DOPPS Practice Monitor (DPM): Emerging Trends & Hot Topics DF20170918 Arbor Research Collaborative for Health May 3rd, 2018 www.dopps.org/DPM

Topics and Speakers Today Welcome and Introduction (5 min) Bruce Robinson Recent US Trends (15 min) Doug Fuller Focus topic: Pruritus (20 min) Hugh Rayner Vascular Access (20 min) Ron Pisoni DF20170918 Bruce Robinson Doug Fuller Hugh Rayner Ron Pisoni

Country/Project-Specific Support: Acknowledgements, 2018 The DOPPS Program would not be possible without the support for independent scientific research to improve patient care from the following organizations: Principal Funders: Amgen Baxter Healthcare Kyowa Hakko Kirin Country/Project-Specific Support: ERA-EDTA, Vifor Fresenius Renal Pharma, Keryx, Amgen, AstraZeneca, Relypsa, Roche, Proteon, Janssen, Hexal, Japanese Society for PD, Societies of Nephrology in Germany, Italy & Spain Public Funding of Projects/Ancillary Studies In: Australia, Canada, France, Thailand, United Kingdom, United States All support for the DOPPS program is provided without restrictions on publications

New AHRQ* grant: To study prevention of peritonitis in PD patients, & to promote knowledge dissemination strategies Investigators: Drs. Jeff Perl and Ron Pisoni (Co-PIs), Neil Boudville, Beth Piraino, Doug Schaubel, Martin Schreiber, IsaacTeitelbaum. Stakeholders: - International Society for Peritoneal Dialysis (ISPD) - ASN (Nephrologists Transforming Dialysis Safety, NTDS) - CDC NHSN members - International Pediatric PD Network (IPPN) - Standardizing Care to Improve Outcomes in Pediatric End- Stage Renal Disease (SCOPE) collaborative - US dialysis providers - Patient representatives *AHRQ = Agency for Healthcare Research and Quality (US DHHS)

Join the conversation on Twitter Follow us @DOPPStudy Use #DOPPS for tweets about today’s presentation

Submitting Questions We welcome your questions throughout the session and will pause to answer them at the end of each section Please submit your questions using the “Chat with Presenter” feature, accessed by the blue icon located at the bottom left corner of the screen DF20160502

Interactive Polling Throughout today’s presentation, we will offer several poll questions about treatment practices in your unit. Please be assured that individual responses will remain confidential. When the poll is opened and displays on your screen, please answer the question and don’t forget to hit the ‘Submit’ button. DF20160502

US DOPPS Practice Monitor: Highlights May 2018 DF20180430 Doug Fuller, MS Arbor Research Collaborative for Health

Stratified random sample (since 2010) US DPM: Monthly data, updates every 4 months; >1500 figures & tables Stratified random sample (since 2010) Now ~200 US facilities, 14,000+ patients with data from 2 LDOs and Visonex DF20170918 www.dopps.org/DPM

Uptake of Newer Medications DF20150112

Iron-containing Phosphate Binder Use – Prior 3 Months – DF20180430 Values for each month reflect any prescription during prior 3 months. Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

ESA Use, by Type – by Dialysis Organization (DO) Size – DF20180430 Overall: 38.5% PEG-EB Values for each month reflect prescription among ESA-treated patients. Source: DOPPS Practice Monitor, April 2018

Anemia DF20150112

Hemoglobin Trends – National Sample – DF20180430 Most recent (single) monthly value; vertical lines extend from 10th to 25th (lower) and 75th to 90th (upper) percentiles; circle represents median. Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

Prescription of Anemia Therapies (% patients) – Prior 3 Months – DF20180502 Values for each month reflect any use during the prior three months. Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

Serum Ferritin – National Sample – DF20180430 Values at each month are based on the most recent measurement obtained within the prior 3 months; vertical lines extend from 10th to 25th (lower) and 75th to 90th (upper) percentiles; circle represents median. Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

Mineral and Bone Disorder DF20150112

Parathyroid Hormone (PTH) – National Sample – DF20180430 Values at each month are based on the most recent measurement obtained within the prior 3 months; vertical lines extend from 10th to 25th (lower) and 75th to 90th (upper) percentiles; circle represents median. Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

Prescription of MBD Therapies (% of Patients) – Prior 3 Months – IV: 54% Oral: 40% DF20180501 Values for each month reflect any prescription during the prior three months. Vitamin D includes active or analog forms. Source: DOPPS Practice Monitor, April 2018

Vitamin D Prescription, by Type – National Sample – DF20180501 Values for each month reflect prescription among patients receiving IV or oral vitamin D (active or analog) Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

Dialysis Dose and Prescription DF20160502

Dialysis Session Length – National Sample – DF20180501 Source: DOPPS Practice Monitor, April 2018

Polling Question 1 Which of the following best describes the trend in ultrafiltration rate (UFR) among hemodialysis patients in your unit? Increasing No change Decreasing

Ultrafiltration rate – National Sample – DF20180501 Source: DOPPS Practice Monitor, April 2018

Polling Question 2 If the average UFR is declining in your unit, what reason best describes the cause of the decline? Better management of water and salt intake Longer average treatment times Practices to preserve residual kidney function Other

Summary of Recent US Trends Darbepoetin use in SDO, independents, and HB units Long-acting ESA use: 63% overall Drives reduction in % subcutaneous ESA use High PTH levels still getting higher PTH 600+ pg/ml: 33% (black pts), 20% (non-black pts) Ongoing reductions in ultrafiltration rate UFR 13+ ml/kg/hr: Declined from 18% to 9% DF20170111

Discussion: Please submit your questions using the “Chat with Presenter” feature, accessed by the blue icon located at the bottom left corner of the screen DF20150112 www.dopps.org/DPM www.arborresearch.org

CKD-associated pruritus: time to think differently Dr Hugh Rayner, MD hughrayner@gmail.com

Trends in prevalence of pruritus among HD patients in the DOPPS How much are you bothered by itchy skin? This shows the extent to which HD patients were bothered by itchy skin during a 4 week period, based upon self-reported data collected from a prevalent cross section of patients. Those moderately to extremely bothered by itchy skin are considered to have pruritus 45% of DOPPS I patients are considered to have pruritus 42% of DOPPS II patients are considered to have pruritus Phase: Years: 1996-2001 2002-2005 2006-2008 2009-2011 2012-2015 N: 6512 7224 6780 7307 7629 Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

Effects on daily life among patients nearly always or always bothered by itchy skin during the past week Frequency of being bothered by:  Never 1 to 3 Always 4 to 6 Being annoyed about your itching 3 15 81 Frustration about your itching 6 17 77 Appearance of your skin from scratching 9 22 69 Feeling depressed about your itching 13 29 58 Feeling embarrassed about your itching 33 45 Effect of itching making it hard to work 23 Effects of itching on desire to be with people 32 35 Effects of itching on interactions with others 37 34 Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

To what extent were you bothered by itchy skin during the past 4 weeks? Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

69% of MDs underestimate pruritus prevalence in their dialysis unit MD estimate matched patient reported pruritus prevalence MD estimate % pts with severe pruritus: 20170201 Supplemental Fig 1 *note: results are from 1 MD per facility MD estimate of severe pruritus pts vs facility % of pts very bothered by itchy skin Interpretation: in 27 facilities that had <5% of patients being very bothered by itchy skin: 74% of MDS estimated that there were <5% of patients in their facilities with severe pruritus (so they were correct!), however also among those facilities 15% of MDS estimated that they had 21-50% patients with severe pruritus (while in fact only <5% pt reported being very bothered) Facility % of patients very much or extremely bothered by itchy skin N Facilities = 27 124 93 Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

Interventions for patients with severe pruritus % of medical directors Rank of importance Most 1 2 3 4 Least 5 Phosphorus control (in patients with high PO4) 60% 16% 15% 8% 1% Increasing dialysis dose (in patients with low Kt/V) 25% 29% 24% 6% Use of prescription medications for pruritus 13% 14% 45% Increasing prescribed treatment time (in patients with short treatment time) 11% 18% 21% 26% Lowering PTH levels (in patients with high PTH) 2% 28% 23% Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

No association with serum phosphorus   To what extent were you bothered by itchy skin during the past 4 weeks? AOR [95% CI] Not at all Somewhat Moderately Very much Extremely Total sample, N 2111 1840 1188 692 425 Phosphorus <3.5 mg/dL 11% 13% 1.00 [0.88, 1.14] 3.5 - <5.5 56% 51% 52% 50% [reference] 5.5 - <6.7 20% 23% 21% 22% 1.01 [0.91, 1.13] ≥ 6.7 15% 14% 16% 1.07 [0.95, 1.21] Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

No association with serum Ca, Ca x PO4 or Kt/V   To what extent were you bothered by itchy skin during the past 4 weeks? Not at all Somewhat Moderately Very much Extremely Calcium (mg/dL) 8.9 (0.8) Calcium x Phosphorus product (mg2/dL2) 43 [36,52] 45 [36,55] 44 [35,52] 44 [36,53] 44 [36,54] Single Pool Kt/V 1.5 (0.3) Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

Breakdown in communication 17% of patients nearly always or always bothered by itchy skin had not reported their symptoms to any healthcare professional 18% of patients nearly always or always bothered by itchy skin used no treatment for it Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

Two itch pathways a) Cowhage b) Histamine

fMRI responses evoked by cowhage itch Papoiu et al fMRI responses evoked by cowhage itch Papoiu et al. J Neurophysiol 112: 1729–1738, 2014 ESRD patients = red-yellow, normal = blue Histamine itch responses were normal 57% of medical directors used oral antihistamines for first-line chronic treatment of pruritus

In total, 4 RCT’s involving Gabapentin 300mg after HD Gunal et al. NDT 2004; 19: 3137-9 In total, 4 RCT’s involving 138 patients with severe CKD-aP show the same effect

Pregabalin 75mg twice weekly 62 patients in RCT Yue J et al Pregabalin 75mg twice weekly 62 patients in RCT Yue J et al. Int Urol Nephrol. 2014 Sleep quality and quality of life also improved significantly

Our experience n=71: 25 CKD (median eGFR = 17, 9 – 30), 40 HD, 6 PD Gabapentin starting dose 100mg after dialysis. If not tolerated, pregabalin 25mg. 85% of patients gained relief of itching with gabapentin or pregabalin Mean severity reduced from 8/10 to 1/10 Rayner HC et al. Nephron Clinical Practice, 2013

The majority of nephrologists do not use gabapentin for pruritus 20170201 **make a note that Jpn uses nalfuarfine (9% in phase 5 that is not shown) Drug use for HD patients with pruritus - Gabapentin 56 10 18 17 24 12 14 49 9 N: Rayner HC et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007

Summary The prevalence of people on haemodialysis very much or extremely bothered by itching declined from 28% in 1996 to 18% in 2015 69% of nephrologists underestimate the prevalence of pruritus in their facility The interventions currently most often used to treat pruritus are not supported by evidence Large numbers of hemodialysis patients with severe pruritus do not receive any treatment

Summary There is wide variation between countries in the use of gabapentin and pregabalin for the treatment of pruritus Overall, the majority of nephrologists never use these drugs Hemodialysis patients’ quality of life could be significantly improved through the systematic raising of awareness, reporting and effective treatment of pruritus

Polling Question 3 Do you find that dialysis patients get a lot of side effects from gabapentin when it is prescribed for itching? Yes No

International Variability in Arteriovenous Fistula Placement Location, Successful Use, Cannulation Time, & Catheter Days R Pisoni, L Zepel, R Fluck, C Lok, R Fluck, H Kawanishi, G Süleymanlar, H Wasse, F Tentori, J Zee, Y Li, D Schaubel, S Burke, H Morgenstern, K Woodside, and B Robinson

Variations in Vascular Access Use

Vascular access usea – prevalent patients DOPPS 5 (2012-2014) % of Patients Figure 1B: Distribution of vascular access use, by country Data from GCC, Russia, Turkey, Belgium, Sweden, and China based on patient’s vascular access at the initial cross-section of DOPPS 5; data from remaining countries based on cross-section of HD patients in August 2013 * Data from GCC, Rus, Tur, Bel, Swe, Chi based on VA at the initial cross-section of DOPPS 5; data from remaining countries based on cross-section of HD patients in Aug 2013 N Patients: a At study entry regardless of time on dialysis since at DOPPS enrollment Pisoni et al. Am J Kidney Dis. 2015;65(6):905-915

Vascular Access in Use – US only – National Sample – DF20180430 Source: US-DOPPS Practice Monitor, April 2018; http://www.dopps.org/DPM

Vascular access by age group US DOPPS 5 (August 2013 cross-section) Figure 2A: Distribution of vascular access use, by age group (US only) Based on cross-section of in-center HD patients in August 2013. Pisoni et al. Am J Kidney Dis. 2015;65(6):905-915

Vascular access by ethnicity US DOPPS 5 (August 2013 cross-section) Figure 2B: Distribution of vascular access use, by ethnicity (US only) Based on cross-section of in-center HD patients in August 2013 Pisoni et al. Am J Kidney Dis. 2015;65(6):905-915

Vascular access by race and sex US DOPPS 5 (August 2013 cross-section) Figure 2C: Distribution of vascular access use, by race and sex (US only) Based on cross-section of in-center HD patients in August 2013. P < 0.05 for difference in catheter use for black females versus males; p <0.001 for difference in catheter use for non-black females versus males. Pisoni et al. Am J Kidney Dis. 2015;65(6):905-915

AV access placement (%) before HDa,b DOPPS 5 (2012-2014) In US: ~80% of new pts start HD with a catheter % of Patients Figure 5C: AV access placed prior to ESRD among patients with ≥ 4 months pre-ESRD care Based on responses to the question “Did the patient have an AV fistula or graft placed prior to start of chronic hemodialysis?” included on the baseline medical questionnaire administered during DOPPS 5. Restricted to patients who saw a nephrologist at least 4 months before starting dialysis. Australia-New Zealand, France, and Turkey not shown due to limited data. N Patients: On dialysis ≤ 60 days at DOPPS enrollment b. Provided ≥4 months of pre-dialysis nephrology care Pisoni et al. Am J Kidney Dis. 2015;65(6):905-915

- With support from Proteon Therapeutics - International variability in AVF placement, successful use, & time to first cannulation of newly created AV fistulae Based upon AVFs created during DOPPS 4 and 5 (2009–2015) in the US, Japan, Europe, Australia and New-Zealand (ANZ). Successful AVF maturation was defined as use for ≥ 30 days - With support from Proteon Therapeutics -

NKF-KDOQI Vascular Access Guideline “There are no randomized controlled trials (RCTs) comparing the recommended anatomic order of distal-to-proximal access construction. However, good surgical practice makes it obvious that when planning permanent access placement, one should always consider the most distal site possible to permit the maximum number of future possibilities for access.” NKF KDOQI 2006 Updates Clinical Practice Guidelines and Recommendations for Vascular Access

Arm location of AVF*, by region Japan Europe/ANZ US DOPPS Phase: N AVFs: Fig 3 Based upon location of AVF in use at study entry in the initial round of each study phase: DOPPS 1 (1996-2001), DOPPS 2 (2002-2004), DOPPS 3 (2005-2008), DOPPS 4 (2009-2012), DOPPS 5 (2012-2015). Europe/ANZ includes France, Germany, Italy, Spain, and UK (DOPPS phase 1) and Australia, New Zealand, Belgium, France, Germany, Italy, Spain, Sweden, and UK (DOPPS phases 2-5). Results were similar when Europe/ANZ was restricted to countries present in all phases. N Fac: *Based upon the access in use in prevalent cross-sections of patients in each study phase. Pisoni et al, AJKD (2018) 71(4): 469-478

Facility distribution of AVF location in the lower arm, by region Facility % of AVFs in lower arm Facility Percentile 95th 75th 50th 25th 5th Vintage: N Fac: Japan Europe/ANZ US Restricted to AVFs created in DOPPS4-5 (2009-2014) in the United States, Europe, Australia and New-Zealand, and Japan; facility distributions for vintage <1 year were similar to <2 years. Pisoni et al, AJKD (2018) 71(4): 469-478

AVF (%) placed in lower arm, by age group, in males Fig 4a AVF placement in lower arm, by age and region Restricted to males Age: N AVFs: Japan Europe/ANZ US Pisoni et al, AJKD (2018) 71(4): 469-478

Adjusted Odds Ratios of AVF Placement Location (Lower vs Upper Arm), by Patient Characteristic in US, for All AVFs Created During the Study Characteristic AOR (95% CI) Male sex (vs female) 1.64 (1.33-2.04) Black race (vs non-black) 0.88 (0.69-1.13) Age, per 5 yrs older 0.98 (0.95-1.02) BMI, per 5-kg/m2 greater 1.01 (0.94-1.09) Cardiovascular disease (vs no) 0.99 (0.76-1.29) Congestive heart failure (vs no) 0.81 (0.62-1.07) Diabetes (vs no) 0.99 (0.77-1.28) Peripheral vascular disease (vs no) 0.64 (0.46-0.90) Dialysis vintage, per 1-yr greater 0.86 (0.80-0.91) N=1709 AVFs Pisoni et al, AJKD (2018) 71(4): 469-478

AVF successful use*, by arm location and region % of AVFs *AVF successful use was defined as use ≥ 30 days Restricted to AVFs created in DOPPS 4 and 5 (2009-2015) in North America, Europe, Australia and New-Zealand, and Japan Pisoni et al, AJKD (2018) 71(4): 469-478

Hazard Ratios of Time from AVF Creation Until Successful Use by Cox Regression: Association with Patient Characteristics – US Only Characteristic HR (95% CI) Male sex (vs female) 1.38 (1.20-1.60) Black race (vs non-black) 0.96 (0.82-1.14) Age, per 5 yrs older 1.01 (0.99-1.04) Dialysis vintage, per 1-yr greater 0.99 (0.96-1.02) BMI, per 5-kg/m2 greater 1.00 (0.95-1.05) Cardiovascular disease (vs no) 1.02 (0.84-1.23) Congestive heart failure (vs no) 0.96 (0.79-1.15) Diabetes (vs no) 0.92 (0.78-1.10) Peripheral vascular disease (vs no) 0.99 (0.79-1.25) Facility % AVF use, per 5% greater 1.00 (0.96-1.04) Facility median blood flow rate, per 20 mL/min greater 1.02 (0.99-1.06) Upper arm vs lower arm 1.29 (1.11-1.50) HR > 1.0 indicates shorter time to successful AVF use or greater AVF use; N=1266 AVFs; in Japan and EUR/ANZ – upper arm location not assoc with higher HR

Very similar results seen for AVFs created in the lower or upper arm Time to First Successful AVF Use, by Region AVFs Very similar results seen for AVFs created in the lower or upper arm Percentile 95th 75th 50th 25th 5th Fig 2a Sample: restricted to AVFs/AVGs that were created within the study and were successfully used for at least 30 days. Excludes AVFs/AVGs that were created within the study and never used. N AVFs: Pisoni et al, AJKD (2018) 71(4): 469-478

Summary Large variability is seen across international regions in AVF use, AVF location, successful use of new AVFs, and time to first successful AVF use. Time until becoming catheter-free differs considerably between Japan, EUR/ANZ, and the US. Lower arm AVF placement is much less common in the US (32%) – even among younger patients and patients new to HD.

Summary (cont.) The large US shift from lower- to upper-arm AVFs during the last 2 decades raises concerns regarding the long-term implications for HD patients: - greater risk of exhausting available sites for future AVFs - greater potential adverse long-term effects of upper-arm AVFs (eg, higher frequency of steal syndrome, symptomatic cephalic arch and central vein stenosis, and high AVF blood flow effects on cardiac function).   Although an upper-arm AVF may provide a higher rate of success for an individual procedure, AVF creation must be viewed in the context of lifetime access planning. Activities to increase awareness, promote best practices, and maximize training could foster increased lower-arm AVF use.

Vascular Access: Mortality Risk Facility Based Model Insert footpath here. Example - U:\slides\ASN 2003 Publication Graphics CD\Working Drafts\Lopes_QoL and Ethnicity\Lopes_QoL and ethnicity_Rev1 Vascular Access: Mortality Risk Facility Based Model RR of Death among Facility Patients per 20% more facility use of indicated access type Recently, we have analysed vascular access as a facility practice, and have found that a patient’s mortality risk is 21% higher for every 20% greater CATHETER use in the dialysis facility compared with AV fistula use. Furthermore, a patient’s mortality risk was found to be 11% higher for every 20% greater GRAFT use in the dialysis facility. These analyses were adjusted for patient demographics, baseline comorbidity, single pool Kt/V, and serum calcium and phosphorus levels. p<0.0001 p=0.008 Ref. *DOPPS 1+2, 1996-2004; n=27,892; adjusted for age, gender, black race, yrs with ESRD, 14 comorbidity classes, weight, facility median treatment time, facility % serum Ca >10 mg/dl, facility % serum PO4 >5.5 mg/dl, whether hosp unit, & accounted for facility clustering effects; stratified by study phase & region. Facility access use adjusted for facility case-mix. Pisoni et al AJKD (2009) Created By:____________________ Date: __________ Contributing Analyst: ____________ Date: __________

Ultimate Polling Question Princess Kate and Prince William welcomed the birth of their third child on April 23rd. What is the child’s first name? William Elizabeth Catherine George Louis Mary Ringo John

US DOPPS Practice Monitor www.dopps.org/DPM Updates every 4 months Next in January 2018 (data through October 2017) DF20170915 Give special thanks to – NNI - Web conference AJKD - Detailed analysis + editorial comment

If you want to re-listen to this WebEx or download the slides, go to: http://www.dopps.org/DPM/EmergingTrends.aspx DF20160502