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
Vol. 36 (6):
657-664, November - December, 2010
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.
words: renal; lithiasis; treatment; clinical; Phyllanthus niruri
stones affect 10-12% of the population 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 supersaturated
solution, crystalluria is often observed in normal individuals, but if
crystals remain apart from each 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 urinary 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 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 urolithiasis. 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).
niruri, popularly known as “stone-breaker” (“quebra-pedras”)
is a plant belonging 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 extracted 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.
The effect of the aqueous extract of Phyllanthus 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 human urine with Phyllanthus niruri did not inhibit the precipitation of CaOx particles and even more crystals were obtained in Phyllanthus niruri-containing 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) employing 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. Crystalluria 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.
Campos and Schor (32) have demonstrated that Phyllanthus niruri exhibited a potent inhibitory effect on CaOx crystal adhesion and/or endocytosis 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.
effect of Phyllanthus niruri has also been evaluated in experimental models
of urolithiasis in rats, mainly those induced by implantation of a calcium
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, mimicking 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 intracrystalline 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 neutralization 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 calculi 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.
initial study (33) addressing the effects of the Phyllanthus niruri administered
in the form of tea did not demonstrate any clinical or biochemical adverse
effects (cardiovascular, renal, hepatic or neurological) even at high
dosage, with excellent tolerability in healthy volunteers. In addition,
tea consumption 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 voiding.
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 properties 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 inducing ureteral relaxation, interfering in the excretion 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 studies are necessary to define whether these effects can be translated into real clinical benefit to treat and/or prevent urolithiasis.
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 reliable, 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 Chinese 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.
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