Andrea Corsonello (1), Claudio Pedone (2), Bruno Mazzei (1), Francesco Corica (3), Raffaele Antonelli Incalzi (2).

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 (3)

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 aging.

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 Cockroft–Gault (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 nell’Anziano (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 people (35,36).

Conclusions
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.

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