B. Baggio, G. Gambaro, G. Bertaglia
Institute of Internal Medicine and Division of Nephrology,
University of Padua, Italy
The biologic price of aging includes progressive deterioration
of renal function and structure. Davies and Shock demonstrated
an age-dependent fall-off in both renal plasma flow using
Diodrast clearances, and a lesser fall-off in GFR as measured
by inulin clearance with a rise in the filtration fraction.
Diodrast clearance, as a measure of renal plasma flow, fell
from 613 to 290 ml/min in the ninth decade of life. The drop
in inulin clearance with aging was from a mean of 122 to a
mean of 65 ml/min between 30 and 90 years respectively (1)
. Wesson analysed all the available literature, and showed
a fall of approximately 10 per cent per decade in renal plasma
flow (2).The fall-off in renal function with age parallels
the anatomical changes, caracterized by the progressive glomerulosclerosis,
the reasons of which in aging kidney are not clear.
Using the creatinine clearance as an index of GFR, Kampmann
et al (3), Rowe et al (4) and Laine et al (5) made the same
observation that GFR declines with age. One problem which
arises with these data is that similar populations were not
studied. Rowe (4) studied healthy age individuals, whilst
Kampmann (3) studied a hospital population, but excluded any
patient with a raised plasma creatinine. Cockroft and Gault
(6) used hospital patients, but included as subjects, whatever
their renal function. A second point is that all these data
were obtained with creatinine methodology, using plasma creatinine
or constructed creatinine clearance nomograms, which are not
an adequate method to estimate GFR in the elderly. Finally
it should be noted that almost without exception these studies
have been cross-sectional and not longitudinal studies, which
to date are generally lacking. Lindeman et al (7) published
an important extended longitudinal study of old people in
Baltimore, some of whom were followed with repeated measurements
for more than 30 years. It is interesting to note that despite
a mean calculated fall-off in creatinine clearance of 0.75
ml/min/year, 92 of 254 individuals studied showed no fall-off
in creatinine clearance, and a few even increased their clearances.
Larsson et al (8) also found no decline in GFR in individuals
between the ages of 70 and 79, although serum creatinine increased
from 91 to 96 micromol/1 in women and from 100 to 107 micromol/
in men. Recently, Feinfeld et al (9) reported the results
of the Bronx Longitudinal Aging study, documenting that the
renal function, evaluated by serum creatinine, was stable
over a three-year period in the majority of the 500 people
These observations suggest that age-dependent decline in
renal function is not a constant, in contrast to what was
thought in the past. The reasons of this variability are not
yet clear, as the general mechanisms of aging are poorly understood.
Researchers wonder how much of the loss in kidney function
with senescence is due to age and how much to other factors,
such as cardiovascular risk factors, hypertension, diabetes,
hyperlipidemia, smoking and/or risk factors related to the
kidney, protein intake and previous renal diseases. The question
arises whether one can identify risk factors that impair renal
function in the elderly. The attempt to demonstrate that the
rate of decline in renal function over time is correlated
with blood pressure was unable to draw any conclusions from
several studies as to whether renal microvascular or parenchimal
pathology is the cause of the hypertension or the hypertension
is the etiology of the accelerated decline in renal function
observed with age. Lindeman (10) found a significant negative
correlation between the mean blood pressure and the rate of
decline in creatinine clearance with time in 446 subjects
in the Baltimore Longitudinal Study on Aging followed over
a period of 8 or more years. On the other hand, when those
subjects with hypertension were not included, the inverse
relationship between mean blood pressure and the rate of decline
in renal function is lost, suggesting that an accelerated
loss of renal function is observed primarily because of the
impact exerted by individuals with blood pressures in the
Leeuw et al (11) evaluated the effects of antihypertensive
treatment on renal function analysing data from a prospective,
double-blind investigation of 840 patients randomly assigned
to placebo or to active treatment; during a five year follow-up
period, serum creatinine levels increased significantly in
treated patients but not in placebo patients, suggesting that
adequate treatment of hypertension may enhance rather than
prevent renal impairment. Fliser (12) performed a comprehensive
study to compare several aspects of renal function in a young
healthy normotensive group and in three groups of elderly
subjects, normotensives, treated and untreated hypertensives,
and elderly patients with compensated mild to moderate heart
failure. Compared to young subjects and normotensive elderly
patients, the old with hypertension and heart failure showed
lower values of glomerular filtration rate and renal plasma
flow, and increased renovascular resistances. Preliminary
results from the Italian Longitudinal Study on Aging, aimed
to evaluate renal function related to age and the most common
cardiovascular risk factors, exclude the hypertension as a
significant variable predicting the pathological level of
Several studies have assessed the impact of hyperlipemia on
renal function and progression of kidney disease and a number
of experimental investigations have suggested that lipids
are involved in renal injury (13).
High cholesterol diets are associated with albuminuria and
glomerular injury in a variety of different animal species;
however, this form of lipid-induced hypercholesterolemia is
relatively modest, and glomerular disease accompanied by proteinuria
is not familiar in primary hyperlipidaemias. This may reflect
a need for a combination with other cardiovascular risk factors
or glomerular predisposing conditions. Although elevated LDL
is not regularly accompanied by renal disease, it is not known
whether the normal glomerulus is susceptible to LDL damage.
In a recent study project to evaluate the association betwen
cardiovascular risk factors, peripheral atherosderosis and
renal function, we found that renal plasma flow, as evidenced
by MAG3 clearance, progressively declined in parallel with
the severity of peripheral atherosderosis and that MAG3 clearance
values were best explaned by the score of systemic atherosclerosis,
serum LDL-cholesterol values and smoking habit. In animals
models, hypercholesterolemia is associated with mesangial
matrix accumulation, focal and segmental glomerulosclerosis
and monocyte infiltration into preinjured glomeruli (13);
hystologic analysis of scarred glomeruli displays features
similar to those found in atherosclerosis(14).
Human mesangial cells express receptors for both HDL and
VLDL (15). LDL and the cholesterol-ester rich VLDL stimulate
mesangial cell proliferation (16). LDL has been shown to stimulate
the synthesis of growth factors, cytokines and other mediators
capable of indudng collagen synthesis and mesangial cell proliferation
analogous to vascular smooth muscle cell proliferation in
atherosclerosis. Additional support for the role of lipids
in renal injury can be obtained from studies in which pharmacological
interventions reduced circulating lipids and ameliorated renal
damage in different models of experimental renal disease (13).
Cigarette smoking is a major risk factor for vascular disease;
it induces a variety of effects on the vascular and hormonal
systems and involved in the development of atherosclerosis,
thrombogenesis, and vascular occlusion (17).
Preliminary report suggests that smoking-related hemodynamic
events may have an acute influence on renal function (18);
other studies reported adverse renal effects of smoking in
dialized IDDM and NIDDM patients, where the smoking habits
increased the relative risk of myocardial infarction; moreover,
several studies have proposed that smoking in diabetes mellitus
is associated with the development and/or progression of diabetic
nephropathy (19). A recent cross-sectional study (17) carried
out to evaluate the effect of chronic cigarette smoking on
renal function showed that compared with nonsmokers, smokers
had a renal function impairment characterized by a normal
GFR and a significant reduction in renal plasma flow as reflected
by MAG3 clearance.
The renal dysfunction was associated with an increase in
plasma endothelin-1 concentration. This finding suggests that
smoke has a significant, detrimental effect on renal function.
The mechanisms of smoking-related arterial damage have not
yet been defined; however, a sympathetic stimulation, with
consequent release of the neurotransmitter nore-pinephrine
and morphologic and functional endothelial changes, characterized
by intimal smooth muscle cell proliferation and alterations
in endothelial-derived vascular tone regulators, seem to play
an important role.
The evidence for a direct role of smoking on the metabolism
of the lipoproteins and the glycosaminoglycans (GAGS) provide
some insights into mechanisms that may operate in vascular
damage. Smoking induces an increased plasma concentrations
and oxidative modification of LDL-cholesterol,which represents
a key process in the development of atherosclerosis (20,21).
Moreover, consistent evidence demonstrates that smoke, by
ipoxic stress induction, has an effect on GAGS metabolism
(22); these substances are the main constituents of the arterial
wall, are synthesized by endotelial and smooth muscle cells
and are capable to interact with lipoproteins, causing the
accumulation of HDL in the arterial; moreover, GAGS are involved
in vasculogenesis and angiogenesis after ischemic injury,
interactions of cells with adhesive proteins and blood vessels,
proliferation of smooth muscle cells during atherogenesis
and interactions with growth factors, enzymes and protease
inhibitors, all biologic processes which play a key role in
the pathogenesis of atherosclerosis and glomerulosclerosis
In conclusion, cross-sectional and longitudinal studies confirm
that age-associated decline of renal function may be the result
of intervening comorbid conditions or cardiovascular risk
factors, rather than an involutional aging process. Among
these, smoking and hyperlipaemia conditions seem to have an
important role in the detrimental effect on renal function.
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