients in Australia. This procedure requires that patients travel to a medical centre, usually 3 times a week for a period of 4 to 5 hours of dialysis per session.

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ACTIVE Study Finds Extended Time on Dialysis Does Not Improve Survival Still, the extended time did produce some benefits that might make it worthwhile in selected patients. E xtended time on dialysis over a 12-month period does not improve survival at 60 months, according to

The mean follow-up time for study participants was 4.25 years (95% confidence interval 4.06–4.44). During follow-up, 31 participants received renal transplants (n=17 in the extended hours group and n=14 in the standard hours hours group). Overall, 18 participants died in the extended-hours group, compared with 20 in the standard-hours group, for a hazard ratio of 0.92; 95% CI 0.49–1.74; P = .79. “After 5 years, 80% of participants were still alive. There was no difference in mortality between the two groups,” said Dr. Smyth. The findings for adjusted and trans- plant-censored analyses were similar. The non-inferiority of extended-hours compared with standard-hours dialysis could not be confirmed, however, and the research team concluded that there were no significant differences between arms in any of the pre-specified subgroups. The pre-specified test for non-inferiority was that the upper limit of the 95% confi- dence interval for the hazard ratio could be no greater than 1.10 (excluding a true mortality increase of greater than 10%). The durability of the longer dialysis inter- vention was poor after the randomized phase, although the extent to which this reflects patient, physician or institutional priorities could not be determined because patients and doctors were not asked as part of the study why they changed back to normal hours of dialysis. Investigators in China, however, indicated that it was unlikely any of their sites there would continue with longer weekly dialysis hours. “Even in Australia, New Zealand and Canada, where our sites were generally keen proponents of longer weekly dialy- sis hours, very few people continued the practice once the randomized period came to an end,” said Dr. Smyth. “Our main study showed that the intensive dialysis was associated with some small improvements in quality of life, such as physical and mental quality of life, but these benefits do not appear to have been enough for the participants to con- tinue with the practice.”

results of the Clinical Trial of IntensiVE (ACTIVE) Dialysis Study, presented at WCN 2019. Despite some demonstrated benefits, most centers did not continue extended dialysis after the study was completed. “We did not find an overwhelming reason for patients to practice either extended or standard weekly dialysis hours. This frees patients and health carers to decide on the weekly dialysis schedule that is best suited to them and their situation,” Brendan Smyth, MBBS, from the George Institute for Global Health in Newtown, New South Wales, told Elsevier’s PracticeUpdate . Earlier studies have shown that people practising more hours of hemodialysis generally live longer. At the same time, however, people in better health are more likely to undergo longer dialysis hours. “The only way to be sure about whether the long dialysis hours themselves led to better outcomes was to randomize a group of willing participants into a trial. ACTIVE is the largest and so the most reliable trial conducted on the question,” said Dr. Smyth. He noted that the longer dialysis hours resulted in slight reductions of some toxins, such as phosphate, the need for slightly fewer medications, a less restric- tive diet, and improved blood pressure. “So, for patients in whom these issues are prominent, extended-hours dialysis is likely to be quite helpful,” continued Dr. Smyth. “Patients who are already doing longer-hours dialysis and who are feeling well can feel comfortable contin- uing with their schedule.” The 200 participants in the study, who were from China, Australia, New Zealand and Canada, were randomly allocated to undergo dialysis for either 24 or 12 hours a week for a 1-year period. The subsequent outcomes and hemodialysis patterns for these participants over the 4 years fol- lowing the main study was reported on at WCN 2019.

Dr. Brendan Smyth

" Even in Australia,

New Zealand and Canada, where our sites were generally keen proponents of longer weekly dialysis hours, very few people continued the practice once the randomized period came to an end. "

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SONAR Study Reveals Potential for Atrasentan to Slow Kidney Disease Progression in Well-Selected Patients Trial is an important example of precisionmedicine.

T he investigational endothelin inhibitor atrasentan shows promise for slowing the pro- gression of kidney disease among patients with type 2 diabetes and diabetic nephropathy, provided they are preselected for good response rate and lack of fluid retention. These are the main findings of the atrasentan and renal events in type 2 diabetes with chronic kid- ney disease Study Of diabetic Nephropathy with atrasentan (SONAR) trial, presented for the first time at WCN 2019. The study authors emphasized that this trial is an example of the future of preci- sion medicine, in which therapies are tailored to individual patients. Endothelin has multiple pathophysiological effects that contribute to the progression of chronic kidney disease. Previous studies of endothelin antagonists among patients with diabetes revealed a reduction in albuminuria but also a potential increase in fluid reten- tion, which could contribute to heart failure. Clinical findings, however, do suggest that, in selected patients, atrasentan can be dosed to provide ben- eficial effects with a minimal risk of adverse events. SONAR was a predictive enrichment trial, mean- ing it was designed to maximize the benefits of and minimize the adverse events of atrasentan by identifying patients who respond to the drug with reduced albuminuria and without weight gain. The rationale, study design, results and clinical implications of the trial were each presented at WCN by separate members of the SONAR Steering Committee.

One of these members is Ricardo Correa-Rotter, MD, of the National Medical Sciences and Nutrition Institute Salvador Zubirán in Mexico City, Mexico. He told the audience that, “Diabetes is a grow- ing problem. … We are now facing a worldwide epidemic in which, by the year 2040, more than 600 million people will be diabetic. And of those who are diabetic, at least 1 in 3 will have diabetic kidney disease. As nephrologists, we have to acknowledge that sometimes we underplay the prognosis of the diabetic patient on dialysis.” He pointed out that the 5-year survival is poorer than for prostate cancer, breast cancer, thyroid cancer, Hodgkin’s lymphoma, and several other serious neoplastic diseases. Inclusion criteria for the SONAR trial included an esti- mated glomerular filtration rate (eGFR) 25 to 75 mL/ min/1.73 m 2 , a urinary albumin-to-creatinine ratio (UACR) between 300mg/m and 5000 mg/g, and a brain natriuretic peptide (BNP) level ≤200 pg/mL. For the trial, 11,087 adult patients with type 2 diabe- tes and diabetic nephropathy were recruited for a 14-day screening period. From there, 5360 of the eligible patients entered a run-in period that was 2 weeks long if they were receiving the maximum dose of a renin-angiotensin system (RAS) inhib- itor or 4 to 12 weeks if they were not. Next, 5117 patients entered the enrichment period, in which they received atrasentan 0.75 mg daily for 6 weeks in an open-label fashion. Those who gained >3kg or developed BNP >300 pg/mL or heart failure stopped therapy and left the trial.

Dr. Ricardo Correa-Rotter

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primary endpoint, which was the compos- ite of doubling of creatinine or end-stage renal disease ESRD (defined as an eGFR 15 mL/min/1.73 m 2 confirmed at 90 days, receiving chronic dialysis, renal transplan- tation, or renal death), occurred in 6.0% of those on active therapy versus 7.9% of those on placebo (hazard ratio 0.65; 5% confidence interval 0.49 to 0.88; P = .005). Similarly, when comparing active therapy to placebo, the hazard ratio for time to 50% eGFR reduction was 0.73 (95% CI 0.55–0.98; P = .038), and the time to the composite cardiorenal outcome of doubling of serum creatinine or ESRD or cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was 0.80 (95% CI 0.54–0.99; P = .049). The eGFR slope over the study period was –2.4 mL/min/1.73 m 2 /year (95% CI –2.7 to –2.1) with active therapy and –3.1 (95% CI –3.4 to –2.8) with placebo, which was significantly different at P = .0005. There were no differences between the two groups with respect to hospi- talization for heart failure or all-cause mortality, although heart failure rates were numerically higher in the treatment arm. Subgroup analyses did not reveal any significant differences in treatment effects. Serious adverse events occurred at a rate of 36.3% with active therapy and 32.3% with placebo (P = .049). This difference was largely driven by higher rates of hypervolemia or fluid retention and ane- mia in the treatment group. Dr. Correa-Rotter concluded in his pres- entation that, “If confirmed, endothelin antagonists like atrasentan could be beneficial for subpopulations of patients who are carefully selected in relation to those who present an adequate response to a good surrogate marker that predicts the long-term benefit, such as albuminu- ria, as we have seen in this study, and excluding patients who either predict a bad response or who may have specific contraindications, like sodium retention or heart failure.” “The 35% reduction in renal events as observed in the SONAR study would con- siderably reduce the residual risk in the studied diabetes patients,” he continued. “In terms of safety, the increased event rate for heart failure, albeit statistically nonsignificant, needs attention and needs to be weighed against the benefits and individualized.”

" If confirmed, endothelin antagonists like atrasentan could be beneficial for subpopulations of patients who are carefully selected in relation to those who present an adequate response to a good surrogate marker that predicts the long-term benefit, such as albuminuria … and excluding patients who either predict a bad response or who may have specific contraindications, like sodium retention or heart failure. "

Among the patients who remained in the trial, the 2648 who responded to atrasentan with a ≥30% UACR reduction were termed “responders” and the 1020 whose UACR reduction was >30% were termed “non-responders”. Both groups of patients were randomized to 0.75 mg of atrasentan or placebo. During the enrichment phase of the trial, there was an overall 30% reduction in albuminuria, including 52% in respond- ers and 8% in non-responders. There was also an overall 0.6 kg body weight increase, with no significant difference in body weight increase between respond- ers and non-responders.

Among the 2648 responders who entered the double-blind phase of the trial, 86% of those on active therapy and 85% of those on placebo remained in the trial, which was stopped prematurely in November 2017 because the 6% predicted event rate was actually closer to 3%. Still, the investigators continued to monitor events for an additional 6 months, which gave them a total of 185 events and 80% power to detect a 35% effect difference. In the responder group, baseline char- acteristics were similar between those on placebo and those on active therapy. There was a 33% difference in rate of albuminuria compared with placebo. The

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Hemodiafiltration Offers Benefits Over Hemodialysis in Pediatric Setting But randomized, controlled trials are needed before it can become standard of care.

C ompared with hemodialysis, hemodiafiltration is safe and effective and is associated with benefits that include a lack of progression in vascular measures, an increase in height, and improved outcomes in the pediatric population, according to a multicenter trial presented at WCN 2019. Presenter Rukshana Shroff, MD, PhD, of the Great Ormond Street Hospital for Children and University College London in the United Kingdom, told Elsevier’s PracticeUpdate that studies such as this are important because, “children on dialysis have a 30% higher mortality compared with their peers. They also have a high burden of comorbidity and a poor quality of life.” For this non-randomized, parallel-arm clinical trial, Dr. Shroff and her colleagues used the International Paediatric Dialysis Network registry to identify 177 children from 28 centers in 10 countries across Europe and North America. Among these children, 133, including 78 on hemodialysis and 55 on hemo- diafiltration, completed 1 year of follow-up. These two groups of patients were similar with regard to age, gender, underlying renal disease, comorbid- ities, dialysis vintage, access type, blood flow and presence of residual renal function. Patients were assessed via imaging studies (eg, carotid intima-media thickness, pulse wave veloc- ity and echocardiogram) and 24-hour ambulatory blood pressure monitoring for mean arterial pres- sure (MAP). In addition, every 6months, researchers assessed anthropometric and biochemical meas- ures and had patients complete health-related quality-of-life questionnaires.

There were 44 dropouts in the trial, primarily due to transplantation (79%). There were no deaths. Among patients who received hemodiafiltration, the median convective volume achieved was 13.33 (interquartile range 12.4–14.5) mL/m 2 /session. The annualized change in carotid intima-media thickness (cIMT) SD score was 10-fold lower in the hemodiafiltration group, compared with the hemodialysis group (0.013 vs 0.48; P = .002;). A propensity score analysis adjusted for potential confounders revealed that children on hemodial- ysis had a +0.47 greater increase in annualized cIMT SD score (95% confidence interval 0.07–0.87; P = .02), compared with those on hemodiafiltration. The 24-hour mean arterial pressure MAP SD score increased among patients on hemodialysis but diminished among those on hemodiafiltration. In addition, serum β2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein were lower and hemoglobin was higher in hemo- diafiltration patients. After adjusting for country and baseline charac- teristics, predictors of higher cIMT SD score and MAP SD score at 12 months were hemodialysis group, higher inter-dialytic weight gain and ultra- filtration rate, and higher β2-microglobulin. The height SD score increased in those who underwent hemodiafiltration but remained static in those on hemodialysis. Importantly, the type of vascular access, blood flow rate, and residual renal function did not correlate with cIMT SD score, which the authors suggested indicates that convective clearance is a significant determinant of outcome.

Dr. Rukshana Shroff

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SGLT2 Inhibitors Benefit Patients With Diabetes and Chronic Kidney Disease Loosening restrictions on use of SGLT2 inhibitors among patients with diabetic kidney disease should be considered. S GLT2 inhibitors reduce the risk of cardiovascular events and slow the loss of kidney function in patients with type 2 diabetes and chronic kidney disease, according to a meta-analysis presented at WCN 2019. The study found no evidence of additional safety concerns with the use of SGLT2 inhibitors. SGLT2 inhibitors are a newer treatment for type 2 diabetes, but they are not currently approved for use in people with reduced kidney function because they are less effective at lowering blood glucose levels in this population, study presenter Brendon Neuen, MBBS, of the George Institute for Global Health based at the University of Oxford in the United Kingdom, told Elsevier’s PracticeUpdate . Current data suggest, however, that these drugs might reduce the risk of cardiovascular events and prevent the loss of kidney function in people with type 2 diabetes and chronic kidney disease. “We wanted to look at all the available data, frompublished studies to regulatory submissions, to determine the effect of SGLT2 inhibitors on cardiovascular, kidney, and safety outcomes in people with type 2 diabetes and chronic kidney disease,” said Dr. Neuen. Data were obtained from 27 studies involving up to 7363 patients. Among individuals with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors reduced the risk of the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with a risk ratio of 0.81 (95%CI 0.70–0.94) as well as hospitalization for heart failure, with a risk ratio of 0.61 (95% CI 0.48–0.78). SGLT2 inhibitors also attenuated the annual decline in kidney function by an annual estimated glomerular filtration rate (eGFR) mean slope difference of 1.35 mL/min/1.73 m 2 /year; 95% CI 0.78–1.93. There was also a reduction in the risk of developing the composite renal outcome of doubling of serum creatinine, end-stage kidney disease, or renal death (risk ratio 0.71, 95% CI 0.53–0.95). The researchers found no evidence of additional risks with SGLT2 inhibition in chronic kidney disease beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes. “Our findings suggest that SGLT2 inhibitors reduce the risk of cardiovas- cular events and progression of kidney disease in people with type 2 diabetes and chronic kidney disease, despite only modest reductions in glycated hemoglobin [HbA1c],” said Dr. Neuen. In fact, HbA1c was lowered by only a mean of –0.29%; 95% CI –0.39 to –0.19. This suggests that the observed reductions in cardiovascular and kidney outcomes with SGLT2 inhibition are not being driven by improved glucose control. “Further, these data suggest that if restrictions on the use of these drugs in people with reduced kidney function are reconsidered, many more additional individuals might benefit from this treatment,” said Dr. Neuen. The research team’s findings are almost entirely consistent with the CREDENCE trial, the first dedicated renal outcome trial of an SGLT2 inhibitor (canagliflozin). “Taken together, these data suggest that SGLT2 inhibition will play an increasingly important role in the management of diabetic kidney disease moving forward,” said Dr. Neuen.

Patient-related outcome measures primarily associ- ated with fluid status, such as post-dialysis recovery time, headaches, dizziness, and cramps, were all less frequent and less severe among those treated with hemodiafiltration, compared with hemodialy- sis. In addition, there was less inter-dialytic weight gain on hemodiafiltration, which the investigators said implies lower ultrafiltration rates per session and greater hemodynamic stability was strongly associated with fewer symptoms. From a lifestyle perspective, children treated with hemodiafiltration had improved school attendance and greater physical activity scores, but there was no difference between the two groups with respect to hospitalization rates. “For patients on in-center dialysis, with equivalent dialysis-durations and blood flow rates, hemodia- filtration appears to be a safe and more effective dialysis modality than conventional hemodialy- sis,” Dr. Shroff said. “It is preferred by patients as post-dialysis recovery times are shorter, and this allows for better school attendance and greater physical activity scores. In addition, children on hemodiafiltration feel better, with fewer headaches and episodes of dizziness or cramps than children on hemodialysis.” Hemodiafiltration “is effective even in those who require a short period on dialysis, such as those who have a donor for transplantation, [as well as] for those with residual renal function,” she noted. Nevertheless, Dr. Shroff pointed out, “A randomized trial is required before hemodiafiltration can be considered the standard of care for children on in-center dialysis.”

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Global Kidney Health Atlas Reveals Worldwide Gaps in Care Education is a key component of improved prevention and treatment of kidney disease.

T he growing burden of kidney disease world- wide combined with the increasing expense of care for kidney failure and evidence regard- ing the value of delaying progression of chronic kidney disease means that access to prevention and treatment should be a major international pub- lic health goal, according to the second Global Kidney Health Atlas, unveiled for the first time at WCN 2019. The first Global Kidney Health Atlas was presented at the International Society of Nephrology (ISN) Global Kidney Policy Forum in Mexico City in 2017 and focused on awareness of chronic kidney dis- ease and detection programs. The latest edition examines the state of kidney health care structures across 160 countries, comprising more than 98% of the world’s population, including a comprehen- sive overview of the current capacity for end-stage kidney disease (ESKD). One of the highlights of the 2019 Atlas is the identification of the top barriers to optimal care ƒ ƒ Patient knowledge or attitude (63% of countries) ƒ ƒ Availability of kidney specialists (60% of countries) ƒ ƒ Other physician availability, access, knowledge and/or attitude (58% of countries) ƒ ƒ Distance from care or prolonged travel time (55% of countries) ƒ ƒ Availability, access and capacity of the healthcare system (55% of countries). for patients with ESKD. This includes: ƒ ƒ Economic factors (64% of countries)

Dr. Peter Kerr

A co-author of the Atlas, Peter Kerr, MD, of Monash University in Clayton, Victoria, told Elsevier’s PracticeUpdate that, “Two-thirds of the world’s population with ESKD is not getting access to renal replacement therapy, whether that be dialysis or transplant. That’s an enormous hole in provision of care.” He noted that the cost of renal replacement ther- apy is high, so discussion needs to focus on early detection and prevention of progression, as well as provision of care when needed. “Most countries in the survey have access to hemodialysis in some form or another, but the number who have access to transplantation is far less,” Dr. Kerr said. “And transplantation has a much better outcome for patients, not only in terms of wellness but also quality of life. There is also an economic component because it’s cheaper to do transplantation, particularly after the first year of dialysis, and also people returning to the workforce is more likely.”

" …transplantation has a much better

outcome for patients, not only in terms of wellness but also quality of life. "

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