Andrea Corsonello (1), Claudio Pedone
(2), Bruno Mazzei (1), Francesco Corica (3), Raffaele Antonelli
Istituto Nazionale di Ricovero e Cura per
Anziani (INRCA) IRCCS, Cosenza, Italy (1)
Chair of Geriatric Medicine, University Campus-Biomedico,
Rome, Italy (2)
Department of Internal Medicine, University of Messina, Italy
Estimation of renal function is important because renal insufficiency
is related to increased mortality, risk of cardiovascular
events and morbidity (1,2). Since in elderly patients serum
creatinine is frequently normal despite reduced renal function
(3), several formulas have been developed to estimate the
glomerular filtration rate (GFR) (4-6). Older and malnourished
patients are at special risk of having depressed GFR with
normal serum creatinine levels (3,7), and older patients in
the acute care hospital are a population at special risk of
having concealed renal failure, because the effects of an
acute illness are added to those of chronic conditions. Recognising
these patients is important in clinical practice because depressed
GFR requires that the doses of drugs cleared by the kidney
be proportionally reduced to prevent adverse drug reactions
(ADRs) and nephrotoxic drugs be avoided.
The aging kidney
Aging-dependent changes in the kidney have been recently reviewed
(8-10). Kidney mass has been reported to be substantially
reduced in old age, by approximately 20 to 25% between the
age of 30 and 80 years (11), and 0.5 cm per decade in length
after middle age (12). However, an ultrasonographic study
showed that in 175 healthy subjects aged 17 to 85 years, renal
length decreased by only 15% between the third and ninth decades
(13). At the light microscopic level, the aging human kidney
is characterized by increased fibrosis, tubular atrophy, and
arteriosclerosis (14,15). The presence of small vessel pathology
in older people without apparent renal disease or hypertension
suggests that even in healthy older people, renal changes
may be secondary to vascular disease and altered vascular
responsiveness. However, in an autopsy study, old age was
found to be associated with increased numbers of sclerotic
glomeruli and interstitial fibrosis (16).
The above morphological changes correspond to important functional
modifications. Studies carried out with the measurement of
inulin or EDTA clearance showed an age-related reduction of
renal clearance of 13-46% (14,17-20). The Baltimore Longitudinal
Study of Aging prospectively found a decrease in creatinine
clearance of 0.75 ml/min/year, although one-third of subjects
had no decrease in renal function for up to 25 years (21),
and in the elderly cohort, serum creatinine and blood urea
nitrogen were stable or decreased slightly over a 6-year period
(22). However, the Baltimore study did not exclude older people
with hypertension, and in a study by Fliser et al (18), much
of the age-related decline in glomerular filtration rate appeared
to be secondary to age-related disease, such as hypertension,
diabetes and congestive heart failure, rather than to normal
Estimating renal function at the bedside
Several equations have been developed to estimate creatinine
clearance and GFR on the basis of easily available variables,
such as serum creatinine, age, gender, antropometric and nutritional
parameters. Unfortunately, none of most commonly used equations
achieved an optimal mix of accuracy and precision in a young-adult
population (23). Furthermore, a noticeable discrepancy between
the CockroftGault (CG) and the Modification of Diet
in Renal Disease (MDRD) formulas, the most widely used, has
been observed in a large population over 65 living in long-term
facilities (24), and these formulas have been found to miss
a consistent proportion of cases with renal failure within
a population of octogenarian in-patients (25).
By collecting extensive data on laboratory and clinical characteristics
of over 30,000 in-patients, the Gruppo Italiano di Farmacovigilanza
nellAnziano (GIFA) study has been a valuable opportunity
to investigate renal function in elderly hospitalized patients
and its relationship with the occurrence of ADRs during hospital
stay. In a recent study, we found concealed renal insufficiency,
i.e. reduced MDRD-estimated GFR with normal serum creatinine,
in 1,631/11,687 patients (13.9%), and it was associated with
male gender and poor nutritional status. In addition, patients
with concealed renal insufficiency were older, had greater
cognitive impairment, and were more physically dependent compared
with subjects having normal renal function. Concealed renal
insufficiency increased the risk of ADR to water-soluble drugs
by 61%, after adjusting for confounding factors, while overt
renal insufficiency doubled the risk. Neither concealed nor
overt renal insufficiency was associated with ADR to other
drugs (26). These findings have been confirmed in a subgroup
of 2,257 diabetic patients enrolled in the GIFA study, where
it has also been demonstrated that only overt renal failure
is associated with a significant reduction in mean daily dose
of drugs cleared by the kidney, such as insulin, glybenclamide,
and digoxin, with respect to that prescribed in patients with
normal renal function or concealed renal failure (27). The
most important implication of these results is that assessing
renal function by estimating GFR may help to avoid drug-related
events by adjusting the dose regimens and reducing the number
of prescribed drugs in patients with concealed or overt renal
dysfunction. Furthermore, data about ADRs in hospitalized
patients probably underestimate the global impact of ADRs
in elderly patients: ADRs occur more commonly in home-dwelling
patients and are an important cause of hospital admission
(28,29), and the estimated cost of drug-related morbidity
and mortality in the ambulatory setting in the United States
ranges from $30.1 to $136.8 billion, with the largest amount
of this total cost explained by drug-related hospitalizations
(30). Thus, using estimated GFR to identify patients at risk
may result in relevant savings with a negligible added cost.
Unfortunately, methods for estimating renal function have
several limitations. Although the present knowledge suggests
that estimating renal function by creatinine clearance or
GFR formulas may represent an useful screening method (31,32),
what formula can be reliably used in elderly patients remains
to be established. Indeed, when we compared the CG- and the
MDRD-estimated renal function in the GIFA study population,
we found that formulas have a good average agreement, but
at the individual level, the CG formula underestimates the
GFR using either of the two MDRD formulas as comparison. Additionally,
the magnitude of the discrepancy was influenced by age, serum
creatinine, and body mass (33). Our results are in line with
others showing that in the elderly population, both the CG
and, to a lesser extent, the MDRD formulas tend to underestimate
the measured GFR and that age and body mass is an important
factor in estimation bias (34). Therefore, the formulas cannot
be used interchangeably to measure renal function in older
Estimating renal function through GFR formulas is an useful
tool for the screening of chronic renal dysfunction. Estimating
GFR in clinical practice routine may help to identify patients
at-risk of developing end-stage renal disease and ADRs to
hydrosoluble drugs. Automatic laboratory reporting of estimated
GFR would enhance early detection of chronic kidney disease,
allow the timely institution of appropriate reno- and cardio-protective
therapies, and better inform decisions regarding the prescription
of renally excreted medications (37). Efforts should be made
to clarify what formula qualifies as more reliable in elderly
hospitalized patients and/or to enhance reliability of these
methods in this population.
1. Go AS, Chertow GM, Fan D, McCulloch
CE, Hsu CY. Chronic kidney disease and the risks of death,
cardiovascular events, and hospitalization. N Engl J Med 2004;
2. Anavekar NS, Pfeffer MA. Cardiovascular
risk in chronic kidney disease. Kidney Int Suppl 2004: S11-5.
3. Lindeman RD. Assessment of renal function
in the old. Special considerations. Clin Lab Med 1993; 13:
4. Cockcroft DW, Gault MH. Prediction of
creatinine clearance from serum creatinine. Nephron 1976;
5. Levey AS, Bosch JP, Lewis JB, Greene
T, Rogers N, Roth D. A more accurate method to estimate glomerular
filtration rate from serum creatinine: a new prediction equation.
Modification of Diet in Renal Disease study group. Ann Intern
Med 1999; 130: 461-70.
6. Levey AS, Greene T, Kusek JW, Beck GJ,
MDRD Study Group. A simplified equation to predict glomerular
filtration rate from serum creatinine. J Am Soc Nephrol 2000;
7. Garg AX, Blake PG, Clark WF, Clase CM,
Haynes RB, Moist LM. Association between renal insufficiency
and malnutrition in older adults: results from the NHANES
III. Kidney Int 2001; 60: 1867-74.
8. McLean AJ, Le Couteur DG. Aging Biology
and Geriatric Clinical Pharmacology. Pharmacol Rev 2004; 56:
9. Silva FG. The aging kidney: a review
- part I. Int Urol Nephrol 2005; 37: 185-205.
10. Silva FG. The aging kidney: a review
- part II. Int Urol Nephrol 2005; 37: 419-432.
11. Beck LH. Changes in renal function
with aging. Clin Geriatr Med 1998; 14:199-209.
12. McLachlan M, Wasserman P. Changes in
sizes and distensibility of the aging kidney. Br J Radiol
13. Miletic D, Fuckar Z, Sustic A, Mozetic
V, Stimac D, Zauhar G. Sonographic measurement of absolute
and relative renal length in adults. J Clin Ultrasound 1998;
14. Fuiano G, Sund S, Mazza G, Rosa M,
Caglioti A, Gallo G, et al. Renal hemodynamic response to
maximal vasodilating stimulus in healthy older subjects. Kidney
Int 2001; 59:1052-1058.
15. Melk A, Halloran PF. Cell senescence
and its implications for nephrology. J Am Soc Nephrol 2001;
16. Neugarten J, Gallo G, Silbiger S, Kasiske
B. Glomerulosclerosis in aging humans is not influenced by
gender. Am J Kidney Dis 1999; 34: 884-888.
17. Davies DF, Shock NW. Age changes in
glomerular filtration rate, effective renal plasma flow and
tubular excretory capacity in adult males. J Clin Invest 1950;
18. Fliser D, Franek E, Joest M, Block
S, Mutschler E, Ritz E. Renal function in the elderly: impact
of hypertension and cardiac function. Kidney Int 1997; 51:
19. Hollenberg NK, Rivera A, Meinking T,
Martinez G, McCullough M, Passan D, et al. Age, renal perfusion
and function in island-dwelling indigenous Kuna Amerinds of
Panama. Nephron 1999; 82: 131-138.
20. Fliser D, Ritz E. Serum cystatin C
concentration as a marker of renal dysfunction in the elderly.
Am J Kidney Dis 2001; 37: 79-83.
21. Lindeman RD, Tobin J, Shock NW. Longitudinal
studies on the rate of decline in renal function with age.
J Am Geriatr Soc 1985; 33: 278-285.
22. Feinfeld DA, Keller S, Somer B, Wassertheil-Smoller
S, Carvounis CP, Aronson M, Nelson M, and Frishman WH. Serum
creatinine and blood urea nitrogen over a six-year period
in the very old. Creatinine and BUN in the very old. Geriatr
Nephrol Urol 1998; 8:131-135.
23. Bostom AG, Kronenberg F, Ritz E. Predictive
performance of renal function equations for patients with
chronic kidney disease and normal serum creatinine levels.
J Am Soc Nephrol 2002; 13: 2140-4.
24. Garg AX, Papaioannou A, Ferko N, Campbell
G, Clarke JA, Ray JG. Estimating the prevalence of renal insufficiency
in seniors requiring long-term care. Kidney Int 2004; 65:
25. Rimon E, Kagansky N, Cojocaru L, Gindin
J, Schattner A, Levy S. Can creatinine clearance be accurately
predicted by formulae in octogenarian in-patients? QJM 2004;
26. Corsonello A, Pedone C, Corica F, Mussi
C, Carbonin P, Antonelli Incalzi R. Concealed renal insufficiency
and adverse drug reactions in elderly hospitalized patients.
Arch Intern Med 2005; 165: 790-795
27. Corsonello A, Pedone C, Corica F, Mazzei
B, Di Iorio A, Carbonin P, Antonelli Incalzi R. Concealed
Renal Failure and Adverse Drug Reactions in Older Patients
With Type 2 Diabetes Mellitus. J Gerontol A Biol Sci Med Sci
2005; 60A: 1147-1151
28. Johnson JA, Bootman JL. Drug-related
morbidity and mortality: a cost-ofillness model. Arch Intern
29. Onder G, Pedone C, Landi F, et al.
Adverse drug reactions as cause of hospital admissions: results
from the Italian Group of Pharmacoepidemiology in the Elderly
(GIFA). J Am Geriatr Soc. 2002;50:1962-1968.
30. Beijer HJ, Blaey CJ. Hospitalisations
caused by adverse drug reactions (ADR): a meta-analysis of
observational studies. Pharm World Sci. 2002;24:46-54.
31. National Kidney Foundation. K/DOQI,
clinical practice guidelines for chronic kidney disease: evaluation,
classification, and stratification. Am J Kidney Dis 2002;39
(2 suppl 1):S1-266.
32. Levey AS, Coresh J, Balk E, Kausz AT,
Levin A, Steffes MW. National Kidney Foundation practice guidelines
for chronic kidney disease: evaluation, classification, and
stratification. Ann Intern Med 2003;139:137-47.
33. Pedone C, Corsonello A, Antonelli Incalzi
R. Estimating renal funtion in older people: a comparison
of three formulas. Age Ageing 2006; 35: 121-126.
34. Verhave JC, Fesler P, Ribstein J, du
Cailar G, Mimran A. Estimation of renal function in subjects
with normal serum creatinine levels: influence of age and
body mass index. Am J Kidney Dis 2005; 46: 233-41.
35. Wasen E, Isoaho R, Mattila K, Vahlberg
T, Kivela SL, Irjala K. Estimation of glomerular filtration
rate in the elderly: a comparison of creatinine-based formulae
with serum cystatin C. J Intern Med 2004; 256: 70-8.
36. Fehrman-Ekholm I, Skeppholm L. Renal
function in the elderly (>70 years old) measured by means
of iohexol clearance, serum creatinine, serum urea and estimated
clearance. Scand J Urol Nephrol 2004; 38: 73-7.
37. Johnson D, Usherwood T. Automated reporting
of GFR - Coming soon to a laboratory near you! Aust Fam Physician
2005; 34: 925-931
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