MR1176 - The Renal Risk in Derby (R2ID) Study

The Renal Risk in Derby (RRID) study is a long term (10 year) prospective cohort study looking at a population of 1741 persons with chronic kidney disease recruited from primary care between 2008 and 2010. The primary objectives on the study are to define the risk of kidney disease (CKD) stage 3 who are cared for in primary care by General Practitioners. Further, the study aims to provide a comprehensive description of these patients and their treatment needs. This is important because the majority of people with CKD stage 3 are never referred to a specialist nephrology service and this population tends not to be included in research studies. The study therefore has broad scope. The current analyses are focussed on cardiovascular events over the first five years of follow up.

University Hospitals of Derby and Burton NHS Foundation Trust aims to continue to use the data to provide insight into the renal and cardiovascular outcomes in the study group. Specifically, the data requested will provide accurate information regarding survival, cause of death, the incidence of acute kidney injury and cardiovascular events in the study cohort. Identifiable data are required to link individual participants to outcomes using the data from NHS Digital to achieve this because it is the only way to ensure that the study team identify al events, regardless of where a participant now resides. University Hospitals of Derby and Burton NHS Foundation Trust have requested data on death and cause of death as well as hospitals admissions because there is a particular interest in the association between CKD and cardiovascular disease. The data requested will allow the study to obtain comprehensive data on fatal and non-fatal cardio vascular events in all participants. This information will provide insights into the association between baseline variables associated with chronic kidney disease and survival as well as important complications including acute kidney injury and cardiovascular events.

Participants were eligible for inclusion if they were 18 years or older and met diagnostic criteria stage 3 (estimated GFR 59-30ml/min1.73m2 on two consecutive blood tests at least 910 days apart). Participants were recruited from General Practitioner surgeries and study visits took place at the participants surgery.

Questions that data requested will be used to address

1. What is the incidence of cardiovascular events in people with Chronic Kidney Diseases (CKD) stage 3 in primary care?

2. Can novel markers of cardiovascular risk (e.g. Cystatin C and Skin Autofluorescence) be used in predicting cardiovascular risk in people with CKD stage 3?

3. Does acute kidney injury impact upon chronic kidney disease progression?

4. Do cardiovascular events impact upon chronic kidney disease progression?

5. What are the determinants of survival in persons with chronic kidney disease?

The data previously requested and currently held include:

1. Date and cause of death of all deaths of participants until 31/12/2015 (including details from death certificates)

2. Date and ICD-10 codes for all hospital admissions for participants until 31/12/2015.

Identifiable data re required so that outcomes can be linked to clinical and biochemical data obtained from each participant baseline. This is essential to enable the study to achieve the primary objectives. University Hospitals of Derby and Burton NHS Foundation Trust have sought to minimise the data required by requesting only data pertaining to outcomes stated in the study protocol.

In the study database, baseline data and outcomes are pseudonymised such that participants are identified only by a study number. Participants can be identified only by referring to a key which is stored separately in a password protected folder. The period covered is the first five years of follow up. In designing the study, the study team assesses that this would be a period of follow up during which the majority of first cardiovascular events would occur and that would provide clinically meaningful assessments of risk. The analysis to date have supported this assessment. Participants were all recruited from Derbyshire but during the course of follow up several have moved out of the area and therefore outcomes that were recorded throughout England were requested.

The lawful basis for processing these data is Processing : Article 6 (1) (e) and Article 9 (2) (j) a “task in the public interest” and “scientific research”. Analysis of the data will improve understanding of outcomes related to chronic kidney disease to facilitate a stratified approach to management so that persons at low risk of adverse outcomes will be spared unnecessary investigation or treatment and persons at high risk receive more intensive monitoring and treatment. As such it is clear that this project is a "task in the public interest".

The sole data controller for this study is University of Derby and Burton NHS Foundation Trust. The Data Processor is also University of Derby and Burton NHS Foundation Trust. At various times during the project the study has been funded by different organisations including Kidney Research UK, The British Renal Society and Dunhill Medical Trust but no other organisation had any role in the design or conduct of the study nor in the processing the data.

The study was approved by the Nottingham 1 Research Ethics Committee and no additional ethical issues have been identified during the course of the study. There are no alternative or less intrusive ways for achieving the purpose.

This application is to continue to hold and process data already obtained from NHS Digital, no further data will be disseminated under this version of the agreement.

The applicant previously provided identifying information (NHS Number, Member Number, Date of Birth, Latest names, gender) for the RRID study cohort to NHS Digital and NHS Digital flagged this cohort to periodically supply notifications of participants’ deaths, exits from NHS registration and information about their hospital admissions from Hospital Episode Statistics. University Hospitals of Derby and Burton NHS Foundation Trust are the sole data controller and data processor for this agreement.

The data supplied to University Hospitals of Derby and Burton NHS Foundation Trust by NHS Digital is then used in analysis of survival, cardiovascular events and acute kidney injury in the study cohort. The data provided by NHS Digital have been coded and entered into the study database in pseudonymised form. These coded data are used in the analysis of risk factors for all cause mortality and cardiovascular events as discussed above. Analysis will help to answer the main aims of the study- to investigate the predictors of progressive renal disease in CKD 3 patients, and to evaluate the risk of cardiovascular events in this population.

The data are stored on a password-secured server. Data is only accessed by individuals within the RRID study who have authorisation from the Chief Investigator to access the data for the purpose described, all of whom are substantive employees of University Hospitals of Derby and Burton NHS Foundation Trust.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

University Hospitals of Derby and Burton NHS Foundation Trust is not permitted to share record level data with any other organisation. There is no flow of the data to other organisations.

There will be no data linkage undertaken with NHS Digital data provided under this agreement that is not already noted in the agreement.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide

Processing of these data has already produced multiple conference presentations and peer reviewed publications as summarised below. Further analysis is in progress and is anticipated to result in further conference presentations and peer reviewed publications at national and international nephrology conferences. It is anticipated that data will be presented at UK Kidney Week ( the official conference of the Renal Association and the British Renal Society) and the annual meeting of the European Renal Association/European Dialysis and Transplant Association in 2021. These conferences are attended by multidisciplinary teams of healthcare professionals involved in the care of people with kidney disease. Following conference presentations, the data will be presented in scientific papers and submitted for publication in peer reviewed international journals.

Two PhD theses based on data from this study have been completed and the PhDs awarded. The first PhD entitled ‘Defining Chronic Kidney Disease Stage 3 in Primary Care’ focussed on an analysis of baseline data and was awarded in 2012. The second PhD entitled ‘Risk Prediction and Outcomes in Chronic Kidney Disease Sage 3: a Prospective Cohort Study in Primary Care’ focussed on analysis of some of the data from the first five years of follow up and was awarded in 2019. A recent paper focussing on cardiovascular events is in the final stages of review by the Journal "PLOS Medicine".

In 2019 the investigators presented data from the study at Kidney Week (3 – 5 June 2019) and the annual meeting of the American Society of Nephrology (5 – 10 November 2019)

Baseline and five year follow-up data from the study has already been published in the scientific literature and presented at international conferences (See below). The main aims of the study are to investigate the predictors of progressive renal disease in CKD 3 patients, and to evaluate the risk of cardiovascular events in this population. The aim is to publish further articles on cardiovascular outcome and risk prediction in this cohort. HES data regarding acute kidney injury will also allow analysis of risks of chronic kidney disease progression. All outputs will only contain aggregated data with small numbers suppressed in line with the HES analysis guide.

Two feedback meetings were held in 2015 to disseminate the findings so far to participants, their family members and GPs. Two meetings were necessary because the number who indicated that they would like to attend exceeded the capacity of the venue.

Ongoing feedback is provided to participants via the study webpage and this will be updated as further information becomes available. Due to the large number of participants and the fact many are now quite elderly, the study is unable to engage directly with them at this stage.

Selected RRID Study Publications:

1. McIntyre NJ, Shardlow A, Fluck RJ, McIntyre CW, Taal MW. Determinants of change in Arterial Stiffness over 5 years in Early Chronic Kidney Disease. Nephrology, Dialysis and Transplantation 2019 ePub 18 September.

2. Shardlow A, McIntyre NJ, Fraser SDS, Roderick P, Raftery J, Fluck RJ, McIntyre CW, Taal MW. The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study. PLoS Med. 2017 Oct 10;14(10): e1002400.

3. Shardlow A, McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Associations of fibroblast growth factor 23, vitamin D and parathyroid hormone with 5-year outcomes in a prospective primary care cohort of people with chronic kidney disease stage 3. BMJ Open. 2017 Aug 23;7(8): e016528.

4. Shardlow A, McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study. PLoS Med. 2016 Sep 20;13(9):e1002128.2.

5. Taal MW, Thurston V, McIntyre NJ, Fluck RJ, McIntyre CW. Impact of Vitamin D Status on the Relative Increase in Fibroblast Growth Factor 23 and Parathyroid Hormone in Chronic Kidney Disease. Kidney Int; published online 15 Jan 2014.Fraser SD, Roderick PJ, McIntyre NJ, Harris S, McIntyre CW, Fluck RJ, Taal MW. Suboptimal blood pressure control in chronic kidney disease stage 3: baseline data from a cohort study in primary care. BMC Fam Pract. 2013 Jun 24;14:88.

6. McIntyre NJ, Fluck RJ, McIntyre CW, Fakis A, Taal MW. Determinants of arterial stiffness in chronic kidney disease stage 3. PLoS One. 2013;8(1):e55444

7. Fraser SD, Roderick PJ, McIntyre NJ, Harris S, McIntyre CW, Fluck RJ, Taal MW. Socio-economic disparities in the distribution of cardiovascular risk in chronic kidney disease stage 3. Nephron Clin Pract. 2012;122(1-2):58-65.

8. McIntyre NJ, Fluck R, McIntyre C, Taal M. Treatment needs and diagnosis awareness in primary care patients with chronic kidney disease. Br J Gen Pract. 2012 Apr;62(597):e227-32.

9. Evans PD, McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Anthropomorphic measurements that include central fat distribution are more closely related with key risk factors than BMI in CKD stage 3. PLoS One. 2012;7(4):e34699.

10. McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Skin autofluorescence and the association with renal and cardiovascular risk factors in chronic kidney disease stage 3. Clin J Am Soc Nephrol. 2011 Oct;6(10):2356-63.

11. McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Risk profile in chronic kidney disease stage 3: older versus younger patients. Nephron Clin Pract. 2011;119(4):c269-76.

The Renal Risk in Derby Study aims to improve knowledge and understanding about disease progression and management of chronic kidney disease stage 3 in primary care. Studies have estimated the prevalence of CKD in the general population to be up to 10 %. The majority of these people are managed in primary care and are not usually included in research studies. University Hospitals of Derby and Burton NHS Foundation Trust have therefore sought to address a major knowledge gap.As such, it is hoped that results from this study will inform future national guidance (specifically, National Institute of Health and Care Excellence CKD guidance) in the management of Chronic Kidney Disease in Primary care , directly benefiting the patients.

The study has already provided a comprehensive analysis of people with CKD stage 3 cared for in Primary Care. The following insights from the study will help GP’s manage people with CKD stage 3 in their daily practice:

1) Only a minority (6%) require referral to a specialist nephrology service; the majority can be managed in primary care without the need for further investigation. This information was published in the British Journal of General Practice in 2012 and will help to reduce unnecessary referrals to secondary care.

2) Blood pressure was adequately controlled in only 58% of participants, a finding confirmed in a national CKD Audit of GP surgeries. These data provide evidence for increased focus on achieving blood pressure control on this population.

3) The majority of patients follow a benign course, with a very low risk of developing end stage kidney disease over 5 years. These data were published in PLOS Medicine in 2016 and allow GP’s to provide reassurance to the majority of people that CKD stage 3 is not associated with high risk of progression to end stage kidney disease (that requires treatment with dialysis or a kidney transplant).

The study has reported important data to inform the management of CKD in primary care including:

1. Only 6% of patients require referral to a specialist centre, confirming that the majority can be adequately managed in primary care.

2. The majority of patients follow a benign course, with a very low risk of developing end-stage kidney disease over 5 years.

3. Correction of vitamin D deficiency in a small proportion of patients may improve survival.

4. The use of serum cystatin C (as suggested by NICE guidelines) in addition to serum creatinine to estimate glomerular filtration rate does not appear to offer benefit in primary care.

5. The study has provided, in 2019, the first longitudinal data identifying uncontrolled blood pressure as the most important factor contributing to the development of arterial stiffness in people with CKD. This emphasizes the need for excellent blood pressure control, something which was achieved in only 58% of participants.

The applicant has published a landmark paper reporting outcomes in the study population over 5 years. Their data show that the risk of progression of CKD over 5 years is relatively low and that some participants even evidenced "remission" of the kidney disease. The most frequent cause of death was found to be cardiovascular disease (Shardlow A, McIntyre NJ, Fluck RJ, McIntyre CW, Taal MW. Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study. PLoS Med. 2016 Sep 20;13(9):e1002128).

The applicant has published a further important paper reporting on the clinical utility of adopting NICE guidance on the use of serum cystatin C to diagnose CKD. Their findings are expected to result in a change in the guidance in future. The NICE Guidelines for management of CKD are currently undergoing revision and we expect that this paper will be used to inform changes on the recommendations for use of cystatin C. (Shardlow A, McIntyre NJ, Fraser SDS, Roderick P, Raftery J, Fluck RJ, McIntyre CW, Taal MW. The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study. PLoS Med. 2017 Oct 10;14(10): e1002400.)