The Journal of Nutrition, Health & Aging

Volume 15, Number 6, 2011

480
Introduction
Traditionally, CRI has been identified by a decrease in GFR,
calculated by clearance techniques (1). It is a widespread
medical trend to predict CRI on the basis of calculations of the
critical value of calculated or eGFR lower than 60 ml/min/1.73
m
2
. This procedure has at least two pitfalls. The first is that
eGFR values do not always indicate the presence of CRI. The
second is that the characteristics of the normal aging process
are neglected. From the physiological point of view, the normal
ageing process is characterized by a decrease in functional
performance, including a decreased GFR, in comparison with
healthy young individuals. Despite this fall, renal function
retains its capability to maintain the equilibrium of the internal
milieu of healthy elderly people (2). Thus, one of the most
difficult tasks for physicians is to determine the presence of
renal insufficiency in aged individuals, particularly those older
than 70 years of age, since functional normality evolves
throughout life and hence has no fixed value. GFR reaches a
peak between 120-130 ml/min/ 1.73 m
2
at the age of 30, and
thereafter decreases at a constant rate of 1 ml/min/year,
although for persons aged 70-110 years, the decline averages
1.05 ml/min/year (3).
Study design
This was a predictive, transversal, non-randomized,
multicentric and multinational study carried out with the
collaboration of 11 nephrologists, 4 internal medicine
physicians, 3 cardiologists, 3 geriatricians, 2 specialists in
clinical biochemistry, 1 specialist in nuclear medicine and 3
family doctors from Argentina, Portugal and Spain.
CRI diagnosis criteria
Chronic renal insufficiency (CRI) and NCRI (patients
without CRI) diagnosis were based on the decision of doctors
after a holistic evaluation of the patient, including clinical
findings, image, and biochemical variables, and not exclusively
on a calculated or eGFR lower than 60 ml/min/1.73 m
2
.
The assembly procedure, including data acquisition, data
evaluation, the detection of variables with discriminative
power, the development and validation of the HUGE formula,
the achievement of our gold standard for the diagnosis of CRI
or NCRI, the confirmed true diagnostic core database (CTDB),
and the matching of the HUGE formula with the MDRD and
CKD-EPI formulas in large database, is shown in the beside
box diagram ( Figure 1).
HAEMATOCRIT, BLOOD UREA AND GENDER (HUGE) AS A SCREENING TEST FOR CRI
THE VALUE OF A FORMULA INCLUDING HAEMATOCRIT, BLOOD UREA
AND GENDER (HUGE) AS A SCREENING TEST
FOR CHRONIC RENAL INSUFFICIENCY
J.A. ALVAREZ-GREGORI
1
, N. R. ROBLES
2
, C. MENA
3
, R. ARDANUY
4
,
R. JAUREGUI
5
, J.F. MACIAS-NUNEZ
6
1. Honorific Professor of Geriatrics. Faculty of Medicine. University of Salamanca. Internal Resident. Casto Prieto Health Centre. Family and Community Medicine Unit. Salamanca.
Spain; 2. Nephrologist. Renal. Unit. University Hospital. Infanta Cristina. Associated Director, Chair FIIPERVA of Vascular Risk Factors, Geriatrics. Badajoz. Spain;
3. Mena C. General Practitioner. County Hospital Don Benito, Badajoz. Spain; 4. Ardanuy R. Professor of Statistics Department Faculty of Sciences. University of Salamanca. Spain;
5. Family and Community Medicine Unit, Buenos Aires, Argentina; 6. Titular Professor of Medicine. Director Chair FIIPERVA of Vascular Risk Factors, Geriatrics. Chief Clinician of
Nephrology Department. University Hospital. University of Salamanca. Spain. Corresponding Author: Macas Nez JF. Titular Professor of Medicine. Director, Chair FIIPERVA of
Vascular Risk Factors, Geriatrics. Chief Clinician of Nephrology. University Hospital. Faculty of Medicine. Avda. Alfonso X el Sabio s/n, Salamanca 37007, Spain. Phone: +34
923234540 ext. 1954, e-mail: jfmacias@usal.es
Abstract: Introduction: Despite increasing use in clinical practice, an estimated glomerular filtration rate value
(eGFR) of <60 ml/min/1.73 m
2
does not necessarily indicate the existence of chronic renal insufficiency (CRI)
and this may lead to an over-estimate of CRI particularly in persons seventy years or older. Aim: To find a
screening test able to differentiate CRI from the decrease in GFR normally associated with the renal ageing
process. Methods: Medical information of 487 individuals of both sexes aged 16-102 was obtained from
nephrologists, internal medicine physicians, cardiologists, geriatricians, family and nuclear medicine doctors
from Argentina, Portugal and Spain. Data were assessed and statistically analysed using logistic regression
techniques. From the discriminative variables it was derived the HUGE formula. Results: A formula including
haematocrit , blood urea, and gender (HUGE), diagnoses CRI regardless of the variables of age, blood
creatinine, creatinine clearance, or other eGFR. The HUGE formula is: L= 2.505458 (0.264418 x Hematocrit) +
(0.118100 x Urea) [+ 1.383960 if male]. If L is a negative number the individual does not have CRI; if L is a
positive number, CRI is present. Our data demonstrate that the HUGE formula is more reliable than MDRD and
CKD-EPI, particularly in persons aged over 70. Conclusions: Our HUGE screening formula offers a
straightforward, easily available and inexpensive method for differentiating between CRI and eGFR < 60
ml/min/1.73 m
2
that will prevent a considerable number of aged healthy persons, as much as 1.700.000 in Spain
and 2.600.000 in UK, to be excluded from clinical assays or treatments contraindicated in CRI.
Key words: Urea, chronic renal insufficiency, screening, haematocrit.
Received June 30, 2010
Accepted for publication August 30, 2010
Figure 1
Expplanatory diagram showing the methodological pathway to
achieve the HUGE formula (according to CONSORT
statement)
Data acquisition
A database template was designed containing the variables
of age, sex, body weight, height, abdominal girth, haemoglobin,
haematocrit , plasma ferritin, vit B12, folic acid levels, blood
urea, blood creatinine, 24-hour diuresis, urinary creatinine,
proteinuria detectable with routine urinanalyses (> 300mg/24
h), blood uric acid, calcium, phosphate, PTH, and C-
Cystatin. It was sent to our collaborators who were asked to
include patients diagnosed with CRI (recorded as 1) and those
with non chronic renal insufficiency (NCRI) (recorded as 0)
seen and followed-up in their current out-patient and in-patient
practice (first group of doctors).
Evaluation of the predictive variables
The received data were sent to a different group of
collaborators (second group of doctors) asking them to classify
persons as CRI or NCRI on the basis of analytical data without
knowledge of the original diagnoses. Our gold standard for CRI
or NCRI was the coincidence between the diagnoses of CRI or
NCRI made for the first group of doctors with the prediction
made for the second group of doctors in the 376 individuals
who met all the criteria required for evaluation.
Calculation of the HUGE formula
The variables that had p-values > 0.10 (Student t test for
independent data) lacked discriminative ability to detect CRI
were: ferritin, folic acid, abdominal perimeter and height. The
rest of the variables with a p value < 0.10, showing good ability
to detect CRI, were: uric acid, vitamin B12, calcium, C-
Cystatin, serum creatinine, urine creatinine, diuresis, age,
weight, iron, haemoglobin, haematocrit, body mass index,
transferrin, vitamin D3, phosphorus, pH (venous), HCO3-
(venous), PTH and blood urea.
A simple model of binary logistic regression was applied (4,
5) to variables with discriminative ability, resulting in the
formula:
Where L is a linear function of the discriminative variables:
L= 2.505458 (0.264418 x Hematocrit) + (0.118100 x
Urea) [+ 1.383960 if male].
Validation of the HUGE formula
The Nuclear Medicine Unit of the University Hospital of
Salamanca provided us with 111 patients in which the GFR had
been obtained using the clearance of Diethylenetriami-
nepentaacetic acid (DTPA) whose records were carefully
revised by a nephrologist and a family doctor to confirm the
already existing diagnosis of CRI or NCRI by clinical and
laboratory means. HUGE was applied to those 111 subjects for
validation purposes.
Confirmed true diagnosis core database. (CTDB)
CTDB was composed of 487 (376+111) individuals with the
coincidence of CRI or NCRI, by the two groups of doctors
already mentioned, which served as the basis for the
calculations that allowed us to re-confirm the reliability of the
HUGE formula and the comparison between HUGE and other
formulae discussed here in. The cross tables technique was
applied to compare the clinical diagnoses with the results
obtained with the HUGE, MDRD and CKD-EPI formulas.
Additional testing of the HUGE formula in large databases
To determine whether the percentage differences of CRI and
NCRI between the HUGE formula and MDRD was statistically
different from that obtained in the 487 subjects of our
confirmed CTDB, we tested larger databases with a total of
125.373 subjects provided by the University Hospital of
Salamanca and our two partner centres, the Infanta Cristina
University Hospital and the County Hospital of Don Benito
(Extremadura, Spain)
Statistics
Variables with no discriminative power to detect subjects
with CRI, (p>0.10) were not included in the model. A simple
model of logistic binary regression was applied to variables
with discriminative power (4, 5). The lowest limits of
confidence for the well classified percentages were calculated
by means of the exact formula that correlates the binomial
distribution with the F of Snedecor (6, 7). The exact bilateral
test of McNemar was applied on the cross tables to check
whether there were statistically significant differences between
CRI or NCRI classified in the validation of HUGE and the
true presence of CRI or NCRI (8). Statistical evaluations of the
data were carried out with SPSS program version 15.0.1 (Nov
2006) Copyright SPSS Inc. 1989-2009.Chicago, Illinois.
Results
Statistical tools were applied to the confirmed true diagnosis
(CRI or NCRI) CTDB of 487 individuals (206 female and 281
male), aged 16-101 years. Biochemical variables from both
groups (CRI and NCRI) are shown in Table 1.
JNHA: GERIATRIC SCIENCE
The Journal of Nutrition, Health & Aging
Volume 15, Number 6, 2011
481
1
1 + e
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HAEMATOCRIT, BLOOD UREA AND GENDER (HUGE) AS A SCREENING TEST FOR CRI
The Journal of Nutrition, Health & Aging
Volume 15, Number 6, 2011
482
Table 1
Descriptive data of the variables in the study.
Variables CRI CRI CRI NCRI NCRI NCRI t-Student
N (cases) Mean St. Dev. N (cases) Mean St. Dev.
AGE (years) 182 72.4011 12.04497 304 55.9079 16.26182 p<0.05 *
Weight (Kgs) 98 68.8643 17.95198 261 84.3920 21.46188 p<0.05 *
Height (cms) 97 163.1546 8.71820 261 163.4751 10.27003 p=0.785
Hb (g/dL) 169 12.3024 2.82276 207 14.5425 2.92542 p<0.05 *
Hto (%) 180 36.3972 5.63808 305 43.3030 4.72725 p<0.05 *
Fe(mg/dL) 85 66.1388 31.03267 131 85.8702 31.90139 p<0.05 *
Folic acid (ng/ml) 45 10.4036 3.87976 124 9.5097 3.38640 p=0.147
B12 vit. (pg/ml) 44 412.0750 246.07483 123 497.2378 273.55242 p=0.071
Urea(mg/Dl) 179 109.5251 60.27049 304 40.5625 13.12152 p<0.05 *
Serum Creat (mg/dL) 182 2.6991 1.96532 305 .8942 .19146 p<0.05 *
Urine Creat (mg/dL) 141 58.0053 44.12296 181 84.0955 61.94116 p<0.05 *
Calcium (mg/dL) 150 9.2307 .82144 156 9.4574 .48364 p<0.05 *
Phosporus (mg/dL) 148 4.1890 2.77665 155 3.4861 .56861 p<0.05 *
Uric Acid (mg/dL) 157 7.2420 2.15782 205 5.5748 1.47978 p<0.05 *
PTH (pg/ml) 101 125.3603 135.87794 144 47.3243 18.16282 p<0.05 *
Vit. D3 (ng/mL) 47 26.6862 20.35758 114 33.0798 13.04105 p<0.05 *
Albumin (g/dL) 77 3.8431 .73161 155 4.5013 .37329 p<0.05 *
Cystatin C 50 1.6554 .55881 154 .8403 .19900 p<0.05 *
Venous Ph 65 7.3143 .08522 42 7.3824 .05127 p<0.05 *
HCO3 (mmol/L) 113 22.8345 4.60589 68 25.0588 3.39865 p<0.05 *
* p < 0.05 There is a significant difference between variables of both groups; (Students t test for the comparison of means of independent data; CI 95%)
Table 2
Comparison between CRI predicted with HUGE, MDRD and CKD-EPI versus real observed CRI in the population of the study
(under and over 70 years old)
Under 70 years Predicted CRI HUGE Predicted CRI MDRD Predicted CRICKD-EPI
N=285 NCRI CRI NCRI CRI NCRI CRI
OBSERVED NCRI 223 7 223 8 226 5
CRI 10 42 2 52 2 52
Chi-Square of Pearson p<0.001 p<0.001 p<0.001
McNemar P=0,629 P=0,109 P=0,453
Phi 0.796 0.892 0.922
Over 70 years Predicted CRI HUGE Predicted CRI MDRD Predicted CRI CKD-EPI
N=201 NCRI CRI NCRI CRI NCRI CRI
OBSERVED NCRI 68 5 60 13 55 18
CRI 9 116 1 127 0 128
Chi-Square of Pearson p<0.001 p<0.001 p<0.001
McNemar P=0,424 P=0,002 P=0,00
Phi 0.851 0.852 0.813
NCRI (Non Chronic Renal Insufficiency); CRI (Chronic Renal Insufficiency)
Table 3
Cross Tables in all subjects, younger and older 70. HUGE vs. MDRD
Whole population MDRD Under 70 MDRD Over 70 MDRD
N=125326 N=84957 N=40369
NCRI CRI NCRI CRI NCRI CRI
HUGE NCRI 90430 7263 HUGE NCRI 72305 2349 HUGE NCRI 18125 4914
CRI 5825 21808 CRI 2936 7367 CRI 2889 14441
483
The Journal of Nutrition, Health & Aging
Volume 15, Number 6, 2011
JNHA: GERIATRIC SCIENCE
We found that the association of haematocrit, urea and
gender (HUGE) according to the following formula:
L= 2.505458 (0.264418 x Hematocrit) + (0.118100 x
Urea) [+ 1.383960 if male]
showed the highest ability to discriminate CRI from NCRI
individuals: If L is lower than 0, it means that the individual
does not have CRI. If L is higher than 0, it means that the
individual suffers from CRI.
In the population below 70 years of age (Table 2), no
significant differences were found by the McNemar exact test
in the cross tables for HUGE, MDRD and CKD-EPI.
In persons aged over 70 years MDRD showed significant
differences with the diagnosis of CRI (p=0.002, MacNemar
test), wrongly classifying 13 subjects as CRI instead of NCRI.
In the case of the CKD-EPI, this mistaken discrimination
occurred in 18 individuals out of 201 (9%) (P= 0.001,
McNemar test), whereas HUGE only misclassified 5 subjects,
with no statistical differences with the true diagnosis of CRI
from our CTDB (p= 0,424. MacNemar tes)t (Table 2).
Comparison between HUGE and MDRD formulae in large
data base are given in Table 3. Out of the 125,373 individuals
included, 40,369 of them were older than 70 years. In this
group, the use of MDRD formula diagnosed 19,355 as suffering
from CRI, whereas the use of HUGE only diagnosed 17,330 as
having CRI, a difference of 10.46 %.
Data concerning sensitivity, specificity, positive predictive
value and negative predictive value of persons aged > 70 years
of the HUGE, MDRD and CKD-EPI formulae with the true
diagnosis of CRI or NCRI in our CTDB are given in Table 4.
Table 4
Comparison of the accuracy between formulae in people over
70 years old
Over 70 years old Sensitivity Specificity PPV NPV
HUGE 92.8 93.15 95.87 88.31
MDRD 99.22 82.19 90.71 98.36
CKD-EPI 100 75.34 87.67 100
Discussion
We believe this study establishes a straightforward, readily
available and inexpensive tool for differentiating CRI from
NCRI based on eGFR < 60 ml/min/1.73 m
2
. The L value
calculated by the HUGE formula is particularly useful in
persons over 70 years of age.
It should be noted that MDRD and CKD-EPI formulae show
differences in the prediction of CRI when compared with the
true observed diagnosis in 6.96% (MDRD) and 8.95 % (CKD-
EPI) of subjects older than 70 years (Table 2). In the large
database of 125.373 subjects, the differences in the prediction
for CRI between the HUGE formula and the MDRD in the
population older than 70 years rose to 10.46 % (see Table 3).
Taking into account the above percentages and the
demographic data of Spain and UK, we have estimated that in
Spain with a population of 45.000.000 inhabitants, 20% of
whom are older than 70, potentially 1.700.000 wrong diagnosis
of CRI would be made based on the analyses performed. For
UK the number would reach 2.600.000, where general
practitioners are asked to carry a register with patients eGFR
<60 ml ml/min/ 1.73 m
2
(9).
The similarity in the value of overdiagnosed percentage of
CRI in subjects included in our CTDB and that observed in
larger data bases may be interpreted as a good index of the
reliability of HUGE.
In an attempt to find out the causes that may explain the
differences observed among HUGE and MDRD formulae we
believe that there are two possible sources of errors. The first is
that as tacitly expressed in the original paper describing MDRD
formula (10): This prediction equation (the MDRD formula)
was not tested in persons without renal disease ., persons <
18 years, elderly persons (persons > 70 years of age)
The second is the widespread tendency to confuse screening
tests with diagnostic tests. For a screening test to be accurate,
its sensitivity, specificity and predictability values, either
positive or negative, must be measured. Otherwise, the use of
eGFR as a screening method may be a double-edged sword,
sometimes wielded clumsily by the well intended (11). The
sensitivity for the detection of early chronic kidney disease has
been enhanced at the expense of lower specificity; this is why
some healthy subjects are wrongly classified as CRI by eGFR
testing (12). In the present study, persons aged over 70 years,
included in our CTDB the specificity was 85% for MDRD and
75% for CKD-EPI, while for HUGE it was 93.15% (Table 4).
In light of the foregoing considerations, MDRD formula
estimations are undoubtedly valuable for managing patients
with proven chronic kidney disease; for example in staging and
monitoring progress. However, the use of eGFR to test patients
without previously recognized CKD is not only controversial,
but maybe ill-advised (13).
Establishing an incorrect diagnosis of CRI by estimating
GFR lower than 60 ml/min/1.73 m
2
provided by routine
laboratory analyses will have, at least three undesirable effects.
First, over diagnosis of CRI may provoke emotional anguish.
Second, the unnecessary referral to nephrology outpatient
clinics will increase expenditure of time and money. Finally,
the wrong diagnosis of CRI may deny individuals appropriate
treatment for other diseases (e.g. oncological, haematological
or others) and also prevent subjects, particularly the elderly,
from being included in clinical trials because the tendency to
equalize CRI to GFR less than 60 ml/min/1.73 (14-16).
Furthermore blood urea correlated better than blood creatinine
with GFR calculated as iohexol clearance (17). Similarly, the
reciprocal of blood urea has been previously identified as an
independent predictor for GFR (10, 18).
Proteinuria is worldwide accepted as a marker of renal injury,
and in our study proteinuria was absent in the NCRI group,
supporting the reliability of HUGE for CRI screening (19, 20).
Conclusions
The HUGE formula with data obtained from a general
population, offers a straightforward readily available and
inexpensive method based on haematocrit plasma urea and
gender to differentiate more accurate than MDRD formulae to
differentiate CRI from eGFR < 60 ml/min/1.73 m
2
, particularly
useful in persons aged over 70 years of age and overcoming the
disadvantages derived from the use of serum creatinine to
calculate GFR.
Conflict of interest: The authors declare no conflict of interest.
Limitations: Our database excluded patients suffering from known liver, heart or lung
insufficiency, acute renal failure, bleeding conditions, anaemic syndromes different from
CRI, undernourished, pregnant, severely ill patients, patients admitted to intensive care
units, and patients on programs of end-of-life geriatric treatment or receiving palliative
oncologic care.
Research Group: Nephrologist: Garcia N., Juncos L. and Musso C. G. (from Cordoba
and Buenos Aires, Argentina), Garrido J. (Viseu, Portugal), Fraile P., Lerma J.L. and
Rodriguez Commes J.L. (Salamanca, Spain), Grande J. (Zamora, Spain), Robles N.R.
(Badajoz, Spain), Rodriguez J.C. (Las Palmas de Gran Canaria, Spain). Internal Medicine
doctors: Calabria F., Funtowic G., Scibona P., Waissman G. (Buenos Aires, Argentina),
and Bueno C., Romero Requena J. (Badajoz, Spain); Cardiologist: Ingaramo R. (Trelew,
Argentina), Puppi L.M., (Buenos Aires, Argentina) and Martin Luengo C. (Salamanca,
Spain); Geriatricians: Jaramillo E. (Cceres, Spain), Rodriguez Maas L. and Pablos
Hernandez C (Salamanca, Spain); Clinical Biochemist: Zaro Bastanzuri M.J. (Badajoz,
Spain) and Garca Garca C. (Salamanca, Spain). Family and Community Doctor: Jauregui
R. (Buenos Aires, Argentina) and from Nuclear Medicine, Ruano R. (Salamanca, Spain)
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