Nephrology Dialysis Transplantation 2005 20(3):482-485; doi:10.1093/ndt/gfh710
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Editorial Comment
Ren sanus in corpore sano: the myth of the inexorable decline of renal function with senescence
Danilo Fliser
Hannover Medical School, Hannover, Germany
Correspondence and offprint requests to: Danilo Fliser, MD, Associate Professor of Medicine, Department of Internal Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30265 Hannover, Germany. E-mail: fliser.danilo{at}mh-hannover.de
Keywords: atherosclerosis; elderly; glomerulosclerosis; hypertension; renal function; renovascular resistance
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Changing structure of the aging kidney
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The first notion of an inexorable loss of renal mass with age
goes back to uncontrolled observations suggesting that the average
kidney weight decreases by up to 40% from young adulthood to
senescence [
1]. It must be emphasized, however, that in none
of these early studies were individuals with comorbid conditions
excluded. These findings therefore conflict with observations
where no significant decrease in renal mass was found in elderly
patients who had suffered traumatic death and in whom renal
disease and/or important comorbid conditions were excluded [
2].
Moreover, imaging studies investigating changes of renal size
and structure showed only a modest decrease until the age of
75 years, whereas thereafter kidney size, calculated volume
and parenchymal thickness were clearly lower [
3]. Thus, loss
of renal mass with aging is moderate, at least until the age
of 70 years, and it seems to affect the renal cortex preferentially.
An important factor that correlates with age-associated changes of renal haemodynamics is thought to be glomerulosclerosis—as much as 30% of glomeruli were found to be hyalinized or sclerosed in apparently healthy elderly individuals [4]. The results of studies on glomerular number in the human kidney have shown a high degree of variability, however, and hence only minor glomerular obsolescence was found in the elderly who had suffered traumatic death [5, 6]. Kasiske [6] also demonstrated that the severity of systemic atherosclerosis has a major impact on the degree of age-related glomerulosclerosis. Based on these findings, it has been concluded that the presence of glomerulosclerosis is indicative of subclinical renal injury from comorbid conditions affecting renal structure.
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Increase of renovascular resistance as a hallmark of renal vascular aging
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Although several past studies documented a decrease in glomerular
filtration rate (GFR) in men as well as in women, most of these
studies did not differentiate clearly between the effect of
comorbid conditions and the effect of aging
per se on renal
function [
7]. For example, in the seminal study by Davis and
Shock [
8] virtually all of the examined individuals >70 years
of age had generalized atherosclerosis and/or disabling diseases,
such as cancer. More recent cross-sectional and prospective
studies documented only a modest decrease or even no change
of GFR in the healthy elderly [
9,
10]. In these and other studies,
many important factors accelerating the age-related decline
of renal function were identified, e.g. hypertension, atherosclerosis
(particularly of the lower limbs), smoking and even dietary
protein intake (
Table 1) [
9,
10–15]. Effective renal plasma
flow (ERPF) decreases proportionally more than GFR, i.e. by
10% per decade from young adulthood to the age of 80 years [
7,
10].
The decrease of ERPF does not concern all renal regions to a
similar extent, however. Hollenberg
et al. [
16] found a significant
decrease in the rapid (cortical) component of blood flow while
medullary flow was preserved. This finding may, in part, explain
the observed increase in the filtration fraction, i.e. the ratio
between GFR and ERPF in elderly individuals [
7,
10,
16], since
the relative contribution of the juxtamedullary glomeruli with
higher filtration fraction increases with age. The decrease
in ERPF out of proportion to the change in mean arterial blood
pressure with age implies that post-glomerular renovascular
resistance (RVR) must be high (
Table 2) [
10]. Indeed, RVR was
found to be significantly increased in normotensive elderly
individuals without cardiovascular disease and this increase
in RVR is even more pronounced in the elderly with cardiovascular
comorbidity, such as hypertension and/or heart failure [
10,
17].
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Table 2. Blood pressure, renal haemodynamics and plasma renin activity in young (n = 24) and elderly normotensive (n = 29) subjects, elderly hypertensive patients (n = 25) and elderly patients with compensated mild to moderate heart failure (n = 14)
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It has been proposed that the marked decrease in ERPF and increase
in RVR with age results from structural changes of the renal
vasculature, i.e. narrowing or even obsolescence of post-glomerular
vessels [
18]. In addition, renal vasodilation after administration
of
L-arginine, acetylcholine and dopamine is impaired markedly
in the elderly [
19–21]. Thus, besides structural alterations,
changes of vascular function play a pivotal role in the age-related
increase of RVR. Vasodilation after administration of acetylcholine
or
L-arginine is known to be nitric oxide (NO)-dependent, and
impaired endothelium-dependent renal vascular relaxation due
to reduced NO generation was found in the elderly, particularly
in the hypertensive elderly [
20]. We have shown recently that
accumulation of the endogenous NO synthase inhibitor, asymmetric
dimethylarginine, with senescence may play a role in the age-related
decrease of renal perfusion [
22]. Taken together, the available
data permit the conclusion that in the healthy elderly GFR is
preserved to some extent, but at the expense of increasing filtration
fraction in a vasoconstricted kidney. This condition is accompanied
by partial non-responsiveness to vasodilatatory agonists, particularly
of the post-glomerular microcirculation.
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Renal aging and sodium handling
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During dietary sodium restriction, the elderly ultimately attain
the same minimum urinary sodium excretion, but the rate of decrease
of urinary sodium concentration is sluggish and, as a consequence,
the net sodium loss is greater than in the young [
23]. Both
less efficient sodium reabsorption in the proximal tubule and/or
reduced activity of the renin–angiotensin–aldosterone
system may contribute to impaired sodium conservation by the
senescent kidney (
Table 2) [
10,
24]. In the normotensive elderly,
inappropriately low basal and stimulated plasma renin activity
are found, i.e. after salt restriction, diuretic treatment or
upright posture [
24]. Although salt deprivation reveals a salt-losing
tendency in the elderly, renal capacity to excrete a salt load
is impaired as well. Among other factors, reduced GFR and decreased
generation of and/or responsiveness to natriuretic substances,
like atrial natriuretic peptide, seem to play a certain role
[
25]. Thus, the elderly individual is characterized by a relative
inability to preserve sodium on the one hand and to excrete
an overload of salt on the other. As a result, the range of
homeostatic adaptation is decreased. This is of considerable
practical importance, since elderly individuals are often threatened
by salt and fluid depletion secondary to diarrhoea, treatment
with diuretics, etc. On the other hand, the propensity to salt
(and fluid) retention may predispose to blood pressure elevation
and possibly explain the good response of blood pressure of
the elderly to salt restriction and/or diuretic treatment.
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The problem of monitoring renal function in the elderly
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In the elderly, serum creatinine is notoriously unreliable as
a precise indicator of GFR due to the fact that the daily production
of creatinine is diminished as a result of reduced muscle mass.
Consequently, the serum creatinine concentration will underestimate
the decline in GFR with age (
Table 2) [
10,
26]. In other words,
the normal range of serum creatinine used for the general population
is inappropriately high for senescent people. As a consequence,
serum creatinine in the upper normal range may already indicate
renal disease and impaired renal function in the elderly. A
better index of GFR in the elderly may be the serum cystatin
C concentration [
27,
28].
Estimation of the creatinine clearance according to different equations (e.g. Cockcroft–Gault formula) was shown to be unreliable in most studies, especially when very old individuals or individuals with comorbidity were examined [10,29]. This limited accuracy may be relevant when doses of drugs with renal elimination must be calculated. Although in healthy elderly subjects pharmacokinetics of drugs which are excreted via the kidneys is only slightly changed [30], in the sick elderly patient age-related changes in renal function may grossly alter pharmacokinetics of these drugs and their active metabolites. Dose reduction may, therefore, be necessary in order to prevent side effects. Because of the limitations of serum creatinine concentration as a marker of renal function, particularly in the undernourished elderly with reduced muscle mass and spuriously low serum creatinine concentration, a timed endogenous creatinine clearance should be assessed for calculations of drug dosage. However, one must keep in mind that many disabled elderly people are not able to collect a reliable timed urine sample. Regular measurements of plasma drug levels are therefore advised whenever indicated and possible.
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Conclusions
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More detailed knowledge on renal function at advanced age may
be of importance on several accounts. Age-related changes may
aggravate deterioration of renal function in elderly individuals
who happen to have renal diseases. In addition, impaired homeostasis
with respect to salt (and fluid) balance has important consequences
for the management of the elderly person who is exposed to the
twin risks of dehydration and fluid overload. Finally, the kidney
is the main route of excretion for many drugs and their active
metabolites. Reduction of renal function with age underlies,
at least in part, the known predisposition of the elderly to
side effects of their medication, such as non-steroidal anti-inflammatory
drugs [
31].
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Acknowledgments
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Conflict of interest statement. None declared.
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