Kunitoshi IsekiClinical Research Support Center, Nakamura Clinic, Okinawa Heart and Renal Association (OHRA)

How to improve your career in Nephrology

APSN CME course, Niigata, 20180607

1974～1982: 2nd Dept. of Int. Med, Kyushu University

Prof. T Omae, Hisayama Study

1982～1986: University of Southern California, Div. of Nephrology

Dr. SG Massry, VM. Campese,“PTH as a uremic toxin”

1986～1987: Fukuoka Red-Cross Hospital, Dr. S Fujimi

1987～1989: 2nd Dept. of Int. Med, Kyushu University, Prof. M Fujishima

1989～2005: 3rd Dept. of Int. Med, Ryukyu University, Prof. K Fukiyama

2005～2015: Dialysis Unit, University Hospital of the Ryukyus

2015～2017: Clinical Research Support Center, Tomishiro Central Hospital

2018～ Clinical Research Support Center, Nakamura Clinic

Muribushi Project for Okinawa Residency Programs

2017-2019: KDIGO, Executive Committee Member

C.V.（Kunitoshi Iseki）

Location of Okinawa in AsiaOkinawa, Population : 1.423 million (as of 2012) Ethnic groups: Ryukyuans (especially native Okinawans), Japanese,as well as American military personnel and their families

CHINA JAPAN

SOUTHKOREA

INDIA

AUSTRALIA

SINGAPORE

PAKISTAN

TURKEY

TAIWAN

INDONESIA

THAILAND

OKINAWAHONGKONG

MALAYSIA

PHILIPPINES

500 km1000 ｋm

2000ｋm1500ｋm

By Google map

Cohorts in Okinawa 1. Okinawa Dialysis Study (OKIDS)

1971-2010（N≈10,000)2. Community-based screening registry (OGHMA)

Longitudinal Database: 1983 to 20133. Specific Health Check & Guidance Cohort (2008-2012)

Okinawan participants 2008 (N=130,000)National database of death certificate (5 million)

4. Nakamura clinic (ONSLEEP): PSG confirmed SAS patients1990-2011 (N=10,854)

5. Tanaka Iin (TIIDAS): DM clinic, 2005-2014 (N=867)6. Tokuyama clinic (OCEANS): CKD clinic, 2004-2014 (N=3,141)7. Tomishiro Central Hospital: Metabolic syndrome 2003-2014

(N=6,980)

A community-based screening 1983 ······· started to file in computer1983 ······· N=106,1821993 ······· N=143,948

Okinawa General Health Maintenance Association

Kidney Int 49: 800-805, 1996Kidney Int 49: S69-S71, 1996

Screening Registry

Registered all ESRD patients in Okinawa1971 to 2000, N=5,246 ESRD: chronic dialysis patients

survived at least 1 month56 dialysis units, 78 physicians

Kidney Int 43: 404-409, 1993Kidney Int 61: 668-675, 2002

Dialysis Registry

vs.

Identification of ESRD patientsPredictors of ESRD

Okinawa Dialysis Study (OKIDS)

Okinawa Dialysis and Transplant Association (ODTA)

ESRD Incidence by Urine Test

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

5

10

15

0

proteinuria ≥3+

proteinuria 2+

Proteinuria 1+

Proteinuria -

Proteinuria ±Cum

ulat

ive

inci

denc

e of

ESR

D (%

)

Time after screening, years

Iseki K, et al. Kidney Int 63, 1468-1474, 2003

Identified by Planning Committee (90)

Did not complete survey (21)

Completed Survey (69)

Excluded because of insufficient data or unable to analyze data for the Conference (16)

Completed Analysis (53) Unable to provide data for the meta-analysis (8)

AGES-Reykjavik/ CAN-CARE/ CAN-Prevent/ CRIC/ OFUS/ Predictors of ESRD in T1DM/ Prevalence of CKD in Veterans/ TromsoIncluded in Meta-Analysis

(45*) N=1,555,332

High Risk(10)ADVANCE/ AKDN ACR/ CARE/ KEEP/KP Hawaii/ MRFIT/ ONTARGET/Pima/ TRANSCEND/ZODIAC

N=266,975

General Population Dipstick (10)AKDN DIP/AusDiab DIP/ Beaver Dam/ESTHER/ MRC Older People/ Ohasama/ Okinawa 83/ Okinawa 93/Severance/ Taiwan

N=1,239,447

General Population ACR (14)ARIC/ AusDiabACR/ Beijing/ CHS/COBRA/ Framingham/ Gubbio/ HUNT/ MESA/NHANES III/PREVEND/ Rancho Bernardo/ REGARDS/ ULSAMN=105,872

CKD(14)AASK/ British Columbia/ CRIB/ Grampian ACR/ Grampian PCR/ MASTERPLAN/ MDRD/ NephroTest/ RENAAL/ STENO/ MMKD/ REIN/ REIN-2/ KP Northwest

N=21,688

CKD PrognosisConsortium

Cohort Selection

Levey AS, et al. Kidney Int. 80:17-28, 2011

2014, Nov. 12. Del Frisco’s Steak House, Philadelphia

High ESRD incidence in AsiaIncidence, pmp ％DM

• Taiwan 476 45%• Brunei 393 NA• Thailand 338 40%• Singapore 319 66%• Japan 290 44%• Rep. of Korea 285 48%• Malaysia 261 64%• Jalisco (Mexico)411 62%• USA 378 45%

USRDS2015China? India?

0

2

4

6

8

10

12

14

16

18

20-29 30-39 40-49 50-59 60-69 70-79 80-

HD pt

GP

Annu

al M

orta

lity,

%

Age

Q1. Poor Survival of HD patients: Why?

JSDT 2005/2006

Q2. Any Effects of Treatment Practice?

30

70

80

90

100

60

50

40

0 1.0 2.0 3.00 1.0 2.0 3.030

70

80

90

100

60

50

40

unadjusted adjusted

Am J Kidney Dis 44:S16-S21, 2004

Japan

Europe

USA

Japan

Europe

USA

year year

Surv

ival

Rat

e, %

Pro: The value of RCT in dialysis methods (Ajay K Singh & Jameela A Kari)Con: RCT have failed in the study of dialysis methods

(Zbylut J Twardowski & Madhukar Misra)Polar Views in Nephrology: Moderator’s view:

Are alternative dialysis strategies superior to conventional dialysis: what Popper tells us…(Wim Van Biesen & Norbert Lameire)

Nephrol Dial Transplant 28: 837-838, 2013

Conventional Dialysis Therapy: Only Experience-Based

No Evidence for ESRD Therapy

Number of randomized controlled trials

Archdeacon et al. CJASN 2013

Q3. Few RCT in Nephrology: Why?

Trials in kidney disease

• Endpoints difficulty• Difficult patient recruitment• High dropout• Burden on patients and sites• Limited site capacity• Growing disengagement from community• Variable regulatory approaches

“If regulatory agencies keep requiring long-term clinicaltrials, we have to quit developing drugs in this field.”by a representative from Roche

Patient reported outcome

• There is no good validated tool to evaluatepatient reported outcome.

• Many tools are too burdensome for patients.• Do not mix up with physical activity (ex. behavior)

and physical function (ex. 6 min walk).

What aspect of life activity is important?

STANDARDIZED OUTCOMES IN NEPHROLOGY (SONG) Randomized trials provide the most reliable evidence about thesafety and effectiveness of interventions to improve health careand patient outcomes. Unfortunately, the potential for trials toinform treatment decisions remains limited because the outcomesreported often do not resonate with what is directly meaningfuland relevant to patients and their clinicians.Further, inconsistent reporting of outcomes across trials preventsassessment of the comparative effect of interventions.Outcome reporting bias, whereby authors cherry-pick theoutcomes they report on the basis of favorable results, may alsooccur when there is not a standardized list of outcomes measuredand reported. Collectively these problems may undermine thereliability of published trials, leading to inefficient use of scarceresearch and health care resources and unintended harm to...

Tong A, Craig J, Nagler EV, et al. Nephrol Dial Transplant 32(12):1963-1966, 2017

Shift our research focus

1. More qualitative methods used in social sciences2. More patient-reported outcomes3. Unmet needs for studies to elucidate racial and ethnic differences

in QOL issues4. Research and policy changes should be driven by experienced

practitioners with current patient contact to ensure that they are relevant to patient needs

5. Support research to improve QOL and discourage cookie-cutter survival studies

6. QOL metrics (pain, depression,,,) needs to be incentivized in clinical practice to drive related research efforts.

Lee MB and Bargman JM. CJASN 11:1083-7, 2016

Introduction to Clinical Research Training （ICRT）

Kenneth B Christopher, MD, SM. ICRT Program Director, Harvard Medical SchoolICRT Japan (Okinawa): 2018 to 2020, Venue: Okinawa Institute of Science and Technology Graduate University (OIST)

ICRT - Goals• Introduce the basic skills and

knowledge required to perform high-quality patient-oriented clinical research

• Develop grant writing skills• Develop manuscript writing skills• Promote teamwork and presentation

skills

ICRT – Key features• Senior faculty from Harvard Medical

School, Harvard School of Public Health and other leading academic institutions

• 24/7 online access to learning materials• Blended approach

– Live and online learning– Face-to-face learning– Team based learning

STATA – Easy to Use

• N=5,000, collected from real data• 31 covariates• 9 outcomes• Writing commands • Analysis exercise

ICRT Workshop-1, Jan 13-17, 2018Workshop-2, July 13-17, 2018

Clinical Research: Key to Success

• Mentor & Collaborator• Communication & Team Work• Unmet Need• Idea for a Solution “Need a Study Plan”

Kenneth Christopher. ICRT 2018 Jan 15

http://www.expertscape.com/ex/kidney+failure%2C+chronic

Expertise in Chronic Kidney Failure: WorldwideBased on 29,660 articles published since 2007In each column, black bars show the relative amount of expertise for each place or person. Longer is better.

Expert

• Kalantar-Zadeh, K (USA)• Kovesdy, C P (USA)• Chertow, G (USA)• Mehrotra, R (USA)• Tonelli, Marcello (Canada)• Johansen, K (USA)• Chan, Chris T (Canada)• Covic, A (Romania)• Zoccali, C (Italy)• Johnson, DW (Australia)

Kidney Disease: Improving Global Outcomes (KDIGO) is an international organization whose mission is to improve the care and outcomes of kidney disease patients worldwide by promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines. Periodically, KDIGO hosts conferences on topics of importance to patients with kidney disease. These conferences are designed to review the state of the art on a focused subject and to ask conference participants to determine what needs to be done in this area to improve patient care and outcomes. Sometimes the recommendations from these conferences lead to KDIGO guideline efforts and other times they highlight areas for which additional research is needed to produce evidence that might lead to guidelines in the future.

Core KDIGO Efforts

Controversies Conferences

Clinical Practice Guidelines

Implementation Task Force

Research

Clinical Practice Conferences

Revision & Updates

KDIGO Controversies Conference on Dialysis Initiation and Prescription (#35) 2018, January 26-28, Madrid, Spain

Co-chair: Christopher Chan, Carol Pollock

KDIGO GUIDELINES

Hepatitis C April 2008Mineral Bone Disorder July 2009Transplant Recipient Oct 2009

Acute Kidney Injury March 2012 Glomerulonephritis June 2012

Anemia August 2012Blood Pressure in CKD November 2012

Diagnosis & Management of CKD Jan 2013Lipid Management Nov 2013CKD-MBD Update July 2017

Living Kidney Donors August 2017

Acknowledgements: Mentors &Colleagues

Ryukyu Univ.: Shuichi Takishita, Yusuke Ohya, Masahiko Tozawa, Kentaro Kohagura, Saori Chinen, Nozomi Tomiyama, Kaori Tokashiki, Akio Ishida,Masanobu Yamasato, Akira Osawa, Yoshihide Ogawa, Seiichi Saito, Yoshinori Oshiro, Sanehiro HokamaOkinawa Dialysis and Transplant Association (ODTA): Shigeki Toma, Shinyu Miyagi, Kiyoyuki Tokuyama, Yoshiki Shiohira, Fujihiko Miyasato, TeiichiMinei, Hajime Ogimi, Choki Mekaru, Yoshinao Uezu, Naoko Nagayoshi, Satoshi Nakazato, Masahiko Yamazato, Kunio Yoshihara, Manabu Arakaki,Kyumei Afuso, Susumu Kiyuna, Kazuo Shiroma, Tadashi Miyara, Masayoshi Itokazu, Yoko Shimoji, Takeshi Tana, Akira Higa, Tadashi Asato, RyujiKobayashi, Tetsuyoshi Asato, Hideo Katsuren, Masato Uechi, Toru Wake, Hiroshi Momozono, Eiho Yamaguchi, Yoichi Uechi, Naomi Asato, TeruoKowatari, Hirohiko Yamada, Shinichiro Yoshi, Hiroshi Sunagawa, Keisho Takeda, Hajime Uehara, Tomotake Taminato, Hisakichi Uchima, YasukiNakasone, Toru Funakoshi, Sakae Miyasato, Tsukasa Higa, Minoru Ikema, Hiroshi Hirano, Katsunari Akamine,Moriki Nishihira, Chiharu Imai,Makoto Ikemura, Hideki Henzan, Ikuo Kyan, Tomohiro Yonaha, Tamayo Naka, Eisho Naka, Shuji Maeshiro, Shigeharu Terukina, Kaoru Shiroma,Takashi Oura, Masato Santo, Kazushi Kinjo, Tomonori Miyasato, Keizo Nishime, Nario Nakamura,Zensho Chinen, Yasuhiko Oshiro, Tamotsu Saito, Tadahiro Sunagawa, Hiroshi Kinjo,Toshihide Shimabukuro, Seigo Nakata, Hiroshi Yogi

Okinawa Chubu Hospital: Seishiro Miyagi, Masao Maeshiro Tokuyama Clinic: Kiyoyuki TokuyamaNakamura Clinic: Hiroshi Nakamura Tanaka Iin: Hideaki Tanaka Urasoe General Hospital: Tomoichiro Kuda Okinawa Health Promotion Foundation (Okinawa General Health Maintenance Association): Yoshiharu Ikemiya, Kozen Kinjo, Masanori Itokazu, Kaoru ShiromaKokuho Rengo: Narumi Shinzato, Okinawa Dietetic Association (ODA): Keiko ArakakiKyokai-Kenpo Okinawa: Kiyono Arakaki, Maki ShinjyoJapanese Society of Nephrology (JSN): Seiichi Matsu, Hiroshi Makino, J-KDR, J-RBR, T. Watanabe, K Yamagata, T Konta, K Tsuruya, T Moriyama, M Kondo, K AsahiJapanese Society for Dialysis Therapy (JSDT): Yoshiharu Tsubakihara, JRDROkinawa Medical Association: Nanbu, Naha, Urasoe, Chubu Branch, Shinyu MiyagiAFCKDI: Y Tsukamoto, Y Yasuda ARC: Vivekanand Jha, KDIGO; John Davis, Tanya Green, Danielle Green, Michael Cheung, Melissa ThompsonCKD-PC: Joseph Coresh, Andy Levey, Kunihiro MatsushitaOkinawa Heart and Renal Association (OHRA): Taku Inoue, Chiho Iseki

Mentors: Kyushu University: Teruo Omae, Satoru Fujimi, Kaoru Onoyama Ryukyu University: Koshiro Fukiyama,University of Southern University (USC): Shaul G Massry, Vito M Campese