Estimated Glomerular Filtration Rate (Blood)

Diagnostic Use

Estimated glomerular filtration rate (eGFR) is calculated using the CKD-EPI Creatinine 2009 equation, from plasma creatinine (in umol/L), age (in years, >=18years) and gender.

Overall accuracy of the equation: about 87% of the eGFR are within 30% of the measured GFR (ref 1). This equation is endorsed by the Australasian Creatinine Consensus Working Group.

eGFR and Definition of Kidney Disease

Chronic Kidney Disease (CKD) is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health (ref 2). CKD involves either of the following 2 criteria:

I . Evidence of kidney damage (with or without decrease in GFR) for >= 3 months, irrespective of underlying cause of the kidney disease:

• Persisting albuminuria (>3 mg/mmol creatinine ratio. First void urine preferable)
• Haematuria after exclusion of urological causes
• Structural abnormalities e.g. from renal imaging
• Pathological abnormalities e.g. from renal biopsy
• Urine sediment abnormalities
• Electrolyte or other abnormalities indicative of tubular disorders
• History of kidney transplantation

The first 4 criteria are described in Kidney Health NZ, BPAC and Kidney Health Australia guidelines (refs. 4-6). The KDIGO 2012 guideline (ref. 2) also included the latter 3 criteria as markers of kidney damage.

II. Decreased GFR (with or without evidence of kidney damage) for >= 3months

Estimated or measured GFR <60 ml/min/1.73 m2 (i.e. GFR categories Grade 3a – Grade 5) A  lthough GFR of 60-89 ml/min/1.73 m2 (G2) is described as “mildly decreased” kidney function, in the absence of evidence of kidney damage a GFR of >=60 ml/min/1.73 m2 (i.e. both G1 and G2) does not fulfill criteria for CKD. On the other hand, in some patients although their eGFR are still within the G1 or G2 category (i.e. >=60 ml/min/1.73 m2), a significant decline (fall of >=20%, ref. 5) from a baseline higher value may reflect a pathologic process even with no other evidence of kidney damage. It will then require a high index of suspicion by the clinician to embark on additional testing or close follow up to detect early onset of CKD (ref. 2).

What is a significant change in serum creatinine and eGFR?

Minor fluctuations in eGFR are common and are not necessarily indicative of progression. Temporary elevation in creatinine (and fall in eGFR) may occur due to factors such as dehydration or recent intake of cooked meat.

There are unavoidable biological and analytical variations in creatinine and calculated eGFR. The intra-individual biological variation of creatinine is around 4.5% (ref. 7). Coupled with the week-to-week analytical variation of LabPlus creatinine assays of around 3.2%, this means 2 consecutive creatinine results from our laboratory will have to differ by more than +/-15% before one can say with 95% confidence that the change cannot be just explained by biological and analytical variation alone (this minimum statistical difference is the ‘Reference Change Value’, or RCV).

With creatinine as one of the variables in the CKD-EPI equation the necessary change (RCV) between two consecutive eGFR results is e.g. around 23%. for a female with creatinine of 100 umol/L and initial eGFR of 51 ml/min/1.73 m2 the required difference would be +/-12 ml/min/1.73 m2, or eGFR outside the range 39-63 ml/min.1.73 m2 (refs. 8,9).

“Drop in eGFR” or “Progression” is indicated by:

• A fall in eGFR of >=25% with a drop in eGFR category (by convention)
• A sustained decline in GFR by >5 ml/min/1.73 m2 per year (preferably monitored by the same method in the same laboratory). The confidence in assessing progression increases with increasing number of plasma creatinine measurements and duration of follow up (ref. 2).

Note that some drugs such as ACE inhibitor and angiotensin receptor blockers cause a predictable fall in eGFR of up to 25%, due to changes in renal blood flow. Such a fall is not regarded as pathological if the patient then reaches and stabilized at a new baseline.

Age and eGFR

Age (>60 years) is a risk factor for CKD , but is among numerous other risk factors such as (refs. 3-6):

• Maori/Pacific/Indo-Asian ethnicity
• Obesity
• Smoking
• Diabetes
• Hypertension
• Cardiovascular disease history
• Systemic diseases that may affect the kidney
• Family history of renal disease/CKD

Age is one of the variables used to calculate eGFR, noting that eGFR does fall slowly in the general population. However, age-related decision points for eGFR are not recommended in adults (ref 10). The reason is that eGFR slowly falls with ‘healthy’ aging, with many elderly falling into the CKD stage 3a (45-59 ml/min/1.73 m2 ) without evidence of active or structural kidney diseases, as defined by the criteria above . An eGFR in this range therefore does not necessarily of itself indicate pathology in the absence of one or more of the above factors (ref. 3).

Conversely, in population studies CKD stage 3a (compared with those with eGFR >=60 ml/min/1.73 m2 ) is associated with a higher cardiovascular (CVD) risk at all ages (ref10). Thus, while eGFR does fall slowly in healthy older individuals it is arguable whether it should be considered purely “physiological” (refs. 2,10).

Regardless, an eGFR <45 ml/min/1.73 m2 (CKD3b) is pathological regardless of whether other factors are present, and is associated with increased risk of renal and cardiovascular complications irrespective of age, particularly if persisting albuminuria is also noted (Refs. 2,11).

Interpretation

Testing for CKD

Targeted testing for CKD should generally be linked to routine cardiovascular disease assessment or diabetes checks. It is recommended to match the eGFR with the degree of albuminuria and assess them against a 2 dimensional grid table (as per figure below, adapted from ref 2) to evaluate risk of future deterioration of kidney function as well as cardiovascular and all cause mortality (Refs. 2-6, 9).

In a stable patient without acute symptoms, an initial eGFR of 45-59 ml/min/1.73 m2 should prompt review of the above other possible risk factors, and should be followed up with a repeat in 3 months, to check that it is stable.  Caution should also be made in prescribing certain potentially nephrotoxic or predominantly renal cleared medications. Earlier follow up may be justified depending on clinical circumstances, e.g. if the patient has been unwell or there are other reasons to suspect acute renal injury.

For guidance on specific measures for monitoring and managing/referring patients in primary care at each colour coded risk level, please refer to Auckland Regional Health Pathways (Medical-Nephrology – Chronic Kidney Disease (CKD) in adults) at  site (click here)

(last accessed 11 6 20), and ref 3.

(adapted from reference 3)

eGFR is UNRELIABLE in the following situations

1. When meat or fish is ingested during the 12 hour period preceding collection of the blood sample used for the creatinine measurement.
2. Acute changes in renal function. eGFR is valid only in subjects in a steady state with respect to plasma creatinine.
3. Dialysis-dependent patients.
4. Patients with unusually high or low muscle mass. In these situations, the glomerular function needs to be assessed by a different method (e.g. 24 hour creatinine clearance)
5. Creatine supplements.
6. Children less than 18 years of age.
7. Pregnancy.
8. Severe liver disease.

An eGFR calculator is available  through the Kidney Health Australia website – see Resources section for link. ( https://kidney.org.au/health-professionals/detect/calculator-and-tools , last accessed 3/7/20)

References

1. Inker LA et al. Estimated glomerular filtration rate from serum creatinine and cystatin C. NEJM 2012; 367:20-29
2. KDIGO CKD work group   KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease  KI supplement  2013; 3(1):1-150
3. Managing Chronic Kidney Disease in primary care. National Consensus statement 2015. Ministry of Health, New Zealand. https://www.health.govt.nz/publication/managing-chronic-kidney-disease-primary-care (last accessed 5/6/2020)
4. Chronic Kidney Disease (CKD) Management in General Practice ? summary guide. 2018, Kidney Health New Zealand. https://www.kidney.health.nz/resources/file/kidneyhealth_complete_pgs-2.pdf (last accessed 5/6/2020)
5. The detection and management of patients with chronic kidney disease in primary care. BPJ (Best Practice Journal ? from BPAC NZ) 66 Feb: 36-45 at: https://bpac.org.nz/BPJ/2015/February/docs/BPJ66-ckd.pdf (last accessed 5/6/2020)
6. Chronic Kidney Disease (CKD) Management in Primary Care (4 ^th edition, 2020) ? Kidney Health Australia, at  https://kidney.org.au/cms_uploads/docs/chronic-kidney-disease-management-in-primary-care-4th-edition-handbook.pdf (last accessed 5/6/2020)
7. European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Biological Variation Database at https://biologicalvariation.eu/ (last accessed 2/7/20)
8. Farrance I et al. Uncertainty in measurement: a review of the procedures for determining uncertainty in measurement and its use in deriving the biological variation of the estimated glomerular filtration rate.  Practical Laboratory Medicine 2018; Nov; 12: e00097
9. Farrance I et al.  ISO/TS20914:2019 ? a critical commentary. Clin Chem Lab Med 2020; 58(8): 1182-1190
10. Johnson DW et al. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations. MJA 2012; 197(4): 224-228
11. Matsushita K et al.  Association of eGFR and albuminuria with all cause and cardiovascular mortality in general population cohorts. Lancet 2010; 375(9731):2073-2081