Should eGFR Thresholds Be Adjusted for Age?

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.