| |

Received: 9 August 2019    Revised: 22 October 2019    Accepted: 10 November 2019

DOI: 10.1111/odi.13236

ORIGINAL ARTICLE

Association between severe periodontitis and chronic kidney

disease severity in predialytic patients: A cross-sectional study

Jasper da Silva Schütz1 | Carolina Barrera de Azambuja1 | Giuliano Reolon Cunha2 |

Juliano Cavagni1  | Cassiano Kuchenbecker Rösing1  | Alex Nogueira Haas1  |
Fernando Saldanha Thomé3 | Tiago Fiorini1

1
Department of Periodontology, School of
Dentistry, Federal University of Rio Grande Abstract
do Sul, Porto Alegre, Brazil Objective: The aim of this cross-sectional study was to evaluate the association be-
2
Medical School, Lutheran University of
tween periodontitis and different severities of chronic kidney disease (CKD) in pre-
Brazil, Canoas, Brazil
3
Department of Nephrology, Hospital de
dialytic patients.
Clínicas de Porto Alegre, Porto Alegre, Brazil Materials and Methods: Demographic, socioeconomic, and medical data of 139 pa-

Correspondence
Tiago Fiorini, Federal University of Rio
Grande do Sul, Ramiro Barcelos Street,
2492. Porto Alegre/RS, 90035-003, Brazil.
Email: fiorinitiago@gmail.com
Funding information
This study was funded by Hospital de
Clínicas de Porto Alegre Research Fund/
(FIPE/HCPA), through projects 150319 and
160428.
tients from the nephrology service of one university hospital in Porto Alegre, Brazil,
were obtained through interview and clinical records. Full-mouth six-sites per tooth
periodontal examinations were performed. Associations between periodontitis,
stages of CKD, and estimated glomerular filtration rate (eGFR) were estimated by
multivariable models adjusted for sex, smoking, vitamin D supplementation, physical
activity, and renal treatment duration. CKD was classified based on eGFR (<60 ml/
min/1.73 m2) estimated by the Chronic Kidney Disease Epidemiology Collaboration
equation.
Results: Patients with severe periodontitis, compared to those without severe peri-
odontitis, had 2.8 (95% CI: 1.25–6.62) and 3.4 (95% CI: 1.27–9.09) times higher risk of
being in stages 4 and 5 of CKD, respectively. Having ≥ 2 teeth with clinical attachment
loss (CAL) ≥6 mm increased 3.9 times the risk of being in stage 5 of CKD. Patients
with severe periodontitis and ≥2 teeth with CAL ≥ 6 mm had 4.4 ml/min/1.732 and
5.2 ml/min/1.732 lower eGFR (p-values < .05), respectively.
Conclusion: Severe periodontitis was associated with poor renal conditions in predia-
lytic CKD patients, strengthening the importance of periodontal evaluation in such
patient population.

KEYWORDS

chronic kidney disease, chronic renal insufficiency, glomerular filtration rate, periodontitis,
risk factors

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved

Oral Diseases. 2020;26:447–456.  |

wileyonlinelibrary.com/journal/odi     447
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448       SCHÜTZ et al.
1 |  I NTRO D U C TI O N
Chronic kidney disease (CKD) includes a variety of renal diseases
comprising patients with minor renal dysfunction up to patients
under dialysis or submitted to kidney transplantation (Shoji et
al., 2012). The prevalence of CKD in the United States is approx-
imately 15% (USRDS, 2018a), and recently a slight increase has
been demonstrated (USRDS, 2014, 2018a), probably associated
with obesity. CKD is a major health problem worldwide due to the
high mortality and comorbidities observed in these patients, in-
cluding diabetes and cardiovascular disease (Luyckx et al., 2017).
According to the most recent Kidney Disease Improving Global
Outcome statement (KDIGO, 2013), CKD is classified based on es-
timated glomerular filtration rate (eGFR < 90 ml/min/1.73 m2) and
albuminuria (>30  mg/g). In addition to suffering of patients and
their families, the costs associated with CKD treatment, only in
the United States, are estimated to be over U$ 64 billion (USRDS,
2018b). Data regarding prevalence/incidence and treatment cost
of the full range of chronic kidney diseases in Latin America are
still scarce, with a recent study reporting an overall prevalence of
8.9% (Barreto et al., 2016).
Traditional risk factors for development of CKD include dia-
betes mellitus, systemic arterial hypertension, male gender, race,
age, smoking, and family history of disease (Luyckx et al., 2017).
In addition, virtually all cardiovascular risk factors, especially dys-
lipidemia, obesity, endothelial dysfunction, and chronic inflam-
matory state, are also correlated with CKD (Luyckx et al., 2017).
In this context, it has been demonstrated that periodontitis has
the potential to deliver microbials into the blood circulation and
also leads to chronic low-intensity systemic inflammation (Loos,
2005), and by these means, has been associated with CKD (Fisher,
Taylor, Shelton, et al., 2008; Kshirsagar et al., 2005). Periodontitis
increases serum levels of several inflammatory biomarkers, such
as C-reactive protein (CRP), IL-1β, IL-6 e TNF-α (Loos, 2005). This
systemic inflammatory status is linked with several other diseases
such as diabetes and atherosclerosis, which, in turn, are also as-
sociated with CKD (Jepsen, Stadlinger, Terheyden, & Sanz, 2015).
Also, both diseases share common risk factors, such as smoking
and diabetes (Lertpimonchai et al., 2019).
The first studies addressing this topic reported results from
large population samples (Fisher, Taylor, Shelton, et al., 2008;
Grubbs et al., 2011; Kshirsagar et al., 2005) and observed positive
associations between periodontitis and CKD. Following, smaller
studies also reported similar results (Bastos et al., 2011; Thorman,
Neovius, & Hylander, 2009). However, this positive association was
not observed in all studies, leading to controversial conclusions
(Fisher, Taylor, Papapanou, Rahman, & Debanne, 2008; Messier et
al., 2012). More recently, a large population-based study did not
corroborate the initial observations (Shin, 2017). Although a re-
cent systematic review observed a robust body of evidence on the
non-directional association of periodontitis and CKD, studies re-
porting directional associations are still scarce (Zhao et al., 2018).
It is important to highlight that the current literature presents
some limitations including secondary analysis of subgroups, par-
tial-mouth protocols of periodontal examinations, case definition
of periodontal disease and lack of a better description of medical
status study participants. Studies especially designed for this pur-
pose with a better control for confounding and evaluating differ-
ent profiles and severities of renal disease patients are warranted
and may clarify some details of this relationship. In addition, socio-
economic and ethnic characteristics of the studied population may
influence the establishment and progression of CKD, as well as its
relationship with other risk factors/modifiers such as periodontal
disease (Barreto et al., 2016).
Although there is a biological plausibility for the association
between periodontitis, CKD, and other associated comorbidities,
few studies have evaluated the effect of periodontal infection on
different severities of established CKD in Latin America (Brito et
al., 2012; Perozini et al., 2017). Health inequalities remain a major
problem in these populations and may lead to differences in dis-
ease occurrence and underlying contributing factors (Barreto et
al., 2016). Thus, clinical studies elucidating the impact of periodon-
titis on different severities of chronic kidney disease in predialytic
individuals are necessary for the establishment of evidence-based
preventive and therapeutic approaches, since these patients may
benefit more due to their impaired systemic response compared
to patients under dialysis. The aim of the present study was to as-
sess the association between periodontitis and stages of CKD and
renal function in predialytic patients. The hypothesis underlining
the study is that the presence of periodontitis is associated with
worsened renal function.
2 | M ATE R I A L S A N D M E TH O DS
2.1 | Study design and sample
The present study follows the Strobe Guideline for reporting obser-
vational studies (von Elm et al., 2007). A cross-sectional observa-
tional study was carried out with individuals in stages 3, 4 and 5
of CKD who underwent renal treatment at a University Hospital of
Porto Alegre (Hospital de Clínicas de Porto Alegre - HCPA), which is
a tertiary care center in south Brazil. Patients were consecutively
enrolled from September 2015 to August 2016. The study proto-
col was approved by the Institutional Review Boards of the Federal
University of Rio Grande do Sul and the University Hospital. Before
entry in the study, participants read and signed an informed consent
form.
Eligibility criteria comprised the following: ≥18  years of
age; eGFR  <  60  ml/min/1.73  m2 (but no dialysis treatment); ≥4
teeth present; and no diagnosis/treatment of HIV infection or
a malignant tumor. Individuals who used antibiotics or immu-
nosuppressive drugs in the last 6  months, received periodontal
treatment in the last 6  months, or under orthodontic treatment
were not included. Patients who did not fulfill the inclusion cri-
teria remained under renal control in the Hospital and reasons
SCHÜTZ et al.
for non-participation in the study were recorded. Patients with
periodontal disease or other oral health problems/conditions
were referred for treatment at the Faculty of Dentistry of Federal
University of Rio Grande do Sul.
2.2 | Sample size
When this study was planned, there were no studies that assessed
the association between periodontitis as the primary exposure and
different stages of CKD as the outcome. Therefore, we were unable
to find appropriate data to calculate the sample size for the study.
Then, we estimated the sample size needed to fit a logistic regres-
sion model with 80% power to find an odds of 3 with prevalence
of individuals in the stages 4–5 of CKD (primary outcome) among
patients with and without severe periodontitis (primary exposure)
equal to 50% and 25%, respectively. Taking into consideration an
alpha and beta errors of 5% and 20%, respectively, it was estimated
that 128 individuals would be needed for the study.
The final sample size of this study comprised 139 individuals. The
power of this sample was calculated considering a chi-square dis-
tribution and alpha of 5%, with the observed occurrence of stages
3 and 4/5 of CKD among individuals with and without severe peri-
odontitis. This calculation resulted in 89% power for the present
study sample.
2.3 | Data collection
Information about demographic, socioeconomic, and behavioral
data, such as oral hygiene habits, dental treatment history, tobacco
exposure, and alcohol consumption were obtained through a struc-
tured questionnaire. Medical history, medications, body mass index
(BMI), blood pressure, and other renal parameters including serum
creatinine, urea, and proteinuria were obtained through the hospital
clinical records.
A full-mouth six-sites per tooth periodontal examination was
carried out by two calibrated periodontists (J.S.S. and C.B.A.) using
a manual periodontal probe (PQW-10 Hu-Friedy Mfg. Co. Inc.). The
following periodontal parameters were assessed: Visible Plaque
and Gingival Bleeding Indices (Ainamo & Bay, 1975), Periodontal
Probing Depth (PPD), Clinical Attachment Loss (CAL), and Bleeding
on Probing (BOP).
The reproducibility of the examiners was estimated by duplicate
examinations in approximately 10% of the study sample. Weighed
kappa values for PPD and CAL were 0.74 and 0.87, respectively.
Intraclass Coefficient Correlation inter-examiner was 0.7 for PPD
and 0.82 for CAL.
A 10-mL blood sample was collected from the antecubital fossa
of all participants. All samples were collected between 8:00 a.m. to
12:00  p.m. All patients were asked to be fasting for, at least, 4  hr
before blood sampling. The samples were stored in EDTA tubes and
immediately centrifuged for analysis of C-reactive protein (CRP) and
|
      449
glycated hemoglobin. All analyses were carried out at the Clinical
Analysis Laboratory of the University Hospital. High-sensitive CRP
was assessed by automated enzymatic colorimetric method (ADVIA
1800, Siemens). Glycated hemoglobin was measured by high-preci-
sion chromatography (Merck-Hitachi L-9100, Merck).
2.4 | Renal Outcomes
Two outcomes of renal function and severity were evaluated. The
glomerular filtration rate (eGFR) in mL/min/1.732 was estimated by
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation (Levey et al., 2009). This variable was analyzed as a contin-
uous outcome of the severity of CKD. Also, individuals were catego-
rized into stages 3, 4, and 5 of CKD according to the National Kidney
Foundation (KDIGO, 2013): stage 3 with eGFR between 30–59 ml/
min/1.732; stage 4 with eGFR between 15–29  ml/min/1.732; and
stage 5 with eGFR lower than 15  ml/min/1.732. Despite some pa-
tients had severe kidney failure (classified as stage 5), they were
clinically stable and asymptomatic, not requiring kidney replacement
therapy. These patients were kept on conservative treatment (anti-
hypertensives, nutritional advice, anti-proteinuric measures, educa-
tional support, control of comorbidities).
2.5 | Periodontal disease case definition
Participants were defined as having severe periodontitis according
to the American Academy of Periodontology criteria and Center for
Disease Control (CDC) (Eke, Page, Wei, Thornton-Evans, & Genco,
2012): ≥1 interproximal site with PPD ≥ 5 mm and ≥2 interproximal
sites with CAL ≥ 6 mm, not on same tooth. This cutoff was applied
due to the low number of cases diagnosed as mild (15%) and moder-
ate (5%) periodontitis, making it not feasible to use various degrees
of severity in the analytical commands.
Moreover, two other descriptors of periodontal condition were
also determined with CAL and PPD as separate parameters, as fol-
lows: ≥2 teeth with interproximal CAL ≥ 6 mm and PPD ≥ 5 mm.
2.6 | Confounders
The following variables were assessed as possible confounders for
the association between severe periodontitis and CKD severity: age,
sex, education level, socioeconomic status, tobacco exposure, body
mass index, physical activity, use of medications (statins, anti-gly-
cemic, and vitamin D supplementation), hypertension, diabetes, and
renal treatment duration.
Socioeconomic status was assessed by the Brazilian Economy
Classification System (Brazil, 2015). This system attributes points ac-
cording to personal goods and educational level of the head of the
family. Individuals were classified into low (≤13 points), medium (14–
22 points), and high (≥23 points) socioeconomic status. Participants
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450       SCHÜTZ et al.
were classified into low (<4 years of study), medium (4–11 years of
study), and high (≥12 years of study) educational status according to
the educational level of the head of the family. Due to the limited num-
ber of smokers in this sample (n = 9), tobacco exposure was assessed
through the calculation of pack-years. Participants were then classi-
fied into never, moderate (<20 pack-years), and heavy smokers (≥20
pack-years). BMI was defined as a person's weight in kilograms divided
by the square of height in meters and classified as normal (<25 kg/m2),
overweight (25–29.9  kg/m2), or obese (>30  kg/m2). Physical activity
was self-reported (yes: ≥3 times/week; no: <3 times/week).
2.7 | Statistical analysis
Crude comparisons between the three stages of CKD were made
by the chi-square test for categorical variables and by the one-way
ANOVA for quantitative variables. The significance level was set at
5% for all analyzes. Statistical commands were conducted using a
statistical package (Stata 14 for Macintosh, STATA Corp.).
Multivariable models were fitted applying the purposeful approach
proposed by Hosmer and Lemeshow (Hosmer & Lemeshow, 2004) for the
selection of variables. In brief, univariable models for stages of CKD were
fitted for each one of the possible confounders and the three periodontal
variables (severe periodontitis, ≥2 teeth with interproximal CAL ≥ 6 mm
and PPD ≥ 5 mm). Thereafter, those variables presenting p-values < .25 in
these univariable models were included in a multivariable model. Variables
remained in the final model if presented p-values < .05 after analysis of
confounding, which was evaluated with the inclusion and removal of
variables and evaluation of the change on other variables’ coefficients of
>20%. Separate models were fitted to each of the three periodontal vari-
ables. For the association between these periodontal definitions and CKD
stages, multinomial regression models were fitted and relative risk ratios
(RRR) and 95% confidence intervals (95%CI) were reported. Associations
between periodontal variables and eGFR were assessed by linear regres-
sion models, and beta coefficients were reported.
3 |   R E S U LT S
Among 703 individuals that were screened, 139 were included
in the study (Figure 1). The main reasons for non-eligibility were
2
eGFR > 60 ml/min/1.73 m and less than 4 teeth present, whereas
the main reasons for non-inclusion were use of antibiotics or im-
munosuppressive drugs in the last 6  months and individuals that
refused to participate.
The sample was composed predominantly by men, with a mean
age of 60.1 years, with medium educational level and socioeconomic
status, and never smokers (Table 1). There were no significant dif-
ferences between stages of CKD for demographics, behavioral vari-
ables, tobacco use, obesity, use of anti-glycemic drugs, and time of
renal treatment. Vitamin D supplementation was significantly more
frequent among individuals in stage 4 of CKD. Regarding medical
parameters, few data for urea and proteinuria (one patient) and for
SCREENING
Reasons for non-elegibility:
703
136 eGFR>60 ml/min/1,73m²
135 ≤4 teeth
Elegibility 22 Malignant tumor
criteria 15 Dialysis
14 HIV+
ELEGIBLE 10 Other
371 Reasons for non-inclusion:
90 Antibiotic/Immunosuppressive
Inclusion
criteria in the ≤6 months
88 Refused participation
6 Periodontal treatment in the ≤6
SELECTED months/Orthodontic treatment
187
48 did not attend the
appointment
INCLUDED
n = 139
F I G U R E 1   Flowchart of the study [Colour figure can be viewed
at wileyonlinelibrary.com]
parathyroid hormone (10 patients) were not updated/available in the
clinical records, and therefore were not collected. Serum levels of
creatinine, urea, and proteinuria were higher in individuals in stage
5 of CKD (Table 2). Also, eGFR was lower in these participants, as
expected. The overall mean number of present teeth was 17.2 ± 7.5,
with high levels of visible plaque and bleeding, but no significant dif-
ferences between stages were observed for these variables. Overall
mean PPD and CAL were 2.63 ± 0.59 and 3.77 ± 1.41, respectively,
without significant differences between groups of CKD. A signifi-
cant proportion of individuals with severe periodontitis was ob-
served among those in stages 4 (55.2%) and 5 (59.4%) compared to
stage 3. This was also observed for individuals having ≥2 teeth with
CAL ≥ 6 mm, but not for individuals with ≥2 teeth with PPD ≥ 5 mm.
During model building, age, educational level, socioeconomic status,
obesity (BMI), hypertension, use of statins, and oral hypoglycemic drugs
were not associated with CKD stages nor were confounders of the asso-
ciation between periodontal parameters and CKD stages. As a result, the
final multivariable multinomial logistic regression models included sex,
tobacco, vitamin D supplementation, physical activity, and renal treat-
ment duration as a result of the purposeful approach applied (Table 3).
Individuals with severe periodontitis and with ≥2 teeth with CAL ≥ 6 mm
presented higher risk to be in stages 4 and 5 of CKD in the univariate
models. These associations remained significant in the multivariable anal-
yses, where participants with severe periodontitis had 2.8 and 3.4 higher
risk to be in stages 4 and 5 of CKD, when compared to individuals with-
out severe periodontitis (p < .05). Also, having ≥2 teeth with CAL ≥ 6 mm
increased 3.9 times the risk of being in stage 5 of CKD (p < .05). Having
≥2 teeth with PPD ≥ 5 mm was not associated with stages of CKD.
SCHÜTZ et al. |
      451

TA B L E 1   Demographic and behavioral

Total Stage 3 Stage 4 Stage 5
data, use of medication and renal
  n (%) n (%) n (%) n (%) p
treatment duration according to CKD
stages (n = 139) Total 139 (100.0) 40 (28.8) 67 (48.2) 32(23.0)  
Age
20–49 years 30 (21.6) 10 (25) 14 (20.9) 6 (18.7) .93
50–64 years 52 (37.4) 15 (37.5) 26 (38.8) 11 (34.4)
≥65 years 57 (41) 15 (37.5) 27 (40.3) 15 (46.9)
Sex
Male 85 (61.2) 29 (72.5) 37 (52.2) 19 (59.4) .2
Female 54 (38.8) 11 (27.5) 30 (47.8) 13 (40.6)
Educational level
Low 25 (18) 5 (12.5) 16 (23.9) 4 (12.5) .45
Medium 67 (48.2) 22 (55) 30 (47.8) 15 (46.9)
High 47 (33.8) 13 (32.5) 21 (28.3) 13 (40.6)
Socioeconomic status
Low 33 (23.7) 8 (20) 17 (25.4) 8 (25) .87
Medium 83 (59.7) 24 (60) 41 (61.2) 18 (56.3)
High 23 (16.6) 8 (20) 9 (13.4) 6 (18.7)
Tobacco exposure
Never 81 (58.3) 26 (65) 38 (56.7) 17 (53.1) .32
Moderate 27 (19.4) 8 (20) 15 (22.4) 4 (12.5)
Heavy 31 (22.3) 6 (15) 14 (20.9) 11 (34.4)
Body mass index
Normal 35 (25.2) 10 (25) 18 (26.9) 7 (21.9) .57
Overweight 54 (38.8) 12 (30) 27 (40.3) 15 (46.9)
Obese 50 (36) 18 (45) 22 (32.8) 10 (31.2)
Statin use
No 63 (45.3) 21 (52.5) 28 (41.8) 14 (43.7) .54
Yes 76 (54.7) 19 (47.5) 39 (58.2) 18 (56.3)
Oral hypoglycemic/Insulin use
No 100 (72) 29 (72.5) 46 (71.7) 25 (78.1) .61
Yes 39 (28) 11 (27.5) 21 (28.3) 7 (21.9)
Vitamin D supplementation
No 109 (78.4) 37 (92.5) 50 (74.6) 22 (68.8) .03
Yes 30 (21.6) 3 (7.5) 17 (25.4) 10 (31.2)
Hypertension
No 32 (23.0) 9 (28.1) 18 (56.3) 5 (15.6) .46
Yes 107 (77.0) 31 (29.0) 49 (45.8) 27 (25.2)
Renal treatment duration
<5 years 86 (61.9) 21 (52.5) 41 (61.2) 24 (75) .14
≥5 years 53 (38.1) 19 (47.5) 26 (38.8) 8 (24)

A similar pattern of association with CKD severity was observed in 4 | D I S CU S S I O N

the analysis of eGFR (Table 4). eGFR was significantly lower in participants
with severe periodontitis and with ≥2 teeth with CAL ≥ 6 mm. Having ≥ 2
teeth with PPD ≥ 5 mm was not associated with eGFR. In the multivari-
able models, eGFR was 4.45 ml/min/1.732 lower in individuals with than
those without severe periodontitis (p = .02), and 5.24 ml/min/1.732 lower
in individuals with than those without ≥2 teeth with CAL ≥ 6 mm (p = .01).
The present study assessed the association between periodontal pa-
rameters with CKD staging/severity in a sample of patients who are
under renal treatment for approximately 4.5 years in a tertiary care
center in south Brazil. The main findings demonstrated that individu-
als with severe periodontitis presented higher risk to be in stages
452      | SCHÜTZ et al.

TA B L E 2   Mean values for medical and periodontal parameters according to CKD stages

Stage 3 Stage 4 Stage 5

  Total (n = 40) (n = 67) (n = 32) p

Medical parameters
Urea (mg/dl)a 102.0 ± 46.1 68.17 ± 25.13 100.46 ± 38.04 147.5 ± 44.14 .004
Creatinine (mg/dl) 3.82 ± 10.2 1.81 ± 0.39 4.61 ± 14.69 4.68 ± 1.03 <.001
Proteinuria (mg/dl)a 1.33 ± 2.61 1.22 ± 2.46 1.14 ± 3.01 1.88 ± 1.74 .004
Parathyroid hormone (pg/dl)b 279.5 ± 245.8 143.4 ± 83.2 253.3 ± 221.2 472.2 ± 288.9 <.001
Glycated hemoglobin (mg/dl) 6.34 ± 1.41 6.41 ± 1.55 6.4 ± 1.46 6.14 ± 1.13 .17
<6.5 (n/%) 95 (68.3) 27 (67.5) 44 (65.7) 24 (75)  
≥6.5 (n/%) 44 (31.7) 13 (32.5) 23 (34.3) 8 (25) .64
C-reactive protein 9.2 ± 19.5 8.79 ± 25.94 10.35 ± 19.19 7.32 ± 7.66 <.001
<3 mg/dl 63 (45.3) 24 (60) 26 (38.8) 13 (40.6)  
≥3 mg/dl 76 (54.7) 16 (40) 41 (61.2) 29 (90.6) .08
Estimated glomerular filtration 24.1 ± 11.2 38.6 ± 7.46 21.44 ± 4.15 11.4 ± 1.93 <.001
rate (mL/min/1.732)
Periodontal parameters
Number of teeth 17.2 ± 7.5 16.65 ± 7.82 17.46 ± 7.37 16.5 ± 7.3 .89
Visible plaque (%) 69.1 ± 21.1 69.06 ± 21.7 67.9 ± 20.1 71.7 ± 22.9 .68
Gingival bleeding index (%) 55.1 ± 31.1 58.7 ± 30.4 52.8 ± 30.7 55.2 ± 32.9 .87
Probing depth (mm) 2.63 ± 0.59 2.61 ± 0.55 2.62 ± 0.6 2.7 ± 0.62 .7
Attachment loss (mm) 3.77 ± 1.41 3.49 ± 1.30 3.74 ± 1.40 4.2 ± 1.51 .67
Bleeding on probing (%) 62.1 ± 27.8 64.3 ± 26.2 60 ± 27.6 63.9 ± 30.4 .66
Severe periodontitis (n/%) 68 (48.9) 12 (30) 37 (55.2) 19 (59.4) .01
≥2 teeth with PPD ≥ 5 mm (n/%) 63 (45.3) 14 (35) 33 (49.2) 16 (50) .29
≥2 teeth with CAL ≥ 6 mm (n/%) 86 (61.9) 19 (47.5) 42 (62.6) 25 (78.1) .02
a
138 observations.
b
129 observations.

4 and 5 of CKD, even when adjusted for major confounders. This
association was observed not only with categorical but also with
continuous outcomes of renal function such as eGFR. These find-
ings as a whole demonstrated that worst periodontal condition was
associated with higher severity of CKD in predialytic patients with
different levels of CKD.
The relationship between periodontitis and CKD has been stud-
ied by approximately 15 years (Craig, Spittle, & Levin, 2002; Rahmati,
Craig, Homel, Kaysen, & Levin, 2002). Large population-based stud-
ies observed higher periodontitis prevalence in individuals with CKD
in comparison to those without CKD (Fisher, Taylor, Shelton, et al.,
2008; Kshirsagar et al., 2005). More recently, it was also observed
that patients with periodontitis and CKD presented higher all-cause
and cardiovascular mortality when compared to those diagnosed
with CKD alone (Ricardo et al., 2015; Sharma, Dietrich, Ferro,
Cockwell, & Chapple, 2016). A systematic review with 4 observa-
tional studies also provides indirect support to our findings, show-
ing that individuals with periodontitis presented 65% higher risk of
having CKD (CI: 1.35–2.01) than healthy individuals or those with
mild periodontitis (Chambrone et al., 2013). In a more recent sys-
tematic review, Deschamps-Lenhardt et al. (Deschamps-Lenhardt,
Martin-Cabezas, Hannedouche, & Huck, 2019) found that individu-
als with severe periodontitis had 2.26 more risk to have CKD, even
after adjustment for major confounders (CI: 1.69–3.01). While a
sub-analysis with only low risk of bias studies confirm the associ-
ation between both diseases, a metanalysis evaluating the impact
of periodontal treatment over CKD was not carried out due to het-
erogeneity in study designs. Additionally, it is important to highlight
that most studies applied partial-mouth protocols of periodontal ex-
amination, which produce systematic bias on the estimates of peri-
odontitis (Kingman, Susin, & Albandar, 2008).
Direct comparisons of the published literature with the present
study are difficult to be performed mainly because of differences
in study design, sample characteristics, and evaluated outcomes.
Importantly, the abovementioned studies tested the hypothesis that
periodontitis may increase the risk of CKD development, which is
different from that of the present study that evaluated the influ-
ence of periodontitis on renal function in already diseased kidney
patients. The findings of the present study may be applied to the
management of CKD patients and their prognosis. Parallel to the
present study and corroborating some of our findings, Iwasaki et
al. (Iwasaki et al., 2012) found that Japanese elders with advanced
SCHÜTZ et al. |
      453

TA B L E 3   Multinomial logistic
Stage 4 Stage 5
regression models of the association
between periodontal condition and CKD   RRR 95% CI RRR 95% CI
stages (reference category: stage 3)
Univariable models
Model 1
Severe periodontitis 2.88** 1.25–6.62 3.41** 1.27–9.09
Model 2
≥2 teeth with PPD ≥ 5 mm 1.80 0.80–4.05 1.86 0.72–4.82
Model 3
≥2 teeth with CAL ≥ 6 mm 1.86 0.84–4.11 3.95** 1.39–11.24
Multivariable models*
Model 1
Severe periodontitis 2.83** 1.15–6.92 3.39** 1.21–9.49
Model 2
≥2 teeth with PPD ≥ 5 mm 1.03 0.84–4.87 2.28 0.82–6.37
Model 3
≥2 teeth with CAL ≥ 6 mm 1.90 0.79–4.59 3.90** 1.30–11.67

Abbreviation: RRR, Relative Risk Ratio.

*Adjusted for sex, tobacco exposure, vitamin D supplementation, physical activity and renal
treatment duration.
**p < .05.

TA B L E 4   Linear regression models of the association between our study and was somehow expected due to the age range of the
periodontal condition and eGFR (mL/min/1.732) studied sample, which was mainly composed by elders. In the same
context, Chen et al. (Chen et al., 2015), in a longitudinal study, found
  Beta 95% CI p
that individuals with periodontal disease were more likely to kidney
Univariable models
function decline (>30% of eGFR) in the second and third year of fol-
Model 1
low-up when compared to those without periodontal disease (OR:
Severe periodontitis −4.51 −8.21 – −0.82 .02 1.62 95% CI 1.41–1.87; OR: 1.59 95% CI 1.37–1.86, respectively).
Model 2 Also, Chang and colleagues (Chang et al., 2017), in another cohort,
≥2 teeth with −1.41 −5.16 – 2.35 .46 found that individuals with more periodontal inflammation were at
PPD ≥ 5 mm
higher risk of CKD progression.
Model 3 The biological plausibility of the association between peri-
≥2 teeth with −5.22 −9.14 – −1.29 .01 odontitis and CKD relies on a persistent immune response orig-
CAL ≥ 6 mm
inated from periodontal infection, which leads to a low-grade
Multivariable models* systemic inflammation (Loos, 2005) and contributes to decreased
Model 1 renal function (Stenvinkel et al., 2008). Moreover, the presence
Severe periodontitis −4.45 −8.07 – −0.85 .02 of periodontal pathogens in periodontal pockets may spread
Model 2 throughout bloodstream inducing a systemic response (Lockhart
≥2 teeth with −2.15 −5.79 – 1.49 .25 et al., 2009). However, it is hard to define the real strength of this
PPD ≥ 5 mm association since both diseases share several risk factors, such
Model 3 as age, smoking, and diabetes. In addition, these conditions have
≥2 teeth with −5.24 −9.09 – −1.40 .01 both been consistently associated with cardiovascular diseases
CAL ≥ 6 mm (Flores et al., 2014; Nascimento, Pecoits-Filho, Lindholm, Riella,
*Adjusted for sex, tobacco exposure, vitamin D supplementation, & Stenvinkel, 2002; Zimmermann, Herrlinger, Pruy, Metzger,
physical activity and renal treatment duration. & Wanner, 1999). The literature evaluating the association be-
tween periodontal disease and CKD utilized several periodon-
levels of periodontal inflammation had higher risk of decreased renal titis definitions, including different cutoffs of PPD and CAL,
function (reduction of eGFR) over 2  years of follow-up. Sharma et PISA (Periodontal Inflamed Surface Area), CPITN (Community
al. (Sharma et al., 2014) found that individuals with predialytic CKD Periodontal Index of Treatments Needs), and radiographic evalu-
(stages 3–5) were more likely to have severe periodontitis (OR: 3.8 ation. Therefore, it has been observed that some of these criteria
95% CI 2.5–5.6). This finding was in agreement with the results of were associated with CKD in specific samples, but not in all of
 |
454       SCHÜTZ et al.
them. Similar to our findings, Perozini et al. (Perozini et al., 2017)
also observed association between CAL (but not PPD) and CKD
in another Brazilian sample. Trying to better understand the in-
fluence of confounders, the present study collected all available
data that could be related with both outcomes. The participants
are submitted to a strict renal care at the University Hospital, and
not only renal function data were recorded, but also socioeco-
nomic and behavioral habits, data related to comorbidities, use of
medications, renal treatment duration, lipid and glycemic profile,
and cardiovascular condition were gathered. Regarding periodon-
tal examination, a six-site per tooth complete protocol was car-
ried out by two trained and calibrated periodontists.
It is important to recognize that the present study has some
limitations. Although the magnitude of the association found
is interesting, the study design could not establish a causal re-
lationship. The present sample is singular, due to the presence
of several comorbidities (hypertension, diabetes, cardiovascular
diseases, use of numerous medicines), which hamper multivariate
models adjustments. However, the patients were under rigorous
monitoring with available data of several medical parameters, use
of medications, and comorbidities and all these data were ana-
lyzed and included in univariable models. Although some of these
variables, such as age and obesity, are common risk factors/in-
dicators for both diseases, in the present sample they were not
associated with CKD stages nor were confounders of the associ-
ation between periodontal parameters and CKD stages. Though
the significance of the associations is robust, confidence intervals
of the regressions are wide. Therefore, the results should be in-
terpreted with caution. In addition, the lack of healthy controls
may represent a shortcoming of the study design. However, the
aim of the study was to evaluate the influence of severe peri-
odontitis over CKD and not its role on the establishment of CKD.
As strengths, the present study is the first that assessed a solely
predialytic sample, associating periodontal disease with different
stages of CKD. The option for individuals with less severe CKD
(predialytic stages) was related to the fact that they could be
more benefited by periodontal therapy due to their less systemic
impairment when compared to patients under dialysis or submit-
ted to kidney transplantation. Besides, several methodological
controls were carried out, as experimental procedures standard-
ization and complete periodontal examination (six-site per tooth
protocol) by trained and calibrated specialists. Monitoring this
sample over the years, as well as other comparison groups (eden-
tulous or healthy participants, for example) and the execution
of interventional trials may provide more data in order to clarify
some important issues related to this association.
5 |  CO N C LU S I O N
The present study demonstrated that severe periodontitis was as-
sociated with higher severity of CKD in predialytic patients. These
results support the possible influence of periodontitis on CKD
severity. Future longitudinal and interventional studies may clarify
the real impact of periodontitis over CKD progression and prognosis.
AC K N OW L E D G M E N T S
Authors would like to acknowledge the collaboration of undergradu-
ate students Alfredo Otto Kirst Neto and Betina Bramraiter Borile
during the entire study.
C O N FL I C T O F I N T E R E S T S
The authors declare that they have no conflict of interest.
AU T H O R S ' C O N T R I B U T I O N
Jasper da Silva Schütz, Carolina Barrera de Azambuja and Giuliano
Reolon Cunha  performed data acquisition, literature searches and
drafted the paper. Juliano Cavagni, Cassiano Kuchenbecker Rösing
and Alex Nogueira Haas  contributed to conceive the study and
designed the investigation, development of the drafts and statisti-
cal analysis. Fernando Saldanha Thomé  provided expert regarding
chronic kidney disease. Tiago Fiorini and Fernando Saldanha Thomé
provided guidance and had been fully engaged in all phases of the
study.  All authors discussed and reviewed the final version of the
manuscript.
ORCID
Juliano Cavagni  https://orcid.org/0000-0003-0062-6604
Cassiano Kuchenbecker Rösing  https://orcid.
org/0000-0002-8499-5759
Alex Nogueira Haas  https://orcid.org/0000-0003-0531-6234
Tiago Fiorini  https://orcid.org/0000-0002-5452-3822
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How to cite this article: Schütz JDS, de Azambuja CB,
Cunha GR, et al. Association between severe periodontitis and
chronic kidney disease severity in predialytic patients:
A cross-sectional study. Oral Dis. 2020;26:447–456. https​://
doi.org/10.1111/odi.13236​