The Renal Protective Potential Effect of Infusion of Anti-urolithiasis

Formula in Urolithiasis Patients: A Randomized Clinical Study

Ulfatun Nisa

, Peristiwan Ridha Widhi Astana

, Saryanto

, Tyas Friska Dewi

and Enggar Wijayanti

Medicinal Plant and Traditional Medicine Research and Development Center, Ministry of Health, Tawangmangu,

Indonesia

Keywords: Renoprotective, Anti–urolithiasis Formula, Urolithiasis Disease

Abstract: Kidney stones and related urological procedures can lead to chronic kidney disease (CKD). The constituent

plants of an anti-urolithiasis formula developed by B2P2TOOT have a potential renoprotective effect, thus

preventing CKD progression. This randomized open-label clinical study with end-blinded observation was

aimed to evaluate the possible renoprotective effect of anti-urolithiasis formula infusions in urolithiasis

patients. Two hundred volunteer subjects were randomly allocated into two groups: anti-urolithiasis herbal

formula (AHF) and commercial polyextract lithotripsy (CPL). Urine tests were performed, and the estimated

glomerular filtration rate (eGFR) was calculated using a CKD-EPI equation at baseline (day 0) and after the

intervention (day 56). The analysis was done within each group and between both groups using paired sample

T-test and independent T-tests. An increase in the eGFR of subjects in the AHF group was found, although it

was not statistically significant (p=0.35). The mean of the eGFR of subjects in the CPL group after the

intervention was lower, also statistically insignificant (p=0.56). Nevertheless, there were significant

differences in the eGFR after intervention between both groups (p=0.044, 95% CI 0.16–12.4). Our findings

suggest that AHF has a slight potential effect on renal function preservation in urolithiasis patients.

1 INTRODUCTION

Urolithiasis has become a worldwide health burden.

Its incidence rates are 10% for men and 5% for

women (D'Costa et al., 2016). The high recurrence

rate of urolithiasis results in health financing issues

and considerable morbidity (Lee et al., 2015). Also,

several studies have revealed that the formation of

stones in the urinary tract has a strong correlation with

adverse renal outcomes. However, the mechanism

underlying kidney stones and diminished kidney

function is likely multifactorial (Alexander et al.,

2012; Coe et al., 2010). Urolithiasis plays a

significant role in influencing the risk of adverse renal

outcomes and prior history of recurrent symptomatic

episodes. Accordingly, it might produce an increased

risk of end-stage renal disease (ESRD). For example,



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the progressive calcification of calcium kidney stones

at the tubular basement membrane and the ducts of

Bellini causes renal damage through progressive

scarring, leading to ESRD (Coe et al., 2010; Evan,

2010).

Urolithiasis management has recently played an

essential role in preventing several future health

complications—one of the standard procedures in the

management of nephrolithiasis is extracorporeal

shock wave lithotripsy (ESWL). ESWL had been

regularly utilized in the management of urolithiasis.

Nevertheless, it might significantly contribute to the

increased risk of recurring stones and result in greater

difficulty when comminuting stones with ESWL

(Evan, 2010). Moreover, it can result in several

complications, leading to kidney function loss

(Shekar Kumaran and Patki, 2011). This hypothesis

Nisa, U., Widhi Astana, P., Saryanto, ., Dewi, T. and Wijayanti, E.

The Renal Protective Potential Effect of Infusion of Anti-urolithiasis Formula in Urolithiasis Patients: A Randomized Clinical Study.

DOI: 10.5220/0010488300910097

In Proceedings of the 1st Jenderal Soedirman International Medical Conference in conjunction with the 5th Annual Scientiﬁc Meeting (Temilnas) Consortium of Biomedical Science Indonesia

(JIMC 2020), pages 91-97

ISBN: 978-989-758-499-2

has suggested a decrease in renal function by

vasoconstriction, and its persistent stone fragments

may induce acute renal injury (Agawane et al., 2019;

Khan et al., 2011; Nizami et al., 2012; Srisubat et al.,

2014). By contrast, another study found no

correlation between ESWL and CKD development

(D'Costa et al., 2016; E. et al., 2008). The

retrospective study revealed that urological

procedures could significantly increase the risk of

developing elevated serum creatinin but were not

significant in progressing CKD itself (D'Costa et al.,

2016). There is no appropriate drug for the treatment

of urolithiasis despite technological advances in the

field of medicine. However, it is worthwhile to

explore the potential benefits of medicinal plants,

which may affect anti-urolithiasis and restore renal

impairments.

Polyherbal treatment can be considered an

alternative approach to treating urolithiasis. The

investigation of phytotherapy for urolithiasis has been

reported in an ethnopharmacology study, in vitro, and

in vivo models (Ahmed et al., 2016; Akanae et al.,

2010; Nisa and Astana, 2018; Patankar et al., 2020;

Yadav, RD., Jain, SK., Alok, Shashi., Mahor, Alok.,

Bharti, JP., Jaiswal et al., 2011). The diuretic activity

of Orthosiphon stamineus is different when combined

with hydrochlorothiazide and furosemide (Adam et

al., 2009). It takes a longer time to produce effects

than synthetic diuretics but, notably, does not include

any side effects (Tiwari et al., 2017). Meanwhile,

Phyllanthus niruri can inhibit lithiasis' growth in rats

(Morán et al., 2013). The administration of

Phyllanthus niruri can decrease mRNA p65NF-κB

and mRNA IL-6 levels in the kidneys of diabetic rats

(Giribabu et al., 2017). Jonnel B.P. et al. revealed that

an increase in Imperata cylindraca extract

concentration is related to decreased serum creatinine

and blood urea nitrogen (BUN) levels. Thus, several

medicinal plants appear to have distinct mechanisms

for urolithiasis that generate synergetic effects to

facilitate stones' passage.

The constituent plants of the anti-urolithiasis

formula developed by the Medicinal Plant and

Traditional Medicine Research and Development

Center (B2P2TOOT-in Bahasa) have a potential

renoprotective effect, which suggests they can serve

as an alternative method of preventing CKD

progression. This method's safety and efficacy have

been proven in clinical trials (Nisa and Astana, 2019).

Several compositions of the AHF had been reported

to have a potential renoprotective effect in a single-

use form. This study aims to evaluate the possible

renoprotective effect of an anti-urolithiasis herbal

formula in urolithiasis patients.

2 MATERIALS AND METHODS

The study was conducted by the Traditional Plant and

Traditional Medicine Research and Development

Center at the Ministry of Health Indonesian and

involved191 urolithiasis patients. The design of the

study was a purposive randomized open-label study

design, with end-blinded observation. We involved

70 physicians, who all have Saintifikasi Jamu (SJ)

certifications as investigators. The ethics committee

approved the study protocol of the National Institute

of Research and Development (LB.02.01/5.2/KE

063/2016) on March 13

, 2017. The principal

investigator was qualified in traditional and allopathic

medicine and clinical trials, in accordance with Good

Clinical Practices (GCP).

Volunteer patients who fulfilled the inclusion

criteria participated in this study. Before participating

in the study, each subject was requested to read and

sign an informed consent form. The inclusion criteria

were: an age of 17-60 years old, a history of

urolithiasis, the presence of a stone<2 cm in diameter,

serum creatinine levels of<2 g/dl, and liver and

kidney function within a normal range. Patients with

complications from severe diseases and those

requiring surgical intervention were excluded from

the study. Eligible subjects were randomized by

computer software into two groups: the AHF and the

CPL group.

In the AHF group, each subject was given an

herbal formula, which consisted of a dried simplisia

of 10 g of S. arvensis, 6 g of O. stamineus, 4 g of

Strobilanthes crispus, 5 g of Imperata cylindrica, 5 g

of C. xanthorrhiza, 4 g of Curcuma domestica, and 3

g of P. niruri. Each subject was requested to prepare

an infusion from the formula. The AHFwas prepared

by boiling 1 L of water, adding the simplisia into the

boiling water, and letting the mixture boil for 15

minutes. Subjects were instructed to drink the filtered

water twice a day for 56 days, after breakfast and

dinner. Meanwhile, in the CPL group, subjects

consumed CPL, which consisted of an extract of 18

mg of O. stamineus, 6 mg of S. crispa, 24 mg of S.

arvensis L., 2.4 mg of P. niruri, and 100 mg of

Plantago major. They took one capsule of CPL four

times daily, also for 56 days.

Demographic data such as age, sex, BMI, history

of stone recurrence, and stone size were recorded at

day 0 of the study. Urine tests (routine and

microscopic), including tests of urine turbidity, pH,

specific gravity, LE, Nitrit, RBC, and albuminuria,

were performed on days 0, 28, and 56 to observe the

fluctuation of urine quality. The kidney's biochemical

parameters

(creatinine and BUN) were measured on

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

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Figure 1: Enrollment, randomization, allocation, follow-up, and analysis

day 0 and day 56, followed by a calculation of the

estimated glomerular filtration rate (eGFR) using a

CKD-EPI equation.

The data were analyzed statistically using a

GraphPad Prism program for statistical analysis

version 8.0. Descriptive data were calculated and

presented in Table 1. To determine differences before

and after treatment, we performed a paired T-test. An

independent T-test was also conducted to determine

the differences between the two groups.

Alternatively, the Wilcoxon test and Mann–Whitney

U-test were used when there was an abnormal data

distribution in the Kolmogorov–Smirnov test results.

3 RESULTS

Based on Figure 1, the total number of patients

recruited in this studywas191 patients. As many as97

and 94 subjects were analyzed in the AHF and CPL

group, respectively. Each group had subjects who

could not continue the intervention because of a

failure to follow up. The baseline characteristics of

patients are summarized in Table 1.



Table 1: Demographic data of patients.

Parameters AHF

(N=97)

CPL

(N=94)

Mean a

e45-55

45-55

Male:female 1.9:1 1.7:1

BMI

(Overweight:normoweight)

1.18:1 1.38:1

History of recurrent

urolithiasis

1 yr

(34%)

1 yr

(33%)

Avera

e size of stone

10.82±8.19 8.07±5.19

Comparing male and female participants between

the two groups were 1.9:1 and 1.7:1 in the AHF and

CPL group, respectively. Each group also had a

similar BMI ratio between overweight and

normoweight participants. The majority of patients

were in the range of 45-55 years old. About 30% of

patients had a history of stone recurrence within one

year before the study started. The mean of the size of

the stone was similar between the two groups. Figure

2A shows information about the mean of the eGFR for

pre-treatment(day 0) and post-treatment(day 56).

There was no significant difference in the eGFR

between the two groups on day 0. However, after 56

days of treatment, there were significant differences in

the eGFR between the AHF group and the CPL group

(p=0.044, 95% CI 0.16 – 12.4).

The Renal Protective Potential Effect of Infusion of Anti-urolithiasis Formula in Urolithiasis Patients: A Randomized Clinical Study

Figure 2: (A) Mean of eGFRfor pre- and post-treatment between the two groups.(B)Mean difference between AHF and CPL

groups. (C)Mean of eGFR before and after treatment in each group.

An increase in subjects' eGFR was found in the

AHF group on day 56 compared with day 0 (2.24

mL/min per 1.73 m2). However, this was not

statistically significant (p=0.35). In the CPL group,

the average eGFR of subjects on day 56 was lower

than on day 0, though this was also not statistically

significant (p=0.56) (Figure 2B). We calculated the

difference in theeGFR value between day 0 and day

56 in each group, as represented in figure 2C. The

difference in the eGFR in the AHF group showed a

positive value, while in the CPL group, it showed a

negative one.

However, the independent T-test analysis showed

no significant differences. Table 2 shows the urine test

parameters of subjects. These results demonstrate that

both groups' urine turbidity had lower scores at the end

of treatment than in the middle or baseline. There was

a statistically significant difference during treatment

compared to the baseline.

Furthermore, the CPL group's urine turbidity had

substantial differences in the middle of treatment

compared to the baseline. From the table, we can also

see that there is no change in any other urine test

parameter (pH, specific gravity, LE, Nitrite, RBC, or

albuminuria).

4 DISCUSSION

This study was conducted to the potential

renoprotective effect of an anti-urolithiasis herbal

formula in urolithiasis patients. The eGFR Anti-

urolithiasis Herbal Formula's group has a significant

Table 2: Effect of treatment on urine test parameters.

Parameters

AHF CPL

0 da

28 da

56 da

0 da

28 da

Urine turbidity 1.95 ± 0.08 1.80 ± 0.08

1.62±0.0

p<0.05

<0.05

1.88 ± 0.08 1.73 ± 0.07

p<0.05

1.68±0.07

p<0.05

Urine pH 5.90 ± 0.09 6.74 ± 0.76 6.47 ± 0.57 5.97±0.096 6.02 ± 0.09 6.01 ± 0,09

Specific gravit

1.014±0.001 1.016±0.002 1.013±0.001 1.000±0.02 1.015±0.02 1.014±0.02

LE 82.55±16.41 74.64±15.85 72.73±15.90 92.02±17.95 91.76±18.06 87.04±18.09

Nitrite 0.04±0.02 0.03±0.02 0.04 ±0.02 0.08 ±0.03 0.05 ± 0.02 0.03 ± 0.02

No.of RBC’s

erHPF

59.10± 9.65 51.01±8.96 53.19±9.42 48.39±8.55 36.83±7.49 36.94±7.66

Albuminuria 20.57 ±3.75 16.94±3.71 17.89±4.05 16.40±2.52 14.84±2.50 12.83±2.20

Mean±SEM, Statistical analysis performed using independent T-test

As compared to day0

As compared to day 28

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difference in day 56 after treatment compared to the

CPL group. However, other parameters have not a

significant difference in both groups. Furthermore,

after urolithiasis formation, the hindrance of urine

flow can cause a decrease in the Glomerular Filtration

Rate (GFR). Therefore, waste material, especially

BUN (Blood Urea Nitrogen), creatinine, and uric

acid, can be collected in the blood(Kaleeswaran et al.,

2019). This study showed that the AHF and CPL had

diuretic activity, preventing the elevation of these

parameters. Following a previously published report,

the improvement of the eGFR in the AHF group

compared to the CPL group was correlated to

decreased urinary stones size (Nisa and Astana,

2019).

Orthosiphon stamineus and Phyllanthus niruri L

are indigenous medicines widely used in

Indonesia(Nisa and Astana, 2018). Meanwhile,

previous studies reported that the content of

rosmarinic acid in Orthosiphon stamineus had

nephroprotective effects in diabetic nephropathy. It

may have conserved glomerular number loss(Almatar

et al., 2014; Tavafi et al., 2011). However, this

complex mechanism remains unclear, and the

antioxidant properties of Orthosiphon stamineus may

play a significant role in this process. The activation

of s cellular oxidation process was associated with

urolithiasis and chronic calculus

pyelonephritis(Boonla, 2018; Ceban et al., 2016).

The potential anti-urolithiasis activity of Phyllantus

niruri plays an essential role in the early stages of

stone formation. Phyllanthus nirurican makes stones

smoother and more fragile, facilitating the dissolution

of calculi (Lee et al., 2016).

On the other hand, most of the AHF's constituents'

main activity is as a diuretic agent. In terms of diuretic

action, various phytoconstituents may interact with a

synergistic effect, leading to enhanced renal output.

The AHF treatment was revealed to increase the GFR

by dual effects of controlling the growth of stones and

may also have a nephroprotective effect. The

renoprotective strategies of the AHF are based on

several mechanisms and are exceedingly complex.

Meanwhile, the antioxidant and anti-inflammatory

effects of AHF may contribute to the preservative

effects of microcirculation.

The present study results show the proportion of

subjects who had a history of recurrence, the rate of

which was 33%. Meanwhile, the ordinary recurrence

rate of kidney stone disease within one year is only

10%(Patankar et al., 2020). Indeed, the high

recurrency of urolithiasis disease was closely

correlated with side effects, leading to renal function

loss progression. Various degrees of renal

insufficiency is associated with urolithiasis as well.

This phenomenon suggests that a combination of

frequent stone episode recurrence, urinary tract

reinfection, and frequent urological interventions

may initiate renal insufficiency. Many studies have

found that urine parameters could serve as predictive

factors for estimating renal function. One of the key

biomarkers of renal damage is albuminuria. Several

studies have reported that this decreases the risk of

renal damage and urine albumin levels(Abebe et al.,

2019). Albuminuria is a dysfunctional endothelial

marker in the renal region, brain, and heart (Mardiana

et al., 2012). Thus, anti-albuminuria was a target for

the renoprotective agent. Remuzi and Bertani

suggested that albuminuria was a severity marker for

renal injury, indicating that an increase in leak plasma

protein is associated with an increase in kidney

damage severity (De Zeeuw et al., 2004). Several

theories attempt to explain how urolithiasis can

induce renal progression. Several mechanisms

underlying nephrolithiasis can lead to CKD

development through scarring and the deterioration of

renal function. This phenomenon may also cause

direct damage to post-calcifications and

crystallization of the tubular lumen, resulting from

recurrent stone obstruction (D'Costa et al

., 2016).

The limitation of this study is the parameters of

renal function, which used an estimated calculation.

It still needs further research for real renal function

parameters.

5 CONCLUSIONS

Our findings suggest that AHF has a slight potential

effect on renal function preservation in urolithiasis

patients.

ACKNOWLEDGEMENTS

This study was a part of the Saintifikasi Jamu formula

(SJ) program that was carried out with the Ministry of

Health's financial support of the Republic of

Indonesia. We would like to thank the Head of

B2P2TOOT in Tawangmangu, Indonesia, and all

staff.

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The Renal Protective Potential Effect of Infusion of Anti-urolithiasis Formula in Urolithiasis Patients: A Randomized Clinical Study