Adiposity and kidney disease: observations from large blood-based prospective cohorts across a wide range of different populations

Lead Research Organisation: University of Oxford
Department Name: Clinical Trial Service Unit

Abstract

The Kidney Research UK 2013 patient survey identified 'prevention of kidney disease' and 'cause of specific kidney diseases' as the second and third priority for renal research after 'finding a cure for kidney disease'. This fellowship focus demonstrably aligns with these priorities. Work I have recently completed using data of 1.4 million adults in England showed that being overweight and obese is a key cause of kidney disease in the UK. Tracking these people for 7 years, nearly 1-in-100 developed permanent serious kidney damage and 1-in-1000 required dialysis or a kidney transplant. Compared to lean people, those who were overweight were at moderately increased risk of permanent serious kidney damage (their risk was increased by about 30- 40%), but risk was doubled among those who were moderately obese (ie, those who had a body-mass index [BMI] between 30-35 kg/m2) and was tripled among those with severe obesity (BMI above 35kg/m2). Diabetes is a common cause of serious kidney damage in the UK and worldwide, and is one of the mechanisms by which obesity may cause permanent kidney damage. Nevertheless, this study found that excess weight increased the risk of kidney damage by a similar amount in people with or without diabetes, and also in people who had 'well-controlled' blood pressure. Taking into account how common overweight and obesity are in the UK, these data suggested that at least one-third of all permanent serious kidney damage in adults in the UK could be due to being overweight or obese, and that despite modern treatments for diabetes and raised blood pressure, obesity remains a major cause of serious kidney disease.

My overall research aim is therefore to study by how much being overweight or obese and deposition of fat in the abdomen (ie, central obesity) increase the risk of developing temporary, permanent and/or progressive kidney damage across a wide range of populations, and then explore the potential causal mechanisms. This will be done using some of the world's largest population studies which have measured people's weight and body fat and collected blood for genetics, then followed them for many years to see if and how kidney problems develop. The following steps in the research process are necessary:

1. Completing the identifying and confirming of people who develop new kidney disease in over 1 million people assessed and then followed in 3 large population studies (China-Kadoorie Biobank, UK Biobank and the Mexico City Prospective Study).

2. Assessing how body weight and central obesity predict the risk of developing different kidney diseases.

3. Confirming adiposity is a causal risk factor for kidney disease, and then focusing on potential mechanisms, where there is some controversy. This work will include use of novel gene-based computational methods in the studies.

Long-term, these studies will be capable of relating how different types of obesity and kidney disease affect risk of other diseases thought to be associated with both conditions, including heart disease, infection and cancer.

Key applications and benefits of this fellowship, beyond personal development and the formation of a new research program focused on obesity, diabetes and kidney disease, include providing:

1. Extending the expertise of a kidney doctor who already has knowledge of how to design and conduct large trials, and providing him with the ability to use specialist genetic analyses to test whether risk factors for kidney disease represent a probable cause, rather than an association with kidney disease. This ensures future clinical trials will test the best questions;

2. Defining reliable kidney outcomes for UK Biobank, China-Kadoorie Biobank and Mexico City Prospective Study users;

3. Providing new and major opportunities for the pharmaceutical industry to test whether biological pathways may reduce or increase risk of kidney diseases.

Technical Summary

1. TO DERIVE RELIABLE OUTCOMES (RENAL AND NON-RENAL) FOR THE MEXICO CITY PROSPECTIVE STUDY AND CKD/ACUTE KIDNEY INJURY (AKI) OUTCOMES FOR 2 OTHER LARGE BLOOD-BASED PROSPECTIVE COHORTS (UK BIOBANK [UKB] & CHINA-KADOORIE BIOBANK [CKB])
For the Mexico City Prospective Study, fieldwork is necessary to confirm successful linkage of participants to hospitalisation records, and verify clinical diagnoses. For CKB, a traditional hospital notes based adjudication process will be undertaken in about 5000 recorded outcomes, including hospitals admissions recorded as CKD, 'acute renal failure', 'unspecified renal failure'. In UKB, data from secondary and primary care will be combined to identify CKD stages and hospitalisation for AKI and these algorithms tested using the baseline measured kidney function.

2. TO ASSESS ASSOCIATIONS BETWEEN MEASURES OF GENERAL/CENTRAL ADIPOSITY AND RISK OF CKD AND ACUTE KIDNEY INJURY ACROSS DIFFERENT POPULATIONS
To quantify the magnitude of associations between measures of general/central adiposity and risk of CKD/AKI across different populations using data from 3 blood-based cohorts (CKB, UKB, and the Mexico City Prospective Study) which have complete baseline adiposity measurements and a large number of prospectively collected outcomes.

3. TO EXPLORE MECHANISMS FOR THE ASSOCIATION BETWEEN INCREASED ADIPOSTY AND CKD RISK, INCLUDING MENDELIAN RANDOMIZATION EXPERIMENTS
Diabetes is a mechanism by which adiposity may cause kidney diseases, but increasing BMI is a CKD risk factor in people without diabetes. To investigate what is causing this association, genotyping data from SHARP, CKB, UKB and eventually the Mexico City Prospective Study will assess whether adiposity is likely to be a cause of non-diabetic kidney disease or not. Whether genetically elevated blood pressure is a mediator of CKD progression or incident CKD will then be assessed. Genotyping/biomarker data will then be used to explore new hypotheses.

Planned Impact

1. Renal trials: The datasets (and my development) will help ensure future renal trials are developed using robust epidemiological evidence, including Mendelian randomization experiments to assess causality, combined with reliable classical epidemiological methods to predict realistic outcome event rates and treatment effect sizes.

2. Population Health Impact: Worldwide, it is estimated that 2 billion people are overweight or obese and 600 million are obese. In the UK, about two-thirds of adults are overweight or obese and 1-in-3 are obese. Levels of obesity are also particularly high in North America, Western Europe, Australasia, parts of Central and South America, the Middle East and some Pacific Islands. Obesity is of particular concern in the low and middle income countries where obesity levels have risen sharply in recent years and the countries have insufficient resources to treat the epidemic of diabetes and increased cardiovascular/infection risk which will result. For example, the obesity epidemic in Mexico and the consequent high prevalence of poorly controlled diabetes is estimated to be a direct or indirect cause of 1-in-3 adult deaths between the ages of 35-74 years between 1998 and 2014. Many of these deaths were attributed to renal disease and its consequences. Assuming causality, this recent work suggests that 1-in-3 cases of 'serious and irreversible' kidney disease in the UK is a direct or indirect result of being overweight or obese.

3. Policy makers: Much like the successes that population health has had in influencing tobacco policy worldwide, generating reliable estimates of the risks associated with increased adiposity from different populations and among different types of people will help inform policy makers' decisions worldwide of the importance of preventing and treating obesity. It will also inform them of the size of the benefits one might expected if the average weight of the population was reduced. Our direct links with the Mexican Ministry for Health and the influence the Mexico City Prospective Study has already had on diabetes policy in Mexico is an example of the major impact this type of research can have on policy.

4. Health professionals: There is lack of reliable prospective data on the optimum measure of obesity to inform public health policy and clinicians, so the National Institute for Clinical Excellence (NICE) is currently limited in the recommendations it offers with regard to measures for assessing obesity. The 2014 NICE guidelines stated that body-mass index (BMI) is "a practical estimate of adiposity in adults" and that clinicians should "think about using waist circumference, in addition to BMI, in people with a BMI less than 35 kg/m2." NICE's Public Health Interventions Advisory Committee also recently identified that there is "a lack of studies that directly compared the association between BMI and the differential health risks for people of different ethnic groups apart from for diabetes" and there is "a lack of studies on health outcomes using waist circumference as the explanatory variable." This research proposal directly addresses some of these uncertainties with respect to kidney disease (and so will in time be expanded to other diseases associated with obesity), and may help identify who should be targeted for particular interventions to reduce risk of kidney disease.

5. Epidemiologists: will benefit from the enhancement of UK Biobank and China-Kadoorie Biobank to include reliable follow-up for renal disease outcomes. More prospective doctorial students may also start to use these resources to study kidney disease and its complications.

6. Understanding of healthcare data in Mexico would not only support the prospective study, but could also improve the quality of future Mexican 'big data' healthcare research (analogous to the vision of the Farr Institute in the UK).

Publications

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Haynes R (2019) Chronic kidney disease, heart failure and neprilysin inhibition. in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

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Herrington WG (2018) Authors' Reply. in Journal of the American Society of Nephrology : JASN

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Herrington WG (2019) Kidney disease trials for the 21st century: innovations in design and conduct. in Nature reviews. Nephrology

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Lamprea-Montealegre JA (2020) Apolipoprotein B, Triglyceride-Rich Lipoproteins, and Risk of Cardiovascular Events in Persons with CKD. in Clinical journal of the American Society of Nephrology : CJASN

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Marthi A (2018) Fibroblast Growth Factor-23 and Risks of Cardiovascular and Noncardiovascular Diseases: A Meta-Analysis. in Journal of the American Society of Nephrology : JASN

 
Description International Society of Nephrology 1st Universal Definition of Kidney Failure
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Development of the 1st Universal Definition of Kidney Failure for implementation in clinical trials as part of core group developing the definitions. Culminating in an international conference in Vancouver, Canada 31st Jan-1st Feb 2020.
URL https://www.theisn.org/
 
Description Body Composition Monitor EMPA-KIDNEY Substudy
Amount £123,227 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 04/2019 
End 06/2023
 
Description EMPA-KIDNEY trial
Amount £79,400,000 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 04/2018 
 
Description MRI EMPA-KIDNEY Substudy
Amount £176,000 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 12/2019 
End 06/2023
 
Description Oxford British Heart Foundation Centre for Research Excellence (BHF-CRE) DPhil studentship
Amount £78,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
 
Description 1st Universal Definition of Kidney Failure (ISN) 
Organisation International Society of Nephrology (ISN)
Country Belgium 
Sector Charity/Non Profit 
PI Contribution Core group member devising collaborative 1st Universal Definition of Kidney Failure
Collaborator Contribution Developed the concept of the 1st International Conference on the 1st Universal Definition of Kidney Failure, held in Vancouver Canada 31st Jan-1st Feb 2020.
Impact 1st Universal Definition of Kidney Failure manuscript.
Start Year 2019
 
Description Chronic Kidney Disease Epidemiology Collaboration 
Organisation Tufts University
Country United States 
Sector Academic/University 
PI Contribution Provision of SHARP data.
Collaborator Contribution Collaborative meta-analysis.
Impact Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies. Coresh J, Heerspink HJL, Sang Y, Matsushita K, Arnlov J, Astor BC, Black C, Brunskill NJ, Carrero JJ, Feldman HI, Fox CS, Inker LA, Ishani A, Ito S, Jassal S, Konta T, Polkinghorne K, Romundstad S, Solbu MD, Stempniewicz N, Stengel B, Tonelli M, Umesawa M, Waikar SS, Wen CP, Wetzels JFM, Woodward M, Grams ME, Kovesdy CP, Levey AS, Gansevoort RT; Chronic Kidney Disease Prognosis Consortium and Chronic Kidney Disease Epidemiology Collaboration. Lancet Diabetes Endocrinol. 2019 Feb;7(2):115-127. doi: 10.1016/S2213-8587(18)30313-9. Epub 2019 Jan 8. PMID: 30635225
Start Year 2018
 
Description Standardizing Outcomes in Nephrology-Dialysis Iniatiative (SONG) - CV outcomes working group 
Organisation University of Sydney
Country Australia 
Sector Academic/University 
PI Contribution Expert opinion
Collaborator Contribution Collaborative multistakeholder initiative.
Impact Cardiovascular Outcomes Reported in Hemodialysis Trials. O'Lone E, Viecelli AK, Craig JC, Tong A, Sautenet B, Roy D, Herrington WG, Herzog CA, Jafar T, Jardine M, Krane V, Levin A, Malyszko J, Rocco MV, Strippoli G, Tonelli M, Wang AYM, Wanner C, Zannad F, Winkelmayer WC, Webster AC, Wheeler DC. J Am Coll Cardiol. 2018 Jun 19;71(24):2802-2810. doi: 10.1016/j.jacc.2018.04.012. Review. PMID: 29903353
Start Year 2017
 
Description The EMPA-KIDNEY trial 
Organisation ANMCO Research Centre
Country Italy 
Sector Public 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation Duke University
Department Duke Clinical Research Institute
Country United States 
Sector Academic/University 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation Fuwai Cardiovascular Hospital
Country China 
Sector Hospitals 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation Tokai University
Country Japan 
Sector Academic/University 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation University of British Columbia
Country Canada 
Sector Academic/University 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation University of Tokyo Hospital
Country Japan 
Sector Hospitals 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description The EMPA-KIDNEY trial 
Organisation University of Wurzburg
Country Germany 
Sector Academic/University 
PI Contribution Oxford proposed trial and setup trial operations Oxford leads scientific direction and a body composition substudy is in development Sponsored and funded by Boehringer Ingelheim
Collaborator Contribution Boehringer Ingelheim provided funding and study sponsorship 8 countries are recruiting from 8 regional coordinating centres (160+ hospitals)
Impact Rationale paper: https://academic.oup.com/ckj/article/11/6/749/5144684
Start Year 2018
 
Description UK Biobank 
Organisation UK Biobank
Department UK Biobank Neurodegenerative Outcomes Working Group
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-chairing renal outcomes working group and developing validated renal outcomes from primary and secondary care data for other users of the UK Biobank resource
Collaborator Contribution Collaboration set up with former Chief Scientist Prof Cathie Sudlow and her programming team (John Nolan) at the University of Edinburgh, now continuing with newly appointed Chief Scientist Prof Naomi Allen.
Impact Algorithmically-derived outcomes for end-stage renal disease have been completed and made available (with release notes) on UK Biobank data sharing Showcase system as part of the UK Biobank core dataset (category 48). All researchers accessing UK Biobank are encouraged to request the core dataset.
Start Year 2015
 
Title EMPA-KIDNEY trial 
Description Empagliflozin (an SGLT2 inhibitor) which has BP, adiposity, blood glucose and CV risk lowering properties: https://www.medicines.org.uk/emc/product/5441/smpc is being tested in a large chronic kidney disease population trial (6000 people). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact EMPA-KIDNEY is in the recruitment phase. 
URL http://www.empakidney.org
 
Description CME-PACE online education: "The clinical landscape of managing patients with CKD: Where are we now and what can we expect?" 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Webcast for educational purposes: "The clinical landscape of managing patients with CKD: Where are we now and what can we expect?"
Year(s) Of Engagement Activity 2019
URL https://pace-cme.org/2019/08/23/the-clinical-landscape-of-managing-patients-with-ckd-where-are-we-no...
 
Description How do SGLT-2 inhibitors work? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Talk XIX International Congress on Nutrition and Metabolism in Renal Disease (ICRNM 2018), Genova, Italy. (June 2018)
Year(s) Of Engagement Activity 2018
 
Description ISN conference on 1st Universal Definition of Kidney Failure talk: Perspectives on adjudication in clinical trials: when, why, and why not? 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Personally gave the ISN conference on 1st Universal Definition of Kidney Failure a talk on: Perspectives on adjudication in clinical trials: when, why, and why not?
Followed by 3 hours of breakout group discussions with trialists, nephrologists, patients, regulators, industry etc. to come to consensus.
Part of 2-day event (31st Jan-1st Feb 2020)
Year(s) Of Engagement Activity 2020
URL http://www.theisn.org
 
Description Invited talk at ERA-EDTA 2019 (Budapest): "The clinical landscape of managing patients with CKD: Where are we now and what can we expect?" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at ERA-EDTA 2019 (Budapest): "The clinical landscape of managing patients with CKD: Where are we now and what can we expect?"
Year(s) Of Engagement Activity 2019
 
Description Kidney Disease posters/talks for the general public on behalf of Kidney Research UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 2x talks at Masonic lodges in Oxfordshire.
2x Showcase events for Kidney Research UK (London and Oxford)
Year(s) Of Engagement Activity 2019
 
Description Renal SpR Club talk: SGLT2 inhibition in CKD 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 30 minute update on SGLT2 inhibition in CKD
Year(s) Of Engagement Activity 2019
URL https://renal.org/clinical/renal-spr-club/spr-club-meetings/
 
Description School Visit: Magdalen College School for talk: "Maths and Medicine: Do the drugs work?" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Discussed clinical trials with A-level maths and science students at the local school as part of a lunch club.
Year(s) Of Engagement Activity 2020
 
Description Taking evidence into practice (expert panel at UKKW 2019) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact See above.
Year(s) Of Engagement Activity 2019
 
Description UK Renal Trial Network Session at UK Kidney Week: Do you know how to design and interpret a clinical trial? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I devised and chaired a 90 minutes UK Renal Trial Network Session at UK Kidney Week, Brighton, June 2020.
Year(s) Of Engagement Activity 2019
URL https://renal.org/uk-kidney-week-2019-programme-update/