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Effect of Cystone[R] on urinary composition and stone formation over a one year period.

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Keywords: Cystone[R] Computerized tomography Herb Kidney calculi Supersaturation Nephrolithiasis Quantitative CT

ABSTRACT

Kidney stones are a common problem for which inadequate prevention exists. We recruited ten recurrent kidney stone formers with documented calcium oxalate stones into a two phased study to assess safety and effectiveness of Cystone[R], an herbal treatment for prevention of kidney stones. The first phase was a randomized double-blinded 12 week cross over study assessing the effect of Cystone[R] vs. placebo on urinary supersaturation. The second phase was an open label one year study of Cystone[R] to determine if renal stone burden decreased, as assessed by quantitative and subjective assessment of CT. Results revealed no statistically significant effect of Cystone[R] on urinary composition short (6 weeks) or long (52 weeks) term. Average renal stone burden increased rather than decreased on Cystone[R]. Therefore, this study does not support the efficacy of Cystone[R] to treat calcium oxalate stone formers. Future studies will be needed to assess effects on stone passage, or on other stone types.

[C] 2011 Elsevier GmbH. All rights reserved.

Introduction

Kidney stones are a global affliction causing a great deal of morbidity and economic loss (Saigal et al. 2005). The prevalence of nephrolithiasis increases as societies become industrialized (Goldfarb 2003; Stamatelou et al. 2003; Sowers et al. 1998). Therefore, the worldwide burden is likely to increase in future years. A method to prevent kidney stones would be an obvious benefit. Existing treatments with evidence that supports their long term efficacy to prevent calcium oxalate kidney stones include dietary and lifestyle changes, as well as chronic use of one of three medications (thiazides, potassium citrate, and allopurinol). No new treatments have been established in decades, and these that are available have inherent problems related to patient compliance, cost, effectiveness and side effects. Therefore, a preventive treatment that would be easy to take, low in cost, safe and effective would be highly desirable.

Cystone[R] tablets are an Ayurvedic treatment for stones, traditionally practiced in India. Many studies and long experience attest to the safety of this compound. It is also claimed that Cystone[R] decreases urinary supersaturation or micropulverizes and expels kidney stones, but existing studies have been limited by small patient numbers, weak methodology, and poor study design including lack of proper controls. Therefore, in this study we rigorously evaluated the ability of Cystone[R] to decrease urine supersaturation and to prevent new stone formation and growth of existing stones via a short-term randomized, placebo-controlled, double-blinded, cross over study (to evaluate effects on urinary chemistries), followed by an open label extension (to evaluate effects on stone burden) (Fig. 1). Quantitative computerized tomography (CT) was used to assess changes in stone burden over the time of the study.

[FIGURE 1 OMITTED]

Materials and methods

Study drug

Cystone[R] is traditionally used for relief of a variety of urological problems including nephrolithiasis and is comprised of the following substances: shilapuspha (Didymocarpus pedicellata) 130mg, Pasanabheda (Saxifraga ligulata Syn. Bergenia ligulata/ciliata) 98mg, Manjishtha (Rubia cordifolia) 32mg, Nagarmusta (Cyperus scariosus) 32mg, Apamarga (Achyranthes aspera) 32 mg, Gohija (Onosma bracteatum) 32 mg, Sahadevi (Vernonia cinerea) 32mg, Shilajeet (Purified) 26mg, and Hajrul yahood bhasma 32 mg. Its purported effect is to "prevent supersaturation of lithogenic substances, control oxamide (a substance that precipitates stone formation) from the intestine and correct the crystalloid-colloid imbalance. Cystone[R] inhibits calculogenesis by reducing stone-forming substances like oxalic acid, calcium hydroxyproline, etc., and causes their expulsion by micropulverization. Cystone[R] causes disintegration of the calculi and crystals by acting on the mucin, which binds the particles together. Cystone[R]'s antimicrobial activity is beneficial in the prevention of urinary tract infections associated with urinary stones and crystalluria. Cystone[R]'s anti[R]spasmodic and anti-inflammatory activities relieve ureteric colic and alleviate symptoms of painful and burning and micturition."(http://himalayaheaIthcare.com/products/cystone.htm). Cystone[R] is manufactured and sold virtually world wide by Himalaya Health Care. In the United States, the product is known as Uricare[R].

Study subjects

Ten patients (4 men, 6 women) with recurrent, analytically confirmed, calcium-containing kidney stones were recruited from the Mayo Stone Clinic. All were Caucasian adults and had passed at least one stone at entry into the study (Table 1). Metabolic activity prior to study entry was defined as an increase in stone size or number documented on a previous CT scan obtained within one year prior to study entry. Only two patients were metabolically active at entry into the study. Exclusions included age under 18 years, pregnancy, refusal to use an effective method of birth control during the study, chronic urinary infection, secondary causes of kidney stones, (e.g., bowel disease, renal tubular acidosis, primary hyperoxaluria) or mental incompetence to give informed written consent on a form approved by the institutional review board. All patients were allowed to continue their existing kidney stone treatment programs. All patients promptly began the study after consenting to be enrolled.
Table 1

Patient characteristics.

                       Stone         Placebo    Metabolic
PT  Age  Race  Gender  composition   detection  activity

1   36   W     F       CaOx 60-70%   No         Active
                       CaP 30-40%

2   71   W     M       CaOx100%      No         Active

3   47   W     F       CaOx100%      No         Indeterminate

4   53   W     M       CaOx100%      No         Active

5   57   W     M       CaOx          No         Indeterminate

6   47   W     F       CaOx 10-20%   Yes        Active
                       CaP 80-90%

7   44   W     F       CaOx 70-100%  No         Inactive
                       CaP 80-90%

8   75   W     M       CaOx          No         Inactive

9   50   W     F       CaOx 40-90%   No         Indeterminate
                       CaP60-100%

10  45   W     F       Calcium       No         Indeterminate

    Risk factors   Relevant
PT                 medications

1   MSK  1+Ca      Self
                   decreased
                   Cystone[R]
                   to 1
                   b.i.d..

2   HTN            HCT 25
                   mg/day

3   FH Obesity     None

4   HCa            None

5   FH HC Obese    None

6   HCa HCP        HCT 25
    Osteoporosis   mg/day
                   Calcium 1600
                   mg/day
                   Fosamax 70
                   mg/week

7   FH             Ammonium
                   chloride 500
                   mg q.i.d.

8   HC HO          None

9   FH,HTN Obese.  None
    HCa

10  LV, HC         None

W-white, F-female, M-male, CaOx-calcium oxalate, CaP-calcium
phosphate, MSK-medullary sponge kidney, HCa-hypercalciuria,
HCi-hypocitraturia, HTN-hypertension, FH-family histort=y, LV-low
urine volume, HO-hyperoxaluria.


Study design and conduct

The protocol is illustrated in Fig. 1. Patients were randomly assigned by Mayo Clinic Research Pharmacy to a 6 week treatment program with Cystone[R] tablets, 2 by mouth twice daily, or identical placebo. This is the dose recommended by the manufacturer. After a 1 week washout the patients crossed over to the alternate treatment for another 6 weeks. Patients provided two 24-h urine collections shortly before starting the study, at the end of the first 6 weeks of treatment, and again at the end of the 6 week cross over, each of which were analyzed for determinants of urinary supersaturation in the Mayo Renal Function Laboratory and calculated using the Equil2 program (Werness et al. 1985). After completing both crossover arms, patients then immediately took Cystone[R] open label in the same dose for an additional 48 weeks, thus ensuring a 52 week total exposure to Cystone[R] during the 59 week study. Quantitative noncontrast multidetector CT exams were all performed on a 64-channel MDCT scanner (Sensation-64, Siemens Medical Solutions, Forschheim, Germany). For the 64-channel technique, patients were in the supine position on the CT table with arms above the head. An initial survey topogram was obtained for positioning purposes (801kVp, 300 mA) from the top of the liver through the pubic symphysis. Subsequent CT images were obtained in a single breath-hold through the kidneys. A standardized acquisition protocol was used for all exams (collimation 64x0.6; gantry rotation time, 0.5 s; table feed, 23 mm/rotation (pitch of 1.2); quality reference 240 mAs; 120kVp and the field of view was adjusted to patient size). Three reconstruction intervals were obtained from the raw data including: 5.0 mm thickness at 5.0 mm intervals (axial), 2.0 mm thickness at 2.0 mm intervals (axial) and 2.0 mm thickness at 2.0 intervals (coronal adjusted to the long axis of the kidneys). The 2.0 mm thickness at 2.0 mm interval (axial) data set was also processed at a free standing 3D workstation (Vitrea, Vital Images. Inc., Minnetonka. MN) by dedi-cated 3D technologists to obtain quantitative calcium scoring data for each kidney. All scored images were reviewed to determine that the included calcifications were consistent with urolithiasis rather than renal arterial or parenchymal calcifications. The scoring programs are typically used for coronary artery calcification quantification and generate both an Agatston score (reported as Agatston Units, AU) and volumetric score (reported as m[m.sup.3]). In the algorithms positive calcification required a minimum density threshold of 130 Hounsfield Units and a minimum area threshold of 3 adjacent pixels of at least 130 Hounsfield Units. In addition to quantified scoring, all images including the axial and reconstructed coronal series were reviewed by the diagnostic radiology service and a clinical report was generated. These images were subsequently sent to a picture archiving and communication system and available for referring clinicians. In addition, all images were reviewed by a radiologist (TJV) in a blinded fashion to score each kidney as increased, no change, or decreased stone burden.

Statistics and randomization

Randomization was accomplished using a table provided by the department of statistics to the study coordinator who was blinded as to whether the patients received placebo or Cystone[R]. Biochemical and supersaturation results were analyzed via a matched pair analysis using the JMP software package (SAS Instituted, Inc.); P values <0.05 were deemed significant.

Results

Table 1 contains demographic and clinical characteristics of the study patients. Patients who consented to participate in the Cystone[R] study tended to have recurrent kidney stones inadequately controlled on their current program. This tended to select a more difficult-to-treat patient population. One patient thought that Cystone[R] could be discriminated from placebo by its "peppery" taste. The other study participants did not identify this difference.

Table 2 displays the 24h urinary supersaturation results. In a matched pair analysis of the initial crossover study no statistically significant differences for any parameter between Cystone[R] treatment as compared to placebo were present. Similarly, the 24-h urine chemistries did not differ after one year on Cystone[R], as compared to values on placebo during the initial crossover period. Therefore, there was no evidence that Cystone[R] altered urinary chemistries after short term (6 weeks) or long term (1 year) usage.
Table 2

Urine supersaturation.

PT        Start        After placebo (6 weeks)    After Cystone[R]
                                                      (6 week)

    CaOx    Br    HAP  CaOx      Br     HAP     CaOx      Br     HAP

1   1.50   1.84  5.59  2.14 *   1.59 *  5.86 *  1.85 *   1.63 *  4.78 *

2   1.61   1.19  4.21  0.90    -0.81    3.03    0.93    -1.39    2.41

3   1.92  -0.78  3.12  1.99     0.43    4.64    2.20     0.36    4.01

4   1.97  -0.57  2.83  2.37     0.58    5.15    2.36     0.14    4.50

5   2.05  -1.45  0.69  1.75     1.59    5.40    1.99     0.16    3.80

6   1.98   1.23  5.90  1.43     0.73    6.69    2.21     1.75    8.01

7   1.90   0.69  6.04  2.19     1.18    5.79    1.71 *   1.05 *  7.31 *

8   2.24   0.98  7.59  1.90    -0.49    2.90    2.04    -0.03    4.11

9   1.45  -0.14  3.09  1.79     1.25    5.13    1.59     0.05    2.95

10  2.08   0.55  3.44  1.92     1.25    5.61

PT  End Cystone [R] ([greater than or equal to] 48 weeks)

    CaOx       Br      HAP

1   2.41 *   1.49 *   5.21 *

2   1.15    -2.82    -0.45

3   1.84     0.08     3.95

4   1.97    -0.09     4.31

5

6   2.22     1.46     7.25

7   1.13    -1.12     5.05

8   2.17    -0.25     4.23

9   1.78     0.06     3.00

10  1.38     0.96     4.25

CaOx-calcium oxalate, Br-calcium phosphate(brushite), HAP-calcium
phosphate(hydroxyapatite).


Table 3 contains results of CT studies at baseline and one year. The blinded radiologist's opinion of changes in kidney stone burden generally agreed with the quantitative data, with the exception of both kidneys in patient 4. We have no explanation for this discrepancy. Patient 4 was excluded from CT analysis because of bilateral stone removal surgery during the study. Therefore, we evaluated 18 of 20 kidneys for stone burden. Spontaneous stone passage occurred from 4 of 18 kidneys during the study. Nevertheless, the official radiology interpretation was that 8 kidneys had increased stone material, 8 kidneys were unchanged, and only 2 kidneys had decreased stone material. Quantitative scoring of renal calcium content in 18 kidneys from these same 9 patients revealed that mean total stone burden per kidney increased over this time period as assessed by the volumetric scoring system (93-114 m[m.sup.3]; P=0.07 by matched pairs analysis) or the Agatston scoring system (108-136AU; P=0.10 by matched pairs analysis). These results did not support an overall positive effect off Cystone[R] on stone burden.
Table 3

CT scores.

Patient   Baseline  Baseline  One year  One year  Radiologist
          volume    Agatston  volume    Agatston  impression

Right
kidneys

 1        10        6         9         6         NC

 2        47        50        58        70        1

 3        0         0         5         2         NC

 5        ND        ND        132       110       NC

 6        29        35        4         1         D

 7        59        58        73        72        NC

 8        159       184       196       217       I

 9        60        65        77        81        NC

10        0         0         0         0         NC

Mean      45.5      49.75     52.75     56.125

SD        52.03021  60.24415  66.43955  74.23407

Pvs.                          0.811732  0.853223
baseline

Left
kidneys

    1     12        8         27        24        1

    2     2         1         0         0         NC

    3     5         4         4         3         D

    5     ND        ND        285       352       I

    6     582       709       790       1053      I

    7     205       257       233       264       1

    8     121       127       143       161       1

    9     203       223       194       229       NC

   10     0         0         3         1         1

Mean      141.25    166.125   174.25    247.7143

SD        198.9829  243.1604  265.7398  371.4645

Pvs.                          0.783027  0.630765
baseline

Patient   Clinical
          events

Right
kidneys

 1       None

 2       None

 3       None

 5       None

 6       PSD ST

 7       None

 8       None

 9       PSD ST?

10       None

Mean

SD

Pvs.
baseline

Left
kidneys

 1       None

 2       None

 3       None

 5       None

 6       None

 7       PSD ST

 8       None

 9       PSD ST?

10       PSD ST

Mean

SD

Pvs.
baseline

I-increased stones, D-decreased stones, NC-no change in stones,
ND-not done, PSD ST-passed stone.


No patients described any side effects attributable to Cystone[R], consistent with previous studies.

Discussion

Current non-surgical therapies of kidney stones take 3 different approaches. Prevention, either primary or secondary is preferred. Indeed, evidence exists that supports the prescription of specific dietary measures and/or drugs for this purpose. Chemolysis (dissolution) of existing stones may be possible with uric acid and some cystine stones. No scientific data supports the feasibility of calcium stone chemolysis, to our knowledge. Expulsion therapy to help pass stones that have moved into the ureter (but not stones resident in the kidney) is, however, supported by recent controlled trials (Hollingsworth et al. 2006).

Randomized controlled studies exist to support the efficacy of thiazides (Ettingeretal. 1988),allopurinol(Ettingeretal. 1986), and potassium magnesium citrate (Ettinger et al. 1997) for secondary prevention of calcium oxalate kidney stones. Side effects, cost, and imperfect prevention make the ready availability of cheap, safe and effective stone prevention therapy highly desirable.

Current treatments for stone prevention typically decrease urinary supersaturation by affecting urinary composition (e.g., decrease calcium excretion). No agent is known that can be safely taken and enter the urine to decrease calcium oxalate crystallization, or perhaps even better dissolve calcium oxalate stones and/or crystals. If such a compound were found, it would represent a new class of treatment for renal stones. Several herbs have been pur-ported to decrease stone risk, or hasten stone passage. However, hard scientific evidence regarding their efficacy is scanty. The Chinese Kampou medicine has been used to treat disease for centuries, including for prevention and treatment of urinary calculi. An experimental study suggested an inhibitory effect of Kampou extracts on in vitro CaOx crystallization (Koide et al. 1995). In this report, the two species from Kampou (Takusya and Kagosou) also were effective for preventing renal crystallization in a rat nephrolithiasis model; similar results were obtained in a second report (Yasui et al. 1999). Chorey-to, another Chinese medicine which contains Takusya, also exhibited a protective effect in rats rendered hyper-oxaluric with ethylene glycol, even though urinary citrate levels fell (Calixto etal. 1998).

Many stone patients in Brazil take a tea made from the annual herb Phyllanthus niruri that grows in the tropical indigenous area and does not cause side effects (Calixto et al. 1998). This natural product has been called "break stone" because it has been used for generations to eliminate gallstones and kidney stones (Calixto et al. 1998). Diverse classes of potentially active com-pounds have been identified from genus Phyllanthus, including alkaloids, flavonoids, lactones, steroids, terpenoids, lignans, and tannins. Some researchers have demonstrated antispasmodic and analgesic activities in Phyllanthus niruri which could explain the popular use of the plant for kidney and bladder stones (Calixto et al. 1998; Santos et al. 1994) The alkaloid extract caused smooth muscle relaxation specific to the urinary and biliary tract which could facilitate the expulsion of both kind of stones (Calixto et al. 1984). Phyllanthus niruri has also been shown to inhibit CaOx endo-cytosis by renal tubular cells (Campos and Schor 1999), another mechanism by which this agent could decrease crystal retention in the kidney, and in a small clinical trial appeared to reduce urinary calcium excretion amongst hypercalciuric stone formers (Nishiura et al. 2004). No toxicity was apparent in the latter study. A Moroccan herb Herniaria hirsuta has similarly been evaluated for effects on CaOx crystallization, including by our group (Atmani et al. 2004). Interestingly, Phyllanthus niruri is purported to act by promoting nucleation of more crystals that achieve a smaller size.

A major shortcoming of prevention trials to date is the lack of adequate end points. Typically, the hard end point in most trials is stone passage rate, even though there has not been any data to suggest that any current treatment prevents passage of preformed stones. This formulation presumes relatively tight correlation between stone burden and stone passage rates. Although it is true that one cannot pass a stone unless it has developed and grown, the time between stone development and passage appears to be variable and unpredictable. Therefore, the ability to accurately measure stone size in vivo over time could represent a valuable surrogate end point for clinical trials in the future. Stone risk, composition, and risk of recurrence all correlate with urinary supersaturation, as calculated using the iterative computer program Equil2 (Parks et al. 1997). Therefore, urinary supersaturation is a second potential surrogate endpoint for clinical trials. In this study we assessed the effect of Cystone[R], a common stone prevention treatment outside of Europe and the United States, on both urinary supersaturation and radiographically assessed stone burden.

The current results did not document any beneficial effect of Cystone[R] on the urinary composition. However, the failure to find statistically significant change in urinary supersaturation does not rule out a beneficial effect. Equil2 only calculates SS based upon the inorganic composition of urine (Werness etal. 1985), and does not take into account the potential effect of potential macromolecular inhibitors such as Tamm-Horsfall protein or osteopontin (Kumar et al. 2005), or smaller molecules such as phytate (Grases et al. 2000). Furthermore, Cystone[R] could exert effects on other ion pairs that can form in urine and influence growth of calcium oxalate crystals, but are not included in the Equil2 calculations (Rodgers et al. 2006).

Cystone[R] is purported to promote stone passage. However, on average stone burden increased rather than decreased in our study. It is important to note that stone formers in this study tended to be those who had failed standard therapy, which may have influenced the end point of stone formation and passage. It is also possible an effect may have been apparent with longer follow up.

No patient reported any side effects from Cystone[R]. This is in accord with previously published studies.

Conclusion

This short term study does not suggest that Cystone[R] affects those urinary chemistries commonly measured and known to influence calcium oxalate stone formation, nor does decrease renal calcium stone burden over a 1 year period. It is possible elements of the urine were affected that are not typically measured (e.g., glycoprotein inhibitors). A longer term study with more patients would be necessary to detect changes in stone events or enhanced stone passage, or effects on other stone types. In any new study of Cystone, the botanical authenticity of each individual herb will need to be documented by the manufacturer using high pressure liquid chromatography. This short term trial failed to find evidence that Cystone[R] prevents kidney stone formation and growth in recurrent calcium oxalate stone formers.

Acknowledgements

The authors wish to thank Beverly Tietje, study coordinator; and Kathy Laabs and Joni Langowski, secretaries, for their invaluable assistance in performing the study and preparing the manuscript, respectively. Funding of the research aspects of the study (2 of the 4 duplicate urine supersaturations, pregnancy testing, and statistical analysis and all Cystone[R] and placebo tablets) were provided by the Mayo Foundation and Himalaya Health Care. The entire design of the study, its supervision, data analysis, manuscript preparation and decision to publish were entirely the work of the authors. None of the authors have any financial interest in Himalaya Health Care. Investigators on this study (J.C. Lieske, T.J. Vrtiska) were supported by the Mayo Clinic O'Brien Urology Research Center (P50 DK083007).

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S.B. Erickson (a), (1) *, T.J. Vrtiska (b), J.C. Lieske (a), (c)

(a) Division of Nephrology & Hypertension, Ma-E19, Mayo Clinic, Rochester, MN 55905, USA

(b) Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN, USA

(c) Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Abbreviations: AU, Agatston Units; CT, computerized tomography; [mm.sup.3], cubic millimeter.

* Cystone[R] tablets and partial study funding were supplied by Himalaya Health Care.

* Corresponding author. Tel.: +1 507 266 7083; fax: +1 507 266 7891.

E-mail addresses: erickson.stephen@mayo.edu, laabs.kathy@mayo.edu (S.B. Erickson).

doi:10.1016/j.phymed.2011.01.018
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Author:Erickson, S.B.; Vrtiska, T.J.; Lieske, J.C.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:1USA
Date:Jul 15, 2011
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