Should eGFR Thresholds Be Adjusted for Age?

Ajay K. Singh, MBBS, FRCP, MBA
Brigham and Women’s Hospital
Harvard Medical School

In a point-counterpoint-editorial contribution in the January 1 issue of Kidney International, Richard Glassock and colleagues1 debate with Andrew Levey and colleagues2 about whether decline in kidney function in the elderly is a normal phenomenon or a manifestation of disease; Brad Rovin3 provides an accompanying editor’s overview.

The debate centers on whether estimated (or measured) glomerular filtration rate (GFR) should be adjusted for age. Is kidney senescence a real thing? Glassock and colleagues argue that it is and that there should be age-adjusted GFR thresholds in place, whereas Levey and colleagues argue that this is not necessary and that it makes diagnosis and classification of CKD more complicated; rather, Levey et al argue that the focus should shift to defining and managing kidney risk.  In his editorial, Brad Rovin leans toward incorporating age thresholds.

No one disputes that there is an age-related decline in GFR. This has been known for decades. A study by Lindeman et al.4 reported longitudinal creatinine clearance measurements in a subset of healthy subjects that had enrolled between 1958 and 1981 in the Baltimore Longitudinal Study of Aging. The mean decrease in creatinine clearance over time was 0.75 mL/min/year. Drawing from more recent studies of healthy kidney donors, Hommos et al also report a similar age-related decline in GFR of ~6 to 7 mL/min/1.73 m2 for every decade beginning after about age 35 to 40 years5.  A 20-year-old with an average GFR of ~107 mL/min/1.73 m2 undergoes a decline GFR over time, and by age 65 years, the GFR is down to an average of about 83 mL/min/1.73m2. By about 75 years of age, the GFR is down to ~76 mL/min/1.73m2. Denic and colleagues6 have reported previously that the decline in GFR of aging has a different histology to that of CKD—aging results in glomerulosclerosis in the superficial cortical region, whereas glomerulosclerosis associated with diabetes and proteinuria is located in the deep and middle regions of the cortex. In addition, in an elegant study, Denic et al. calculate single nephron GFR in healthy adults and suggest that glomerular hyperfiltration is not a feature of the aging kidney7.

Yet, Levey and colleagues make valid points in that classifying an individual to a particular CKD group is not the the end of a patient’s work-up, and other clinical and laboratory tools are frequently used to prevent misclassification of kidney disease. While this is obviously true, the reality is that for elderly patients who were told that they have a GFR <90 mL/min/1.73m2 and have a diagnosis of CKD, there is a risk of eliciting alarm and anxiety. For these patients, knowing that reduced GFR is not a disease but likely reflects aging could be reassuring. Likewise, for primary care physicians, it might be reassuring to them that a referral to a nephrologist is not necessary because their patient does not have a disease. Overall, avoiding labeling a reduced GFR as CKD might reduce healthcare costs through less frequent testing and fewer doctor visits. Glassock and colleagues point out epidemiological studies suggest that the reduced GFR of aging does not appear to have deleterious adverse consequences. Besides, they argue, the public policy implications of overestimating the burden of kidney disease are not trivial. With an aging population, teasing out a portion of the population that might have reduced GFR but does not have a disease could allow better allocation of healthcare resources. These elderly people do just fine, at least with respect to kidney issues.

The other point that Levey and colleagues make is that age thresholds don’t really inform treatment decisions. They argue that what patients really want to know about is prognosis, and that this can be provided by kidney risk equations that they and others have developed. They recommend that the focus should shift to determining the cause of kidney disease rather than continuing to dwell on classification. To be sure, patients probably want to know what the cause of their reduced GFR is and they would probably benefit in understanding the prognosis related to their CKD in order to make informed decisions about treatment. However, properly classifying someone (CKD or no CKD) and then, among those with CKD, predicting risk seems the best of both worlds.

Brad Rovin in his accompanying editorial suggests that we use age adjustment for classifying patients with reduced GFR. I ended up agreeing with him. While the case that Levey and colleagues make for staying the course is forcefully argued and well reasoned, is not sufficiently convincing. Overall, the take homes for me were as follows: (1) both measured and estimated GFR decline with age beginning in the thirties and this decline is senescence and physiological; (2) the histology of this kidney function decline is different from that of the typical pathology one might see with common causes of CKD, and reinforces the point that, at least in the elderly, it is not a disease process per se; and (3) clarifying the distinction between kidney senescence and kidney disease could be important in caring for patients.

References

1. Glassock RJ, Delanaye P, Rule AD. Should the definition of CKD be changed to include age-adapted GFR criteria? YES. Kidney Int. 2020;97:34–37; https://doi.org/10.1016/j.kint.2019.08.033

2. Levey AS, Inker LA, Coresh J. Should the definition of CKD be changed to include age-adapted GFR criteria?” Con: the evaluation and management of CKD, not the definition, should be age-adapted Kidney Int. 2020 97;37–40; https://doi.org/ 10.1016/j.kint.2019.08.032

3. Rovin B. Do kidneys grow old gracefully?  Kidney Int. 2020 97, 40–41; https://doi.org/ 10.1016/j.kint.2019.08.031

4. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985 Apr;33(4):278-85. PubMed PMID:3989190.

5. Hommos MS, Glassock RJ, Rule AD. Structural and functional changes in human kidneys with healthy aging. J Am Soc Nephrol. 2017;28:2838–2844.

6. Denic A, Ricaurte L, Lopez CL, et al. Glomerular volume and glomerulosclerosis at different depths within the depths of the human kidney. JASN. August 2019, 30 (8) 1471-1480; doi.org/10.1681/ASN.2019020183

7. Denic A, Mathew J, Lerman LO, et al. Single-nephron glomerular filtration rate in healthy adults. N Engl J Med. 2017;376:2349–2357.