Phyllanthus niruri as a Promising Alternative Treatment for Nephrolithiasis

Abstract

In spite of considerable efforts to identify effective treatments for urolithiasis, this is a goal yet to be achieved. This review summarizes experimental and clinical data evaluating the effect of the plant Phyllanthus niruri, a plant with worldwide distribution, as a potential agent to prevent and/or to treat urolithiasis The review is based on data from the literature and on the results obtained by our group from either in vivo/in vitro experiments or clinical studies. Phyllanthus niruri has been shown to interfere with many stages of stone formation, reducing crystals aggregation, modifying their structure and composition as well as altering the interaction of the crystals with tubular cells leading to reduced subsequent endocytosis. The clinical beneficial effects of Phyllanthus niruri may be related to ureteral relaxation, helping to eliminate calculi or to clear fragments following lithotripsy, or also to a putative reduction of the excretion of urinary crystallization promoters such as calcium. No adverse renal, cardiovascular, neurological or toxic effects have been detected in either of these studies. Altogether, these studies suggest a preventive effect of Phyllanthus niruri in stone formation or elimination, but still longer-term randomized clinical trials are necessary to confirm its therapeutic properties.

Full text

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Phyllanthus niruri as Treatment for Nephrolithiasis
International Braz J Urol Vol. 36 (6): 657-664, November - December, 2010
Phyllanthus niruri as a Promising Alternative Treatment for
Nephrolithiasis
Mirian A. Boim, Ita P. Heilberg, Nestor Schor
Renal Division, Federal University of Sao Paulo, Unifesp, Sao Paulo, Brazil
ABSTRACT
In spite of considerable efforts to identify effective treatments for urolithiasis, this is a goal yet to be achieved. This review
summarizes experimental and clinical data evaluating the effect of the plant Phyllanthus niruri, a plant with worldwide
distribution, as a potential agent to prevent and/or to treat urolithiasis The review is based on data from the literature and
on the results obtained by our group from either in vivo/in vitro experiments or clinical studies. Phyllanthus niruri has
been shown to interfere with many stages of stone formation, reducing crystals aggregation, modifying their structure and
composition as well as altering the interaction of the crystals with tubular cells leading to reduced subsequent endocytosis.
The clinical beneficial effects of Phyllanthus niruri may be related to ureteral relaxation, helping to eliminate calculi or to
clear fragments following lithotripsy, or also to a putative reduction of the excretion of urinary crystallization promoters
such as calcium. No adverse renal, cardiovascular, neurological or toxic effects have been detected in either of these stud-
ies. Altogether, these studies suggest a preventive effect of Phyllanthus niruri in stone formation or elimination, but still
longer-term randomized clinical trials are necessary to confirm its therapeutic properties.
Key words: renal; lithiasis; treatment; clinical; Phyllanthus niruri
Int Braz J Urol. 2010; 36: 657-64
INTRODUCTION
Urinary stones affect 10-12% of the popula-
tion in industrialized countries. Their incidence has
been increasing over the last years and the age of
onset is decreasing. In addition, the recurrence rate
is high, more than 50% after 10 years (1,2). Genetic,
metabolic, environmental and dietetic factors are
involved in the pathogenesis of urolithiasis, all of
them propitiating the crystallization of salts inside the
renal tubules, further retention and growing to form
a stone (3). Given that urine is normally a supersatu-
rated solution, crystalluria is often observed in normal
individuals, but if crystals remain apart from each
Review ArticleReview Article
doi: 10.1590/S1677-55382010000600002
other, they are washed away by urine flow. However,
under certain circumstances they bind each other due
to chemical and electrical forces triggering the process
of aggregation. The crystals or aggregates then attach
to the epithelium which allow them to grow further
and form the stone (4). Moreover, calcium oxalate
(CaOx) crystals, the main constituent of human uri-
nary calculi, may adhere in a specific manner to the
plasma membrane of epithelial cells and this process
is followed by endocytosis of the crystals resulting
in cell damage or death (5,6). Damaged cells exhibit
a proliferative response, increase the synthesis of
fibrogenic substances promoting additional stimulus
for crystal growth (7,8). In addition, dead cells detach

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Phyllanthus niruri as Treatment for Nephrolithiasis
from the basement membrane and the cellular debris
will adhere to other crystals resulting in a stone nidus.
Thus, the cellular pathways involved in endocytosis of
CaOx crystals can constitute potential targets for drugs
designed for the prophylaxis and/or treatment of uro-
lithiasis. Different substances have been described as
modulators of adhesion and/or endocytosis processes
(9-11) but none of them seem to be suitable for clinical
use. On the other hand, alternative treatments such
as the traditional herbal treatments can compliment
pharmacotherapies for prevention and/or treatment of
urolithiasis with less expense and perhaps fewer side
effects, as reviewed by Miyaoka and Monga (12).
We have been evaluating the effects Phyl-
lanthus niruri on several stages of stone formation as
well as its potential therapeutic potential in lithiasic
patients. Experimental and clinical studies performed
by our group and by others have produced interesting
and hopeful data concerning the potential therapeutic
use of Phyllanthus niruri to treat and/or to prevent
stone formation. These data are summarized in this
review.
PHYLLANTHUS NIRURI
Phyllanthus niruri, popularly known as
“stone-breaker” (“quebra-pedras”) is a plant belong-
ing to the Euphorbiaceae family with a worldwide
distribution and it is used in folk Brazilian medicine
for patients with urolithiasis (13). More than 50
compounds were identified in the Phyllanthus niruri,
including alkaloids, flavanoids, lignans and triterpenes
(14). Among these substances, the triterpenes have
been found to inhibit the cytotoxicity induced by
calcium oxalate (15) as well as to reduce excretion
of stone forming constituents (16) and the markers
of crystal deposition in the kidneys (17). Moreover,
methanol extract from the leaves of Phyllanthus niruri
containing substances such as lignans and phyllanthin
showed a uricosuric activity in hyperuricemic rats
(18). According to Calixto et al. (19) alkaloids ex-
tracted from plants of the genus Phyllanthus present
an antispasmodic activity leading to smooth muscle
relaxation, mostly evidenced in the urinary tract,
which would facilitate the elimination of urinary
calculi. These data strongly suggest that Phyllanthus
niruri may be a potential source of many substances
with antilithiasic properties.
Interestingly, given that the maintenance of
normal levels of calcium is critical to the function
of many plants including plant rigidity, protection,
detoxification (heavy metals or oxalic acid), ion bal-
ance and even light reflection (20), and because high
cellular free calcium concentration may be dangerous
for these organisms, higher plants (plants exhibiting
a vascular system) developed a very efficient way
to neutralize Ca+2 ions, by forming complexes with
oxalate (21). Oxalate producing plants, which include
many crop plants, accumulate oxalate and as much as
90% of the total calcium in the form of CaOx crystals.
Curiously, as shown in Figure-1, refractive CaOx
crystals seen in the leaves of Phyllanthus niruri are
kept equidistant, do not aggregate hence not forming
stones. Therefore, understanding the basic molecular
strategies by which some plants are able to package
CaOx crystals may provide insights into the potential
utilization of these plants to prevent/treat urolithiasis
(22).
IN VITRO STUDIES
The effect of the aqueous extract of Phyl-
lanthus niruri on crystallization process of CaOx in
human urine has also been investigated in a model of
in vitro precipitation of CaOx in human urine (23).
Barros et al. (24) observed that the pre-incubation of
Figure 1 – CaOx crystals observed in Phyllanthus niruri leaves
observed under light microscopy.

659
Phyllanthus niruri as Treatment for Nephrolithiasis
human urine with Phyllanthus niruri did not inhibit
the precipitation of CaOx particles and even more
crystals were obtained in Phyllanthus niruri-contain-
ing urine, but the crystals were proportionally smaller
than those in urine samples without Phyllanthus
niruri. Moreover, they observed that after 24 hours,
the precipitated crystals formed large agglomerates in
untreated urine, but the crystals remained dispersed in
urine with Phyllanthus niruri (Figure-2). The authors
concluded that Phyllanthus niruri did not decrease the
number of crystals but induced a marked reduction of
particle size and crystal aggregation. Similar results
were obtained by Atmani E and Khan SR (25) employ-
ing a different plant species (Herniaria hirsute), which
is used in folk medicine in the Mediterranean area for
its diuretic properties and to treat kidney stones. Crys-
talluria is a common event observed even in non-stone
forming individuals. CaOx crystals are found in urine
under several forms including monohydrate (COM)
and dihydrate (COD) forms. Unlike COD, which is
predominantly found in normal individuals, COM
crystals have higher capacity to aggregate and adhere,
and is the main form excreted by the nephrolithiasis
patients (26-28). In the model of in vitro precipitation
of CaOx using human urine from healthy individuals,
Phyllanthus niruri induced an increase in COD forms
and reduced the amount of COM crystals, responsible
for higher potential risk for stone formation.
Besides CaOx crystallization, it has been
shown that the methanol extracts of Phyllanthus
niruri showed an inhibitory activity of the enzyme
xanthine oxidase in vitro (29) which was attributed
to compounds such as flavonoids, polyphenols and
tannins (30,31). Therefore, together with its uricosuric
property (18), this enzymatic inhibition activity makes
Phyllanthus niruri a potential antihyperuricemic
agent.
STUDIES IN CULTURED CELLS
Campos and Schor (32) have demonstrated
that Phyllanthus niruri exhibited a potent inhibitory
effect on CaOx crystal adhesion and/or endocytosis
Figure 2 – Light microscopy of CaOx crystals formed immediately (0 hr) and 24 hours after the addition of sodium oxalate solution in
normal human urine and after in the absence and presence of Phyllanthus niruri. X100 and X400.

660
Phyllanthus niruri as Treatment for Nephrolithiasis
by an immortalized cell line derived from canine
kidney (MDCK cells) representative of the medullar
collecting duct. This type of inhibitory effect occurred
even when high doses (2.5 to 5-fold the upper limit
in human urine) of CaOx have been employed and
without causing cell toxicity.
EXPERIMENTAL MODELS IN RATS
The effect of Phyllanthus niruri has also been
evaluated in experimental models of urolithiasis in
rats, mainly those induced by implantation of a cal-
cium oxalate (CaOx) crystal into the bladder (vesical
foreign body method). This experimental model of
urolithiasis is obtained with no significant metabolic
or systemic alterations and the vesical CaOx seed acts
as a supporting surface allowing organic and inorganic
material to precipitate over the central nidus, mimick-
ing a spontaneous calculus growth. It was initially
shown that rats drinking Phyllanthus niruri tea ad
libitum, presented decreased rate of stone growth (33).
These effects occurred independently of any relevant
modification in the urinary excretion of elements
known to promote crystallization and stone formation,
including calcium, oxalate, uric acid, pH, etc. In order
to evaluate if the beneficial effect of Phyllanthus niruri
could be mediated by modifications of the inhibitors
of stone formation, such as citrate, magnesium and/or
glycosaminoglycans, Freitas et al. (34) administered
1.25 mg/mL/day of Phyllanthus niruri for 42 days in
rats with vesical CaOx seed. This chronic treatment
induced a significant reduction in the calculi growth,
in the absence of any modification in the volume
diuresis or alterations in the urinary concentration of
lithogenic elements including calcium and oxalate.
Phyllanthus niruri administration did not modify the
urinary excretion of citrate and magnesium, indicating
that the putative antilithogenic effect of Phyllanthus
niruri was not primarily mediated by modifications
in these inhibitors. In contrast, it was observed that
Phyllanthus niruri induced a decrease in the urinary
excretion of glycosaminoglycans (GAGs) compared
with lithiasic animals receiving water. In contrast, the
content of GAGs was higher in calculi taken from
treated animals suggesting that the inhibitory effect
Phyllanthus niruri on crystal growth might have been
related to higher incorporation of GAGs into the
calculi. The adsorption of these macromolecules into
the calculi lead to stones with a predominant intrac-
rystalline amorphous organic matrix. Taken together,
these results suggested that Phyllanthus niruri was
able to prevent the aggregation of calcium oxalate to
the pre-existent crystal without interfering with the
incorporation of GAGs into organic matrix. Although
the underlying mechanism remains to be clarified,
some possible hypotheses can be raised: 1) a neu-
tralization of negative charges of GAGs reduced the
negative pole for progressive deposition of cations; 2)
active components of the plant could have chelated
and/or competed with calcium for binding sites on the
crystal surface; 3) effects of Phyllanthus niruri itself
on other proteins including Tamm-Horsfall protein,
nephrocalcin, osteopontin, prothrombin fragment 1,
etc, modulating crystallization, aggregation and cal-
culi growth and 4) Phyllanthus niruri could reduce the
crystal adhesion to the tubular epithelium. Essentially,
these results suggest that Phyllanthus niruri could
interfere with the calculi growth or prevent stone
formation rather than dissolving pre-formed stones.
In order to better mimic what is observed
in clinical practice, Barros et al. (35) using a vesical
foreign body model in rats, compared the efficacy of
Phyllanthus niruri treatment started concomitantly
with CaOx seed implantation with the same treatment
started 30 days after the seed implantation (when the
vesical calculus was completely formed). As repre-
sented in Figure-3, the early treatment (Figure-3A)
caused a significant inhibition in the calculi growth
compared with non-treated animals (Figure-3B), as
previously observed (34). In contrast, the treatment
initiated after the stone formation, did not prevent
the calculi to grow further neither propitiated calculi
elimination; however it induced drastic changes in
the shape and texture of the preformed calculi (Fig-
ure-3C). Stones taken from Phyllanthus niruri treated
animals were more homogeneous and contained more
compact surfaces (Figures 3D and 3E) in contrast
to the spicule-shaped surface taken from untreated
animals (Figure-3F). This result suggests that Phyl-
lanthus niruri probably interferes with the biominer-
alization process, by promoting a different interaction
between the crystal and the macromolecules of the
organic matrix. Although Phyllanthus niruri had not

661
Phyllanthus niruri as Treatment for Nephrolithiasis
Figure 3 – Upper and lower panels show the stereomicroscopy and scanning electronic microscopy respectively of the calculi taken
from animals untreated (A and D), animals treated from the beginning (B and E) and from later treated animals (C and F).
A B C
D EF
prevented the calculi growth, the treatment resulted
in the formation of calculi with smoother surfaces,
which could at least, contribute to less painful calculi
voiding.
CLINICAL STUDIES
The initial study (33) addressing the effects
of the Phyllanthus niruri administered in the form
of tea did not demonstrate any clinical or biochemi-
cal adverse effects (cardiovascular, renal, hepatic or
neurological) even at high dosage, with excellent
tolerability in healthy volunteers. In addition, tea con-
sumption in the same dose by nephrolithiasis patients
for a period of 3 months, led to an apparent increased
elimination of calculi compared to patients drinking
placebo. These results were probably ascribed to the
antispasmodic and relaxant effects of Phyllanthus
niruri upon ureteral muscle, facilitating calculi void-
ing.
Subsequently, another study by Nishiura et
al. (36), also in our Service, evaluated the effect of a
lyophilized 2% aqueous extract of Phyllanthus niruri,
in an additional series of 69 lithiasic patients in the
form of 450 mg capsules (three times a day) compared
with placebo (Chicorium sativum). In this short-term
follow-up conducted during a three-months period,
no significant differences in calculi voiding and/or
pain relief between the groups taking Phyllanthus
niruri or the placebo were detected. However, as
patients were classified according to the presence of
metabolic disturbance, a significant reduction in the
mean urinary calcium excretion was observed only
among hypercalciuric patients. The phytochemical
and pharmacological properties of this plant have
been accounted for the action of different substances
such as Rutin, beta-amylin, beta-sitosterol, caffeic
acid, geranin, quercetin, niruside and repandusinic
acid. Although none of these compounds has been
shown to have an effect on calciuria to date, such
potential beneficial effect of Phyllanthus niruri for
hypercalciuric patients needs to be further confirmed
in longer-term studies involving a higher number of
subjects.
Micali and coworkers (37) observed that
patients submitted to extracorporeal shock wave
lithotripsy and treated with Phyllanthus niruri during

662
Phyllanthus niruri as Treatment for Nephrolithiasis
3 months presented lower incidence of residual stone
fragments, mainly those in lower calyceal location
compared with non-treated patients. According to
these investigators, the efficacy and the lack of side
effects of Phyllanthus help improve overall outcomes
after extracorporeal shock wave lithotripsy and could
be useful as either an alternative or an adjunctive
therapy in the treatment of urolithiasis.
Table-1 summarizes the main findings in
all studies. Given the experimental characteristic of
these studies, except for the clinical ones (Grade of
recommendation B), an exact level of evidence is not
applicable.
CONCLUSION AND PERSPECTIVES
The experimental studies summarized here
suggest that Phyllanthus niruri might interfere with
important steps of the calculi formation including
crystal aggregation and internalization by the tubular
cells, crystal structure and composition. These proper-
ties of Phyllanthus niruri may constitute an important
advantage in the prevention of lithiasis, inhibiting
calculus growth and keeping the crystals dispersed
in the urine, with their consequent easier elimination.
Although clinical studies are less abundant, available
data point to beneficial effects of Phyllanthus by in-
ducing ureteral relaxation, interfering in the excretion
Table 1 – Summary of main findings.
Studies Main Findings Reference
Models in vitro Inhibition of CaOx crystal adhesion and/or endocytosis
Reduction in crystals aggregation
Increase in COD forms and reduced COM crystals
32
24
24
Models in vivo Decreased rate of stone growth
Increase intracrystalline amorphous organic matrix
Changes in the shape and texture of the preformed calculi
34,35
34
35
Clinical Increased calculi voiding
Reduction in urinary calcium excretion in hypercalciuric patients
Reduction in residual stone fragments after extracorporeal shock
wave lithotripsy
33
36
37
COM = calcium oxalate monohydrate; COD = calcium oxalate dihydrate.
of promoters of urinary crystallization such as calcium
or helping to clear fragments following lithotripsy. It
is important to consider however, that although it is
clear that Phyllanthus niruri can interfere with many
steps of the stone formation, longer-term clinical stud-
ies are necessary to define whether these effects can
be translated into real clinical benefit to treat and/or
prevent urolithiasis.
CONFLICT OF INTEREST
None declared.
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Accepted after revision:
May 26, 2010
Correspondence address:
Dr. Mirian A. Boim
Renal Division, UNIFESP
Rua Botucatu, 740
04023-900, São Paulo, SP, Brazil
Fax: + 55 11 5904-1684
E-mail: mirian@nefro.epm.br
EDITORIAL COMMENT
The authors provide a nice review on the herb
Phyllanthus niruri whose properties appear in fact to
be promising assets in stone disease prevention and
treatment. However, care must be taken to properly
design future clinical studies in a way to provide re-
liable, consistent and reproducible data. As a major
concern, I would point out the definition of accurate
dosage and mode of intake. In a recent review on Chi-
nese herbs used for managing stone disease, Miyaoka
et al. (1) found several clinical trials demonstrating the
likely benefits on stone prevention. However, the lack
of standardization on dose and compounds between
studies evaluating the same herbs made it extremely
difficult to compare them and draw a sustainable
conclusion. As a result, although used for hundreds
of years with practical evidence of clinical benefits,
Chinese herbs still strive to enter the armamentarium
of stone therapy as a global consensus.
REFERENCE
1. Miyaoka R, Monga M: Use of traditional Chinese
medicine in the management of urinary stone disease.
Int Braz J Urol. 2009; 35: 396-405.
Dr. Ricardo Miyaoka
Division of Urology
University of Campinas, UNICAMP
Campinas, SP, Brazil
E-mail: rmiyaoka@uol.com.br