Download oral health in patients with chronic kidney disease

Department of Oral and Maxillofacial Diseases,
Head and Neck Center,
Helsinki University Hospital and Faculty of Medicine,
University of Helsinki
Helsinki, Finland
ORAL HEALTH IN PATIENTS WITH
CHRONIC KIDNEY DISEASE
± EMPHASIS ON PERIODONTITIS
Karita Nylund
Academic dissertation
To be presented with the permission of the Faculty of Medicine, University of Helsinki,
for public examination in the Faltin Hall, Surgical Hospital, Kasarmikatu 11-13, Helsinki,
on June 1st, 2017, at 12 noon
Helsinki 2017
SUPERVISORS
Hellevi Ruokonen
DDS, PhD, MSc
Department of Oral and Maxillofacial Diseases
Head and Neck Center
Helsinki University Hospital
Helsinki, Finland
Jukka H Meurman
MD, PhD DOdont, Professor
Department of Oral and Maxillofacial Diseases
Head and Neck Center
Helsinki University Hospital and University of Helsinki
Helsinki, Finland
REVIEWERS
Patrik Finne
MD, PhD, Docent
Abdominal Center, Helsinki University Hospital
Helsinki, Finland
Anders Gustafsson
DDS, PhD, Professor, Dean of Research
Department of Dental Medicine
Karolinska Institutet
Huddinge, Sweden
ISBN 978-951-51-3257-4 (nid.)
ISBN 978-951-51-3258-1 (PDF)
OPPONENT
Søren Jepsen
DDS, PhD, Professor
University of Bonn,
Bonn, Germany
CONTENTS
LIST OF ORIGINAL PUBLICATIONS
3
ABBREVIATIONS
4
ABSTRACT
6
INTRODUCTION
8
REVIEW OF THE LITERATURE
11
Common oral diseases
11
Signs and symptoms of the mouth
11
Pathogenesis of periodontal diseases
12
Host immune system
14
Pro-inflammatory mediators
15
Prevalence and risk factors of periodontal diseases
17
Diagnostic methods of periodontitis
17
Classification of periodontitis
18
Classification of oral inflammatory burden
20
Prevention and treatment of chronic periodontitis
21
Kidneys
21
Anatomy and function
21
Classification, prevalence, and causes of kidney diseases
23
End-stage renal disease
24
Immunodeficiency in chronic kidney disease
25
Mortality among kidney patients
25
Oral infections and systemic diseases
26
ϭ
Periodontitis and systemic inflammation
Diabetes
26
27
Hyperglycemia and periodontitis
28
Impact of periodontitis on diabetes
29
Atherosclerotic cardiovascular disease
30
Chronic kidney diseases
30
Association between other systemic diseases and periodontitis
31
Oral manifestation of chronic kidney disease
32
Predialysis stage
32
Dialysis
33
Post-transplantation stage
34
AIMS OF THE STUDY
35
PARTICIPANTS AND METHODS
36
Participants
36
Methods
39
Oral and radiological examination
39
Salivary analyses
40
Questionnaire study
41
Statistical analyses
41
Ethical aspect
42
RESULTS
43
DISCUSSION
49
CONCLUSION
57
ACKNOWLEDGEMENTS
58
REFERENCES
60
ORIGINAL PUBLICATIONS
Ϯ
LIST OF ORIGINAL PUBLICATIONS
The present thesis is based on the following original publications, referred to in the text by
their Roman numerals I-IV. This thesis also contains some unpublished data.
I
Nylund K, Meurman J.H, Heikkinen A.M, Honkanen E, Vesterinen M,
Ruokonen H. Oral health in predialysis patients with emphasis on periodontal
disease. Quintessence Int 2015; 46: 899-907.
II
Nylund K.M, Meurman J.H, Heikkinen A.M, Honkanen E, Vesterinen M,
Furuholm J.O, Tervahartiala T, Sorsa T, Ruokonen H.M. Periodontal
inflammatory burden and salivary matrix metalloproteinase-8 concentration
among patients with chronic kidney disease at the predialysis stage.
J.Periodontol 2015; 86: 1212-1220.
III
Ruokonen H, Nylund K, Furuholm J, Meurman J.H, Sorsa T, Kotaniemi K,
Ortiz F, Heikkinen A.M. Oral health and mortality in patients with chronic
kidney disease. J.Periodontol 2017; 88: 26-33.
IV
Nylund K.M, Meurman J.H, Heikkinen A.M, Furuholm J.O, Ortiz F, Ruokonen
H.M. Oral health in patients with renal disease: a longitudinal study from
predialysis to kidney transplantation. Clin Oral Investig 2017 Apr 20. doi
10.1007/s00784-017-2118-y.
[Epub ahead of print].
Original publications may be reprinted with the permission of the publisher.
ϯ
ABBREVIATIONS
ACVD
Atherosclerotic cardiovascular diseases
AER
Albumin excretion rate
AGE
Advanced glycation end-product
AMP
Antimicrobial peptide
BMS
Burning mouth syndrome
CAL
Clinical attachment loss
CDC/AAP
Centers for Disease Control and Prevention/the American
Academy of Periodontology
CD4
Cluster of differentiation 4
CD8
Cluster of differentiation 8
CHD
Coronary heart disease
CKD
Chronic kidney disease
COPD
Chronic obstructive pulmonary disease
CPI
Community Periodontal Index
CPITN
Community Periodontal Index of Treatment Needs
CVD
Cardiovascular disease
DM
Diabetes mellitus
DMFT
Decayed, Missing, Filled Teeth
EFP
European Federation of Periodontology
ESRD
End-stage renal disease
GCF
Gingival crevicular fluid
GFR
Glomerular filtration rate
HbA1c
Glycosylated hemoglobin
IQR
Interquartile range
IL
Interleukin
Ig
Immunoglobulin
KDIGO
Kidney Disease: Improving Global Outcomes
LDD
Low dose doxycycline
LPS
Lipopolysaccharide
ϰ
MACE
Major adverse cardiovascular event
MAMP
Microbe-associated molecular pattern
MMP
Matrix metalloproteinase
NET
Neutrophil extracellular trap
NHANES
National Health and Nutrition Examination Survey
NHEFS
National Health and Nutrition Examination Survey - Epidemiologic
Follow-up Study
NIDDM
Non-insulin dependent diabetes mellitus
NKF-KDOQI
National Kidney Foundation - Kidney Disease Outcomes Quality
Initiative
PCR
Polymerase chain reaction
PGE-2
Prostaglandin-2
PIBI
Periodontal Inflammatory Burden Index
PISF
Peri-implant sulcular fluid
PLGRP-1
Peptidoglycan recognition receptor -1
PMN
Polymorphonuclear leukocyte
PPD
Periodontal pocket depth
PRR
Pattern recognition receptor
PSD
Polymicrobial synergy and dysbiosis
RANKL/OPG
Receptor activator of nuclear factor kappa B
ligand/osteoprotegerin
ROS
Reactive oxygen species
RRT
Renal replacement therapy
SDD
Subantimicrobial dose doxycycline
TDI
Total Dental Index
TIA
Transient ischemic attack
TIMP
Tissue inhibitor of matrix metalloproteinase
TLR
Toll like receptor
71)Į
Tumor necrosis factor alpha
TREM1
Triggering receptor expressed on myeloid cells 1
WHO
World Health Organization
ϱ
ABSTRACT
Periodontitis has been associated with systemic diseases such as diabetes and
atherosclerosis, cardiovascular diseases, and even chronic kidney disease (CKD) through
low-grade systemic inflammation, although no causality can be drawn. CKD is an
increasing problem worldwide, and has adverse effects on oral health. The main risk
factors of CKD are diabetes mellitus (DM), hypertension and obesity. Diabetic nephropathy
is the main reason for entering dialysis in Finland and cardiovascular diseases (CVD) play
a crucial role in mortality among CKD patients.
The general aim of this thesis was to study oral health with an emphasis on periodontitis
among CKD patients, and to determine the differences between diabetic nephropathy and
other CKD patients (Study I) and whether salivary MMP-8 concentration can reflect an oral
inflammatory burden at the predialysis stage (Study II). In the follow-up prospective cohort
study (III), the goal was to examine whether oral inflammatory burden was associated with
mortality among the study patients and clarify the cause of death of patients who had been
enrolled in our previous study. A further aim was to compare oral health at the predialysis
stage and at follow-up (Study IV).
The hypotheses were that diabetic nephropathy patients have worse oral health than other
CKD patients, at both predialysis and post-transplantation stages, and that salivary MMP-8
associates with worse oral inflammatory burden. The mortality rate was assumed to be
higher among diabetic nephropathy patients. The main expected reason for death was
cardiovascular disease.
This series of studies were further clinical oral investigations of CKD patients originally
examined in 2000±2005 in the Department of Oral and Maxillofacial Diseases of Helsinki
University Hospital at the predialysis stage (Vesterinen et al. 2011). The periodontal health
of 144 CKD patients was now studied in more detail at the predialysis stage, and 118
salivary samples were analyzed for MMP-8. Of these 144 patients, 53 took part in the
follow-up study (2013±2015); 65 patients had died, and 26 had dropped out.
The same periodontist (HR) conducted the clinical oral examination at the predialysis and
post-transplantation stages, and the patients underwent a full clinical and radiographic oral
examination. Radiological- and salivary analyses, questionnaires, hospital-, and mortality
records were available for the study. The severity of the periodontitis was assessed using
ϲ
the definition of the Centers for Disease Control and Prevention/the American Academy of
Periodontology (CDC/AAP) whenever possible, and other indices used were the
Periodontal Inflammatory Burden Index (PIBI) (Lindy et al. 2008), the Total Dental Index
(TDI) (Mattila et al. 1989), and the DMFT index (WHO 1997).
The clinical oral parameters of patients with diabetic and other CKDs were analyzed, at
both baseline and follow-up.
Patients with diabetic nephropathy indeed had worse oral health at the predialysis stage,
with two or more sites having periodontal pocket depths (PPD) of •PP, and higher TDI
scores than the patients with other CKDs (p< 0.05), (Study I). Higher salivary MMP-8
concentration was associated with worse oral health (deep periodontal pockets, higher
PIBI and TDI) than with lower MMP-8 concentration (p< 0.05), (Study II).
The 157-month follow-up study showed that the most frequent causes of death were
cardiovascular diseases, followed by infection and cancer. The survival rate of diabetic
nephropathy (23.8%) patients and other patients with CKD (59.9%; log-rank test p <
0.001) differed statistically significantly. In the multivariable Cox regression model, fewer
teeth, higher age, and diabetic nephropathy diagnosis were statistically significant
independent risk factors for death. The deceased patients had fewer teeth (p< 0.001) and
higher TDI scores (p< 0.05) than those who survived (Study III).
Most of the surviving patients who took part in the re-examination had undergone a kidney
transplant (51/53), of which 46 transplants were functioning. Comparison of the two stages
of kidney disease revealed that patients had more teeth, and more often had calculus,
deep periodontal pockets, and higher TDI and PIBI scores (p< 0.05) at the predialysis
stage than at the post-transplantation stage. Patients at the post-transplantation stage,
however, took more drugs daily and had dental appointments more frequently in a year
than the patients at the predialysis stage. Overall oral health was worse at the predialysis
stage (Study IV).
In conclusion, the present study supports the existing protocol of the Helsinki University
Hospital, according to which oral examination, accurate diagnosis, and proper treatment of
oral infection foci are mandatory at the predialysis stage for reducing systemic
inflammation among CKD patients. Since diabetic nephropathy is associated with poorer
oral health, this group of patients needs significant attention in oral care.
ϳ
INTRODUCTION
Periodontitis is a bacteria-induced chronic inflammatory disease that affects a large portion
of the adult population worldwide, also in Finland (Jin et al. 2011, Pihlstrom et al. 2005,
Periodontitis:Current Care Guidelines 2016). Without treatment, it may lead to tooth loss in
susceptible patients. CKD is defined as a deficiency in kidney structure or function that
lasts over three months, and has an adverse effect on health (Inker et al. 2014). Its
prevalence is over 10% in many countries, a number that is rising alarmingly (Eckardt et
al. 2013). Principal risk factors for CKD are hypertension, diabetes, and obesity, although
periodontitis as an inflammatory disease has also been proposed to be a non-traditional
risk factor for CKD (Cignarelli and Lamacchia 2007, Fisher et al. 2008, Jha et al. 2013).
Periodontitis may also accelerate poor glycemic control by increasing insulin resistance,
whereas diabetes, in turn, may lead to abnormal hyper-inflammatory reaction to
periodontal pathogens (Chapple et al. 2013, Southerland et al. 2006).
The worldwide prevalence of diabetes among adults was 4.7% in 1980, compared to 8.5%
in 2014 (WHO, Global report on diabetes 2016). According to the International Federation
of Diabetes, one adult in ten will have diabetes by 2040, corresponding to 642 million
people (www.idf.org). The increasing prevalence of type 2 diabetes is explained by risk
factors such as overweight, high blood pressure, impaired glucose tolerance, unhealthy
diet, physical inactivity, and increasing age (www.idf.org).
CKD is diagnosed by decreased glomerular infiltration rate (GFR) or by increased albumin
concentration in the urea, i.e. albuminuria. When the functional capacity of kidneys falls
below 10% of normal capacity, end-stage renal disease (ESRD) is diagnosed (Bots et al.
2007). Treatment modalities for renal replacement therapy (RRT) are dialysis, either
hemodialysis or peritoneal dialysis, and finally kidney transplantation. Diabetic
nephropathy is the most common reason for dialysis treatment in Finland.
Oral infections such as periodontitis should be regarded as one of the risk factors for the
progression of CKD and diabetic nephropathy due to low-grade systemic inflammation. In
fact, periodontitis may predict the development of ESRD and nephropathy in type 2
diabetes (Shultis et al. 2007, Chapple et al. 2013).
CKD patients are prone to premature death, mostly explained by CVD, followed by
infections (Stenvinkel 2002, Kato 2008). Atherosclerotic CVDs are explained by
ϴ
dyslipidemia, hypertension, smoking, and inflammation, in which periodontitis and other
oral infections may play a significant role (Tonetti et al. 2013).
Oral health among CKD patients has mostly been studied during dialysis or the posttransplantation stage (Bots et al. 2007, Summers et al. 2007, Craig 2008, Akar et al. 2011,
Kaushik et al. 2013, Schmalz et al. 2016). Both stages have their own characteristics,
which are also reflected in oral health.
However, only a few studies have examined oral health at the predialysis stage which is, in
fact, an important stage in the course of kidney disease (Souza et al. 2008, Thorman et al.
2009, Vesterinen et al. 2011). At our hospital, all patients are referred for a dental
examination at the predialysis stage, during which the foci of oral infections are diagnosed
and treated prior to entering RRT.
A 3XE0HGVHDUFKIRU³SUHGLDO\VLV´ and ³RUDOKHDOWK´XQWLO2FWREHUyielded 20 results,
6 of which were from our research group (Vesterinen et al. 2007, 2011, 2012, Nylund et al.
2015a, 2015b, Ruokonen et al. 2016). Twelve studies of the remaining 14 were studies of
orally administered drugs or vitamins, and the remaining two were clinical studies, one
from Sweden by Thorman and co-workers (2009), and the other from Brazil by Souza and
co-workers (2008).
The cross sectional study by Thorman and co-workers showed that uremic CKD patients
in predialysis, hemodialysis or in peritoneal dialysis had worse overall oral health (higher
DMFT index, more loss of attachment, more periapical- and mucosal lesions) than the
healthy controls (Thorman et al. 2009).
The Brazilian cross-sectional research by Souza and co-workers showed that the general
oral health status was poor among most (233/286, 88%) CKD patients, regardless of their
treatment modality (predialysis, hemodialysis, peritoneal dialysis, or transplantation).
However, transplant patients had less oral halitosis than patients with other treatment
modalities (Souza et al. 2008).
A cross sectional study by our research group showed that CKD patients with diabetic
nephropathy had lower stimulated salivary flow rates and more caries than patients with
other kidney diseases at the predialysis stage (Vesterinen et al. 2011).
ϵ
To the best of our knowledge, only one longitudinal clinical study has followed CKD
patients from the predialysis to the post-transplantation stage, and this is our own research
group¶VVWXG\ (Vesterinen et al. 2007).
This present study is divided into two investigations: baseline (predialysis) and follow-up
(post-transplantation) studies. The purpose of the first part (Studies I and II) was to study
oral health with an emphasis on periodontal disease by comparing diabetic nephropathy
with other CKD patients. Oral inflammatory burden was compared with salivary MMP-8
concentration. In the second part (Studies III and IV), a longitudinal study examined the
association between oral inflammatory burden and mortality and causes of death among
CKD patients and, secondly, compared the oral health of the patients during their
predialysis and post-transplantation stages.
The results of this series of studies are expected to help clinicians understand the
differences between the oral health, with an emphasis on periodontitis, of diabetic
nephropathy and other CKD patients at different stages of kidney disease. A further
purpose was to determine whether the treatment of oral infections at the predialysis stage
is indeed effective.
ϭϬ
REVIEW OF THE LITERATURE
Common oral diseases
Dental caries and periodontal diseases are the most prevalent biofilm diseases in oral
cavities (Shay 2002, Rosier et al. 2014). These multifactorial diseases constitute a major
economic burden worldwide, and like other behavioral biofilm diseases, could mostly be
prevented by good oral self-care. According to the ³Health 2011´ survey in Finland, one in
five people (aged •OLYLQJLQthe northern or southern part of the country had at least one
caries lesion, and this was more common among men (28%) than women (14%) (Health
2011 survey, www.julkari.fi/bitstream/handle/10024/90832/Rap068_2012_netti.pdf).Along
the same lines was the finding WKDWSHULRGRQWDOGLVHDVHDWOHDVWRQHSHULRGRQWDOSRFNHW•
4mm deep) was more common among men (70%) than among women (56%) (Health 2011
survey).
Other prevalent oral lesions include candidiasis, recurrent herpes labialis, recurrent
aphthous ulcers, hairy tongue, and lichen planus (Gonsalves et al. 2007). Oral mucosal
lesions can be classified as ulcerative, vesicular and bullous lesions; red, white or
pigmented, and benign or malign (Greenberg et al. 2008). The most common opportunistic
oral infection is oral candidiasis, which is mostly caused by Candida albicans. Other
candida species found in oral cavities are C. glabrata, C. tropicalis, C. pseudotropicalis, C.
guilliermondii, C. dubliniensis, and C. krusei (Jordan and Lewis 2004). Candidiasis is often
described as affecting the very young, very old, or very sick (Greenberg et al. 2008). Its
predisposing factors are, for example, immunosuppressive disease or medication, poor
oral health, endocrine disorders, smoking, and hyposalivation (Greenberg et al. 2008).
Signs and symptoms of the mouth
Xerostomia is a subjective symptom of dry mouth which does not always go hand in hand
with physical signs of salivary gland hypofunction (MacEntee and Donnelly 2016).
Hyposalivation, as an objective term, is defined when unstimulated salivary flow rate is <
0.1ml/min, and stimulated salivary flow rate is < 0.7 ml/min (Saleh et al. 2015).
Medication such as antihypertensive drugs, antidepressants, and antihistamines;
polypharmacy in general; radiation therapy; ageing; systemic diseases such as Sjögren¶s
ϭϭ
syndrome or other rheumatic diseases; and diabetes may disturb salivary gland function
and result in reduced salivary flow (Saleh et al. 2015, MacEntee and Donnelly 2016).
Hyposalivation predisposes to many disorders such as dysphagia (difficulty in swallowing),
dysgeusia (altered taste sensation), dysphonia, pain, burning mouth, and oral infectious
diseases such as caries and periodontal diseases, or even life-threatening bacterial and
yeast infections and aspiration pneumonia (Saleh et al. 2015, Mac Entee and Donnelly
2016).
About 90% of saliva is produced by the major salivary glands: the parotid, submandibularand sublingual glands. Saliva is mainly composed of water (90%) with electrolytes and
proteins such as immunoglobulins; and antifungal, antibacterial and digestive enzymes
(Saleh et al. 2015). Normally daily saliva volume varies from 0.5 to 1 liters per day. Saliva
is indeed an important lubricant of oral and upper gastrointestinal mucosa, and has
antimicrobial, buffering and demineralization properties.
Burning mouth syndrome (BMS) is defined as unknown chronic burning pain in oral
mucosa with no explanatory factor. BMS has been linked to other chronic pain syndromes
and is also associated with peripheral or central neuropathic disorder, but its pathogenesis
and etiology remain unknown (Moisset et al. 2016).
Pathogenesis of periodontal diseases
Periodontal diseases (gingivitis and periodontitis) are historically known as bacteriainduced inflammatory diseases that affect the supportive structures of the teeth
(Socransky and Haffajee 1992). Gingivitis is a reversible process that affects gingiva,
although it may develop into irreversible state periodontitis, in which the polymicrobial
biofilm triggers the host response, leading to destruction of the periodontium and, finally, to
tooth loss in a susceptible patient (Offenbacher 1996). It is now recognized that a dysbiotic
biofilm is necessary for periodontitis to develop, but that in itself, it is insufficient to cause
the disease. Individual susceptibility to periodontitis is principally determined by the host¶V
immune-inflammatory response to microbiota (Preshaw 2008, van Dyke and van
Winkelhoff 2013). Immunosuppressive state, genetic, dermatological, neoplastic,
hematological or granulomatous disorders may also have periodontal manifestations
(Page and Kornman 1997, Pihlstrom et al. 2005).
ϭϮ
In 1998, Socransky and co-workers introduced six subgingival microbial complexes:
³yellow´, ³green´ and ³purple´ complexes were considered early colonizers of the tooth
surfaces, and Gram-negative ³orange´ and ³red´ complexes comprised ³WUXH
periodontopathogHQV´. These are Prevotella intermedia, Prevotella nigrescens,
Peptostreptococcus micros, Campylobacter gracilis, Campylobacter rectus,
Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola.
Aggregatibacter actinomycetemcomitans (previously Actinomyces
actinomycetemcomitans) is another species often seen in periodontitis, especially in young
patients (Socransky et al. 1998). Virulent factors such as fimbriae, adhesion molecules,
proteases and leukotoxins help putative bacteria colonize and compete for ecological
niches and to evade the host (Offenbacher 1996). The ³red´ complex has shown the
strongest association with periodontal pocket formation (Socransky et al. 1998).
The oral cavity provides a habitat for over 700 bacteria species, of which 150±200 can be
found in most individuals and 30±100 species in a single site (Gorr and Abdolhosseini
2011, Hasan and Palmer 2014). However, new molecular techniques have shown that the
number of species in the mouth may be thousands, although the role of most of them is so
far unknown (Keijser et al. 2008). The mouth serves as a moist, warm environment, with
non-shedding surfaces that enable the formation of thick, well-organized biofilm (Marsh
and Devine 2011). Although periodontopathogenic biofilm is needed for the initiation of
periodontitis, several systemic and local risk factors are involved in modifying susceptibility
to the disease. Genetic, ethnic, age, gender, environmental (nutrition, pH, atmosphere,
temperature, smoking, diabetes, stress) and host defense factors determine the
composition of oral microbiota and play an important role in disease expression
(Offenbacher 1996, Marsh and Devine 2011). Smoking may affect the composition of the
biofilm in general and may also affect the immune system and impair the host¶V defense by
inhibiting granulocyte function (Hilgers and Kinane 2004, Söder et al. 2002).
$FFRUGLQJWR³HFRORJLFDOSODTXHK\SRWKHVLV´, changes in environmental conditions may
disrupt the host-microbe homeostasis. An increase in the amount of biofilm triggers the
host to increase gingival crevicular fluid (GCF), thus providing not only host defense
molecules but also nutrients for harmful proteolytic and anaerobic bacteria (Marsh and
Devine 2011).
ϭϯ
Since knowledge regarding the composition and synergistic effects of subgingival
microbiota has expanded through the development of microbiological methods,
periodontitis is now believed to be initiated not only by single microorganisms, but also by
polymicrobial synergy and dysbiosis (PSD) (Hajishengallis and Lamont 2012, Lopez et al.
2015). In the V\QHUJLVWLFDQGG\VELRWLFPLFURELDOFRPPXQLW\PRGHO³NH\VWRQHSDWKRJHQV´
such as P. gingivalis have the capacity to modulate the host¶V immune system and tip the
balance from homeostasis to dysbiosis (Hajishengallis and Lamont 2012). The
cRORQL]DWLRQRI³NH\VWRQHSDWKRJHQV´LQthe biofilm increases the communication of
different species and the expression of virulence factors, thus elevating the pathogenicity
of the entire community (Hajishengallis and Lamont 2012, Lamont and Hajishengallis
2015).
Host immune system
The host defense mechanisms and innate and adaptive immunity work together to try to
preserve health and prevent disease (Table 1).
Innate immunity comprises non-specific mechanisms such as the barrier function of the
epithelium and specific pattern recognition receptors (PRRs) that recognize bacterial
substances such as lipopolysaccharides (LPS), GCF with antimicrobial peptides (AMPs),
polymorphonuclear leucocytes (PMN) and macrophages, and saliva with protective
enzymes such as lysozyme and peroxidase (Gorr and Abdolhosseini 2011, Hasan and
Palmer 2014).
PMNs, the most important phagocytic cells, predominate in the early periodontal lesion in
the gingival crevice and in the epithelium (Nussbaum and Shapira 2011). Neutrophils are
considered the first line of defense during inflammation and infection. They can kill
bacteria intracellularly (oxygen dependent or oxygen independent pathways) or
extracellularly, the latter having the potential to damage collateral connective tissue by
releasing neutrophil cytoplasmic granules or neutrophil extracellular traps (NETs) into
extracellular space (Brinkmann et al. 2004, Nussbaum and Shapira 2011). Activated
neutrophils release proteinases and are capable of producing cytokines and chemokines.
Neutrophil disorders that affect neutrophil number (e.g. agranulocytosis, cyclic
neutropenia), chemotaxis or function (leucocyte adhesion deficiency syndrome, Papillon-
ϭϰ
Lefevre syndrome) predispose individuals to infections such as periodontitis (Nussbaum
and Shapira 2011).
In periodontitis, the acute inflammatory response is protective. However, in susceptible
patients, the response to remove inflammatory cells fails, and inflammation becomes
chronic when adaptive immunity takes place, and plasma cells and lymphocytes
predominate (Nussabaum and Shapira 2011, van Dyke and van Winkelhoff 2013).
Adaptive immunity is characterized by specificity with an ³LPPXQRORJLFDOPHPRU\´
(Ebersole et al. 2016). This is triggered by cytokines, which activate cell-mediated (T-cell)
and humoral immunity (B-cell). Bacterial antigens are presented by macrophages and
dendritic cells to T- and B lymphocytes. Antibodies (IgA, IgG, and IgM) are secreted when
B cells recognize antigens by cell surface immunoglobulins (Igs) (van Dyke and van
Winkelhoff 2013). Secretory IgA inhibits bacterial adhesion to mucosal surfaces, thus
preventing infection (Hasan and Palmer 2014). More antibodies, enzymes and immune
cells are then secreted into GCF by inflammation.
T-cells, on the other hand, express CD4+ and CD8 cell surface proteins, which act as
receptors for antigens. T-cell activation turns them into helper T-cells (CD4+), (producing
interleukins) or cytotoxic T-cells (CD8) (van Dyke and van Winkelhoff 2013).
Pro-inflammatory mediators
Pro-inflammatory mediators comprise cytokines such as tumor necrosis factor-Į71)-Į
interleukin (IL)-ȕ,/-6, and IL-8, chemokines, immunoglobulins and proteolytic enzymes,
e.g. matrix metalloproteinases (MMP)-8 and MMP-9 (Rathnayake et al. 2013a). Cytokines
do not work alone but in complex networks (Preshaw and Taylor 2011). The PRRs of
innate immune cells (macrophages, dendritic cells and PMNs) recognize microbeassociated molecular patterns (MAMPs) and produce pro-inflammatory cytokines. These
cytokines further determine the pathway of T-cell differentiation and the subclasses of
immunoglobulins (Preshaw and Taylor 2011). The balance between pro- and antiinflammatory cytokines determine the extent of periodontal destruction.
Type I collagen is the main extracellular matrix component in periodontal tissues and its
destruction is regarded as one of the key factors in the destruction of periodontal tissues
ϭϱ
(Golub et al. 1997). MMPs are groups of structurally alike proteolytic enzymes, capable of
degrading extracellular matrix and basement membranes. Human 23 MMPs
(collagenases, gelatinases, membrane-type MMPs, stromelysins and other MMPs) take
part in organogenesis, normal tissue turnover, immunity response in periodontitis, and
tissue destruction (Sorsa et al. 2004, 2006). The balance between MMPs and their
regulatory proteins such as the tissue inhibitors of matrix metalloproteinases (TIMPs) may
be disrupted by microbial virulence factors, hormones, cytokines and growth factors,
resulting in tissue destruction, also seen in periodontitis, peri-implantitis and cancer.
Collagenolytic matrix metalloproteinases collagenase-2 (MMP-8) and collagenase-3
(MMP-13) have shown to associate with severe periodontitis (Sorsa et al. 2004, 2006,
Leppilahti et al. 2011). MMP-8 is produced by PMNs, epithelial cells, fibroblasts,
endothelial cells, monocytes, macrophages and plasma cells, and is the main collagenase
in inflamed gingival tissue (Sorsa et al. 2004, 2006).
Table 1. The immune system
INNATE IMMUNITY
ADAPTIVE IMMUNITY
Epithelial barrier
Epithelial cells: e.g. AMPs, IL-1ȕ, IL-8
Pattern recognition receptors (PRRs): e.g. TLRs
Gingival crevicular fluid: e.g. AMPs, PMNs, complement
PMNs
Monocytes, macrophages
Peripheral dendritic cells
Mast cells
Saliva: e.g. lactoferrin, lysozyme, peroxidase
Lymphocytes
Cell-mediated immunity (T-cells)
Humoral immunity (B-cells)
AMP = antimicrobial peptide, IL = interleukin, TLR = toll-like receptor, PMN= polymorphonuclear leukocyte
ϭϲ
Prevalence and risk factors of periodontal diseases
Periodontal infections (gingivitis and periodontitis) are common inflammatory disorders,
affecting up to 90% of the world¶s population, and severe periodontitis affects
approximately 5±15% of the population worldwide (Papapanou 1996, Pihlstrom et al.
2005, Demmer and Papapanou 2010). These percentages vary according to ethnicity and
socioeconomic status, since non-white and people with low socioeconomic status are
more often affected. Older age is related to periodontitis, perhaps because of the
cumulative effects of true behavioral risk factors such as bad oral hygiene habits and
smoking or underlying health and systemic risk factors such as diabetes (Lalla and
Papapanou 2011, Scannapieco and Cantos 2016). According to the ³Health 2000´ survey
in Finland, the prevalence of gingivitis was 74% and periodontitis 64% (defined by at least
one pocket with a •PP-deep periodontal pocket). A severe form of periodontitis (defined
by at least one site with a •PP-deep periodontal pocket) was detected in 21% of
participants (Health 2000 Survey, http://www.terveys2000.fi/indexe.html).
Periodontitis is a multifactorial disease with several risk factors, such as poor oral hygiene,
smoking, and systemic disorders such as diabetes, rheumatoid arthritis, osteoporosis and
obesity (Lockhart 2012). Periodontitis is characterized as a complex disease with
polygenic variation (Laine et al. 2012). According to twin- and family studies, genetics
could explain about 50% of susceptibility to periodontitis (Laine et al. 2012). However,
although the risk factors for periodontitis at the individual level may be explained by
genetic, microbial and environmental factors, no specific gene or gene polymorphism has
been found that could explain all forms of periodontitis.
Diagnostic methods of periodontitis
Periodontitis usually develops without symptoms and is diagnosed conventionally by
clinical (measuring PPD with bleeding on probing, loss of clinical attachment) and
radiological (alveolar bone loss) examination. Putative periodontopathogens can be
detected by routine analyses, cultivation or by PCR (Mostajo et al. 2011). However, these
diagnostic methods provide information on destruction that already has occurred. Proper
diagnosis should determine whether the disease is present; identify the type, distribution,
activity, and severity of the disease, and provide an explanation for the underlying
pathologic process.
ϭϳ
Interest is currently paid to the ³DFWLYHSKDVH´GLDJQRVWLFWHVWVRIPROHFXODUELRPDUNHUV
such host inflammatory biomarker neutrophil collagenase MMP-8, which can be detected
in GCF and saliva (Pihlstrom et al. 2005, Sorsa et al. 2004, 2006, 2011). New
inflammatory biomarkers and a combination of different markers are being researched.
MMP-8 levels seem to increase in oral fluids due to periodontitis, and to decrease after
treatment (Mäntylä et al. 2006, Rathnayake et al.2013a, Leppilahti et al. 2014a,b,
Leppilahti et al. 2015, Nwhator et al. 2014). During periodontitis, MMP-8 is mainly
produced by PMN cells. Smoking seems to reduce the levels of MMP-8 by suppressing
inflammatory cells and reducing the flow rate of GCF and saliva (Mäntylä et al. 2006,
Sorsa et al. 2011, Leppilahti 2014a). High baseline MMP-8 levels in smokers have shown
to strongly predict weak treatment responses (Leppilahti 2014b).
As mentioned above, host-derived biomarkers of tissue destruction can be detected in oral
fluids such as saliva, GCF/ peri-implant sulcular fluid (PISF) and mouth-rinse. GCF/PISF is
detected in one site with microliter levels, whereas saliva or mouth-rinse provide more
comprehensive information in milliliter levels. Since saliva is easy to collect non-invasively,
attention is nowadays paid on saliva and mouth-rinse as diagnostic tools.
Higher salivary MMP-8 concentration has also been associated with, for example,
systemic diseases such as diabetes, previous heart surgery (Rathnayake et al. 2013b),
and acute myocardial infarction (Budunelli et al. 2011). Salivary biomarkers may thus
reflect not only oral but also systemic inflammation (Miller et al. 2010, Rathnayake 2013a).
Classification of periodontitis
The WHO Community Periodontal Index of Treatment Needs (CPITN) or Community
Periodontal Index (CPI), as later renamed, has been widely used in epidemiological
studies (Ainamo et al. 1982). This index provides the highest score per mouth sextant. CPI
ranges from 0 to 4, where 0 mirrors health, 1 equals bleeding, 2 equals calculus, 3 equals
a pocket depth of 4mm or 5mm, and 4 mirrors a pocket depth of •PP+RZHYHUthe
limitation of this index is that it only takes into account a few teeth with deepened
periodontal pockets, and not attachment loss (Leroy et al. 2010). Today, epidemiological
studies mainly use pocket depth measurement together with an assessment of attachment
loss when classifying periodontitis.
ϭϴ
The CDC/AAP have recommended using case definitions of severe, moderate and mild, or
no periodontitis in epidemiological studies, (Table 2), (Page and Eke 2007). These
definitions take into account periodontal pocket measurements in combination with clinical
attachment loss (CAL). Severe periodontitis is defined as two or more teeth with a (CAL) of
•PPDWLQWHUSUR[LPDOVLWHV, and one or more teeth with a pocket depth of • 5 mm at
interproximal sites. Moderate periodontitis is defined as two or more teeth with a CAL of •
4mm at interproximal sites, or two or more teeth with a pocket depth of • 5mm. None or
mild periodontitis is recorded when the criteria of neither moderate nor severe periodontitis
definition are fulfilled (Page and Eke 2007).
Table 2. Definition of periodontitis by CDC/AAP
Disease severity
Severe
Clinical attachment loss (CAL)
Periodontal pocket depth (PPD)
•LQWHUSUR[LPDOVLWHVZLWK•PP&$/*
Moderate
•LQWHUSUR[LPDOVLWHVZLWK•PP&$/
None or mild
Neither severe nor moderate form
*
$1'•LQWHUSUR[LPDOVLWHZLWK•PP33'
25•LQWHUSUR[LPDOVLWHVZLWK•PP33'*
*
not on same tooth
CDC/AAP= Centers for Disease Control and Prevention / the American Academy of Periodontology
ϭϵ
Classification of oral inflammatory burden
Oral inflammatory burden can be assessed by recording different indices such as the PIBI
and the TDI, as shown in Tables 3 and 4, (Mattila et al. 1989, Lindy et al. 2008). The
DMFT index takes into account decayed, missing and filled teeth (WHO 1997).
Table 3. Determination of Periodontal Inflammatory Burden (PIBI, 28 teeth)
3,%, ™1PRGPPD+ 2 Nadv PPD)
Nmod= number of sites with moderate periodontal lesions (4±5mm)
1DGY QXPEHURIVLWHVZLWKDGYDQFHGSHULRGRQWDOOHVLRQV•PP
PPD=periodontal pocket depth
Table 4. Determination of Total Dental Index (TDI, 32 teeth)
Oral Disease
Score
Caries
no caries lesions
0
1±3 caries lesions
1
4±7 caries lesions or no teeth in maxilla or mandible 2
Periodontitis
Periapical lesions
Pericoronitis
• 8 caries or radix or no teeth
3
4±5mm deep periodontal pocket
1
• 6mm deep periodontal pocket
2
Pus in gingival pocket
3
1 periapical lesion or vertical bone pocket or both
1
2 periapical lesions
2
• 3 periapical lesions
3
Absent
0
Present
1
ϭϬ
dŽƚĂůĞŶƚĂů/ŶĚĞdž
ϮϬ
Prevention and treatment of chronic periodontitis
Proper diagnosis is vital for accurate treatment. In Finland, the Current Care Guidelines
for periodontitis were generated by the working group set by the Finnish Medical Society
Duodecim and the Finnish Dental Society Apollonia. They represent evidence-based
guidelines for clinical practice, diagnosis, and the treatment of chronic periodontitis
(Periodontitis: Current Care Guidelines, 2016). Periodontal treatment primarily targets
professional mechanical bacterial debridement, i.e. scaling and root planing, and patients¶
self-care to eliminate biofilm and plaque retentions and to prevent the re-colonization of
bacteria. Behavioral motivations, for example, smoking cessation are an essential part of
treatment. Local or systemic antibiotics, laser treatments, and surgery may be combined
with mechanical treatment. The benefits of systemic antibiotics should be balanced against
their systemic side effects and antibiotic resistance (Jepsen and Jepsen 2016). Systematic
maintenance care is needed to achieve long-term success.
Host modulation therapy, such as low dose doxycycline (LDD) treatment has proven to be
a viable option for treating chronic inflammatory periodontal disease (Lalla and Papapanou
2011). LDD inhibit MMPs without an antimicrobial effect, but still suppresses connective
tissue breakdown (Golub et al. 1992). The purpose of host modulation is to return the
balance between pro- and anti-inflammatory mediators (Preshaw 2008). A recent review
article claims that host modulation therapy, a 20 mg subantimicrobial dose of doxycycline
(SDD) twice daily, is effective not only in periodontitis but also in diabetes, arthritis, and
among postmenopausal women with local and systemic bone loss (Golub et al. 2016).
Kidneys
Anatomy and function
Two bean-shaped kidneys, at the level of T12 to L3 vertebrae lie on each side of the spine
in the retroperitoneal space. Kidneys are about 10 cm long, 5 cm wide and 2.5 cm thick,
and are partly protected by the lowest rib (Moore 1992). They contain about one million
functional units, nephrons with glomerulus and long tubules in which reabsorption of many
solutes and water take place (Eckardt et al. 2013). See Figure 1 for details.
Ϯϭ
Kidneys remove the excretion end products of metabolism, regulate erythrocyte production
using the erythropoietin hormone, regulate blood pressure through the renin-angiotensin
system, participate in calcium homeostasis by hydroxylating D vitamin to its active form,
regulate electrolyte concentrations, and maintain acid-base and fluid balance (Moore
1992, Craig 2008, Thorman et al. 2009). Kidney function is assessed by GFR, which can
be estimated using a serum creatinine concentration (Craig 2008).
Laboratory tests may include complete blood count, serum electrolytes, blood urea
nitrogen, calcium, the parathyroid hormone, glucose, and glycosylated hemoglobin. Urine
tests may involve analyzing, for example urine electrolytes, creatinine, and total protein
concentrations. Imaging techniques including renal ultrasound are also routinely used
(Greenberg et al. 2008).
Figure 1. Kidney and nephron (http://unckidneycenter.org)
Source: with permission from the UNC Kidney Center
22
Classification, prevalence and causes of kidney diseases
Acute kidney injury is defined as changes in kidney function that ODVWIRU”PRQWKV
(Eckardt et al. 2013). According to the US National Kidney Foundation - Kidney Disease
Outcomes Quality Initiative¶V (NKF-KDOQI) clinical practice guidelines, CKD is defined as
abnormalities in kidney structure or function lasting over three months, with implications for
health (Inker et al. 2014). Classification of CKD is based on a cause, GFR and albuminuria
categories (Inker et al. 2014) (Table 5). At the Helsinki University Hospital, the predialysis
stage is defined as mid-stages 4 and 5. According to KDIGO (Kidney Disease: Improving
Global Outcomes), albuminuria is categorized as Categories 1 to 3. Category 1 represents
normal or mildly increased excretion with an albumin excretion rate (AER) of < 30mg/24
hours. In category 2, AER is 30±300 mg/24 hours (moderately increased excretion), and in
category 3, AER is > 300 mg/24hours, representing severely increased excretion (Inker et
al. 2014).
Table 5. Classification of Chronic kidney disease (CKD) stages by GFR
CKD stage
Kidney function
GFR (ml/min/1.73 m2)
1
normal
> 90
2
mildly impaired
60±89
3
moderately impaired
30±59
4
severely impaired
15±29
5
end stage kidney failure
< 15
GFR= glomerular filtration rate
The prevalence of CKD is increasing worldwide, and affects 8±16% of individuals globally
(Jha et al. 2013). The prevalence of acute kidney disease varies because of several
different definitions and is estimated to be over 1% (Lameire et al. 2013).
The main risk factors of chronic kidney failure are diabetes, hypertension, and obesity in
developed as well as many developing countries, while glomerulonephritis and unknown
reasons are more common in Asia and sub-Saharan Africa (Cigranelli and Lamacchia
2007, Jha et al. 2013). Other etiological causes of CKD are systemic autoimmune
Ϯϯ
diseases, polycystic kidney disease, obstructive uropathy, chronic pyelonephritis, and
other low-grade systemic inflammatory diseases, such as periodontitis (Fisher et al. 2008,
Eckardt et al. 2013). In Finland, diabetic nephropathy is the most common cause for
dialysis treatment, followed by glomerulonephritis, polycystic kidney disease and
nephrosclerosis (Finnish Registry for Kidney Diseases 2014).
Acute kidney injury, on the other hand, is often associated with bacterial infection, sepsis
or ischemia-reperfusion injury (Imig and Ryan 2013).
Diabetes as an inflammation-associated disease may contribute to renal inflammation and
further to the development of diabetic nephropathy. Renal inflammation can result from
metabolic and renal hemodynamic routes caused by hyperglycemia, reactive oxygen
species (ROS), and AGEs, or glomerular hypertension and endothelial dysfunction (Imig
and Ryan 2013).
End-stage renal disease
When CKD has progressed to ESRD, RRT (dialysis or kidney transplantation) is needed.
ESRD state is reached when the functional capacity of kidneys has decreased below 10%
of their normal function (Bots et al. 2007). Over two million people worldwide were treated
for ESRD in 2010, but because of disparities in access to RRT, an estimated six million
people were untreated (Robinson et al. 2016). In 2014, 4540 patients were in RRT in
Finland, of which 343 were in peritoneal dialysis treatment, 1474 in hemodialysis
treatment, and 2722 were living with kidney transplants (Finnish Registry of Kidney
Diseases 2014).
Kidney transplantation is the preferable choice of ESRD as it improves survival and quality
of life, and is cost-effective compared to dialysis (Jensen et al. 2014, Ortiz et al. 2014,
Sanchez-Escuredo et al. 2015, Robinson et al. 2016,). In 2014, 240 kidney transplants
were made in Finland (Finnish Registry for Kidney Diseases 2014). Prior to entering
kidney transplantation, the candidate patient must be screened for infections, including
oral infections, before immunosuppressive medications can be administered.
Ϯϰ
Immunodeficiency in chronic kidney disease
CKD is regarded as an immunosuppressive state due to factors such as uremic toxins,
immune cell dysfunction, mainly caused by hypercalcemia related to secondary
hyperparathyreoidism, and a lack of supportive cytokines, D-vitamin deficiency, and
dialysis treatment (Hannula 2009). Immunosuppressive therapy understandably also
causes immunodeficiency.
Mortality among kidney patients
Patients with ESRD have higher death rates compared with general population (de Jager
et al. 2009). CVD are the main causes of death among patients with CKD, followed by
infections (Stenvinkel 2002, Kato et al. 2008.) Traditional risk factors for atherosclerotic
CVD are dyslipidemia, diabetes, hypertension, and smoking, which do not, however,
explain all cases of CVDs (Stenvinkel 2002). Other risk factors include genetic
components such as family history of atherosclerotic disease, male gender, metabolic
syndrome, obesity, depression, and lack of exercise (Lusis 2000). Oxidative stress and
inflammation have been postulated to be non-traditional risk factors for CVD (Stenvinkel
2002). Aortic stiffness has also been explained by excess phosphate in the arteries due to
secondary hyperparathyreoidism in CKD, which is already seen in patients with CKD stage
3 (Hannula 2009).
According to the European Dialysis and Transplant Association Registry, the five-year
survival rate was 52% for patients who underwent dialysis treatment and 91% for patients
who had undergone a kidney transplant (Pippias et al. 2015). In Finland, age-standardized
mortality among patients receiving RRT has decreased over the years, (85 deaths per
1000 patient years), reflecting good quality of treatment (Finnish Registry for Kidney
Diseases 2014).
Ϯϱ
Oral infections and systemic diseases
³)RFDOLQIHFWLRQ´, such as oral infection, has been held responsible for the initiation and
progression of a number of systemic diseases since the late 19th and the early 20th century
(Scannapieco 1998). However, the theory did not become popular at the time, partly due
to a lack of sufficient evidence for classifying and identifying oral microorganisms.
Since dental treatment has developed in recent decades, and the world¶V population is
aging, it is logical that people retain natural teeth in their mouths for longer than before.
However, teeth and periodontal niches may serve as reservoirs for microbiota and might
predispose to systemic infections. These are seen especially in the elderly, whose visual
and motoric skills for oral self-care have deteriorated; in immunocompromised patients
suffering from chronic inflammatory diseases such as diabetes, CKD or rheumatoid
arthritis; or in patients undergoing immunosuppressive treatment.
Oral diseases such as dental caries, mucosal lesions and periodontitis, or dental
procedures such as tooth extraction, periodontal or endodontic treatment, or even tooth
brushing and flossing may help the invasion of oral micro-organisms into the systemic
circulation through dental pulp, mucosal surface or periodontal pockets. Transient oral
bacteremia predisposes to systemic infections such as endocarditis, joint infections and
brain abscesses, and upregulates inflammatory reactions, rendering the body liable to
other systemic conditions and other diseases such as diabetes or atherosclerosis
(Lockhart et al. 2008, 2009, 2012, Zhang et al 2013, Scannapieco et al. 2016).
The association between periodontitis and CVD (among other systemic chronic diseases)
is well known (Meurman et al. 2004). A recent study suggested that endodontic lesions are
also independently associated with coronary artery disease, especially with acute coronary
syndromes explained by systemic inflammation (Liljestrand et al. 2016).
Periodontitis and systemic inflammation
Although no causal relationship can be drawn between periodontitis and systemic
diseases, many studies have shown a possible association with diabetes, cardiovascular
diseases, pregnancy complications, pneumonia, chronic obstructive pulmonary disease,
rheumatoid arthritis, obesity, metabolic syndrome, cancer, and CKD (Desvarieux 2005,
Ϯϲ
Lalla and Papapanou 2011, Lockhart et al. 2012, Linden et al. 2013, Tonetti and Van Dyke
2013). An inflamed periodontal pocket epithelium of 8±20 cm2 is an open door for bacteria
and their products. The latter include LPS, peptidoglycan (PGN), cytotoxins, proteases and
haemagglutinins, as well as locally produced pro-inflammatory mediators such as IL-1ȕ,
IL-6, TNF-Į, and prostaglandin E2 (PGE2) which is produced by host cells (neutrophils,
macrophages and lymphocytes) into bloodstream (Hujoel et al. 2001, Preshaw and Taylor
2011, van Dyke and van Winkelhoff 2013). These pro-inflammatory mediators may act as
inflammatory stimuli at a distant site and cause problems for the patient (Lalla and
Papapanou 2011).
Diabetes
DM is a metabolic disorder with an abnormal blood glucose level caused by lack of insulin
related to pancreatic beta-cell dysfunction, or insulin resistance (Chapple et al. 2013). As a
metabolic disorder, insulin disturbances may lead to abnormal glucose, fat and protein
metabolisms, creating different pathologies in multiple organs (Southerland et al. 2006).
According to the World Health Organization (WHO), 442 million people worldwide were
suffering from diabetes in 2014, compared to 108 million in 1980, and the number is still
increasing (WHO 2016). Diabetes caused 1.5 million deaths in 2012 worldwide (WHO
2016).
Type-1 diabetes (DM1) (5±10% of cases) is a form that results from autoimmune
destruction of the insulin-producing beta cells in the pancreas. The subsequent lack of
insulin leads to increased blood and glucose levels. Type-2 diabetes (DM2) is a metabolic
disorder characterized by hyperglycemia in the context of insulin resistance and a relative
lack of insulin. DM1 mostly affects children, whereas DM2 mostly affects older patients
(85±90%), but may also be seen among children. Gestational form affects 1±5% of cases
(Otomo-Corgel et al 2012).
DM1 results from a complex interaction between genes and environmental factors,
although no specific environmental risk factor has been found (WHO 2016). In contrast,
well-known risk factors for DM2 are obesity and overweight, combined with genetic
background, physical inactivity, and smoking (WHO 2016).
Ϯϳ
Glycosylated hemoglobin level (HbA1c) is indicative of the metabolic control in the
preceding two to three months. According to the American Diabetes Association, the
diagnosis of diabetes in adults is made using two tests of Hb$F•PPROmol)
(Standards of Care 2016).
With elevated HbA1c, diabetes may lead to known complications such as retinopathy,
neuropathy, nephropathy, cardiovascular complications, and delayed wound healing
(Otomo-Corgel et al. 2012). Löe suggested in 1993 that periodontitis should be recognized
as the sixth complication of DM (Löe 1993). Today, the bidirectional relationship between
these two chronic diseases, diabetes and periodontitis, is well accepted, and both may be
present for years before symptoms (Taylor et al. 1998, Chapple et al. 2013).
Hyperglycemia and periodontitis
Different mechanisms have been proposed to link diabetes to periodontitis
(microangiopathy, alterations in GCF, collagen metabolism, subgingival flora, genetic
factors, and host response) (Taylor et al. 1998). Many cross-sectional and longitudinal
studies, together with meta-analyses, have shown a greater prevalence of advanced
periodontitis among diabetic versus non-diabetic patients (Oliver & Tervonen 1994, Collin
et al. 1998, Khader et al. 2006). Emrich and co-workers found that diabetes tripled the risk
of periodontitis among 1 342 PIMA Indians (Emrich et al. 1991). Taylor and co-workers
confirmed these cross-sectional statements with a longitudinal study of PIMA Indians,
which showed non-insulin dependent diabetes mellitus (NIDDM) to be a risk factor for
more severe alveolar bone loss progression in two-year follow-up (Taylor et al. 1998).
Hyperglycemia leads to an abnormal hyper-inflammatory response to
periodontopathogens in the periodontium (Southerland et al. 2006, Nishimura et al. 2007,
Otomo-Corgel et al. 2012). Cell surface receptors (RAGEs) for advanced glycation end
products (AGEs) in gingiva are expressed, and RAGE-AGE interaction leads to immune
dysfunction, exaggerated inflammatory response and oxidative stress, thus further
accelerating AGE and pro-inflammatory cytokine formation, the destruction of tooth
supported structures, and impaired wound healing (Lalla and Papapanou 2011, Chapple et
al. 2013, Taylor et al. 2013).
Ϯϴ
So far, hyperglycemia has shown no relationship with periodontal microbiota (Taylor
2013). However, diabetic patients with periodontitis seem to have elevated numbers of
pro-inflammatory mediators such as IL-1ȕ, IL-6, and increased RANKL/OPG ratios
compared with systemically healthy controls with periodontitis. This partly explains bone
resorption in periodontitis (Salvi et al. 1997). However, it is noteworthy that diabetic
patients with well-controlled blood sugar levels are not at an increased risk of periodontitis
(Kowall et al. 2015).
Impact of periodontitis on diabetes
Untreated periodontitis may increase systemic pro-inflammatory mediators, causing insulin
resistance. The European Federation of Periodontology (EFP) and the American Academy
of Periodontology (AAP) have confirmed that in patients with severe periodontitis, the
disease adversely affect blood glucose levels (HbA1c) (Chapple et al. 2013).
Taylor and co-workers were the first to show, in a five-year follow-up study in 1996, that
severe periodontitis at baseline among the NIDDM Gila River Indian Community (tribe of
PIMA Indians, Arizona) resulted in poorer glycemic control (HbA1c > 9%) than that among
those without severe periodontitis (Taylor et al. 1996). Severe periodontitis was assessed
by attachment loss of 6 mm or more on at least one index tooth, and radiographic bone
loss of 50% in at least one tooth.
A study of 9 296 nondiabetic participants of NHANES I (National Health and Nutrition
Examination Survey) and its Epidemiologic Follow-up Study (NHEFS) showed that severe
tooth loss at baseline resulted in the incidence of diabetes with an odds ratio (OR) of 1.7
(p< 0.05), (follow-up period of 17 ± 4 years) (Demmer et al. 2008).
A recent systematic Cochrane collaboration review of 35 studies on diabetic patients found
that the mean percentage reduction in HbA1c by conventional periodontal therapy was
0.29% at three to four months (Simpson et al. 2015).
Ϯϵ
Atherosclerotic cardiovascular disease
Atherosclerotic cardiovascular diseases (ACVD) comprise coronary heart disease (angina
pectoris and myocardial infarction), ischemic cerebrovascular disease (TIA and stroke),
and peripheral arterial disease (Tonetti et al. 2013).
As classic risk factors for ACVD, such as hypertension, diabetes, smoking and
hypercholesterolemia explain only 30±60% of the disease, chronic infection and
inflammation has been proposed as another risk factor (Scannapieco 1998, Li et al. 2000).
Since 1989, the association between dental infections and acute myocardial infarction has
been extensively studied. At our hospital, Mattila and co-workers found that patients with
acute myocardial infarction had worse oral health than age- and sex-matched controls
(Mattila et al. 1989). A recent study by Beukers and co-workers showed an independent
association between periodontitis and ACVD in over 60 000 Dutch patients (Beukers et al.
2016).
Vascular cell wall injury (mechanical, immunological or biochemical) leads to adhesion
molecule expression by endothelial cells. Monocytes adhere and migrate through the cell
wall, phagocytose low-density lipoproteins and release pro-inflammatory cytokines,
inducing inflammatory cascades (Cullinan and Seymor 2013). LPS from Gram-negative
bacteria is toxic to endothelial cells, and promotes adhesion molecule expression. LPS
may also help macrophages transform into foam cells, promoting inflammation and further
atherosclerosis (Cullinan and Seymor 2013). Bacteria and their products from oral cavities
may thus activate host inflammatory mechanisms in the periphery, favoring the formation,
maturation and exacerbation of atheroma (Tonetti et al. 2013).
Chronic kidney disease
Inflammation and atherosclerosis, both related to periodontitis, are shown to predispose
patients to CKD (Scannapieco and Cantos 2016). Rahmati and co-workers were the first to
show an association between serum IgG to periodontal bacteria (P.gingivalis) and
elevated level of C-reactive protein in hemodialysis patients (Rahmati et al. 2002). A crosssectional study by Kshirsagar and co-workers showed that a reduction in GFR was
connected to periodontal disease (Kshirsagar et al. 2005). Chambrone and co-workers in
ϯϬ
turn concluded in their systematic review that fairly strong evidence exists to support an
association between periodontitis and CKD (Chambrone et al. 2013).
Association between other systemic diseases and periodontitis
Infection can be a risk factor for pregnancy complications such as preterm birth (< 37
weeks of gestation) and low birth-weight (< 2500 g) infants. Oral inflammatory burden such
as periodontitis may be one route of infection associated with preterm birth (Heimonen et
al. 2009). Increased bacterial spreading or pro-inflammatory cytokines could affect the
placenta and further drive preterm birth forward. However, many studies show opposite
results, and more research is needed (Cullinan and Seymor 2013, Walia and Saini 2015).
A systematic review and meta-analysis by Kim and co-workers concluded that mothers at
a high risk of preterm birth could benefit from periodontal treatment (Kim et al. 2012).
In hospitalized and elderly patients, aspirated microbiota may cause bacterial aspiration
pneumonia (Garcia et al. 2001, Scannapieco and Cantos 2016). Normally, healthy
subjects may aspirate 50% of oropharyngeal contents, which are eliminated by the host
immune system without harm (Garcia et al. 2001). Aspiration pneumonia is often
correlated with dysphagia, but other reasons such as a high number of decayed teeth,
Staphylococcus aureus and Streptococcus sobrinus bacteria in the saliva, the presence of
P. gingivalis in plaque, dependence in feeding and oral care, chronic obstructive
pulmonary disease, and diabetes have all shown a correlation with aspiration pneumonia
(Terpenning et al. 2001).
Chronic obstructive SXOPRQDU\GLVHDVH&23'DIIHFWVDERXWRI• 40-years
worldwide, and is a leading cause of morbidity and mortality (Halbert et al. 2006,
Scannapieco and Cantos 2016). Inflammation, mostly due to toxic chemicals from
smoking, is the most significant factor in the development of COPD. Chronic infection such
as periodontitis has shown to associate with COPD by triggering pro-inflammatory events
and further influencing the frequency of disease exacerbation (Scannapieco and Cantos
2016).
Inflammation plays a crucial role in autoimmune diseases such as rheumatoid arthritis. In
the light of current knowledge, genetic and environmental factors trigger autoantibodies to
autoantigens such as citrullinated proteins (Scannapieco and Cantos 2016). One
explanation for the association between periodontitis and rheumatoid arthritis could be the
ϯϭ
ability of P. gingivalis to produce peptidylarginide that can citrullinate proteins (Wegner et
al. 2010).
Obesity is known to be a hyperinflammatory state with insulin resistance. A recent study by
Suvan and co-workers showed an independent association between periodontitis and
obesity (Suvan et al. 2015). Obesity may indeed alter the inflammatory state, thus also
predisposing the individual to periodontitis (Suvan et al. 2015).
Oral manifestation of chronic kidney disease
CKD may be accompanied by other systemic diseases with oral mucosal manifestations.
Aphthous ulcers of oral mucosa may be associated with Behcet¶s disease, which is linked
to rapidly progressive glomerulonephritis; or with systemic lupus erythematosus (SLE),
which is characterized by lupus nephritis (Summers et al. 2007). ³Strawberry gingivitis´
may be the first manifestation of systemic vasculitis, Wegener¶s granulomatosis
(Ruokonen et al. 2009). Macroglossia may be due to deposits of amyloids (Summers et al.
2007).
CKD patients may also present many oral changes due to medication or the disease itself
affecting teeth, oral mucosa, periodontium, and the salivary glands (Summers et al. 2007,
Akar et al. 2011). Reported changes in teeth include pulp narrowing, enamel hypoplasia,
dental caries, and periodontitis (Gaili et al. 1991, Vesterinen et al. 2011, Kshirsagar et al.
2005, Summers et al. 2007). Hyposalivation due to diabetes or medication is harmful, as it
increases microbial colonization, thus enhancing oral diseases.
The different stages of CKD, namely predialysis-, dialysis and the post-transplantation
stage may manifest in different ways in oral health. Different CKD diagnoses, such as
diabetic nephropathy, have also shown characteristic oral health manifestations.
Predialysis stage
Uremic patients have shown a worse DMFT index and more periodontal loss of
attachment and periapical lesions than sex- and age-matched controls (Thorman et al.
2009, Vesterinen et al. 2011). At the predialysis stage, protein intake is restricted, while
ϯϮ
sufficient energy is secured by intake of carbohydrates (Thorman et al. 2009). This may
detrimentally affect dental and oral health.
Diabetic patients should be informed of their greater risk of periodontitis, the adverse
effects of poor glycemic control on periodontitis, and the increased risk of systemic
problems such as cardiovascular complications or the progression of CKD (Chapple et al.
2013).
Dialysis
Oral health often deteriorates in patients receiving hemodialysis therapy (Schmalz et al.
2016). As hemodialysis treatment is time consuming, usually requiring four to six hours
three times per week, treatment may be stressful for the patient. This may lead to having
no strength to maintain proper oral health. Moreover, dialysis is regarded as an
immunosuppressive state which further affects oral health.
Symptoms such as oral malodor (ammonia-like smell, typical for uremic patients), dry
mouth (xerostomia), and taste changes (metallic taste) have been reported in dialysis
patients (Kaushik et al. 2013). Medication such as antihypertensive drugs and diuretics
may predispose to poor oral health through hyposalivation. This may also affect denture
retention and cause difficulties in speaking and eating. The reduction of fluid intake may
cause general weakening and a reduced salivary flow rate. These changes may lead to
problems in mucosa and predispose to oral fungal and viral infections, as well as coated
tongue, sialdenitis, oral ulceration, enamel hypoplasia, increased dental calculus
formation, and caries development (Summers et al. 2007, Akar et al. 2011, Kaushik et al.
2013, Schmalz et al. 2016). In contrast, some studies have shown a prevalence of
reduced caries in ESRD, perhaps due to the protective, neutralizing role of urea in saliva
and plaque (Al Nowaiser et al. 2003).
In oral health care, attention should be paid to prolonged bleeding time after tooth
extraction or periodontal treatment due to heparin administration in hemodialysis, drugs
used for treatment (GFR is decreased), and the need for antibiotic prophylaxis (vascular
access sites protection) (Craig 2008).
ϯϯ
Post-transplantation stage
Transplant patients may have oral manifestations such as gingival hyperplasia due to
immunosuppressants (cyclosporine) and antihypertensive drugs (calcium channel
blockers). Cyclosporine-induced gingival hyperplasia ranges from 22% to 58%, and is
more prevalent among young patients and patients with increased dental plaque
accumulation or an increased drug dosage (Craig et al. 2008, Akar et al. 2011).
Transplant patients are also prone to virus infections, ulcers and oral malignancies
(Summers et al. 2007). Fungal infections are found in 20±30% of transplant patients, and
may manifest as angular cheilitis, pseudomembranous or erythematous ulcerations
(Summers et al. 2007). In their two-year follow-up investigation, Bots and co-workers
found that xerostomia and thirst decreased, and unstimulated salivary flow rate increased
after kidney transplantation compared to dialysis state (Bots et al. 2007).
Oral health care professionals should pay attention to the fact that a patient with a
transplanted organ needs immunosuppressive drugs for the rest of their life. These drugs
may predispose patients to oral inflammations and fungal and viral infections as well as
malignancies or gingival overgrowth induced by cyclosporine and calcium channel
blockers. Therefore, oral examination of transplant patients calls for special attention,
preferably in a specialist clinic (Kaswan et al. 2015, Rezvani et al. 2014). Antibiotic
prophylaxis is mandatory when treating transplant patients.
ϯϰ
AIMS OF THE STUDY
This study examined the oral health of CKD patients in detail, with an emphasis on
periodontal disease; first at baseline (predialysis stage, Study I and Study II), and
secondly at follow-up (post-transplantation stage, Study III and Study IV). Studies I and II
are based on the patients previously described by our group (Vesterinen et al. 2011,
2012). The main hypotheses were that oral health, periodontitis in particular, is more
severe among diabetic nephropathy patients than other CKD patients, and worse at the
predialysis stage than at the post-transplantation stage.
The main objectives of the current study were:
1. To examine the oral health, with an emphasis on periodontal disease, of CKD
patients at the predialysis stage, and to compare the periodontal health of diabetic
nephropathy patients and CKD patients with other etiology (Study I).
2. To investigate the association between periodontal inflammatory burden and
salivary MMP-8 concentration among CKD patients at the predialysis stage (Study
II).
3. To determine whether oral inflammatory burden associates with mortality and to
identify causes of death among CKD patients (Study III).
4. To compare, on the individual level, patients¶ oral health at the baseline predialysis
stage with that at the follow-up post-transplantation stage (Study IV).
ϯϱ
PARTICIPANTS AND METHODS
This study is an ongoing clinical investigation of CKD patients examined in 2000±2005
(baseline) (Vesterinen et al. 2011) and 2013±2015 (follow-up). Originally, 178 CKD
patients were referred from the Department of Nephrology to the Department of Oral and
Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland, for examination and
treatment of oral foci of infection prior to ESRD treatment.
For inclusion, all patients had to have an estimated glomerular filtration rate of <
20mL/min/1.73 m2, confirmed by a nephrologist. Thus, the patient had to be at the
predialysis stage, which corresponds to mid CKD Stage 4 (eGFR < 30 mL/min/1.73 m 2)
and Stage 5 (eGFR < 15mL/min/1.73 m2), in terms of the criteria used in our Department
of Nephrology. Patients below this eGFR are referred for renal replacement therapy.
Children (< 18-year-olds), pregnant or breastfeeding women, prisoners, and physically or
mentally disabled patients were excluded.
Due to the definition of the predialysis stage, 30 patients were excluded from the original
studies. Of the remaining 148 patients, two had missing periodontal status records and two
had missing saliva samples at the time of the first study, leaving 144 CKD patients for
further investigation.
The study was approved by the Ethical Committee of the Hospital District of Helsinki and
Uusimaa (Dnro 305/13/03/02/2012) and registered in the hospital database for clinical
trials. Written informed consent was obtained from all the patients, and the ethical
principles of the Declaration of Helsinki were followed throughout the study.
Participants
PART 1 (Studies I and II) Baseline studies I and II were cross-sectional studies.
Study I was a clinical study of oral health, with an emphasis on periodontal disease.
Clinical oral and x-ray examinations were conducted in 2000±2005. Clinical and medical
data were obtained from the hospital records of 144 patients (47 women), aged 23±83. Of
these, 52 had diabetic nephropathy and of this 52, 22 suffered from DM2.
ϯϲ
Study II was an MMP-8 salivary study of 118 predialysis patients and 11 systemically and
periodontally healthy controls. Twenty-six salivary samples of the 144 patients could not
be examined at the time of MMP-8 analysis due to missing samples.
PART 2 (Studies III and IV) Studies III and IV were follow-up studies with 157 months of
observation.
Study III is a follow-up prospective cohort study of 144 CKD patients. Of these, 65 had
died and 79 survived during the follow-up period of maximal 157 months. The study
focused on their risk factors of mortality. The cause of death could be recorded for 62
participants, of which 32 had had diabetic nephropathy. Three patients had died outside
our hospital district and their cause of death could not be verified. Only ten patients of the
65 (15%) who has died had undergone a kidney transplant.
Study IV. Of the 144 CKD patients, 79 had survived and were invited to re-examination
between 2013 and 2015. Of these, 26 patients dropped out, leaving 53 participants willing
to participate in the follow-up examination. The study was a longitudinal clinical study that
focused on comparing the oral health variables of the predialysis and follow-up stages. Of
the 53 patients, 51 had undergone a kidney transplant and 46 transplants were functioning
at the time of the examination. Figure 2 shows a flow diagram of the study.
ϯϳ
N= 144
(N= 52 diabetic nephropathy)
Predialysis stage (Study I, II)
(N= 33 diabetic nephropathy)
Deceased (Study III)
N= 79
Re-called for follow-up study
N= 65
N= 53
N= 26
Drop outs
(N= 11 diabetic nephropathy)
Follow-up stage (Study IV)
Figure 2. Flow diagram of the study
ϯϴ
Methods
Medical records with blood sample analyses from the hospital records were available for
the study. Mortality records for Study III were obtained from the Causes of Death National
Database of Statistics Finland.
Oral and radiological examination
The clinical oral examinations at baseline in 2000±2005 and at follow-up stage in 2013±
2015 were conducted by the same periodontist (HR). The medical records were carefully
re-examined for the retrospective and follow-up studies.
Patients underwent a full clinical oral examination, including a mucosal periodontal and
cariological examination. The number of teeth and implants were recorded, as were fixed
or removable prosthesis and their condition. Mucosal lesions such as gingival overgrowth,
coated tongue, ulcers, lichen planus and leukoplakia were also recorded, as well as
attrition, erosion, diastemas, and mobility of teeth.
Periodontal recordings were made of all teeth (max 32) and PPDs were measured at six
sites per tooth with a WHO probe. PPDs were further categorized as no periodontal
pocket, one or more sites with probing depths of •PP±VLWHVZLWK• 6mm-deep
periodontal pockets, and two or more further VLWHVZLWK•PP-deep periodontal pockets.
Furcation lesions were recorded. Recessions and clinical attachment levels, as well as
bleeding on probing, were recorded at the follow-up stage.
The CDC/AAP¶V definition of periodontitis was used, according to which, severe
periodontitis is when two or more teeth have a CAL of •PPDWinterproximal sites, and
one or more teeth with a PPD of •PPDWLQWHUSUR[LPDOVLWHV0RGHUDWHSHULRGRQWLWLVLV
defined by two or more teeth with a CAL of •PPDWLQWHUSUR[LPDOVLWHVRUWZRRUPRUH
teeth with a PPD of •PPDWLQWHUSUR[LPDOVLWHV&DVHV that do not fulfil the criteria
mentioned above are classified as mild or no periodontitis (Page and Eke 2007).
The following indices were also calculated from dental records and categorized into two
groups by medians:
ϯϵ
The DMFT (decayed, missing, filled teeth) index was calculated from 32 teeth in
accordance with WHO criteria, except for the ³PLVVLQJYDOXH´which also took wisdom teeth
into account.
TDI was calculated from 32 teeth, taking into account caries, periodontitis, periapical- and
pericoronitis lesions. This index ranges from 0 to 10 (Mattila et al. 1989).
PIBI was calculated from 28 teeth. This index adds moderate periodontal pockets (4±
PPWRWKHZHLJKWHGQXPEHU[RIGHHS•PPSHULRGRQWal pockets (Lindy et al.
2008).
Panoramic jaw X-rays were taken of all patients at the predialysis and follow-up stages.
Periapical and bite-wing x-rays were taken when needed. A specialist in oral radiology at
our hospital analyzed the X-rays. Baseline X-ray analyses of 17 of the 144 patients were
missing, leaving 127 available analyses for Study I and III, and 108 available analyses of
the 118 patients for Study II. For Study IV, five analyses were missing, leaving a total of
101 analyses available. The radiologist measured alveolar bone loss in each tooth in the
cervical, middle, and apical thirds of the root lengths. X-ray analyses were further divided
into sextants and finally, maximum alveolar bone loss (either horizontal or vertical) was
recorded. Signs of periapical or pericoronitis lesions, cysts and tumors in the X-rays were
also recorded. In some cases, when needed, dental radiographs were taken in addition to
the panoramic jaw X-rays.
Salivary analyses
Unstimulated and stimulated saliva samples were collected for five minutes in graded test
tubes and the results were given in ml/min by recording salivary flow rates. Patients were
asked not to eat or smoke for at least 60 minutes before the examination. Unstimulated
saliva was collected first, after which paraffin wax was used to stimulate salivary flow.
Samples were centrifuged for four minutes at 8000 x g at 4 o C, and the supernatants were
frozen at -75 o C for later analyses.
From the stimulated saliva, MMP-8 was detected by time-resolved immunofluorometric
assay (IFMA) (Rathnayake et al. 2013a,b, Mäntylä et al. 2006, Leppilahti et al. 2014a,b,
Gursoy et al. 2010). Catching and tracing monoclonal antibodies (8708 and 8706, Medix
Biochemica, Kauniainen, Finland) specific to MMP-8, were used. The tracing antibody was
ϰϬ
labeled by europium-chelate (Hemmilä et al. 1984). Samples were diluted in an assay
buffer (20mM Tris-HCL (pH7.5), 0.5M NaCl, 5mM CaCl2, 50mM ZnCl2, 0.5% bovine
serum albumin, 0.05% sodium azide, and 20 mg/L dietylenetriaminepenta-acetic acid) and
incubated for one hour, followed by incubation with a tracer antibody for another hour.
Fluorescence was measured five minutes after enhancement solution was added, using
IFMA.
Questionnaire study
Self-reported oral health questionnaires were already collected at predialysis and later at
follow-up. The questionnaires elicited education, oral health self-care, smoking habits, oral
symptoms of xerostomia, consideration of the role of oral health in kidney disease, and last
dental appointment.
Statistical analyses
A software program (SPSS statistical version 21 and 22) was used for statistical analyses.
Cross-tabulation and the Pearson chi-square test were used to compare the categorical
variables in Studies I, II, III, IV. Mean HbA1c values were compared between groups by
independent samples t-test, and multivariable analyses were conducted using binary
logistic regression with HbA1c values higher or lower than median as the binary outcome
variable.
Study I: As in the previous study by Vesterinen et al. (2011) the oral health of diabetic
nephropathy patients and other CKD patients were compared. Oral health at KLJKHU•
%) and lower (< 6.5 %) HbA1c values was also compared.
Study II: The concentration of MMP-8 as a continuous variable was compared according
to the CKD diagnosis and HbA1c values, as well as according to sex-, age-, smoking
status, number of teeth, TDI and PIBI scores, alveolar bone loss, and PPD categories by
independent two- samples t-test and Mann-Whitney U test.
Study III: The Kaplan-Meier survival curve was calculated and the survival distributions of
the patient groups were compared with the log-rank test. Cox proportional hazards
regression models were used to analyze the association of clinical oral parameters and
ϰϭ
other explanatory variables with patient survival. In survival analysis, death was the event
and all surviving patients were right-censored at the end of follow-up on August 31st 2015.
Study IV: The oral health data regarding the within-subject changes in the baseline
(predialysis) and follow-up (post-transplantation) recordings were compared. P-values
were calculated using the McNemar test for categorical variables, and the Wilcoxon
signed-rank test for continuous variables. In the comparison between diabetic nephropathy
and other CKD groups, continuous variables were compared using the Mann-Whitney U
test and categorical variables using the Pearson chi-square or Fisher test.
Ethical aspect
This study was approved by the ethical committee of the Helsinki and Uusimaa Hospital
District. It was conducted in accordance with the principles of the Declaration of Helsinki
(Dnro 305/13/02/2012). Written informed consent was obtained from all patients.
ϰϮ
RESULTS
Baseline results at the predialysis stage are presented in Studies I and II. Basic
demographic and clinical characteristics are given in Tables 6 and 7.
Oral health with an emphasis on periodontal disease (Study I)
Diabetic nephropathy patients (N= 52) were compared with other CKD patients (N= 92).
Other CKD diagnoses included polycystic kidney disease (N= 31), nephrosclerosis (N= 1
6), immunoglobulin A (IgA)-nephropathy (N= 13), focal segmental glomerulosclerosis (N=
9), and membranous glomerulonephritis (N= 4).
Mean HbA1c was 5.7% (±0.8) in the other CKD group, and 8.2% (± 1.6) in the diabetic
nephropathy group (p<0.001).
The prevalence of periodontal pockets was high (88%) among CKD patients in general.
One or more periodontal pockets were observed in 90% of the diabetic nephropathy
patients and in 87% of those with other CKD diagnoses.
Patients with diabetic nephropathy diagnosis had worse periodontal health than those with
other CKD diagnoses. Diabetic nephropathy patients more often had two or more sites
with a PPD of •PP, and their TDI was higher than that of the other CKD patients (p<
0.05). Moderate periodontitis diagnosis, assessed by two or more interproximal sites ZLWK•
5mm-deep periodontal pockets (not on the same tooth) was more common among diabetic
nephropathy patients (61.5%) than among those with other CKD diagnoses (47.8%), and
higher PIBI scores were more common among diabetic nephropathy patients (55.8%) than
other CKD patients (45.7%), although these results were not statistically significant.
Diabetes was diagnosed in six patients of the other CKD group, although this was not the
reason for kidney disease. Thus we also compared patients with different HbA1c values.
Higher HbA1c •%•PPROPRODVVRFLDWHGPRUHRIWHQwith deep periodontal
pockets (• VLWHVZLWK• PPGHHSSRFNHWVPRGHUDWHSHULRGRQWLWLVGLDJQRVLV•
interproximal sites ZLWK• 5mm deep pockets ± not on same tooth), and higher PIBI (p<
0.05). Patients with a higher HbA1c had a higher TDI score (51.1%) than patients with
lower HbA1c (40.7%), but this result was not statistically significant. In the multivariable
ϰϯ
analysis, no oral health parameters, PIBI, TDI, deep periodontal pockets, or background
variables of sex, age or smoking habits significantly associated with the HbA1c levels.
There were no statistically significant differences in the number of teeth, alveolar bone loss
or background variables of age, sex or smoking when diabetic nephropathy patients were
compared with other CKD patients. However, current smokers had a statistically
significantly higher TDI score than non-smokers.
Association of salivary MMP-8 with oral inflammatory burden, with an emphasis on
periodontal disease (Study II)
Salivary MMP-8 could be analyzed in 118 of the 144 patients. Twenty-six salivary samples
were missing and could not be analyzed at the time of detection. Salivary samples from 11
systemically and periodontally healthy individuals were used as controls.
Higher salivary MMP-8 concentration was associated with poorer oral health. Patients with
deep periodontal pockets (two or more sites with a PPD of • 6mm), higher median PIBI
and TDI associated statistically significantly with higher MMP-8 concentrations (p< 0.05).
Diabetic nephropathy patients had higher concentrations of salivary MMP-8 (148.66 ±
‫ڦ‬JPOthan the other CKD patients (116.47 ± ‫ڦ‬JPORUFRQWUROV± 93
‫ڦ‬g/ml). The results were not statistically significant, however. Smoking, sex, age, number
of or different group of medication (antimicrobial or anti-inflammatory drugs, ACE blockers,
vitamin D or statins) had no statistically significant effect on salivary MMP-8 concentration.
ϰϰ
The follow-up results are presented in Studies III and IV. Basic demographic and clinical
characteristics are given in Tables 6 and 7.
Association between oral inflammatory burden and different CKD diagnosis with
mortality (Study III)
Maximal follow-up time was 157 months. All 144 patients examined in 2000±2005 were
called for re-examination in 2013±2015. Of these, 65 had died and 79 survived, of whom
53 attended the re-examination. The cause of death of 62 patients was verified.
The most frequent cause of death among the CKD patients was a major cardiovascular
event (MACE) (N = 31), followed by infection (N = 13) and malignant disease (N = 10).
Eight patients died for other reasons: one due to a pulmonary embolism, one due to
calciphylaxia, three due to complications from diabetes, and three due to other chronic
long-term illnesses. MACE included myocardial infarction, endocarditis, atherosclerotic
heart disease, valvular heart disease, cardiomyopathy, cardiac arrest, pulmonary edema,
congestive cardiac failure, and cerebrovascular stroke. Infections included pneumonia,
sepsis, peritonitis, and herpes encephalitis. Malignant diseases comprised pancreatic
carcinoma, lymphoma, melanoma, prostate-, urethral-, ovarian-, and colon cancer, and
one primary cancer of unknown etiology.
When comparing oral health at baseline (predialysis stage), the deceased had less teeth
than the patients who survived. They also had higher TDI scores, diabetes more often and
were older. However, these observations were crude unadjusted results.
In univariate analysis, moderate periodontitis (HR 1.70, 95% CI 1.019-2.834), number of
teeth (HR 0.94, 95% CI 0.913-0.965), older age (HR 1.05, 95% CI 1.024-1.071 per oneyear increment), number of medications (HR 1.13, 95% CI 1.042-1.227), and diabetic
nephropathy diagnosis (HR 2.8, 95% CI 1.684-4.953) were associated with mortality.
However, in the multivariable Cox regression model, older age (HR 1.03, 95% CI 1.0071.058), number of teeth (HR 0.95, 95% CI 0.916-0.981) and diabetic nephropathy
diagnosis (HR 2.9, 95% CI 1.711-4.837) were significant independent risk factors for death
(p< 0.05). Therefore, having more teeth seemed to lower the risk of death (HR< 1) (Figure
3). The 10-year survival rate of diabetic nephropathy patients was 28%, and of the other
CKD patients 62% (p< 0.001). The overall 10-year survival rate was 50%.
ϰϱ
Figure 3.
Survival analysis calculated using Kaplan-Meier survival curve for patients with 28–32 teeth (0–4
missing), 23–27 teeth (5–9 missing), and 0–22 teeth (10–32 missing). The log-rank test found a
statistically significant difference between the 10-year survival rates of patients with 0–22 teeth
(27.9%), 23–27 teeth (52.2%), and 28–32 teeth (77.3%) (p<0.001).
Longitudinal study from predialysis (baseline) to post-transplantation (follow-up)
(Study IV)
Tables 6 and 7 show the basic demographic and clinical characteristics at follow-up.
Comparison of within-subject changes at the predialysis and post-transplantation stages
shows that oral health was better overall at follow-up, when most patients (51 of 53,
96.2%) had undergone a kidney transplant. Of these transplants, 46 (90.2%) were
46
functioning, whereas five patients had returned to dialysis. At baseline, patients more often
had calculus, deep periodontal pockets, higher TDI and PIBI scores, more teeth, and
higher salivary flow rates than they did at follow-up. Overall, oral health was poorer at the
predialysis stage than at follow-up.
The oral health of the CKD diagnoses groups was also compared at follow-up, as it was in
the predialysis stage analyses. At follow-up, diabetic nephropathy patients more often had
plaque, more frequent Candida infections, used more drugs daily, and had lower
stimulated salivary flow rates than the patients with other CKD diagnose.
Table 6. Demographic characteristics of CKD patients at baseline (predialysis) and follow-up
(post-transplantation), in Study I and IV.
Predialysis stage (N= 144)
Post-transplantation stage (N= 53)
Diabetic nephropathy
Other CKD
(N= 52, 36.1%)
(N= 92, 63.9%)
38 (73.1%)
14 (26.9%)
59 (64.1%)
33 (35.9%)
0.271
Age (median)
30 (57.7%)
” 54 yrs
22 (42.3%)
> 54 yrs
43 (46.7%)
49 (53.3%)
0.207
Sex
Men
Women
p*
” 61
> 61
Diabetic nephropathy
Other CKD
(N= 11, 20.8%)
(N= 42, 79.2%)
p*
8 (72.7%)
3 (27.3%)
26 (61.9%)
16 (38.1%)
0.505
6 (54.5%)
5 (45.5%)
21 (50%)
21 (50%)
0.788
Diabetes
No
Yes
0 (0%)
52 (100%)
86 (93.5%)
6 (6.5%)
0.000
0 (0%)
11 (100%)
39 (92.7%)
3 (7.3%)
0.000
Smoking**
No
Yes
23 (67.6%)
11 (32.4%)
48 (68.6%)
22 (31.4%)
0.924
5 (83.3%)
1 (16.7%)
26 (83.9%)
5 (16.1%)
0.974
Number of
daily drugs***
14 (26.9%)
2±8
38 (73.1%)
9±22
66 (71.7%)
26 (28.3%)
0.000
1 (1.9%)
10 (90.9%)
27 (64.3%)
15 (35.9%)
0.001
3±9
10±19
* p-values obtained from Pearson chi-square test. Bold values represent significant (p< 0.05) values.
**Smoking refers to current smokers, former smokers were excluded
*** Number of daily drugs categorized by median values
ϰϳ
4.5 (2±14.8)
0±111
3 (2±4)
0-9
24 (18±28)
4±32
32 (61.5%)
20 (38.5%)
20 (38.5%)
32 (61.5%)
8 (2±22.5)
0±83
4 (3±4)
2-7
25 (19.3±28)
9±32
0.37 (0.17±0.5)
0±1.00
1.2 (0.7±1.8)
0.06±3.60
0-1 ZLWK•PP
•ZLWK•PP
Moderate periodontitis‚
No
Yes
DMFT**
min-max
Non-stimulated
salivary flow-rate**
min-max (ml/min)
Stimulated
salivary flow-rate**
min-max (ml/min)
1.55 (1.0±2.0)
0.14±4.60
0.4 (0.19±0.6)
0±2.60
75 (81.5%)
17 (18.5%)
12 (13.0%)
80 (87.0%)
0.030
0.418
0.312
0.032
0.162
0.113
0.008
0.540
0.324
0.144
p*
0.52 (0.26±0.62)
0±2.81
0.26 (0.20±0.36)
0±0.76
25 (19±31)
15±32
3 (1±-3)
0±5
2 (0±7)
0±30
5 (71.4%)
2 (28.6%)
10 (90.9%)
1 (9.1%)
4 (36.4%)
7 (63.6%)
3 (27.3%)
8 (72.7%)
20 (16±25)
0-28
Diabetic nephropathy
(N= 11, 20.8%)
1.2 (0.7±1.85)
0.02±3.20
0.33 (0.18±0.61)
0±1.10
23 (16.75±27)
8±33
1 (0±2)
0±5
0 (0±1)
0±4
33 (84.6%)
6 (15.4%)
40 (95.2%)
2 (4.8%)
24 (57.1%)
18 (42.9%)
30 (75%)
10 (25%)
25 (19±28)
3-30
Other CKD
(N= 42, 79.2%)
Post-transplantation stage (N= 53)
*p-value (unadjusted) obtained from Pearson chi-square for categorical and from Mann-Whitney for continuous variable
** Median distribution, (IQR=interquartile rage)
ΎΎΎFungal analysis of 26 patients missing at baseline and of 2 patients at follow-up
‚At follow-up: patients with gingival hyperplasia (N=6) and 1 patient with severe periodontitis (CDC/AAP) in diabetic nephropathy group excluded
TDI**
min-max
PIBI**
min-max
48 (52.2%)
44 (47.8%)
5 (9.6%)
47 (90.4%)
PPD (sites)
ZLWK•PP
•ZLWK•PP
50 (70.4%)
21 (29.6%)
29 (61.7%)
18 (38.3%)
Fungal infection***
No
Yes
26 (20±28)
0-32
24 (14±27)
2-31
Other CKD
(N= 92, 63.9%)
Number of teeth**
min-max
Diabetic nephropathy
(N= 52, 36.1%)
Predialysis stage (N= 144)
Table 7. Clinical characteristics of CKD patients at predialysis and post-transplantation stages in Study I and IV
ϰϴ
0.004
0.417
0.350
0.065
0.075
0.397
0.580
0.219
0.003
0.101
p*
DISCUSSION
Rationale for the study
CKDs are an increasing public health concern globally, along with diabetes, hypertension,
and obesity, which are their main risk factors. According to the literature, CVD is the most
common cause of death among kidney disease patients, followed by infection and cancer
(Stenvinkel 2002, Kato et al. 2008). Since oral infections such as periodontitis are
associated with systemic diseases such as diabetes and cardiovascular diseases, oral
FDYLW\VKRXOGEHUHJDUGHGDVDQ³LQIODPPDWLRQsource´of these chronic systemic
inflammatory diseases. Only a few studies have examined and followed up periodontal
health among CKD patients both at predialysis and further at post-transplantation stage,
therefore this study is unique. According to our knowledge, it is also the first study to
investigate the association between oral health, with an emphasis on missing teeth, and
mortality among CKD patients.
Inflammation is indeed a key factor in many chronic diseases, diabetes and periodontitis
included. There is a well-known two-way relationship between diabetes and periodontitis,
both of which may stay asymptomatic for years (Taylor et al. 1998, Chapple et al. 2013).
Periodontitis is also believed to be a non-traditional risk factor for CKD (Fisher et al. 2008).
In their cross-sectional study, Kshirsagar and co-workers found an association between
reduced GFR and periodontal disease (Kshirsagar et al 2005). This association could be
explained by direct damage by periodotopathogens to nephron units, its vasculature or by
a chronic host inflammatory response to periodontopathogens, leading kidney damage
(Kshirsagar et al. 2005).
Methodological considerations
As in the original study by Vesterinen and co-workers (2011) we decided to compare two
groups of CKD patients: diabetic nephropathy and other CKD, when exploring differences
in oral health with an emphasis on periodontitis at both the predialysis and follow-up
stages. Unfortunately, age- and sex-matched controls were lacking.
ϰϵ
Since diabetes was also diagnosed in 6 out of 92 other CKD patients, we decided to
compare patients with different HbA1c values in Studies I and II. As , the two-way
relationship between diabetes and periodontitis is well known and generally accepted, we
assumed that diabetic nephropathy patients would also have worse periodontal health
than the other CKD patients. According to our knowledge, no other clinical longitudinal
study has investigated the differences between these two subgroups of CKD from
predialysis to post-transplantation, with an emphasis on periodontitis.
We have previously studied oral health among CKD patients in general, and the
periodontal data in the research were reported by the fairy crude World Health
Organization (WHO) CPITN index (Vesterinen et al. 2011). This index is a practical tool for
population studies and was developed for the purpose of assessing periodontal treatment
needs (Ainamo et al. 1982). Since it provides the highest score per mouth sextant, it takes
into account only a few teeth. In the present study, the periodontal status was thus
analyzed in more detail at six sites in 32 teeth.
The clinical and radiographic oral and periodontal examination combined with salivary
analyses were conducted very precisely, as explained earlier. Data were then collected
from the patients´ files. Periodontal pocket depths were calculated from periodontal status
sheets not only from sextants but at six sites per tooth in 32 teeth. Periodontal pockets
were further FDWHJRUL]HGDVQRSHULRGRQWDOSRFNHWRQHRUPRUHVLWHVZLWKSURELQJGHSWKV•
PPWRVLWHVZLWK•PPGHHSSRFNHWWZRRUPRUHVLWHVZLWK•PPGHHSSHULRGRQWDO
pockets. We thought that since we included wisdom teeth, two or more sites with deep
pockets were more accurate than only one deep pocket due to the possibilities of
³SVHXGRSRFNHWV´ Further, we decided to use PIBI to describe the inflammatory burden of
periodontitis. This index emphasizes deep pockets and is calculated from six sites in 28
teeth. We were willing to use a well-accepted case definition for periodontitis: The
CDC/AAP definition. However, since CAL was not reported at baseline, only periodontal
pockets could be utilized for the classification. Thus, we included the definition of moderate
periodontitis when two or more teeth had a PPD of • 5mm at interproximal sites (not on
the same tooth) excluding the severe and mild forms. In addition, holistic oral inflammatory
burden was assessed by using TDI, since it takes into account not only periodontitis but
also the caries, periapical-, and pericoronitis lesions from 32 teeth.
ϱϬ
Ethical aspects
The study was approved by the Ethical Committee of the Hospital District of Helsinki and
Uusimaa and written informed consent was obtained from all the patients. Finland is a
welfare state in which social welfare and health care are guided by the Ministry of Social
Affairs and Health. According to the Constitution of Finland, public authorities must
guarantee equal health care services in both preventive primary health care and in highly
specialized medical care to everyone. Patients with CKD are later possible kidney
transplant candidates and are therefore screened and treated for oral inflammatory foci.
Patients who were willing to participate in our studies were examined and treated at both
the Department of Nephrology and the Departments of Oral and Maxillofacial Diseases at
the University Hospital, Helsinki, Finland. The hospital environment is ideal for these
patients as it offers a variety of specialized consultation, the possibility to monitor the
medically compromised patient and the necessary laboratory tests. Unfortunately,
worldwide, there is inequity in access to RRT, as it is estimated that over 6 million patients
cannot access the affordable treatment of RRT (Robinson et al. 2016).
General discussion of results
Our observation in the cross-sectional baseline study at predialysis stage (Study I) was
that CKD patients with diabetic nephropathy and with high HbA1c values •%•
48mmol/mol) indeed had poorer oral health with emphasis on periodontitis, determined by
deep periodontal pockets and PIBI scores in addition with higher TDI compared with the
other CKD patients and with those who had low HbA1c values (< 6.5%, < 48mmol/mol).
This finding supplements our earlier study which found no differences when using a fairly
crude CPI to describe the periodontal health of this same patient material (Vesterinen et al.
2011). After multivariable analyses, no oral health parameters, PIBI, TDI, deep
periodontal pockets, or background variables of sex, age or smoking habits significantly
associated with the HbA1c levels. Although we lacked a control group, our finding is in line
with a study by Thorman and co-workers in which uremic patients showed a worse DMFT
index, more periodontal loss of attachment and periapical lesions than age- and sexmatched controls (Thorman et al. 2009). Since oral diseases such as periodontitis cause
low grade systemic inflammation, potential sources of inflammation should be diagnosed
ϱϭ
and treated early, at the latest at the predialysis stage, prior to entering kidney
replacement therapy ± dialysis or kidney transplantation.
The diagnosis of periodontitis has conventionally been based on clinical and radiological
examination. Since there is variation in the definition of periodontitis, biomarkers or their
combinations reflecting oral inflammation could supplement clinical oral examination or
even serve as a screening tool. Oral fluids contain many potential biomarkers associated
with local or systemic diseases such as IL-ȕ-6 and -8, TNF-Į003-8,-9, TIMP-1, and
sTREM-1 (Rathnayake et al. 2017, Bostanci et al. 2013). A specific biomarker test that
could provide additional information of oral inflammatory burden could be helpful,
especially for hospitalized patients or when screening risk groups such as CKD patients. In
fact, oral fluid (GCF, PISF, mouth rinse or saliva) chair-side/point-of care diagnostics of
host-inflammatory biomarker MMP-8 could provide an insight into predicting, diagnosing
and determining the progressive phases of periodontitis, and help in monitoring treatment
success and medication (Sorsa et al. 2016). In Study II, as hypothesized, salivary MMP-8
concentration indeed reflected oral inflammatory burden among our CKD patients.
Elevated salivary MMP-8 associated significantly with poorer oral health assessed by deep
periodontal pockets and higher PIBI and TDI scores. This finding is in line with other
clinical oral fluid MMP-8 studies which have shown MMP-8 to associate with severe
periodontitis (Sorsa et al. 2004, 2006, Leppilahti et al. 2011, Rathnayake et al. 2013a). An
important finding was that there was no statistically significant association between the
total number of daily drugs (N =2±22) or the specific subgroup of medications assessed,
whether antimicrobial or anti-inflammatory, (N = 19 subgroups according to the Finnish
catalog of drugs; Pharmaca Fennica Lääketietokanta) and salivary MMP-8 concentrations.
Smoking seemed to depress MMP-8 concentration, but not statistically significantly when
compared with non-smokers. Salivary MMP-8 screening could be a beneficial aid for the
diagnostics of oral foci of infections at the predialysis stage.
As said earlier, among CKD patients the main cause of death is CVD, followed by
infections, and this was also the case in our study (Study III). The primary cause of death
among CKD patients was a MACE (N= 31) followed by infections (N= 13). In the literature,
CVDs are mostly explained by dyslipidemia, smoking, hypertension and excess
phosphate, although low-grade systemic inflammation such as chronic oral infections have
been proposed to explain part of the disease. The main finding in our third study (Study
III) was a statistically significant difference between the 10-year survival rates of patients
ϱϮ
with 0±22 teeth (27.9%), 23±27 teeth (52.2%), and 28±32 teeth (77.3%) according to the
log-rank test (p < 0.001). This finding could indeed reflect long-lasting low-level oral
inflammation among the patients. This finding is new among CKD patients and is in line
with studies on missing teeth and mortality. A prospective cohort study of 7674 patients
with 12 years follow-up showed that the number of teeth was highly predictive for all-cause
mortality of CVD and CHD, and revealed a seven-fold risk of mortality due to CHD in
subjects with < 10 teeth compared to those with > 25 teeth (Holmlund et al. 2010).
According to a Finnish population-based survey, even a few missing teeth may predict
cardiovascular events, diabetes and death (Liljestrand et al. 2015). In the present study,
10-year survival rate was 28% among diabetic nephropathy patients and 62% among
those with other CKD diagnoses, indicating a higher risk of mortality among diabetic
nephropathy patients.
Since poor oral health is associated with systemic diseases in general, and missing teeth
with cardiovascular disease mortality, CKD patients and clinicians should be informed and
motivated regarding the importance of regular oral examination, accurate diagnosis and
proper treatment in order to reduce the systemic inflammation at every stage of the CKD
(Meurman et al. 2004, Holmlund et al. 2010).
The second part of the present follow-up study (Study IV) focused on comparing the oral
health variables of the 53 CKD patients at predialysis and follow-up. To the best of our
knowledge, our earlier study is the only longitudinal study to follow up CKD patients (N =
9) from predialysis to the post-transplantation stage (Vesterinen et al. 2007). The patients
were now followed up for 157 months, at which point most patients had already received a
kidney transplant (51 patients out of 53). Of the transplants, 46/51 were functioning at the
time of our investigation. Oral health was better overall at the follow-up stage. At
predialysis, more calculus and deep periodontal pockets were detected, as well as higher
PIBI and TDI scores. The number of teeth was also higher, and higher salivary flow rates
were measured than at follow-up, at which time oral health was better overall. This finding
is promising as regards the efficacy of the focus eradication protocol followed in our
hospital, where all patients are examined and treated by a dentist at the predialysis stage,
prior to entering dialysis or being put on the renal transplantation list. We might speculate
that treating the foci of oral infections at predialysis stage has indeed long-lasting effects,
although patients are enrolled for supportive therapy after predialysis stage and this might
also have an impact.
ϱϯ
At follow-up, diabetic nephropathy patients were compared with the other CKD patients, as
at the predialysis stage. Our observation was that diabetic nephropathy patients had lower
stimulated salivary flow rates, showed more dental plaque and candidiasis, and used more
drugs daily (for example calcium channel blockers) than the other CKD patients. It was
surprising, however, that the diabetic nephropathy patients did not consider oral health
care as important for their kidney disease, as did the other CKD patients. However,
analysis of the questionnaire results revealed no difference between the oral self-care of
the groups.
Previously, kidney diseases and oral health have mostly been investigated during dialysis
and at the post-transplant stage. Bots and co-workers observed that salivary flow rate
increased after transplantation, and bleeding on probing decreased (Bots et al. 2007).
They discussed that the salivary flow rate is reversible and is restored after transplantation
(Bots et al. 2007). Thorman and co-workers, on the other hand, found in their crosssectional study, that uremic patients in predialysis or dialysis had higher DMFT index
scores, more periodontal loss of attachments and more periapical lesions compared with
the healthy sex- and age-matched controls (Thorman et al. 2009). A recent multinational
study on over 4000 dialysis patients showed that oral diseases such as dental erosion
΀47%, (95% CI 45.3 ± 48.8)΁and moderate or severe periodontitis ΀20.6%, (95% CI 19.4 ±
21.9)΁ were very common among hemodialysis patients (Palmer et al. 2016).
Our longitudinal study (over 13 years) is important, as it is the first to provide follow-up
information of 144 CKD patients¶ oral health from predialysis to post-transplantation stage.
Limitations of the study
Limitations of the present series of studies were the lack of control group, and that the
number of participants was quite low. Age- and sex-matched healthy controls would have
yielded valuable information. Another limitation is that we could not relate oral health and
progression of CKD, as we did not examine the patients at dialysis stage but examined
this small number of patients (N = 53) in two stages, first at the predialysis stage (mid-CKD
stages 4 and 5) and secondly at follow-up (after transplantation). Moreover, CKD patients
at Stages 1 to 3 would have provided more valuable information for attempting to relate
oral health to CKD progression. However, we found that the survival rate was lower for
those who had less teeth at predialysis stage, which we might speculate reflects the
ϱϰ
accumulation of oral inflammation throughout the patient¶s life. As this was a continuing
investigation of the original study conducted in 2000±2005, these weaknesses could not
be avoided due to the nature of the original study protocol. However, our original aim was
to study the eventual differences in oral health parameters between diabetic and nondiabetic CKD patients. Our hypothesis was that diabetic patients would show more
problems in this regard, and this hypothesis was indeed confirmed by our results. The
drawbacks of Studies I and II were that we could not take into account bleeding on
probing, Plaque Index or CAL, as the parameters had not been reported systemically at
baseline.
Strengths of the study
The strength of our study was the longitudinal design in which patients were followed from
the predialysis to the post-transplantation stage (total follow up time over 13 years) in our
university hospital which is the only national center for organ transplant operations. This is
a unique study not only because of its longitudinal design but also since the same
experienced periodontist performed the oral health examinations on all the patients, at
both the predialysis and post-transplantation stages. In this way, we avoided interexaminer variation.
Practical relevance
Since predialysis patients are potential dialysis patients and later potential transplantation
recipients, oral infectious foci should be diagnosed and treated at the early predialysis
stage to avoid serious consequences such as later graft infection. Helenius-Hietala and
co-workers observed that poor oral health in liver transplant patients indeed affects
prognosis (Helenius-Hietala et al. 2013). Accordingly, poor oral health has shown to
associate with an increased risk of acute one-year rejection one year after renal
transplantation (Zwiech et al. 2013).
The number of patients with ESRD is increasing, and patients seek dental care at different
stages of renal disease. The present series of studies presented observations of oral
health, comparing diabetic nephropathy patients with patients with other CKD diagnoses.
Since oral inflammatory diseases are mostly treatable risk factors for many systemic
ϱϱ
complications, the importance of cooperation between physicians and dentists cannot be
overemphasized.
Further research
Since CKDs together with their main risk factor of diabetes are increasing, more long-term
follow up studies with a larger number of CKD patients and a control group are needed to
evaluate the effect of oral infection burden on the progression of CKD and quality of life of
these patients. Saliva as a diagnostic fluid of oral and systemic inflammation is an
interesting topic and could be explored further to analyze different molecular biomarkers
and their combinations in screening, predicting, diagnosing and determining the
progressive phases of oral and systemic diseases. CKD patients in the dialysis phase
need special attention. For example the infection sources of peritonitis or sepsis are not
currently fully understood and the mouth may be one infection source that should be
studied in more detail within these patients. Further studies on these issues are ongoing.
ϱϲ
CONCLUSIONS
This thesis consists of four further clinical oral studies of CKD patients originally examined
in 2000±2005 at the predialysis stage in the Department of Oral and Maxillofacial Diseases
of Helsinki University Hospital (Vesterinen et al. 2011).
The main objectives were: to study oral health, with an emphasis on periodontitis, among
CKD patients in more detail than in the previous study (Vesterinen et al. 2011) (Study I); to
investigate whether salivary MMP-8 concentration can reflect oral inflammatory burden at
the predialysis stage (Study II); to clarify the association between oral inflammatory burden
and mortality (Study III); and to compare oral health at predialysis and follow-up (Study IV).
The following conclusions can be drawn from these studies:
In general, the pUHYDOHQFHRISHULRGRQWDOGLVHDVH33'•VLWHZLWK•PP was high (88
%) among CKD patients at the predialysis stage and patients with diabetic nephropathy
had poorer periodontal health. As patients at the predialysis stage are prospective dialysis
patients and kidney transplant recipients, potential sources of systemic inflammation, such
as periodontitis, should be diagnosed and treated on time. Patients with diabetic
nephropathy should receive special attention.
Higher salivary MMP-8 concentration was associated with poorer oral health (Study II).
Salivary MMP-8 screening could thus be a beneficial aid for infection foci diagnostics
among CKD patients.
According to the follow-up study, fewer teeth significantly associated with risk of death
even after adjustment for the known risk factors age and diabetes (Study III). Most
frequent cause of death among CKD patients was a major adverse cardiovascular event,
followed by infection and then malignant disease. Risk of death was higher among patients
with diabetes nephropathy (Study III).
As was shown in Study IV, oral health was better at follow-up than in the predialysis stage
during which oral infection treatment was performed. However, diabetic nephropathy
patients should be paid special attention, as oral health with an emphasis on periodontitis
seems to be poorer among this special group of patients.
ϱϳ
ACKNOWLEDGEMENTS
This thesis was conducted at the Departments of Nephrology and Oral and Maxillofacial
Diseases of the Helsinki University Hospital, Helsinki, Finland and at the Institute of
Dentistry, University of Helsinki, Finland during 2012±2017.
This study was financially supported by the Finnish Dental Society Apollonia, the Finnish
:RPHQ'HQWLVW¶V$VVRFLDWLRQDQGDQ(92JUDQW7<+,ZRXOGOLNHWRWKDQNWKH
former Head of the Department of Oral and Maxillofacial Diseases, Professor Christian
Lindqvist and the present Head Docent Risto Kontio for giving me the opportunity to
conduct the study. I would also like to thank the former Deans of the Department of Oral
and Maxillofacial Diseases (former Institute of Dentistry), Professor Jarkko Hietanen and
Docent Hanna Thorén. From the Department of Nephrology I wish to thank Docent Eero
Honkanen.
My warmest gratitude goes to my supervisors Chief Dentist Hellevi Ruokonen (DDS, PhD,
MSc) and Professor Jukka Meurman (MD, DDS, PhD) who suggested this interesting
research topic to me and have supported and trusted me during these years. Hellevi, your
great clinical and research experience and deep interest in the treatment of kidney patients
has inspired me in my work. Jukka, I have been privileged to work in your research group,
your enormous expertise in oral health and systemic diseases and supportive attitude has
greatly encouraged me in my research.
I am deeply grateful to Professor Timo Sorsa (DDS, PhD) for your inspiring, supportive
attitude and extensive knowledge in biomarkers, such as MMP-8. It was you who first
introduced me to the scientific world 15 years ago, so it has been an honor to work
together again.
I wish to express my warm thanks to Mari Heikkinen (DDS, PhD) and Jussi Furuholm
(DDS) for lending me your great expertise in statistics. Without your wonderful help I could
not have done this work.
I am also grateful to all my other co-authors: Maarit Vesterinen (MD, DDS, PhD), Eero
Honkanen (MD, PhD), Fernanda Ortiz (MD, PhD) and Karoliina Kotaniemi (DDS). Maarit,
your excellent thesis inspired me to continue the research of these chronic kidney patients.
ϱϴ
Eero and Fernanda, thank you for giving me new insights into and knowledge of kidney
patients, and Karoliina, thank you for your valuable contribution in Study III.
From the scientific laboratory of the Institute of Dentistry I express my sincere thanks to
Kirsti Kari, MSc, the former Head of the laboratory, DDS; Docent Taina Tervahartiala and
Research Technician Saija Perovuo. From the Department of Oral and Maxillofacial
Diseases I would like to thank Assistant Head Nurse Anne Rouvali.
I warmly thank the monitoring group Docent Pirkko Pussinen and Docent Patrik Finne for
your kindness and support.
I sincerely thank the reviewers of this thesis Docent Patrik Finne (MD, PhD) and Professor
Anders Gustafsson (DDS, PhD) for your wise and valuable ideas and corrections.
I would also like to thank all the other PhD students and researchers whom I have been
privileged to get to know at Biomedicum.
I would like to thank my dear colleaques: Jenni, Heidi and Laura for encouraging me in my
research and sharing interesting congresses with me; Riikka, Nora, and Aulikki for long,
enjoyable discussions not only on the field of research but also on the field of clinical
cases and life itself. I would also like to thank Anja Nieminen who introduced me the
amazing world of periodontology as my teacher of periodontology during my studies in
dentistry.
I warmly thank my dear parents Kaija and Antero, and my beloved sisters Katja and
Katriina for listening to me whenever I needed it. Your sense of humor has always cheered
me up!
Last but not least I want to thank from the bottom of my heart my dear husband Ville and
my precious children Aada and Antton for your endless patience that has helped me to
finish this thesis. I love you all!
Helsinki, May 2017
Karita Nylund
ϱϵ
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