Archives of Oral Biology 102 (2019) 205–211

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Archives of Oral Biology

journal homepage: www.elsevier.com/locate/archoralbio

Oral mucosa and salivary findings in non-diabetic patients with chronic T

kidney disease
Jovan Marinoskia, , Marija Bokor-Braticb, Igor Miticc, Milos Cankovicd
⁎

a
Private Dental Clinic “Dr Mladenovic”, Lasla Gala 30, 21000, Novi Sad, Serbia
b
University of Novi Sad, Faculty of Medicine, Dental Clinic of Vojvodina, Oral Medicine Section, Hajduk Veljkova 12, 21000, Novi Sad, Serbia
c
University of Novi Sad, Faculty of Medicine, Clinical Centre Vojvodina, Clinic of Nephrology and Clinical Immunology, Hajduk Veljkova 3, 21000, Novi Sad, Serbia
d
University of Novi Sad, Faculty of Medicine, Dentistry Department, Oral Medicine Section, Hajduk Veljkova 3, 21000, Novi Sad, Serbia

ARTICLE INFO ABSTRACT

Keywords: Introduction: Chronic kidney disease (CKD) and dialysis treatment could affect oral mucosa and cause qualitative
Chronic kidney disease or quantitative changes of saliva.
Oral mucosa Objective: The aim of the study was to investigate oral manifestations, unstimulated salivary flow rate (USFR),
Saliva salivary pH value and biochemical composition of saliva in non-diabetic patients with CKD.
Urea
Design: The study group (PD) consisted of 50 pre-dialysis patients diagnosed with CKD, positive control group
Creatinine
(HD) of 25 haemodialysis patients and negative control (H) of 25 age and gender-matched healthy persons.
Creatinine clearance rate (CrCl) was calculated from the blood creatinine using the Cockcroft-Gault formula.
After a detailed intraoral examination, whole unstimulated saliva samples were collected to determine salivary
pH value, and biochemical composition using a spectrophotometric method.
Results: Statistical analysis revealed that PD subjects had more oral lesions (p < 0.05) and symptoms
(p < 0.001) than controls. The mean CrCl was significantly lower (p < 0.05) in CKD subjects with pale mu-
cosa, xerostomia, dysgeusia, and uremic odour, comparing to those without listed symptoms. PD subjects had
significantly decreased USFR and increased pH, urea and creatinine than H controls (p < 0.05). A moderately
strong positive correlation between serum and salivary creatinine in both PD (p < 0.05) and HD (p < 0.05)
groups was found.
Conclusion: This study confirmed that xerostomia and dysgeusia are major symptoms among pre-dialysis pa-
tients. Their presence along with uremic odour and pale mucosa is directly related to decreased kidney function.
On the diagnostic point, decreased USFR, especially hyposalivation and increased salivary creatinine, should be
considered a significant indicator of CKD in stages before dialysis therapy.

1. Introduction
Early diagnosis of chronic kidney disease (CKD) requires blood
sampling, which is an invasive procedure that is accompanied by an-
xiety and discomfort to patients. In view of this, comparative devel-
opment of science and technology has contributed to the detailed ex-
amination of saliva in order to identify the biomarkers of pathological
processes and standardise their values as well (Ilyin, Belkowski, &
Plata-Salamán, 2004). The importance of performing saliva analyses
has been emphasised in the past two decades, mainly because of the
non-invasive, simple and economic procedure of saliva collection. Un-
like serum, saliva has been recently described as a ‘real-time’ fluid
(Champatyray et al., 2015), showing the current state of health at the
moment of collection, mainly because of the exocrine production of the
salivary glands. Systemic disorders within CKD and effects of dialysis
treatment could affect a wide range of tissues and organs, including
alterations in the flow of saliva, its pH value and its biochemical
composition (Tomas et al., 2008). The diagnostic potential of saliva in
terms of determining the clinical and laboratory markers of kidney
disorders has been examined in only few previous studies, showing
different results (Bayraktar, Kazancioglu, Bozfakioglu, Yildiz, & Ark,
2004; Bots, Brand, Poorterman et al., 2007; Bots, Brand, Veerman et al.,
2007; Obry, Belcourt, Frank, Geisert, & Fischbach, 1987;). Although a
broad variety of oral manifestations have been reported in patients with
CKD, there are contradictory opinions among authors regarding the
distribution of oral mucosal lesions and oral symptoms depending on
the stage of the disease. Most of the studies indicated the presence of at
least one oral sign or symptom in 95% of the patients in different stages

⁎
Corresponding author.
E-mail address: marinoski85@gmail.com (J. Marinoski).

https://doi.org/10.1016/j.archoralbio.2019.04.021
Received 5 December 2018; Received in revised form 29 April 2019; Accepted 29 April 2019
0003-9969/ © 2019 Elsevier Ltd. All rights reserved.
J. Marinoski, et al.
prior to the implementation of dialysis treatment (Oyetola, Owotade,
Agbelusi, Fatusi, & Sanusi, 2015). In contrast, clinically healthy oral
mucosa and lack of symptoms in almost 80% of end-stage patients have
been published earlier (Gavalda et al., 1999). The occurrence of oral
manifestations in patients with CKD appears to be associated with
malnutrition, restrictive diets, poor oral hygiene, immunosuppression
and influence of medicaments and uremic toxins on oral tissues (Patil,
Khaandelwal, Doni, Rahuman, & Kaswan, 2012; Proctor, Kumar, Stein,
Moles, & Porter, 2005). The objective of this study was to investigate
the oral manifestations, salivary pH value, unstimulated salivary flow
rate (USFR) and the biochemical composition of saliva (urea and
creatinine concentration) in non-diabetic patients with CKD.
2. Materials and methods
2.1. Study design and subjects
This cross-sectional clinical study was performed at the Department
of Oral Medicine, Clinic for Dentistry of Vojvodina, Novi Sad, Serbia, in
the period between September 2014 and December 2015. The sample
comprised 75 non-diabetic patients diagnosed with CKD, who were
treated at the Clinic of Nephrology and Immunology, Clinical Center of
Vojvodina, Novi Sad, during this period, along with 25 healthy subjects
who were visiting the Clinic for Dentistry of Vojvodina for regular
check-ups. Potential participants who used antibiotics or corticosteroids
or underwent immunosuppressive therapy in the last three months and
those with incomplete medical documentation or any systemic disease,
such as diabetes mellitus, neoplasms, autoimmune diseases, infectious
diseases or psychiatric diseases, were not included in the present study.
Based on the above-mentioned criteria, three groups were created: a
study group (PD), comprising 50 pre-dialysis patients (31 males and 19
females, age range: 18–82 years, average age: 59.06 ± 14.30 years)
diagnosed with CKD by a nephrologist; a positive control group (HD),
comprising 25 end-stage patients (18 males and seven females, age
range: 28–80 years, average age: 54.92 ± 13.60 years) regularly un-
dergoing haemodialysis treatment; a negative control group (H), com-
prising 25 healthy subjects (16 males and nine females, age range:
28–80 years, average age: 54.20 ± 12.67 years).
2.2. Sample size calculation
Using the multivariate analysis of variance (MANOVA) statistical
test, four salivary parameters (USFR, pH, urea and creatinine) were
analysed among the three groups of subjects. Power calculation in-
dicated that, with a minimum of 25subjects in each group, the study
would have 88% power and 95% level of confidence, which provides a
good balance between accuracy and reliability.
2.3. Ethical issues
We received ethical clearance and approval from the Local Ethical
Committee of the Dental Clinic for the present study. Participants were
provided with information regarding the risk and benefits of the study,
and written informed consent was obtained from each of them.
2.4. Medical data collection
Data regarding the age, gender, body weight and height (the body
mass index [BMI] was calculated) and oral symptoms were collected
using a questionnaire tailored for this study. The presence of a uremic
odour was determined after the patient provided an affirmative con-
firmation to the question of whether his/her breath has an unpleasant
and pungent odour that resembles that of ammonia. In the ques-
tionnaire, findings of the clinical examination of the oral mucosa,
clinical tests and laboratory analyses of the saliva were also recorded.
Data of serum laboratory analyses performed in the last 24 h were
206
Archives of Oral Biology 102 (2019) 205–211
obtained from the medical records of both PD and HD patients.
2.5. Assessment of renal function
The glomerular filtration rate was determined through the creati-
nine clearance (CrCl) calculation based on serum creatinine levels,
gender and body weight. For this purpose, the Cockcroft–Gault formula
(Botev, Mallie, Wetzels, Couchoud, & Schuck, 2011) was used:
(140 number of years) × Constant*
CrCl = ,
Serum creatinine levels (mmol/L)
where Constant* is 1.23 for males and 1.04 for females.
2.6. Clinical assessment of the oral mucosa
The oral mucosal lesions determined by the clinical examination
were classified as pale mucosa, red lesions (enanthem, ecchymosis,
petechiae or haematoma), white lesions (white patches, plaque or
keratosis), pigmented lesions and oral mucosal defects (erosion and
ulceration).
When examining the dorsal surface of the tongue, hypertrophy of
the filiform papillae was determined on the basis of the subjective as-
sessment of the observer that their length was longer than 3 mm. A
diagnosis of a coated tongue was made if hypertrophy was associated
with a greyish-white coating on it.
2.7. Measurement of the salivary pH value
Salivary pH values were determined using a standard pH paper in-
dicator with a sensitivity of 0.5 (Neutralit; Merck, Darmstadt,
Germany). A strip of the paper indicator was placed on the base of the
tongue and withdrawn by the observer in 5 s, after being soaked by
saliva. The values of pH were determined by comparing the change in
colour of the paper strips in relation to the attached scale. pH values
from 6.5 to 7.0 were considered normal.
2.8. Saliva collection and laboratory analysis
Whole saliva specimens were collected in the morning between 8:00
AM–10:00 AM. The subjects were instructed not to eat, drink, smoke or
perform any oral hygiene for at least 2 h before saliva collection.
Comfortably seated and trained to avoid swallowing their saliva, all
subjects were asked to lean forward and to spit all the saliva they made
for 10 min into a 5 mL labelled, sterilised polypropylene tube (SARST-
EDT, Nümbrecht, Germany; product: 62.526.028). Only the liquid
component (not the foam) of saliva was measured. The volume of saliva
and the collection time were used to calculate the USFR. The normal
value of secreted unstimulated whole saliva was ≥0.1 mL/min. The
tubes were loaded into a specific transport rack placed in a holding
fridge (+4 °C) and then safely transported to the laboratory within 2 h
of saliva collection. The saliva samples were immediately centrifuged at
4000 rpm for 15 min. The concentrations of uremic toxins (urea and
creatinine) were determined using an automated Beckman Coulter
AU480 system, applying conventional spectrophotometric techniques,
kinetic UV and enzymatic tests, respectively. Total protein levels were
also estimated in order to normalise salivary urea and creatinine con-
centration. For this purpose, Biuret method and colorimetric assay were
used. To normalise the salivary toxins to salivation, all subjects with
CKD were divided into three subgroups depending on the intensity of
salivation: A (USFR ≤ 0.1), B (USFR = 0.11−0.30) and C
(USFR ≥ 0.31).
2.9. Statistical analysis
Data were presented as frequency distribution, mean ( X ) ±
J. Marinoski, et al. Archives of Oral Biology 102 (2019) 205–211

standard deviation (SD). First, a Kolmogorov–Smirnov test was per-

0.045 0.386 / 0.667

formed to determine whether dependent variables across the groups

0.164 0.667 0.667

follow the normal distribution. Statistically significant differences be-

p- value, PD/H
tween the groups were determined using analysis of variance (ANOVA)

< 0.001

< 0.001
< 0.001
< 0.001
or MANOVA for interval variables and chi-squared test or Fisher’s exact

0.001 /
0.008

0.001

0.004
0.174

0.546

0.659
test for nominal characteristics. A post hoc analysis was performed
using LSD and Games–Howell tests for variables whose variances were

/
/
significantly different and variables whose variances were not, respec-

0.037 0.333 0.123

0.186 0.667 0.667

tively. Pearson’s correlation coefficient was calculated for measuring

p- value, PD/HD
the degree of relationship between salivary and serum parameters (urea

0.027 0.333
and creatinine), and it was represented as an r -value. Statistical ana-
lyses were performed using SPSS version 14.0 for Windows (IBM Corp,

0.027
0.025

0.016

0.043
0.559
0.172

0.593

0.057
0.189

0.060
0.452
Armonk, NY, USA).

/
/
p - value, PD/HD/H
3. Results

0.041 0.220 0.072

0.031 0.164 0.164

< 0.001 0.220

3.1. Sample characteristics and oral manifestations

< 0.001

< 0.001
< 0.001
< 0.001
0.008

0.041

0.032

0.010
0.688

0.262
0.665

0.602

0.456

0.314
According to the calculated CrCl value, no significant difference was
found in the prevalence of each CKD stadium in PD group ( p = 0.568).
In addition, no differences between all three groups in relation to

2 (8) 0 (0) 0 (0) 0 (0)

gender ( p = 0.688), age ( p = 0.262) and mean values of BMI

(0) 0 (0) 0 (0)

( p = 0.665) were confirmed, which indicates the homogeneity of the

54.20 ± 1267
26.56 ± 4.62
sample.

(0) 0 (0)
H n = 25
Oral mucosal lesions were observed more frequently in the PD

16 (64)
9 (36)

(16)
1 (4)
2 (8)

(0)

(0)
(0)

(4)
(4)
(0)
(0)
group than in the controls ( p = 0.007). Pale oral mucosa (50%) was the

0
0
0
0
0
4
1
1
0
0
predominant manifestation in PD, more prevalent than in both HD

2 (8) 0 (0)1 (4)1 (4)

(24%) and H (4%) (< 0.001). The chi-squared test showed a similar

2 (8) 0 (0) 0 (0)

relationship between the groups regarding red lesions ( p = 0.008),

54.92 ± 13,60
26.68 ± 5.25
white lesions ( p = 0.041) and mucosal defects ( p = 0.032). Other ob-
HD n = 25

0 (0) 1 (4)
served lesions showed a little prevalence (Table 1). According to a
18 (72)

15 (60)
7 (28)

6 (24)
4 (16)

7 (28)

9 (36)

6 (24)
2 (8)

1 (4)
1 (4)

0 (0)
clinical assessment of the dorsal surface, the diagnosis of the coated
tongue was set in 50% PD, more frequently than H (16%) ( p = 0.004)
and without a difference to HD (28%) ( p = 0.057). 9 (18) 5 (10) 0 (0) 1 (2)
PD subjects expressed more pronounced oral symptomatology than
H controls did, with xerostomia (< 0.001), dysgeusia ( p < 0.001) and 4 (8) 1 (2) 1 (2)
59.06 ± 14,30
25.75 ± 5.18

uremic odour ( p < 0.001) confirmed as major oral symptoms. In

11 (22) 0 (0)
PD n = 50

comparison to HD controls, a significantly higher number of PD ex-

31 (62)
19 (38)

25 (50)
15 (30)

11 (22)

25 (50)

30 (60)
40 (80)
16 (32)
pressed dysgeusia ( p = 0.043), borderline significance ( p = 0.060) was
6 (12)

5 (10)
3 (6)

obtained for xerostomia while no difference in relation to uremic odour

( p = 0.452) (Table 1).
13 (13) 5 (5) 1 (1) 1 (1)

3.2. Mean CrCl and oral manifestations in patients with CKD

Sample characteristics and oral manifestations in CKD and healthy subjects.

6 (6) 1 (1) 1 (1)

56.81 ± 13.79
26.21 ± 5.03

11 (11) 1 (1)
All n = 100

By observing all patients with CKD, the relationship between the

kidney function and noticeable oral lesions/symptoms was examined.
65 (65)
35 (35)

32 (32)
21 (21)

12 (12)

36 (36)

40 (40)
55 (55)
22 (22)
8 (8)

4 (4)

6 (6)

The estimated mean CrCl values were significantly lower (< 0.05) in
subjects with pale oral mucosa, xerostomia, dysgeusia and uremic
n (%)
n (%)

n (%)
n (%)
n (%)

(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)

odour when compared to those without these listed manifestations. In

n
n
n
n
n
n
n
n
n
n

relation to mucosal defects and coated tongue, no significant differ-

ences were found regarding the mean CrCl values (< 0.05) (Fig. 1).
Enanthem Ecchymosis Petechiae

White patch Plaque Keratosis

3.3. Analysis of salivary parameters

Multivariate tests (F = 19.357, p < 0.001) showed a significant

Pigmented lesions

Erosion Ulceration

difference in salivary parameters between all groups. Subsequently,

Mucosal defects

Burning mouth
Coated tongue

Uremic odour
White lesions
Pale mucosa

univariate tests confirmed the existing difference in relation to the

Haematoma
Red lesions

Xerostomia
Dysgeusia

mean USFR, pH, urea and creatinine (Table 2). The post hoc analysis
Female

showed that PD had a lower USFR compared to controls (< 0.05),

Male

higher pH compared to H ( p < 0.05) and similar to HD ( p > 0.05).

The analysis of biochemical parameters revealed that PD had sig-
Oral manifestations

nificantly higher creatinine then H (< 0.001) and HD ( p = 0.042).

Oral symptoms
Characteristics

Regarding urea, there was difference only to H (< 0.001) and no dif-
ference compared to HD ( p = 0.097) controls (Table 3). The ANOVA
Gender
Table 1

test showed that subgroups A, B and C did not differ significantly in

BMI
Age

terms of the mean values of urea ( p = 0.260) and creatinine

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J. Marinoski, et al. Archives of Oral Biology 102 (2019) 205–211

4. Discussion

Fig. 1. Relationship between kidney function and significant oral manifesta-
tions in patients with CKD.
( p = 0.455), which indicates that the salivation intensity does not af-
fect the concentration of uremic toxins.
According to the obtained USFR, 14 (28%) PD and 4 (16%) HD
subjects corresponded to hyposalivation (Table 4). Fisher’s test revealed
a significant difference between the PD and H groups ( p = 0.003).
However, both groups with CKD did not differ significantly ( p = 0.390)
towards the cut-off point set previously (≤0.1 mL/min).
There was a moderately strong positive correlation between serum
and salivary creatinine in both PD (r = 0.584; p < 0.001) and HD
(r = 0.581; p = 0.002) groups. A similar relationship for urea was de-
termined only in the PD group (r = 0.440; p = 0.001), whereas no
significant correlation was obtained between serum and salivary urea in
the HD group (r = 0.145; p = 0.491) (Fig. 2).
Considering that oral signs and symptoms are sometimes the only
objective indicators of systemic diseases, dentists could play a key role
in the early diagnosis of CKD. In addition, since most of the salivary
biomolecules are derived from serum (Williamson, Munro, Pickler,
Grap, & Elswick, 2012), laboratory analyses of the components of saliva
could be particularly important in the early asymptomatic stages of
CKD.
It should be noted that patients with diabetes mellitus were not
included in this study, even though this disease is considered to be one
of the leading etiological factors for CKD (Hahr & Molitch, 2015). The
main reason is the well-known association between diabetes and the
occurrence of mucosal abnormalities and variations in the salivary flow
and composition (Chomkhakhai, Thanakun, Khovidhunkit,
Khovidhunkit, & Thaweboon, 2009). Although it has been confirmed in
several recent studies (Schmalz et al., 2017; Swapna, Koppolu, &
Prince, 2017) that there is no difference in the oral health conditions
between diabetic and non-diabetic patients with CKD, it should be
mentioned that these studies were mostly focused on dental and peri-
odontal examinations of patients receiving haemodialysis therapy.
Our results have shown that oral lesions were observed more fre-
quently in PD patients than in controls. However, clinically healthy oral
mucosa was observed in more than 50% of PD and 75% of HD patients.
Pale mucosa was the only clinical change of the oral mucosa associated
with decreased glomerular filtration (< 0.05). Despite the fact that
anaemia mostly affects end-stage patients, a significantly high number
of PD patients (50%) had pale mucosa, suggesting that the short-term
therapeutic effect of the dialysis treatment (Bots, Brand, Poorterman
et al., 2007; Bots, Brand, Veerman et al., 2007) has contributed to the
improvement of the clinical picture. Other authors (Belazelkovska,
2013) reported a similar prevalence (53.3%) in a study comprising 30
pre-dialysis patients with different stages of CKD. These data indicate
the possibility of interpreting pale oral mucosa as a clinical marker of

Table 2
Mean values of saliva parameters in the examined groups.
Salivary parameters Group p- value, PD/HD/H

PD HD H
X ± SD X ± SD X ± SD

USFR (mL/min) 0.21 ± 0.14 0.30 ± 0.16 0.51 ± 0.19 < 0.001
pH 7.11 ± 0.57 6.88 ± 0.22 6.52 ± 0.49 < 0.001
Urea (mmol/L) 18.75 ± 9.63 18.53 ± 8.14 4.65 ± 2.08 < 0.001
Urea (mmol/g of protein) 21.82 ± 16.13 20.97 ± 12.53 6.63 ± 2.75 < 0.001
Creatinine (μmol/L) 38.32 ± 33.71 74.48 ± 60.14 4.60 ± 1.64 < 0.001
Creatinine (μmol/g of protein) 44.89 ± 39.60 83.00 ± 69.75 7.07 ± 3.88 < 0.001
Total protein (g/l) 1.00 ± 0.74 1.16 ± 0.68 0.75 ± 0.36 0.542

Unstimulated salivary flow rate: USFR.

Table 3
Statistical differences in values of saliva parameters between study and control groups.
Salivary parameters Group I Group II Difference in mean values (I-II) P-value Statistical test

USFR (mL/min) PD HD −0.0976 0.013 LSD

H −0.3048 < 0.001
pH PD HD 0.05 0.820 Games-Howell
H 0.41 0.040
Urea (mmol/g of protein) PD HD 0.83 0.0967 Games-Howell
H 15.19 < 0.001
Creatinine (μmol/g of protein) PD HD −38.12 0.042 Games-Howell
H 37.82 < 0.001

Unstimulated salivary flow rate: USFR.

Fisher's least significant difference test: LSD.
The nonparametric post-hoc test: Games-Howell.

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J. Marinoski, et al. Archives of Oral Biology 102 (2019) 205–211

Table 4
Distribution of subjects according to the cut-off point for hyposalivation.
USFR (mL/min) Group Total p- value p- value (Fisher) PD/HD p- value (Fisher) PD/H
(χ2)
PD HD H PD/HD/H

≤0,1 Yes N 14 4 0 18 0.011 0.390 0.003

% 28% 16% 0% 18%
No N 36 21 25 82
% 72% 84% 100% 82%

Unstimulated salivary flow rate: USFR.

Fig. 2. The relationship between salivary and serum biochemical parameters in both groups with CKD.

renal impairment, in stages prior to dialysis therapy.
Xerostomia, dysgeusia and uremic odour were the most prevalent
symptoms among subjects with CKD, associated with a decreased renal
function (< 0.05). Our results within the PD group were similar to
those obtained in one Indian study (Patil et al., 2012), in which xer-
ostomia was also confirmed as a major finding in almost 90% of pre-
dialysis patients. In contrast, a group of Chinese authors (Kho, Lee,
Chung, & Kim, 1999) reported a lower prevalence of this symptom
(32.9%) in patients on haemodialysis compared to our results. Ac-
cording to the current knowledge, decreased USFR caused by some anti-
hypertensive drugs, dehydration and fluid intake restriction between
dialysis treatments is considered the main factor affecting the onset of
this symptom in patients with CKD (Abuelo, 2007).
Dysgeusia was the second most common oral symptom seen in 60%
of PD and 36% of HD subjects. Other authors (Bots et al., 2006) pointed
out the prevalence of ‘metallic’ taste in 31–42% of patients with CKD.
The taste alteration in the present study could be explained by the di-
rect effect of uremic toxins on oral chemoreceptors, which is consistent
with the finding of increased salivary urea in both the PD and HD
groups.
In accordance with the results of previous studies (Chuang, Sung,
Kuo, Huang, & Lee, 2005; Oyetola et al., 2015), the uremic odour was
the third most prevalent oral symptom. The general opinion is that this
uremic odour comes from ammonia compounds formed during the
hydrolysis of urea in the saliva. Considering that we have shown sta-
tistical significance in relation to decreased values of USFR in patients
with CKD, it is necessary to refer back to the study whose authors (Keles
et al., 2010) determined a negative correlation between the presence of
uremic odour and the USFR values in patients with CKD.
Evaluation of the functional capacity of salivary glands showed that
the mean values of USFR within the PD group (0.21 ± 0.14 mL/min)
were significantly lower than within the HD (0.30 ± 0.16 mL/min)

209
J. Marinoski, et al.
and H (0.51 ± 0.19 mL/min) groups but still responded to normal
salivation. The toxic effect of uremic compounds, anti-hypertensive
therapy and emotional stress are possible factors for the existing dif-
ference to healthy subjects (Bayraktar et al., 2004; Porter, Scully, &
Hegarty, 2004). On the other hand, the short-term therapeutic effect of
dialysis treatment that increases the USFR (Bots, Brand, Poorterman
et al., 2007; Bots, Brand, Veerman et al., 2007) could explain the dif-
ference between the PD and HD groups. Evaluation of the USFR seems
to be important only in order to highlight the statistical differences in
the mean values between diseased and healthy persons. Surprisingly,
there are insufficient data in the literature related to the presence of
hyposalivation (≤0.1 mL/min), found in 28% of PD and 16% of HD
subjects in this study. A group of authors (Thorman, Lundahl, Yucel-
Lindberg, & Hylander, 2010) documented decreased salivary secretion
in 70 out of 100 subjects with CKD by setting the cut-off point at
0.3 mL/min. In addition, Turkish authors (Bayraktar et al., 2004) have
also revealed mean values that corresponded to hyposalivation; how-
ever, unlike the present methodology, they examined the stimulated
salivary flow rate.
Hydrolysis of nitrogenous compounds caused by bacterial urease
results in the production of carbon dioxide and an ammonium ion,
having a distinct alkalising potential (Obry et al., 1987). The current
assay showed that the mean pH values in the PD group (7.11 ± 0.57)
were statistically higher compared to those obtained in the H group
(6.52 ± 0.49), which was also confirmed in several previous studies
(Abdellatif, Hegazy, & Youssef, 2011; Bayraktar et al., 2009; Tomas
et al., 2008). However, we did not specify that haemodialysis treatment
contributes to a significant drop of pH in the HD group (6.88 ± 0.22),
which was at the upper limit of the reference range.
Our findings of salivary urea and creatinine determined in the PD
and HD groups, respectively, were consistent with the results of other
authors (Tomas et al., 2008) who revealed similar urea
(17.03 ± 18.48 mmol/L) and creatinine (30.07 ± 16.60 μmol/L) le-
vels in pre-dialysis patients and slightly higher urea (26.28
± 28.94 mmol/L) and creatinine (99.01 ± 80.70 μmol/L) levels in
dialysis patients. In another study of 60 pre-dialysis subjects
(Yajamanam, Vinapamula, Sivakumar, Bitla, & Rao, 2016), lower
mean urea (11.62 ± 0.50 mmol/L) and higher creatinine (45 ±
24.09 μmol/L) levels were observed. Variations in the average con-
centrations of uremic toxins found in the literature are probably the
result of the sample differences in terms of size, gender, BMI values,
disease stage and applied therapies.
The mean value of salivary urea obtained within the PD and HD
groups reached 70% of serum concentration. However, the salivary
creatinine concentration in both groups was about 12 times lower than
that of serum. The existing difference for creatinine may be due to the
physical characteristics of its molecule. With a diameter of 3.2 Å and a
molecular weight of 113Da, creatinine is considered a relatively large
molecule that, unlike urea, hardly reaches the salivary acinus. It also
exhibits low lipid solubility, an additional factor that makes its trans-
port across the cells difficult (Chiou & Pu, 1979). Concerning this, other
authors (Lloyd, Broughton, & Selby, 1996) previously concluded that
salivary creatinine may reach a maximum of 10% of the serum con-
centration, which is consistent with the results of this study.
In the present study, a significant positive correlation between
serum and salivary urea (r = 0.440) and creatinine (r = 0.584) within
the PD group and creatinine (r = 0.581) in the HD group was shown. In
agreement with the ranking suggested by Evans (Evans, 1996), Pear-
son’s coefficient values corresponded to a moderately strong positive
correlation (range: 0.4–0.59). Regarding this point, several studies with
a similar sample size (Ahmed, Mehmood, & Dawani Suad Roshan, 2015;
Bayraktar et al., 2004) revealed an identical correlation strength, unlike
others (Bader, Kora, El-Shalakany, & Mashal, 2015; Venkatapathy et al.,
2014) obtaining high positive correlations within larger samples.
Moreover, we found a significant association for creatinine in both the
PD and HD groups, which indicates that dialysis treatment did not have
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Archives of Oral Biology 102 (2019) 205–211
a strong impact on the analysis outcome. In addition, it should be noted
that creatinine, unlike urea, is considered a more credible diagnostic
parameter for CKD.
An important limitation of this study was the absence of patients in
the first stage and only 6% matching the second. In this respect, further
research including all stages with approximately equal distributions
should be performed in order to investigate the potential association
between salivary concentrations of uremic toxins and the corresponding
stage. Although the first three stages of CKD are mostly asymptomatic,
the impact of the socio-cultural and economic factors on our environ-
ment (Vukovic, Bjegovic, & Vukovic, 2008) may contribute to the ‘late
detection’ of these patients.
In conclusion, in this study, we confirmed that xerostomia and
dysgeusia are major symptoms among pre-dialysis patients. In addition,
our results showed that their presence along with uremic odour and
pale mucosa is directly related to decreased kidney function. On the
diagnostic point, decreased USFR, especially hyposalivation and in-
creased salivary creatinine, should be considered a significant indicator
of CKD in stages prior to the implementation of dialysis therapy.
However, more research is needed to standardise the optimal labora-
tory method that will make salivary diagnostics play an important role
in routine health monitoring.
Funding
This research did not receive any specific grant from any funding
agencies in the public, commercial, or not-for-profit sectors.
Conflict of interests
All authors declare no conflict of interest.
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