A national audit of estimated glomerular filtration rate and proteinuria reporting in the UK

Introduction

Estimation of glomerular filtration rate (GFR) is integral to the assessment of renal function. Formal measurement of GFR using exogenous tracer techniques is the standard for assessment but, due to their laborious and time-consuming nature, do not lend themselves to use outside of research situations or where accurate results are crucial to drug dosing.

For most patients, the measurement of serum creatinine has become the established means of estimating GFR. Other markers of renal function, such as cystatin C, have been proposed to replace creatinine as they do not seem to have many of the latter's limitations. ¹ However, for various reasons, which are likely to include cost and speed of the analysis, they have not as yet supplanted creatinine in routine use.

Accurate assessment of GFR is crucial to the identification of patients with chronic kidney disease (CKD), where early detection and treatment may help slow decline in renal function. Equations for adjusting serum creatinine concentration values using other analytes and/or patient demographics to generally help better reflect true GFR have been used for several decades, ^2,3 but these have traditionally only been applied to a minority of patients. In the last 10 years, there has been a widening of the groups in which estimation of GFR has been suggested. ⁴ In the UK in 2006, for example, the Department of Health in England asked that all National Health Service (NHS) laboratories routinely report an estimated GFR (eGFR) when a serum creatinine measurement was made. ⁵ The equation chosen was to be based on the one derived from the Modification of Diet in Renal Disease (MDRD) Study participants where only three other variables were included, namely age, gender and ethnicity. ⁶

The rapid introduction of eGFR to the UK, followed by a swift evolution in the recommendations about how it should be applied, meant it was not certain that laboratories were using the same criteria when reporting this or other biochemical assessments of CKD. This national audit therefore sought to determine how eGFR and urine protein is currently reported by UK laboratories in comparison to current guidelines recommended by the National Institute for Health and Clinical Excellence (NICE). ⁷

Methods

A questionnaire was devised by the authors and the National Clinical Biochemistry Audit Group for distribution to all known NHS laboratories within the UK in August 2010 (see online Appendix at http://acb.rsmjournals.com/cgi/content/full/acb.2011.011083/DC1). It was based on a questionnaire already distributed and validated by the North East Audit Group of the Association for Clinical Biochemistry. The audit standards were derived from the 2008 NICE guidance on CKD. ⁷

The questionnaire was distributed electronically using SurveyMonkey (www.surveymonkey.com) to single named individuals within each hospital. Returned questionnaires had their results collated electronically.

Results

One hundred and sixty-four questionnaires were sent and 131 returned, giving a response rate of 80%, although for many questions there were a maximum of 109 respondents, corresponding to 66% of those originally polled. Eighty-three laboratories used a Jaffe method to measure creatinine and five used the O'Leary method. Thirty-eight laboratories used an enzymatic creatinine method, 12 of whom employed dry slide technology.

The following describes the selected NICE audit standards together with the responses received:

NICE audit standard: ‘Whenever a request for serum creatinine measurement is made, clinical laboratories should report an estimate of GFR (eGFR) using a prediction equation in addition to reporting the serum creatinine result’.

Only 43 laboratories (46%) of the 109 responders to this question replied reporting eGFR in all adult requests. Five of these laboratories also reported eGFR in all samples from paediatric patients. Twenty-three (36%) centres only reported eGFR on requests originating from primary care while eight laboratories would only report eGFR if the calculation was specifically requested.

Patient group exceptions to reporting eGFR were varied. The vast majority of laboratories (92%) did not report eGFR on subjects who were younger than 18 years. Other reasons for not reporting eGFR included women known to be pregnant (27%), emergency inpatients (25%), any inpatients (21%) and hospital outpatients (5%), with a variety of other exclusions such as renal failure, patients on an intensive care unit and oncology patients being used in other instances.

NICE audit standard: ‘Interpret reported values of eGFR 60 mL/min/1.73 m² or more with caution, bearing in mind that estimates of GFR become less accurate as the true GFR increases.’

The upper limit above which an eGFR value would not be reported was asked. Sixty-six of the 106 responding to the question (62%) reported this as being ≥90 mL/min/1.73 m², with 32 (30%) as ≥60 mL/min/1.73 m². Other responses included ‘60–200’, with one being ‘ > 150’ and four centres reporting eGFR values with no upper limit.

NICE audit standard: ‘Where indicated, apply a correction factor for ethnicity to reported GFR values (multiply eGFR by 1.21 for African-Caribbean ethnicity).’

One hundred and four of 109 respondents (95%) did not attempt to make computed adjustments to take account of ethnicity. However, 65 (60%) did place the ‘correction factor’ on the report while 64 (59%) communicated the fact via a CKD guideline. Thirty-two laboratories (29%) used both means, while 31 (28%) used neither.

NICE audit standard: ‘Use the IDMS (isotope dilution mass spectrometry)-traceable simplified MDRD (Modification of Diet in Renal Disease) equation to estimate GFR, using creatinine assays with calibration traceable to a standardised reference material.’

Ninety-three of 109 respondents (85%) to this question used the recommended ‘175’ IDMS 4-variable MDRD equation while nine laboratories (8%) stated they used the original ‘186’ 4-variable MDRD equation.

NICE audit standard: ‘Advise people not to eat any meat in the 12 hours before having a blood test for GFR estimation.’

Only 10 of 109 respondents (9%) to this question published any such advice.

NICE audit standard: ‘To detect and identify proteinuria, use urine ACR (albumin:creatinine ratio) in preference, as it has greater sensitivity than PCR (protein:creatinine ratio) for low levels of proteinuria. For quantification and monitoring of proteinuria, PCR can be used as an alternative. ACR is the recommended method for people with diabetes.’

Fifty-four of 109 respondents (50%) used ACR in non-diabetic subjects, 40 (37%) used PCR and 13/15 of the remainder used both. For diabetes, 96/109 (88%) used ACR, four laboratories (4%) used PCR and 7/9 of the remainder used both.

Taken together, only 16 of the surveyed laboratories reported eGFR values in all adult patients (some of these excluding pregnancy when known), with an IDMS-traceable equation, with upper value thresholds of either ≥60 or ≥90 mL/min/1.73 m², who inform in some way of the need to adjust for ethnicity and who measure at least ACR in diabetic and non-diabetic subjects. If providing advice regarding the effect of meat on creatinine measurement was seen as a prerequisite for full NICE adherence then only one laboratory fulfilled all these criteria.

Discussion

This national audit has shown that there has been rapid and widespread adoption of eGFR reporting in the UK following the recommendation by the Department of Health (DoH) that it be implemented in April 2006. However, although there is good consistency in the way eGFR values are calculated, there remains variation in how NICE guidance for reporting has been applied.

The patient groups that laboratories thought should or should not have eGFR reported was a major source of discrepancy with its use in hospital patients being particularly dichotomous. The reasons as to why fewer than half of centres reported eGFR in this clinical situation remain speculative, but could have been related to the speed and manner of the implementation of eGFR, in England at least. In April 2006, a letter from the DoH was sent to all English NHS laboratories recommending that they report eGFR starting the same month. ⁸ The ‘key focus’ was on delivering this service to primary care in order to correspond with the introduction of the renal element of the Quality and Outcomes Framework for general practitioners. It seems possible that this document, together with the accompanying fact sheet highlighting the conditions in which eGFR had not been validated (including acute renal failure, pregnancy, muscle wasting disorders, amputees and malnutrition) ⁵ may have led many laboratories to assume it was only a measure aimed at – or appropriate for – patients outside of hospital. The 2008 NICE guidance recommended eGFR be calculated ‘whenever a creatinine measurement is made’, ⁷ but did not explicitly dispel the notion that it was unsuitable for hospital use. It did, however, reaffirm that the guideline did not apply to children or during pregnancy.

Another disparity in the UK is the upper limit above which an eGFR value will not be reported. Just under two-thirds and one-third of laboratories have thresholds of 90 and 60 mL/min/1.73 m², respectively, with the remainder having values higher than these. The 2006 DoH fact sheet provided to laboratories originally suggested an upper limit value for eGFR reporting of 89 mL/min/1.73 m². The 2008 NICE guidance then recommended exercising caution with values of 60 mL/min/1.73 m² or above but did not stipulate this number become a new threshold. This is in contrast to Scotland where the Scottish Intercollegiate Guidelines Network (SIGN) recommendations ⁹ do specify this threshold and this was indeed followed by the six Scottish laboratories who replied to this question. One of the audit responders whose laboratory reports an upper limit for eGFR of >150 mL/min/1.73 m² justified their stance by stating that the coefficient of variation of the estimate at high ‘true’ GFR values seemed no different from that of lower ones. While true, there has also been concern that ‘normal’ eGFR values calculated in healthy subjects exhibit a significant negative bias when compared with GFR which has been formally assessed. ¹⁰

This audit has also shown a diversity of approaches to adjusting eGFR values to take account of ethnicity, ranging from the ‘conversion factor’ being included with every report to there being no formal advice on adjustment. It seems likely this inconsistency is at least partly due to the rarity with which ethnic background is included as part of the dataset forwarded with a creatinine request. The small proportion (9%) of laboratories giving advice around avoiding meat before a creatinine measurement could reflect an assumption that this information would best be provided by the requester rather than the laboratory.

Overall, taking a conservative view of defining overall adherence to NICE guidance, only 16 of the 132 laboratories who responded to the audit achieved it, although 12 who did not comply were from Scotland or Northern Ireland where NICE guidance does not strictly apply. There is also only a minority (28%) who are following a recommendation from the Association for Clinical Biochemistry that a traceable enzymatic method for creatinine measurement be used, accepting that many laboratories may, due to contractual reasons, be unable to change immediately. ¹¹

The recommendations regarding which test to use to detect proteinuria have also changed since 2006. In 2007, the UK Renal Association Clinical Practice Guidelines recommended measuring the PCR for the detection of non-diabetic kidney disease, with ACR being reserved for patients with diabetes. ¹² The following year, the NICE guidance stated that ACR was the preferred test for both, a fact reiterated by the DoH in 2009. ¹³ This change in non-diabetic subjects may go some way towards explaining why over a third of respondents currently continue to report PCR in these patients, as might the fact that there is an economic disincentive to change to ACR since it tends to be more expensive than PCR. Also, SIGN guidelines recommend using PCR in non-diabetic subjects and four of the six Scottish responders to this question were using this in preference to ACR.

Taken together, there is an impression that the rapidly developing guidance for biochemical CKD assessment between 2006 and 2009 has left laboratories at various stages of implementation with many, perhaps unwittingly, far from adherent to the latest recommendations. Whatever the cause, this audit has highlighted that these centres may need to reconsider their own service against current NICE criteria. There may also be a role for the clinical biochemistry profession to clarify the recommended upper limit for eGFR reporting as well as explicitly reiterating the patient groups where it should not be calculated.

Nonetheless, the mere fact that eGFR reporting has become pervasive at all in the UK is in marked contrast to some other countries, such as the USA where the eGFR equation originated. There, only 80% of laboratories responding to a College of American Pathologists survey in June 2010 reported eGFR, ¹⁴ despite evidence that primary care physicians would refer patients sooner for specialist opinion when the serum creatinine was expressed as eGFR. ¹⁵

In summary, this national audit has found that the various national initiatives from 2006 onwards have resulted in the swift adoption of eGFR in the UK. However, variation exists in how it is reported, with few laboratories currently matching existing NICE guidance recommendations. A reassessment of biochemical CKD assessment by most laboratories therefore seems warranted.

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Not applicable.

Guarantor: ESK.

Contributorship: ESK suggested the regional audit be expanded nationally. HV and ESK adapted the questionnaire (see acknowledgements) and ESK wrote the paper with HV.

Acknowledgements: The questionnaire was kindly placed into SurveyMonkey format and distributed by Mike Lester of the Association for Clinical Biochemistry.