Agreement between equations estimating glomerular filtration rate

in elderly nursing home residents and in hospitalised patients:

implications for drug dosing

Andrea Corsonello Claudio Pedone Fabrizia Lattanzio Roberto Semeraro Francesco

D'AndriaMaurizio Gigante Anna Coppola Giancarlo Cadeddu Irma Laino Raffaele Antonelli
Incalzi

Age and Ageing, Volume 40, Issue 5, 1 September 2011, Pages 583589,
https://doi.org/10.1093/ageing/afr011
Published: 10 March 2011

Abstract
Background: detecting chronic kidney disease (CKD) may have important implications for the
management of older and frail people. We aimed at investigating whether clinical setting
(nursing home: NH versus hospital: H) affects the agreement between glomerular filtration rate
(GFR) values estimated by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI),
Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations.
Design: observational study.
Setting: comparison between NH residents and H patients.
Subjects: we used data from 177 NH residents, and 439 H patients.
Methods: the agreement between estimating equations and the odds of a discrepancy >25%
between formulas in relation to setting (NH versus H) were investigated.
Results: the agreement between MDRD and CKD-EPI formulas was good either in NH (k = 0.82)
or H (k = 0.87) patients, while corresponding figures for CG indicate only a fair agreement with
CKD-EPI (k = 0.50 for both populations). Setting (NH versus H) was associated with
discordance between MDRD and CKD-EPI (OR = 3.97; 95% CI = 1.759.01), but not between CG
and EPI (OR = 1.25; 95% CI = 0.871.81).
Conclusions: in NH residents, MDRD and CKD-EPI formulas yield highly concordant GFR
values, but CG behaves differently in up to one-third of patients. Such findings have important
implications in dosing drugs cleared by the kidney. Setting should be taken into consideration
in studies for validation of GFR equations.
Keywords: glomerular filtration rate, nursing home, hospital, drugs, elderly
Issue Section: Research Papers

Introduction

Chronic kidney disease (CKD) is very common in nursing home (NH) residents [1] and
represents a risk factor for drug overdosage and adverse drug reactions (ADRs) [2].
Unfortunately, sarcopenia, whose prevalence in NH residents ranges between 40 and 85%
[3], reduces creatinine production making serum creatinine (Scr) a poorly reliable marker
of CKD, whereas logistic difficulties prevent the measurement of the glomerular filtration
rate (GFR) by radionuclide or iothalamate-based methods in NH residents. These
methodological problems impact guidelines for drug dosing in these patients. Indeed, most
of the regulatory authorities mandate the use of the Cockcroft-Gault (CG) formula, which
estimates creatinine clearance (CCr) and antedates the Modification of Diet in Renal
Disease (MDRD) by 23 years, to adjust dosing, but recently the MDRD has been occasionally
suggested as the reference equation [4]. More important, following recommendation by the
National Kidney Foundation [5], the MDRD-derived GFR is more and more frequently part
of computer generated laboratory reports. This might improperly lead to adjust drug
dosing according to MDRD equation that actually estimates something different from what
CG measures (i.e. GFR versus CCr). Finally, a third equation, the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) [6], has recently been proposed as more accurate
than the MDRD in the upper range of GFR values and is gaining growing popularity, but it
has been developed and tested in a youngadult population.

On average, MDRD seems more accurate than CG in the CKD population, while CG formula
should be preferred to the MDRD for estimating renal function in at-risk subjects with
normal Scr, e.g. diabetics and stage 1 and 2 CKD patients, and in elderly patients [7].
However, it is unknown whether in NH residents CG and MDRD are plagued with a risk of
misclassification comparable with that observed in hospitalised and severely diseased
patients [8]. Therefore, the present study was aimed at comparing results provided by CG,
MDRD and CKD-EPI formulas in NH residents and to verify whether discrepancy mirrors
that characterising elderly people admitted to acute care medical wards (H). The final
objective of our analysis was to assess to which extent the discrepancy in estimated CCr or
GFR impacts adjustment of drug dosing.

Methods

NH patients
Data were collected in a 80-beds skilled NH facility in Taranto, Italy, as previously
described [9]. Reasons for admission to the NH were most frequently acute disabling
conditions (e.g. hip fracture or stroke) in patients with several comorbid conditions and
little or no rehabilitation potential. Over a 8-month period, 210 patients were initially
screened. Of them, 30 patients were excluded because we could not reliably measure
weight and/or height, and 3 patients were excluded because of missing values for any of
the variables used to calculate estimated GFR, leaving 177 patients for the analysis.

H patients
We used data from a collaborative observational study group, the PharmacosurVeillance in
the elderly CarePVC, based in community and university hospitals located throughout
Italy, aimed at surveying drug consumption, occurrence of ADRs and quality of hospital
care [10]. Overall, 690 patients were enrolled in the study. 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 = 67), leaving a final sample of 439 patients
for the analysis. All of them were successfully tracked during the follow-up period.
Renal function estimates
Scr was measured by standardised Jaffe method in all laboratories of participating centres
while patients clinical status was stable, and in the absence of dehydration or
hyperhydration. The cut-off used for Scr was 1.26 mg/dl in males and 1.04 mg/dl in
females [11]. CCr was estimated by CG [12], and GFR through MDRD [13] and CKD-EPI [6]
formulas.

Since the MDRD and CKD-EPI formulas are corrected for body surface area (BSA), while CG
formula is not, we resolved to adjust CG-estimated values for BSA in order to minimise
discrepancies between the three different methods.

Analytic approach
Outcomes of this study were: the agreement between CCr/GFR formulas, the impact of
setting on discrepancies between formulas and the implication of discrepancy on drug
dosing.

In both study populations, demographics, socioeconomic and clinical data were collected
together with detailed information on pharmacological therapy, cognitive status (mini-
mental state examination, MMSE), mood (Geriatric Depression Scale, GDS) and disability
(basic activities of daily living, ADL). The number of diagnoses was used as an index of
overall comorbidity. Selected diagnoses known to be associated with CKD, such as
hypertension, congestive heart failure, diabetes, COPD, coronary heart disease and
cerebrovascular disease, were also separately considered in the analysis. Body mass index
and serum albumin were also included in the analysis as indices of nutritional status.

First, we compared socio-demographic and clinical characteristics of NH and H patients

using one-way ANOVA for continuous variables, and Chi-square test for categorical ones.
Therefore, we investigated the agreement between formulas either in NH or H population.
We used the 95% limits of agreement [14], i.e. the average difference 1.96 SD of the
average difference. The agreement of the estimating equations in identifying people with
normal or mildly reduced renal function (estimated CCr or GFR 60 ml/min/1.73 m2 BSA),
moderate CKD (estimated CCr or GFR between 30 and 59.9 ml/min/1.73 m2 BSA, inclusive)
and severe CKD (estimated CCr or GFR <30 ml/min/1.73 m2 BSA) was evaluated using
the k statistic. We considered CKD-EPI as a reference equation because recent evidence
suggests that it gives the best estimation of GFR, although its accuracy is close to that of the
MDRD [15].

Second, in order to evaluate whether the risk of overestimating renal function was setting-
dependent, we estimated the odds of an absolute discrepancy (>25%) between MDRD and
CKD-EPI in the NH compared with the H population. The latter analysis was repeated using
the CG-BSA formula instead of the MDRD.

Finally, we provided some examples of how differences in the estimated CCr or GFR as a
function of the formula used translates in drug dosage adjustment [16, 17]. To this aim, we
selected out renally cleared cardiovascular drugs and antibiotics which are commonly
prescribed in elderly and frail population of nursing home residents [18].

All analyses were performed using SPSS (version 10.0; SPSS, Inc., Chicago, IL, USA).

Results

General characteristics of NH and H populations are reported in Table 1. Overall, NH

residents were older and more severely ill than H patients. The mean (SD) GFR or CCr
values estimated by EPI, MDRD and CG-BSA were 63.5 (22.1), 71.5 (29.2) and 54.0 (21.9)
ml/min/1.73 m2 in NH patients, respectively. The corresponding figures in H patients were
57.1 (20.6), 61.5 (23.6) and 48.3 (18.3) ml/min/1.73 m2, respectively. Normal Scr levels
were observed in 69.5% of NH residents and in 61.0% of H patients.
Table 1.
General characteristics of the two populations studied

NH patients H patients P-
(n = 177) (n = 439) value

Age, years 81.9 7.9 79.7 5.9 0.001

Gender, female 62.1 55.1 0.111

BMI, kg/m2 26.0 5.0 25.2 4.2 0.033

Serum albumin, g/dl 3.5 0.6 3.6 0.6 0.077

Serum creatinine, mg/dl 1.1 0.6 1.4 1.8 0.010

Dependent in at least 1
BADL 52.5 30.3 0.001

Cognitive impairment 65.0 50.3 0.001

No. of diagnoses 7.0 2.5 4.6 2.1 0.001

Hypertension 55.9 71.8 0.001

Congestive heart failure 4.5 22.6 0.001

Diabetes 31.6 25.5 0.122

COPD 26.0 36.7 0.011

Coronary heart disease 11.3 28.2 0.001

Cerebrovascular disease 31.1 15.0 0.001

Fracture 28.8 1.6 0.001

 NH patients H patients P-
(n = 177) (n = 439) value

Dementia 5.6 9.3 0.133

The average agreements of the MDRD and CG-BSA formulas with the CKD-EPI formula are
shown in Table 2, upper panel: the MDRD equation on average yielded higher and CG-BSA
lower values than CKD-EPI, both in the NH and H populations.

Table 2.
Average agreement (upper panel) and agreement between MDRD-, CG- and CKD-
EPI-based classification of renal function (lower panel)

Average 95% agreement

agreement intervals

Upper panel

Nursing home patients (n = 177)

MDRD 7.9 12.320.1

CG-
BSA 9.5 26.97.9

Hospital patients (n = 439)

MDRD-
GFR 4.3 6.114.7

CG-
BSA 8.8 22.54.9
 Average 95% agreement
agreement intervals

CKD-EPI

<30
(n = 15) 3059 60+ (n = 102)
% (n = 60) % % Weighted

Lower panel

Nursing home patients (n = 177)

MDRD

<30 73.3 0 0

3059 26.7 80.0 1.0

60+ 0 20.0 99.0 0.82

CG-
BSA

<30 100 23.3 0

3059 0 73.3 37.3

60+ 0 3.3 62.7 0.50

 Average 95% agreement
agreement intervals

CKD-EPI

<30
(n = 43) 3059 60+ (n = 209)
% (n = 187) % % Weighted

Hospital patients (n = 439)

MDRD

<30 90.7 0 0

3059 9.3 84.0 0

60+ 0 16.0 100 0.87

CG-
BSA

<30 100 13.9 0

3059 0 84.0 49.8

60+ 0 2.1 50.2 0.50

The agreement between MDRD and CKD-EPI formulas in identifying patients with normal
or mildly reduced renal function, moderate and severe CKD was good either in NH or H
patients, while corresponding figures for CG-BSA indicate only a fair agreement with CKD-
EPI in both study populations (Table 2, lower panel).

All patients carrying discordance between MDRD and CKD-EPI had normal Scr values, the
corresponding proportion among patients with concordant values was 61.9%. Mean
estimated GFR was higher in patients with discordant values (CKD-EPI: 90.7 7.2 versus
57.6 20.6 ml/min/1.73 m2, P 0.001; MDRD: 123.6 17.2 versus
61.8 22.9 ml/min/1.72 m2, P < 0.001). Correlates of discordance greater than 25% of
CKD-EPI value are shown in Table 3. Dependence and setting were significantly associated
with discordance between MDRD and CKD-EPI, while female gender was a negative
correlate of discordance (Table 3, upper panel).

Table 3.
Correlates of the observed discordance between GFR formulas

MDRD versus CKD-EPI

Crude
Discordance 25% Discordance >25% OR
of CKD-EPI of CKD-EPI (95%
value n = 591 value n = 25 CI)

Upper panel

1.01
(0.95
Age, years 80.3 6.5 80.8 8.1 1.07)

0.34
(0.14
Gender, female 58.2 32.0 0.79)
MDRD versus CKD-EPI

Crude
Discordance 25% Discordance >25% OR
of CKD-EPI of CKD-EPI (95%
value n = 591 value n = 25 CI)

0.96
(0.88
BMI, kg/m2 25.4 4.5 24.7 2.9 1.05)

0.76
Serum albumin, (0.40
g/dl 3.6 0.6 3.5 0.7 1.41)

3.22
Dependent in at (1.40
least 1 BADL 35.5 64.0 7.42)

2.21
Cognitive (0.91
impairment 53.8 72.0 5.36)

1.08
(0.93
No. of diagnoses 5.3 2.4 5.8 2.9 1.26)

0.61
(0.27
Hypertension 67.7 56.0 1.36)

0.40
Congestive heart (0.10
failure 17.8 8.0 1.73)
MDRD versus CKD-EPI

Crude
Discordance 25% Discordance >25% OR
of CKD-EPI of CKD-EPI (95%
value n = 591 value n = 25 CI)

0.84
(0.33
Diabetes 27.4 24.0 2.13)

0.76
(0.31
COPD 33.8 28.0 1.85)

0.43
Coronary heart (0.13
disease 23.9 12.0 1.48)

1.02
Cerebrovascular (0.38
disease 19.6 20.0 2.78)

2.54
(0.91
Fracture 9.0 20.0 7.04)

0.96
(0.22
Dementia 8.3 8.0 4.20)

Study group

H 72.6 40.0 1.0

MDRD versus CKD-EPI

Crude
Discordance 25% Discordance >25% OR
of CKD-EPI of CKD-EPI (95%
value n = 591 value n = 25 CI)

3.97
(1.75
NH 27.4 60.0 9.01)

CG-BSA versus CKD-EPI

Discordance 25% of Discordance >25%

CKD-EPI of CKD-EPI Crude OR
value n = 412 value n = 204 (95% CI)

Lower panel

1.19
(1.15
Age, years 78.2 5.8 84.6 6.2 1.23)

0.59
(0.42
Gender, female 61.4 48.5 0.83)

0.85
(0.83
BMI, kg/m2 27.1 4.0 21.8 3.0 0.87)

0.61
Serum albumin, (0.45
g/dl 3.7 0.6 3.5 0.7 0.82)
MDRD versus CKD-EPI

Crude
Discordance 25% Discordance >25% OR
of CKD-EPI of CKD-EPI (95%
value n = 591 value n = 25 CI)

1.81
Dependent in at (1.28
least 1 BADL 32.0 46.1 2.56)

1.42
Cognitive (1.01
impairment 51.7 60.3 1.99)

0.90
(0.86
No. of diagnoses 5.4 2.4 5.1 2.6 1.03)

0.77
(0.54
Hypertension 69.2 63.2 1.09)

0.46
Congestive heart (0.28
failure 20.6 10.8 0.77)

0.54
(0.36
Diabetes 31.1 19.6 0.81)

0.73
(0.50
COPD 35.9 28.9 1.04)
 MDRD versus CKD-EPI

Crude
Discordance 25% Discordance >25% OR
of CKD-EPI of CKD-EPI (95%
value n = 591 value n = 25 CI)

0.82
Coronary heart (0.55
disease 24.5 21.1 1.23)

0.58
Cerebrovascular (0.36
disease 22.3 14.2 0.91)

3.23
(1.86
Fracture 5.8 16.7 5.62)

1.11
(0.61
Dementia 8.0 8.8 2.03)

Study group

H 72.8 68.1 1.0

1.25
(0.87
NH 27.2 31.9 1.81)

The prevalence of normal Scr level was 69.1% in discordant patients and 60.7% in
concordant patients (P = 0.04) when considering CG versus CKD-EPI. Although differences
were not statistically significant, mean GFR or CCr values were higher in patients with
discordant values also in this analysis (CKD-EPI: 60.6 17.6 versus
58.1 22.8 ml/min/1.73 m2, P = 0.176; CG-BSA: 66.8 20.6 versus
63.1 27.9 ml/min/1.73 m2, P = 0.100). Setting did not affect discordance between CG-BSA
and CKD-EPI. Age, dependence and cognitive impairment were significant direct correlates
of discordance, while female gender, BMI and serum albumin, as well as selected diagnoses
such as congestive heart failure, diabetes and cerebrovascular disease qualified as negative
correlates of the outcome (Table 3, lower panel).

In the Appendix 2, Supplementary data available in Age and Ageing online, we present
dosage adjustment needed in relation to GFR or CCr values for selected drugs frequently
used in NH residents. To provide an example of how adjustment depends upon the
equation used to estimate renal function, one could consider a 85-year-old male patient
having 1.3 mg/dl Scr and a body weight of 70 kg. Such patient will have a CG-BSA-
estimated CCr of 39.0 ml/min/1.73 m2, a MDRD-estimated GFR of 52 ml/min/1.73 m2 and a
CKD-EPI-estimated GFR of 50 ml/min/1.73 m2. Such different estimates will lead to
extremely different dosage adjustment for selected drugs frequently used in elderly and
frail patients (see Appendix 1, Supplementary data available in Age and Ageing online, for
examples).

Discussion

We found selected, but potentially important discrepancies between formulas estimating

GFR in a NH population. Malnutrition characterised the 204 patients for whom the CG-BSA
discrepancy exceeded 25% of the CKD-EPI-based GFR value and might be causally related
to the discrepancy due to the preminent role of body weight in the CG formula. Structural
differences between formulas also likely account for discrepancy. Indeed, the CG intends to
measure the CCr, whereas the MDRD is a proxy of the GFR. CCr is influenced by tubular
secretion and extrarenal clearance of creatinine as well as by drugs affecting the renal
handling of creatinine [19]. For this reason, CCr usually exceeds GFR, whereas CG usually
provides lower values than MDRD and age and weight are main source of discrepancy [20].
This makes CG and MDRD formulas not interchangeable in the estimation of renal function.
Implications of present findings are straightforward: dosing requirement of a given drug
cleared by the kidney will dramatically change depending upon the formula used to obtain
GFR or CCr. This is especially true for the CG-BSA versus MDRD or CKD-EPI-based values.
Indeed, most of the official summaries of product characteristics provided by
manufacturers refer to CG, and very few examples of MDRD-based dosing adjustment are
available, as for everolimus. Surprisingly, to calculate maintenance dose of digoxin, the
manufacturer suggests to calculate CCr as (140 Age)/Scr, to be multiplied for 0.85 for
females, without providing any reference for this, and to initiate the treatment with
spironolactone in patients with severe heart failure the manufacturer recommend to
ascertain that patient's Scr is lesser or equal to 2.5 mg/dl (see Appendix 1, Supplementary
data available in Age and Ageing online, for web references). Interestingly, the draft version
of the Guidance for IndustryPharmacokinetics in Patients with Impaired Renal
FunctionStudy Design, Data Analysis, and Impact on Dosing and Labeling of the Food and
Drug Administration (see web reference in Appendix 1, Supplementary data available in
Age and Ageing online), CG and MDRD are simply reported as the two most commonly used
serum-creatinine-based equations used to estimate renal function. However, the formula
used and, then, the values obtained will translate in different dosing regimens. Selected
examples are provided in Appendix 1, Supplementary data available in Age and Ageing
online. It is evident that discrepancy between formulas might result in underdosing and,
then, lack of efficacy, or overdosing and, then, risk of ADRs.

In analogy with our findings, an important discrepancy in estimated renal function

between CG and MDRD has been observed in a multiethnic NH population, and dose
reduction in two test drugs, amantadine and digoxin, would have been more commonly
required for CG-estimated CCr than for MDRD-estimated GFR [21]. Also in a very large
population with acute coronary syndrome, computing CCr or GFR according to CG or MDRD
differently impacted the antithrombotic dose adjustment in a consistent proportions of
patients [22], and the CG-based adjustment was judged more reliable. Furthermore, in a
hospitalised population with mean age of 82 years treated by LMWH the MDRD
overestimated GFR with regard to CG by about 30 ml/min, with important effect on dose
adjustment [23]. These findings should deter form adjusting the dose by an equation
different from that recommended by the drug manufacturer, at least in the frail elderly.
When no reference equation is recommended (e.g. for enoxaparin, ramipril and
amantadine) (see Supplementary Data for web references; Supplementary data are
available in Age and Ageing online) and dosing informations refer to measured CCr, a
measure difficult to obtain in frail patients [24], it would be logical to use the equation
known to be more valid in the population of interest. Unfortunately, we only know that CG-
BSA outperforms MDRD in accuracy, if the reference standard is the CCr [9, 25]. On the
other hand, MDRD was found to be highly accurate in a cross-sectional analysis of 10
studies validating MDRD versus iothalamate-based measurement of GFR [26]. However,
the studied populations were young or adult and, then, did not represent an average NH
population. On the other hand, it should also be observed that NH residents usually are not
amenable to direct measurement of GFR due to the lack of related facilities. As a
consequence, subjects who might gain the greatest benefit from the direct measurement of
renal function almost invariably depend upon indirect assessment. Furthermore, surrogate
measures of renal function other than estimated CCr or GFR, such as serum cystatin C, have
not passed the proof of clinical practice [27]. Thus, good sense and personal experience are
occasionally called to compensate for lack of reliable guidelines.

Limitations of this study deserve consideration. First, the quality of data collection in a
multicentre population is unlikely to reach the degree of accuracy achieved in a single
centre highly skilled nursing home. Second, patients for whom no estimate of height and/or
weight was available, i.e. the most disabled and at greatest risk of renal failure and ADRs,
could not contribute to our analysis. Third, we take care of measuring Scr and weight when
the patient was normally hydrated, but we relied on clinical judgment and laboratory
analyses, not on bio-impedenziometry. Finally, our study did not include a direct
measurement of GFR. Thus, we cannot draw any definitive conclusion about the
relationship between setting and accuracy of the equations studied.

Conclusions

This study shows that in a frail NH population MDRD and CKD-EPI formulas yield highly
concordant GFR values, but CG-BSA behaves differently in up to one-third of patients. As a
general rule, it seems reasonable to adjust renally cleared drugs dosing according to the
recommendation provided by the manufacturer and, if no equation is recommended, refer
to the one proved more reliable in the reference population. Research on the validity of
available equations in NH patients, having a gold standard GFR measurement, is highly
desirable and could improve the management of a dramatically rising proportion of elderly
people.

Key points

- MDRD and CKD-EPI formulas yield highly concordant GFR values also in a frail NH
population.
- The agreement between CG-BSA and CKD-EPI is only fair in both populations.
- These findings have relevant implications, especially in dosing drugs. It seems reasonable
to adjust renally cleared drugs dosing according to the recommendation provided by the
manufacturer and, if no equation is recommended, refer to the one proved more reliable in
the reference population.
- Further research on the validity of available equations in NH patients, having a gold
standard GFR measurement, is highly desirable and could improve the management of a
rapidly expanding population.

Conflicts of interest

None declared.

Funding

The PVC study was partially supported by a grant from the Italian Ministry of Health (RF-
INR-2005-127640). A complete list of participating centres has been previously published
[10].
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