The data supports the approach of the guidelines and demonstrates a reassuringly wide range of sample times for an acceptably accurate single-sample GFR result.
Choosing the optimal sampling time requires a balance between mean absolute difference and standard deviation. For example, it would be unwise to choose 2h as the best sampling time for low GFR, even though the mean difference results are closest to zero, due to the large standard deviation; even if the mean difference is close to zero a high proportion of results will have much larger differences. We looked firstly at the standard deviation when choosing the best sample time for each GFR range, then checked that the mean difference gave suitable accuracy.
The results of this study suggest slightly different recommended single-sample times compared with the 2018 guidelines. For the GFR range where 6h sampling was recommended (30-50 mL/min/1.73m2), 4h sampling performs significantly better in terms of mean absolute difference, so even though the standard deviation is lower we have recommended 4h sampling for this GFR range. For the 30-40 mL/min/1.73m2 GFR range the results from the reference GFR comparison indicate that 6h has a slightly lower mean absolute difference also, however only six GFR measurements were present in the data in this range. We recommend that the 6h sample time is replaced with 4h sampling in a revised version of the guidelines in the interests of accuracy and simplified departmental logistics.
The recommended single-sample times on the basis of this study for estimated GFR range are given in Table 5. We have also removed the 3h sample as it conferred a benefit only for one decade of GFR range (see Table 3b), and only by a very small margin. We hope that this simplified sampling regime will increase the routine use of single-sample GFR in UK hospitals. Table 5 does not include the results from previous work which recommends a 24h sample time for GFR less than 25 mL/min/1.73m2.
Table 5
Proposed recommended single-sample times to use with the Fleming formula based on estimated BSA normalised GFR .
Estimated BSA normalised GFR (mL/min/1.73m2) | Recommended single-sample time |
80+ | 2h |
30-80 | 4h |
One immediately obvious feature from Figures 1 and 2 is how far away the single-sample, and by inference the slope-intercept GFR result, is from the reference GFR: the average differences are much larger and the error bars wider (note: different y-axis scales). We believe this to be due to the overestimation of GFR by the abbreviated techniques; the clearance of tracer from the plasma has not yet reached a terminal exponential at the start of sampling, so the gradient of a slope-intercept measurement flattens as 8h is reached. This is compensated for at high GFR by the inherent underestimation due to the Brochner-Mortensen correction reaching a maximum value. It is not the purpose of this work to propose an improved single-sample formula to correct for this, and such a systematic difference in GFR results would have a far-reaching clinical impact which it is not practical to implement. Our primary focus is to provide an equivalent accuracy single-sample GFR to the slope-intercept method in current clinical use.
To estimate GFR, we recommend using a recent eGFR result calculated from a serum creatinine blood test, if one exists. A 2019 study found that an eGFR threshold of 40 mL/min/1.73m2 was appropriate for selecting patients where the GFR was subsequently measured as less than 25 mL/min/1.73m2. Although that study reported a large variation in the accuracy of using eGFR to predict measured GFR, we hope that the results from our study reassure the Nuclear Medicine community that there is a wide range of suitable sample times for an acceptably accurate single-sample GFR result. Pertinent to this discussion is the inherent variability in GFR measurement: estimates of the repeatability of GFR measurement on the same patient over time suggest a variation of approximately 10% and a study by Wilkinson et al. found a coefficient of variation of 12% in duplicate measurements of the same patient when permitted free exercise, and 8% when at rest. The differences we have measured between GFR calculated with slope-intercept and single sample techniques are within these patient dependent variations.
If no previous eGFR measurement is available, the clinical indication for the GFR test can guide the choice. A 2013 UK audit3 of GFR measurement reported the following referral reasons: oncology patients for assessment pre-chemotherapy (70%); potential live renal donor (16%); monitoring of chronic kidney disease (10%); others (4%). Hopefully it is clear from the referral reason whether reduced renal function is suspected. If the referral is for monitoring of chronic kidney disease then there is reason to expect reduced renal function, whereas if the clinical indication is first assessment pre-chemotherapy or live renal donor then the choice of single-sample time can be guided by the normal range of GFR for the patient age.
It is worth noting here that for a live renal donor where expected GFR is high and the donor is relatively young, a blanket policy of, for example, 4 hour single-sample time could give a significant error in GFR which could affect clinical management in this group, see Table 6 for more details. This would have most clinical impact where the measured GFR was close to the donation threshold, however given the inherent variability of GFR measurement as previously mentioned, decision making of donor eligibility in this GFR range is already tricky. The British Transplant Society Guidelines for Living Donor Kidney Transplantation recommend that the decision of suitability for donation in these cases should be individualised and based on a discussion of the estimated lifetime risk of developing end stage renal disease (ESRD) without donation. An online calculator for ESRD risk is referenced which takes into account additional clinical and demographic factors.
Table 6
Mean difference and standard deviation of differences for single-sample GFR depending on GFR range and single-sample time.
Single-sample time (mL/min/1.73m2) | n | GFR range (mL/min/1.73m2) | Mean difference in GFR (mL/min/1.73m2) | Standard deviation of differences (mL/min/1.73m2) |
2h | 1380 | 80+ | -2.08 | 3.50 |
1333 | 30-80 | 0.19 | 5.81 |
4h | 2168 | 80+ | -2.40 | 5.70 |
2057 | 30-80 | 1.95 | 2.56 |