Does Concealed Chronic Kidney Disease Predict Survival of Older Patients Discharged from Acute Care Hospitals?

Abstract

We aimed at verifying whether unrecognized chronic kidney disease (CKD) (i.e., reduced estimated glomerular filtration rate in spite of normal serum creatinine) has prognostic significance in an unselected population of older patients discharged from 11 acute care hospitals located throughout Italy. Our series consisted of 396 participants aged 70 and older. Estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease (MDRD) study equation. We compared three groups: Normal renal function (normal serum creatinine levels and normal eGFR), concealed (normal serum creatinine levels and reduced eGFR), or overt (increased creatinine levels and reduced eGFR) renal failure. The relationship between renal function and 1-year mortality was evaluated using Kaplan–Meier curves and Cox regression analysis including potential confounders. Overall, 56 patients died over a cumulative follow-up time of 335 months, with an estimated incidence rate of 16.7/100 person-year (PY). The corresponding figures in patients with normal renal function, concealed CKD, and overt CKD were 9.8/100 PY (95% CI, 5.7–15.7), 28.3/100 PY (95% CI, 13.6–52.1), and 23.0 (95% CI, 15.4–33.0), respectively (log rank test p = 0.006). According to the fully adjusted model, both concealed (hazard ratio [HR], 2.35; 95% CI, 1.09–6.01) and overt CKD (HR, 2.09; 95% CI, 1.05–5.34) were significantly associated with the outcome. Concealed CKD contributes to profile the elderly patient at greater risk of death after being discharged from acute care medical wards. If confirmed in broader populations, this finding might have both clinical and epidemiological implications.

Introduction

C hronic kidney disease (CKD) increases in prevalence with age¹ and is frequently associated with chronic diseases such as congestive heart failure, coronary artery disease, diabetes mellitus, and chronic obstructive pulmonary disease.^2
–4 Available data clearly indicate that CKD carries negative prognostic implications in both general and selected diseased populations.^3,5,6 Thus, identifying CKD might be important for prognostic and therapeutic purposes.

In elderly populations, sarcopenia secondary to age itself and aging-related conditions frequently depress serum creatinine levels, making them a poor indicator of CKD.⁷ The condition characterized by normal or low serum creatinine, despite depressed glomerular filtration rate (GFR), is known as unrecognized or concealed CKD.⁸ Unrecognized CKD is associated with increased risk of adverse drug responses (ADRs) to water-soluble drugs that is comparable to that observed in patients with overt renal failure, i.e., in those with increased serum creatinine.⁸ Thus, identifying patients with unrecognized renal failure may help to prevent ADRs by optimizing doses of prescribed drugs. Additionally, unrecognized CKD has recently been found to predict reduced 1-year survival in patients hospitalized for heart failure in a multicenter observational survey.⁹ It is likely, yet unproven, that this conclusion applies also to broader geriatric population at risk of malnutrition.

Many conditions frequently coexisting with CKD could affect survival in an elderly population and, then, need to be accounted for in estimating the association between concealed CKD and survival. The availability of several potential confounders in the PharmacosurVeillance in the Elderly Care (PVC) database^10,11 allowed us to verify whether unrecognized CKD has prognostic significance in an unselected population of older patients discharged from an acute care hospital.

Methods

The present study uses data from a collaborative observational study group, the PVC, based in community and university hospitals located throughout Italy and aimed at surveying drug consumption, occurrence of adverse drug reactions, and quality of hospital care.^10,11 The methods of the PVC study were extensively described previously.^10,11 Briefly, all patients consecutively admitted to 11 acute care medical wards and three long-term care/rehabilitation units from April 1 to June 30, 2007 were asked to participate in the study. After obtaining a written informed consent, a study physician with specific training completed a questionnaire for each patient at admission to hospital and updated it daily. A training session was carried out at the coordinating center as previously described.¹⁰

Data collection included demographic, socioeconomic, and clinical data, with special emphasis on pharmacological therapy and comprehensive geriatric assessment covering the following domains: cognitive (Mini Mental State Examination [MMSE]),¹² mood (Geriatric Depression Scale [GDS]),¹³ disability (Basic, Activities of Daily Living [ADL], and Instrumental Activities of Daily Living [IADL]),^14,15 co-morbidity (Cumulative Illness Rating Scale [CIRS]),¹⁶ and physical performance (ability to stand with the feet together in the side-by-side, semitandem, and tandem positions, time to walk 6 meters, and time to rise from a chair and return to the seated position five times without using arms).¹⁷ Once discharged, patients were followed up every 3 months for 1 year. All patients and/or their relative/caregiver were contacted by telephone call to program the follow-up visit. Each follow-up visit gathered information about functional status, changes in drugs prescriptions, and occurrence of ADRs, defined as any noxious, unintended, and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis, or therapy.¹⁸ For patients who died during the follow-up period, date and place of death were retrieved by certificates of death exhibited by relatives or caregivers. The municipal registers were consulted when neither patients nor relatives or caregivers could be contacted.

Overall, 762 patients were initially screened in the survey period, but 72 (9.4%) refused to participate, leaving a final sample of 690 patients. Twenty-five patients who died during hospital stay were excluded from the analysis, as were patients enrolled in long-term care/rehabilitation units (n = 159) and patients having missing values for any of the variables used to calculate estimated GFR (n = 110), leaving a final sample of 396 patients for the analysis. All of them were successfully tracked during the follow-up period.

The study protocol was approved by the Ethical Committee of the Italian National Research Center on Aging (INRCA), Ancona, Italy.

Analytic approach

The outcome of the present study was 1-year survival of patient discharged from participating acute care medical wards.

Estimated GFR (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation¹⁹: \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland, xspace} \usepackage{amsmath, amsxtra} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} \begin{align*} 170^{*}[\rm {serum \ creatinine}]^{-0.999} \ ^{*}[\rm {age}]^{-0.176} \ ^{*}[\rm {blood \ urea}]^{-0.170} \ ^{*}[\rm {serum \ albumin}]^{0.318} \ ^{*}(0,762 \ \rm {for \ women}) \ ^{*}(1,180 \ \hbox {for Afro-American subjects}) \end{align*}\end{document}

The MDRD formula was preferred over other formulas such as the Cockroft–Gault because it seems to be more accurate in older people.²⁰ Patients were categorized according to their renal function as having normal renal function (eGFR ≥60 mL/min per 1.73 m²), concealed (normal serum creatinine and eGFR less than 60 mL/min per 1.73 m²), or overt (increased serum creatinine and eGFR less than 60 mL/min per 1.73 m²) CKD. We remind that eGFR <60 mL/min per 1.73 m² marks the threshold for moderate renal dysfunction in Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines classification.²¹ Serum creatinine was measured by the standardized Jaffe method in all laboratories of participating centers. The cutoff used for serum creatinine was 1.26 mg/dL in males and 1.04 mg/dL in females.²²

First, we investigated the prevalence of concealed and overt CKD in the study population, and we compared sociodemographic and clinical characteristics of patients grouped according to whether they had normal renal function or concealed or overt CKD. Afterward, we compared dead and survived patients with regard to factors known to affect the prognosis in frail populations: Age, sex, cognitive impairment, physical impairment (dependency in activities of daily living, being unable at physical performance items), depressive symptoms, nutritional status (body mass index [BMI], serum albumin less than 3.5 g/dL), anemia (hemoglobin <13 g/dL for males and <12 g/dL for females), overall co-morbidity, and selected co-morbid conditions (such as hypertension, heart failure, atrial fibrillation, coronary artery disease, diabetes, stroke, cerebrovascular disease, peripheral vascular disease, and chronic obstructive pulmonary disease [COPD]).

Kaplan–Meier survival curves with the Mantel–Cox log-rank test were used to compare crude survival of patients with different degrees of renal dysfunction. The time from hospital discharge through the day of death was used as the time-to-failure variable for the model. Survivors were censored on the day of the last follow-up visit. We used a Cox regression model to obtain a deconfounded estimate of the relative risk of mortality in patients with concealed or overt renal failure compared to people with normal renal function. The proportional hazard assumption was tested graphically, plotting the log-minus-log survival function over time. The model was adjusted for all the variables that were associated with mortality and/or renal function in the crude analysis, as well as for known confounders. All analyses were performed using SPSS (version 10.0; SPSS, Inc., Chicago, IL).

Results

Clinical characteristics of patients with different degrees of CKD

Patients excluded from the analysis because of missing data were older (mean age 81.5 years; standard deviation [SD], 6.0) and less frequently female (49.1%), had similar prevalence of dependency in Basic Activities of Daily Living (BADL) (30.0%), lower prevalence of dependency in IADL (82.7%), cognitive impairment (42.7%), and depression (34.5%), and lower burden of overall co-morbidity (CIRS co-morbidity score, 2.9; SD, 1.9; CIRS severity score, 1.7; SD, 0.4). The main characteristics of the study population are reported in Table 1. The prevalence of concealed and overt renal failure was 11.4% and 38.6%, respectively. Patients with either concealed or overt renal dysfunction were older, had greater cumulative co-morbidity, and showed a greater prevalence of hypoalbuminemia, inability to perform tandem position, heart failure, atrial fibrillation, and peripheral vascular disease with respect to patients with normal renal function. Female sex was distinctly less frequent among patients with concealed renal failure (Table 1). The mean GFR values in patients with normal renal function and concealed and overt CKD were 75.7 (SD, 16.3), 51.5 (SD, 8.1), and 30.1 (SD, 10.6) mL/min per 1.73 m² (p = 0.001), respectively. The corresponding figures for serum creatinine values were 0.90 (0.21), 1.07 (0.13), and 1.9 (1.2) mg/dL, respectively. All patients with increased creatinine levels had GFR values less than 60 mL/min per 1.73 m².

Table 1.

General Characteristics of Patients Divided According to Their Renal Function

	All N = 396	Normal renal function n = 198	Concealed CKD n = 45	Overt CKD N = 153	p
Age, years	79.7 ± 5.9	78.6 ± 5.7	80.3 ± 5.6	81.0 ± 6.0	0.001
Sex, females	221 (55.8)	124 (62.6)	11 (24.4)	86 (56.2)	0.001
Actual smokers	19 (4.8)	12 (6.1)	2 (4.4)	5 (3.3)	0.475
Alcohol consumption greater than 1/2 L wine equivalent	11 (2.8)	6 (3.0)	2 (4.4)	3 (2.0)	0.642
Loss of at least one BADL	126 (31.8)	52 (26.3)	16 (35.6)	58 (37.9)	0.057
Loss of at least one IADL	357 (90.2)	171 (86.4)	43 (95.6)	143 (93.5)	0.037
Cognitive impairment	209 (52.8)	95 (48.0)	23 (51.1)	91 (59.5)	0.099
Depressive symptoms	161 (40.7)	76 (38.4)	14 (31.1)	71 (46.4)	0.121
CIRS severity	1.9 ± 0.3	1.8 ± 0.3	1.9 ± 0.3	1.9 ± 0.4	0.001
CIRS co-morbidity	3.9 ± 1.8	3.5 ± 1.7	4.1 ± 1.7	4.3 ± 1.9	0.001
BMI, kg/m²	25.7 ± 4.1	26.1 ± 4.1	25.3 ± 3.3	25.3 ± 4.3	0.197
Hypoalbuminemia	144 (36.4)	55 (27.8)	22 (48.9)	67 (43.8)	0.001
Anemia	154 (38.9)	55 (27.8)	13 (28.9)	86 (56.2)	0.001
Being unable to stand with the feet together in the side-by-side, semitandem, and tandem positions	100 (25.3)	36 (18.2)	16 (35.6)	48 (31.4)	0.004
Being unable to walk 6 meters	104 (26.3)	44 (22.2)	17 (37.8)	43 (28.1)	0.081
Being unable to rise from a chair and return to the seated position 5 times	111 (28.0)	59 (29.8)	14 (31.1)	38 (24.8)	0.524
Hypertension	282 (71.2)	139 (70.2)	29 (64.4)	114 (74.5)	0.384
Heart failure	96 (24.2)	33 (16.7)	10 (22.2)	53 (34.6)	0.001
Atrial fibrillation	63 (15.9)	17 (8.6)	11 (24.4)	35 (22.9)	0.001
Coronary artery disease	112 (28.3)	49 (24.7)	12 (26.7)	51 (33.3)	0.202
Diabetes	108 (27.3)	46 (23.2)	12 (26.7)	50 (32.7)	0.143
Stroke	53 (13.4)	23 (11.6)	8 (17.8)	22 (14.4)	0.493
Cerebrovascular disease	66 (16.7)	38 (19.2)	9 (20.0)	19 (12.4)	0.196
Peripheral vascular disease	101 (25.5)	37 (18.7)	10 (22.2)	54 (35.3)	0.002
COPD	150 (37.9)	80 (40.4)	19 (42.2)	51 (33.3)	0.326

CKD, Chronic kidney disease; BADL, Basic Activities of Daily Living; IADL, Instrumental Activities of Daily Living; CIRS, Cumulative Illness Rating Scale; BMI, body mass index; COPD, chronic obstructive pulmonary disease.

Survival analysis

Overall, 56 patients died over a cumulative follow-up time of 335 months, with an estimated incidence rate of 16.7/100 person-year (PY) (95% CI, 12.6–21.7). The corresponding figures in patients with normal renal function, concealed CKD, and overt CKD were 9.8/100 PY (95% CI, 5.7–15.7), 28.3/100 PY (95% CI, 13.6–52.1), and 23.0 (95% CI, 15.4–33.0), respectively (log-rank test p = 0.006).

Patients who died during the follow-up period were older (mean age 83.0 [SD, 6.4] vs. 79.2 [SD, 5.7] years, p = 0.001) and had a greater prevalence of dependency in at least one BADL (67.9% vs. 25.9%, p = 0.001), cognitive impairment (75.0% vs. 49.1%, p = 0.001), hypoalbuminemia (64.3% vs. 31.8%, p = 0.001), and inability to stand with the feet together in the side-by-side, semitandem, and tandem positions (53.6% vs. 20.6%, p = 0.001) when compared with survivors. Mean GFR value were 44.1 (SD, 20.7) in nonsurvivors and 57.2 (SD, 25.4) in survivors (p = 0.003), respectively.

Patients with either concealed or overt CKD had similarly reduced cumulative survival with respect to patients with normal renal function (Mantel–Cox = 7.870, p = 0.005; Breslow = 7.665, p = 0.006). The survival curves of patients grouped according to their renal function are shown in Fig. 1. Multivariable Cox regression analysis showed that both concealed (p = 0.019) and overt (p = 0.036) CKD were significantly associated with the outcome. Dependency in at least one BADL (p = 0.009), and hypoalbuminemia (p = 0.007) were also significantly associated with mortality (Table 2). Similar results were obtained when analysis was repeated adjusting for cumulative co-morbidity (concealed CKD: hazard ratio (HR), 2.73, 95% CI, 1.18–5.85, p = 0.008; overt CKD: HR. 2.19, 95% CI. 1.03–5.99, p = 0.040) or heart failure, atrial fibrillation, diabetes, and peripheral vascular disease as individual co-morbid conditions (concealed CKD: HR, 2.28, 95% CI, 1.13–4.71, p = 0.009; overt CKD: HR, 2.07, 95% CI, 1.01–5.01, p = 0.047).

FIG. 1.

Kaplan–Meier curves of patients with normal renal function or concealed or overt chronic renal failure (CRF).

Table 2.

Cox Regression Analysis of Selected Risk Factors to 1-Year Mortality

	HR ^a	95% CI ^a
Age	1.02	0.97–1.07
Sex, female	0.92	0.52–1.63
BMI, kg/m²	1.07	0.96–1.14
Dependency in at least one BADL	2.32	1.10–5.33
Cognitive impairment	1.49	0.73–3.06
Anemia	1.69	0.91–3.14
Hypoalbuminemia	2.01	1.08–3.73
Being unable to stand with the feet together in the side-by-side, semi-tandem, and tandem positions	1.0	0.50–2.05
Renal function
Normal	1.0
Concealed CKD	2.35	1.09–6.01
Overt CKD	2.09	1.05–5.34

Calculated by entering simultaneously all variables into the multivariable Cox regression model.

HR, Hazard ratio; CI, confidence interval; BMI, body mass index; BADL, Basic Activities of Daily Living; CKD, chronic kidney disease.

Discussion

This study clearly demonstrates that concealed CKD carries prognostic implications comparable to that of overt CKD in an elderly population discharged form medical wards of acute care hospitals. Interestingly, the average value of GFR was 51.5 ± 8.1 mL/min per 1.73 m² in the concealed and 30.1 ± 10.6 mL/min per 1.73 m² in the overt CKD group, and none of the concealed group but 47.7% of the overt CKD group had GFR <30 mL/min per 1.73 m². Thus, a lesser prognostic impact of concealed CKD on mortality would be expected. It is likely that factors different from the purifying function of the kidney contributed to affect the prognosis. Indeed, concealed CKD patients had nonsignificantly lower serum albumin levels and greater prevalence of inability to stand in the tandem position with regard to the overt CKD group. This might reflect worse nutritional status and decreased muscle mass, which would reduce serum creatinine, thus concealing CKD; these are known as prognostic indicators in the elderly.^23,24 Unfortunately, no direct index of sarcopenia was available nor could BMI be used as a surrogate index because fat-free mass is frequently depleted despite well-preserved or even increased BMI.²⁵ It should also be considered that an accelerated decline of endocrine and paracrine functions of the kidney might contribute to equate the prognostic weights of concealed and overt CKD. For instance, although hemoglobin levels were reduced only in overt CKD group in our study, erythropoietin secretion starts to decline in the earliest stages of kidney disease in the selected population, such as in diabetic patients, when GFR is still well preserved.²⁶ Furthermore, the 1-α hydroxylation of vitamin D has been reported to decline for GFR <60 mL/min per 1.73 m².²⁷ Reduced serum vitamin D, in turn, results in increased parathyroid hormone (PTH) serum levels and ensuing negative metabolic and cardiovascular effects.²⁸ Unfortunately, vitamin D levels were not available in our study, and this issue warrants further investigations. Finally, impaired kidney function might favor cardiovascular complications through several mechanisms.²⁹ Thus, it is likely, yet unproved, that the comparable prognostic weights of concealed and overt CKD, despite different severity of GFR impairment, at least to some extent reflect the concurrent prognostic implications of deteriorated endocrine and paracrine functions of the kidney.

Approximately 1 out of 5 patients with CKD could not be recognized only on the basis of serum creatinine levels in our study. This finding confirms that concealed CKD is highly prevalent in elderly populations.⁸ Indeed, an automated computation of GFR has been suggested as a useful means for detecting CKD and, thus, making the physician aware of it.³⁰ Given that concealed CKD is a well-known risk factor for adverse drug reactions,^8,31 its detection would improve both choice and dosing of the drugs, which is of paramount importance in elderly and frail patients. Incidentally, in our study, overdosing hydrosoluble drugs might have contributed to worsen the prognosis of patients with concealed CKD. However, we could not formally test this hypothesis given that pharmacosurveillance information was not completely available. Nevertheless, the observation pertaining to elderly diabetics of a large pharmacosurveillance survey supports this hypothesis.³¹

Although the prognostic role of CKD is recognized increasingly in several populations.^3,5,,6 including community-dwelling older people,³² the evidence regarding the prognostic significance of concealed CKD is limited. The only study we could find on PubMed search by matching the words “chronic renal failure” or “chronic kidney disease” with the words “unrecognized,” “concealed,” or “occult,” and “survival” or “mortality” for the 1999–2009 period has been carried out in a population of 4,102 patients with heart failure discharged from acute care hospitals. In this study, Amsalem et al. observed a gradient risk for 1-year mortality among patients with unrecognized (HR, 1.22; 95% CI, 0.97–1.53) and recognized (HR, 1.79; 95% CI, 1.45–2.20) CKD, the mean eGFR values of the groups being 48 ± 8 and 32 ± 12 mL/min per 1.73 m², respectively.⁹ This finding, obtained in a population having mean age of 73 years, reflects the established linear association between the severity of CKD and long-term survival in heart failure populations.³ A comparable graded association between kidney dysfunction and mortality has also been reported in a very large and broad adult population (mean age 52 years).⁵ The comparison of these studies and ours suggests that this grading smoothes in elderly and very frail population. Alternatively, the size of our sample might be insufficient to define the GFR–survival relationship optimally.

This study has several limitations. First, GFR was estimated and not measured directly. However, the MDRD formula is known to perform acceptably also in elderly and diseased populations.²⁰ Second, the lack of measures of muscle mass prevented us from assessing the hypothesized link between sarcopenia and concealed GFR. Third, the GFR cut off of 60 mL/min per m² might not be appropriate for very old patients, because an age-adjusted cutoff has recently been suggested to distinguish normal from abnormal GFR.³³ However, we preferred to conform to current guidelines on the definition of kidney disease.²¹ Differences between patients included in the analyses and those excluded because of missing data represent a potential source of bias. Finally, the study was originally designed for pharmacosurveillance proposes and not to investigate the association between CKD and survival. Thus, we could not take into account some potential confounders, e.g., body composition and sarcopenia. However, we have taken into account selected variables that are strictly correlated with these confounders, such as serum albumin and BMI, to minimize this bias. Additionally, the high goodness-of-fit of the multivariable regression model (−2 log likelihood = 588.771, p < 0.001) supports the strength of our observations, even if the sample could not have sufficient power to draw a definitive conclusion.

In conclusion, concealed CKD and even only moderate kidney dysfunction (corresponding to GFR = 45–59 mL/min per 1.73 m²) contribute to profile the elderly patient at greater risk of death after being discharged from acute care medical wards. Research is needed to verify whether this conclusion applies also to other geriatric and frail populations. Meanwhile, the current evidence suggests that GFR should be systematically calculated in elderly patients with normal serum creatinine. Detecting CKD would help interpret conditions such as anemia or hyperparathyroidism and improve drug prescription, which in themselves are important clinical goals.

Footnotes

Acknowledgments

The PharmacosurVeillance in the Elderly Care (PVC) study was partially supported by a grant from the Italian Ministry of Health (RF-INR-2005-127640). A complete list of participating centers has been previously published.^10,11

Author Disclosure Statement

All authors declare to have no conflict of interest with this manuscript.

References

Coresh

, Selvin

, Stevens

, Manzi

, Kusek

, Eggers

, Van Lente

, Levey

. Prevalence of chronic kidney disease in the United States. JAMA, 2007; 298:2038–2047.

Joseph

, Koka

, Aronow

. Prevalence of moderate and severe renal insufficiency in older persons with hypertension, diabetes mellitus, coronary artery disease, peripheral arterial disease, ischemic stroke, or congestive heart failure in an academic nursing home. J Am Med Dir Assoc, 2008; 9:257–259.

McAlister

, Ezekowitz

, Tonelli

, Armstrong

. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation, 2004; 109:1004–1009.

Incalzi

, Corsonello

, Pedone

, Battaglia

, Paglino

, Bellia

. Extrapulmonary Consequences of COPD in the Elderly Study Investigators. Chronic renal failure: A neglected comorbidity of COPD. Chest, 2010; 137:831–837.

, Chertow

, Fan

, McCulloch

, Hsu

. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med, 2004; 351:1296–1305.

Mahon

, Blackstone

, Francis

, Starling

3rd , Young

, Lauer

. The prognostic value of estimated creatinine clearance alongside functional capacity in ambulatory patients with chronic congestive heart failure. J Am Coll Cardiol, 2002; 40:1106–1113.

Lindeman

. Assessment of renal function in the old. Special considerations. Clin Lab Med, 1993; 13:269–277.

Corsonello

, Pedone

, Corica

, Mussi

, Carbonin

, Antonelli Incalzi

. Concealed renal insufficiency and adverse drug reactions in elderly hospitalized patients. Arch Intern Med, 2005; 165:790–795.

Amsalem

, Garty

, Schwartz

, Sandach

, Behar

, Caspi

, Gottlieb

, Ezra

, Lewis

, Leor

. Prevalence and significance of unrecognized renal insufficiency in patients with heart failure. Eur Heart J., 2008; 29:1029–1036.

10.

Corsonello

, Pedone

, Lattanzio

, Lucchetti

, Garasto

, Di Muzio

, Giunta

, Onder

, Di Iorio

, Volpato

, Corica

, Mussi

, Antonelli Incalzi

. Pharamacosur Veillance in the Elderly Care Study Group. Potentially inappropriate medications and functional decline in elderly hospitalized patients. J Am Geriatr Soc, 2009; 57:1007–1014.

11.

Corsonello

, Pedone

, Lattanzio

, Lucchetti

, Garasto

, Carbone

, Greco

, Fabbietti

, Incalzi

. Regimen complexity and medication nonadherence in elderly patients. Ther Clin Risk Manag, 2009; 5:209–216.

12.

Folstein

, Folstein

, McHugh

. “Mini-mental state” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 1975; 12:189–198.

13.

Lesher

, Berryhill

. Validation of the Geriatric Depression Scale—Short Form among inpatients. J Clin Psychol, 1994; 50:256–260.

14.

Katz

, Ford

, Moskowitz

, Jackson

, Jaffe

. Studies of illness in the aged. The Index of Adl: A standardized measure of biological and psychosocial function. JAMA, 1963; 185:914–919.

15.

Lawton

, Brody

. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist, 1969; 9:179–186.

16.

Conwell

, Forbes

, Cox

, Caine

. Validation of a measure of physical illness burden at autopsy: the Cumulative Illness Rating Scale. J Am Geriatr Soc, 1993; 41:38–41.

17.

Guralnik

, Simonsick

, Ferrucci

, Glynn

, Berkman

, Blazer

, Scherr

, Wallace

. A short physical performance battery assessing lower extremity function: Association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol, 1994; 49:M85–M94.

18.

World Health Organization. International Drug Monitoring: The Role of the Hospital. Geneva, Switzerland: World Health Organization, 1969WHO Technical Report Series No. 425.

19.

Levey

, Bosch

, Lewis

, Greene

, Rogers

, Roth

. 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.

20.

Stevens

, Coresh

, Greene

, Levey

. Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med, 2006; 354:2473–2483.

21.

K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis, 2002; 39:S1–S266.

22.

Jones

, McQuillan

, Kusek

et al. Serum creatinine levels in the US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis, 1998; 32:992–999.

23.

Persson

, Brismar

, Katzarski

, Nordenstrom

, Cederholm

. Nutritional status using mini nutritional assessment and subjective global assessment predict mortality in geriatric patients. J Am Geriatr Soc, 2002; 50:1996–2002.

24.

Wannamethee

, Shaper

, Lennon

, Whincup

. Decreased muscle mass and increased central adiposity are independently related to mortality in older men. Am J Clin Nutr., 2007; 86:1339–1346.

25.

Zamboni

, Mazzali

, Fantin

, Rossi

, Di Francesco

. Sarcopenic obesity: A new category of obesity in the elderly. Nutr Metab Cardiovasc Dis, 2008; 18:388–395.

26.

Mojiminiyi

, Abdella

, Zaki

, El Gebely

, Mohamedi

, Aldhahi

. Prevalence and associations of low plasma erythropoietin in patients with type 2 diabetes mellitus. Diabet Med, 2006; 23:839–844.

27.

K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis., 2003; 42:S1–S201.

28.

Reis

, von Muhlen

, Michos

, Miller E

III

, Appel

, Araneta

, Barrett-Connor

. Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis, 2009; 207:585–90.

29.

Kendrick

, Chonchol

. Nontraditional risk factors for cardiovascular disease in patients with chronic kidney disease. Nat Clin Pract Nephrol, 2008; 4:672–681.

30.

Johnson

, Usherwood

. Automated reporting of GFR—coming soon to a laboratory near you! Aust Fam Physician, 2005; 34:925–931.

31.

Corsonello

, Pedone

, Corica

, Mazzei

, Di Iorio

, Carbonin

, Incalzi

. for the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA). Concealed renal failure and adverse drug reactions in older patients with type 2 diabetes mellitus. J Gerontol A Biol Sci Med Sci, 2005; 60:1147–1151.

32.

Roderick

, Atkins

, Smeeth

, Mylne

, Nitsch

, Hubbard

, Bulpitt

, Fletcher

. CKD and mortality risk in older people: A community-based population study in the United Kingdom. Am J Kidney Dis, 2009; 53:950–960.

33.

Douville

, Martel

, Talbot

, Desmeules

, Langlois

, Agharazii

. Impact of age on glomerular filtration estimates. Nephrol Dial Transplant, 2009; 24:97–103.