Association of severe periodontitis with microalbuminuria ... · risk factor for impairment of...
Transcript of Association of severe periodontitis with microalbuminuria ... · risk factor for impairment of...
Umeå University
Umeå International School of Public Health
Department of Public Health & Clinical Medicine
Association of severe periodontitis with microalbuminuria and
chronic kidney disease
Author: Shabnam Salimi
Umeå, 2010
Supervisors:
Nawi Ng: Umeå University, Sweden
Afshin Parsa: University of Maryland, USA
I
Abbreviation:
AAP American Academy Periodontology
ACR Albumin to Creatinine Ratio
ARIC Atherosclerosis Risk in Communities
BOP Bleeding on Probing
CAL Clinical Attachment Loss
CDC Centers for Disease Control and Prevention
CEJ Cementoenamel junction
CHF Cardiac Heart Failure
CKD Chronic Kidney Disease
COPD Chronic obstructive pulmonary disease
CRP C-Reactive Protein
CVD Cardio Vascular Disease
eGFR Estimated Glomerular Filtration Rate
ESRD End Stage Renal Disease
FGM Free Gingival Margin
HbA1c Hemoglobin type A1c
HTN Hypertension
MEC Mobile Examination Centers
NHANESIII The National Health and Nutrition Examination
Surveys phase III
NIDR National Institute of Dental Research
PD Pocket Depth
PSU Primary Sampling Unit
PPS Probability Proportional to Size
Standardized Serum creatinine Serum creatinine -0.23
USA United State of America
WHR Waist to Hip Ratio
II
Abstract
Background: Chronic kidney disease (CKD) is a major global health burden because of its significant morbidity
and mortality. A significant association between periodontitis, chronic inflammation, and cardiovascular diseases
(CVD) has been demonstrated. The chronic inflammation may be causal in promoting endothelial dysfunction and
associated CVD outcomes. Inflammation and endothelial dysfunction in kidneys can cause damage to the glomerulus,
initially causing the leaking of proteins into the urine, which is clinically identified as microalbuminuria, the early
manifestation of kidney endothelial cell dysfunction which is potentially reversible. This will subsequently lead to the
impairment of kidney function noted by a decrease in the renal glomerular filtration rate (GFR). As such, we
hypothesized that severe periodontal disease, as a common chronic infectious and inflammatory state, is associated
with microalbuminuria, which can be reversible and impaired kidney function.
Objective: To determine the association of severe periodontitis with microalbuminuria and chronic kidney disease
Method: A total of 13,958 participants 20 years old or above were included in this study from NHANESIII 1988-
1994 population based database. An adapted CDC definition was used to define periodontitis. Severe periodontitis was
defined as two or more interproximal sites with ≥6-mm clinical attachment loss (CAL), not on the same tooth, and one
or more interproximal sites with ≥5-mm pocket depth (PD) or complete edentulous. Moderate periodontitis was
defined as two or more interproximal sites with ≥4mm CAL, not on the same tooth, or two or more interproximal sites
with ≥ 5mm PD, not on the same tooth. The association between severe periodontitis and microalbuminuria (ACR 30-
300 mg/g) and CKD (estimated GFR<60ml/min/1,73m2) was analyzed using multivariate logistic regression,
adjusting for demographic, socioeconomic, health behavior, HbA1c, hypertension, serum lead, lipid profiles, and BMI.
Results: Proportion of severe periodontitis among women and men was 10.5% and 9.3 %, respectively. Overall
prevalence of microalbuminuria (30≤ACR<300mg/g) and CKD was 6.7% (7.8% in women and 5.4% in men) and 4.1%,
respectively. There was significant association between CRP as inflammatory factor and microalbuminuria after
adjustment for hypertension, HbA1c and other risk factors. In the multivariate analysis, there was a significant
association between severe periodontitis and both microalbuminuria (OR: 1.32; CI: 1.03-1.70) and CKD (OR=1.62;
CI:1.31-2.01).
Conclusion: Severe periodontitis is, independent of established risk factors, significantly associated with
inflammatory markers, microalbuminuria and CKD. These findings suggest that periodontal disease, potentially
through an inflammatory pathway, may relate to microalbuminuria and progression to CKD. These findings further
add to the plausibility of a biological association between periodontal disease and vascular related disease stated such
as CVD and CKD. Although our findings overall consistent with previous studies and have strong biological
plausibility and evidence of dose response, as a cross sectional analysis, we cannot demonstrate causality regarding
temporality. Considering the high prevalence of periodontal disease and the significant disease burden of CKD, a
longitudinal study to define temporality and prove causality are well warranted. Also, in public health point of view,
considering oral health in primary health care with allocating insurance and treatment of periodontitis is of
paramount importance to prevent microalbuminuria and later chronic kidney disease.
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Contents
1. Introduction........................................................................ .................. ....................................1
1.1 Anatomy and physiology of Kidney.......................................................................1
1.2 Chronic kidney disease definition ..................................................................... ...1
1.3 Epidemiology of CKD.............................................................................................1
1.4 Pathology of CKD...................................................................................................2
1.5 Indicators of kidney function................................................................................2
1.6 Periodontal disease as a non-traditional risk factor for CKD...............................3
1.6.1 Periodontal disease definition...............................................................................3
1.6.2 Case definition of periodontitis in epidemiologic studies....................................4
1.7 Risk factors for progression of periodontitis........................................................5
1.7.1. Putative risk factors…………………………………………………………………………………..5
1.7.2 Established risk factors.........................................................................................5
1.8 Periodontitis as cause of peripheral vascular disease...........................................6
1.9 Justification of Study.............................................................................................6
2. Hypothesis and Objectives....................................................................................................8
3. Methods......................................................................................................................................9
3.1 Methods applied in NHANES III..........................................................................9
3.2 Definition of applied variables ................................................................. ..........11
3.3 Exclusion criteria and sample size .................................................................... .13
3.4 Analysis and statistical methods ....................................................................... .13
4. Results.......................................................................................................................................15
4.1 Descriptive summary ........................................................................................ .15
4.2 Univariate analysis ............................................................................................ .17
4.3 Multivariate Analysis...........................................................................................22
5. Discussion.................................................................................................................................27
6. Conclusion................................................................................................................................30
7. Acknowledgment.....................................................................................................................31
8. Reference .................................................................................................................................32
1
1. Introduction
Chronic kidney disease (CKD) is a leading of cause of morbidity and mortality in the USA and
the epidemic global increase in end stage renal disease (ESRD) resulted from CKD, along with
the marked increase in associated CVD is recognized as a one of the global public health chal-
lenges. As a result, primary and secondary prevention is crucial and searching for more
comprehensive nontraditional risk factor for CKD can help in more efficient stratification of the
individuals at risk, the development of preventative measures and treatment modalities.1
1.1 Anatomy and physiology of Kidney Kidneys are one of the important organs of the body which are constituted from segmented
nephrons, blood vessels, and filtering capillaries. Kidneys have multiple functions with diverse
mechanisms as excretion of waste products and foreign chemicals, control of blood pressure and
keeping the electrolyte and water balance, regulation of acid-base balance, controlling osmolarity
of body fluid and concentration of electrolytes, secretion, excretion and metabolism of
hormones. 2
The most significant function is filtering plasma and eliminating substances and materials that
are not needed for body. Indeed, the substances contain urea due to amino acids metabolism,
creatinine from muscle creatine, uric acid from nucleic acids and products due to hemoglobin
breakdown like bilirubin and metabolites of the hormones. Eventually, kidneys should remove
these waste materials from the filtrate and blood. 2
The nephrons which are functional unit of kidney produce urine and are not regenerated. Each
nephron is structured by afferent arteriole, bunch of glomerular capillaries named glomerulus
which filter large amounts of fluid from the blood and long tubule that converts the fluid to urine
on the way to collecting duct, pelvis of the kidney efferent arteriole, proximal and distal tubules.
The anatomy of the fenestrated endothelial cells in the glomerular capillary and epithelial cells in
tubular systems are developed to filtrate the renal blood. Afferent arteriole conducts blood to
nephron and then it enters into a glomerular capillary for filtration of most amounts of fluid. The
ratio of glomerular filtration rate (GFR) to renal plasma flow determines the filtration fraction.2
1.2 Chronic kidney disease definition Chronic kidney disease (CKD) is associated with diminished kidney function and progressive
decline in glomerular filtration rate (GFR). In many studies the CKD is defined as estimated GFR
<60ml/min/1.73m2. 2-5
1.3 Epidemiology of CKD Chronic kidney disease is a worldwide major public health problem with its fast-growing number
of patients with end stage renal disease and enhance in mortality and morbidity. It is, also, one
of the main health burdens in the United State. Coresh et al reported that 4.2% of individuals
above 20 year-old had GFR 15 to 59 ml/min per 1.73 m2 in NHANESIII. The prevalence of end-
2
stage renal disease is higher in Japan followed by Taiwan and USA. In USA, the rate of patients
who need treatment is estimated to enhance up to 60% by 2010.3 Likewise, premature death
among people with CKD is three-fold higher than general population. In the USA, a number of
106,912 patients tolerated ESRD during 2005. CKD and following ESRD lead to congestive heart
failure (CHF) and cardiovascular disease (CVD) as a result of increased cardio vascular risk
factors. Some evidence shows that adverse outcomes can be prevented by early diagnosis and
intervention.3, 6, 7
1.4 Pathology of CKD Diabetic mellitus especially type 2, leads to diabetic nephropathy that is the most common cause
of CKD. In addition, hypertensive nephropathy is another common reason of CKD among old
population. The basis of nephrosclerosis caused by vascular disease is the same as which makes
the coronary heart disease and cerebrovascular disease. Atherosclerotic vascular disease among
the old patients is the manifestation of generalized vascular disease. The majority of this
population does not show the last stages of CKD as they die due to cardiovascular and
cerebrovascular diseases. The early stage of CKD is revealed by microalbuminuria and minor
reduction in GFR which in recent studies are shown as a risk factor for CVD.3, 6
Beside all causes, chronic inflammation has been proposed as one of the probable pathologies for
CKD. Regarding some common causes leading to CVD and CKD; some epidemiological studies
demonstrated the chronic inflammation as another potential predictor for CKD and CVD.
Although causal relation between CVD and chronic systemic inflammation has not been proved,
some cohort, nested case control and Meta analysis investigations revealed the link between
inflammation and CVD. Different mechanisms have been suggested about the impact of
inflammation in pathogenesis of CVD. Chronic systematic infection leads to elevated
inflammatory markers level including C reactive protein (CRP), interleukin-6, haptoglobin and
fibrinogen.5 In some studies it is reported that elevated CRP damaged vascular endothelium
leading to microalbuminuria. Thus, microalbuminuria is recognized as the laboratory indicator
of damage to the endothelial cells. In some epidemiologic studies microalbuminuria is a risk
factor for cardiovascular disease. Based on these evidences, microalbuminuria is the early
manifestation of renal damage due to endothelial dysfunction before decrease in GFR which
later leads to macroalbuminuria and more advanced kidney failure manifested by decreased
GFR.6-14
1.5 Indicators of kidney function CKD at the early stage is manifested with microalbuminuria which later in extended stages leads
to macroalbuminuria. Albuminuria is indicated by urinary albumin-to-creatinine ratio (ACR)
which is reported in mg/g. Microalbuminuria is defined as ACR > 30 mg/g to less than 300
mg/g and individuals with ACR ≥300mg/g are classified as having macroalbuminuria.2,3
3
The recommendation of National Kidney Foundation and American Society of Nephrology is to
use creatinine to estimate GFR (eGFR), within clinical settings. Among the young the normal
range of GFR is 120-130 mL/min/1.73m2 which decreases with age. Most common sequels of
CKD occurs with a GFR <60 mL/min/1.73m2. 2-4
1.6 Periodontal disease as a non-traditional risk factor for CKD For long time, diabetic mellitus, hypertension and atherosclerosis diseases has been known as
risk factors of kidney dysfunction. Based on new studies, chronic inflammation is speculated as
risk factor for impairment of kidney function. Periodontitis, as longtime inflammation is posed as
one of the non-traditional risk factors.
1.6.1 Periodontal disease definition
Periodontal disease is the chronic inflammation of the tissues supporting tooth and one of the
most prevalent oral diseases. It is occurs due to the interaction of gram negative bacteria and the
host inflammatory response.15,16 With the extension of inflammation and chronic irritation, there
would be loss of connective tissue fibers and ligaments that attach gum to the teeth and alveolar
bone near to the tooth. With the progression of inflammation to deeper structure, there would
be destruction of the collagen and connective tissue and loss of alveolar bone (attachment loss)
which eventually lead to loss of tooth. 9, 17
With degeneration of junctional epithelium, a “pocket” epithelium which proliferate apically and
laterally and ultimately a true pocket is formed which is suitable for opportunistic bacteria.17
Pocket depth (PD), the distance from the margin of gingival, is an index to find current
periodontitis. In practice, clinical attachment loss (CAL) is one of the methods to define previous
and long term periodontitis. CAL is the distance from cement-enamel junction to the base of the
sulcus or periodontal pocket.9, 17
The plaque produced by bacteria in the oral cavity it finally calcifies and alters to calculus (Fig1).
Calculus is a trap which enhances the growth of the constructed plaque and irritates gingival
more. Then it is known as secondary aetiology of periodontitis as primary one is the plaque
produced by bacteria. 17
Calculus can develop along the gum line or within the narrow sulcus between the teeth and the
gingival, which are called supragingival and subgingival respectively. Calculus can result in
chronic gingivitis and eventually periodontitis.
Almost all individuals with periodontitis demonstrate substantial subgingival calculus. So,
Calculus is another index to diagnose periodontitis. 17
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Fig 1. Calculus: Adapted from color atlas of dental hygiene17
A.
B. Fig2. Periodontal tissues and disease destruction. (A) A tooth with the periodontal tissues (cementum, connective tissue, and alveolar bone), healthy on the left side and on the right side compromised due to periodontal disease. The arrows indicate the corresponding areas. (B) Radiograph of molar teeth. Local destruction supporting alveolar bone due to periodontal disease is demonstrated by the right arrow, while bone levels are shown to be optimal by the left arrow9
1.6.2 Case definition of periodontitis in epidemiologic studies
There are various definitions based on different criteria to define periodontitis, yet there is no
unique agreement on a standard definition which is required as case definition implementing in
population-based studies to allow data interpretation in diverse global epidemiologic studies.18, 19
It is important to know that periodontitis which has acute and chronic components cannot be
measured merely by a single variable. When trying to capture the lifetime periodontitis burden,
attachment loss (CAL), appears to be the most reliable. As a result, this measure should be a
primary variable utilized in studies of risk factors for chronic periodontitis. To evaluate a risk
factor on current status of periodontitis, combination of attachment loss and bleeding on
probing depth (BOP) and Pocket Depth is acceptable. 11 In 2003, the Division of Oral Health at
the Centers for Disease Control and Prevention (CDC) in collaboration with American Academy
Periodontology (AAP) reviewed various conducted studies to develop a standardized clinical
definition for periodontitis in epidemiologic studies.19-21
Based on the Page R C and Eke P I study, the definition applied to NHANESIII is ≥ 1 tooth with
CAL ≥3mm + PD≥ 4 mm at the same site. In NHANES 1999-2000 the case definition of
periodontitis is ≥3 sites with CAL ≥4mm +≥ 2sites with PD ≥3mm. 18
Likewise, several definitions of periodontitis have been utilized in national survey in USA. Two
definitions are provided based on CDC, one for severe periodontitis and another for moderate
periodontitis. The case definition for severe periodontitis requires two or more interproximal
sites with ≥6-mm CAL, not on the same tooth, and one or more interproximal sites with ≥5-mm
PD. Moderate periodontitis was defined as two or more interproximal sites with ≥4-mm CAL,
not on the same tooth, or two or more interproximal sites with ≥5-mm PD, not on the same
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tooth. Also, the radiographic pattern and extent of alveolar bone loss and gingival inflammation
measured as bleeding on probing, or a combination of these measures is applied for the
definition. Although, some of these measures have been used in surveys (for example, PD and
CAL), others are not suitable in population based surveys, for example, radiographic
measurements.22
Measurement at interproximal sites is important because, unlike buccal or lingual sites,
periodontitis usually commence at these sites and is most severe at interproximal sites.
Moreover, the effects of gingival recession on accuracy of the PD measurements are minimized.
At least two sites with CAL ≥6 mm, not on the same tooth, are demanded since it is probable to
have abnormal CAL without having periodontitis. For many reasons both CAL and PD indexes
are necessary. CAL is considered as the gold standard for diagnosing the severity of the disease
and reasonably considered a more accurate measure than PD. Utilizing only CAL, however, could
mistakenly include some periodontal healthy sites since attachment loss can come along with
gingival recession which is non-inflammatory status. Gingival recession can take place when a
tooth with periodontitis is treated successfully or the disease resolved by itself without returning
to normal status. Furthermore, attachment loss can be due to non-inflammatory causes.22, 23
In ARIC study CAL was measured in 6 tooth sites to increase the accuracy of measurement. The
periodontitis was determined in three various levels regarding the degree of periodontitis as: 1)
severe periodontitis: 2 or more interproximal sites (not on the same tooth) with a clinical
attachment level of 6 mm or greater and 1 or more pocket depths of 5 mm or greater; 2) initial
periodontitis: 2 or more interproximal sites with a 4-mm or greater clinical attachment level (not
on the same tooth); and 3) healthy/gingivitis: individuals who did not meet criteria 1 and 2. 24
1.7 Risk factors for progression of periodontitis
1.7.1 Putative risk factors
Periodontitis is often associated with age, gender, obesity, metabolic syndrome, dental hygiene,
socioeconomic status, race/ethnicity and probable genetic factors.
1.7.2 Established risk factors
- Specific Plaque, bacteria
- Environmental factors
There is excessive inflammatory response resulting in more severe periodontitis in smokers.
Tobacco smoking is a strong predicting factor for periodontitis in some longitudinal studies.
Moreover, it is manifested that quitting smoking shows less tooth loss and lower incidence of
periodontitis. Cigarettes smoke impact on attachment to root surface of tooth.19
6
Diabetes mellitus is another risk factor for progression of periodontitis. In addition, high
association between poor metabolic control (HbA1c ≥7%) and periodontitis among patients with
diabetic mellitus is reported.19
1.8 Periodontitis as cause of peripheral vascular disease In recent decade many studies manifested the association between periodontitis and systemic
diseases. Especially, some studies showed significant link between cardiovascular disease (CVD)
and periodontal disease.24 Likewise, some investigations showed the role of periodontitis in
other systemic disease enclosing stroke, diabetes mellitus and pre-term pregnancy.25, 26
1.9. Justification of Study Kidney disease is associated with significant economic and health burden and is increasing in
prevalence and chronic kidney disease (CKD) has a global prevalence of 7% which is increasing
at an alarming rate.
microalbuminuria as an early marker of renal dysfunction is similarly associated with CVD
morbidity and mortality. On the other hand, inflammation appears to be a common mediator
between renal disease progression and CVD outcomes. Also, periodontal disease is the most
prevalent cause of chronic inflammation and has been associated with CVD outcomes and with
CKD.
Inflammation has a vital role in the pathologic pathway inducing endothelial damage, and
vascular dysfunction. In some studies even mild systemic inflammation is associated with
cardiovascular disease, although the causality has not been established so far. Periodontitis as a
chronic systemic inflammation affects on the tissues around teeth leading to loss of attachment
and increasing both local and systemic inflammation and associated markers such as serum
levels of CRP and fibrinogen. Such inflammation can also cause systemic endothelial
dysfunction. In Kidney tissue, inflammatory factors impact on the glomerular endothelium
leading to micro and then macroalbuminuria, which are early manifestation of kidney
dysfunction, compared to decreased GFR.
Some studies evaluated the predictor values of such inflammatory disease as periodontal disease
in GFR and also macroalbuminuria in last stages of kidney function. Since microalbuminuria, is
an early manifestation that is readily measurable and can be reversible by early treatment, as
shown in previous studies in diabetic nephropathy, it is paramount of usefulness in early
diagnosis of nephropathy. As such, we decided to evaluate the association between periodontal
diseases and microalbuminuria in NHANESIII. We also wish to further explore the association
between periodontal disease and established CKD, as a marker of sever disease.
Specifically, using the NHANESIII survey, we plan to examine the association between CDC
classification schemes for periodontal disease with established measures of renal function. These
measures will include microalbuminuria and creatinine based measures of estimated glomerular
7
filtration rate (eGFR). For our evaluation of periodontal disease we used measures
encompassing, chronic exposure and disease burden, as opposed to measures of acute
periodontitis, since they may not be as relevant to the long-term development of vascular related
disease, such as CKD.
Also in the previous studies in NHANESIII, the applied definitions for periodontitis did not
include pocket depth, in definition of periodontitis. Our primary interest is accumulated disease
burden. Despite bleeding, gingivitis and probing depth indicating current disease, attachment
loss measurement manifests the accumulated disease burden and not accurately current disease
activity.23 Measurement at interproximal sites is vital because, periodontitis usually begins at
these sites and is most severe at interproximal sites. Moreover, the effects of gingival recession
on accuracy of the PD measurements are minimized. Yet, in previous studies minimizing the
influence of gingival recession in accuracy of measurement was not taken into account. Thus, in
this study, we include only interproximal site which is mesiobuccal, as only mesiobuccal sites
were measured in NHANESIII.
Since there is no unique definition for population-based surveillance of periodontitis, we decided
to choose the employed epidemiologic definition by CDC-AAP for periodontitis and include
edentulous status as a criteria of sever periodontitis.
We will also contrast the effect of periodontal disease classification and case definition on the
related association with the existing established renal disease classifications, which include
microalbuminuria as early manifestation of kidney function and eGFR <60 mL/min/1.73m2 as
the standard measure of CKD case definition.
8
2. Hypothesis and Objectives
We hypothesized that severe periodontal disease is associated with microalbuminuria and
chronic kidney disease.
The study objectives are:
Objective 1: To study the association between severe periodontal disease and
microalbuminuria.
Objective 2: To study the association between severe periodontal disease and established chronic kidney disease.
9
3. Methods 3.1 Methods applied in NHANESIII
Study design
The cross sectional National Health and Nutrition Examination Survey (NHANESIII) carried out
by National Center for Health Statistics from 1988 to 1994. The study was conducted in multi-
stage, stratified clustered probability sample of non-institutionalized civilian US residents of US.
This multi-stage cluster sampling was conducted in various stages:
The sample represented the total civilian, noninstitutionalized population, in the 50 states and
the District of Columbia of US. The first stage of the design comprised of selecting a sample of
81 PSU’s (primary sampling unit) that were mostly individual counties. In a few cases,
adjacent counties were combined to keep PSU's above a minimum population size. Then, the
PSU's were stratified and selected with probability proportional to size (PPS). Thirteen large
counties (strata) were chosen with certainty (probability of one). For practical reasons, these
13 certainty PSU's were divided into 21 survey locations. After the 13 certainty strata were
selected, the remaining PSU's in the United States were grouped into 34 strata, and two PSU's
were selected per stratum (68 survey locations). The selection was done with PPS and without
replacement. Thus, the NHANES III sample is composed of 81 PSU's or 89 locations.
The 89 locations were divided into two groups randomly, one for each phase. The first group
included 44 and the other 45 locations. One set of PSU's was designated to the first three-year
survey period (1988-91) and the other allocated to the second three-year period (1991-94).
For most of the sample, the second stage of the design included area segments composed of city
or suburban blocks, combinations of blocks, or other area segments in places where block
statistics were not produced in the 1980 Census. In the first phase of NHANES III, the area
segments were used only for a sample of persons who lived in housing units built before 1980.
For units built in 1980 and later, the second stage consisted of sets of addresses selected from
building permits issued in 1980 or later. These are referred to as "new construction segments."
In the second phase, 1990 Census data and maps were used to define the area segments.
The third stage of sample design comprised of households and particular types of group
quarters, such as dormitories. All households and eligible group quarters in the sample segments
were listed, and a subsample was designated for screening to identify potential sample persons.
The subsampling rates enabled production of a national, approximately equal-probability
sample of households in most of the United States with higher rates for the geographic strata
with high Mexican-American populations. Within each geographic stratum, there was a nearly
equal-probability sample of households across all 89 stands.
The fourth stage of sample selection included persons within the sample of households or group
quarters. All eligible individuals within a household were listed, and a subsample of them was
selected based on sex, age, and race or ethnicity. The definitions of the sex, age, race or ethnic
10
classes, subsampling rates, and selection of potential sample persons within screened
households were developed to provide approximately self-weighting samples for each sub
domain within geographic strata and at the same time to maximize the average number of
sample persons per sample household. Based on previous NHANES studies, this increased the
overall participation rate.
Data Collection in NHANESIII
Data for NHANES III were collected through two phases. The data was collected through
interview, examination and laboratory tests.
In household interviews the individuals are asked about demographic, socioeconomic, and
health-related questions; and this followed by the extensive physical examinations, dental
examinations, health and dietary interviews, and laboratory tests which were conducted in
mobile examination centers (MECs).
Household Interviews
The interviewers performed all interviews in household level and then scheduled certain
appointments for examinations which were conducted in the MEC.
Advance Letter, Confidentiality and informed consent form
Before interview, a letter was sent to the household which explained the purpose of study and
why it is important and the participant’s right comprising confidentiality of information taken
and informs them that the interviewer will come to the household. In the first interview only
verbal consent was enough but to be included in examination in MEC signed consent form was
necessary to show the willingness of the participant in the survey otherwise the participant was
excluded due to refusal.27
Household Interviews and examination in Mobile Examination Center (MEC)
Interview
During interview demographic, socioeconomic, environmental data and history of diseases were
assessed by a designed questionnaire.
Exam Team Responsibilities
One physician reviewed the participant’s medical history, managed the medical examination
and recorded the results of examination and blood tests.
For measuring blood pressure, a mercury sphygmomanometer was utilized based on the
standardized blood pressure measurement protocols recommended by the American Heart
Association.28
One expert dentist conducted the dental exam and a health technician recorded the dentist’s
exam findings. Three medical technicians carried out urine and blood tests then recorded the
results and prepared and shipped specimens to different laboratories for more specific tests.
11
Dental Examination
In NHANESIII, not everybody received dental examination. In oral examination those who had
medical problems examination were excluded. The list of these health problems asked at the first
questionnaire at the beginning of oral exam was heart problems like congenital heart murmurs,
heart valve problems, congenital heart disease, and bacterial endocarditis, Rheumatic fever,
kidney disease requiring dialysis, hemophilia, having pacemaker or other artificial material in
heart veins or arteries, hip, joint or bone replacement.29 Also participants with age less than 20
years were excluded.
In NHANES III, only two quadrants were examined randomly and a computer program selected
the random quadrant to evaluate the periodontal status. Buccal and mesiobuccal sites of two
quadrants were assessed.
Periodontal Destruction
Examination of the periodontal status included loss of attachment and periodontal pocket depth.
The examination included only permanent full erupted teeth. Only two sites were assessed:
buccal and mesiobuccal (interproximal ).
- Clinical Attachment Loss (CAL): Clinical attachment loss is the distance from the
cementoenamel junction (CEJ) to bottom of the pocket in millimeters (mm).
- Pocket depth (PD): Pocket depth is the distance from the free gingival margin (FGM)
to the bottom of the sulcus
The NIDR periodontal probe was used to measure the buccal and mesiobuccal sites. For each
site, first, the distance from the free gingival margin (FGM) to the CEJ, and second, the distance
from the FGM to the bottom of the pocket was measured.
3.2 Definition of applied variables The designated variables encompassing outcome of interest, independent variables including
sociodemographic status, life styles, health behaviour and laboratory assays are summarized in
table 1.
12
Table 1. Studied variables including main outcomes and independent variables.
Variables Definitions and categories
Outcomes variables
Albumin Creatinine Ratio (ACR) Normal: ACR<30 mg/g(Reference),Microalbuminuria:Albumin Creatinine Ratio ≥30 mg/g and <300mg/g, macroalbuminuria: ACR≥300
Chronic Kidney Disease status Normal:eGFR≥60ml/min/1.73m2(Reference);CKD=eGFR<60
ml/min/1.73m2
Independent variables
Main risk factors of interest
Periodontitis* (non-traditional risk
factor)
Severe periodontitis: Two or more interproximal sites with ≥6-mm
CAL, not on the same tooth, and one or more interproximal sites with ≥5-mm PD or complete edentulous, Moderate: Two or more interproximal sites with ≥4-mm CAL, not on the same tooth, or two or more interproximal sites with ≥5-mm PD, not on the same
tooth. Mild or healthy: Non severe nor moderate (Reference)
Edentulous Loss of all natural teeth
Socio-demographic variables
Age 20-59 (Reference) ; ≥60 years
Gender Man(Reference) , Women
Marital Status Married(Reference), Widowed, divorced, single
Race ethnicity Non Hispanic white, Non Hispanic Black, Mexican-American or other(Reference)
Country of Birth US(Reference), Non US
Education >12 years (Reference) , ≤12 years
Last visit by doctor ≤1year (Reference), >1 year
Last visit by dentist ≤1 years (Reference), >1 years
Annual income ≥20000$ (Reference), <20000$
Smoking** (traditional risk factor) Current smoker1, Former smoker2, non-smoker3 (Reference)
Health variables
Hypertension(traditional risk factor )
Average Systolic blood pressure≥140mmHg or Diastolic blood pressure ≥90 or currently taking prescription to control hypertension
Heart disease History of heart attack, congestive heart failure, angina or stroke
WHR ≤ 0.8 for women and ≤ 1.0 for men (Reference);≥0.8 if men ,≥1.0
if women
Laboratory assays
CRP (C- Reaction Protein) CRP: <0.22 mg/dl(Reference) ,0.22≤CRP≤1.0mg/dl, >1mg/dl
Fibrinogen <450 mg/dl (Reference); ≥450 mg/dl
HbA1c(GlycosylatedHemoglubine) <7% (Reference); ≥7%
Total Cholesterol <240mg/dl(Reference); ≥240mg/dl
HDL** ≥35mg/dl(Reference); <35mg/dl
Serum Lead <10 ug/dl(Reference); ≥10 ug/dl
Standardizedserum creatinine Serum creatinine-0.23 (mg/dl) to calculate GFR27,29,30
*Severe periodontitis in this study is determined regarding CDC definition for severe periodontitis or
complete edentulous 1. Positive answer to “Have you smoked at least 100 cigarettes in lifetime” and
“Do you smoke now” or serum cotinine ≥15 ng/ml 2. Positive answer to “Have you smoked at least
100 cigarettes in lifetime” 3. Neither former nor current smoker, ** High density lipoprotein
13
3.3 Exclusion criteria and sample size
The following exclusion criteria were used in the selection of study subjects from the NHANES
III database:
1. Age less than 20 year-old
2. Currently pregnant
3. Currently in menstruation period
4. Individuals with no serum creatinine measurement
5. Medical problems with contradiction to having oral examination.
After considering exclusion criteria, 13,958 participant’s data were included in this study.
3.4 Analysis and statistical methods NHANESIII is a complex multistage, stratified and clustered study. Due to the non-random
selection of subjects, sample weights were applied in the analysis. Sample weights in NHANES
III were utilized to achieve the following objectives:
- To compensate for different probabilities of selection among subgroups (age-sex-race-
ethnicity subdomains; persons living in different geographic strata sampled at different
rates)
- To reduce biases arising from the fact that nonrespondents may be different from the
participants.
Weighting took into account several aspects of the study: the specific probabilities of selection
for the oversampled individual domains, as well as nonresponse and differences between the
sample and the total population. Differences between the sample and the population may appear
due to sampling variability, different coverage of demographic groups, and perhaps other types
of response errors, such as differential response rates or misclassification errors.
According to the NHANESIII analysis guideline, MEC and home examination weights was more
suitable as weighting variable .27 The weighting was based on the probability of selection of each
case which was depends on three factors: 1) the person’s age-sex-race/ethnicity domain; 2) the
density stratum; and 3) the PSU. The following provides a brief description of each of the three
components.
Older persons, children, Mexican-Americans, and black individuals were oversampled to insure
a minimum sample size for each analytic domain so that estimates of the health status of the
participants in each domain could be made with satisfactory precision. The oversampling in
NHANES III was part of a pattern established in the sample design. The population was
decomposed into 52 subdomains: 7 age groups by sex for black and Mexican-American persons
and 12 age groups by sex for white persons and other racial groups combined. After defining age-
sex-race/ethnicity subdomains, variable sampling rates were extracted to ensure the appropriate
sample sizes to allow analyses of the data for each subdomain.
14
Also, the density strata were considered by dividing the census blocks (or counting districts) in
each sampled PSU into six classes with each class having a different level of concentration of
Mexican-American individuals. Blocks with high concentrations of Mexican-American persons
were oversampled to increase the sample produced for this group. In addition, for the PSU
factor, it was introduced to adjust the basic weights to reflect the effect of the relatively fixed
sample size within each PSU in NHANES III on the sample weights. The reason for the relatively
fixed sample size by PSU was to have a manageable and efficient field procedure. However, the
use of nearly a fixed number of examinations per PSU implied that NHANES III would not
consist of exact self-weighting samples. The more details of weighting is explained in
NHANESIII guide line.27
The raw data from NHANESIII data base transferred to STATA 8 with STAT transfer program 9.
To test the hypothesis of association between periodontitis and traditional and non- traditional
risk factors with microalbuminuria and CKD, univariable analysis was employed. Afterwards,
backward stepwise multivariable logistic regression model was deployed to take into account the
statistically significatnt risk factors recognized in the univariable analysis. The 95% confidence
interval (CI) was used to assess statistical significance. We identified the significant risk factors
for microalbuminuria and CKD in univariable model. The OR derived in the multivariable
logistic regression model were applied to estimate the odds of decreased eGFR(CKD) or
microalbuminuria among those with risk factors. As there was strong association between
HbA1c and history of diabetes, just HbA1c was included in analysis to prevent collinearity.
Furthermore, HbA1c data was well captured whereas there was more missing data related to the
“history of diabetes” variable.
15
4. Results
4.1 Descriptive summary Table1 shows the main characteristics of the men and women who participated in the study. One
fourth of the women were over the age of 60. Almost one third of women had a lower level of
education, while in men higher education than 12 years had the same proportion as lower level
(p<0.005). Regarding marital status, the majority were married in both men and women
(p<0.005). Both sex had equal distribution with respect to country of birth. (Table 2) Table2. Description of demographic data
Men n=6,878(51%)
Women n=7080(49%)
Age
20-59
60+
81.2%
18.8%
74.8%
25.2%
Ethnicity Mexican- American &others Non-Hispanic white
Non-Hispanic black
13.3% 77.2%
9.5%
12.8% 75.7%
11.5%
Marital status Married Widowed Divorced Single
71.0% 2.3% 7.7% 19.0%
61.0% 12.0% 13.7% 13.3%
Education >12 years ≤12 years
55.5% 44.5%
62.0% 38.0%
Country of Birth USA Non USA
85.7% 14.3%
86.3% 13.7%
Income ≥20000$
<20000$
71.0%
29.0%
63.4%
36.6%
About 8% of women showed microalbuminuria but above 5% of men experienced
microalbuminuria while macroalbuminuria had higher proportion among men compared to
women (p<0.005). Moreover, chronic kidney disease was 5.1% among women Vs 3.2% in men
(p<0.005). Although moderate periodontitis had higher proportion among men, more women
endured severe periodontitis (p<0.005). Almost half of women never smoked in their life time
while 35% of men were current smoker. Furthermore, distribution of hypertension, control of
diabetes and history of cardiovascular disease had similar pattern in both sex (p>0.05). Less
than one fifth of men experienced serum lead more than 10 ug/dl. Also, three forth of women
had WHR≥0.8 which was almost three times more than WHR≥1.0 in men (p<0.005). The
proportion of other risk factors is summarized in table 3. Among the participants without CKD
(eGFR>60), 23% of the study subject experienced microalbuminuria and 8.6% had
macroalbuminuria.
16
Table.3 Distribution of outcomes and risk factors in men and women Men¥ Women¥
Albuminuriaᶲ
No(ACR<30) Micro (30≤ACR<300) Macro(≥300)
93.4% 5.4%
1.2%
91.3% 7.8%
0.9%
CKDᶲ
eGFR≥60 eGFR<60
96.8% 3.2%
94.9% 5.1%
Periodontitisᶲ
No/Mild moderate Severe or Edentulous
81.0% 9.7% 9.3%
83.0% 6.5% 10.5%
Smoking ᶲ
Never smoked
Former smoker
Current smoker
35.6%
28.7% 35.7%
53.6%
19.3% 27.1%
Hypertension No Yes
76.7% 23.3%
76.0% 24.0%
CVDᶲ
No Yes
90.0% 10.0%
91.7% 8.3%
BMI <25 25-30 >30
40.6% 40.0% 19.4%
48.4% 26.2% 25.4%
WHRᶲ
<0.8if men ,<1.0 if women
≥0.8 if men ,≥1.0 if women
73.0%
27.0%
24.0%
76.0%
Last visit by dentistᶲ
< 1 years ≥1year
62.8% 38.2%
68.0% 32.0%
Last visit by doctor ᶲ
<1 years ≥1year
73.0% 27.0%
87.8% 12.2%
HbA1c HbA1c<7 % HbA1c≥7 %
96.3% 3.7%
96.0% 4.0%
CRPᶲ
<0.22 ≥0.22 &<1.0 ≥1.0
78.0%
17.5% 4.5%
65.7%
25.4% 8.9%
Fibrinogen
<450 ≥450
95.0% 5.0%
94.4% 5.7%
Total Cholesterolᶲ (mg/dl)
<240 ≥240
83.4% 16.6%
78.7% 21.3%
HDLᶲ (mg/dl)
≥35 <35
81.8%
18.2%
94.0%
6.0%
Leadᶲ (ug/dl)
<10 ≥10
94.8% 5.2%
98.9% 1.1%
¥ .Weighted percent, ᶲp<0.05
17
The prevalence of macroalbuminuria was higher in people with poor kidney function (eGFR<60)
as compared to people with better kidney function eGFR >60 (p<0.05). As microalbuminuria is
the early manifestation of kidney endothelial cell dysfunction which is potentially reversible,
hence, in univariate and multivariate analysis, microalbuminuria (30≤ACR<300) was compared
against no albuminuria (ACR<30 mg/g).
4.2 Univariate analysis Univariable logistic regression models (OR crude), illustrated in Tables 3 and 4, demonstrate the
unadjusted association between single predictor variables and the outcome binary ACR and CKD
categories. The percentages in the second and third columns in Table 3 and 4 indicate the
weighted proportion.
The prevalence of microalbuminuria among women was significantly higher than men while
CKD had higher proportion in men compared to women. The likelihood of having CKD in Non-
Hispanic white was 2.47 times more than Mexican-American and other ethnicities. (Table 5)
Among widowed group less than one fifth had microalbuminuria and proportion of CKD was the
same in this group while single individuals were less probable to have microalbuminuria or CKD.
Country of birth was not significant risk factor for microalbuminuria whereas those who were
born in non USA countries were less likely to suffer from CKD. The odds of microalbuminuria
were 50% higher among those for whom it took more than one year to be visited by a dentist. In
contrast, microalbuminuria was more frequent among those visited a doctor in less than one
year compared to those who so do not. (Table 4 and Table 5)
About one third of the individuals with HbA1c >7% had microalbuminuria while it was 15%
among hypertensive individuals. In addition, 15% of the participants with severe periodontitis
manifested microalbuminuria. The prevalence of CKD in the hypertensive individuals, those
with HbA1c>7% and the participants with sever periodontitis was above one tenth, 12.2%, 14.05
and 13.7%, respectively. The prevalence of microalbuminuria and CKD regarding other risk
factors is summarized in Table 4 and 5.
In the univariate logistic regression model, considering periodontitis as non-traditional risk
factor of microalbuminuria, severe periodontitis or edentulous had almost three times higher
probability of experiencing microalbuminuria compared to no/mild periodontitis while those
with moderate periodontitis had about two times higher likelihood to have microalbuminuria.
The probability of having microalbuminuria among women was higher by 48% compared to
men. Similarly, in the elder, microalbuminuria was 3.51 times more common than the younger.
There was no significant association between non-Hispanic black and microalbuminuria.
Although being Non-Hispanic white sounds protective factor against microalbuminuria, it was
not significant. Regarding marital status, single condition looked protective factor against
microalbuminuria while widowed individuals were more probable to have microalbuminuria
compared to married status.
18
Table4: The Univariate association between the other risk factors and microalbuminuria
Risk Factors ACR <30 mg/g (93.3%)
30≤ACR<300mg/g (6.7%)
OR Crude*
(95% CI)
Periodontitis No/Mild
Moderate Severe or Edentulous
94.5%
90.2% 85.3%
5.5%
9.8% 14.7%
1.00
1.90(1.50-2.50) 3.00(2.30-3.97)
Sex Men Women
94.5% 92.1%
5.5% 7.9%
1.00
1.48 (1.15- 1.93)
Age 20-59 60+
95.4% 85.4%
4.6% 14.6%
1.00
3.51(2.86- 4.31)
Ethnicity Mexican-American or others
Non-Hispanic white Non-Hispanic black
92.9%
93.7% 91.2%
7.1%
6.3% 8.8%
1.00
0.87(0.61- 1.25) 1.25(0.88- 1.76)
Marital status Married Widowed
Divorced Single
94.0% 80.3%
92.2% 95.2%
6.0% 19.7%
7.8% 4.8%
1.00
3.81(2.98- 4.90)
1.20(0.84- 1.65) 0.67(0.50-0.90)
Education >12years ≤12 years
95.2% 92.0%
4.8% 8.0%
1.00
1.70(1.35- 2.16)
Country of Birth USA Non USA
93.4% 93.1 %
6.6% 6.9%
1.00
1.04(0.72- 1.50)
Income
≥20000$
<20000$
94.6%
90.9%
5.4%
9.1%
1.00
1.74(1.43-2.12)
Smoking Never smoked Former smoker Current smoker
93.9% 91.8% 93.6%
6.1% 8.2% 6.4%
1.00
1.36(1.08- 1.73) 1.04(0.79- 1.36)
Hypertension No Yes
95.9% 84.5%
4.1% 15.5%
1.00
4.28(3.42- 5.36)
CVD No
Yes
93.7%
88.8%
6.3%
11.2%
1.00
1.88(1.47- 2.41)
BMI <25 25-30
>30
94.6% 93.0%
89.3%
5.4% 7.0%
10.7%
1.00
1.32(1.02- 1.72)
1.70(1.34- 2.17)
WHR <0.8if men ,<1.0 if women ≥0.8 if men ,≥1.0 if women
95.8% 91.4%
4.2% 8.6%
1.00
2.17(1.74- 2.70)
Last visit by dentist <1 years ≥1year
94.3% 91.6%
5.7% 8.4%
1.00
1.51(1.17- 1.95)
Last visit by doctor <1 years
≥1year
92.8%
95.5%
7.2%
4.5%
1.00
0.61 (0.46-0 .81)
19
Table 4(continue)
* OR Crude = Unadjusted odds ratio for the association between chronic kidney disease and the
suspected/recognized risk factors in sample
The likelihood of microalbuminuria was 1.70 times higher in individuals with lower level of
education, as compared to those with higher level of education, and 1.74 times higher in
individuals with low income, as compared to those with higher income.
Shorter period till being visited by dentist were protective factors to have microalbuminuria
whereas longer time to see a doctor or health professional was posed as a protective factor.
Individuals with hypertension, HbA1c>7% and CVD as traditional risk factors had significant
association with microalbuminuria.
Likewise, inflammatory factors encompassing CRP and fibrinogen were significant risk factors
for having microalbuminuria. That is, the likelihood of having microalbuminuria in the group
with higher CRP was almost four times more than the lowest one and odds of having
microalbuminuria in the individual with higher serum fibrinogen was 2.16 (CI: 1.48- 3.15). The
more exposure to lead, the higher the likelihood was to have microalbuminuria. Also, among
lipid profiles, higher HDL had 71 % less likely to have microalbuminuria (Table 4).
ACR <30 mg/g 30≤ACR<300 mg/g
OR Crude* (95% CI)
HbA1c HbA1c<7 % HbA1c≥7 %
94.2% 67.8%
5.8% 32.2%
1
7.77(5.91-10.22)
CRP
<0.22 ≥0.22 &<1.0 >1.0
94.9% 90.8% 89.9%
5.1% 9.2% 10.1%
1.00 1.90(1.46- 2.48) 3.77(2.91- 4.90)
Fibrinogen <450 ≥450
91.4% 83.1%
8.6% 16.9%
1.00
2.16(1.48- 3.15)
Total Cholesterol (mg/dl) <240
≥240
96.9% 91.8%
3.1% 8.2%
1.00 1.93(1.56- 2.40)
HDL(mg/dl) ≥35
<35
94.0%
90.2%
6.0%
9.8%
1.00
1.71(1.34- 2.18)
Lead(ug/dl) <10 ≥10
93.5% 86.1%
6.5% 13.9%
1.00
2.32(1.65- 3.28)
20
Table5. Proportion and univariate association between the risk factors and CKD Risk Factors No CKD (95.8%) CKD (4.2%) OR Crude
* (95% CI)
Periodontitis No/Mild Moderate
Severe or Edentulous
97.8% 95.4%
87.85%
2.2% 4.6%
12.2%
1.00
2.11(1.51-2.95)
6.05(4.66-7.86)
Sex Men Women
94.9% 96.8%
5.1% 3.2%
1.00
1.64 (1.26-2.13)
Age 20-59 60+
99.0% 84.4%
9.0% 15.6%
1.00
20.65(15.16- 28.13)
Ethnicity Mexican- American &others Non-Hispanic white
Non-Hispanic black
98.0% 95.4%
96.7%
2.0% 4.6%
3.3%
1.00
2.47( 1.32-4.60)
1.72(0.89- 3.29)
Marital status Married Widowed Divorced
Single
96.5% 81.3% 97.0%
98.8%
3.5% 18.7% 3.0%
1.2%
1.00
6.42(5.07- 8.13) 0.87(0.59- 1.28)
0.33(0.20-0.54)
Education >12years ≤12 years
97.4% 94.8%
2.6% 5.2%
1.00
2.04(1.56- 2.67)
Country of Birth
USA Non USA
95.7% 97.0%
4.3% 3.0%
1.00 0.66(0.74- 0.96)
Income ≥20000$
<20000$
97.8%
94.3%
2.2%
5.7%
1.00
2.66(2.06-3.43)
Smoking Never smoked Former smoker Current smoker
96.0% 93.2% 97.8%
4.0% 6.8% 2.2%
1.00
1.72(1.41- 2.11) 0.51(0.35- 0.75)
Hypertension
No Yes
98.5% 87.8%
1.5% 12.2%
1.00 9.55(7.59- 12.02)
CVD No Yes
96.8% 86.4%
3.2% 13.6%
1.00
4.80(3.87- 5.97)
BMI <25 25-30 >30
96.6% 95.9% 94.5%
3.4% 4.1% 5.6%
1.00
1.21(0.96- 1.52) 1.67(1.33- 2.10)
WHR
<0.8if men ,<1.0 if women ≥0.8 if men ,≥1.0 if women
98.4% 94.5%
1.6% 5.5%
1.00 3.53(2.70- 4.63)
Last visit by dentist <1 years ≥1year
97.0% 94.5%
3.0% 5.5%
1.00
1.70(1.34- 2.14)
Last visit by doctor <1 years ≥1year
95.3% 98.5%
4.7% 1.5%
1.00
0.31 (0.21-0 .47)
21
Table5. (Continued)
* OR Crude = Unadjusted odds ratio for the association between chronic kidney disease and the
suspected/recognized risk factors in sample
Table 5 illustrates the association between various risk factors and CKD using univariate
analysis. In the individual with moderate peritonitis and severe periodontitis or edentulous, the
probability of CKD was raised with increase in severity.
In women odds of having CKD was 64% more than men. The older individuals were almost 20
times more likely to have CKD compared to the younger. In addition, the widowed group was
more probable to have CKD. The less the education, the more likely they have CKD.
Moreover, those who experienced longer period till being visited by a doctor were 69% less
probable to develop CKD. Likewise, CKD is less common among those who were born in non-US
countries. The odds of having CKD were significantly higher in the participants with
hypertension (OR=9.55), higher level of glycosylated hemoglobin (OR=4.2) and CVD
(OR=4.80). The association between other risk factors with CKD is summarized in Table 5.
Risk Factors No CKD (95.8%) CKD (4.2%) OR Crude * (95% CI)
HbA1c HbA1c<7 % HbA1c≥7 %
96.3% 86.0%
3.7% 14.0%
1.00
4.20(3.16- 5.59)
CRP <0.22 ≥0.22 &<1.0
>1.0
66.9% 24.7%
8.4%
50.8% 33.3%
15.9%
1.00
2.13(1.71- 2.65)
3.67(2.73- 4.94)
Fibrinogen <450 ≥450
93.3% 6.71%
86.1% 13.9%
1.00
2.86(2.04- 3.99)
Total Cholesterol(mg/dl) <240 ≥240
80.9% 19.1%
64.7% 35.3%
1.00
2.77(2.13- 3.60)
HDL (mg/dl) ≥35 <35
89.1% 10.95
82.3% 17.75
1.00
1.74(1.31- 2.30)
Lead (ug/dl) <10 ≥10
95.3% 4.7%
92.1% 7.9%
1.00
2.22(1.45- 3.41)
22
4.3 Multivariate Analysis At the first step of multivariable analysis for both microalbuminuria and CKD outcomes, all
significant and insignificant risk factors from univariate analysis were taken into account to
evaluate the effects of severe periodontitis for microalbuminuria and CKD, adjusted
simultaneously adjusted association for all variables. Although macroalbuminuria was excluded
while analyzing for microalbuminuria, it was taken into account when analyzing CKD.
Afterwards, in each step of back-ward stepwise logistic regression, the non-significant from each
group of risk factors were excluded. The result including the first and last models is summarized
in Table 5 and 6. Since there was high collinearity between CRP and fibrinogen, fibrinogen was
not taken into account in the multivariate logistic regression analysis.
The crude OR for having microalbuminuria among people with severe periodontitis was 3.00
(95% CI: 2.30-3.97). Sex, ethnicity, education, country of birth and income were not significant
which excluded from second model. (Second model is not illustrated in the table 6). In the third
model, last visit by dentist or doctor, smoking, CVD and BMI were not taken into account in the
analysis as the result of no significant association with microalbuminuria. In the last model
encompassing only the significant risk factors such as age, marital status, hypertension, HbA1c,
CRP, HDL and serum Lead, the odds of having microalbuminuria in individuals with severe
periodontitis remained significant (OR: 1.32;CI:1.03-1.7). (Table 6) In the last model, those with
severe periodontitis status were 32% more likely to have microalbuminuria compared to
individuals without periodontitis. On the other hand, moderate periodontitis was not significant
in association with microalbuminuria while adjusted for other risk factors although OR crude
was significant. (Table 4 and Table 6) The widowed individuals remained in higher risk by 83%
to have microalbuminuria when adjusted for other variables whereas the being single was not
significant any more. Moreover, the higher the CRP, the higher likelihood of enduring
microalbuminuria when adjusted for other risk factors encompassing traditional ones. In
addition, those with higher HDL were less probable to have microalbuminuria by 35% while total
cholesterol was not risk factor in the last model. Likewise, serum lead remained a significant risk
factor for microalbuminuria. (Table 4 and Table 6)
23
Table 6. Multivariable logistic regression analysis of risk factors of microalbuminuria
Risk Factors Model 1 ORadj *(95%CI)
(last model) ORadj * (95%CI)
Periodontitis No/Mild Moderate Severe or Edentulous
1.00
1.06(0.77-1.46) 1.33(1.04-1.69)
1.00
1.11(0.82-1.50) 1.32(1.03-1.70)
Sex
Men Women
1.00 1.33(0.97-1.81)
Age 20-59 60+
1.00 1.55(1.24-1.95)
1.00
1.60(1.28-2.00)
Ethnicity Mexican- American &others
Non-Hispanic white Non-Hispanic black
1.00
0.73(0.48-1.10) 0.92(0.63-1.35)
Marital status
Married Widowed Divorced Single
1.00 1.67(1.19-2.35) 1.10(0.77-1.56) 1.07(0.76-1.50)
1.00 1.83(1.35-2.48) 1.16(0.83-1.63) 1.06(0.78-1.44)
Education >12years
≤12 years
1.00
1.00(0.98-1.02)
Country of Birth USA Non USA
1.00 1.15(0.75-1.76)
Income ≥20000$
<20000$
1.00
1.05(0.86-1.29)
Last visit by dentist <1 years ≥1year
1.00
1.16(0.9-1.5)
Last visit by doctor <1 years ≥1year
1.00
0.79(0.58-1.06)
Smoking
Never smoked Former smoker Current smoker
1.00 1.19(0.9-1.58) 1.15(0.85-1.56)
Hypertension No Yes
1.00
2.59(2.09-3.2)
1.00
2.54(2.08-3.11)
CVD No Yes
1.00
0.91(0.69-1.2)
BMI
<25 ≥25 & ≤30 >30
1.00 0.98(0.77-1.23) 0.90(0.66-1.24)
HbA1c HbA1c<7 % HbA1c≥7 %
1.00
4.12(2.95-5.75)
1.00
4.21(3.09-5.75)
24
Table6. (Continued)
*OR adj = adjusted odds ratio for the association between chronic kidney disease and the
suspected/recognized risk factors in sample
Model 1: Goodness of fit: F-adjusted test statistic = 5.251, p= 0.000
Model final: Goodness of fit: F-adjusted test statistic = 1.251, p = 0.291
F-adjusted mean residual goodness-of-fit test was applied and suggested no evidence of lack of
fit in the last model (F-adjusted test statistic = 1.251, p = 0.291). (Table 6)
Table 7 illustrates the multivariate logistic regression analysis of traditional and non-traditional
risk factors of chronic kidney disease in this study.
In the first model adjusted for all the risk factors, the significant and insignificant ones which
were input in the univariate analysis, odds of having CKD in severe periodontitis group was 49%
more than those with no periodontitis or mild but moderate periodontitis was not significant risk
factor.
In the last model, socio demographic, health behavior and laboratory assays with a p-value
<0.05 were excluded stepwise. Eventually, adjusted for significant risk factors including age,
marital status (widowed), since last time visited by a doctor, hypertension, CVD, CRP, total
cholesterol and HDL, odds of having CKD in severe periodontitis group remained significant
(OR: 1.62;CI: 1.31-2.01). (Table 7)
Risk Factors Model 1 ORadj(95%CI)
(last model) ORadj(95%CI)
CRP <0.22 ≥0.22 &<1.0 >1.0
1.00
1.33(1.01-1.74) 2.23(1.57-3.16)
1.00
1.35(1.04-1.76) 2.35(1.73-3.19)
Total Cholesterol(mg/dl)
<240 ≥240
1.00 1.02(0.80-1.31)
HDL(mg/dl) ≥35 <35
1.00
1.51(1.17-1.94)
1.00
1.35(1.04-1.75)
Lead (ug/dl) <10
≥10
1.00
1.86(1.33-2.61)
1.00
1.92(1.40-2.62)
25
Table 7. Multivariable regression analysis of risk factors of CKD
Risk Factors Model 1 ORadj* (95%CI)
(last model) ORadj* (95%CI)
Periodontitis No/Mild Moderate Severe or Edentulous
1.00
0.84(0.59-1.19) 1.49(1.19-1.86)
1.00
0.83(0.59-1.15) 1.62(1.31-2.01)
Sex Men Women
1.00 1.28(0.92-1.77)
Age 20-59 60+
1.00 7.40(5.32-10.30)
1.00
8.04(5.90-10.96)
Ethnicity Mexican- American &others
Non-Hispanic white Non-Hispanic black
1.00
1.48(0.8-2.75) 1.05(0.53-2.09)
Marital status Married Widowed Divorced Single
1.00
1.36(1.03-1.81) 1.02(0.61-1.70) 0.79(0.44-1.41)
1.00
1.58(1.22-2.05) 1.07(0.71-1.63) 0.87(0.51-1.49)
Education
>12years ≤12 years
1.00 1(0.99-1.01)
Country of Birth USA Non USA
1.00
1.15(0.76-1.72)
Income ≥20000$
<20000$
1.00
1.33(0.99-1.78)
Last visit by dentist <1 years
≥1year
1.00
1.12(0.90-1.40)
Last visit by doctor <1 years ≥1year
1.00
0.56(0.37-0.85)
1.00
0.54(0.35-0.84)
Smoking Never smoked Former smoker Current smoker
1.00
1.17(0.89-1.54) 0.73(0.53-0.99)
Hypertension No
Yes
1.00
2.68(2.07-3.46)
1.00
2.85(2.2-3.69)
CVD No Yes
1.00
1.77(1.41-2.22)
1.00
1.92(1.52-2.42)
BMI <25 ≥25 & ≤30 >30
1.00
0.81(0.61-1.08) 1.00(0.74-1.36)
HbA1c HbA1c<7 %
HbA1c≥7 %
1.00
1.18(0.85-1.63)
26
Table7. (Continued)
*OR adj = adjusted odds ratio for the association between chronic kidney disease and the
suspected/recognized risk factors in sample
Model 1: Goodness of fit: F-adjusted test statistic = 236.88, p= 2.029 Last model: Goodness of fit: F-adjusted test statistic= 170675.36, p=8.370
The likelihood of having CKD among the older was almost 8 times as much as the younger.
Those who were widowed, had CVD, higher total cholesterol or lower HDL were more likely to
manifest chronic kidney disease.
In individuals with more than one year since to visit doctor, CKD was less common by 46.
(Table7)
Among those who had hypertension and severe periodontitis, the probability of getting CKD
was 4.62 times as much as those with neither severe periodontitis nor hypertension (CI:3.31-
6.45) (analysis is not depicted in the table 7).
Despite the result for having microalbuminuria, lipid profile (higher total cholesterol and lower
HDL) remained risk factor to have CKD after adjustment for other risks while serum lead was
not significant risk factor for CKD.
Risk Factors Model 1 ORadj (95%CI)
(last model) ORadj (95%CI)
CRP <0.22 ≥0.22 &<1.0 >1.0
1.00
1.42(1.08-1.87) 1.72(1.17-2.55)
1.00
1.44(1.12-1.85) 1.95(1.33-2.85)
Total Cholesterol (mg/ml) <240 ≥240
1.00
1.59(1.21-2.08)
1.00
1.63(1.22-2.18)
HDL (mg/dl) ≥35
<35
1.00
1.84(1.26-2.69)
1.00
1.71(1.22-2.40)
Lead(ug/dl) <10
≥10
1.00
1.81(1.04-3.15)
27
5. Discussion Chronic kidney disease (CKD) is posed as a significant global challenge and burden of public
health. Evaluation of predictors of CKD is a complex issue due to existence of association
between CKD and age, race and other chronic diseases such as diabetes, hypertension and
cardiovascular disease (CVD). CKD is a crucial public health burden regarding its morbidity and
mortality. 4, 24
Albumin to creatinine ratio above 30 and less than 300 mg/g is an early manifestation of renal
cell damage, which can lead to decreased GFR and CKD.1 Also, periodontitis which can be
controlled is known as the non-traditional risk factor for some systemic diseases such as CVD by
effect on the endothelial cells.4
In addition to the traditional risk factors encompassing diabetes and hypertension, the non-
traditional risks factors as periodontitis are speculated with their influence on endothelium
structure and function through infection-driven inflammatory markers in the kidney. In many
studies, the association between periodontitis and cardiovascular disease was revealed through
inflammatory mechanism .7, 9,11,24,25,31-38
In a study conducted by Tonetti et al, they showed intensive periodontitis treatment leads to
improvement in endothelial function via decrease in inflammatory factors. 11 In the research
conducted by Salzberg et al in 2006 , it is proved that patients with severe periodontitis had
statistically significant elevated serum CRP compared to those without periodontitis.39 Likewise,
Paraskeva et al disclosed that there is strong evidence that serum CRP is highly associated with
periodontitis.40 In a study was performed by Navarro et al in 2003, the association between
urinary albumin excretion and inflammatory factors in the patients with diabetes type2 was
depicted.41 In our study there was significant association between higher increased CRP and
microalbuminuria (OR: 2.35, CI: 1.73-3.19) indicating significant association between
microalbuminuria and the inflammatory factor.
Kshirsagar et al in ARIC study (Atherosclerotic Risk in Community) concluded the existence of
association between periodontal disease and prevalent renal insufficiency.13 They studied 2,276
individuals with initial periodontitis and 947 with severe periodontitis. In their study an
association between periodontitis and CKD was also remarked (OR: 2.00; 95% CI: 1.23 to 3.24).
But, in this study edentulousness, for which periodontitis is the primary cause was excluded 41.
Also microalbuminuria was not taken into account as one of the main outcomes. Moreover, the
definition of periodontitis was not based on new CDC definition, albeit measured 6
interproximal Sites which increase the accuracy of measurement.22
In our study we extended the findings by demonstrating an association with CRP and
microalbuminuria, and employed an updated definition of periodontitis while focusing on
chronic and severity of periodontal disease.
28
There are challenges regarding case definition to determine periodontitis across researches.
Although many studies assessed the association between periodontitis and chronic kidney
disease or CVD, there is dearth of uniformity in the definition of periodontitis in epidemiologic
studies.18-23
Fisher et al42 in 2009 studied a prediction model for CKD including periodontitis. In their study
they considered one or more sites with CAL ≥4mm and bleeding on the same tooth as definition
of periodontitis. Also they defined the edentulous status as alternative indicator of severe
periodontitis. The main outcome was CKD (eGFR<60ml/min/1.73m2). The result after
adjustment for various risk factors were OR: 1.60, CI: 1.07 to 2.39 and OR: 2.03, CI: 1-31 to 3.14
in order for periodontitis and edentulous states. The CDC definition adapted in our study 17
combines severe status with edentulous as indicator of severe periodontitis and the odds of
developing CKD was 62% (OR adjust=1.62, CI: 1.31-2.01). In previous study, inflammatory factors
or microalbuminuria were not taken into account except t macroalbuminuria (OR: 3.41, CI: 1.82
to 6.41). Yet, in the current survey microalbuminuria was one of the main outcome as early
manifestation of kidney dysfunction which can potentially be reversible.
Although nephrotoxic effect of lead have been known, in non of the former studies serum lead
was controlled as a risk factor in the analysis43 . In the current study, there was significant
association between higher serum lead and microalbuminuria adjusted for other risk factors
(OR: 1.92, CI: 1.40-2.62).
In a similar study44 Fisher et al took into consideration CRP and other serologic markers but not
microalbuminuria as early manifestation of kidney dysfunction which can be potentially reversed
by treatment of periodontal disease as common source of chronic inflammation.
On the other hand, gingival recession which can be the result of periodontitis and even after
treatment leads to false positive in measurement of CAL and periodontitis was not considered
not in the former neither in the latter studies. While, in the present study we considered
interproximal site (mesiobuccal) to measure CAL plus pocket depth which diminish the
likelihood of this bias since accuracy of periodontitis measurement by utilizing these indices
together are less influenced by gingival recession. In another survey, Fisher et al proved the
association between edentulous as a single risk factor and chronic kidney disease. Similarly,
microalbuminuria was not studied. 45
In 2009, Garcez et al in a case-control study assessed the oral health status of individuals with
mild decrease in eGFR (60-89 ml/min). They considered various oral health status as number of
decayed, missing or filled teeth, supra gingival inflammation, pocket depth, CAL and dental
mobility. There was no alteration of the oral health between case and control groups which can
be justified as the consequence of small sample size. 46
In current survey, the relationship between smoking status and microalbuminuria was not
statistically significant albeit reverse association with CKD which is counter to some but not all
29
other studies.44, 45 This result can be due to the method of definition for smoking since those who
were known as former smoker or never smoker but with high serum cotinine were indicated as
current smoker, yet cotinine can be higher in passive smokers or in those who snuff nicotine
instead of smoking while in Fisher et al study, there was significant association between both
former and current smokers with CKD. 44, 46
WHR and BMI had no significant association neither with microalbuminuria nor CKD. With
respect to various studies which reviewed traditional and non-traditional risk factors for CKD
and also microalbuminuria, subsequent risk factors were taken in to account in the model: age,
sex, marital status, HbA1c, HDL, serum lead.
As the limitation, this study utilized NHANESIII data the number of interproximal sites
measured is restricted to only mesiobuccal site while if were measured in six interproximal sites
the result could be altered probably toward stronger association.
Another important limitation of this study is its design which is cross-sectional which cannot
assess temporality. To measure causality of periodontitis as exposure, it is necessary that it
precedes the progression of microalbuminuria or CKD. Also, there is no uniform definition for
periodontitis to be able to compare the result with all other conducted studies.
Despite all limitations in this study, there is some evidence that warrant considering severe
periodontitis as risk factor of microalbuminuria and CKD (Table 5 and 6). Our findings overall
consistent with previous studies and have strong biological plausibility. Moreover, severe
periodontitis has stronger association with microalbuminuria or CKD compared to no
periodontitis, on the other hand, no association between moderate periodontitis and
microalbuminuria or CKD, which strengthen the probable causality regarding dose response.
Also, in NHANES data questionnaire, laboratory tests and examination were conducted in
unbiased methods.
30
6. Conclusion
Severe periodontitis had association with microalbuminuria as early indicator of endothelia
damage in kidney glomerular system which can be reversible at the early stage.
From a public health perspective, we suggest that the association between periodontitis with
inflammatory markers and both microalbuminuria and CKD have reasonable probability of
being causal. If this link is indeed true, then the treatment of periodontitis may in addition to
improving oral health may impede the development of microalbuminuria and CKD. Thus, oral
health and dental insurance in a public health system should be one of the priorities and we
believe that the current evidence is strong enough to warrant longitudinal studies to help further
elucidate causality and that clinical trials of periodontal treatment, which are beneficial to
participants and plausible, should also be evaluated in respect to potential reduction in
microalbuminuria.
31
7. Acknowledgment
This research was performed by utilizing data from NHANESIII conducted by National Center
for Health Statistics. My gratefulness goes to Nawi Ng, my supervisor from Umea University,
department of public health and epidemiology that always kept me on track by his significant
and scientific guidance and his generosity of sharing knowledge.
Particular thanks to Afshin Parsa, the second supervisor that his Nephrology knowledge and
advice lightened the way of the work. Also, deep appreciation goes for Public Health and
Epidemiology Department that provided me with the great opportunity to raise my knowledge
embedded in this research.
Eventually, especial thanks to my parents that were always my best encourager. Their spirits
may in peace.
32
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