Abstract
In the British Medical Journal, Smellie 1 recently presented an Association for Clinical Biochemistry discussion document relating to harmonization of routine laboratory test profiles, including renal (urea, creatinine and electrolytes, ‘U&Es’), liver and thyroid function test profiles. Regarding the former, Smellie asked whether the estimated glomerular filtration rate (eGFR) should always be routinely reported alongside creatinine as part of the kidney function test due to ‘quality and potential safety concerns’, citing invalidity of the test in situations such as pregnancy, extreme body habitus, acute changes in renal function and amputees.
Kidney disease is silent but common, harmful but treatable. 2 The only reason for requesting creatinine is to assess kidney function. Routine reporting of eGFR alongside creatinine has proved a useful tool for clinicians in the detection and management of chronic kidney disease (CKD) – to drop it would represent a backwards step. Creatinine and eGFR are key measures for clinicians because of the high frequency of CKD and acute kidney injury (AKI), and of their association with each other. 3 Kidney function test results need to be interpreted in the context of the individual patient – this is true for both eGFR and creatinine. In the situations Smellie cites, the eGFR is more unreliable because the creatinine concentration from which it is derived is also an inaccurate reflection of kidney function. Kidney function is more difficult to assess in these situations; omitting eGFR reporting would not make it easier. While eGFR and its use in the classification of CKD is not without its problems, we need to look at practical solutions to refine the current system.
Glomerular filtration rate (GFR) is accepted as the best measure of kidney function but its direct measurement is too cumbersome for routine clinical practice. Several equations have been developed as a surrogate for measured GFR, with the Modification of Diet in Renal Disease (MDRD) Study equation being the most widely used to estimate GFR. 4 The current CKD classification system was developed in 2002 by the Kidney Disease Outcomes Quality Initiative (KDOQI). It categorizes individuals into five stages depending on the evidence of kidney injury and GFR and recommends the use of eGFR in practice. 5
In England, national routine reporting of eGFR with every creatinine result, calculated using the isotope dilution mass spectrometry traceable MDRD equation, was implemented in 2006 to coincide with the introduction of a CKD domain into the Quality and Outcomes Framework (QOF). 6,7 This initiative was lead by the clinical biochemistry community in collaboration with the Renal Association. The QOF required the general practitioners to keep a register for all those 18 y and over with a GFR (in practice an eGFR) less than 60 mL/min/1.73 m2. Blood pressure control in CKD patients has been central to the QOF and the framework has been refined over time with addition of proteinuria. The National Institute for Health and Clinical Excellence has further refined the CKD classification system, splitting stage 3 into 3A (45–59 mL/min/1.73 m2) and 3B (30–44 mL/min/1.73 m2) and using the suffix ‘p’ to denote the presence of proteinuria. 8
The KDOQI classification system has attracted considerable criticism with calls for changes. The main issues of contention have been well summarized as falling into five areas: accuracy of eGFR using the MDRD equation, over-diagnosis of CKD in the elderly population, appropriateness of the cut-offs between the stages, lack of consideration regarding aetiology of the CKD and eGFR acting as a covert means of introducing screening for CKD. 9 There have been several proposals as to how the classification system can be improved including the inclusion of albuminuria alongside eGFR 10,11 and a tightening of the eGFR threshold for referral in older adults with no signs of kidney injury to 45 mL/min/1.73 m2. 12
A large meta-analysis of the predictive risk of eGFR and albuminuria in the general population with over five million person years by the Chronic Kidney Disease Prognosis Consortium in 2010 reported that eGFR <60 mL/min/1.73 m2 and albuminuria were both predictors of all-cause mortality and cardiovascular mortality, independently of each other and of other more traditional cardiovascular risk factors. 11 The Consortium therefore supported the threshold of eGFR ≤60 mL/min/1.73 m2 as the trigger for further evaluation in the KDOQI classification system but suggested that albuminuria stages also be included in the staging of CKD independently of eGFR to reflect these findings.
Certainly, eGFR calculated using the MDRD Study equation is not perfect and the newly developed CKD Epidemiology Collaboration (CKD-EPI) equation is promising. 13 A recent study of 1.1 million adults found the CKD-EPI equation to be a better risk predictor for mortality and kidney failure. Of note it reclassified 35% of those placed in stage 3A using the MDRD Study equation in a general population cohort to higher GFR categories. 14
Any creatinine-based equation will suffer from the problems associated with the inherent presumption that creatinine production is similar across the population and constant over time. 15 Cystatin C has been proposed as a more accurate alternative to creatinine for estimating GFR and a recent report found that eGFR calculated using a combined creatinine-cystatin C equation was closer to measured GFR than equations using cystatin or creatinine alone. 16 However, measurement of cystatin C is currently more expensive and its benefits beyond the addition of albuminuria to the current staging system would require a persuasive health economic case given the larger system change needed to implement it as a replacement to creatinine. We must also keep in mind the wider implications of any change to the GFR-estimating equation such as the calculation of drug dosages in renal disease and the need for a consistency of approach to avoid confusion among clinicians. The British National Formulary revised its drug dosage guidance for adjustment in renal disease from creatinine clearance using the Cockroft and Gault 17 formula to eGFR calculated using the MDRD Study equation with some exceptions in 2009.
The routine reporting of eGFR and its alignment to the QOF has achieved a great deal to raise the profile of CKD among health practitioners, with the representation of eGFR as percentage kidney function helping to demystify kidney disease for both clinicians and patients. The reporting of eGFR is a key component of early CKD detection and data from the UK Renal Registry show a gradual decline in the number of patients with late presentations (i.e. requiring renal replacement therapy [RRT] within 90 d of diagnosis) to renal services. For patients starting RRT, the percentage of those presenting late has steadily reduced between 2005 and 2009, with the inverse being true for those presenting within a year or more of needing dialysis. 18 There are also studies showing that decline in renal function as reflected by eGFR can be slowed with enhanced models of care. 19,20 Therefore, despite its relative crudeness, eGFR appears to be sensitive to local intervention: more education and research is needed in maximizing its value for improving outcomes.
There is still a lot to do in improving outcomes for patients with kidney disease. While over half of all CKD patients are now being diagnosed in primary care, 21 not all patients are currently being informed of their diagnosis and there are still many opportunities to reduce vascular and kidney risk factors. 22 We need to arrive at a consensus regarding the use of albuminuria in the classification of CKD, improve our understanding of the link between CKD and AKI and reduce the incidence of AKI in the CKD population. Let us move forwards, not back.
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