1
TITLE PAGE
Title: Effect of repeated treatment with Praziquantel on kidney parenchymal change.
Authors: Panuwat Prathumkam1, Bandit Thinkamrop2 , <Others to be added>
Affiliations:
1
Data Management and Statistical Analysis Center (DAMASAC), Faculty of Public Health, Khon
Kaen University, Thailand
2
Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen University,
Thailand
Corresponding authors:
Name:
Bandit Thinkamrop
Address: Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen
University, Khon Kaen, 40002, Thailand
Telephone:+66-85-0011123
Fax:
+66-43-362075
e-Mail:
bandit@kku.ac.th
Type of contribution:
Original research results
Number of words in the abstract:
232
Number of words in the text:
1,381
Number of tables:
3
Number of figures:
1
2
ABSTRACT
Background: Praziquantel (PZQ) has been the mainstay of liver-fluke control. Favorite raw fermented or
uncooked fish in northeast of Thailand caused re-infections and repeated treatments. Since PZQ and its
metabolites are excreted in the kidney. However, Nephrotoxic effects of PZQ are unknown.
Objective: To investigate a relationship between repeated treatments with PZQ and kidney parenchymal
change.
Methods: A cross-sectional study was carried out on participants from the Cholangiocarcinoma
Screening and Care Program (CASCAP). Subjects were 40 years or older, had been infected with liverfluke or had been treated with PZQ. Kidney parenchymal change was diagnosed by ultrasonography.
Number of treatments with PZQ and other potentially confounding factors that associated with kidney
abnormality were determined by odds ratio (ORs) and 95% confidence interval (95%CI) using multiple
logistic regression.
Results: Among 56,555 subjects with a mean age of 53.8 (±9.45) years, 57.9% were female. The overall
prevalence of treatment with PZQ was 43.6% (95%CI: 43.2 to 44.0). Compared with non-treatment, one
treatment (OR 1.13; 95%CI: 1.04 to 1.23), two treatments (OR 1.33; 95%CI: 1.16 to 1.52), three
treatments (OR 1.56; 95%CI: 1.21 to 2.00) and more than three treatments (OR 1.70; 95%CI: 1.40 to
2.07) with adjusted for all other factors including age, gender, diabetes mellitus and alcohol consumption.
Conclusions: Repeated treatment with PZQ may cause kidney parenchymal change. The necessity for
policy change to provide health education about realization and prevention on repeated treatment with
PZQ.
Keywords: praziquantel, repeated treatment, kidney parenchymal change, renal parenchymal change.
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INTRODUCTION
Opisthorchis viverrini (OV), common name Southeast Asian liver-fluke, is a parasite from
Opisthorchiidae family. OV infection was acquired when people eat raw or undercooked fish[1] and
endemic throughout Thailand, Lao People's Democratic Republic, Vietnam and Cambodia[2]. In
Northeast Thailand - a highest incidence of liver-fluke infection and Cholangiocarcinoma (CCA) in the
world, Praziquantel (PZQ) has been the mainstay of anthelmintic for liver-fluke control and widely
distributed.
Raw fish and fermented fish in several favorite dishes across this region caused high re-infections
and repeated treatments with PZQ [3]. In pharmacokinetic, PZQ was found to concentrate especially in
the liver and kidneys[4]. Since 80% of PZQ and its metabolites are excreted in the kidneys[5].
However, little is known about effects of repeated treatment with PZQ on kidney parenchymal change
(KPC).
This study aimed to investigate a relationship between repeated treatments with PZQ and KPC.
MATERIALS AND METHODS
Study design
This study was conducted at primary and secondary hospitals around 21 provinces in Northeast
Thailand as part of the Cholangiocarcinoma Screening and Care Program (CASCAP, www.cascap.in.th).
All people in risk group who have age more than 40 years and have been infected or treated with liverfluke were carried out in 2013-2015 as a cross-sectional data. Subjects with incomplete information were
excluded. A total 57,687 subjects were included in the analysis.
Study outcome
Ultrasound examinations were performed in secondary hospital by doctor or radiologist. The type
and classification of kidney abnormality were defined as renal cyst, parenchyma change, post
nephrectomy and renal stone.
Statistical analysis
Demographic characteristics of subjects were described using frequency and percentage for
categorical data such as gender, age, education level, occupation, smoking, alcohol consumption and
diabetes mellitus. For continuous data such as age of subjects was described by mean, standard deviation,
median, minimum and maximum.
Prevalence of KPC was calculated in percentage based on a normal approximation to the
binomial distribution. Number of treatments with PZQ and other potentially confounding factors that
associated with KPC were determined by odds ratio (ORs) and 95% confidence intervals (95%CIs) using
multiple logistic regression.
All analysises were performed using R version 3.2.2 (The R foundation for statistical computing).
All statistics test were two-sided and a p-value of less than 0.05 was considered statistical significant.
This project was approved by …….
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RESULTS
A total 105,919 subjects were registered in CASCAP database. From the 60,281 subjects
who had Ultrasound examination results, there were 3,726 subjects excluded from the study due
to incomplete information of data, hence 56,555 subjects were included in the analysis (Fig.1)
Figure 1. Classification diagram
All subjects in CASCAP Database
n = 105,919
Exclude due to no U/S diagnosis.
n = 45,638
Ultrasonography Screening
n = 60,281
Exclude due to incomplete info.
n = 3,726
Included in analysis
n = 56,555
Never had treatment with PZQ
n = 31,592 (56.4%)
Had treatment with PZQ
n = 24,436 (43.6%)
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Demographic Characteristics
Among 56,555 subjects with a mean age 53.8 (±9.4) years ranging from 25.2 to 99.8 years. More
than half of them were female (57.9%), and most of them graduated from primary school (74.7%) and
work as farmer (79.9%) (Table 1.)
Table 1. Demographic and characteristic
Characteristics
Gender
Male
Female
Age in years
Less than 40
40 to 44
45 to 49
50 to 54
55 to 59
60+
Mean (±SD)
Median (Min : Max)
Education level
None
Primary
Secondary (M1)
Secondary (M2)
Certificate
Bachelor
Higher than bachelor
Occupation
Unemployed
Farmer
Labor
Own business
Government official/State enterprises
Others
Smoking
No
Yes
Alcohol consumption
No
Yes, current or previous
Diabetes Mellitus
No
Yes
Number Percent
23,739 42.1
32,685 57.9
1,083
9,069
10,417
10,093
8,524
13,235
53.8
52.8
2.1
17.3
19.9
19.3
16.3
25.3
±9.4
(25.2 : 99.8)
500
41,902
4,275
5,051
882
2,625
846
0.9
74.7
7.6
9.0
1.6
4.7
1.5
1,373
44,803
3,164
1,686
3,386
1,678
2.5
79.9
5.6
3.0
6.0
3.0
42,623 76.5
13,078 23.5
31,029 54.9
25,526 45.1
53,694 94.9
2,861 5.1
Prevalence of Kidney Parechymal Change (KPC)
From 56,555 subjects, the overall prevalence of KPC was 5.9%. KPC was found in 8.4% in male,
but only 4.1% in female. Prevalence of KPC was linearity increased from 5.2%, 6.2%, 7.5%, 7.8% and
9.7% for none, one, two, three and more than three treatments with PZQ. The association between
Number of treatments with PZQ and KPC from crude analysis were highly significant compared with
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none treatments: one treatment (OR 1.20; 95%CI: 1.11 to 1.30), two treatments (OR 1.52; 95%CI: 1.34 to
1.74), three treatments (OR 1.82; 95%CI: 1.43 to 2.30) and more than three treatments (OR 1.95; 95%CI:
1.61 to 2.35). Other factors were significant associated such as gender, age, education level, occupation,
smoking, alcohol consumption and diabetes mellitus. (Table 2)
Table 2. Prevalence of kidney parenchymal change and odds ratio of the factors.
Factors
Overall
Number of treatment with PZQ
None
One
Two
Three
More than three
Gender
Male
Female
Age
Less than 40
40 to 44
45 to 49
50 to 54
55 to 59
60+
Age in years
Education level
None
Primary
Secondary (M1)
Secondary (M2)
Certificate
Bachelor
Higher than bachelor
Occupation
Unemployed
Farmer
Labor
Own business
Government
Others
Smoking
No
Yes
Alcohol consumption
No
Yes, current or previous
Diabetes Mellitus
No
Yes
Number
% KPC
56,555
5.9
29,850
18,634
3,625
857
1,320
5.2
6.2
7.5
7.8
9.7
1
1.20
1.52
1.82
1.95
23,739
32,685
8.4
4.1
1
0.47
1,083
9,069
10,417
10,093
8,524
13,235
1.8
3.3
4.0
4.9
6.4
10.3
1
1.93
2.30
2.91
3.86
6.44
1.051
1.21 – 3.08
1.45 -3.66
1.83 – 4.63
2.43 – 6.12
4.08 – 10.17
1.05 – 1.06
0.70 – 1.46
0.55 – 1.19
0.54 – 1.16
0.54 – 1.39
0.40 – 0.92
0.28 – 0.82
Crude
OR
95% CI
p-value
<0.001
1.11 – 1.30
1.34 – 1.74
1.43 – 2.30
1.61 – 2.35
<0.001
0.44 – 0.51
<0.001
500
41,902
4,275
5,051
882
2,625
846
6.2
6.3
5.1
5.0
5.4
3.9
3.1
1
1.01
0.81
0.79
0.87
0.61
0.48
1,373
44,803
3,164
1,686
3,386
1,678
8.7
6.0
6.0
4.3
3.8
6.2
1
0.67
0.66
0.47
0.41
0.69
42,623
13,078
5.0
8.7
1
1.80
31,029
25,526
5,0
7.0
1
1.43
53,694
2,861
5.7
9.6
1
1.75
<0.001
<0.001
<0.001
0.55 – 0.81
0.52 – 0.84
0.35 – 0.64
0.32 – 0.53
0.53 – 0.91
<0.001
1.67 – 1.94
<0.001
1.33 – 1.53
<0.001
1.53 – 1.99
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Factors associated with kidney parenchymal change.
Using multiple logistic regressions, the association between number of treatments with PZQ and
KPC was adjusted for all other factors including gender, age, alcohol consumption, and diabetes mellitus.
The risk of number of treatments with PZQ still remained significant compared with none treatments: one
treatment (OR 1.13; 95%CI: 1.04 to 1.23), two treatments (OR 1.33; 95%CI: 1.16 to 1.52), three
treatments (OR 1.54; 95%CI: 1.21 to 2.00) and more than three treatments (OR 1.70; 95%CI: 1.40 to
2.07). (Table 3.)
Table 3. Adjusted odds ratio of factors associated with kidney parenchymal change.
Factors
Overall
Number of treatment with PZQ
None
One
Two
Three
More than three
Gender
Male
Female
Age in years
Alcohol consumption
No
Yes, current or previous
Diabetes Mellitus
No
Yes
Education level
None
Primary
Secondary (M1)
Secondary (M2)
Certificate
Bachelor
Higher than bachelor
Number
% KPC
56,555
5.9
29,850
18,634
3,625
857
1,320
23,739
32,685
Crude
OR
Adj.
OR
95% CI
5.2
6,2
7.5
7.8
9.7
1
1.20
1.52
1.82
1.95
1
1.13
1.33
1.54
1.70
8.4
4.1
1
0.47
1.05
1
0.54
1.05
0.50 – 0.59
1.04 – 1.05
1.06 – 1.26
pvalue
<0.001
1.04 – 1.23
1.16 – 1.52
1.21 – 2.00
1.40 – 2.07
<0.001
31,029
25,526
5,0
7.0
1
1.43
1
1.16
53,694
2,861
5.7
9.6
1
1.75
1
1.58
500
41,902
4,275
5,051
882
2,625
846
6.2
6.3
5.1
5.0
5.4
3.9
3.1
1
1.01
0.81
0.79
0.87
0.61
0.48
1
1.30
1.30
1.23
1.19
0.93
0.82
<0.001
<0.001
<0.001
1.38 – 1.80
0.007
0.88 – 1.92
0.86 – 1.97
0.81 – 1.86
0.72 – 1.97
0.60 – 1.45
0.47 – 1.42
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DISCUSSIONS
Explaining the findings
<copy narrative parts of the Results followed by explaining each important findings in turn , 5-10 references needed
here in this section where about half of them are the same as the one cited in the Introduction section of the
manuscript>
Strength of the study
<to be written>
Limitation of the study



Can selection bias distort the findings?
o Selection bias
Can information bias distort the findings?
o Recall bias
Can confounding bias distort the findings?
Conclusions
There was association between number of treatment with PZQ and kidney parechymal change.
Repeated treatment with PZQ may cause kidney parechymal change. The necessity for policy change to
provide health education about realization and prevention on repeated treatment with PZQ.
Recommendations
<to be written>
Acknowledgements:
Funds:
[5-7]
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REFERENCES
1.
2.
3.
4.
5.
6.
7.
Laha T, Pinlaor P, Mulvenna J, Sripa B, Sripa M, Smout MJ, Gasser RB, Brindley PJ, Loukas A:
Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini. BMC genomics
2007, 8:189.
Young ND, Campbell BE, Hall RS, Jex AR, Cantacessi C, Laha T, Sohn WM, Sripa B, Loukas A,
Brindley PJ et al: Unlocking the transcriptomes of two carcinogenic parasites, Clonorchis
sinensis and Opisthorchis viverrini. PLoS neglected tropical diseases 2010, 4(6):e719.
Hinz E, Saowakontha S, Pipitgool V: Opisthorchiasis control in northeast Thailand: proposal for
a new approach. Applied parasitology 1994, 35(2):118-124.
Olliaro P, Delgado-Romero P, Keiser J: The little we know about the pharmacokinetics and
pharmacodynamics of praziquantel (racemate and R-enantiomer). The Journal of antimicrobial
chemotherapy 2014, 69(4):863-870.
Patzschke K, Putter J, Wegner LA, Horster FA, Diekmann HW: Serum concentrations and renal
excretion in humans after oral administration of praziquantel--results of three determination
methods. European journal of drug metabolism and pharmacokinetics 1979, 4(3):149-156.
Devidas A, Lamothe F, Develoux M, Mouchet F, Sellin B: Ultrasonographic assessment of the
regression of bladder and renal lesions due to Schistosoma haematobium after treatment with
praziquantel. Annales de la Societe belge de medecine tropicale 1989, 69(1):57-65.
Chen MG, Fu S, Hua XJ, Wu HM: A retrospective survey on side effects of praziquantel among
25,693 cases of schistosomiasis japonica. The Southeast Asian journal of tropical medicine and
public health 1983, 14(4):495-500.