Kidney senescence and renal function evaluation in the elderly JNEPHROL 2010; 23 (S15): S46-S54 www.sin-italy.org/jnonline – www.jnephrol.com How to assess renal function in the geriatric population Filippo Aucella, Claudio Carmine Guida, Vincenzo Lauriola, Michele Vergura Nephrology and Dialysis Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia Italy Nephrology and Dialysis Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia - Italy Nephrology and Dialysis Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia - Italy Nephrology and Dialysis Unit, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia - Italy Abstract The myth of the inexorable decline of The progressive decline of renal function with aging is not inevitable, because it is mainly due to comorbid conditions such as hypertension and diabetes. However, in the elderly there is a high prevalence of chronic kidney disease leading to the need for strategies to control cardiovascular risk – death being far more common than dialysis at all stages of kidney function. Serum creatinine, the most widely used surrogate marker of glomerular filtration rate (GFR), is inaccurate with increasing age, particularly in sick and/or malnourished elderly people; it shows the socalled creatinine blind area, and substantial variation between laboratory analytical methods. An alternative endogenous marker is serum cystatin C: it correlates better with renal function and has the potential advantage of improved precision of the assay, but its measurement is still much more expensive. Current guidelines recommend that the 2 most commonly used equations to estimate GFR – the Modification of Diet in Renal Disease Study or Cockcroft-Gault equations – be used to estimate GFR in the clinical setting. Both show relevant bias, with underestimation of GFR in subjects with normal or mild renal impairment, a bias limited by using the more recent Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Nonetheless, keeping in mind that a decreased renal function in the elderly is not benign, current GFR equations facilitate detection, evaluation and management of the disease, and they should result in improved patient care and better clinical outcomes. Key words: Aging, Cockcroft-Gault equation, Creatinine clearance, Cystatin C, Estimated glomerular filtration rate, Modification of Diet in Renal Disease equation S46 renal function with senescence When we talk about physiology, we refer to the normal function of organs, whereas “insufficiency” or “failure” is a pathological status. In this regard, we should keep in mind that renal aging is a physiological rather than a pathological process. Therefore, it is not correct to speak about the aging kidney function as a “physiological renal insufficiency”: that represents a gross conceptual error because the aging kidney is able to maintain the extracellular volume equilibrium in conditions of health, although its resources and ability to adapt to challenges of restriction or overload are limited (1). Old uncontrolled observations, including in individuals with comorbid conditions, suggested that the average kidney weight decreases by up to 40% from young adulthood to senescence (2). These findings clearly disagree 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 (3). 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 (4). So the loss of renal mass with aging is moderate, preferentially affecting the renal cortex, at least until the age of 70 years. Glomerulosclerosis is the main age-associated change of renal hemodynamics (5). The degree of age-related glomerulosclerosis is clearly related to the severity of systemic atherosclerosis, and the presence of glomerulosclerosis is indicative of subclinical renal injury from comorbid conditions affecting renal structure (6). The kidneys of elderly people are more sensitive to negative influences from other coexisting comorbid conditions, and aging causes the appearance of albuminuria most often © 2010 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2010; 23 (S15): S46-S54 together with other coexisting factors such as male sex or uncontrolled hypertension. But advanced age alone is not harmful for the kidneys (7). Based on all of this, Danilo Fliser has clearly defined as a myth the inexorable decline of renal function with senescence (8). Decline of renal function in normal aging: rate and clinical impact The Baltimore Longitudinal Study of Aging (BLSA), the first continuing scientific examination of human aging, was started in 1958 and has been an important source of information on the aging kidney (9). This seminal study, with an observation period of at least 5 years using ageadjusted standards for creatinine clearance, apparently confirmed the previously postulated progressive decline of renal function with aging. The estimated average annual change in creatinine clearance (CrCl) was 0.26 ml/min per 1.73 m2 in the age group 20 to 39 years and became 1.51 ml/min per 1.73 m2 after the age of 80. However, Lindeman and coworkers could identify 3 subgroups of these elderly persons above 65 years: one of these showing apparently no change in glomerular filtration rate (GFR), a second group with hypertension and mild reduction of GFR and a third with edema and proteinuria, probably due to unrecognized cardiac and renal disease, showing a relevant impairment of renal function with aging (Fig. 1) (9). So, clearly it was shown that comorbidity has an important impact on changes in GFR with age. In fact, while BLSA participants were selected to be “healthy,” the diagnostic technology available at that time may have failed to detect subclinical cardiovascular and kidney disease. This is important because the distinction between age-unrelated renal changes and progressive renal insufficiency is associated with a different prognosis. Moreover, one of the most important findings of the BLSA was that kidney function varied between persons at all ages, and when declines with aging were noted, they occurred at substantially different rates. In some individuals with an accelerated decline in CrCl, the presence of undetected, subclinical diseases could not be excluded. Indeed, Rowe et al (10) showed that in restricting the analysis to individuals without diabetes or any degree of hypertension, the decline was much less accentuated. Perhaps more important for nephrologists is the fact that some BLSA participants showed periods of 5 years or even 10 years without a significant decline of renal function. Although the number of these individuals was small, and few were older than 70 years of age, they challenge the notion that the decline of kidney function with age is unavoidable. Another recent large, community-based study from Cana- da with about 10,000 subjects above the age of 66 years, investigated the same issue, and the major finding was that the majority of elderly subjects have no or minimal progression of kidney disease over 2 years (11). An increased risk of death, as opposed to dialysis, was also evident, with a risk of death 6 or 60 times greater than the risk of dialysis in subjects with a mean study estimated glomerular filtration rate (eGFR) of 30-59 ml/min. Thus, among the vast majority of older persons with chronic kidney disease (CKD), even when this is quite advanced (i.e., eGFR 15-29 ml/min per 1.73 m2), death is a more common outcome than progression to end-stage renal disease (ESRD). The results from the Cardiovascular Health Study also indicate little or no progression of CKD in the majority of older adults; a deterioration in kidney function of 426.5 mmol/L (0.3 mg/dL) was seen in less than 3% of subjects (mean age 73 years) who were followed for at least 3 years (12). These results are consistent with a prior study (13) based on 28,000 health maintenance organization enrollees (mean age 65) with a baseline eGFR of 90 ml/min per 1.73 m2 followed for 5 years, in whom death once again was far more common than dialysis at all stages of kidney function. All of above-mentioned studies underline the low rate of progression of kidney dysfunction in the majority of community-dwelling elderly subjects without diabetes mellitus, which is reassuring given the high prevalence of CKD in this population (14). So, strategies aimed at slowing progression of kidney disease should consider the underlying risk factors for progression and the negligible loss of kidney function that occurs in the majority of older adults. However, the higher rates of progression for subjects with mean study eGFR of 30 ml/min per 1.73 m2 or less, both with and without diabetes mellitus, emphasize the importance of targeted provision of care in patients with CKD. All CKD patients require aggressive cardiovascular risk reduction (15), but not all elderly CKD patients require an emphasis on therapy to delay progression of kidney disease. These high-risk patients can be identified by the presence of diabetes mellitus, substantial proteinuria and a mean eGFR of 30 ml/min 1.73 m2 or less. It is these same patients who are likely to receive the most benefit with referral to specialized and multidisciplinary care (11). Factors affecting GFR with aging Nowadays, patients 75 years and older currently represent one of the fastest growing contingents of the ESRD population, most likely reflecting both population aging and the high overall prevalence of CKD in the elderly (16). Thus, a critical challenge for health systems and providers carS47 Aucella et al: Assessment of renal function in the elderly Fig. 1 - Rate loss of renal function, glomerular filtration rate as measured by creatinine clearance (CrCl), in healthy subjects (group A), in patients with arterial hypertension (group B) and in patients with proteinuria (group C) (data from Lindeman et al (9)). ing for older patients with CKD lies in identifying the relatively small proportion, but large absolute number, of older patients with CKD who are at greatest risk for progressive loss of renal function and ultimate need for dialysis. The main factors affecting GFR with aging were investigated in several studies (Tab. I). Bleyer at el (12) published a retrospective study, the Cardiovascular Health Cohort, of more than 4,000 nondiabetic subjects above the age of 65 years. They made an analysis 3 years apart with 2 measurements of serum creatinine, and suggested that 3 very preventable or treatable conditions – hypertension, smoking and vascular disease – which are associated with large and small vessel disease, are highly associated with clinically important changes in renal function in an older population. It is important and significant that current smoking habits and elevated systolic blood pressure, two conditions amenable to treatment, were significant predictors of renal functional decline in individuals at least 65 years of age. These findings discourage the notion that years of hypertension and smoking have already resulted in damage in this age group and that, therefore, their continued presence in the older population is unlikely to affect outcomes. The results of this study indicate that cessation of smoking and reduction in systolic blood pressure in people over 65 could result in decreased risks of renal insufficiency in this older group. A large study from Japan (17) included 120,000 subjects, and about 15% of them were older than 70 years – a quite large part of the population, about 15,000 people. There was an age-specific incidence of CKD stage 1 or 2 in the elderly compared with those 40 years of age or younger, but the difference was not dramatic – about 6% versus 3%. Moreover, the usual suspects were identified as risk factors for progression: high blood pressure defined by any variable, treated hypertension, diabetes and impaired glucose tolerance. Importantly, current smoking and obesity also came out to be important confounders of age-related changes in GFR (17). The Systolic Hypertension in the Elderly Program (SHEP) study (18) also showed that in the elderly population with isolated systolic hypertension, systolic blood pressure was clearly a determinant of the progression of CKD. TABLE I FACTORS AFFECTING RENAL FUNCTION WITH AGING Physiological Pathological • Low protein diet • Vegetarian habit • • • • • • • • • S48 Atherosclerosis/glomerulosclerosis Hypertension Heart failure Diabetes/glucose intolerance Obesity Smoking habit Drugs Inflammation markers Hyperlipemia JNEPHROL 2010; 23 (S15): S46-S54 More recently, the relationship between renal function estimated by different equations and all-cause and cardiovascular mortality over a 6-year follow-up was investigated among participants in the Invecchiare in Chianti (InCHIANTI) study (19), and a clear influence of renal function on risk of death was shown. Finally, the Health, Aging, and Body Composition Study (20), which included men and women older than 70 years, has shown a correlation between inflammatory markers known to be increased in patients with atherosclerosis and cardiac disease, and thus markers of microinflammation in the cardiovascular system, and cystatin C, but not with creatinine or eGFR. It may be argued that serum cystatin C is a more sensitive marker than eGFR for detecting the association of inflammation with kidney disease, especially among persons without CKD. Serum marker of renal function GFR estimation based on serum creatinine alone is not an ideal method, especially in elderly persons, because it is influenced by a number of variables such as age, sex of individual, muscle mass, diet and medications that block creatinine’s tubular secretion. Moreover, this easyto-measure GFR marker has one important limitation, the so-called creatinine blind area: when serum creatinine increases above the normal range, GFR has already decreased by at least 40% in a younger person and even more so in an elderly person (Fig. 2) (21). It is also to be underlined that the rate of creatinine production is lower in elderly people due to the age-related diminution of muscle mass and that the normal range of serum creatinine for the general population may be inappropriately high for senescent people. As a consequence, serum creatinine in the upper normal range may already indicate severe impairment of renal function in elderly people (22). Cystatin C is a cysteine proteinase inhibitor that is produced by nearly all human cells and released into the bloodstream, from which it is freely filtered by the kidney glomerulus and metabolized by the proximal tubule. Although the relative contribution of factors other than GFR, to serum cystatin C concentrations remains to be determined, the association of serum cystatin C with GFR seems to be independent of age, sex and muscle mass, in contrast to serum creatinine (23). Whereas elevated serum creatinine levels detect only the small subset of elderly individuals with the most impaired kidney function who are at increased risk for cardiovascular disease (CVD), cystatin C has a linear association with clinical CVD (15, 24). Studies have shown cystatin C to be an accurate marker of subtle changes in GFR in elderly people Fig. 2 - The blind area of creatinine as marker of glomerular filtration rate. and diagnostically superior to serum creatinine with a significantly better correlation with GFR (23, 25). In CKD stages 2-3, the correlation between the gold standard Cr 51 ethylenediaminetetraacetic acid (51Cr-EDTA) clearance and serum cystatin C was better than the correlation between 51Cr-EDTA clearance and serum creatinine, and also than the reciprocal of serum creatinine (26). It has been reported that cystatin C correlates better with 51CrEDTA clearance than creatinine clearance calculated from the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) Study formulas. Another potential advantage of cystatin C is the improved precision of the assay compared with that for creatinine, but it must be emphasized that its measurement is still much more expensive than that of creatinine, which precludes its widespread and repetitive use. Estimation of serum cystatin C is no longer technically difficult: it should be used to minimize diagnostic errors in patients with mild to moderate impairment of kidney function or in female patients. Finally, the results of recent large prospective epidemiological studies indicated that increased serum cystatin C levels, even in the range of relatively normal kidney function, independently predict cardiovascular outcome in the elderly, and therefore may also indicate unsuccessful aging (27). Glomerular filtration rate assessment Although measured GFR is considered the best overall measurement of kidney function, it is often not practical S49 Aucella et al: Assessment of renal function in the elderly in clinical or epidemiological settings. Thus, there are few studies of measured GFR in older adults, and they have small sample sizes (28). Creatinine clearance as measured from a 24-hour urine collection can be used to measure GFR, but it is vital to remember the high likelihood of inaccurate collection, especially in some elderly people with cognitive impairment or who are bedridden. It is important therefore to check for adequacy of urinary collection before interpretation of clearance. Twenty-four-hour urine collection for the estimation of GFR has been shown by many studies to be not any more reliable and frequently less reliable than serum creatinine–based equations. Moreover, it may overestimate GFR because creatinine is also secreted, particularly with advanced renal insufficiency. However, in individuals with variations in dietary intake (e.g., vegetarian diet or creatine supplements) or muscle mass (e.g., amputation, malnutrition or muscle wasting), as is seen in many elderly persons, 24-hour urine collection may be a preferred method because many of these factors are not specifically taken into account in prediction equations. GFR assessment may also be performed by invasive methods. The most reliable method is the measurement of the renal clearance of specific markers of GFR, for example inulin, radioactive markers including 51Cr-EDTA or 99mTc diethylenetriamine pentaacetic acid (DTPA) or radio-contrast agents including 125I-iothalamate, because these markers are excreted only by glomerular filtration. However, they are invasive, time-consuming, costly and cumbersome. Their use is therefore mostly restricted to research purposes, but they may be required in elderly people when an accurate measurement of GFR is essential: for example, for the calculation of drug doses for chemotherapy (21). Glomerular filtration rate estimation GFR is usually estimated (eGFR) from serum levels of endogenous filtration markers, most commonly creatinine and recently cystatin C; however, factors other than filtration, including generation, tubular secretion or reabsorption and extrarenal elimination affect these markers. Thus current guidelines recommend that the 2 most commonly used equations to estimate GFR, which are both serum creatinine–based – the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) Study equation – be used to estimate GFR in the clinical setting (29). Essentially, compared with serum creatinine, these equations increase the accuracy of eGFR vis-a-vis measured GFR by accounting for variables such as age and weight S50 in the former equation, and age, sex and race in the latter one. Their main limitation is the underestimation of GFR in patients with normal and moderately reduced levels of renal function. In fact, they have been reported to be less accurate in patients without kidney disease, muscle wasting or inflammation, all conditions that might interfere with the accuracy of creatinine or cystatin C–based estimating equations in older people with frailty or comorbidities. In elderly people, the CG formula may severely underestimate GFR, particularly in the oldest old (30). Moreover, these 2 equations can yield disparate estimates of renal function in a given individual. Inconsistency in the estimates provided by these 2 equations not only influences population-based estimates of CKD prevalence, but also has the potential to complicate patient management. Gill et al clearly reported that elderly patients were assigned to a different stage of CKD 60% of the time when the CG equation was used instead of the MDRD equation. Overall, these authors estimated that 20% fewer patients would be qualified for a dose reduction of amantadine based on MDRD eGFR versus CG estimates of CrCl (31). A similar report was made by Carnevale et al comparing the Mayo Clinic equation as well (32). The MDRD formulas for GFR estimation were derived by computer modeling from the 1,628 patients of the MDRD Study population (33). There have been some validation studies of the MDRD equation in the elderly concluding that it is better than the CG equation (34-36). However, there are also papers reporting a better performance for the CG formula (19). The InChianti study addressed the question of whether measured and estimated CrCl in older individuals is a significant predictor of mortality. The 24-hour CrCl, CG and MDRD-derived equations (full and simplified) were calculated at enrollment, and all-cause mortality and cardiovascular mortality were prospectively ascertained by Cox regression over a 6-year follow-up. In a Cox model adjusted for demographics, physical activity, comorbidities, proteinuria and inflammatory parameters, participants with CrCl 60-90 ml/min per 1.73 m2 and CrCl <60 ml/min per 1.73 m2 were, respectively, 1.70 and 1.91 times more likely to die over the follow-up, compared with those with CrCl >90 ml/min 1.73 m2. Using the CG equation, the group with values <60 ml/min per 1.73 m2 had a significantly higher all-cause mortality compared with those with values >90 ml/min per 1.73 m2. The classification based on the MDRD formulas did not provide any significant prognostic information. As suggested by the authors, CrCl and CG eGFR may be better prognostic indicators than MDRDderived equations because they incorporate a stronger effect of age. JNEPHROL 2010; 23 (S15): S46-S54 In any case, at this time, the majority of papers agree that the MDRD Study equation shows better performance than the CG equation (34-36). The most widely used form of the MDRD Study equation in elderly people is the 4-variable version or the version that was abbreviated from the original 6-variable version. This is especially advantageous for elderly patients compared with the CG formula or CrCl measurement, because it only requires serum creatinine, age, sex and race, and not weight or any urine collections. Although the MDRD formula may be more precise in elderly patients with CKD, it has not been shown to be without bias in patients with GFR greater than 60 ml/min per 1.73 m2. A new cystatin and creatinine-based estimating equation (37), developed in a pooled sample in which the mean age was 52 years, reduces bias by 50% and offers small but consistent improvements in precision and accuracy, compared with the most commonly used equation. In addition, accuracy of creatinine-based equations does not differ significantly from that of cystatin C–based equations in populations studied thus far, but equations based on the combination of the 2 markers might provide the best accuracy (37, 38). Non-GFR determinants affecting each marker, such as low muscle mass and possibly obesity, might lead to systematic overestimation or underestimation of GFR in specific individuals. Another Italian study compared the MDRD and Mayo Clinic quadratic estimate of GFR (MCQ) estimates of GFR with the measurement of CrCl in 24-hour urine collection in 73 oldest old patients (32). The main finding was that the tested equations for estimation of GFR and the measured 24-hour CrCl provide significantly different results, so that they may not be used interchangeably in clinical practice. It has also to be noted that differences in calibration of creatinine assays between laboratories can lead to differences in GFR estimation and thus is an important limitation of estimation equations in general. Recently a new equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, to estimate GFR in adults, from serum creatinine by using a large database pooled from 10 studies was developed (39). The CKD-EPI equation was shown to be more accurate than the widely used MDRD Study equation: it has lower bias, especially at an eGFR greater than 60 ml/min per 1.73 m2; however, its precision remains limited. The improved accuracy of the CKD-EPI equation overcomes some of the limitations of the MDRD Study equation and has important implications for public health and clinical practice. Improved accuracy of the CKD-EPI equation could have important implications for public health and clinical practice. Nowadays the CKD-EPI equation might be considered the new gold standard, and it could replace the MDRD Study equation in general clinical use to estimate GFR. Finally, a simple method to estimate CrCl at the bedside that might allow caregivers to approximate renal function without formally replacing the standard formulas has recently been proposed (40). The new formulas, eCCr, are eCCr (male) = weight/creatinine; and eCCr (female) = weight × 0.84/creatinine; both with weight in kg. eCCr appears to give a good rough estimate of CrCl, easily calculated at the bedside, which might alert clinicians to the need to assess a change in drug dosing, or to more formally estimate the patient’s level of renal function. The MDRD Study formulas should, of course, be used for CKD staging. Clearly, improved measures of kidney function in older patients are needed to better estimate the prevalence of CKD (41). Not one size for all ages To address this objective and better define the overall risk of the geriatric patient, Roderick et al (42) suggested the division of CKD stage 3 into 2 substages: 3a (eGFR 45-59 ml/min per 1.73 m2) and 3b (eGFR 30-44 ml/min per 1.73 m2). They found that in people 75 years and older, an eGFR less than 45 ml/min per 1.73 m2 was an independent predictor of poor survival, especially in the first 2 years of follow-up, largely because of increased cardiovascular mortality. The same finding was also noted in previous studies (43) which suggested not using the same eGFR cutoff points in the elderly as for younger age groups, and that the former group would probably benefit from a finer categorization of the 30-59 ml/min per 1.73 m2 eGFR groups (Fig. 3). We should probably redefine the present CKD classification system in which everybody with an eGFR <60 ml/ min is defined as at-risk. In this setting, 2 main options has been suggested: either introduce age- and sex-specific cutoff values or define only subjects with an eGFR below 45 as always at-risk. The level of 45 should be chosen because at that level metabolic derangements arise in our patients. So it is not only the risk for cardiovascular end points and the risk for ESRD that we should consider but also age and quality of life. At higher levels, over 45, we should pay more attention to additional signs of chronic kidney damage such as microalbuminuria, macroalbuminuria, erythrocyturia or abnormalities on an ultrasound. The term preclinical has been used to describe conditions S51 Aucella et al: Assessment of renal function in the elderly Conclusions Fig. 3 - Mortality rate by age and estimated glomerular filtration rate (eGFR, in ml/min per 1.73 m2) (data from O’Hare et al (43)). that predate the development of clinical disease and are directly associated with adverse health consequences. So, preclinical kidney disease clearly shows a direct analogy to prehypertension and prediabetes. It has been proposed to describe patients with a creatinine-based eGFR >60 ml/min per 1.73 m2 and a cystatin C level >1.0 mg/L (equivalent to an eGFR of approximately 75 ml/min per 1.73m2) as suffering from preclinical kidney disease. On the basis of these criteria, 39% of the Cardiovascular Health Study sample, in which the mean age is 75 years, do not meet the GFR-based criteria for CKD, but have preclinical kidney disease. The incidences of death and CKD, defined on the basis of creatinine-based eGFR, is higher among these patients than it is among patients with eGFR >60 ml/min per 1.73 m2 and low cystatin C (44). Not only did these participants have increased mortality and cardiovascular risk compared with those with cystatin C levels less than 1.0 mg/L, but they were also at substantially increased risk for progression to CKD after 4 years of follow-up. Furthermore, participants with elevated cystatin C concentrations who progressed to subsequent CKD had statistically significantly increased mortality and cardiovascular risk compared with participants with elevated cystatin C levels who did not progress to CKD. Taken together, these findings suggest that elevated cystatin C concentrations capture a state of preclinical kidney disease that is highly prevalent among community-dwelling elderly persons. S52 First of all, it needs to be underlined that the so-called ageassociated loss of GFR critically depends on comorbid conditions such as hypertension and diabetes. Evidence from the Cardiovascular Health Study (44) strongly suggests that unlike standard cardiovascular risk factors, which become less predictive in older adults, markers of kidney function are strong risk factors for a wide range of adverse outcomes. So, it needs to be recognized that a decreased kidney function in the elderly, either clinical or preclinical, is not benign (45). Because the measurement of serum creatinine is notoriously unreliable as an indicator of GFR in elderly patients, more reliable GFR estimates should be employed whenever indicated: for example, timed creatinine clearance, estimated GFR using a serum creatinine–based formula or serum cystatin C. Except in situations such as drug dosage adjustment and in some cases of offering transplant options, in practical terms, the change in GFR is more important than the absolute cutoff value. Although novel methods such as cystatin C–based measures are being explored, GFR estimation is still largely creatinine-based. It needs to emphasized that reporting eGFR, although having limitations, is especially useful in the elderly whose serum creatinine so poorly reflects GFR. Recognizing CKD in the elderly should benefit them even if ESRD is unlikely, because it should improve drug dosing and reduce nephrotoxin exposure. The MDRD Study equation identified large numbers of patients who met Kidney Disease Outcomes Quality Initiative (KDOQI) criteria for moderate CKD. Most of these patients were elderly, and many had “very” moderate reductions in eGFR that were not associated with an increased relative or absolute risk for death. The main limitation of current GFR estimates is the greater inaccuracy in populations without known CKD than in those with the disease. Nonetheless, current GFR estimates facilitate detection, evaluation and management of the disease, and they should result in improved patient care and better clinical outcomes. Financial support: The present study did not receive any financial support. Conflict of interest statement: None declared. Address for correspondence: Filippo Aucella, MD Chief of the Nephrology and Dialysis Unit IRCCS “Casa Sollievo della Sofferenza” Hospital Viale Cappuccini IT-71013, San Giovanni Rotondo (FG), Italy [email protected] JNEPHROL 2010; 23 (S15): S46-S54 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Macias-Nunez JF, Lopez-Novoa JM. Physiology of the healthy aging kidney. In: Macias-Nunez JF, Cameron JS, Oreopoulos DG, eds. The aging kidney in health and disease. New York: Springer; 2008. Tauchi H, Tsuboi K, Okutomi J. Age changes in the human kidney of the different races. Gerontolica. 1971;17:87-97. Kasiske BL, Umen AJ. The influence of age, sex, race and body habitus on kidney weight in humans. Arch Pathol Lab Med. 1986;110:55-60. Emamian SA, Nielsen MB, Pederson JF, Ytte L. Kidney dimension at sonography: correlation with age, sex and habitus in 665 adult volunteers. Am J Radiol. 1992;160:83-86. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec. 1992;232:194-201. Kasiske BL. Relationship between vascular disease and age associated changes in the human kidney. Kidney Int. 1987;31:1153-1159. Król E, Rutkowski B, Czarniak P, Kraszewska E. Aging or comorbid conditions: what is the main cause of kidney damage? J Nephrol. 2010;23:444-452. Fliser D. Ren sanus in corpore sano: the myth of the inexorable decline of renal function with senescence. Nephrol Dial Transplant. 2005;20:482-485. 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. Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol. 1976;31:155-163. Hemmelgarn BR, Zhang J, Manns BJ, et al. Progression of kidney dysfunction in the community-dwelling elderly. Kidney Int. 2006;69:2155-2161. Bleyer AJ, Shemanski LR, Burke GL, et al. Tobacco, hypertension, and vascular disease: risk factors for renal functional decline in an older population. Kidney Int. 2000;57:2072-2079. Keith DS, Nichols GA, Gullion CM, et al. Longitudinal followup and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659-663. Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1-12. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154-2169. 16. Collins AJ, Foley R, Herzog C, et al. Excerpts from the United States Renal Data System 2007 annual data report. Am J Kidney Dis. 2008;51:S1-S320. 17. Yamagata K, Ishida K, Sairenchi T, et al. Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study. Kidney Int. 2007;71:159-166. 18. Young JH, Klag MJ, Muntner P, Whyte JL, Pahor M, Coresh J. Blood pressure and decline in kidney function: findings from the Systolic Hypertension in the Elderly Program (SHEP). J Am Soc Nephrol. 2002;13:2776-2782. 19. Pizzarelli F, Lauretani F, Bandinelli S, et al. Predictivity of survival according to different equations for estimating renal function in community-dwelling elderly subjects. Nephrol Dial Transplant. 2009;24:1197-1205. 20. Keller CR, Odden MC, Fried LF, et al. Kidney function and markers of inflammation in elderly persons without chronic kidney disease: the Health, Aging, and Body Composition Study. Kidney Int. 2007;1:239-244. 21. Fliser D. Assessment of renal function in elderly patients. Curr Opin Nephrol Hypertens. 2008;17:604-608. 22. Swedko PJ, Clark HD, Paramsothy K, Akbari A. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med. 2003;163:356-360. 23. 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. 24. Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352:2049-2060. 25. Carbonnel C, Seux V, Pauly V, et al. Estimation of the glomerular filtration rate in elderly inpatients: comparison of four methods. Rev Med Interne. 2008;29:364-369. 26. Hojs R, Bevc S, Ekart R, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in patients with mild to moderate impairment of kidney function. Nephrol Dial Transplant. 2006;21:1855-1862. 27. Sarnak MJ, Katz R, Fried LF, et al; Cardiovascular Health Study. Cystatin C and aging success. Arch Intern Med. 2008;168:147-153. 28. Wesson L Jr. Renal hemodynamics in physiological states. In: Wesson L Jr, ed. Physiology of the human kidney. New York, NY: Grune and Stratton; 1969:96-108. 29. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(Suppl 1):S1-S49. 30. Fliser D, Franek E, Joest M, et al. Changes of renal function in the elderly: influence of hypertension and cardiac function. Kidney Int. 1997; 51:1196–1204. 31. Gill J, Malyuk R, Djurdjev O, Levin A. Use of GFR equations to adjust drug doses in an elderly multi-ethnic group: a cautionary tale. Nephrol Dial Transplant. 2007;22:2894-2899. 32. Carnevale V, Pastore L, Camaioni M, et al. Estimate of renal function in oldest old inpatients by MDRD study equation, Mayo Clinic equation and creatinine clearance. J Nephrol. 2010;23:306-313. S53 Aucella et al: Assessment of renal function in the elderly 33. Levey AS, Bosch JP, Lewis JB, et al. 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;130:461-470. 34. 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;38:73-77. 35. Lamb EJ, Webb MC, O’Riordan SE. Using the Modification of Diet in Renal Disease (MDRD) and Cockcroft and Gault equations to estimate glomerular filtration rate (GFR) in older people. Age Ageing. 2007;36:689-692. 36. 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;46:233-241. 37. Stevens LA, Coresh J, Schmid CH, et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis. 2008;51:395-406. 38. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function: Measured and estimated glomerular filtration rate. N Engl J Med. 2006;354:2473-2483. S54 39. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-612. 40. Ali F, Boldur A, Winchester JF, Homel P, Feinfeld DA. A quick and simple estimate of creatinine clearance. J Nephrol. 2010;23:408-414. 41. Anderson S, Halter JB, Hazzard WR, et al. Prediction, progression, and outcomes of chronic kidney disease in older adults. J Am Soc Nephrol. 2009;20:1199-1209. 42. Roderick PJ, Atkins J, Smeeth L, et al. CKD and mortality in older people: a community-based population study in the United kingdom. Am J Kidney Dis. 2009;53:950-960. 43. O’Hare AM, Bertenthal D, Covinsky KE, et al. Mortality risk stratification in chronic kidney disease: one size for all ages. J Am Soc Nephrol. 2006;17:846-853. 44. Shlipak MG, Katz R, Sarnak MJ, et al. Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med. 2006;145:237-246. 45. Coresh J, Astor B. Decreased kidney function in the elderly: clinical and preclinical, neither benign. Ann Intern Med. 2006;145;299-301.
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