Decreased Salivary Flow Rate as a Dipsogenic Factor In
Transcript of Decreased Salivary Flow Rate as a Dipsogenic Factor In
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
1/12
Decreased Salivary Flow Rate as a Dipsogenic Factor inHemodialysis Patients: Evidence from an ObservationalStudy and a Pilocarpine Clinical Trial
Junne-Ming Sung,* Shih-Chen Kuo, How-Ran Guo, Shu-Fen Chuang, Szu-Yuan Lee,
and Jeng-Jong Huang*Departments of *Internal Medicine and Operative Dentistry, National Cheng Kung University Hospital; Institute of
Clinical Pharmacy and Department of Environmental and Occupational Health, College of Medicine, National Cheng
Kung University; and Department of Internal Medicine, Kuos General Hospital, Tainan, Taiwan
Decreased salivary flow rate causes xerostomia (symptoms of oral dryness) in patients who undergo hemodialysis (HD);
however, whether it thus contributes to thirst and excess interdialytic weight gain (IDWG) remains undetermined. In the
observational study, 3 mo of data of 90 stable HD patients were collected, and sensations of thirst and xerostomia were
assessed by 100-mm visual analog scales (VAS). Multivariate analyses revealed that the VAS oral dryness score was an
independent determinant for thirst, daily IDWG, and IDWG%. Unstimulated whole salivary flow rate (UWS) was measured
in 45 participants and was negatively correlated with VAS oral dryness score (r0.690,P< 0.001), daily IDWG (r0.361,
P 0.016), and daily IDWG% (r 0.302, P 0.045). In the interventional trial, the test drug was 5 mg of oral pilocarpinesolution or placebo. Sixty hyperdipsic HD patients (IDWG% > 2%/d) were randomly assigned to either the sequence
pilocarpine (2 wk)washout (3 wk)placebo (2 wk)washout (2 mo)placebo (3 mo) or placebo (2 wk)washout (3 wk)
pilocarpine (2 wk)washout (2 mo)pilocarpine (3 mo) with 35 participants completing the trial. During the 2-wk crossover
period (the first to seventh weeks), pilocarpine increased UWS and decreased xerostomia and thirst. The IDWG2d
decreased
(by approximately 0.2 kg; P 0.013) but not IDWG3d. During the 3-mo interventional period, pilocarpine increased UWS but
decreased both IDWG2d
(by 0.76 kg; P 0.021) and IDWG3d(by 1.07 kg; P 0.007). It also modestly increased serum albumin
and decreased mean BP. Pilocarpine-related adverse effects were generally mild. In conclusion, decreased salivary flow is a
dipsogenic factor in HD patients, and pilocarpine can alleviate it.
J Am Soc Nephrol16: 34183429, 2005. doi: 10.1681/ASN.2005040346
Failure to restrict fluid is the rule rather than the excep-tion in patients who undergo long-term hemodialysis
(HD), despite frequent exhortations from staff, includ-
ing warning about the complications of fluid overload (15).
Three types of interventions for reducing thirst (the urge to
drink) and interdialytic weight gain (IDWG) are identified in
the literature: dialysis protocol related (increasing frequency
and varying sodium concentration) (69), pharmaceutical (an-
giotensin-converting enzyme inhibitors [ACEI]) (1013), and
dietetic interventions (10,14). However, no definite effective-
ness could be shown (5), which might be explained by the fact
that many of the underlying mechanisms for thirst and drink-
ing behavior remain unknown.
Known dipsogenic factors (factors that cause thirst and high
fluid intake) in HD patients include high sodium intake, potas-
sium depletion, increased blood urea, sugar and angiotensin II
(Ang II) levels, and psychologic factors (2,3,5,1016). Anotherpotential dipsogenic factor is the reduction of salivary flow
rate. Recently, Brunstrom et al.(17) demonstrated that healthy
volunteers consume more water and drink more frequently in
the xerostomic state, which is induced by decreasing saliva in
the oral cavity. Because xerostomia (symptoms of oral dryness),
which is caused by the reduction of salivary flow, is prevalent
among HD patients (1823), it is conceivable that the decreased
salivary flow leads to thirst and excess IDWG. Some observa-
tional studies (24,25) have described an association between
xerostomia and IDWG in HD patients; however, other known
dipsogenic factors (e.g., blood urea, Ang II, sugar level) were
not controlled in those studies. In addition, no interventional
trial in the literature indexed by Medline has demonstrated the
impact of the decreased salivary flow on IDWG. Therefore,
whether the decreased salivary flow influences fluid intake in
HD patients remains undetermined.
We conducted a 3-mo prospective observational study fol-
lowed by a trial of pilocarpinea parasympathomimetic agent
that has been shown effectively to increase salivary flow in
radiation-induced xerostomia or Sjogren syndrome (26 29)to
determine whether the reduction of salivary flow contributes to
exaggerated thirst and excess IDWG in HD patients and
whether pilocarpine can alleviate it.
Received April 3, 2005. Accepted July 26, 2005.
Published online ahead of print. Publication date available at www.jasn.org.
Address correspondence to: Dr. Jeng-Jong Huang, Division of Nephrology, De-
partment of Internal Medicine, National Cheng Kung University Hospital, 138
Sheng-Li Road, Tainan, Taiwan 70428, R.O.C. Phone: 886-6-2766138; Fax: 886-
6-3028036; E-mail: [email protected]
Copyright 2005 by the American Society of Nephrology ISSN: 1046-6673/1611-3418
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
2/12
Materials and MethodsThe study protocol was approved by ethics committees of National
Cheng Kung University Hospital and Kuos General Hospital, Tainan,
Taiwan, and adhered to the Declaration of Helsinki. Informed consent
was obtained from each participant.
In the observational study, we collected prospective data from De-
cember 2002 to February 2003 on 90 participants who were recruited
from a pool of 217 patients who were undergoing HD at the outpatient
dialysis unit of the Kuos General Hospital. Inclusion criteria were age
older than 18 yr, HD three times weekly for at least 6 mo, daily urine
output 200 ml, and stable clinical conditions including stable dry
weight and hematocrit. Exclusion criteria were hemodynamic instabil-
ity preventing sufficient ultrafiltration, hospitalization within the pre-
ceding 3 mo, dementia or terminal diseases, logistic impossibility of
investigation, anxiety or depression (which cause xerostomia possibly
as a result of the dysfunction of both brain and salivary glands), use of
xerogenic medications (including anticholinergics, antidepressants, an-
tipsychotics, antihistamines, antiparkinsonian agents, and diuretics),
and unwillingness to participate in this study.
The inclusion and exclusion criteria for the interventional trial
(March to October 2003) were the same as those in the observational
study except that only hyperdipsic patients (IDWG% 2%/d [10]) wereincluded, and patients who were using the xerogenic medications were
included when these drugs could be stopped at least 14 d before
entering and throughout the trial.
Assessment of IDWGThe body weight was determined using an Electronic Chair Scale
(American Scale Co., New York, NY), and participants were weighed
before and after each dialysis session. All patients were routinely asked
to disrobe (except for their underwear), remove their shoes, and put on
a clean gown before entering the dialysis unit. The patient was offered
two options: to finish his or her meal before starting dialysis or to eat
his or her meal within 1 h after starting dialysis. After choosing an
option, the patient was asked to continue with it throughout the study
periods. If the patient chose to eat after starting dialysis, then the meal
would be weighed to guide the setting of the ultrafiltration rate. IDWG
is defined as the difference between the predialysis weight and the
weight at the end of the previous dialysis session, and IDWG% is
obtained by dividing IDWG by the patients target dry weight. The
IDWG was expressed as daily IDWG, daily IDWG%, IDWG2d, and
IDWG3das indicated. The target dry weight was determined according
to standard clinical criteria (30) and was reviewed continuously by
nephrologists. To allow better assessment of the changes of IDWG, we
set the ultrafiltration rate according to the IDWG in each dialysis
session and corrected the postdialysis body weight to the target dry
weight. Because we recruited patients with stable dry weight and
excluded patients with hemodynamic instability preventing sufficientultrafiltration, the target dry weights did not change, and the postdi-
alysis body weights of the participants were comparable with target
dry weights throughout the study.
Assessment of Xerostomia, Thirst, and Stress ofFluid Restriction
Participants first were asked to respond to two-point categorical
questions (yes or no) on sensations of xerostomia and thirst during each
study period and then to questions about their sensations of five
xerostomic items (oral dryness, oral comfort, requirement to sip liquid
to speak, sleep, and chew and swallow), thirst, and stress of fluid
restriction by 100-mm self-rating visual analog scales (VAS) with the
negative and the positive on the left and right, respectively (e.g., 100
mm extremely dry). VAS scores of speak, sleep, chew, and swallow
were estimates of the requirement to sip liquid to speak, sleep, chew,
and swallow. These VAS questions for xerostomia were identical to
those in two previous Phase III trials that led to the Food and Drug
Administration approval of pilocarpine for treatment of radiation-in-
duced xerostomia (26,31) and in a multicenter clinical trial of pilo-
carpine in patients with Sjogren syndrome (32). A trained investigator,
blind to the clinical data, administered all questionnaires.
Saliva CollectionThe unstimulated salivary flow rate (UWS) and test drugstimulated
(by pilocarpine or placebo) whole salivary flow rates were determined
before commencement of HD unless otherwise specified. Participants
were instructed not to eat, drink, smoke, chew gum, or perform oral
hygiene for at least 60 min before the collection. Whole saliva was
collected for 10 min using an established spitting technique (33,34). Test
drugstimulated whole saliva was collected at 30, 60, and 90 min after
stimulation as indicated. The collection volumes were determined
gravimetrically (assuming specific gravity of 1.0), with saliva flow rates
expressed in milliliters per minute. The salivary collection was per-
formed by a trained investigator who was blind to all clinical data.
Study MedicationsAs pilocarpine tablets were not licensed in Taiwan during the study
period, 5 mg of pilocarpine OPD solution (1% pilocarpine ophthalmic
solution; Shionogi Co. Taipei, Taiwan) was used, a dose that is recom-
mended as safe and effective for Sjogren syndrome (27). The placebo
was a 3:7 mixture of normal saline and Milli-Q water. The sodium
concentration of the two solutions was identical, with both adminis-
tered in fixed doses (10 drops four times/d, 30 min before each meal
and at bedtime). Ten drops of pilocarpine OPD solution is equivalent to
5 mg of pilocarpine.
Study ProtocolObservational Study. Age, gender, underlying diseases, HD du-
ration, and the use of ACEI or Ang II receptor antagonists (AIIA) were
recorded. Mean values of Kt/V, normalized protein catabolic rate
(nPCR), daily IDWG, daily IDWG%, hematocrit, and biochemistry val-
ues were calculated from monthly predialytic data. VAS scores of
xerostomia and thirst and UWS were assessed twice in the study period
(middle and end), and the mean values were used for analyses. Plasma
Ang II and atrial natriuretic peptide (ANP) levels were determined at
the end of the observational period.
Pilot Study before Clinical Trial. No previous study has docu-
mented the effect of pilocarpine on salivary flow in HD patients with
hyposalivation (UWS 0.150 ml/min [34]); therefore, we performed a
pilot study to evaluate whether pilocarpine could increase salivary flowand the time course of its effect in this population. Fifteen patients were
randomly selected from 60 eligible candidates (who were hyperdipsic
and were expected to have hyposalivation) of the interventional trial,
and 15 healthy control subjects were enrolled. The UWS and test
drugstimulated (by pilocarpine or placebo) whole salivary flow rates
were compared.
Interventional Clinical Trial.
Short-Term, Single-Blind, Placebo-Controlled, Crossover Clinical Trial Pe-
riod. After a run-in period, 60 participants were randomized to either
protocol pilocarpine (2 wk)washout (3 wk)placebo (2 wk) or placebo
(2 wk)washout (3 wk)pilocarpine (2 wk) (Figure 1) on the basis of a
balanced block randomization list technique by numbered containers.
A third party that was not involved in the conduct of the study
generated the allocation sequence, assigned participants to their
J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3419
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
3/12
groups, and maintained the test drugs. The sequence was concealed
until interventions were assigned. Pilocarpine and placebo solutions
had identical appearance and packaging, and the participants were
blinded as to the test drug. Before entering and at the end of each
treatment and washout period, laboratory and UWS measurements
were conducted under fasting state, and VAS scores of xerostomia,
thirst, and stress of fluid restriction were obtained. The mean IDWG 2dand IDWG3d during each study period were calculated, and each
participant was queried about possible adverse events.
Long-Term, Single-Blind, Placebo-Controlled Clinical Trial Period. Fif-
teen participants who had completed the short-term pilocarpine (2
wk)washout (3 wk)placebo (2 wk) protocol received the placebo
treatment, and 20 who had completed the placebo (2 wk)washout (3
wk)pilocarpine (2 wk) protocol received pilocarpine treatment (Figure
1). Each treatment lasted for 3 mo, and clinical data and laboratory
measurements were made before and after each treatment. The UWS
and VAS scores of xerostomia, thirst, and stress of fluid restriction of
each patient were assessed. The mean IDWG2d and IDWG3d were
calculated in the last study month.
Withdrawal, Outcome Measures, and Sample Size in the Interven-
tional Trial. Patients were withdrawn when they missed 30% ofthe
doses of either regimen, experienced severe adverse effects or acute
illness requiring hospitalization, or were unwilling to continue. An
adverse event was defined as any clinically significant change in phys-
ical signs or symptoms or a significant change in laboratory test results.
The primary outcomes were changes in the VAS scores of xerosto-
Figure 1. Flow diagram of the progression through the phases of the pilocarpine interventional trial.
3420 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 3418 3429, 2005
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
4/12
mia, thirst, and stress of fluid restriction; UWS; and mean IDWG2dand
IDWG3d in each intervention period. The secondary outcomes were
changes in mean BP, adverse events, and blood test results.
Under the scenario of a two-sided significance level of 0.05 and a
power of 0.8 (aerror of 0.2), a sample size of 52 (26 in each group) was
found to be sufficient for a t test to detect a standardized effect size of
0.80. We added four more participants in each group to accommodate
possible dropouts.
Statistical AnalysesIn the observational study, data were expressed as mean SD, and
Spearman correlation coefficient was used to assess the correlations
between continuous variables. Predictors that showed the significance
level of 0.15 in the correlation analyses and the known dipsogenic
factors (2,3,10) were included in the multiple linear regressions with
stepwise selections and thereby to identify factors that were indepen-
dently associated with VAS thirst score, daily IDWG, and daily
IDWG%. The multivariate analyses were repeated forcing all variables
left in the stepwise selection model, together with gender, the presence
of diabetes, use of ACEI or AIIA, nPCR, sodium, potassium, and Ang
II levels into the final regression model. In the interventional trial, data
were expressed as mean SEM, and Mann-Whitney Uand Wilcoxonsigned-rank tests were applied to evaluate differences in unpaired and
paired continuous variables respectively. 2, Fisher exact, and McNe-
mar tests were applied to evaluate differences in categorical variables.
The ANOVA with baseline and washout measurement model were
applied to evaluate the efficacy and carryover effect of drugs. All
statistical analyses were conducted using the statistical software SAS at
the two-tailed significance level of 0.05.
ResultsObservational Study
Ninety patients (42 men and 48 women) were enrolled in theobservational study. The mean age was 57.1 14.3 yr, and
patients were on HD for 51.3 43.6 mo. Causes of the ESRD
included chronic glomerulonephritis (26.6%), diabetes (23.3%),
hypertension (13.3%), tubulointerstitial nephritis (11.1%), lupus
nephritis (3.3%), adult polycystic kidney disease (2.2%), and
unknown (20%). The salient characteristics and predialytic bio-
chemical data of the 90 participants are presented in Table 1.
Sixty-two (68.9%) patients reported abnormal sensation of xe-
rostomia. The VAS oral dryness score in the 90 participants was
49.2 25.2 mm, and the mean daily IDWG and IDWG% were
1.4 0.4 kg and 2.3 0.6%, respectively. The VAS thirst score
was 47.1 24.5 mm, which was significantly correlated withdaily IDWG (r 0.842,P 0.001) and IDWG% (r 0.542,P
0.001).
The correlation coefficients between various predictors and
Table 1. Clinical data of 90 HD participants in the observational study a
Variables N(%) or Mean SD
Kt/V 1.4 0.2nPCR (g/kg per d) 1.2 0.2Pre-HD SBP/DBP (mmHg) 133.8 11.6/78.4 5.4
Post-HD SBP/DBP (mmHg) 125.5
8.8/74.2
5.2Daily IDWG (kg/d)/daily IDWG% 1.4 0.4/2.3 0.6VAS score of thirst (mm) 47.1 24.5Sensation of abnormal xerostomia 62 (68.9)VAS score of oral dryness (mm) 49.2 25.2VAS score of oral comfort (mm) 44.0 21.2VAS score of speak (mm) 37.0 24.1VAS score of sleep (mm) 37.2 22.3VAS score of chew and swallow (mm) 38.1 24.3BUN (mg/dl) 72.7 18.2Sodium (mmol/L) 137.3 2.1Potassium (mmol/L) 5.0 0.6Hematocrit (%) 28.5 4.0Serum albumin (g/dl) 3.9 0.3AST/ALT (U/L) 18.0 10.0/19.6 14.6ALK-P (U/L) 129.0 44.3Uric acid (mg/dl) 6.2 1.1Fasting cholesterol/triglycerides (mg/dl) 178.4 37.5/166.5 106.0Plasma Ang II (pg/ml) 185.8 75.9Plasma ANP (pg/ml) 1326.3 708.1Fasting blood sugar (mg/dl) 104.7 41.5Hemoglobin A1c (n 28) 7.0 1.5
aHD, hemodialysis; nPCR, normalized protein catabolic rate; SBP, systolic BP; DBP, diastolic BP; IDWG, interdialytic weightgain; IDWG%, IDWG/target dry weight; VAS, visual analog scales; AST, aspartate aminotransferase; ALT, alanineaminotransferase; ALK-P, alkaline phosphatase; BUN, blood urea nitrogen; Ang II, angiotensin II; ANP, atrial natriureticpeptide.
J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3421
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
5/12
VAS of thirst, daily IDWG, and daily IDWG% are shown in
Table 2. We omitted time on HD, post-HD systolic and diastolic
BP, alanine aminotransferase, serum creatinine, fasting blood
sugar, lipid profiles (fasting triglycerides and cholesterol), and
plasma osmolality and ANP levels in the table because none of
the correlation coefficients had aP 0.15, and none was left or
forced into the final model of multiple linear regressions with
stepwise selections. The VAS xerostomia scores seemed to be
correlated with VAS of thirst, daily IDWG, and IDWG%. In
multiple regression analyses (Table 3), daily IDWG was inde-
Table 2. Correlates of VAS thirst score, mean daily IDWG, and daily IDWG% in the observational study
VariablesVAS of Thirst Daily IDWG Daily IDWG %
r P r P r P
Age 0.436 0.001 0.502 0.001 0.432 0.001Kt/V 0.259 0.014 0.239 0.023 0.074 0.489
nPCR 0.011 0.920 0.181 0.089 0.135 0.205Pre-HD SBP 0.233 0.027 0.244 0.021 0.138 0.196Pre-HD DBP 0.190 0.073 0.159 0.134 0.066 0.534VAS oral dryness 0.932 0.001 0.828 0.001 0.555 0.001VAS oral comfort 0.884 0.001 0.725 0.001 0.477 0.001VAS speak 0.495 0.001 0.426 0.001 0.254 0.016VAS sleep 0.612 0.001 0.465 0.001 0.148 0.165VAS chew and swallow 0.607 0.001 0.458 0.001 0.302 0.004BUN 0.380 0.001 0.449 0.001 0.429 0.001Sodium 0.180 0.090 0.181 0.088 0.171 0.108Potassium 0.029 0.783 0.038 0.724 0.132 0.216Hematocrit 0.098 0.360 0.160 0.131 0.058 0.588Serum albumin 0.001 0.991 0.169 0.111 0.189 0.075AST 0.161 0.130 0.142 0.181 0.024 0.821ALK-P 0.075 0.481 0.215 0.042 0.067 0.531Uric acid 0.150 0.159 0.230 0.029 0.013 0.900Plasma Ang II 0.022 0.838 0.047 0.658 0.151 0.156
Table 3. Multiple linear regression analyses for thirst, daily IDWG, and daily IDWG% in the observation period(final models)a
VariablesVAS of Thirst (R2 0.876) IDWG (R2 0.720) IDWG % (R2 0.437)
(95% CI) P (95% CI) P (95% CI) P
Age 0.019 (0.037 to 0.002) 0.032 0.003 (0.007 to 0.001) 0.123 0.009 (0.019 to 0.001) 0.046Gender 0.249 (0.135 to 0.634) 0.200 0.016 (0.078 to 0.111) 0.732 0.141 (0.353 to 0.072) 0.191Diabetes 0.264 (0.714 to 0.186) 0.246 0.003 (0.110 to 0.103) 0.949 0.106 (0.359 to 0.147) 0.407Use ACEI
or AIIA0.009 (0.386 to 0.403) 0.95 0.008 (0.101 to 0.085) 0.870 0.129 (0.091 to 0.350) 0.247
Kt/V 0.993 (1.993 to 0.007) 0.052 nPCR 0.235 (0.012 to 0.459) 0.040 Pre-HD SBP 0.004 (0.001 to 0.008) 0.085 VAS oral
dryness0.580 (0.411 to 0.749) 0.001 0.099 (0.076 to 0.122) 0.001 0.098 (0.045 to 0.152) 0.001
VAS oralcomfort
0.322 (0.145 to 0.500) 0.001
BUN 0.005 (0.006 to 0.016) 0.380 0.003 (0.000 to 0.006) 0.027 0.009 (0.002 to 0.015) 0.007Sodium 0.031 (0.128 to 0.065) 0.520 0.013 (0.035 to 0.010) 0.265 0.014 (0.068 to 0.039) 0.590Potassium 0.047 (0.253 to 0.346) 0.757 0.002 (0.047 to 0.069) 0.949 0.133 (0.035 to 0.301) 0.120Hematocrit 0.012 (0.000 to 0.024) 0.043 Plasma Ang II 0.002 (0.001 to 0.005) 0.121 0.000 (0.000 to 0.001) 0.647 0.001 (0.000 to 0.003) 0.145
aCI, confidence interval; ACEI, angiotensin-converting enzyme inhibitor; AIIA, Ang II receptor antagonist.
3422 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 3418 3429, 2005
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
6/12
pendently associated with the nPCR, VAS oral dryness score,
and blood urea nitrogen and hematocrit levels. Daily IDWG%
was independently associated with age, VAS oral dryness
score, and blood urea nitrogen level. This indicates that xero-
stomia is an independent determinant for IDWG in HD pa-
tients.
The UWS was measured in 45 of the 90 participants, and the
demographic data of these 45 participants did not differ fromthose of the other participants (data not shown). The UWS was
normal (0.250 to 0.500 ml/min [35]) in 13 (29%) participants,
and the overall mean was 0.162 0.107 ml/min. Twenty (44%)
participants had hyposalivation (UWS 0.150 ml/min [34]),
and 4 (8%) had no measurable saliva. The UWS was signifi-
cantly correlated with VAS scores for oral dryness (r 0.690,
P 0.001; Figure 2A), oral comfort (r 0.523, P 0.035),
speaking (r 0.452,P 0.043), and sleeping (r 0.391,P
0.048) but not the VAS chew and swallow score (r 0.257,
P 0.084). The UWS was modestly correlated with IDWG (r
0.361, P 0.016; Figure 2B) and IDWG% (r 0.302, P
0.045). These data demonstrated that the xerostomia in our
participants was correlated with the decreased UWS, which
might be a target of intervention for reducing IDWG.
Pilot Study before Clinical TrialFifteen hyperdipsic HD patients (age 52.3 5.1 yr; duration
of HD 38.4 8.2 mo; mean daily IDWG% 2.8 0.9%/d) and 15
age-matched healthy control subjects (age 54.9 5.1 yr) were
enrolled for pilocarpine and placebo treatment (Figure 3). Al-
though pilocarpine treatment increased the salivary flow rate,
the rate did not increase to the baseline level of healthy control
subjects. The time course of the pilocarpines effect on thewhole salivary flow rate in HD patients was comparable to that
in healthy control subjects, and no effect on salivary flow rate
was noted with the placebo treatment. In addition, the predi-
alysis UWS and pilocarpine-stimulated whole salivary flow
rates were significantly greater than those of postdialysis at
each time point. This demonstrated that the hydration status
could affect the salivary flow rate in HD patients.
Interventional Clinical TrialShort-Term, Single-Blind, Placebo-Controlled, Crossover
Study Period. Sixty hyperdipsic patients were enrolled and
randomly assigned to one of the two treatments (Figure 1), and35 participants who completed this study period were included
in the analyses. After the pilocarpine treatment, we demon-
strated a significant improvement in UWS and the VAS scores
of oral dryness, oral comfort, and speaking, with overall im-
provements in thirst and stress of fluid restriction. A modest
but statistically significant decrease in IDWG2d(approximately
0.2 kg;P 0.013) was also observed, but no significant change
was found in IDWG3dor blood test results (Table 4). A total of
25 patients withdrew during this study period, and the reasons
for withdrawals and adverse effects in the remaining 35 partic-
ipants are presented in Table 5.
Long-Term, Single-Blind, Placebo-Controlled Study Pe-
riod. Thirty-five participants completed this study period,
among whom 20 received placebo treatment and 15 received
pilocarpine treatment. There was no significant between-group
difference in age, gender, time on HD, and underlying diseases
that caused ESRD. After 3 mo of pilocarpine treatment, signif-
icant improvements were observed in three of the five xeros-
tomia-related items (oral dryness, oral comfort, and speaking),
VAS scores for thirst and stress of fluid restriction, UWS,
IDWG2d(2.95 0.31versus3.71 0.32;P 0.021), and IDWG3d(3.31 0.45versus4.38 0.22;P 0.007; Table 6). Pilocarpine
treatment was also associated with decreased BP, increased
serum albumin, and a near-significant increase in serum so-
dium. No such effects were observed in the placebo treatment
group. Adverse effects were generally of mild or occasionally
moderate severity and mostly appeared within the first several
days of drug administration and improved within 2 wk. The
most frequent side effect was sweating (in nine participants
[45%] in the pilocarpine treatment group), and other adverse
effects included anorexia, dizziness, headache, dyspepsia, and
diarrhea. There was no withdrawal in this study period.
DiscussionTo our knowledge, this study is the first report to document
the impact of decreased salivary flow rate on the thirst and
IDWG in HD patients on the basis of both observational and
Figure 2. The unstimulated salivary flow rate (UWS) in 45 he-modialysis (HD) patients. (A) The UWS was significantly cor-related with visual analog scales (VAS) score of oral dryness(r 0.69,P 0.001). (B) The UWS was modestly correlatedwith mean daily interdialytic weight gain (IDWG; r 0.361,
P 0.016).
J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3423
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
7/12
Figure 3.Effect of pilocarpine and placebo on whole salivary flow rate of hyperdipsic (IDWG% 2%/d) HD patients (n 15) and
healthy control subjects (n 15) in the pilot study. aP 0.001 as compared with the baseline level of healthy control subjects; bP 0.01 as compared with the pre-HD baseline levels of HD patients; cP 0.05 as compared with the pre-HD baseline levels of HDpatients;dP 0.05 as compared with baseline levels in each group;eP 0.01 as compared with baseline levels in each group. Errorbars SE.
Table 4. Results of short-term (2 wk), single-blind, placebo-controlled, crossover intervention perioda
Sequence of Treatment Baseline Course 1(2 wk)Washout
(3 wk)Course 2
(2 wk)OEP
COP
UWSP-C 0.11 (0.02)b 0.14 (0.02) 0.08 (0.04) 0.09 (0.03) 0.017 0.194C-P 0.09 (0.02) 0.10 (0.03) 0.09 (0.02) 0.15 (0.02) 0.325
VAS of thirstP-C 74.8 (3.5) 55.4 (4.8) 75.4 (3.5) 71.6 (4.2) 0.001 0.706C-P 65.4 (3.7) 64.0 (4.0) 67.9 (2.9) 34.3 (2.0) 0.254
VAS of fluid restrictionP-C 68.5 (10.2) 39.7 (8.7) 56.7 (10.9) 62.3 (10.2) 0.023 0.824C-P 72.3 (8.9) 68.9 (9.2) 59.7 (10.4) 41.7 (9.4) 0.728
VAS of oral drynessP-C 71.8 (3.7) 46.2 (3.0) 70.3 (3.6) 65.8 (4.5) 0.001 0.517C-P 64.2 (3.0) 52.9 (3.3) 65.2 (2.8) 31.5 (2.1) 0.075
VAS of comfortP-C 66.4 (5.8) 48.7 (5.1) 65.8 (5.3) 60.4 (5.4) 0.008 0.829C-P 56.6 (3.7) 50.8 (3.8) 57.0 (3.0) 28.7 (3.0) 0.187
VAS of speakP-C 44.7 (8.0) 34.2 (7.2) 48.4 (8.3) 51.7 (6.6) 0.034 0.949C-P 31.7 (6.0) 31.8 (6.0) 35.0 (6.5) 21.1 (4.4) 0.408
IDWG2 dP-C 3.69 (0.23) 3.51 (0.23) 3.68 (0.19) 3.68 (0.23) 0.013 0.789C-P 3.45 (0.18) 3.57 (0.21) 3.49 (0.18) 3.29 (0.19) 0.565
IDWG3 dP-C 4.41 (0.22) 4.32 (0.23) 4.48 (0.25) 4.37 (0.2) 0.514 0.246C-P 4.34 (0.25) 4.15 (0.22) 4.24 (0.19) 4.13 (0.18) 0.310
aOE, overall treatment effects; CO, carryover effects; UWS, unstimulated whole salivary flow rate; P-C, pilocarpine, placebo(n 15); C-P, placebo, pilocarpine (n 20); IDWG3 d, mean interdialytic weight gain during a 3-d period; IDWG2 d, meaninterdialytic weight gain during a 2-d period.
b
Mean (SE).
3424 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 3418 3429, 2005
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
8/12
interventional data. These findings have an important implica-
tion for the care of HD patients because thirst and fluid over-
load are unsolved stressors in the daily life of many patients
(15). We demonstrated that pilocarpine treatment increased
UWS and reduced both the subjective feeling of thirst and the
objective IDWG. It also led to a modest decrease in the mean
arterial BP and an increase in the serum albumin level.
Taiwan has the highest incidence and the second highest
prevalence of dialysis in the world (36). A nationwide survey at
the end of 2001 showed that the mean patient age was 56.1
9.8 yr and that the causes of ESRD include chronic glomerulo-
nephritis (32%), diabetic nephropathy (29%), and hypertension
(6%) (37). The demographic data of our participants (Table 1)
were comparable to that survey. Xerostomia was reported by
68.9% of the 90 participants in our observational study, which
also agreed with other studies (19,25). Measurement of UWS is
the most reliable method for quantifying the salivary function
(38), and the mean UWS (0.162 0.107 ml/min) of our patients
was significantly lower than the normal reference value of 0.25
to 0.5 ml/min (35). We also found that hyperdipsic patients had
extremely low baseline UWS (0.09 ml/min in the pilot study
[Figure 3]; 0.11 and 0.09 ml/min in each group, respectively, in
the interventional trial [Tables 4 and 6]), which was comparable
with that of patients who received radiotherapy for head andneck tumors (0.113 ml/min) (39). Such low flow rates indicate
massive salivary gland damage (approximate 75% of total sal-
ivary glandular tissue) (40). The results suggest a high preva-
lence of severe salivary gland dysfunction in HD patients,
especially in hyperdipsic ones.
The multivariate analyses in our study revealed that VAS
oral dryness score (a xerostomic score) was an independent
determinant of thirst, IDWG, and IDWG% in HD patient-
s (Table 3). We also demonstrated that the UWS was correlated
with several VAS scores for xerostomia, daily IDWG, and
IDWG%, especially oral dryness score (Figure 2), suggesting
that xerostomia in our participants was caused by the de-creased UWS, which is in agreement with other studies show-
ing that uremic xerostomic symptoms are associated with sal-
ivary gland dysfunction (1820). These observational data
strongly suggested that decreased salivary flow might contrib-
ute to IDWG, and the subsequent pilocarpine interventional
trial further confirmed the dipsogenic effect of decreased saliva
flow. Whereas pilocarpine has a weak central dipsogenic ef-
fect (17,41), it is unlikely that pilocarpine reduces IDWG by
directly inhibiting the thirst center. The results of this study
agree with previous physiologic researches (17,42,43), suggest-
ing an oropharyngeal factor that influences drinking. Ramsayet
al. (42) found that dehydrated dogs drank water rapidly butstopped well before normal blood osmolality was restored. This
early inhibition of thirst (and vasopressin secretion) occurred
even when the water was drained from the stomach through a
gastric fistula to prevent rehydration. These observations sug-
gest neural inputs from the oropharynx to the brain that al-
lowed dogs to regulate their drinking volume (42). This phe-
nomenon has been confirmed in humans by Figaro et al.(43).
Brunstromet al.(17) induced a xerostomic state by placing two
absorbent rolls in each cheek to reduce salivary flow and con-
firm that decreased salivary flow may cause more fluid intake
in healthy volunteers. Our study further demonstrated that the
magnitude of decreased salivary flow rate was sufficient to
cause exaggerated thirst and large IDWG in hyperdipsic HD
patients.
The mechanism of salivary gland dysfunction in HD patients
is unknown; however, some researchers (18,19) have proposed
that it is caused by dehydration and direct uremic injury. In
normal individuals, there is a relationship between the salivary
flow rate and body hydration, and the UWS is larger in well-
hydrated status than that in dehydrated status (3335). This
relationship is maintained in dialysis patients and can be dem-
onstrated by Figure 3, which shows that the predialysis UWS
and pilocarpine-stimulated whole salivary flow rates were sig-
nificantly greaterbut modestthan those of the postdialysis
period in each corresponding time point. In HD patients with
Table 5. Withdrawal and adverse effects in short-term (2wk) intervention period (60 hyperdipsic patients)
PilocarpinePhase
(n %)
PlaceboPhase
(n %)
Withdrawal in the precrossover
period (n 17)
9 (30.0) 8 (26.7)
sweating 4 (13.3) 0 (0)vomitinga 1 (3.3) 0 (0)headache 1 (3.3) 1 (3.3)diarrhea 1 (3.3) 1 (3.3)noncompliance 3 (10.0) 6 (20.0)
Withdrawal in the postcrossoverperiod (n 8)
2 (9.1) 6 (28.6)
sweating 1 (4.5) 0 (0)nauseab 1 (4.5) 0 (0)palpitation 1 (4.5) 0 (0)dizziness 0 (0) 1 (4.8)noncompliancec 0 (0) 5 (23.8)
Adverse effects (n 35)sweatingc 24 (68.6) 3 (8.6)vomitingc 6 (17.1) 0 (0)nausea 4 (11.4) 0 (0)diarrhea 3 (8.6) 0 (0)asthenia 3 (8.6) 1 (2.9)hypertension 2 (5.7) 0 (0)headache 1 (2.9) 1 (2.9)abdominal distension 1 (2.9) 1 (2.9)dizziness 1 (2.9) 2 (5.7)myalgias 1 (2.9) 0 (0)insomnia 1 (2.9) 0 (0)
taste change 1 (2.9) 0 (0)palpitation 1 (2.9) 1 (2.9)visual blurring 1 (2.9) 0 (0)abdominal pain 1 (2.9) 1 (2.9)
aOne case withdrew because of sweating and vomiting.bOne case withdrew because of sweating and nausea.cP 0.05.
J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3425
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
9/12
persistent large IDWG, it is possible that large IDWG increases
UWS initially; however, large IDWG also leads to large ultra-
filtration in dialysis session; it thus compromises the tissue
perfusion and causes damage of salivary glands. In such a
condition, the UWS will decrease with time, and the effect of
hydration to increase UWS may be attenuated subsequently.
Because low UWS further increases fluid intake, the hyperdip-
sic HD patients will have lower UWS eventually. In addition,
Bots et al.(25) argued that salivary glands maintain their secre-
tory capacity because they observed a remarkable difference
between UWS and chewing-stimulated whole salivary flow. In
our trial, however, pilocarpine treatment only modestly in-
creased the salivary flow rate. Noteworthy, any mechanical
stimulation would increase the fluid from a nonsalivary gland
source, such as gingival crevicular fluid, and might interfere
with the interpretation of salivary function tests (18,44). Recent
studies (20,45) demonstrated that the uremic salivary dysfunc-
tion is associated with glandular atrophy, fibrosis, and accu-
mulation of fibrillar components, which suggest that uremic
salivary dysfunction is not only a functional disturbance but
also an organic change.
Pilocarpine exerts its effect through cholinergic stimulation
of saliva from residual salivary gland tissues, and an increase of
a relatively modest amount of saliva seems to be sufficient to
overcome the xerostomia (40). Although pilocarpine alleviated
the subjective feeling of xerostomia, thirst, and the stress of
fluid restriction in our 2-wk interventional trial period, the
objective reduction in IDWG was minimal; it took 8 to 12 wk to
demonstrate a significant reduction in IDWG. As xerostomia
develops insidiously (2729,40) and fluid intake is a mild form
of addiction (1416), the delay in the reduction of IDWG is
reasonable. This suggests that prolonged pilocarpine treatment
is required to see benefits in IDWG. A 2-wk crossover study of
Bots et al. (46) evaluated the effect of chewing gum or saliva
Table 6. Results of long-term (3 mo), single-blind, placebo-controlled intervention perioda
VariablePilocarpine (n 20) Placebo (n 15)
Pd Pe
Before After Pb Before After Pc
UWS (ml/min) 0.11 (0.03) 0.15 (0.02) 0.008 0.09 (0.03) 0.10 (0.02) 0.506 0.312 0.038
Whole saliva 60 min
after drug
0.21 (0.04) 0.25 (0.04) 0.123 0.11 (0.04) 0.09 (0.02) 0.765 0.023 0.006
VAS thirst (mm) 78.1 (2.8) 49.1 (3.4) 0.007 75.4 (3.2) 62.5 (4.5) 0.31 0.605 0.031
VAS stress of fluidrestriction (mm)
62.7 (3.4) 25.4 (2.3) 0.003 58.9 (12.7) 62.5 (9.4) 0.213 0.453 0.004
VAS oral dryness(mm)
67.8 (3.9) 48.8 (3.1)
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
10/12
substitute on thirst, xerostomia, and IDWG and found no
change in IDWG. The 2-wk period might be too short, and the
inclusion of both hyperdipsic and nonhyperdipsic patients
might make the effect of deceasing IDWG difficult to demon-
strate. Furthermore, other researchers have demonstrated that
saliva substitutes and chewing gum were generally ineffective
in treating xerostomia caused by a variety of diseases, including
Sjogren syndrome, radiation treatment, and idiopathic salivarygland dysfunction (2628,40,47). In addition, gustatory and
masticatory stimulation have only short effect, and their long-
term use may irritate the oral tissue (13,40). Our long-term
pilocarpine trial also showed a modest increase in albumin
level and a reduction in mean BP. The increase of serum albu-
min might be due to a change of appetite after alleviation of
xerostomia, and the BP change might be secondary to the
decrease in IDWG. Although pilocarpine has a parasympa-
thetic effect, previous studies did not observe an antihyperten-
sive property (2629). Furthermore, pilocarpine tended to in-
creased serum sodium, suggesting that fluid intake, rather than
salt, was influenced.The dryness symptoms that are experienced by HD patients
possibly are not restricted to the oral cavity but also involve the
whole body. General exocrine gland dysfunction has been de-
scribed in HD patients, including the reduced acid secretion,
impaired peptic secretion, dry eyes, and cutaneous xerosis
(20,4850). The pharmacologic properties of pilocarpine sug-
gest that it can stimulate exocrine gland secretion in other organ
systems besides the oral cavity. Although we did not assess
effects of pilocarpine on extra-oral sicca symptoms in this
study, previous research has shown its beneficial effects on
extra-oral symptoms in patients with Sjogren syndrome, in-
cluding dry eyes, nasal dryness, dry skin, vaginitis sicca, andthe inability to expectorate (27,28). It will be intriguing to assess
extra-oral effects in further studies.
The most prevalent pilocarpine-related adverse effects in our
study included sweating, vomiting, and diarrhea (Table 5). De-
spite the high incidence of sweating, this and other adverse
effects were perceived as minor by most patients and improved
within 2 wk. The withdrawal rate as a result of pilocarpine-
related adverse effects was 15.3% (8 of 52) in this trial. Approx-
imately 34.6% (18 of 52) of participants experienced a mild
bitter taste during pilocarpine treatment, whereas 9.8% (5 of 51)
of participants had the same perception during placebo treat-
ment. However, this had no impact on the single-blind design
of our study. Each participant was told that we would provide
two solutions for xerostomia, and although to some partici-
pants the pilocarpine solution tasted a little bitter, they did not
know which of the solutions contained the pilocarpine during
the study period.
There were several limitations to our interventional trial.
Although long-term effectiveness and safety of pilocarpine
treatment for radiation-induced xerostomia (26,31) and Sjogren
syndrome (32) have been documented, those of this treatment
in HD patients have not been established in our study because
of the small sample size and short duration. In addition, only
clinically stable patients were enrolled in our study; therefore,
it remains uncertain whether our findings can be generalized to
individuals with multiple concurrent diseases. In addition, a
portion of the patients complained of inconvenience and the
bitter taste of the pilocarpine solution, and it is reasonable to
speculate that tablets will improve compliance and eliminate
unfavorable taste.
In conclusion, our study clearly demonstrated the dipsogenic
effect of decreased salivary flow in HD patients. In the 3-mo
clinical trial, pilocarpine significantly alleviated the exagger-ated thirst and large IDWG of hyperdipsic HD patients. On the
basis of these findings, we suggest that pilocarpine could serve
as a therapeutic agent to reduce IDWG in hyperdipsic HD
patients. Further large-scale trials, preferably with pilocarpine
tablets, should be conducted to confirm its long-term effects.
AcknowledgmentsThis study was supported by the Cheng Kung University Hospital
Research Committee research grants NCKUH-2003-05 and NCKUH-
2004-63.
This study is registered as ISRCTN41671411 (http://www.controlled-
trials.com/isrctn/trial//0/41671411.html).We thank the hemodialysis unit staffs of the Kuos General Hospital,
Tainan, Taiwan, for help.
References1. Baldree KS, Murphy SP, Powers MJ: Stress identification
and coping patterns in patients on hemodialysis. Nurs Res31: 107112, 1982
2. Abuleo JG: Large interdialytic weight gains: Causes, con-sequences and corrective measures. Semin Dial 11: 2532,1998
3. Kimmel PL, Varela MP, Peterson RA, Weihs KL, SimmensSL, Alleyne S, Amarashinge A, Mishkin GJ, Cruz I, Veis JH:Interdialytic weight gain and survival in hemodialysis pa-tients: Effects of duration of ESRD and diabetes mellitus.Kidney Int 57: 11411151, 2000
4. Rahman M, Fu P, Sehgal AR, Smith MC: Interdialyticweight gain, compliance with dialysis regimen, and age areindependent predictors of blood pressure in hemodialysispatients.Am J Kidney Dis 35: 257265, 2000
5. Mistiaen P: Thirst, interdialytic weight gain, and thirst-intervention in hemodialysis patients: A literature review.Nephrol Nurs J28: 601615, 2001
6. Kooistra MP, Vos J, Koomans HA, Vos PF: Daily home
haemodialysis in the Netherlands: Effects on metaboliccontrol haemodynamics and quality of life. Nephrol DialTransplant13: 28532860, 1998
7. Barre PE, Brunelle G, Gascon-Barre M: A randomized dou-ble blind trial of dialysate sodiums of 145 mEq/L, 150mEq/L and 155 mEq/L. ASAIO Transplant 34: 338341,1988
8. Cybulsky AV, Matni A, Hollomby DJ: Effects of high so-dium dialysate during maintenance hemodialysis.Nephron41: 5761, 1985
9. Daugirdas JT, AI Kudsi RR, Ing TS, Norusis MJ: A doubleblind evaluation of sodium gradient hemodialysis. Am JNephrol5: 163168, 1985
10. Giovannetti S, Barsotti G, Cupisti A, Morelli E, Agostini B,
Posella L, Gazzetti P, Dani L, Aloisi M, Antonelli A, Baldari
J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3427
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
11/12
G, Nerucci B, Caprioli R, Palla R: Dispogenic factors oper-ating in chronic uremia on maintenance hemodialysis.Nephron66: 413420, 1994
11. Oldenburg B, MacDonald GJ, Shelley S: Controlled trial ofenalapril in patients with chronic fluid overload undergo-ing dialysis. BMJ296: 10891091, 1998
12. Kuriyama S, Tomonari H, Sakai O: Effects of cilazapril onhyperdipsia in hemodialyzed patients. Blood Purif14: 35
41, 199613. Rogers PW, Kartzman NA: Renal failure, uncontrolled
thirst and hyperreninemia. Cessation of thirst with bilat-eral nephrectomy. JAMA225: 12361238, 1973
14. Molaison EF, Yodrick MK: Stage of change and fluid intakein dialysis patients. Patient Educ Counsel 49: 512, 2003
15. Kaplan DA, Czaczkes TW: Personality factors in chronichemodialysis patients causing non-compliance with themedical regimen.Psychosom Med34: 333344, 1972
16. Procci WR: Dietary abuse in maintenance hemodialysispatients.Psychosomatics19: 1624, 1978
17. Brunstrom JM: Effect of mouth dryness on drinking behav-ior and beverage acceptability. Physiol Behav 76: 423429,
200218. Kho HS, Lee SW, Chung SC, Kim YK: Oral manifestations
and salivary flow rate, pH, and buffer capacity in patientswith end-stage renal disease undergoing hemodialysis.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88: 316319, 1999
19. Kao CH, Hsieh JF, Tsai SC, Ho YJ, Chang HR: Decreasedsalivary function in patients with end-stage renal diseaserequiring hemodialysis. Am J Kidney Dis 36: 1110 1114,2000
20. Postorino M, Catalano C, Martorano C, Cutrupi S, MarinoC, Cozzupoli P, Scudo P, Zoccali C: Salivary and lacrimalsecretion is reduced in patients with ESRD.Am J Kidney Dis
42: 722728, 200321. Wu KS, Huang JJ, Kuo SC, Chuang SF, Sung JM: UremicstomatitisA forgotten uremic symptom. Dial Transplant34: 30-32: 46, 2005
22. Merril A, Peterson LJ: Gingival hemorrhage secondary touremia.Oral Surg29: 530535, 1990
23. Chuang SF, Sung JM, Kuo SC, Huang JJ, Lee SY: Oral anddental manifestations in diabetic and nondiabetic uremicpatients receiving hemodialysis. Oral Surg Oral Med OralPathol Oral Radiol Endod 99: 689695, 2005
24. Wirth JB, Folstein MF: Thirst and weight gain during main-tenance hemodialysis.Psychosomatics 23: 11251134, 1982
25. Bots CP, Brand HS, Veerman ECI, Valentijn-Benz M, Van
Amerongen BM, Valentijn RM, Vos PF, Bijlsma JA, Beze-mer PD, ter Wee PM, Amerongen AVN: Interdialyticweight gain in patients on hemodialysis is associated withdry mouth and thirst. Kidney Int66: 16621668, 2004
26. Johnson JT, Ferretti GA, Nethery WJ, Valdez IH, Fox PC,David NG, Muscoplat CC, Gallagher SC: Oral pilocarpinefor post-irradiation xerostomia in patients with head andneck cancer. N Engl J Med 329: 390395, 1993
27. Fox PC, Atkinson JC, Macynski AA, Wolff A, Kung DS,Valdez IJ, Jackson W, Delapenha RA, Shiroky J, Baum BJ:Pilocarpine treatment of salivary gland hypofunction anddry mouth (xerostomia). Arch Intern Med 151: 11491152,1991
28. Papas AS, Fernandez MM, Castano RA, Gallagher SC,
Trivedi M, Shrotriya RC: Oral pilocarpine for symptomatic
relief of dry mouth and dry eyes in patients with Sjogrensyndrome. Adv Exp Med Biol 438: 973978, 1998
29. Nusair S, Rubinow A: The use of oral pilocarpine in xero-stomia and Sjogren syndrome.Semin Arthritis Rheum 28:360367, 1999
30. Charra B, Laurent G, Chazot C, Calemard E, Terrat JC,Vanel G, Ruffet M: Clinical assessment of dry weight.Nephrol Dial Transplant11[Suppl 2]: 1619, 1996
31. Zimmerman RP, Mark RJ, Tran LM, Juillard GF: Concom-itant pilocarpine during head and neck irradiation is asso-ciated with decreased posttreatment xerostomia. Int J Ra-diat Oncol Biol Phys 37: 571575, 1997
32. Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, SalisburyPL 3rd, Tran-Johnson TK, Muscoplat CC, Trivedi M, Gold-lust B, Gallagher SC: Pilocarpine tablets for the treatmentof dry mouth and dry eye symptoms in patients withSjogren syndrome. A randomized, placebo-controlled,fixed-dose, multicenter trial.Arch Intern Med159: 174181,1999
33. Navazash M: Methods for collecting saliva.Ann N Y Acad
Sci694: 7277, 199334. Mulligan R, Navazash M, Wood GJ: A pilot study compar-ing three salivary collection methods in an adult popula-tion with salivary gland hypofunction.Spec Care Dentist15:154157, 1995
35. Navazesh M, Christensen C, Brightman V: Clinical criteriafor the diagnosis of salivary gland hypofunction.J Dent Res71: 13631369, 1992
36. US Renal Data System: USRDS 2004 Annual Data Report,Bethesda, National Institutes of Health, National Institutesof Diabetes and Digestive and Kidney Diseases, 2005
37. Huang SJ, Yang WC, Chen SC, Dialysis Evaluation Com-mittee of Taiwan Society of Nephrology: Annual report of
Dialysis Evaluation Committee 2001. Acta Nephrol Taiwan14: 139228, 2002
38. Wang SL, ZT, Lin J, Zhu XZ, Dong H, Zang YG: Investi-gation of the clinical value of total saliva flow rate. ArchOral Biol 43: 3943, 1998
39. Rieke JW, Hafermann MD, Johnson JT, LeVeque FG,Iwamoto R, Steiger BW, Muscoplat C, Gallagher SC: Oralpilocarpine for radiation induced xerostomia: Integratedefficacy and safety results from two prospective random-ized clinical trials. Int J Radiat Oncol Biol Phys 31: 661669,1995
40. Sreebny LM, Valdini A: Xerostomia, a neglected symptom.Arch Intern Med147: 13331337, 1987
41. Fregly MJ: Attenuation of pilocarpine-induced drinking bychronic treatment with estrogen.Proc Soc Exp Biol Med164:178183, 1980
42. Thrasher TN, Keil LC, Ramsay DJ: Drinking, oropharyn-geal signals and inhibition of vasopressin secretion indogs.Am J Physiol 253: R509R518, 1987
43. Figaro MK, Mack GW: Regulation of fluid intake in dehy-drated humans: Role of oropharyngeal stimulation. Am JPhysiol273: R1740R1746, 1997
44. Ferguson DB: Salivary electrolyte. In:Human Saliva: Clini-cal Chemistry and Microbiology, Vol 1, edited by Tenovuo JO,Boca Raton, CRC Press Inc., 1989, pp 7599
45. Kinashi M, Ohbayashi S, Ohbayashi M: Detection of amy-
loid-like fibrils using labial salivary gland biopsy in pa-
3428 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 3418 3429, 2005
-
7/25/2019 Decreased Salivary Flow Rate as a Dipsogenic Factor In
12/12
tients with nondialysis renal insufficiency.Am J Nephrol 9:435437, 1989
46. Bots CP, Brand HS, Veerman ECI, Korevaar JC, Valentinjn-BenzM, Bexemer PD, Valentijn RM, Vos PF, Bijlsma JA, ter Wee PM,Van Amerongen BM, Amerongen AVN: Chewing gum and asaliva substitute alleviate thirst and xerostomia in patients onhemodialysis. Nephrol Dial Transplant 20: 578584, 2005
47. Van der Reijden WA, van der Kwaak JS, Vissink A, Veer-
man EC, Nieuw Amerogen A: Treatment of xerostomia
with polymer-based saliva substitutes in patients withSjogren syndrome. Arthritis Rheum 39: 5763, 1996
48. Takahashi S, Morita T, Koda Y, Murayama H, Hirasawa Y:Gastrointestinal involvement of dialysis-related amyloid-osis.Clin Nephrol30: 168171, 1988
49. Sacs EF, Bloch HM, Milne FJ: Pancreatic supplementationin end-stage renal disease. Nephron37: 120122, 1984
50. Avram MM: High prevalence of pancreatic disease in
chronic renal failure. Nephron18: 6871, 1977
Access to UpToDate on-line is available for additional clinical informationat http://www.jasn.org/
J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3429