CJASN ePress. Published on December 9, 2021 as doi: 10.2215/CJN.

10580821

The Kidney in Normal Aging

A Comparison with Chronic Kidney Disease

Aleksandar Denic ,1 Richard J. Glassock,2 and Andrew D. Rule 1

CJASN 17: –, 2022. doi: https://doi.org/10.2215/CJN.10580821

The prevalence of diagnosed CKD is high among indi- functional nephrons they were born with (nephron 1
Division of
viduals older than 65 years. Since GFR declines with endowment) by the time they are in their seventies.
Nephrology and
normal aging, this phenomenon is due in part to the This attrition of nephrons is accompanied by an Hypertension, Mayo
use of a single, absolute threshold of an eGFR ,60 ml/ increase in global glomerulosclerosis, but not segmen- Clinic, Rochester,
min per 1.73 m2 persisting for at least 3 months to tal glomerulosclerosis, and the increase in interstitial Minnesota
2
define CKD regardless of age or the concomitant pres- fibrosis/tubular atrophy (IF/TA) is minimal com- Department of
Medicine, Geffen
ence of other signs of kidney injury, including abnor- pared with CKD (3). This nephron loss ultimately School of Medicine,
mal albuminuria. Arguably, the eGFR criteria for CKD leads to a reduction in cortex volume with aging. University of California,
diagnosis should be age adapted, in order to account Whole kidney GFR closely follows this decline in Los Angeles, California
for the normal physiologic age-related decline in eGFR nephron number, maintaining the single nephron
and avoid overdiagnosis of CKD in the elderly (1). GFR unchanged at least before age 70 years (4). Correspondence:
Dr. Aleksandar Denic,
Many elderly subjects with a stable eGFR between 45 Hypertrophy of remaining functional glomeruli is not
Mayo Clinic, 200 1st
and 59 ml/min per 1.73 m2 and no accompanying observed in healthy aging. Correspondingly, albumin- Street SW, Rochester,
abnormal albuminuria are erroneously labeled as hav- uria is also not a feature of healthy aging, unlike CKD. MN 55905. Email:
ing CKD (1). However, “bona-fide” CKD, of varying Studies in patients who undergo nephrectomy for denic.aleksandar@
etiologies, can also coexist with the physiologic changes renal cancer provide evidence for a decline in whole mayo.edu
in the kidney brought about by normal aging. Here, we kidney GFR with aging beyond 70 years even with
attempt to describe the aging-related changes in the minimal amounts of IF/TA (5).
kidneys occurring in otherwise healthy individuals as While IF/TA appears to be less prominent when
compared with those with CKD. due to nephron loss from aging rather than from
In response to stress and/or damage, cells can CKD, the pattern of IF/TA with aging is also informa-
either undergo apoptosis or enter a state of senes- tive. Analysis of large wedges of unaffected kidney
cence, evidenced by changes in morphology and tran- tissue from patients undergoing radical nephrectomy
scriptional profile, a secretory phenotype, and resis- for tumors reveals that older patients have a more
tance to apoptosis. Since the ability to regenerate new scattered pattern of IF/TA at the same %IF/TA as
cells and tissues tends to decrease with aging, restor- younger patients (6). This suggests: (1) IF/TA foci
ing a balance between cellular dysfunction and repair atrophy into smaller IF/TA foci with contraction of
progressively diminishes during normal aging. Super- the cortex, which increases their density; and (2) this
imposition of various harmful factors such as oxida- atrophy helps explain the minimal extent of %IF/TA
tive stress (oxygen radicals and profibrogenic media- in older individuals despite significant loss of neph-
tors) and mitochondrial injury upon the intrinsic age- rons. These findings are also consistent with age-
related changes, as occurs in disease, can further pro- related global glomerulosclerosis where atrophy and
mote cellular and organ deterioration (2). Other disappearance of sclerosed glomeruli leads to under-
disease-specific injurious processes, such as inflamma- detection of nephron loss (3). Increased IF/TA density
tion and ischemia, can further augment these changes. independent of %IF/TA is also prognostic for pro-
Thus, physiologic aging and disease-related injury gressive CKD (6). Taken together, at the same %IFTA,
commonly coexist, and their inter-relationships are a more long-standing process with more nephron loss
complex and not easily studied. Therefore, a detailed has a worse prognosis than a more “acute” process
exposition of the kidney alterations in physiologic with larger foci of IF/TA (6).
aging in apparently healthy persons is invaluable in During the past decade, there has been an increased
dissecting the contributions of aging per se to observed interest in podocyte dysfunction in kidney aging.
alterations attending CKD. Podocytes are fully differentiated, long-lived, post-
Several studies have investigated various aspects of mitotic cells, with a minimal regeneration capacity.
micro- and macrostructural changes and functional Hodgin and colleagues found decreasing podocyte
alterations of the human kidney in normal, physio- density with older age, from .300 per 106 mm3 in
logic aging, even among the healthiest populations. young kidneys to ,100 per 106 mm3 in old kidneys (7).
Healthy living kidney donors lose up to a half of the Moreover, older age podocytes are stressed with a

www.cjasn.org Vol 17 January, 2022 Copyright © 2022 by the American Society of Nephrology 1
2 CJASN

Disease states that lead to

Aging
glomerular hyperfiltration
?

Arteriosclerosis

Ischemia

• Suppression of SIRT1/PGC-1D signaling Cellular senescence and Podocyte loss due to:
• Decreased expression of PPARD upregulation of expression in • Increased stress
• Decreased expression of Klotho tubular and endothelial cells • Higher detachment rate

Oxidative stress
p16 p19 p21 Dasatinib
Dasatinib
Quercet in
Quercetin
1. Basement membrane injury:
• Reduced laminins
• Reduced collagen IV and VIII More extensive global
Sclerosis and progressive
2. Increase in extracellular matrix: sclerosis and interstitial
atrophy of nephrons
• Collagens I, III, VI, and XV fibrosis/tubular atrophy
• Fibrinogen
• Nephronectin
Normal age-related decline Accelerated decline in
in nephron number and eGFR nephron number and eGFR
with no albuminuria with albuminuria

Figure 1. | Conceptual diagram of nephron loss from aging as well as the impact of states of glomerular hyperfiltration leading to accel-
erated nephron loss and albuminuria.

higher detachment rate. Importantly, the kidneys studied Molecular evidence suggests that kidney aging and some
were not restricted to healthy individuals and the impact of causes of CKD share common biologic processes. Proteo-
comorbidities with aging may have influenced this finding. mic profiling of extracellular matrix composition in mouse
If glomerular hyperfiltration is superimposed upon normal and human kidneys has revealed a proteomic signature
aging effects, then podocyte detachment rates may acceler- common for both kidney aging and disease (11). The main
ate, leading to more significant reductions in GFR and findings were a reduction in components of basement
increases in albuminuria. membrane (such as laminins, and collagens type IV and
Ischemia and progressive cellular senescence may be VIII) and increased amounts of extracellular matrix pro-
another important aspect of kidney aging. The primary teins (collagens I, III, VI, and XV, and fibrinogens and
events underlying an ischemia-related hypothesis for kid- nephronectin). Collagen VI increased early in both aging
ney aging are that arterio- and arteriolo-sclerosis causes an and disease models, possibly as an attempt to strengthen
ischemia-driven collapse of the glomerular architecture the thinning of basement membranes underlying progres-
and, ultimately, global glomerulosclerosis. As a result of sion of IF/TA.
chronic ischemia, a series of molecular changes ensue, such A conceptual diagram of processes that impact aging or
as upregulation of p16, p19, and p21 expression in tubular that lead to accelerated aging and nephron loss is shown in
cells (8). Mesangial expansion and IF/TA in aging mice can Figure 1. Absence of albuminuria in normal age-related
be linked with inflammation, apoptosis, and oxidative eGFR decline suggests that this functional decline is not
stress (9). The evidence for oxidative stress as a potential tightly and causally linked to podocytopenia; however, in
causative factor was supported by a systematically disease processes that lead to glomerular hyperfiltration,
decreased expression of Sirt1, PGC-1a, ERR-1a, PPARa, the presence of albuminuria suggests a direct link to podo-
and Klotho in the oldest mice (24 months of age). It has cyte dysbiosis. Further work is needed to clarify these
been suggested that novel therapeutic approaches targeting distinct pathways as mechanisms for progressive decline
these signaling molecules could alleviate processes that in nephron number. Many challenges exist, but much
influence the rate of aging in kidneys. Of importance, potential clinical utility may also accrue as we become
ischemia-related cellular senescence markers accumulate in more facile in distinguishing age-related from disease-
human kidneys supplied by stenotic renal arteries (8). related changes in the kidney. Overlap in the cellular biol-
Senolytic agents (dasatinib and quercetin) hold promise in ogy of normal aging and at least some forms of progressive
reducing kidney atrophy, damage, and declining function CKD is evident. Development of senolytic therapeutic
by clearing p21-positive senescent cells (8). Future studies agents hold promise in hopefully slowing down the effects
may determine a role for senolytic agents in treating age- of aging per se and the accelerated forms of aging that can
related changes in the kidney (10). accompany some forms of CKD.
CJASN 17: –, February, 2022 Kidney Aging versus CKD, Denic et al. 3

Disclosures A call for an age-adapted definition. J Am Soc Nephrol 30:

A. Denic reports employment with Mayo Clinic. R.J. Glassock 1785–1805, 2019
reports consultancy agreements with American Journal of Nephrol- 2. Yang H, Fogo AB: Cell senescence in the aging kidney. J Am
Soc Nephrol 21: 1436–1439, 2010
ogy, Anteris Bio, Aurinia, BioCryst, Bioscience, Calliditas, Chemo- 3. Denic A, Lieske JC, Chakkera HA, Poggio ED, Alexander MP,
Centryx, Equillium, Forsee Pharma, Horizon, Ionis, Karger Publi- Singh P, Kremers WK, Lerman LO, Rule AD: The substantial
cations, NIH, Novartis, Omeros, Otsuka Pharma, RenaSight loss of nephrons in healthy human kidneys with aging. J Am
(Natera), River3Renal, Sentien, Therini Bio, Travere (Retrophin), Soc Nephrol 28: 313–320, 2017
4. Denic A, Mathew J, Lerman LO, Lieske JC, Larson JJ, Alexander
UpToDate (Wolters-Kluwer), Vertex, Vivace, and Walden; owner-
MP, Poggio E, Glassock RJ, Rule AD: Single-nephron glomeru-
ship interest in Reata, Inc; receiving honoraria from Aurinia, lar filtration rate in healthy adults. N Engl J Med 376: 2349–
EcoR1, Karger Publications, and Wolters-Kluwer (UpToDate); 2357, 2017
serving as a scientific advisor or member of American Journal of 5. Li P, Gupta S, Mothi SS, Rennke HG, Leaf DE, Waikar SS,
Nephrology, BioCryst, Calliditas, JASN, Novartis, Otsuka, Rena- McMahon GM: Histopathologic correlates of kidney function:
Insights from nephrectomy specimens. Am J Kidney Dis 77:
Sight, Travere, University Kidney Research Organization, and 336–345, 2021
UpToDate; speakers bureau for Aurinia; and other interests/rela- 6. Ricaurte Archila L, Denic A, Mullan AF, Narasimhan R, Bogo-
tionships with ASN-Open Forum Communities. A.D. Rule reports jevic M, Thompson RH, Leibovich BC, Sangaralingham SJ,
employment with Mayo Clinic; serving as an Associate Editor of Smith ML, Alexander MP, Rule AD: A higher foci density of
interstitial fibrosis and tubular atrophy predicts progressive
JASN and a Section Editor of Mayo Clinic Proceedings; serving as a CKD after a radical nephrectomy for tumor. J Am Soc Nephrol
scientific advisor or member of NIDDK – CKD Biomarker Consor- 32: 2623–2633, 2021
tium External Expert Panel; and other interests/relationships with 7. Hodgin JB, Bitzer M, Wickman L, Afshinnia F, Wang SQ,
UpToDate. O’Connor C, Yang Y, Meadowbrooke C, Chowdhury M, Kiku-
chi M, Wiggins JE, Wiggins RC: Glomerular aging and focal
global glomerulosclerosis: A podometric perspective. J Am Soc
Funding Nephrol 26: 3162–3178, 2015
This study was supported by the U.S. Department of Health 8. Kim SR, Puranik AS, Jiang K, Chen X, Zhu XY, Taylor I, Kho-
and Human Services National Institutes of Health National Insti- dadadi-Jamayran A, Lerman A, Hickson LJ, Childs BG, Textor
tute of Diabetes and Digestive and Kidney Diseases grant R01- SC, Tchkonia T, Niewold TB, Kirkland JL, Lerman LO: Pro-
gressive cellular senescence mediates renal dysfunction in
DK90358. ischemic nephropathy. J Am Soc Nephrol 32: 1987–2004,
2021
Acknowledgments 9. Lim JH, Kim EN, Kim MY, Chung S, Shin SJ, Kim HW, Yang
The content of this article reflects the personal experience and CW, Kim YS, Chang YS, Park CW, Choi BS: Age-associated
molecular changes in the kidney in aged mice. Oxid Med Cell
views of the author(s) and should not be considered medical advice
Longev 2012: 171383, 2012
or recommendation. The content does not reflect the views or opin- 10. Franzin R, Stasi A, Ranieri E, Netti GS, Cantaluppi V, Gesualdo
ions of the American Society of Nephrology (ASN) or CJASN. L, Stallone G, Castellano G: Targeting premature renal aging:
Responsibility for the information and views expressed herein lies from molecular mechanisms of cellular senescence to senolytic
trials. Front Pharmacol 12: 630419, 2021
entirely with the author(s).
11. Randles M, Lausecker F, Kong Q, Suleiman H, Reid G, Kolatsi-
Joannou M, Tian P, Falcone S, Davenport B, Potter P, Van Agt-
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