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Departments ofPharmacology & Therapeutics, and Department of Pediatrics,
University ofFlorida College ofMedicine,
Gainesville, Florida 32610, USA
The renal excretion of drugs and/or their active or inactive metabolites can involve
the processes of glomerular filtration , active or passive tubular secretion, and/or
active or passive tubular reabsorption (Weiner, 1971). Hydrophilie compounds, like
the polycationic aminoglycosides, experience !ittle passive reabsorption; their urine/
plasma concentration ratios approximate 100,and their cIearance is similar to that of
inulin or creatinine. Lipophilic compounds, like catTeine, are filtered, but reabsorbed
so rapidly that their urine/plasma concentration ratios approach I (Aldridge, Aranda
& Neims, 1979). Under these circumstances renal excretion is most inefficient with
clearance only approximating urine flow rate. Several organic acids such as
penicillin, and organic bases such as procainamide, are secreted actively by the
tubule . This presentation concerns the relations hip between the various processes of
renal excretion and age. There is no doubt that the impairment ofthe renal excretion
of drugs at the two extremes of age has therapeutic and toxicological implications
(Morselli, 1976; Kampmann & Molholm Hansen , 1979; Schmucker, 1979). My
purpose is not to present original research, but rather to explore the issue from the
perspective ofsomeone interested in development in general.
We can begin with a summary ofwhat my conception ofthe relationship between
renal function and age was at the time I was asked to review the subject at this
symposium. I suspect that it does not ditTer much from that held by most of you who
do not work directly in the freld: I) The ability of the newborn infant to eliminate
drugs by way of the kidney is severely impaired; 2) there is a plateau of function
typical of 'healthy young adults'; and 3) renal excretory processes in the elderly are
impaired - but not to the same extent as the neonatal deficiency. The rest of this
presentation deals with a cIoser look at the details ofthissummary.
When in life is renal function in the broad sense maximal?
The answer is not simple. One consequence of the organization of our cIinical
specialties is that most things end up being compared to the situation prevailing in
young adults . It is absurd to equate function in the young adult to maximal function .
The syncytiotrophoblast of the placenta is deteriorating before birth. The thymus,
the ductus arteriosus, the ductus venosus, the organ of Zuckerkandl and brown fat
have performed many of their major functions before puberty. In comparison to
many other systems or organs, the kidneys mature early in life. Body weight increases
23-fold after birth; kidney weight increases but lO-fold over the same 20 years. The
data ofWeil (1955) and Winberg (1959) amply document the generalization that renal
function is 'rnature' before the age of2 years (Table I).
Table 1 Maturity ofrenal functionat age2-yearsa
-Data fromWeil(1955) and Winberg(1959).
Is there a plateau in renal function between age 2 and 30 years?
Or does the capacity ofthe kidney to excrete drugs begin to deteriorate at the age of2
or 3 years? The data for individuals aged 2 to 20 years is surprisingly sparse in
comparison to neonatal and adult investigations (Altman & Dittmer, 1974).
Nonetheless, it seems reasonable to conclude that whether or not there is a plateau
depends on the denominator selected for expression of function. If we express results
per unit surface area or cardiacoutput, a plateau seems to exist. If we use basal
metabolic rate as our denominator, renal function may increase slightly during the
first decade. If, however, we compute clearance per unit body weight, the various
measures of renal function decrease at the rate of about 2.5% per year from age 2
years. A decline is still obvious when results are expressed in terms of kidney weight
or of total body water. It is beyond the scope ofthis presentation and my knowledge
to designate the best denominator. Sufftee it to say that renal function is maximal
early in childhood and by some measures begins to decline at that time. An
interesting and perhaps related observation is that systolic arterial blood pressure
gradually increases from 90 mm Hg at age 2 years to 145 mm Hg at age 80 years , with
the 'young adult' value of 120 mm Hg perhaps merel y being one point on a
What happens after age 30 years?
Extending the original observations ofLewis & Alving (1938), Davies & Shock (1950)
documented the continuous and significant decrease in glomerular filtration rate
(GFR) that occurs with increasing age. Typical da ta concerning inulin clearance have
been compiled by Lindeman (1975). GFR per square meter decreases at the rate of
1-2% per year. This change is not trivial; the GFR at 80 years of age is only about
one-half of what it was at age 30 years (Lindernan, 1975; Kampmann & Molholm
Hansen, 1979). Interestingly, variability does not seem to increase appreciably ifat all
The active tubular secretion oforganic acids and the maximal capacity to transport
them decrease also with increasing age. The decrease is roughly proportional to the
decrease in GFR (Davies & Shock, 1950; Lindernan, 1975).
Insight into several of the effects of ageing on renal function can be gained by
examination of data concerning penicillin excretion reported by Kampmann,
Molholm Hansen, Siersbaek-Nielsen & Laursen (1972) and depicted in Table 2. Two
RENAL ELIMINATION OF DRUGS AT VARIO US AGES 119
Table 2 Penicillin half-life influenced by probenecid and by age-dependent variations in
endogenouscreatinine clearance -
Creatinine clearance (mi mirr")
Urine creatinine (mg kg-1day'')
aDatafrom Kampmann et al. (1972).
groups of subjects of mean age about 30 and 80 years were compared. Although
serum creatinine concentration did not change presumably because of its decreased
production rate in the elderly, endogenous creatinine c1earance at age 80 was only
42% of the value at age 30. The elimination rate constant for penicillin, wh ich is
filtered and actively secreted as an organic acid, decreased to 43% of the original
value in the same interval. Probenecid, which inhibits the tubular secretion of
penicillin, decreased its elimination rate constant by 67 and 58%, in the young and
elderly subjects, respectively. This study, of course, was cross-sectional, not
The roughly parallel changes in glomerular filtration and tubular secretion imply a
constant filtration fraction . Glomerular permeability does not seem to change with
increasing age; nor does the capacity to concentrate or dilute when appropriate
corrections are made (Kampmann & Molholm Hansen, 1979):
Defmitive answers probably await clarification of the ageing process per se
(Lindernan, 1975). One example will help to demonstrate the complexity of the
problem. In the rat the capacity for hypertrophy and hyperplasia in the remaining
correlated with the age-dependent decrease in renal function. For example, the
decrease in function paralIeIs decreasing cardiac output and renal blood flow. But
cause-effect conclusions are hazardous. The role ofvascular tone and atherosclerosis
remain to be clarified (Lindernan, 1975). The 'intact nephron hypothesis' ofBricker,
Morrin & Kirne (1960) proposes that the number of functional nephron units
several exceptions. Perhaps the report of Drayer, Camacho, Kluger & Reidenberg
(1980) at this meeting indicating that the renal tubular secretion of procainamide
deteriorates more rapidly with age than does creatinine c1earance is just such an
drug distribution and serve to underscore the inadequacy of half-life as an indicator
of c1earance during ageing. Indeed, with increasing age the c1earances, but not
elimination rate constants ofpropicillin, lithium and practolol decrease (Kampmann
Table 3 Examples offactoTSthat confound study ofthe decrease in renal function with age.
What about renal function at the other extreme of age?
Let us now focus on the renal function ofnewborns, infants and young children. The
formation of new glomeruli begins at about the 6th week of gestation and is
completed by the 36th week of pregnancy. Urine is produced by the foetus. At 22
weeks of gestation all glomeruli are juxtamedullary, and the juxtamedullary
nephrons are correspondingly more mature morphologically than the outer cortical
nephrons at birth. At birth, kidney exhibits several distinctive features: glomerular
diameter and surface area are decreased,glomerular thickness is increased, and there
is marked anatomical glomerular-tubular heterogeneity (Loggie, Kleinman & Van
Maanan, 1975; Braunlich, 1977; Morselli, 1976). Glomerular permeability is
There is no doubt that the process ofglomerular frltration is impaired at birth. But
someconfusion exists with regard to the degree of impairment and the age at which
maximal function is attained . Sehreiter (1966) reported that GFR as measured by
inulin clearance per kg cell mass is about 30% ofthe adult value at birth, and reaches
the adult value within a week . If data had instead been expressed per unit surface
area, the adult value for GFR would not be attained until2.5 to 5 months after birth
(Gladtke & Heimann, 1975; Rane & Wilson, 1976).
There is appreciable variability in GFR in the first few postnatal days. As the GFR
increases, individual variability tends to decrease. Besides the inherent and poorly
understood features ofrenal development generally, the immediate neonatal GFR is
(Loggie er al., 1975; Morselli, 1976; Braunlieh, 1977; Tavani, Calcagno, Zimmet,
Flamenbaum, Eisner & lose , 1980).
Clinically, the neonatologist distinguishes normal and low-birth-weight infants,
and further classifies low-birth-weight infants into those born prematurely and those
who are small because ofintrauterine growth retardation. These classifications playa
clinically significant role in allowing the physician to anticipate clinical course,
problems, and even the pharmacokinetic profiles ofcertain drugs (MeCracken, 1974;
Neirns, Aranda & Loughnan, 1977). The complexity of the problem, however, is
highlighted by a study ofMyers, Roberts & Mirhig (1977) dealing with the influence
of such factors on the renal elimination of amikacin (Table 4). Only half-lives, not
at birth. Hypoxemia had little discernible effect on the half-life of amikacin in the
heavier infants, but was associated with marked prolongation in the smaller ones.
When the hypoxemic infants were removed from comparison, birth weight had little
effect on this measure of GFR. Although not shown in this slide, the effect of
gestational age was still important. This has been reemphasized recently for
gentamiein (Szefler, Wynn, Clarke, Buckwald, Shen & Schentag, 1980). Several
factors that could influence GFR such as gestational age, birth weight, intrauterine
RENAL ELIMINAnON OF DRUGS AT VARIOUS AGES 121
and postnatally tend to vary in dependent fashion, a feature which often complicates
Table 4 Amikacin serum half-life in relation to birth weight and hypoxemia °
-Data from Myers et al. (1977).
Low birth weight Term birth weight
Does the postnatal maturation of tubular function parallel that of glomerular
The degree ofimpairment ofPAH clearance at birth may exceed, and its subsequent
rate of maturation may lag behind, the circumstances of glomerular filtration. Even
when expressed per unit weight by Sehreiter (1966) adult values are not achieved
until nearly 2 months after birth. When expressed per unit surface area maximal
values are not obtained until nearly the 7th month postnatally (Rane & Wilson,
1976). Maximal tubular transport capacities for organic acids may not be obta ined
until the 9th or 10th month ofage (Gladtke & Heimann, 1975). It should be noted that
in the newborn PAH clearance substantially underestimates renal plasma flow.
Certain other factors merit consideration. Studies by Hook and colleagues (Hirsch
& Hook, 1970; Hewitt & Hook, 1978) have revealed that exposure to organic acids
such as PAH and penicillin can induce increased tubular secretory capability. The
relationship between these findings and the utilization of nonesterified fatty acids is
particularly intriguing. What role postnatal exposure to substrate organic acids play
in normal development is unresolved. There is also a difference in urinary pH
between newborns and adults; its diurnal cycle is not fully established even at the end
ofthe first postnatal year (Krauer, 1975).
Finally, as with our discussion of deterioration of renal function in the elderly,
some caution concerning extrapolation ofresults from drug to drug, even ifthey are
both excreted by seemingly analogous processes, seems appropriate. The patterns of
activity toward four different substrates of glutathione S-transferase mature at
different rates in rat kidney (Jaeger, Haies & Neims, unpublished experiments). Each
activity represents in essence aresolvable transferase or 'Iigandin' as assessed by
electrofocusing or columnchromatography. Ifligandins are involved in organic acid
transport, we might anticipate subtle differences in the maturational sequence for
different drug substrates. Only further investigation will reveal whether or not
clinically significant differences between such drugs will exist, but the need to study
each drug in the population in which it is to be used remains.
The therapeutic and toxicological significance of impaired renal function at the
extremes ofage extends weil beyond its impact on the pharmacokinetic profile ofthe
drug in question. Metabolites with pharmacological activity might accumulate; some
might even act to induce or inhibit hepatic drug metabolism. Several other effects can
also be hypothesized. The status of renal function could also influence the plasma
concentration-response curve of drugs that act on kidney, such as the nephrotoxic
action of gentamiein (Milner, Milner & Lancaster, 1979) and the diuretic effect of
Let us concl ude by recalling the fact that drugs are eliminated through a series of
sequential and /or parallel and competing reactions including renal filtration and
secretion and hepatic metabolism. It is somewhat artificial to consider any one
process in isolation. In the newborn human being, caffeine is metabolized very
slowly. Its plasma half-life is 4 days; caffeine accounts for more than 80 % of excreted
product but the process is very slow because of the virtual equilibration of caffeine
between tubular urine and plasma (Aldridge el al., 1979). By early childhood,
metabolism matures, c1earance increases, and the plasma half-life decrease s to about
2 h coincident with production ofpartially demethylated xanthines and urates. Some
are excreted by filtration with partial reabsorption and some are actively secreted .
Both the plasma and urinary metabolite time curves reflect the sum of these various
processes, many ofwhich mature at different rates.
Renal function varies appreciably with age. The newborn is deficient in both
glomerular filtration and renal tubular functions. Both processes mature within
several months, the former more rapidly than the latter. Renal function is c1early
mature before age 2 years; depending on the denominator chosen for expression of
function, an age-dependent decrease in renal function may begin as early as that age .
The progressive decrease with age in both glomerular and tubular functions is
substantial and has c1in ical consequences in the elderly.
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of American Societies for Experimental Biology.
Braunlich, H. (1977). Kidney development: drug elimination mechanisms. In Drug Disposition
During Development, ed. Morselli, P. L., pp. 89-100. New York: Spectrum .
Bricker, N. S., Morrin, P. A. F. & Kirne, S. W., Jr. (1960). The pathologie physiology of chronic
Bright's disease- an exposition ofthe 'intact nephron hypothesis'. Am. J. Med., 28, 77-98.
Davies, D. F. & Shock, N. W. (1950). Age changes in glomerular filtration rate, effective renal
plasma flow, and tubular excretory capacity in adult males. J. clin. lnv est., 29,496--,507.
Drayer, D., Camacho, M., Kluger, J. & Reidenberg, M. (1980). Effect of age on the renal
excretion by man of procainamide and its active metabolite N-acetylprocainamide.
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Gladtke , E. & Heimann, G. (1975). The rate of development of elimination functions in kidney
and liver of young infants. In Basic and Therapeutic Aspects ofPerinatal Pharmacology,
ed. Morselli, P. L., Garattini, S. & Sereni, F., pp. 393-403 . New York: Raven.
Hewitt, W. R. & Hook, J. B. (1978). Alteration of renal cortical palmitate utilization and
p-aminohippurate (PAH) accumulation after penicillin treatment of neonatal rabbits. J.
Pharmac. exp. Ther.. 207,726-736.
Hirsch, G. H. & Hook, J. B. (1970). Maturation of renal organic acid transport : substrate
stimulation by penicillin and p-aminoh ippurate (PAH). J. Pharmac. exp. Ther., 171,
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