Critical Reviews in Clinical Laboratory Sciences

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Diagnostic utility of protein to creatinine ratio (P/

C ratio) in spot urine sample within routine clinical
practice

Joanna Kamińska, Violetta Dymicka-Piekarska, Justyna Tomaszewska,

Joanna Matowicka-Karna & Olga Martyna Koper-Lenkiewicz

To cite this article: Joanna Kamińska, Violetta Dymicka-Piekarska, Justyna Tomaszewska,

Joanna Matowicka-Karna & Olga Martyna Koper-Lenkiewicz (2020): Diagnostic utility of protein to
creatinine ratio (P/C ratio) in spot urine sample within routine clinical practice, Critical Reviews in
Clinical Laboratory Sciences, DOI: 10.1080/10408363.2020.1723487

To link to this article: https://doi.org/10.1080/10408363.2020.1723487

© 2020 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
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Published online: 14 Feb 2020.

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CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES
https://doi.org/10.1080/10408363.2020.1723487

REVIEW ARTICLE

Diagnostic utility of protein to creatinine ratio (P/C ratio) in spot urine

sample within routine clinical practice

skaa , Violetta Dymicka-Piekarskaa
Joanna Kamin , Justyna Tomaszewskab, Joanna Matowicka-Karnaa
and Olga Martyna Koper-Lenkiewicza
a
Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, Poland; bScientific Student’s Club at the
Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, Poland

ABSTRACT ARTICLE HISTORY

The spot (random) urine protein to creatinine ratio (P/C ratio) is an alternative, fast and simple Received 12 September 2019
method of detecting and estimating the quantitative assessment of proteinuria. The aim of the Revised 30 December 2019
work was to review the literature concerning the usefulness of spot urine P/C ratio evaluation in Accepted 27 January 2020
the diagnosis of proteinuria in the course of kidney disease, hypertension, gestational hyperten-
KEYWORDS
sion, preeclampsia, immunological diseases, diabetes mellitus, and multiple myeloma, and in the P/C ratio; proteinuria; ACR -
diagnosis of proteinuria in children. We searched the PubMed and Google Scholar databases albumin to creatinine ratio;
using the following keywords: proteinuria, spot urine protein to creatinine ratio, spot urine P/C spot urine sample; 24-h
ratio, protein creatinine index, PCR (protein to creatinine ratio), P/C ratio and methods, Jaffe ver- urine collection
sus enzymatic creatinine methods, urine protein methods, spot urine protein to creatinine ratio
versus ACR (albumin to creatinine ratio), proteinuria versus albuminuria, limitations of the P/C
ratio. More weight was given to the articles published in the last 10–20 years. A spot urine P/C
ratio >20 mg/mmol (0.2 mg/mg) is the most commonly reported cutoff value for detecting pro-
teinuria, while a P/C ratio value >350 mg/mmol (3.5 mg/mg) confirms nephrotic proteinuria. The
International Society for the Study of Hypertension in Pregnancy recommends a P/C ratio of
30 mg/mmol (0.3 mg/mg) for the classification of proteinuria in pregnant women at risk of
preeclampsia. A high degree of correlation was observed between P/C ratio values and the pro-
tein concentration in 24-h urine collections. The spot urine P/C ratio is a quick and reliable test
that can eliminate the need for a daily 24-h urine collection. However, in doubtful situations, it is
still recommended to assess proteinuria in a 24-h urine collection. The literature review indicates
the usefulness of the spot P/C ratio in various disease states; therefore, this test should be avail-
able in every laboratory. However, the challenge for the primary care physician is to know the limi-
tations of the methods used to determine the protein and creatinine concentrations that are used
to calculate the P/C ratio. Moreover, the P/C ratio cutoff used should be determined in individual
laboratories because it depends on the patient population and the laboratory methodologies.

Abbreviations: ACR: albumin to creatinine ratio; AER: albumin excretion rate; AUC: area under
the ROC curve; CARI: Caring for Australians with Renal Impairment; CKD: chronic kidney disease;
CV: coefficient of variation; ESRD: end stage renal disease; GFR: glomerular filtration rate; IDMS:
isotope dilution mass spectrometry; ISSHP: International Society for Hypertension in Pregnancy;
KDOQI: Kidney Disease Outcomes Quality Initiative; LVH: left ventricular hypertrophy; MM: mul-
tiple myeloma; NICE: National Institute for Health and Care Excellence; NKF: National Kidney
Foundation; NPV: negative predictive value; P/C ratio: protein to creatinine ratio; PCR: protein to
creatinine ratio; PER: protein excretion rate; PPV: positive predictive value; ROC: receiver operat-
ing characteristic

Background [1]. In states such as nephrotic syndrome, the amount

Proteinuria is one of the main symptoms of kidney dis- of urinary protein excreted directly reflects disease
ease. Assessment of proteinuria is helpful in establish- activity [2]. In nephrotic syndrome, severe proteinuria
ing a diagnosis, monitoring the course of the disease
3.5 g/d (so-called nephrotic proteinuria) is associated
and assessing the effectiveness of applied treatment with the presence of hypoalbuminemia, edema, sodium

CONTACT Joanna Kami
nska joanna.kaminska@umb.edu.pl Department of Clinical Laboratory Diagnostics, Medical University of Białystok,
Waszyngtona 15A St., 15-269 Białystok, Poland
ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-
nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed,
or built upon in any way.
2 J. KAMIŃSKA ET AL.
retention, and hyperlipidemia, as well as thrombo-
embolic and infection complications [3].
The aim of the work was to review the literature on
the suitability of the protein to creatinine ratio (P/C
ratio) in a single urine sample in the diagnosis of pro-
teinuria in the course of kidney diseases, hypertension,
gestational hypertension, preeclampsia, immunological
diseases, diabetes mellitus, MM, and in the diagnosis of
proteinuria in children. Alternative names for the spot
(random) urine P/C ratio are protein to creatinine ratio
(PCR) and protein creatinine index (PCI). In addition, the
review was aimed at answering the follow-
ing questions:
 Are the reference values for the spot urine P/C ratio
established?
 Can the spot urine P/C ratio be a fast and reliable
test to confirm/exclude proteinuria?
 Can the spot urine P/C ratio be useful in everyday
medical practice for the diagnosis and monitoring of
patients with renal insufficiency and other disease
states that are accompanied by proteinuria, thus
eliminating the need for a 24-h urine collection?
 How does the value of a spot urine P/C ratio correl-
ate with protein excretion in a 24-h urine collection?
 Do factors such as patient’s race, course and multi-
plicity of pregnancy, type of sample used, and
method used affect the useful of the spot urine P/C
ratio for assessing proteinuria?
Search strategy
We searched the PubMed and Google Scholar data-
bases for articles publish from 1975 to the end of 2019.
We began the search at 1975, because that year marked
the start of studies concerning the analysis of P/C ratio,
its application in comparison with the 24-h urine collec-
tion, and methods of urine protein measurement. No
language restrictions were applied, but most of the
cited papers were published in English. We have
included 138 references in our work. More weight was
given to the articles published in the last 10–20 years,
which represented more than 85% of all publications.
We used the following keywords and terms: protein-
uria, spot urine protein to creatinine ratio, spot urine P/
C ratio, protein creatinine index, PCR (protein to creatin-
ine ratio), P/C ratio and methods, Jaffe versus enzymatic
creatinine methods, urine protein methods, spot urine
protein to creatinine ratio versus ACR (albumin to cre-
atinine ratio), proteinuria versus albuminuria, limitations
of the P/C ratio.
We included studies if they covered any of the fol-
lowing aspects:
 ratio test: the spot urine protein to creatinine ratio
(P/C ratio) and/or albumin to creatinine ratio (ACR)
 “gold standard” of method of protein estimation:
the protein (total protein/albumin) excretion in 24-
h urine collection
 diagnostics usefulness of spot urine P/C ratio in kid-
ney disease, nephropathy, glomerulonephritis,
hypertension, preeclampsia, eclampsia, diabetic
nephropathy, lupus nephritis, MM, children with
proteinuria
 spot urine P/C ratio for assessing proteinuria
depending on selected factors: race, type of sample
used, method used, course and multiplicity of preg-
nancy, the glomerular filtration rate (GFR) value,
stage of chronic kidney disease
 threshold value: spot urine P/C ratio in physio-
logical and pathological states
We excluded studies that evaluated the protein to
creatinine ratio and ACR estimated with semiquantita-
tive methods (dipstick methods) or that were calculated
from the 24-h urine collection.
In the manuscript and tables, all values are given in
SI units; conventional units are given in the brackets
(e.g. mg/mg for the urine P/C ratio or mg/g for ACR).
Methodology aspects
Proteinuria evaluation
The “gold standard” method for the assessment of pro-
teinuria is the quantitative determination of the protein
concentration in a 24-h urine collection, the so-called
“timed urine collection”. It allows protein fluctuations
during the day and day-to-day readings to be taken
into account. However, it is time-consuming and
troublesome for the patients and sometimes it involves
errors that can significantly affect its accuracy (Figures 1
and 2) [4–6].
An alternative, fast and simple method of quantita-
tive evaluation of urinary protein excretion may be the
assessment of the P/C ratio, which is obtained by divid-
ing the protein concentration by the creatinine concen-
tration in a spot urine sample.
More than 30 years ago Ginsberg et al. [7] used the
spot urine P/C ratio to estimate proteinuria quantita-
tively on a daily basis. The authors assumed that in
patients with stable renal function and reasonably con-
stant excretion of creatinine [mg/dL] and protein [mg/
dL] in the urine during the day, the calculation of the
 CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 3

Figure 1. Reasons of diagnostic inaccuracy using 24-h urine collection [4–6].

Figure 2. Advantages and disadvantages of 24-h urine collection [4–6].

protein to creatinine ratio eliminated the need to meas-
ure the protein concentration in a 24-h urine collection.
In their study, they observed high correlations of the
P/C ratio results determined in three urine samples col-
lected during the day with the quantitative protein
excretion in the 24-h urine collection (r ¼ 0.96, r ¼ 0.93,
r ¼ 0.94, respectively) and slightly weaker correlations
when using a sample taken at night and upon waken-
ing (r ¼ 0.78 and r ¼ 0.83, respectively). The authors
pointed out that these slight differences may have
resulted from changes in the body position (orthostatic
proteinuria) and from various physical activities during
4 J. KAMIŃSKA ET AL.
the day and night. They also emphasized that the spot
urine P/C ratio results should be interpreted with cau-
tion and its possible limitations should be considered,
especially in young, muscular men and in young, frail
women/children (debilitated, weakened), in whom
excretion of urinary creatinine may not be constant and
may differ significantly from normal, as it depends on
age, sex, weight, and muscle mass [7].
Numerous studies have investigated the use of the
spot urine P/C ratio for the quantitative assessment of
proteinuria not only in kidney disease but also in other
disease states that are accompanied by protein-
uria [1,7–13].
In 2002, the USA National Kidney Foundation (NKF),
in its recommendations for the evaluation, classification
and stratification of chronic kidney disease, indicated
that the screening dipstick test should be used in a
spot urine sample for screening and monitoring of pro-
teinuria in children and adults. It is not usually neces-
sary to collect timed samples (overnight or 24-h). In
contrast, patients with a positive dipstick test (1þ or
greater) should have proteinuria confirmed using a
quantitative measurement: spot urine P/C ratio or ACR
within a period of 3 months. For adults with an
increased risk of chronic kidney disease, the P/C ratio
can be used to quantify proteinuria if ACR is high (56.5
to 113 mg/mmol) [500–1000 mg/g] [14,15].
Threshold value for spot urine P/C ratio
The spot urine P/C ratio may be expressed in different
units, i.e. in mg/mg, mg/g, mg/mmol, and it is often
reported simply as a numerical value (without units,
especially when it is reported in mg/mg). The use of dif-
ferent units can lead to difficulties in interpreting the
results for both the physician and the patient.
Therefore, in this review, for comparison of the P/C ratio
cutoffs in different disease states, all P/C ratio values
were converted to SI units (mg/mmol), while conven-
tional unit (mg/mg) values are given in brackets.
Ginsberg et al. and Kristal et al. indicated a value
<20 mg/mol (0.2 mg/mg) as a reference value for the
P/C ratio and >350 mg/mmol (3.5 mg/mg) for the differ-
ential diagnosis of nephrotic proteinuria [7,16]. Chitalia
et al. gave slightly different cutoff values, i.e. 26 mg/
mmol (0.26 mg/mg) for the detection of proteinuria and
320 mg/mmol (3.2 mg/mg) for nephrotic proteinuria
[17]. Similar cutoff points of P/C ratio were also indi-
cated by Patil et al.: >20 mg/mmol (0.2 mg/mg) and
>30 mg/mmol (0.3 mg/mg) as values corresponding to
proteinuria of >0.2 g/d and >0.3 g/d, respectively [5].
These authors also found that a P/C ratio value of
12 mg/mmol (0.12 mg/mg) (sensitivity 100%, specificity
98%) distinguished abnormal protein concentration
from normal protein concentration in the general popu-
lation. Patil et al. additionally established a cutoff value
of 16 mg/mmol (0.16 mg/mg) to distinguish normal
from elevated urine protein concentration in patients
with low risk renal disease; this cutoff had almost ideal
sensitivity and specificity (95% and 100%, respectively)
and no false positive results. In order to differentiate
nephrotic proteinuria, they used the value of 260 mg/
mmol (2.6 mg/mg) (sensitivity 100%, specificity 96%).
When clinical suspicion of nephrotic syndrome was low,
they recommended using a cutoff of 320 mg/mmol
(3.2 mg/mg) (sensitivity 80%, specificity 100%) [5].
In the 2004 Australian guidelines, Caring for
Australians with Renal Impairment (CARI), proteinuria
was classified as a spot urine P/C ratio
20 mg/mmol
(0.2 mg/mg), which corresponded to an ACR of

3.4 mg/mmol (30 mg/g), and the P/C ratio was recom-
mended as the initial test for evaluation of proteinuria
in high risk populations (hypertension patients, and
patients with known vascular disease and a family his-
tory of renal disease) [18].
Table 1 presents the 2012 National Kidney
Foundation (USA) guidelines for defining the three cat-
egories of albuminuria and the corresponding values of
proteinuria measured by various methods: albumin
excretion rate (AER), ACR, P/C ratio, and protein excre-
tion rate (PER) [19]. However, such diversity in the
reporting of proteinuria/albuminuria can be misleading
and difficult to interpret.
On the other hand, the 2014 National Institute for
Health and Care Excellence Guidelines (NICE, UK) empha-
sized that there is no consistent definition of proteinuria.
The upper limit is about 0.15 g/d, which is equivalent to
a P/C ratio of 15 mg/mmol (0.15 mg/mg) [20].
Methods of protein and creatinine evaluation
To our knowledge, no studies in the literature have
assessed creatinine and protein levels using different
methods and comparing how these affect spot urine P/C
ratio results. However, our review of the literature dem-
onstrated the diversity of methods used to assess the
spot urine P/C ratio, which may result in variable deter-
minations between laboratories. Some publications
lacked information on the protein and creatinine assess-
ment methods used to calculate the P/C ratio [2,7,21].
Protein
For protein concentration evaluation, a large variety of
methods have been used, largely because there is no
 CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 5

reference method. It should be noted that dry chemis- pathological samples, where the protein can be very
try, turbidimetric and dye-binding methods do not give elevated, it may be necessary to dilute samples because
comparable analytical sensitivity and specificity for all the protein concentration is higher than the linearity of
proteins (Table 2). Urine is a complex biological fluid, the method. Other factors that may affect the precision
and there is high intra- and inter-individual variability in and accuracy of urine protein results include different
the excretion rate of different proteins [22]. High analyt- amounts and composition of proteins from sample-to-
ical variability was noted among the colorimetric and sample, the presence of non-protein interfering sub-
turbidimetric methods used for total urinary protein stances, and the high content of inorganic ions [27,28].
concentration evaluation [22]. The biuret method with An additional problem is the lack of a standard refer-
ethanolic phosphotungstic acid as precipitant corre- ence material (calibrator material) for total protein
lated well with the Coomassie Brilliant Blue method, evaluation in the urine [25]. The study of Marshall and
but poor relationships were observed with the Ponceau Williams [29] indicated that the use of urinary protein
S and biuret-trichloroacetic acid methods [23]. Most (rather than human albumin) as a calibrator significantly
methods for total urine protein evaluation react more improved comparability between the Coomassie
strongly with albumin than with globulins [24–26]. Brilliant Blue, pyrogallol red-molybdate, trichloroacetic
Moreover, in the normal physiological state, the protein acid, and benzethonium chloride protein methods and,
concentration in the sample is low and some methods to a lesser extent, comparability with the trichloroacetic
are not sensitive enough to detect them. In the case of acid, and Ponceau S methods.
Table 1. Albuminuria categories (A1, A2, A3) and relationship Analysis of data from French laboratories showed
among proteinuria measured by different tests. Modification that for the assessment of protein concentration in
based on [19]. urine, the turbidimetric method with benzethonium
Categories chloride and colorimetric method with pyrogallol red
A1 Normal A2 A3 were the most commonly used methods. The pyrogallol
to mildly Moderately Severely red method was characterized by a high coefficient of
Units increased increased increased
AER mg/24h <30 30–300 >300
variation (CV) between laboratories. In turn, the pyroca-
PER mg/24h <150 150–500 >500 techol violet method gave urinary protein concentra-
ACR mg/mmol <3 3–30 >30
mg/g <30 30–300 >300
tion results that were 10–15% higher compared to
P/C ratio mg/mg <0.15 0.15–0.50 >0.50 those obtained with the pyrogallol red method. In con-
mg/mmol <15 15–50 >50 trast, the pyrogallol red method gave results 10–20%
mg/g <150 150–500 >500
Urine dipstick test Negative to trace Trace to 1þ 1þ or greater higher than those obtained with the benzethonium
ACR: albumin-creatinine ratio; AER: albumin excretion rate; P/C ratio: pro- chloride method [22]. These differences may be related
tein-creatinine ratio; PER: protein excretion rate.
to the limitations of existing pyrogallol red methods:

Table 2. Limitations of methods used for urine protein and creatinine evaluation.
Protein evaluation methods Limitations
Dry chemistry, semi-quantitative method  Dedicated mainly to albumin
 Reaction with pyrocatechol violet-dye  High risk of false positive results in the case of: alkaline samples, samples with the presence of
urease-positive bacteria alkalizing urine, when the patient takes the quinine derivatives
Turbidimetry  Lack of standardization of the method resulting from:
 Sulfosalicylic acid  using different precipitants with different concentrations
 Trichloroacetic acid  lack of a constant reaction temperature
 Benzethonium chloride  no constant reaction time from the addition of a precipitating substance to the reading
 Ammonium chloride  affected by turbidity of the samples or by xanthochromia

Dye-binding methods  Overestimated result in:

 Pyrogallol red  the presence of high concentration of iron (II) ions
 hematuria
 the case of taking: acetaminophen (Paracetamol), certain antibiotics from the group of penicillin
and aminoglycosides

Other methods
 Ponceau-S  Difficult to perform, requires decantation
 Coomassie Brilliant Blue G-250  Incomplete precipitation of low molecular weight proteins by trichloroacetic acid

Creatinine evaluation methods Limitations

Colorimetric method  The analytical specificity, sensitivity and analytical precision is systematically better for the enzymatic
 Enzymatic assays compared to the Jaffe assays
 Jaffe  Picrate (Jaffe method) can also react with pseudochromogens: acetoacetate, pyruvate, ketoacids,
proteins, glucose, ascorbic acid, bilirubin or even some drugs
6 J. KAMIŃSKA ET AL.
variability of reagent composition between manufac-
turers (such as the presence or lack of sodium dodecyl
sulfate), different calibration materials, or underestima-
tion of the results when free light chains are present
[30,31]. On the other hand, according to Pupkova and
Prasolova [32] the pyrogallol red-molybdate method is
superior to the sulfosalicylic acid method.
Data from the United Kingdom National External
Quality Assessment Scheme of urinary total protein
measurement indicated that the CV between laborato-
ries for variety of methods used was 12.4% [27]. In prac-
tice, this means that a patient could have a total urine
protein concentration result of 200–400 mg/L or a spot
urine P/C ratio of 30–60 mg/mmol (0.3–0.6 mg/mg) [27].
Currently there is no reference method for urine protein
evaluation; as well, calibrators need to be improved to
reduce interlaboratory CVs. Therefore, it is not surpris-
ing then Labquality (out-of-laboratory control program,
https://www.labquality.fi/en/eqas, http://sowa-med.pl/
wp-content/uploads/2016/05/Zakresy-błeR du-dopuszc-
zalnego-3.pdf) specifies ± 50% as the maximum permis-
sible error for total urine protein.
Creatinine
Urine creatinine concentration is most often assessed
by the colorimetric modified Jaffe method, and less fre-
quently by the more expensive enzymatic method
[33–38]. In the Jaffe method, creatinine reacts with pic-
rate, giving a yellow-orange color that is proportional
to the creatinine concentration. However, this reaction
is not entirely specific because picrate also reacts with
other compounds known as pseudochromogens
(Table 2) [39–43]. Over the past decades, various tech-
nical improvements (kinetic and/or rate-blanked assay,
compensated Jaffe assay, etc.) have improved the preci-
sion of creatinine evaluation using the Jaffe method
[39]. Enzymatic assays measuring creatinine concentra-
tion use several different enzymes [41,42]. Studies indi-
cated that the analytical specificity, sensitivity and
precision are better for the enzymatic assays compared
to the Jaffe assays [43,44]. Therefore, Delanaye et al.
[39] highlighted that the enzymatic method should be
used preferentially in pediatric patients or patients with
hyperfiltration and also in specific clinical situations
(e.g. jaundice, ketoacidosis) where the Jaffe method is
known have interferences. Moreover, random error
(analytical imprecision) due to the intrinsic performance
of the measurement is lower for enzymatic (CV approx.
2%) than for Jaffe assays (CV approx. 5.5%) [43,45,46].
According to Myers et al. [45], if the creatinine method
is calibrated to the isotope dilution mass spectrometry
(IDMS) assay, a total analytical error goal for creatinine
measurement should not exceed 10%.
It is well established that the most accurate and
reproducible method for creatinine concentration
measurement is the IDMS assay. Therefore, the
Creatinine Standardization Program (https://www.
niddk.nih.gov/health-information/communication-pro-
grams/nkdep/laboratory-evaluation/glomerular-filtra-
tion-rate/creatinine-standardization) has requested
manufacturers to standardize their creatinine assays to
an IDMS reference measurement procedure to ensure
that the same sample will give the same result in any
laboratory in the world, whatever method and manu-
facturer is used. This is possible if all the calibrators are
“traceable” to IDMS [47,48]. It should be noted that
most enzymatic assays are standardized to IDMS
[44,49], but some dry chemistry enzymatic methods
and especially Jaffe methods give results that are not
standardized to the reference method [50,51]. It should
be emphasized that the studies comparing different
methods of creatinine concentration evaluation were
carried out mainly in serum [39,41,46,48]. Interestingly,
the study of Apple et al. [52] did not find that urine cre-
atinine concentration results depended on the method
used (enzymatic versus Jaffe versus high-performance
liquid chromatography). The study of Srivastava et al.
[53] also confirmed that differences in the evaluation of
urine creatinine concentration using various methods
(Jaffe versus enzymatic versus enzymatic method trace-
able to IDMS) were rather small, while more significant
differences were observed for serum tests. The authors
concluded that this may be due to the lower serum cre-
atinine concentration compared to urine, because the
majority of analytical methods for creatinine show
higher inaccuracy at lower concentrations [53]. In sum-
mary, the recommendations for creatinine measure-
ments are to use an enzymatic assay to decrease
random errors and an IDMS traceable assay to decrease
systematic errors [39,44,49].
Given the above, the variety of methods employed,
which are subject to certain limitations, do not allow
comparison of P/C ratio results between laboratories.
Therefore, for the diagnosis of proteinuria, a physician
using the P/C ratio should use results obtained in a sin-
gle laboratory using the same analytical conditions.
Understanding the methodological limitations and the
use of a single laboratory for analysis should ensure the
suitability of P/C ratio measurements in everyday med-
ical practice and its application to diagnosis, monitoring
and evaluation of the effectiveness of the treatment
undertaken [24–28,31].

Clinical findings
Spot urine P/C ratio and kidney diseases
Proteinuria is the main symptom of kidney disease, and
proteinuria monitoring is necessary for patients with
chronic kidney disease (CKD). It is worth noting that not
all patients with CKD have proteinuria, whereas its pres-
ence allows the identification of patients who are at sig-
nificantly more risk of disease progression. Literature
data confirms that the evaluation of the P/C ratio in a
single urine sample is a good alternative to a 24-h urine
collection for the assessment of proteinuria, especially
in patients with renal insufficiency [17,21,27,54].
Chitalia et al. [17] in patients with glomerular renal
failure evaluated the P/C ratio in random urine samples
taken at two times during the day and observed an
almost perfect correlation in both samples with the pro-
tein concentration in 24-h urine collections (r ¼ 0.97
and 0.99, p < 0.05) [17]. Studies of Montero et al. also
indicated a positive correlation of the results of the
spot urine P/C ratio with the protein concentration in
24-h urine collections in patients with different degrees
of kidney failure. The best correlation of spot urine P/C
ratio results with protein concentrations in 24-h urine
collections (r ¼ 0.828, p < 0.001) was observed when
proteinuria ranged from 0.3–3.5 g/d (300–3449 mg/d).
Interestingly, for protein concentrations below 0.3 g/d
(300 mg/d), the correlation was lower (r ¼ 0.498,
p < 0.001), while in the course of nephrotic syndrome,
no correlation was observed [54]. Also, Jyoti et al.
observed excellent correlation (r ¼ 0.93, p < 0.001) of
the spot urine P/C ratio (557 mg/mmol, 5.57 mg/mg)
with the protein concentration in 24-h urine collections
(5.71 g/d) in patients with different types of glomerulo-
nephritis [55].
In turn, Kristal et al. found a high correlation of spot
urine P/C ratio results with protein excretion in 24-h
urine collections and observed that it did not depend
on the severity of proteinuria, while it was slightly
dependent on the glomerular filtration rate [16]. In a
study conducted by Ahmed et al., in the group of
patients with different types of glomerulonephritis,
positive correlations of spot urine P/C ratio results with
protein concentrations in 24-h urine collections were
found in relation to GFR values [21]. A high degree of
correlation (r ¼ 0.987) between these two results was
observed in patients with GFR in the range of 30–59 ml/
min/1.73m2, while moderate correlation (r ¼ 0.535) was
seen in patients with advanced renal failure (GFR <
15 ml/min/1.73m2). In addition, the authors found the
following correlations of the spot urine P/C ratio with
protein concentration in 24-h urine collections in the
CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 7
following ranges: <0.2 g/d (r ¼ 0.721); 0.2–1.0 g/d
(r ¼ 0.788); 1.0–3.4 g/d (r ¼ 0.688); 3.5–6.0 g/d (r ¼ 0.728).
Ahmed et al. emphasized that they did not observe a
correlation between these tests when the protein excre-
tion reached values above 6 g/d [21]. Ali et al. divided
the patients whose protein concentrations exceeded
0.5 g/d into five subgroups depending on their GFR val-
ues based on the ranges used to classify CKD; they
found a significant positive correlation between the
spot urine P/C ratios and the protein concentrations in
24-h urine collections regardless of the GFR value
(r ¼ 0.80 to r ¼ 0.96). They emphasized that the mean
protein concentration in the 24-h urine collections
(3.49 ± 3.0 g/d) and the P/C ratio values 536 ± 465 mg/
mmol (5.36 ± 4.65 mg/mg) were not similar only in the
group of patients with CKD stage 5, and they hypothe-
sized that the spot urine P/C ratio may overestimate
protein excretion at lower levels of GFR [33]. On the
other hand, Price et al. conducted a meta-analysis of
the results of 16 studies (1,781 patients) concerning the
usefulness of the spot urine P/C ratio and protein evalu-
ation in 24-h urine collections in patients with renal dis-
ease or with preeclampsia. The authors concluded that
the spot urine P/C ratio was useful primarily for the
exclusion of the presence of significant proteinuria and
its use should reduce the number of unnecessary 24-h
urine collections. However, when the P/C ratio results
were above the cutoff value, they stated that the quan-
titative assessment of proteinuria in 24-h urine collec-
tions should be performed [56].
The usefulness of the spot urine P/C ratio to assess
proteinuria compared to protein concentration in 24-h
urine collections was also analyzed in patients who
underwent renal transplantation. In the majority of
these studies, a strong or very strong positive correl-
ation between these two tests was observed (r ¼ 0.772
to r ¼ 0.998) [34,57–61]. Wahbeh et al. emphasized that
the spot urine P/C ratio was a precise, convenient and
reliable method for estimating urinary protein excretion
in patients after kidney transplantation, especially those
with low proteinuria [34]. The authors also pointed to
the excellent diagnostic usefulness of a cutoff >43 mg/
mmol (0.43 mg/mg) to detect proteinuria in these
patients (area under the receiver operating characteris-
tic [ROC] curve, AUC ¼ 0.967, p < 0.001, sensitivity
100%, specificity 90%, accuracy 90%). Additionally,
using the Bland-Altman plot, they demonstrated that
the limits of agreement for both proteinuria evaluation
methods was þ0.77 to 1.06 g/d. At the same time,
they emphasized that their study focused on assessing
the correlation of both tests, and not determining the
limits of agreement between them [34].
8 J. KAMIŃSKA ET AL.
In contrast, Talreja et al. indicated that ACR, P/C ratio
and albumin and protein excretion in 24-h urine collec-
tions were similar predictors of doubling serum creatin-
ine, kidney transplant rejection and patient death [60].
Therefore, a random urine sample was an appropriate
alternative to a 24-h urine collection to measure protein
excretion in patients after kidney transplantation [60].
On the other hand, Akbari et al. recommended the veri-
fication of P/C ratio and ACR measurements by means
of protein concentration in 24-h urine collections
before important diagnostic and therapeutic decisions
were taken (e.g. before biopsy or before changes of
immunosuppressive agents) [61].
Spot urine P/C ratio and lupus nephritis
Lupus nephritis may occur in systemic lupus erythema-
tosus at the onset of the disease or many years after
the diagnosis. Proteinuria, in addition to abnormalities
in the urine sediment (granular casts, cellular casts,
hematuria) and impaired renal function, are the main
findings in lupus nephropathy. Therefore, the assess-
ment of proteinuria in patients with lupus nephritis is a
screening test, but it is also important to monitor the
treatment and progression of kidney disease [8,62,63].
Leung et al. recommended the use of the spot urine
P/C ratio both as a screening test and for proteinuria
monitoring in patients with lupus nephritis [64].
Medina-Rosas et al. conducted a meta-analysis of the
results of 13 studies on the use of the spot urine P/C
ratio in the course of lupus nephropathy [63]. Based on
8 studies, they noticed a high overall correlation
(r ¼ 0.8) between the P/C ratio and protein concentra-
tion in 24-h urine collections; however, the correlation
decreased significantly with severe proteinuria. A study
by Birmingham et al. [65], which was included in the
meta-analysis [63], found especially poor correlation
between these two tests (r ¼ 0.5, p ¼ 0.001) if the pro-
teinuria ranged from 0.5–3.0 g/d. In clinical practice, a
high degree of correlation of results for these two tests
was found when proteinuria exceeded 1 g/d. The meta-
analysis emphasized that several pitfalls that could lead
to erroneous conclusions regarding the suitability of
the P/C ratio. Firstly, the spot urine P/C ratio was vali-
dated to differentiate nephrotic and non-nephrotic pro-
teinuria, not to assess accurately the urine protein
concentration [63]. Secondly, the P/C ratio does not
take into account changes in protein excretion during
the day and between-day. Thirdly, the size of the
patient groups in many studies was mostly below 50,
which did not allow the formulation of unambiguous
conclusions. Fourthly, the studies analyzed only the
correlation between the spot urine P/C ratio and pro-
tein concentration in 24-h urine collections and did not
analyze the agreement of the two methods; the
Bland-Altman plot results showed the P/C ratio was not
a useful tool for accurate proteinuria measurement
during the day [63].
On the other hand, Solorzano et al. [66] observed a
very strong correlation of protein concentrations in
24-h urine collections with spot urine P/C ratio results
(r ¼ 0.901) in patients with lupus nephropathy.
However, the authors emphasized that the absolute val-
ues differed between these two methods (80 mg/mmol
(0.8 mg/mg) for P/C ratio vs. 1.0 g/d), which did not
allow the interchangeability of the tests, especially
when they were to be used to determine the activity of
disease. They suggested repeating the protein urine
evaluation two to three times using both methods if it
is necessary to select one test for ongoing assessment
of proteinuria and disease activity in a given patient
[66]. Choi et al. [67] indicated that the spot urine P/C
ratio was an excellent alternative to 24-h urine collec-
tions in the case of clinically significant proteinuria in
patients with lupus nephropathy. In their opinion,
when the spot urine P/C ratio was >100 mg/mmol
(1.0 mg/mg), then the patient could directly qualify for
renal biopsy, whereas when the P/C ratio was between
50–100 mg/mmol (0.5–1.0 mg/mg), the proteinuria
should be confirmed in a 24-h urine collection before
any important decision was made [67].
The Kidney Disease Improving Global Outcomes and
the American College of Rheumatology and the
European League Against Rheumatism/European
Dialysis and Transplant Association recommend the use
of spot urine P/C ratio to assess proteinuria in clinical
trials and to monitor the course of lupus nephrop-
athy [68–70].
Spot urine P/C ratio and diabetic nephropathy
Diabetic nephropathy, which accounts for about 20% of
cases of chronic renal failure, is the most common
cause of end-stage renal failure [71]. Therefore, early
detection and quantitative assessment of proteinuria in
the course of diabetes is important both in diagnosis
and in treatment. Only single studies on the usefulness
of the spot urine P/C ratio in the estimation of protein-
uria in patients with diabetes are available in the litera-
ture [72], and in most cases the evaluation of albumin
concentration is used [73–75]. Biradar et al. [72]
observed a strong correlation (r ¼ 0.925, p < 0.001)
between the P/C ratio (130 ± 155 mg/mmol, 1.3 ±
1.55 mg/mg) and protein concentration in 24-h urine

collections (1.6 ± 1.7 g/d). ROC curve analysis showed
that a cutoff of 30 mg/mmol (0.3 mg/mg) for the P/C
ratio was an excellent predictor of significant protein-
uria in diabetic nephropathy (AUC ¼ 0.947, sensitivity
81%, specificity 100%), and thus the P/C ratio might be
a reasonable and faster alternative for the detection of
proteinuria in these patients [72]. Yadav et al. also
observed a strong correlation of the spot urine P/C ratio
values with proteinuria results from 24-h urine collec-
tions in patients with diabetes (r ¼ 0.892, p < 0.001).
They indicated the value of 15 mg/mmol (0.15 mg/mg)
as the P/C ratio cutoff point to detect significant pro-
teinuria in these patients (AUC ¼ 0.88, sensitivity 97%,
specificity 74%) [10].
Interestingly, Ren et al. [76] conducted a meta-analysis
that included 32 studies and over 2,500 patients with
diabetic nephropathy that assessed proteinuria in 24-h
urine collections; they showed that the use of the spot
urine P/C ratio in this group of patients was rare and
suggested the need for research in large groups of
patients to determine acceptable threshold values of the
P/C ratio for diabetic patients to detect proteinuria [76].
Spot urine P/C ratio and hypertension
The most common causes of proteinuria in patients
with primary and secondary hypertension are lack of
diagnosis and treatment and inadequate therapy, but
also the use of antihypertensive drugs may increase
proteinuria, e.g. angiotensin converting enzyme inhibi-
tor administered with an angiotensin receptor antagon-
ist. Persistent non-compensated hypertension can lead
to hypertensive nephropathy and consequently end
stage renal disease (ESRD) [77].
Studies of Toto et al. [78] in a population of African-
Americans with longstanding hypertension who
received one of three hypertensive drugs (metoprolol,
amlodipine, ramipril) show that two-thirds of partici-
pants had spot urine P/C ratios below 22 mg/mmol
(0.22 mg/mg). Urinary protein excretion was increased
regardless of blood pressure correction and was higher
in patients with hypertension receiving amlodipine. The
authors did not notice differences in the rate of GFR
decline in the group where the P/C ratio was 22 mg/
mmol (0.22 mg/mg) regardless of the treatment
involved. In contrast, in the group with P/C ratios
>22 mg/mmol (0.22 mg/mg) receiving amlodipine, a
decrease in GFR was 2-times faster compared to
patients receiving ramipril and about 1.2 times faster
compared to patients treated with metoprolol. The
authors emphasized that the urine protein excretion in
hypertensive patients was an independent prognostic
CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 9
factor and should be controlled along with blood pres-
sure, because only a reduction in both parameters
would result in a slower rate of decrease in renal func-
tion and a reduced risk of ESRD [78].
Ahsan et al. evaluated the diagnostic usefulness of
the spot urine P/C ratio in predicting proteinuria and
nephropathy in hypertensive patients in India. They
observed a strong positive correlation between the spot
urine P/C ratio and daily proteinuria and showed that
the values of the spot urine P/C ratio >20 mg/mmol
(0.2 mg/mg) and >30 mg/mmol (0.3 mg/mg) allowed
accurate estimation of the occurrence of proteinuria
above >0.15 g/d and >0.3 g/d in these patients. In add-
ition, they recommended the cutoff value of the P/C
ratio of 80 mg/mmol (0.8 mg/mg) as a good screening
tool (sensitivity 95%) for predicting nephropathy in
Indian hypertensive patients. In their opinion, the spot
urine P/C ratio should be used routinely as a screening
test in all patients with hypertension for longer than
5 years, circumventing the inconvenient 24-h urine col-
lection, so that the doctor could make a diagnosis and
start treatment earlier [35,36].
Forlemu et al. [13] assessed left ventricular hyper-
trophy (LVH) in hypertensive patients. They noted
increased spot urine P/C ratios in hypertensive patients
with LVH (86 mg/mmol, 0.86 mg/mg) compared to indi-
viduals with hypertension but without LVH (50 mg/
mmol, 0.50 mg/mg). The authors suggested that P/C
ratio may be a useful routine screening test in patients
with hypertension and LVH, and a useful test for moni-
toring proteinuria in high-risk patients with untreated
hypertension. Ravikumar et al. also emphasized the
relationship of the spot urine P/C ratio value >30 mg/
mmol (0.3 mg/mg) with the occurrence of LVH, espe-
cially in patients with stage 2 hypertension (blood pres-
sure
160/100 mmHg) [79].
Spot urine P/C ratio and preeclampsia
Hypertension in or after the 20th week of pregnancy
with proteinuria and organ symptoms may indicate pre-
eclampsia, which is associated with the risk of develop-
ing eclampsia [80]. According to the guidelines of the
International Society for Hypertension in Pregnancy
(ISSHP), diagnosis of pregnancy proteinuria should fol-
low the pattern shown in Table 3.
In severe preeclampsia, hypertension of
160/
110 mm Hg, proteinuria in the test strip þ 3/massive
proteinuria >5 g/d and organ symptoms are often
found. In such cases, the diagnosis is clear, and treat-
ment should start immediately. The assessment of pro-
tein concentration in a 24-h urine collection is difficult
10 J. KAMIŃSKA ET AL.
Table 3. Pregnant proteinuria [80].
Pregnant proteinuria
1. Proteinuria should be pre-evaluated during routine urinalysis
by means of a strip test
 Positive result if
1 þ [300 mg/L (30 mg/dL)]
 Negative result
2. Proteinuria evaluation using the spot urine P/C ratio
 Abnormal result
30 mg/mmol (0.3 mg/mg)
3. Heavy proteinuria
 >5 g/day
Note: Proteinuria is not required to recognize preeclampsia.
Evaluate the P/C ratio.
Further diagnosis of proteinuria with the P/C ratio is not necessary.
It is associated with a severe condition of the newborn.
to justify due to the long wait time for the result in rela-
tion to the complications that may occur at any time. In
less severe states, it is often recommended to assess
the proteinuria in 24-h urine collections to confirm pre-
eclampsia [81–84].
Since 2001, the ISSHP has recommended the use of
a spot urine P/C ratio cutoff point at 30 mg/mmol
(0.3 mg/mg) for the classification of proteinuria in
women at risk of preeclampsia [82].
In the last decade, there have been many studies on
the usefulness of the spot urine P/C ratio as an easy
and fast test for the diagnosis of proteinuria accompa-
nying preeclampsia [11,37,84–91]. Lokhande et al. [84]
observed a significantly higher P/C ratio in women with
mild preeclampsia (68 ± 24 mg/mmol. 0.68 ± 0.24 mg/
mg) compared to healthy women (22 ± 7 mg/mmol,
0.22 ± 0.07 mg/mg). In addition, using the ROC curve,
they determined the AUC ¼ 0.95 for the P/C ratio cutoff
of 30 mg/mmol (0.3 mg/mg), confirming its diagnostic
usefulness for classifying proteinuria in women at risk
of preeclampsia. However, the authors emphasized that
the use of ISSHP-compatible P/C ratio cutoff resulted in
failure to identify significant proteinuria in approxi-
mately 6% of women (sensitivity and specificity equal
to 94%) [84].
Research by Cade et al. [11] also indicated that a
spot urine P/C ratio equal to 30 mg/mmol (0.3 mg/mg)
allowed the prediction of significant proteinuria in
women with preeclampsia (95% sensitivity, 67% specifi-
city). They observed a strong positive correlation of the
spot urine P/C ratio with the protein concentration in
24-h urine collections (r ¼ 0.98, p < 0.001). Interestingly,
among the women who were assessed by a spot urine
P/C ratio and not a 24-h urine collection, they did not
find a significant increase in the diagnosis of severe
hypertension and the need for magnesium sulfate infu-
sion [11]. A strong correlation between the results of
the P/C ratio and the protein concentration in 24-h
urine collections (r ¼ 0.896) in women with preeclamp-
sia was also observed by Basharat et al. [85].
There is divergent data in the literature on the
threshold value of the spot urine P/C ratio in the diag-
nosis of preeclampsia. Shreya et al. [86] and
Rathindranath et al. [87] indicated that a P/C ratio of
20 mg/mmol (0.2 mg/mg) corresponded to proteinuria
at 0.3 g/d and a P/C ratio <19 mg/mmol (0.19 mg/mg)
allowed the exclusion of preeclampsia with 100% sensi-
tivity. Another study showed that a P/C ratio 20 mg/
mmol (0.2 mg/mg) could exclude significant proteinuria
(
0.3 g/d) with 100% specificity, and a P/C ratio

40 mg/mmol (0.4 mg/mg) confirmed significant pro-
teinuria in preeclampsia with 100% sensitivity; the
authors proposed a P/C ratio of 33 mg/mmol (0.33 mg/
mg) as the optimal cutoff [37].
Vald
es et al., based on ROC curve analysis, deter-
mined that a spot urine P/C ratio of 36 mg/mmol
(0.36 mg/mg) was the appropriate limit for the evalu-
ation of proteinuria in the diagnosis of preeclampsia
(sensitivity 73%, specificity 91%, positive predictive
value [PPV] 95%). In contrast, a high spot urine P/C ratio
threshold of 458 mg/mmol (4.58 mg/mg) corresponding
to severe proteinuria (sensitivity 100%, negative pre-
dictive value [NPV] 100%) was in their opinion an excel-
lent diagnostic tool to rule out severe disease without
the need to assess other laboratory parameters, and it
also avoided unjustified therapy with magnesium sul-
fate or urinary catheter placement. The authors also
showed that a spot urine P/C ratio of 36 mg/mmol
(0.36 mg/mg) was a more diagnostically reliable cutoff
(sensitivity 86%, specificity 100%, PPV 100%, NPV 50%)
in the assessment of preeclampsia in the course of
pregnancies terminated before 34 weeks compared to
those above 34 weeks (sensitivity 63%, specificity 90%,
PPV 89%, NPV 64%) [88]. In contrast to the above-men-
tioned examples, Kucukgoz Gulec et al. [89] proposed a
threshold value for the spot urine P/C ratio of 53 mg/
mmol (0.53 mg/mg) for proteinuria >0.3 g/d (sensitivity
81%, specificity 93%).
Interesting data was presented by Bhatti et al. [90]
who emphasized the dependence of P/C ratio on ethni-
city. The authors indicated that a spot urine P/C ratio
cutoff of 30 mg/mmol (0.3 mg/mg) gave unsatisfactory
proteinuria detection results in 41% of African-
American and 23% of Caucasians pregnant women. In
the Caucasian population, they proposed a cutoff of
21 mg/mmol (0.21 mg/mg) as a value that allowed
detection of proteinuria with 100% sensitivity. In add-
ition, they emphasized that the use of a spot urine P/C
ratio in these women significantly reduced the cost of
diagnostics [90]. In contrast, in the population of

pregnant African-American women, they suggested
that quantitative assessment of protein in 24-h urine
collection, and not the spot urine P/C ratio, should be
used for the assessment of proteinuria. This is because
African-American women excrete more creatinine in
the urine compared to Caucasian women with similar
height and weight [92,93].
The study of Gaddy-Dubac et al. [94] showed that
the use of a P/C ratio cutoff of >30 mg/mmol (0.3 mg/
mg), according to ISSHP, resulted in less than accept-
able accuracy of proteinuria estimation at 0.3 g/d (sensi-
tivity 33%, specificity 85%). The authors suggested that
ethnic diversity and different courses of pregnancy
might contribute to unsatisfactory results in the use of
the P/C ratio [94].
Various reports in the literature have shown that the
values of the P/C ratio depended on the time of day at
which the urine samples were collected [91,95]. In
women with primary hypertension and the risk of
developing preeclampsia, Vardonk et al. [95] observed
the lowest P/C ratio of 60 mg/mmol (0.6 mg/mg) at
08:00 h, the highest value of 79 mg/mmol (0.79 mg/mg)
at 12:00 h, and a value of 73 mg/mmol (0.73 mg/mg) at
17:00 h. In order to detect proteinuria, they determined
the best cutoff for the P/C ratio depending on the time
of urine collection: 50 mg/mmol (0.5 mg/mg) at 08:00 h,
42 mg/mmol (0.42 mg/mg) at 12:00 h, and 35 mg/mmol
(0.35 mg/mg) at 17:00 h. They observed that fluctua-
tions in the P/C ratio values based on the time of urine
collection were explained by differences in the physical
activity of the women during the day, variable blood
pressure, emotional state and posture. They empha-
sized that for these women, P/C ratio tests were import-
ant for the rapid identification of clinically important
proteinuria at any time of the day [95]. Chandramathy
et al. [91] also assessed the time of day for P/C ratio
measurements that best correlated with the protein
concentration in 24-h urine collections. They observed
P/C ratios of 47 mg/mmol (0.47 mg/mg) for samples
taken in the morning (sensitivity 75%, specificity 75%);
40 mg/mmol (0.4 mg/mg) for samples taken at noon
(sensitivity 89%, specificity 91%); and 45 mg/mmol
(0.45 mg/mg) for samples taken at night (sensitivity
86%, specificity 80%). Surprisingly, based on the find-
ings of Chandramathy et al., the best time for urine col-
lection for a P/C ratio evaluation was 12:00 h [91].
Haghighi et al. [96] also evaluated the P/C ratio in
urine samples for the estimation of proteinuria in the
risk assessment of preeclampsia at several different
time points in the day. They found a positive correlation
of P/C ratio determined in samples collected over 4 h,
8 h, 12 h (day) and 12 h (night) compared to the
CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 11
assessment of proteinuria in 24-h urine collections.
Moreover they determined the best cutoff values for
the P/C ratio in individual samples: the P/C ratios were:
for a 4-h sample, 28 mg/mmol (0.28 mg/mg) (sensitivity
88%, specificity 98%); for an 8-h sample, 24 mg/mmol
(0.24 mg/mg) (sensitivity 95%, specificity 95%); for a 12-
h (day) sample, 25 mg/mmol (0.25 mg/mg) (sensitivity
97%, specificity 98%); and for a 12-h (night) sample,
23 mg/mmol (0.23 mg/mg) (sensitivity 95%, specificity
97%). According to the authors, the measurement of P/
C ratio in several-hour urine samples might be a good
alternative to 24-h urine collections for detecting pro-
teinuria in pregnant women with suspected preeclamp-
sia, especially when there is insufficient time for a 24-h
urine collection [96].
Studies have also assessed whether proteinuria
>0.3 g/d or a spot urine P/C ratio 30 mg/mmol
(0.3 mg/mg) is a good criterion for the assessment of
pathology during pregnancy and whether such protein-
uria can be observed in a normal pregnancy. Tanamai
et al. [97] found that in healthy pregnant women with
normal, uncomplicated pregnancy, a P/C ratio
30 mg/
mmol (0.3 mg/mg) is very common just before delivery,
at the term and during the peripartum period. The
highest values of the P/C ratio were observed 6 h after
delivery. Therefore, they emphasized that a P/C ratio of
30 mg/mmol (0.3 mg/mg) in healthy pregnant women
with an uncomplicated pregnancy during this period
may be an unreliable criterion for the assessment of
proteinuria in the diagnosis of preeclampsia, and that
separate cutoff values for women examined just before
delivery, during and immediately after delivery should
be established [97]. In another study [98], post-delivery
spot urine P/C ratio values in healthy pregnant women
were found to be significantly higher compared to pre-
delivery values and exceeded the 30 mg/mmol (0.3 mg/
mg) threshold. The P/C ratio value 2 h after vaginal
delivery was 46 mg/mmol (0.46 mg/mg), and 4 h after
cesarean delivery, 54 mg/mmol (0.54 mg/mg). On the
basis of these results, the authors emphasized that spot
urine P/C ratio measurements were unreliable in the
immediate postpartum period regardless of mode of
delivery. Therefore, P/C ratio cutoff values other than
the 30 mg/mmol (0.3 mg/mg) should be considered for
suspected preeclampsia in close proximity to delivery.
During delivery and in the postpartum period in
patients who were administered magnesium sulfate
prophylactically, the spot urine P/C ratio may not be
reliable in assessing proteinuria [98].
Additionally, in the risk assessment of preeclampsia,
it is important to know whether the spot urine P/C ratio
is determined in the urine of patients who have
12 J. KAMIŃSKA ET AL.
singleton or multiple pregnancies. Osmundson et al.
[99] emphasized that women pregnant with twins
could excrete more protein daily and more often have
proteinuria, but that they were not always hypertensive.
Therefore, other criteria for the diagnosis of preeclamp-
sia should be developed for women in twin pregnan-
cies [99]. Other authors indicated that, while the values
of the P/C ratio in singleton and twin pregnancies in
the initial period may be similar, they were significantly
higher in twin pregnancies at the end of the third tri-
mester (34–38 weeks of pregnancy) [100].
Independently and in parallel with the P/C ratio, the
ACR may be used to estimate proteinuria during preg-
nancy [101–103]. A strong positive correlation (r ¼ 0.95,
p ¼ 0.001) was found between these two tests. An ACR
of 13.4 mg/mmol has been shown to correspond to a
P/C ratio of 30 mg/mmol (0.3 mg/mg). The authors sug-
gested that clinicians should use the test that is less
expensive, that has fewer methodological limitations,
and that they are more familiar with [101]. Interestingly,
Waugh et al. [103] observed that ACR had a better diag-
nostic efficacy (sensitivity 99%) when estimating pro-
teinuria in predicting severe preeclampsia as compared
to the P/C ratio (sensitivity >90%).
Spot urine P/C ratio and myeloma kidney
In the course of MM, proteinuria may be the result of
the accumulation in the urine of Bence-Jones proteins,
i.e. monoclonal immunoglobulin light chains (j, k), but
also of albumin and other proteins [104]. The
International Myeloma Working Group recommends
the assessment of proteinuria in 24-h urine collection in
the diagnosis of MM and periodically during treatment
and monitoring of disease activity, especially because
test strips do not detect monoclonal protein [105,106].
The usefulness of the spot urine P/C ratio in estimat-
ing proteinuria in patients with MM was first assessed
by Wozney et al. [12], who showed a good positive cor-
relation (r ¼ 0.81, p < 0.001) of the P/C ratio with the
protein concentration in 24-h urine collections. In
patients with MM, for selected protein concentrations
in 24-h urine collections, they determined P/C ratio cut-
off values: 25 mg/mmol (0.25 mg/mg) for proteinuria

0.3 g/d (sensitivity 83%, specificity 81%); 41 mg/mmol
(0.41 mg/mg) for proteinuria
0.5 g/d; 57 mg/mmol
(0.57 mg/mg) for proteinuria
1.0 g/d; and 371 mg/
mmol (3.71 mg/mg) for proteinuria
3.5 g/d. In add-
ition, they noticed that the P/C ratio was significantly
higher in patients with positive urine immunofixation
(37 mg/mmol, 0.37 mg/mg) compared to patients with
negative urine immunofixation (10 mg/mmol, 0.10 mg/
mg, p ¼ 0.00), especially in the group of patients with
light chain MM. The authors emphasized that the spot
urine P/C ratio was useful as a screening test for assess-
ing proteinuria in the course of MM.
To assess proteinuria in three patients with MM,
Talbot et al. [107] evaluated the P/C ratio together with
routine urinalysis. In one patient, they obtained a P/C
ratio of 71 mg/mmol (0.71 mg/mg), while in the other
two cases, the P/C ratio was 166 mg/mmol (1.66 mg/
mg) and 178 mg/mmol (1.78 mg/mg). High values of
the P/C ratio in these patients were associated with
positive urine immunofixation in two cases, while in the
third patient, urine immunofixation was not per-
formed [107].
The above-mentioned studies demonstrate the pos-
sibility of using the spot urine P/C ratio to assess pro-
teinuria in patients with MM, although it should be
emphasized that these are single reports and that fur-
ther evaluation in a larger group of patients is required.
Spot urine P/C ratio and children
Proteinuria in children is usually found accidentally dur-
ing routine urinalysis and occurs in about 10% of
school-age children; however only in 0.1% of them is it
confirmed in subsequent laboratory tests [108,109]. The
most typical causes are orthostatic proteinuria (induced
by standing) or functional (transient) proteinuria [108].
According to Leung et al. [108,110], when the result
of the test strip for protein is trace, the test strip for
protein should be repeated using the first morning
sample; when the result is negative or trace, the test
strip for protein should be repeated within a year to
check that proteinuria has not recurred; and when the
result is positive
1þ, the test strip for protein should
be repeated on a first morning sample and the P/C ratio
should be calculated. If the spot urine P/C ratio is
20 mg/mmol (0.2 mg/mg), or 50 mg/mmol (0.5 mg/
mg) for children under 2 years of age, and the other
parameters in the urine screening test are normal, then
orthostatic or functional proteinuria is very likely, and a
checkup should be carried out within a year. However,
if spot urine P/C ratio is >20 mg/mmol (0.2 mg/mg), or
>50 mg/mmol (0.5 mg/mg) for children under 2 years of
age, or the urine test results are abnormal (e.g. hema-
turia, leukocyturia, active urinary sediment), persistent
proteinuria or proteinuria of clinical significance is more
likely and testing should be extended to exclude or
confirm kidney disease.
Quantitative evaluation of proteinuria in 24-h urine
collections in children is very rarely used due to the
great difficulty of complete collection [108,110]. Values
 CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 13

Table 4. Urinary protein excretion in children. Modification >200 mg/mmol (2.0 mg/mg) [19,68]. Newborns are
based on [108,110]. more likely to lose protein in the urine due to reduced
Type of test Age/Condition Values reabsorption in the proximal tubules. In contrast, in
Spot urine P/C ratio Children from >50 mg/mmol or
6 months to 2 years >500 mg/g or
children above 2 years of age, it is recommended to
>0.5 mg/mg adopt adult standards for protein in the urine, i.e.
Children >2 years >20 mg/mmol or <150 mg/L in a spot urine sample and <0.15 g/d [19].
>200 mg/g or
>0.2 mg/mg Warady et al. [111] indicated that in children with per-
Nephrotic syndrome >220 mg/mmol or sistent proteinuria, elevated spot urine P/C ratio values
>2200 mg/g or
>2.2 mg/mg may be an important predictor of chronic renal disease
Protein Children <6 month of age >8 mg/m2/h or progression (>200 mg/mmol (2.0 mg/mg) in children
concentration in 24-h >0.24 g/1.73m2/d
urine collection Children >6 month of age >4 mg/m2/h or with non-glomerular kidney disease and >50 mg/mmol
>0.15 g/1.73m2/d (0.5 mg/mg) in children with glomerulonephritis) [111].
Nephrotic syndrome >40 mg/m2/h or
>3 g/1.73m2/d Importantly, the use of the P/C ratio to assess protein-
Children 100–150 mg/m2/d uria may be limited in children with low muscle mass
Newborns >0.3 g/m2/d
and severe malnourishment because the P/C ratio
depends on creatinine excretion [112].

Table 5. Limitations of the spot urine P/C ratio evaluation

[5,21,29,33,39,45,54,92,93,101,113–116].
Reference Limitations
[5] Spot urine P/C ratio does not take into account protein
excretion in the urine during the day and from day-
to-day
[21] Lack of correlation between spot urine P/C ratio and
protein concentration evaluated in 24-hour urine
collection, if daily protein excretion exceed 6 g/day
and GFR <15 mL/min/1.73m2
[92,93] Spot urine P/C ratio result depends on ethnicity (lower
values are observed in the African-Americans,
because they excrete more creatinine to urine
compared to Caucasians with similar height
and weight)
[101] Spot urine P/C ratio result depends on muscle mass,
which indicates its limited use in children/patients
with low muscle mass and severely undernourished
(the risk of false positive results when the urine
sample is excessively diluted or creatinine in the
urine 2.65 mmol/L (30 mg/dL))
[54,113] Poor or lack of correlation between spot urine P/C ratio
and protein concentration in 24-hour urine collection
in patients with minimal change disease or
membranous nephropathy with nephrotic-range
proteinuria
[114] The protein concentration may be overestimated or
underestimated, especially when urine creatinine
levels are 3.45 mmol/L (39 mg/dL) or
5.48 mmol/L
(62 mg/dL)
[33,115] The spot urine P/C ratio may be overestimated at GFR
levels 10 mL/1.73m2
[29,39,45,116] The diversity of methods used to assess protein and
creatine concentration make the comparison of spot
urine P/C ratio results between
laboratories impossible
GFR: glomerular filtration rate; P/C ratio: protein-creatinine ratio.
for urinary protein excretion in children are given in
Table 4.
NKF KDOQI (Kidney Disease Outcomes Quality
Initiative) defined proteinuria in children as normal/
minimal when the P/C ratio is <50 mg/mmol
(0.5 mg/mg), increased when it is 50–200 mg/mmol
(0.5–2.0 mg/mg), and nephrotic when it is
Limitations of the spot urine P/C ratio evaluation
The spot urine P/C ratio is a rapid and simple method
for estimating the concentration of urinary protein
excretion but is not free from limitations. Table 5
presents the most frequently reported limitations of the
spot urine P/C ratio evaluation [5,21,29,33,39,45,54,
92,93,101,113–116].
Conclusions
The spot urine P/C ratio can be useful in everyday med-
ical practice for the rapid exclusion/confirmation of pro-
teinuria as well as for the quantitative estimation of
proteinuria in many clinical conditions associated with
proteinuria, i.e. kidney disease, kidney transplantation,
lupus nephropathy, hypertensive nephropathy, pree-
clampsia, diabetic nephropathy, myeloma kidney as
well as in proteinuria in children (Table 6) [5,10,12–17,
21,27,33–37,54,55,60,61,63,65,67,70,72,79,82,84,86,87,89,
90,94,96,97,99,103,108,110,113,115,117–130].
A strong correlation of the spot urine P/C ratio with
the protein concentration in 24-h urine collections was
observed. The spot urine P/C ratio is a rapid and reliable
test that can eliminate the need for a 24-h urine collec-
tion. On the other hand, the comparability of both
methods has been rarely assessed. In doubtful situa-
tions, the assessment of proteinuria based on the P/C
ratio should be supported by an evaluation of the
protein concentration in a 24-h urine collection
(Table 7) [103,131–138].
A spot urine P/C ratio value of 20 mg/mmol (0.2 mg/
mg) is the most frequently reported cutoff point for
determining the presence or absence of proteinuria,
and a P/C ratio of 350 mg/mmol (3.5 mg/mg) is used for
14 J. KAMIŃSKA ET AL.

Table 6. Key points in the evaluation of the spot urine P/C ratio in different states [5,10,12–17,21,27,33–37,54,55,60,
61,63,65,67,70,72,79,82,84,86,87,89,90,94,96,97,99,103,108,110,113,115,117–130].
References Key points
Kidney disease
[16,33] In patients with lower levels of GFR, especially those with CKD stage 5, urinary protein excretion may be overestimated,
indicating spot urine P/C ratio results dependent on the GFR value
[21,54] The spot urine P/C ratio stronger correlated with protein concentration in 24-h urine collection if the proteinuria ranged
from 0.3–3.5 g/day (300–3449 mg/day) compared to patients with nephrotic syndrome >3.5 g/day (>3500 mg/day); no
correlation was observed when the protein excretion exceeds 6 g/day
[34,60] Spot urine P/C ratio is a precise, convenient and reliable method for estimating urinary protein excretion in patients after
kidney transplantation, especially with low proteinuria
[61] Verification of the P/C ratio by means of protein concentration in 24-h urine collection is needed before important
diagnostic and therapeutic decisions e.g. Before biopsy or before the change of immunosuppressive agents
[17,21,27,54,55,113] The evaluation of the P/C ratio in a single urine sample is a good alternative to 24-h urine collection for the assessment of
proteinuria, especially in patients with renal insufficiency and with different types of glomerulonephritis (e.g. patients with
immunoglobulin A nephropathy)
[118] Spot urine P/C ratio was as useful as protein/day in predicting outcomes in chronic kidney disease patients and is more
convenient for patients, clinicians, and laboratories
Lupus nephritis (LN)
[67] The patient with LN should be directly qualified for renal biopsy if the spot urine P/C ratio is >100 mg/mmol (1.0 mg/mg)
[65,117] Clinical decisions in LN patients should not rely on the spot P/C ratio results, as they can yield false-positive or false-
negative diagnoses of glomerulonephritis compared to 24-h urine collection results
[63,64,70,117] Spot urine P/C ratio is both a screening test and proteinuria monitoring assay in patients with LN, if proteinuria exceeds
1 g/day
Diabetic nephropathy
[10] P/C ratio of 15 mg/mmol (0.15 mg/mg) predicted significant proteinuria in diabetic nephropathy (sensitivity 97%,
specificity 74%)
[72] P/C ratio of 30 mg/mmol (0.3 mg/mg) predicted significant proteinuria in diabetic nephropathy (sensitivity 81%,
specificity 100%)
[119] In diabetes mellitus protein evaluation in 24-h urine collection should be performed instead of the spot urine P/C ratio
Hypertension
[35] Spot urine P/C ratio of 80 mg/mmol (0.8 mg/mg) with 95% sensitivity predicted nephropathy in hypertensive patients
[36] Spot urine P/C ratio should be used routinely as a screening test in all patients with hypertension duration >5 years
[13,79] The relationship between the spot urine P/C ratio values >30 mg/mmol (0.3 mg/mg) and the presence of left ventricular
hypertrophy in patients with second stage of primary hypertension was observed
Preeclampsia
[90] Spot urine P/C ratio should not be used to detect significant proteinuria in pregnant African-American women
[94] Spot urine P/C ratio results were unsatisfactory to estimate proteinuria at different course of pregnancy, e.g. medical
complication including: overweight, obesity, diabetes, and smoking, symptomatic or asymptomatic bacteriuria
[96] Spot urine P/C ratio in a several-hour urine samples (4-h, 8-h, 12-h, daily/night sample) could be a good alternative to
detect proteinuria in pregnant women with suspected preeclampsia, especially when there was insufficient time to 24-h
urine collection
[97] Spot urine P/C ratio of 30 mg/mmol (0.3 mg/mg) was unreliable for suspect preeclampsia in close proximity to delivery
[99] In multiple pregnancies women the diagnosis of preeclampsia should be made on P/C ratio cutoff other than 30 mg/mmol
(0.3 mg/mg)
[36,37,80,84,86, For the estimation of proteinuria in women at risk of preeclampsia different cutoff values of the spot urine P/C ratio were
87,89,90,103] recommended: 20 mg/mmol (0.2 mg/mg); 21 mg/mmol (0.21 mg/mg); 33 mg/mmol (0.33 mg/mg); 36 mg/mmol (0.36 mg/
mg); >40 mg/mmol (0.40 mg/mg);
40 mg/mmol (0.40 mg/mg); 53 mg/mmol (0.53 mg/mg), however the most frequently
recommended cutoff point was 30 mg/mmol (0.30 mg/mg)
[120] Spot urine P/C ratio in preeclamptic women >900 mg/mmol (9.0 mg/mg) (9 g/day), or >500 mg/mmol (5.0 mg/mg) (5 g/day) in
women over 35 years, was associated with a greatly increased probability of adverse maternal and fetal outcomes
[121] Spot urine P/C ratio between 30–35 mg/mmol (0.30–0.35 mg/mg) is an optimal threshold value to detect proteinuria
>0.3 g/day
[122] Spot urine P/C ratio was highly predictive to detect proteinuria >1g/day and it could be used as a rapid, alternative test in
preeclamptic women
[123] Spot urine P/C ratio
75 mg/mmol (0.75 mg/mg) in normotensive pregnant women was sufficient to detect significant
proteinuria
[124] Spot urine P/C ratio is a better tool for estimation of proteinuria in preeclampsia than the dipstick test
Myeloma kidney
[12] Spot urine P/C ratio is a useful screening test for assessing proteinuria in the course of multiple myeloma, taking into
consideration that the dipstick test does not detect Bence-Jones protein
Children
[108,109] In children the spot urine P/C ratio is a good alternative to 24-h urine collection for evaluation of proteinuria
In physiology children <2 years of age should have the P/C ratio 50 mg/mmol (0.5 mg/mg), while >2 years of age the P/C
ratio should be 20 mg/mmol (0.2 mg/mg)
(continued)
 CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 15

Table 6. Continued.
References Key points

Type of sample
[14,15, 115,125,126] NKF K/DOQI guidelines and other authors suggested that untimed (spot) urine samples should be used to detect and
monitor proteinuria in children and adults; a first-morning sample is preferred, but when it is not available a random
sample could be accepted taking into account that daily activity may affect the amount of excreted protein in the urine
[5,127] The ability to use a random urine sample is an advantage of the P/C ratio evaluation
Glomerular filtration rate
[16,21,33] Spot urine P/C ratio results are influenced by the GFR: good correlation between spot urine P/C ratio and the protein
excretion in 24-h urine collection was observed in patients with GFR in norm or slightly decreased; weak relationship was
observed at GFR <15 mL/min/1.73m2
General
[56] Spot urine P/C ratio is fast and simple method for the exclusion of significant proteinuria and may reduce the number of
unnecessary 24-h urine collections the P/C ratio initially was validated to differentiate nephrotic from non-nephrotic
proteinuria
[115] Spot urine P/C ratio could be used as an alternative to urine protein evaluation in 24-h collection in patients with GFR
>10 mL/min/1.73m2
[119] We still lacks recommendations which methods of urine protein and creatinine concentrations evaluation should be used to
minimize interlaboratory differences
[54,90,128–130,135] The use of spot urine P/C ratio is a convenient and competitively priced method in patients with proteinuria <3.5 g/day
CKD: chronic kidney disease; GFR: glomerular filtration rate; LN: lupus nephritis; NKF K/DOQI: National Kidney Foundation Kidney Disease Outcomes
Quality Initiative; P/C ratio: protein-creatinine ratio.

Table 7. The utility of ACR, the spot urine P/C ratio and the protein/day evaluation in different clinical conditions [103,131–138].
Reference Utility
[103] Study analyzed the accuracy of quantitative assessments of the spot urine P/C ratio and ACR at different cutoffs in
predicting severe preeclampsia compared to protein/day measurement in pregnant women with hypertension and
suspected proteinuria. Authors conclude that in this group of patients proteinuria should be initially checked in dipstick
screening test and if the result is positive, the ACR should be performed; in the case of ACR being unavailable an
alternative should be the spot urine P/C ratio. The recommended cutoffs for clinically significant proteinuria should be
8 mg/mmol for ACR and 30 mg/mmol (0.3 mg/mg) for the spot urine P/C ratio. Authors do not recommendthe evaluation
of protein/day in hypertensive pregnant women.
[131] Authors conclude that annual screening for dip-stick proteinuria, followed by ACR or the spot urine P/C ratio confirmation,
in addition to GFR measurement and treatment with ACEI or ARB for albuminuria or proteinuria is cost-effective for
preventing ESRD or death in diabetic patients or in non-diabetic subjects who have hypertension or are aged > 60 years.
[132] Highlights that there is no consensus regarding the utility of the ACR and the spot urine P/C ratio evaluation, e.g.:
 the UK CKD guidelines, Scottish Intercollegiate Guidelines Network and Caring for Australians with Renal Impairment
Guidelines recommend the use of ACR for diabetic patients, while spot urine P/C ratio should be applied for non-
diabetic CKD
 the Kidney Disease Quality Outcomes Initiative Guidelines recommend ACR, whereas spot urine P/C ratio may be use if
the ACR is high >56.5–113 mg/mmol creatinine (500–1000 mg/g)
[133] Study analyzed 117 spot urine samples to evaluate the relationship between ACR and the spot urine P/C ratio at the cutoffs
recommended by the NICE guidance on CKD. Authors did not found discordant results between ACR and the spot urine
P/C ratio at cutoffs recommended by NICE: 30 mg/mmol and 50 mg/mmol (0.50 mg/mg), , respectively.
[134] Based on the literature review authors conclude that ACR might be recommended for the diabetic while the spot urine P/C
ratio for the non-diabetic individuals.
[135] Authors retrospectively analyzed 6842 patients results and found that:
 the relationship between ACR and the spot urine P/C ratio is non-linear
 the spot urine P/C ratio correlated more with protein/day as compared to ACR (r ¼ 0.91, p < 0.001 and r ¼ 0.84,
p < 0.001, respectively). Moreover, in the urine protein range 0.3–1 g/day there was a significantly greater scatter
with ACR.
 the difference between the spot urine P/C ratio and ACR is less in the ACEi/ARB-treated patients
 the spot urine P/C ratio is a more sensitive and specific test as compared to ACR for detection of significant proteinuria
(>0.5 or >1 g/day) in unselected patients attending a hospital kidney department
[136] Authors retrospectively analyzed 602 patients with established diagnosis of CKD and found that:
 ACR strongly, significantly correlated with the spot urine P/C ratio (r ¼ 0.94, p < 0.001) at all albuminuria ranges; on the
other hand at normal albuminuria range such correlation was not observed
 univariate and multivariate linear regression analysis found that similar clinical features were associated with both ACR
and the spot urine P/C ratio
[137] The study analyzed 438 patients with IgAN and showed that:
 ACR strongly, significantly correlated with the spot urine P/C ratio (r ¼ 0.87, p < 0.001); however better correlation was
observed at lower ranges of proteinuria (r ¼ 0.87, p < 0.001)
 both, ACR and the spot urine P/C ratio correlated with protein/day (r ¼ 0.71, p < 0.001 and r ¼ 0.74, p < 0.001,
respectively)
 ACR had better usefulness in predicting IgAN progression as compared to the spot urine P/C ratio and protein/day
[138] The CKD in children study showed that there is no difference in the ability of ACR and the spot urine P/C ratio in predicting
time to GFR decline of 50%
ACEi: angiotensin-converting-enzyme inhibitors; ACR: albumin to creatinine ratio; ARBs: angiotensin receptor blockers; CKD: Chronic Kidney Disease; GFR:
glomerular filtration rate; IgAN: IgA nephropathy; NICE: National Institute for Health and Clinical Excellence.
16 J. KAMIŃSKA ET AL.

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