Title: Accuracy of glomerular filtration rate (GFR) estimation using creatinine and cystatin C and albuminuria for monitoring disease progression in patients with stage 3 chronic kidney disease: a prospective longitudinal study in a multiethnic population
Funder: Department of Health and Social Care

Abstract: Design. 1) A prospective longitudinal cohort study to estimate accuracy in eGFR and changes in eGFR. 1300 people will be followed for 3 years with reference (measured) GFR and test (estimated GFR [eGFR] and ACR) measurements at baseline and 3 years. Test measurements will also be undertaken every 6 months, as recommended in NICE guidance. People will be recruited over 6 centres and will include a representative sample of Asians and African-Caribbeans, and people with diabetes and proteinuria. 2) A sub-study of patterns of disease progression of 300 people (100 each of Caucasian, Asian and African-Caribbean origin; in each case containing subjects at high [proteinuria/diabetes] and low risk of kidney disease progression) Additional reference GFR measurements will be undertaken after 1 and 2 years to enable a model of disease progression to be built. 3) A study of biological variability to establish reference change values (RCVs) for reference GFR measurement and its estimated surrogates. 4) A modelling study of the performance of monitoring strategies on detecting progression, utilising estimates of accuracy, patterns of disease progression and estimates of measurement error from studies 1), 2) and 3). 5) A model based cost-effectiveness analysis of alternative monitoring strategies. Setting. Primary and secondary care. Target population. Adults with stage 3 CKD (GFR 30-59 mL/min/1.73 m2) proportionally enriched to include people more likely to have progressive kidney disease (i.e. those with proteinuria and/or diabetes) and including Asians and African-Caribbeans. Health technologies being assessed. Estimated GFR using simplified ID-MS traceable version of the MDRD equation and three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, using either creatinine or cystatin C or a combination of both, in addition to urinary ACR. Creatinine and cystatin C will be measured using methods traceable to the international reference method. We will assess the performance of monitoring rules utilising these tests at various time intervals. Measurement of cost and outcomes. Iohexol measured GFR will be the reference measure of GFR against which each GFR estimating equation will be compared. The performance of the GFR estimating equations will be evaluated by assessing bias, precision and accuracy (expressed as P30, the measure of error variability commonly used in this context and being the percentage of eGFR values within 30% of ‘true’ GFR). We will also consider error in the change in eGFR, across multiple time points. Large error will be accepted as greater than 3 mL/min/1.73 m2/year or a greater than 5%/year difference in slope between measured and eGFR. Data will be modelled as a linear function of time utilising all available (maximum 7) eGFR time points compared to the difference between final and baseline reference GFR values. The percentage of participants demonstrating large error with the respective GFR estimating equations will be compared. Predictive value will be compared by dividing subjects based on whether or not they show progressive decline in kidney function over the 3 years and the sensitivity and specificity of each of the eGFRs to identify progressive disease will be tested using receiver-operator curve analysis. ACR (in addition to the various eGFRs) will be tested as a predictor of progression. The rate of decline in reference GFR measured every year in a substudy will be modelled over time using a longitudinal linear or nonlinear (exponential decline) random coefficients regression model to estimate disease progression and error. The health economic component will use primary data collection to develop a comprehensive cost database for each diagnostic approach enabling cost-effectiveness modelling of the optimal strategy. Sample size. 1300 (see ‘additional information’), including at least 165 African-Caribbean and 165 South Asians. Sample size justification: We estimated the minimal clinically significant difference between P30 values to be 5% (e.g. a change from 81% to 86%). A sample size of 1300 (including allowance for a dropout rate of 15%-20%) provides 90% power to detect a clinically significant difference in P30 allowing identification of the most accurate GFR estimating equation. Confidence intervals (95%) on estimates of P30 in the ethnic subgroups will be less than 10 percentage points wide. Project timetable (including recruitment rate). The study will commence on 1st April 2013. 0-6 months: regulatory approvals, staff appointments, staff training. 0-12 months: sub-study of biological variation. 7-24 months: Longitudinal study patient recruitment and baseline reference GFR and associated tests (220 participants per centre with research nurses undertaking 1-2 baseline reference GFRs at each site per working day and collecting contemporaneous samples for eGFR and ACR). 13-54 months: 6 monthly blood and urine tests. 43-60 months: 3 year/final follow-up tests. 55-60 months; health economics and model building. 61-66 months: study closure, detailed health economic analysis, report writing, dissemination. Additional points. GFR equations: the MDRD equation is used routinely to estimate GFR but is negatively biased and imprecise. A revised equation, the CKD-EPIcreatinine is thought to partially address these issues [1, 2]. Observational data suggests cystatin C and ACR are superior to creatinine-based eGFR in identifying people most likely to have progressive or clinically significant disease [3] but this has not been tested against a reference measure of GFR. Newer GFR-estimating equations are available which include cystatin C, either alone or in combination with creatinine [4]. Standard clearance of inulin, including urine collection, remains the "gold-standard" method for GFR measurement but few studies use this. We have chosen iohexol clearance as the reference measure of GFR for our study because it is equivalent to inulin clearance, is non-radioactive, can be measured accurately and precisely, and is relatively cheap [5]. NICE guidance recommends that eGFR is checked every 6 months in stage 3 CKD [6]. [1] Levey, Ann Int Med 2009;150:604-12 [2] Earley, Ann Int Med 2012;156:785-95 [3] Peralta, JAMA 2011;305:1545-52 [4] Inker, NEJM 2012;367:20-9 [5] Schwartz, Clin J Am Soc Nephrol 2009;4:1832-43 [6] NICE, 2008, http://publications.nice.org.uk/chronic-kidney-disease-cg73

Lay abstract: Addressing the question The best overall measure of kidney function is accepted to be the glomerular filtration rate (GFR), which measures the ability of the kidney to filter blood and is widely used in clinical practice. A low GFR suggests poor kidney function. An estimate of GFR can be obtained from a simple blood test. In 2006 the Department of Health recommended that all NHS laboratories in England should routinely estimate and report GFR using equations based on the measurement of a substance in blood called creatinine. Similar recommendations were made throughout the rest of the UK and internationally. Creatinine is normally filtered and excreted by the kidneys but if the kidneys have reduced function its concentration in blood increases. Hence a high creatinine concentration in blood equates to poor kidney function (i.e. low GFR). The equations for estimating GFR adjust for some of the other factors that affect blood creatinine concentration (e.g. age, gender and race). The introduction of GFR reporting as part of routine clinical practice in the UK, together with more widespread detection of kidney disease through testing for excess protein in urine (proteinuria/albuminuria), has increased the number of patients diagnosed with chronic kidney disease (CKD): approximately one in seven of the UK population have been diagnosed with CKD using these methods. However, there are concerns regarding the accuracy of this testing and its ability to detect deterioration in kidney function. More accurate testing would facilitate identification and monitoring, ultimately improving outcomes for patients with CKD, whilst reducing risks of misdiagnosis. Cystatin C, a small protein that can be measured in blood, has been proposed as an improved marker of GFR. Critically, cystatin C is approximately ten times more expensive to measure than creatinine. Our proposal is to assess the accuracy of current and alternative tests of kidney function against a reference test (see below) in a large group of people (1300 over six centres) with moderate (stage 3) CKD who will be followed over a three year period. The population will include people with diabetes and proteinuria, and people of African-Caribbean and Asian descent. The study addresses all of the outcomes outlined in the commissioning brief, and is of sufficient size and breadth to ensure reliable results. How and where the research will be carried out The study will recruit people from hospital clinics and from primary care at six major UK centres (Birmingham, Canterbury, Derby, London, Leicester, Salford). Participants will undergo reference GFR testing at study entry with a second follow-up reference test three years later. The reference test involves injecting a small amount of iohexol, a non-radioactive iodine-containing substance widely used for this purpose, into a vein and taking blood samples over the next 4 hours to see how quickly the iohexol disappears from the blood stream. The rate at which iohexol disappears (is ‘cleared’ by glomerular filtration and renal excretion) is equivalent to the level of kidney function. The reference test is used in routine clinical practice in some centres. Routine blood tests for monitoring kidney function, in addition to blood cystatin C and urinary albumin, will be done every six months during the study period. Outcomes Iohexol measured GFR will be accepted as the reference (‘gold standard’) measure of kidney function against which each GFR-estimating equation will be compared. The alternative estimated measures of GFR, derived from measuring substances (creatinine and cystatin C) in the blood, will be compared against the reference test. An important outcome is how much the reference test changes over the three years of the study, and how well the surrogate measures reflect this change. We will also collect accurate test cost data for subsequent cost-effectiveness analysis (e.g. do the relative costs of the tests justify any change in practice due to improved performance of one test compared to another?). Ethics We will obtain multicentre research ethics approval. Participants will need to provide informed consent; those who are unable to do so will not be enrolled in the trial. There is no investigational medicinal product involved in this study. The main risk is of allergy to iodine contained within the reference test. This is very rare and individuals with a known allergy to iodine will be excluded. Governance arrangements for the trial will be supervised by Birmingham Clinical Trials Unit, and the trial will be run according to the principles of Good Clinical Practice (GCP). Team To answer the broad range of questions posed by the commissioning brief requires a diverse range of expertise. We have assembled a team with expertise in carrying out test evaluation studies in people with kidney disease in primary and secondary care together with clinical biochemistry and large trials expertise, patient representation, statistics and health economics. Several of the team members have a track record of collaborating with each other, and are well placed to deliver the mix of outcomes demanded by this brief. Justification of costs Costs are sought to employ a research nurse for each study centre, who will coordinate recruitment and consent and perform the reference GFR (iohexol) clearance procedures, blood sampling and data entry. We included costs for the Birmingham Clinical Trials Unit (BCTU) to employ a trial manager, data programmer and statistician (all with senior oversight). The BCTU team will ensure overall coordination of the study, develop and run the study contract processes, data management and verification system, and site monitoring (including source data verification) to ensure the study is conducted to the highest standards of ‘good clinical practice (GCP). Other personnel costs are sought for the health economist, who will coordinate and analyse the health economics component. Funds are sought to cover the costs of outcomes specified in the brief; basically various tests of kidney function. We have included costs for archiving and dissemination, steering group and data monitoring, in line with Medical Research Council trials guidelines and for a patient advisory group. Costs are also included to reimburse participants for travel and parking costs incurred whilst attending for the reference test.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL