J Periodont Res 2016 © 2016 John Wiley & Sons A/S.

All rights reserved Published by John Wiley & Sons Ltd

JOURNAL OF PERIODONTAL RESEARCH

doi:10.1111/jre.12390

S. Almeida1, C. M. Figueredo1,
Periodontal treatment in C. Lemos2, R. Bregman2,
R. G. Fischer1

patients with chronic kidney

1
Department of Periodontology, Faculty of
Odontology, Rio de Janeiro State University,
Rio de Janeiro, Brazil and 2Nephrology

disease: a pilot study

Division, Pedro Ernesto University Hospital,
Faculty of Medicine, Rio de Janeiro State
University, Rio de Janeiro, Brazil

Almeida S, Figueredo CM, Lemos C, Bregman R, Fischer RG. Periodontal

treatment in patients with chronic kidney disease. A pilot study. J Periodontal Res
2016; doi:10.1111/jre.12390. © 2016 John Wiley & Sons A/S. Published by John
Wiley & Sons Ltd

Background and Objective: This pilot cohort study evaluated the effect of peri-
odontal treatment on renal function, metabolic markers and asymmetric
dimethylarginine (ADMA) in patients with pre-dialysis chronic kidney disease
(CKD) presenting chronic periodontitis.
Material and Methods: Twenty-six patients with CKD and severe chronic peri-
odontitis were selected. Periodontal parameters included plaque index, bleeding
on probing, probing pocket depth and clinical attachment level. Estimated
glomerular filtration rate (eGFR), triglycerides, total cholesterol, albumin and
ADMA levels were evaluated at baseline, 90 and 180 d after periodontal
therapy. eGFR was evaluated by the Modification of Diet in Renal Disease
equation.

Results: All periodontal clinical parameters significantly improved (p < 0.05)

180 d after periodontal therapy. There was a significant improvement on the med-
Ricardo Guimara ~es Fischer, MD, DDS, MDSc,
ian values (25%; 75% percentiles) of eGFR from 34.6 (27; 44.7) mL/min/1.73 m2 PhD, Faculdade de Odontologia, Universidade
on baseline to 37.6 (29.7; 57) mL/min/1.73 m2 on day 90, and to 37.6 (28.6; 56) do Estado do Rio de Janeiro, Boulevard 28 de
mL/min/1.73 m2 (p < 0.05) on day 180. ADMA levels significantly reduced 180 d Setembro, 157, Vila Isabel- Rio de Janeiro –
RJ – Brazil, CEP: 20551-030
after periodontal treatment. No significant differences were observed at the med- Tel: +55- 21- 25876382
ian values of metabolic markers comparing baseline and 180 d after periodontal Fax: +55-21-25234298
treatment. e-mail: ricfischer@globo.com
Key words: asymmetric dimethylarginine;
Conclusions: The results point to a link of kidney disease with endothelium dys- chronic kidney disease; glomerular filtration
function and periodontitis, suggesting that periodontal treatment may be benefi- rate; periodontitis
cial to the course of CKD. Accepted for publication March 21, 2016

It is well known that patients with
chronic kidney disease (CKD) present
a high risk of cardiovascular disease
(CVD) (1). This risk is partially
explained by the presence of tradi-
tional risk factors. Non-traditional
risk factors, such as inflammation, are
implicated in the high prevalence of
CVD in patients with CKD (2,3).
Chronic periodontitis is a chronic
inflammatory disease of infectious ori-
gin involving destruction of the
supporting structures of the teeth
including ligament and bone, which
may lead to tooth loss (4). The patho-
genesis of periodontitis involves
inflammatory and immunological pro-
cesses that elicit the production of
cytokines, prostaglandins (5) and in
some cases, acute phase reagents, such
as C-reactive protein (6). Moreover,
periodontal treatment has been associ-
ated with reduction of C-reactive pro-
tein and interleukin 6 levels (7,8) and,
increased vasodilation induced by
acetylcholine, indicating that peri-
odontitis may be a cause of inflamma-
tion and endothelial dysfunction (9,
10), and thereby of cardiovascular
events (8,11,12). Nitric oxide (NO)
has physiological functions, such as
vasodilation and inhibition of adhe-
sive expression. Asymmetric dimethy-
larginine (ADMA) is an endogenous
inhibitor of NO metabolism and, ele-
vated ADMA levels have been
2 Almeida et al.
associated with endothelial damage
and cardiovascular events (13,14).
Periodontitis may be one source of
chronic inflammation in patients with
CKD. Although periodontitis has
been associated with increased inflam-
mation in patients on hemodialysis
(15), its relation with inflammation
and increased cardiovascular risk in
patients with CKD is still unknown
(16). Few studies evaluated the effect
of periodontal treatment on the pro-
gression of renal disease (17). There-
fore, the aim of this cohort study was
to evaluate the effect of periodontal
treatment on renal function, meta-
bolic markers (triglycerides, choles-
terol, albumin) and ADMA in
patients with CKD on regular treat-
ment and, with chronic periodontitis.
Material and methods
Study population
Twenty-six patients (13 men, mean
age = 59.8  12 years) were enrolled
for treatment at the CKD Interdisci-
plinary Treatment Center, Pedro
Ernesto University Hospital, Rio de
Janeiro State University (HUPE-
UERJ). These patients were under
careful control at the nephrology
ambulatory, including regular use of
medication and diet control for at
least 6 mo. Moreover, the biochemical
profile and arterial blood pressure
were normal, as suggested by the
guidelines of the renal society. Eligibil-
ity for the study included the following
criteria: (i) age equal or above
30 years; (ii) minimum of 6 mo of
treatment at this center with a good
adherence in returning for their regu-
lar control appointments every 3 mo;
(iii) CKD stages 3 and 4, with esti-
mated glomerular filtration rate
(eGFR; Modification of Diet in Renal
Disease [MDRD] equation) (18)
higher than 20 mL/min/1.73 m2 and
lower than 70 mL/min/1.73 m2; (iv)
minimum of 12 teeth (19); and (v)
diagnosis of generalized severe chronic
periodontitis (20). Patients with gener-
alized chronic periodontitis should
present at least 30% of the periodon-
tal sites with probing pocket depth
(PPD) > 4 mm, while patients with
severe periodontitis should present at
least two sites with clinical attachment
level > 6 mm, and PPD > 5 mm (20).
The exclusion criteria were pregnancy,
previous periodontal therapy and sys-
temic conditions that contraindicated
periodontal therapy or that might
affect the progression or treatment of
periodontitis, history of endocarditis,
and use of antibiotics or anti-inflam-
matory drugs in the last 3 mo. The
study protocol was approved by the
Committee on Ethics and Research of
the HUPE-UERJ. The aims of the
investigation and the nature of the
study were fully explained to the sub-
jects who gave their informed consent
before enrollment (Fig. 1).
Periodontal examination included
(i) plaque index (PI) and (ii) bleeding
on probing (BOP), both recorded as a
dichotomous variable: present or
absent, (iii) PPD, measured from the
Assessed for eligibility (n = 192)
Enrollment (n = 26)
Periodontal examination
Baseline
Laboratory analysis
Periodontal treatment
90 d
Periodontal examination
Laboratory analysis
180 d
Periodontal examination
Laboratory analysis
Fig. 1. Flowchart of the study.
gingival margin to the bottom of the
periodontal pocket, (iv) clinical attach-
ment loss, measured from the cement
enamel junction to the bottom of the
periodontal pocket. PI and BOP were
recorded at four sites per tooth
(mesiobuccal, buccal, distobuccal and
lingual), and PPD and clinical attach-
ment level in six sites per tooth
(mesiobuccal, buccal, distobuccal,
mesiolingual, lingual and distolingual).
The clinical evaluation was performed
by an experienced periodontists with a
manual, calibrated pressure probe
(PCR 15, DB764R; Aesculap,
Tuttlingen, Germany), with a probing
force of 0.20 N. Measurements were
approximated to the nearest millime-
ter. An intra-examiner calibration was
performed. Previously to the study, 10
non-study subjects were used for the
calibration of the examiner
(kappa = 0.91).
Excluded (n = 166)
Not meeting criteria (n = 163)
Refuse to participate (n = 3)
Other reasons (n = 0)

Periodontal treatment
Periodontal treatment was conducted
by a single experienced periodontist.
Subjects received oral hygiene instruc-
tions, including a demonstration of
utilization of dental floss and brush-
ing technique (Bass technique),
supragingival scaling using manual
instruments (Gracey curettes; Hu-
Friedy, Chicago, IL, USA) and a
sonic device (Sonic borden 2000N;
KaVo, Joinville, SC, Brazil). Subgin-
gival scaling and root planing was
performed at each site with PPD
≥ 4 mm. There was no limit of
appointments but, in general, patients
were seen in four to six 60 min ses-
sions of subgingival scaling, during
2 wk. Oral hygiene instructions were
reinforced at each appointment. Local
anesthesia was used whenever neces-
sary. After the treatment phase,
patients were instructed to follow oral
hygiene instructions (patients received
manual toothbrush, toothpaste con-
taining sodium fluoride and dental
floss) and recalled 6 mo later. The
patients were recalled 3 and 6 mo
after the last appointment for peri-
odontal therapy for reassessment of
the periodontal parameters and to
repeat the blood examination.
Serum markers
On the same morning of the periodon-
tal appointments, blood samples were
drawn from a peripheral vein. Eight
millimeters of venous blood was drawn
into VacutainerÒ (Becton-Dickinson,
Juiz de Fora, MG, Brazil) serum sepa-
rator tubes containing clot activator.
The tubes were kept at room tempera-
ture and centrifuged, within 1 h after
collection, in the Central Laboratory
of HUPE-UERJ. Tubes were immedi-
ately placed on ice, coded, and frozen
until analysis, that was blinded to the
allocation group. Triglycerides and
total cholesterol were measured using
an automated analyzer (Mega, Bayer,
Leverkusen, Germany), while serum
albumin was verified by dye-binding
using bromocresol green reagents on
Astra-8 Analyzer (Beckman Instru-
ments, Fullerton, CA, USA). Crea-
tinine was measured by the modified
Periodontal therapy in chronic kidney disease
Jaffe method. eGFR was evaluated
90 d before baseline (based on values
obtained in the medical files), on base-
line, and 90 and 180 d after periodon-
tal treatment.
Statistical methods
The main outcome in this study was
change in MDRD values. With a
sample size of 24 patients, there was
an 80% power to detect, at a 0.05
level, a mean increase of 10% in the
MDRD values. A second power cal-
culation was included to verify the
effect of periodontal treatment on the
reduction of PPD and clinical attach-
ment level values. Based on a previ-
ous study (7) the sample size
calculation indicated that with a sam-
ple size of 22 patients, there was a
80% power to detect, at a 0.05 level,
a 50% reduction in the mean percent-
age of sites with PPD and clinical
attachment level ≥ 6 mm. Twenty-six
patients were included expecting for
drop-outs. As all the patients com-
pleted the study, all 26 patients were
included in the analysis. Kol-
mogorov–Smirnov and Shapiro–Wilk
tests were used to assess if variables
were normally distributed. Normally
distributed variables were reported as
mean ( SD) while median (in-
terquartile range) were used to
describe non-normally distributed
data. To verify differences between
clinical and laboratory values at base-
line, 3 mo after baseline and 6 mo
after periodontal therapy, paired t-test
and Wilcoxon rank test were used to
compare normally distributed and
non-normally distributed data, respec-
tively. All statistical analyses were
carried out with a statistical program
(IBM SPSS Statistics for Windows,
Version 19.0; IBM Corp., Armonk,
NY, USA) with a significance level of
5% (p < 0.05).
Results
The studied group consisted of 26
patients (13 men, mean
age = 59.8  12 years). There were 16
non-white patients and three smokers
(> 10 cigarettes/d). The mean ( SD)
number of teeth was 16 ( 6.5).
3
Further baseline characteristics of the
studied subjects are summarized in
Table 1.
Mean percentage of sites with PI,
BOP, PPD 4–5 mm, PPD ≥ 6 mm,
clinical attachment level 4–5 mm and
clinical attachment level ≥ 6 mm were
significantly reduced 6 mo after peri-
odontal treatment (Table 2).
Analyses were done excluding the
three smokers, and the overall results
were similar. Therefore, these three
patients were maintained in the sam-
ple. There was a significant improve-
ment on the median values (25%;
75% percentiles) of eGFR from 34.6
(27; 44.7) mL/min/1.73 m2 on baseline
to 37.6 (29.7; 57) mL/min/1.73 m2 on
day 90, and to 37.6 (28.6; 56) mL/
min/1.73 m2, on day 180. A signifi-
cant decrease of median values (25%;
75% percentiles) of ADMA after
180 d of periodontal treatment, from
4.2 (3.5; 4.8) (lmol/mL) on baseline
to 3.8 (3.2; 4.6) (lmol/mL) (p = 0.03).
There were no significant changes in
the median values (25%; 75% per-
centiles) of triglycerides, total choles-
terol and albumin (Table 3).
Discussion
The aim of the present cohort pilot
study was to evaluate the effect of peri-
odontal treatment on the renal func-
tion of patients with CKD with severe
chronic periodontitis over a short per-
iod. The results showed a significant
increase in the median value of
MDRD and a reduction on ADMA
levels in patients with severe chronic
periodontitis. This is the first study to
observe a possible benefit of the con-
trol of periodontal inflammation in the
maintenance of renal function. A
Table 1. General data of the studied
patients
Variables
Age (years) 59.8 (12)
Body mass index (kg/m2) 25.4 (5.2)
Pre-dialysis treatment (years) 3.4 (2.3)
Gender male (%) 48.3
Diabetics (%) 20.7
Smokers (%) 11.5
Means ( SD) of age, body mass index
and years of treatment.
4 Almeida et al.

Table 2. Median values (25%; 75% percentiles) of clinical measurements at baseline, and 90 and 180 d after periodontal treatment

Baseline 90 d p Values* 180 d p Values**

No. of teeth 16 (9; 21) 16 (9; 21) 0.32 16 (9; 21) 0.32
CAL 4–5 mm (% sites) 37.8 (33; 46) 14.6 (10.6; 27.1) < 0.001 17.5 (9.4; 31.9) < 0.001
CAL ≥ 6 mm (% sites) 18.1 (5.6; 52.1) 12.3 (3.1; 44.9) < 0.001 10.1 (3.8; 36.1) 0.001
PPD 4–5 mm (% sites) 35.6 (28.2; 41.7) 3.3 (0; 8.7) < 0.001 1.8 (0.5; 7.9) < 0.001
PPD ≥ 6 mm (% sites) 3 (1.8; 9.8) 0 (0; 0.2) < 0.001 0 (0; 0.2) < 0.001
BOP (%) 58.3 (37.7; 76) 31.7 (17.1; 42.3) < 0.001 25 (17.5; 36.1) < 0.001
PI (%) 68.2 (49.4; 80) 34.7 (25; 43.9) < 0.001 36.8 (19.8; 44) < 0.001

BOP, bleeding on probing; CAL, clinical attachment level; PI, plaque index; PPD, probing pocket depth.
*Statistical difference between 90 d and baseline, calculated by the Wilcoxon signed rank test.
**Statistical difference between 180 d and baseline, calculated by the Wilcoxon signed rank test.

Table 3. Median values (25%; 75% percentiles) of triglycerides, cholesterol, albumin, ADMA and eGFR (MDRD equation), 90 d before
periodontal treatment, at baseline, and 90 and 180 d after periodontal treatment

90 d Baseline p Values* 90 d p Values** 180 d p Values***

Triglycerides (mg/dL) 139 (115;182) 133 (96.5; 197,5) 0.63 119 (86;166.5) 0.32 111 (97.5;172) 0.45
Cholesterol (mg/dL) 185 (151; 208) 171 (164; 216) 0.16 176 (149; 209) 0.87 184 (156; 213) 0.74
Albumin (g/dL) 4.1 (3.9; 4.5) 4.2 (4; 4.4) 0.92 4.2 (4; 4.4) 0.86 4.1 (3.9; 4.3) 0.14
ADMA (lmol/mL) 4.2 (3.5; 4.8) – 3.9 (3.2; 4.9) 0.10 3.8 (3.2; 4.6) 0.03
MDRD (mL/min/1.73 m2) 37.5 (24; 52.3) 34.6 (27; 44.7) 0.41 37.6 (29.7; 57) 0.005 37.6 (28.6; 56) 0.03

ADMA, asymmetric dimethylarginine.

*Statistical difference between 90 d and baseline, calculated by the Wilcoxon signed rank test.
**Statistical difference between baseline and 90 d, calculated by the Wilcoxon signed rank test.
***Statistical difference between baseline and 180 d, calculated by the Wilcoxon signed rank test.

recent review points to a lack of stud-
ies regarding the possible positive
effect of periodontal treatment on
renal function (17). A case report eval-
uated the effect of periodontal treat-
ment over the general health of a
patient with CKD and observed a
worsening of kidney disease with mul-
tiple infections, including periodontitis
(4). Graziani et al. (21) observed a
reduction in the cystatin C levels, sug-
gesting a possible role of periodontal
treatment in kidney function and
inflammation. Lee et al. (22) con-
cluded that surgical periodontal treat-
ment reduced end stage renal disease
risk in a retrospective cohort study
based on insurance claims data. These
authors did not evaluate CKD pro-
gression and surgical periodontal treat-
ment was based on procedure codes.
Souza et al. (23) investigated the
impact of oral health indicators,
chronic periodontitis and its treatment
on survival rates in a group of patients
undergoing hemodialysis. The authors
concluded that patients with chronic
periodontitis had a higher risk of death
compared with patients without
chronic periodontitis and to a lesser
extent for treated patients. These
results were based on univariate analy-
sis. However, these differences were
not maintained after adjustments for
confounders in the multivariate model.
The presence of CKD has been
associated with a high prevalence of
CVD (24,25), mainly in older, hyper-
tensive and diabetic patients (26). The
association of CKD and CVD is
related among other factors to inflam-
mation, which may contribute to
endothelial dysfunction (27). Inflam-
mation and vascular damage may
influence the progression of renal dis-
ease (28).
Periodontitis is known as a chronic
low-grade inflammatory disease of the
teeth supporting tissues, may lead to
tooth loss over the years and may
increase proinflammatory cytokines in
blood (6,7,29).
Although the association between
endothelial dysfunction and periodon-
titis is not fully understood, a chronic
inflammation due to a chronic infec-
tion may explain some effects on the
endothelium. Subgingival periodontal
bacteria in subjects with periodontitis
may act as a source of gram-negative
bacteria and their toxic products such
as lipopolysaccharide induce the host
cells to secrete cytokines. The bacteria
accompanied by the inflammatory
mediators are spilled into the blood,
instituting a condition consistent with
systemic inflammation (30,31). Studies
suggested a direct relationship
between the inflammatory mediators
and endothelial dysfunction (32,33).
Recent studies showed a reduction
of inflammatory biomarkers and an
improvement of endothelial func-
tion after periodontal treatment
(8,10,12,33). These data suggest that
periodontitis may be a risk factor for
CVD.
Endothelium dysfunction includes
a reduction in NO bioavailability.
ADMA is an endogenous inhibitor
of NO synthases and is used to eval-
uate endothelial function. Elevated
ADMA levels decrease the physiolog-
ical functions of NO, such as vasodi-
lation and inhibition of adhesive
molecules expression (14,34). Clinical
studies showed elevated levels of
ADMA in patients with high risk for
CVD and in those with renal dys-
function (13). Elevated ADMA is a
strong predictor of progression of the
disease in patients with eGFR
between 25 and 40 mL/min/1.73 m2

(14). In the present study, the signifi-
cant reduction of ADMA levels after
periodontal treatment may indicate
an improvement of the endothelial
function and a better prognosis for
the evolution of CKD. The increase
of eGFR after periodontal treatment
suggests that this approach may con-
tribute to stabilize kidney function,
particularly in those presenting severe
periodontitis.
Limitations of the present study
were the small number of the studied
patients, lack of a control group and
lack of an inflammatory marker mea-
surement. In addition, the estimation
of renal function may not be accurate
for this group. CKD-Epidemiology
Collaboration equation could have
been used, instead of the MDRD
equation.
In conclusion, the present data
showed a statistically significant
increase in the median value of eGFR
and a reduction in ADMA levels
after periodontal treatment in patients
with CKD. These improvements may
have no clinical significance. How-
ever, the findings suggest a benefit
from the periodontal treatment on
endothelium and renal function, pos-
sibly by reducing inflammation and it
may indicate a new therapeutic
approach to prevent CVD in this
population. Longer observational
periods are mandatory to reinforce
these findings.
Acknowledgements
This study was supported by resources
from Rio de Janeiro State Research
Foundation (FAPERJ, grant no. E-26/
111439/2008), and from Rio de Janeiro
State University. The authors declare
that there are no conflicts of interest in
this study.
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