Evaluation of three herbal compounds used for the management of lower urinary tract disease in healthy cats: a pilot study

Abstract

Objectives

Lower urinary tract disease (LUTD) occurs commonly in cats, and idiopathic cystitis (FIC) and urolithiasis account for >80% of cases in cats <10 years of age. Although several strategies have been recommended, a common recommendation is to induce dilute urine resulting in more frequent urination and to dilute calculogenic constituents. In addition to conventional therapy using modified diets, traditional Chinese and Western herbs have been recommended, although only one – choreito – has published data available. We evaluated three commonly used herbal treatments recommended for use in cats with LUTD: San Ren Tang, Wei Ling Tang and Alisma. We hypothesized that these three Chinese herbal preparations would induce increased urine volume, decreased urine saturation for calcium oxalate and struvite, and differences in mineral and electrolyte excretions in healthy cats.

Methods

Six healthy spayed female adult cats were evaluated in a placebo-controlled, randomized, crossover design study. Cats were randomized to one of four treatments, including placebo, San Ren Tang, Wei Ling Tang or Alisma. Treatment was for 2 weeks each with a 1 week washout period between treatments. At the end of each treatment period, a 24 h urine sample was collected using modified litter boxes.

Results

Body weights were not different between treatments. No differences were found in 24 h urinary analyte excretions, urine volume, urine pH or urinary saturation for calcium oxalate or struvite between treatments.

Conclusions and relevance

The results of this study do not support the hypothesis; however, evaluation of longer-term and different dosage studies in cats with LUTD is warranted.

Introduction

Lower urinary tract disease (LUTD) occurs commonly in cats, but the incidence is unknown. Previous estimates of the incidence in the USA and the UK are 0.85–1.0% per year.^1,2 These estimates were based on the presence of clinical signs only and did not consider actual diagnoses. The proportional morbidity rate for lower urinary signs in cats, defined as the frequency with which cases are seen at veterinary hospitals, has been reported to be 10%,³ although 1–6% is more commonly reported.^3,4 In a cross-sectional study of 15,226 cats examined at 52 private practices, cats were likely to be examined because of renal disease, cystitis, feline urologic syndrome and inappetence.⁵

Any disorder of the lower urinary tract may cause signs of LUTD. In two prospective studies, one of 141 cats and one of 109 cats with LUTD,^6,7 idiopathic cystitis was diagnosed most commonly, accounting for 50–65% of diagnoses. In a retrospective study performed at the Universities of Georgia and Tennessee of 110 cats >10 years of age with LUTD, bacterial cystitis was diagnosed most commonly.⁸ Urolithiasis accounts for 15–30% of cases of lower urinary tract signs in cats,^6–8 with calcium oxalate and struvite accounting for 80–90% of feline uroliths.⁹

Increasing urine volume is recommended for managing cats with urolithiasis and idiopathic cystitis.¹⁰ By increasing water intake, and thus urine volume, urinary concentrations of calculogenic minerals and potential initiators of urinary bladder pain and inflammation are reduced. In addition, larger urine volumes typically increase the rate of urine passage through the urinary system and voiding frequency, thereby reducing retention time for crystal formation and growth or for diffusion of potentially noxious substances across the bladder uroepithelium. Feeding cats a canned food is the most practical means of increasing water intake and lowering calcium oxalate urine saturation and concentration of potential initiators of bladder pain.^10–12 Although increased urine volume is associated with decreased urinary saturation for calcium oxalate in healthy and calcium oxalate uroliths-forming cats,^13–18 the target urine specific gravity is unknown. In two studies, urine saturation for calcium oxalate was significantly lower when urine specific gravity was 1.044–1.046 and 1.034–1.040.^13,19 The recommendation is to dilute urine to a specific gravity of ⩽1.045, although others recommend ⩽1.025.^20–23

In addition to conventional therapy using modified diets, traditional Chinese and Western herbs have been recommended, although only one – choreito – has published data available.^24–27 Alternative and complementary treatments are being incorporated into conventional medicine and are called integrative medicine.

We evaluated three commonly used herbal treatments recommended for use in cats with LUTD: San Ren Tang, Wei Ling Tang and Alisma. The objective of the study was to evaluate the influence of the three treatments on urine volume and urine saturation for calcium oxalate and struvite and to compare these results with those obtained by administration of a placebo.

Materials and methods

Six healthy spayed female adult cats were evaluated in a randomized, crossover design study. Cats were fed an adult feline dry maintenance diet at 70(BW_kg^0.75)²⁸ and adjusted to maintain weight throughout the study. Cats were randomized to one of four treatments, including a placebo, which was an empty gelatin capsule, or one of three herbal preparations (Table 1): Alisma, San Ren Tang and Wei Ling Tang, which were administered at 500 mg per 4.5 kg body weight q12h PO (Kan Herb Company). Treatments were administered for 2 weeks, each with a 1 week washout period between treatments, in a four-way crossover design. At the end of each treatment period, a 24 h urine sample was collected from each cat using modified litter boxes.²⁹ Urine volume was measured, and urine saturation for struvite and calcium oxalate was estimated using EQUIL 93b (College of Medicine, The University of Florida, Gainesville, FL, USA).

Table 1

Composition of three herbal supplements administered: Alisma, San Ren Tang and Wei Ling Tang

Scientific name	Plant part	Pinyin name	Common name
Alisma
Alisma orientale	Rhizome	Ze xie	Asian water plantain
San Ren Tang (three-seeds combination)
Tetrapanax papyrifer	Pith	Tong cao	Rice paper
Armeniacae amarum	Seed	Xing ren	Bitter apricot
Coix lachryma-jobi	Seed	Yi yi rem	Coix seed, Job’s tears
Cardamomi rotondi	Fruit	Bai dou kou	Round cardamom
Cardamomi rotondi	Rhizome	Ban xia	Crow-dipper
Lophatheri gracilis	Leaf	Dan zhu ye	Lopatherum
Magnolia officinalis	Bark	Hou po	Magnolia bark
Magnesium silicate		Hua shi	Talcum
Wei Ling Tang (harmonize the stomach with five herbs and poria)
Atractylodes macrocephala	Rhizome	Bai zhu	White Atractylodes
Atractylodes lancea	Rhizome	Cang zhu	Black Atracylodes
Citri reticulatae	Peel	Chen pi	Dried tangerine peel
Ziziphi jujubae	Fruit	Da zao	Jujube
Poria cocos	Sclerotium	Fu ling	Poria, China root
Glycyrrhiza uralensis	Root	Gan cao	Licorice root
Magnolia officinalis	Bark	Bou po	Magnolia bark
Cinnamomum cassia	Bark	Rou gui	Cinnamon bark
Zingiberis recens	Rhizome	Sheng jiang	Ginger rhizome
Tetrapanacis papyriferi	Pith	Tong cao	Rice paper
Alisma orientale	Rhizome	Ze xie	Asian water plantain

A Shapiro–Wilk test was used to evaluate data for normal distribution, and if data were normally distributed ANOVA was used. If data were not distributed normally, then a Kruskal–Wallis test was performed. If global analysis revealed a significant effect, then a Bonferonni–Dunn post-hoc test was used to analyze the data for each treatment. P <0.05 was considered significant. This study was approved by the Institutional Animal Care and Use Committee of The University of Tennessee.

Results

Body weights were not different between treatments. No differences were found in 24 h urinary analyte excretions, 24 h urine volume, urine pH or 24 h urinary saturation for calcium oxalate or struvite between treatments (Table 2).

Table 2

Results of body weight, 24 h parameters, and relative supersaturation for struvite (RSSs) and calcium oxalate (RSSco) for six adult spayed female domestic shorthair cats receiving placebo (P), Alisma (A), Sun Ren Tang (S) or Wei Ling Tang (W)

Parameter	P	A	S	W	P value
Body weight (kg)	5.22 ± 1.21	5.23 ± 1.32	5.25± 1.22	5.22 ± 1.22	0.99
Urine volume (ml/kg/day)	11.5 ± 3.49	11.0 ± 4.97	14.0 ± 9.16	9.30 ± 3.23	0.66
pH	6.30(5.89–6.99)	6.17(6.17–6.63)	6.40(5.96–7.21)	6.28(5.88–6.51)	0.77
Sodium (mEq/kg/day)	1.20(1.05–1.70)	1.06(0.65–1.64)	1.40(0.81–1.01)	1.07(0.55–2.07)	0.53
Potassium (mEq/kg/day)	1.63(1.36–2.45)	1.57(1.13–2.74)	1.58(1.08–4.28)	1.46(1.03–2.10)	0.54
Calcium (mg/kg/day)	0.64(0.16–1.45)	0.68(0.14–1.38)	0.83(0.17–1.16)	0.62(0.14–1.68)	0.99
Magnesium (mg/kg/day)	0.52(0.11–0.97)	0.54(0.14–1.12)	0.45(0.09–1.28)	0.54(0.36–1.27)	0.97
Ammonia (pM/kg/day)	104(22.2–247)	75.5(26.4–445)	104(24.8–291)	56.5(26.0–120)	0.58
Phosphorus (mg/kg/day)	24.4(21.4–40.8)	24.5(16.6–31.9)	24.1(14.2–64.2)	18.0(15.9–34.2)	0.56
Oxalate (pM/kg/day)	18(15–24)	16(13–24)	18(14–54)	13(11–23)	0.25
Citrate (pM/kg/day)	43.0(6.02–61.6)	33.8(6.39–51.7)	42.6(5.97–59.2)	25.0(6.61–71.8)	0.91
Chloride (mEq/kg/day)	1.69(1.43–3.04)	1.68(0.98–2.62)	1.67(1.03–4.03)	1.58(0.96–2.36)	0.85
Creatinine (mg/kg/day)	41.0(29.4–54.0)	38.8(28.8–44.7)	35.8(28.9–120.2)	32.4(24.5–46.3)	0.42
RSSs	0.022(0.006–0.074)	0.030(0.007–0.148)	0.038(0.007–0.921)	0.029(0.005–0.058)	0.81
RSSco	3.62(2.83–6.75)	4.89(2.41–9.09)	3.95(2.41–5.73)	5.50(2.48–10.05)	0.78

Data are as mean ± SD if normally distributed or as median (range) if not normally distributed

Discussion

Urolithiasis and idiopathic cystitis are responsible for >80% of cases of LUTD in cats <8–10 years of age.^6,7 Treatment can be frustrating, especially for cats with idiopathic cystitis, as therapies have either not been evaluated in controlled trials or have not been shown to be effective when evaluated in controlled clinical trials.^{10,12,30–37} When managing urolithiasis, decreasing urine saturation with calculogenic minerals is important.³⁸ Thus, it has been recommended to increase urine volume to aid with the management of urolithiasis and idiopathic cystitis in cats. This may be accomplished by feeding a canned diet,¹⁰ feeding a diet with a higher sodium chloride content,³⁹ administering a diuretic,⁴⁰ providing supplemental fluid therapy,³² or using traditional Chinese or Western herbal preparations that induce a diuresis.

The three traditional Chinese medical herbal preparations evaluated in this study are purported, in part, to induce a diuresis. Some herbal preparations are thought to decrease urinary calcium excretion; however, this was not found in the current study with these preparations. Several of the compounds contained in the preparations may also have anti-inflammatory and anticalculogenic effects. A different theory is that anti-inflammatory properties of these herbal preparations decrease inflammatory protein excretion that may serve as a nidus for crystallization and urolith formation. Healthy cats were evaluated in this study and they did not appear to have urinary tract inflammation; therefore, this was not evaluated.

Choreito, a Chinese herbal diuretic, has been shown to decrease urinary saturation for struvite and the magnitude of struvite crystalluria in cats;^24–27 however, no other herbal compounds have been evaluated in cats. Alisma is a genus of flowering plants in the family Alismataceae, members of which are commonly known as water plantains. It has been shown in experimental studies in rodents to inhibit calcium oxalate formation and nephrocalcinosis;^41–43 however, it has not been evaluated in cats. As a single preparation used in this study, it did not decrease urinary saturation for calcium oxalate or struvite nor did it induce a diuresis. San Ren Tang (three-kernels decoction) is composed of eight compounds (Table 1), which are used to promote urination and may have anti-inflammatory effects.^44–48 Wei Ling Tang is composed of 11 compounds that are used to promote urination,^49–51 decrease nephrocalcinosis and crystal formation,⁴³ provide antioxidation^52–56 and are anti-inflammatory.^57–59 Neither of these herbal preparations induced a diuresis or decreased urinary saturation for calcium oxalate or struvite.

Despite these potential beneficial effects, the results of this study did not demonstrate a diuretic effect for the three herbal preparations nor did they decrease urinary saturation for struvite or calcium oxalate when compared with placebo. There are several potential reasons for this lack of response and several limitations of this study. A small number of healthy adult female cats were evaluated and an effect may be found in cats with LUTD while being absent in healthy cats. The treatment periods were for 2 weeks and it is possible that beneficial effects require longer administration. The dosage of herbal compounds was based on that recommended by the company providing the preparations; however, these are not based on pharmacokinetic–pharmacodynamic studies. Therefore, a different dosage may yield different results.

Conclusions

The results of this study do not support the use of San Ren Tang, Wei Ling Tang or Alisma for increasing urine volume or for decreasing urine saturation for calcium oxalate or struvite. No adverse events occurred during the study; therefore, these herbal compounds appear safe in cats. Longer and dosage escalation studies are warranted.

Footnotes

Accepted: 21 November 2017

Conflict of interest

Dr Marsden is a consultant for Kan Herb Company, 380 Encinal St, Suite 100, Santa Cruz, CA 95060, USA, which provided herbal supplements and placebo.

Funding

Dr Daniels was funded through the Center of Excellence, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA.

References

Lawler

Sjolin

Collins

. Incidence rates of feline lower urinary tract disease in the United States. Feline Pract 1985; 15: 13–16.

Willeberg

. Epidemiology of naturally occurring feline urologic syndrome. Vet Clin North Am Small Anim Pract 1984; 14: 455–469.

Foster

. The ‘urolithiasis’ syndrome in male cats: a statistical analysis of the problems, with clinical observations. J Small Anim Pract 1967; 8: 207–214.

Osborne

Kruger

Johnston

, et al. Feline lower urinary tract disorders. In: Ettinger

(ed). Textbook of veterinary internal medicine. Philadelphia, PA: WB Saunders, 1989, pp 2057–2082.

Lund

Armstrong

Kirk

, et al. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J Am Vet Med Assoc 1999; 214: 1336–1341.

Kruger

Osborne

Goyal

, et al. Clinical evaluation of cats with lower urinary tract disease. J Am Vet Med Assoc 1991; 199: 211–216.

Buffington

Chew

Kendall

, et al. Clinical evaluation of cats with nonobstructive urinary tract diseases. J Am Vet Med Assoc 1997; 210: 46–50.

Bartges

. Lower urinary tract disease in older cats: What’s common, what’s not? In Management of Feline Lower urinary Tract Disease. Topeka, KS: Hill’s Pet Nutrition, 1998, pp 29–38.

Lulich

Osborne

Albasan

. Canine and feline urolithiasis: diagnosis, treatment, and prevention. In: Bartges

Polzin

(eds). Nephrology and urology of small animals. Chichester: Wiley-Blackwell, 2011, pp 687–706.

10.

Markwell

Buffington

Chew

, et al. Clinical evaluation of commercially available urinary acidification diets in the management of idiopathic cystitis in cats. J Am Vet Med Assoc 1999; 214: 361–365.

11.

Bartges

Kirk

. Nutrition and lower urinary tract disease in cats. Vet Clin North Am Small Anim Pract 2006; 36: 1361–1376.

12.

Gunn-Moore

Shenoy

. Oral glucosamine and the management of feline idiopathic cystitis. J Feline Med Surg 2004; 6: 219–225.

13.

Buckley

Hawthorne

Colyer

, et al. Effect of dietary water intake on urinary output, specific gravity and relative supersaturation for calcium oxalate and struvite in the cat. Br J Nutr 2011; 106 Suppl 1: S128–S130.

14.

Passlack

Burmeier

Brenten

, et al. Short term effects of increasing dietary salt concentrations on urine composition in healthy cats. Vet J 2014; 201: 401–405.

15.

Hezel

Bartges

Kirk

, et al. Influence of hydrochlorothiazide on urinary calcium oxalate relative supersaturation in healthy young adult female domestic shorthaired cats. Vet Ther 2007; 8: 247–254.

16.

Markwell

Buffington

Smith

. The effect of diet on lower urinary tract diseases in cats. J Nutr 1998; 128: 2753S–2757S.

17.

Lombardo

Bartges

Kirk

, et al. Safety and influence of long term hydrochlorothiazide and diet on urinary saturation with calcium oxalate in healthy cats [abstract]. J Vet Intern Med 2007; 21: 646.

18.

Lulich

Osborne

Lekcharoensuk

, et al. Effects of diet on urine composition of cats with calcium oxalate urolithiasis. J Am Anim Hosp Assoc 2004; 40: 185–191.

19.

Hawthorne

Markwell

. Dietary sodium promotes increased water intake and urine volume in cats. J Nutr 2004; 134: 2128S–2129S.

20.

Kirk

Ling

Osborne

, et al. Clinical guidelines for managing calcium oxalate uroliths in cats: medical therapy, hydration, and dietary therapy. In: Managing urolithiasis in cats: recent updates and practice guidelines. Topeka, KS: Hill’s Pet Nutrition, 2003, pp 10–19.

21.

Palm

Westropp

. Cats and calcium oxalate: strategies for managing lower and upper tract stone disease. J Feline Med Surg 2011; 13: 651–660.

22.

Lulich

Berent

Adams

, et al. ACVIM small animal consensus recommendations on the treatment and prevention of uroliths in dogs and cats. J Vet Intern Med 2016; 30: 1564–1574.

23.

Bartges

Callens

. Urolithiasis. Vet Clin North Am Small Anim Pract 2015; 45: 747–768.

24.

Buffington

Blaisdell

Kawase

, et al. Effects of choreito consumption on urine variables of healthy cats fed a magnesium-supplemented commercial diet. Am J Vet Res 1997; 58: 146–149.

25.

Buffington

Blaisdell

Kawase

, et al. Effect of choreito on struvite solubility in cats. Feline Pract 1992; 20: 13–17.

26.

Buffington

Blaisdell

Komatsu

, et al. Effects of choreito and takushya consumption on in vitro and in vivo struvite solubility in cat urine. Am J Vet Res 1997; 58: 150–152.

27.

Buffington

Blaisdell

Komatsu

, et al. Effects of choreito consumption on struvite crystal growth in urine of cats. Am J Vet Res 1994; 55: 972–975.

28.

Bartges

Kirk

Lauten

. Calculating a patient’s nutritional requirements. Vet Med 2004; 99: 632.

29.

Bartges

Kirk

Moyers

. Influence of alkalinization and acidification on urine saturation with calcium oxalate and struvite and bone mineral density in healthy cats. Urol Res 2004; 32: 172.

30.

Chew

Bartges

Adams

, et al. Randomized placebo-controlled clinical trial of pentosan polysulfate sodium for treatment of feline interstitial (idiopathic) cystitis [abstract]. J Vet Intern Med 2009; 23: 690.

31.

Chew

Buffington

Kendall

, et al. Amitriptyline treatment for severe recurrent idiopathic cystitis in cats. J Am Vet Med Assoc 1998; 213: 1282–1286.

32.

Barsanti

Finco

Shotts

, et al. Feline urologic syndrome: further investigations into therapy. J Am Anim Hosp Assoc 1982; 18: 387–390.

33.

Gunn-Moore

Cameron

. A pilot study using synthetic feline facial pheromone for the management of feline idiopathic cystitis. J Feline Med Surg 2004; 6: 133–138.

34.

Trought

. Treatment for cystitis. Vet Rec 1973; 92: 80.

35.

Willeberg

. Diets and the feline urological syndrome: a retrospective case-control study. Nord Vet Med 1975; 27: 15–19.

36.

Tucker

Keating

. Use of a copper intracystic device to treat urinary obstruction in male cats. Vet Med Small Anim Clinician 1980; 75: 435–436.

37.

Buffington

Westropp

Chew

, et al. Clinical evaluation of multimodal environmental modification (MEMO) in the management of cats with idiopathic cystitis. J Feline Med Surg 2006; 8: 261–268.

38.

Bartges

Osborne

Lulich

, et al. Methods for evaluating treatment of uroliths. Vet Clin North Am Small Anim Pract 1999; 29: 45–57.

39.

Laflamme

Long

. Effects of dietary sodium chloride on health parameters in mature cats. J Feline Med Surg 2009; 11: 435–441.

40.

Hezel

Bartges

Kirk

, et al. Influence of hydrochlorothiazide on urinary calcium oxalate relative supersaturation in healthy adult cats [abstract]. J Vet Intern Med 2006; 20: 741.

41.

Cao

Liu

Radman

, et al. An experimental study of effect of different extracts of Alisma orientalis on urinary calcium oxalate stones formation in rats. Zhongguo Zhong Yao Za Zhi 2003; 28: 1072–1075.

42.

Cao

Liu

Zhou

, et al. The effects of the active constituents of Alisma orientalis on renal stone formation and bikunin expression in rat urolithiasis model [article in Chinese]. Zhonghua Yi Xue Za Zhi 2004; 84: 1276–1279.

43.

Liu

Sato

Kishikawa

, et al. Effectiveness of a traditional Chinese medicine, Wulingsan, in suppressing the development of nephrocalcinosis induced by a high phosphorus diet in young rats. Med Electron Microsc 2001; 34: 103–114.

44.

Guo

Song

Han

. Clinical observation on ziyin tongbi decoction in treating benign prostatic hyperplasia. Zhongguo Zhong Xi Yi Jie He Za Zhi 2008; 28: 1082–1085.

45.

Goto

Asama

Ogawa

. Sho-saiko-to-ka-kikyo-sekko as an alternative treatment for chronic tonsillitis to avoid surgery. Complement Ther Clin Pract 2010; 16: 216–218.

46.

Kaneko

Chiba

Horie

, et al. Effect of Scutellariae radix ingredients on prostaglandin E(2) production and COX-2 expression by LPS-activated macrophage. In Vivo 2009; 23: 577–581.

47.

Tsai

Cheng

Kung

, et al. Beneficial effects of magnolol in a rodent model of endotoxin shock. Eur J Pharmacol 2010; 641: 67–73.

48.

Taniguchi

Homma

Takano

, et al. Pharmacological effects of urinary products obtained after treatment with saiboku-to, a herbal medicine for bronchial asthma, on type IV allergic reaction. Planta Med 2000; 66: 607–611.

49.

Satoh

Yasuda

Nagai

, et al. The effects of crude drugs using diuretic on horse kidney (Na+ + K+)-adenosine triphosphatase. Yakugaku Zasshi 1991; 111: 138–145.

50.

Wang

Sun

. Clinical study of rapid bladder filling agent. Zhongguo Zhong Xi Yi Jie He Za Zhi 1992; 12: 533–534.

51.

Shimojo

Stewart

. Apparent mineralocorticoid excess syndromes. J Endocrinol Invest 1995; 18: 518–532.

52.

Aksoy

Dogan

Iriadam

, et al. Protective and therapeutic effects of licorice in rats with acute tubular necrosis. J Ren Nutr 2012; 22: 336–343.

53.

Wojcikowski

Stevenson

Leach

, et al. Antioxidant capacity of 55 medicinal herbs traditionally used to treat the urinary system: a comparison using a sequential three-solvent extraction process. J Altern Complement Med 2007; 13: 103–109.

54.

Hamed

Ali

El-Rigal

. Therapeutic potential of ginger against renal injury induced by carbon tetrachloride in rats. Scientific World Journal 2012; 2012: 840421. DOI: 10.1100/2012/840421.

55.

Ramudu

Korivi

Kesireddy

, et al. Ginger feeding protects against renal oxidative damage caused by alcohol consumption in rats. J Ren Nutr 2011; 21: 263–270.

56.

Onwuka

Erhabor

Eteng

, et al. Protective effects of ginger toward cadmium-induced testes and kidney lipid peroxidation and hematological impairment in albino rats. J Med Food 2011; 14: 817–821.

57.

Aggarwal

. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Rev Nutr 2010; 30: 173–199.

58.

Shimoda

Shan

Tanaka

, et al. Anti-inflammatory properties of red ginger (Zingiber officinale var Rubra) extract and suppression of nitric oxide production by its constituents. J Med Food 2010; 13: 156–162.

59.

Grzanna

Lindmark

Frondoza

. Ginger – an herbal medicinal product with broad anti-inflammatory actions. J Med Food 2005; 8: 125–132.