Therapeutic Effects of Parenteral Vitamin C (Ascorbic Acid) on Struvite Crystalluria in Domestic Male Cats

Document Type: Infectious agents- Diseases- Surgery

Authors

1 Department of Internal Medicine, Faculty of veterinary Medicine, University of Tehran, Tehran , Iran

2 Department of Internal Diseases, Faculty of Veterinary Medicine, University of Tehran, Tehran- Iran

3 Department of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran

4 Department of radiology and surgery, faculty of veterinary medicine, university of Tehran

Abstract

BACKGROUND:  Struvite crystals (Magnesium Ammonium Phosphate) are one of the most common causes of urolith formation in cats. Presence of these crystals in urea leads to urinary obstruction and idiopathic cystitis. The prevalence of urinary crystals has increased in recent years, thus there has been a growing interest in development of noninvasive, fast responsive therapies. Vitamin C is a safe compound with antioxidant properties. This vitamin is known as urine acidifier as well. Since struvite crystals are more soluble in acidic pH, it could be expected that vitamin C application could improve crystals dissolution as well as their disposal. It could also prevent other complications. OBJECTIVES: This study was designed to analyze the effects of vitamin C in reducing the rate and intensity of struvite crystals with current long term therapies such as diet alteration, acidifier’s applications and diuretics. METHODS: Ten male domestic cats with clinical signs of lower urinary tract disease were selected. Struvite crystalluria was confirmed by urine analysis and ultrasonography. Cats were divided to treatment and control groups each containing 5 cats. Both groups were treated by conventional therapies for two weeks, however, during the 1st week the treatment group received injectable vitamin C (100 mg/kg, every 24h, SC) and the control group received oral DL Methionine (200mg/cat, every 8h), in addition to conventional therapies. Urine was collected at days 0, 7 and 14 and its pH, specific gravity and number of crystals were calculated. Presence of floating echogenic foci was evaluated using ultrasound. RESULTS: Significant decrease in struvite crystalluria was observed in both groups. However, in group treated by vitamin C this decrease was faster and more effective. In addition, in case of obstruction, vitamin C showed better therapeutic effects. CONCLUSIONS: According to these results, vitamin C injection could be a therapeutic approach in treatment of urinary tract obstructions where fast response is needed to avoid further complications. Oral methionine seems to be a suitable choice for prophylaxis in patients with moderated signs and relatively high urine pH or continuing therapy to prevent recurrence of disease. 

Keywords


Article Title [Persian]

بررسی میزان تاثیر تزریق ویتامین C تزریقی در کاهش میزان و شدت کریستال‌های استروویت در مقایسه با پروسه‌های درمانی طولانی مدت معمول

Authors [Persian]

  • عبدالعلی ملماسی 1
  • تارا نظری 2
  • سید محمد مجتهدزاده 2
  • سعید بکایی 3
  • روشنک مختاری 4
  • شبنم بابازاده 2
  • سهیل تولایی 2
1 گروه بیماری های داخلی، دانشکده دامپزشکی، دانشگاه تهران، تهران، ایران
2 گروه بیماری های داخلی، دانشکده دامپزشکی، دانشگاه تهران، تهران، ایران
3 گروه بهداشت و کنترل مواد غذایی دانشکده دامپزشکی-دانشگاه تهران-تهران-ایران
4 گروه جراحی و رادیولوژی، دانشکده دامپزشکی، دانشگاه تهران، تهران، ایران
Abstract [Persian]

 
زمینه مطالعه: کریستال‌های استروویت (منیزیم آمونیوم فسفات) یکی از شایع‌ترین علل تشکیل سنگ‌های‌ دستگاه ادراری در گربه‌ها هستند. این کریستال‌ها از علل شایع انسداد ادراری و ایجاد سیستیت ایدیوپاتیک هستند. در سال‌های اخیر، بروز کریستال-های ادراری افزایش یافته و جستجو برای یافتن درمان‌هایی که بتوانند با کم‌ترین تهاجم و در کوتاه‌ترین زمان به نتیجه برسند، اهمیت ویژه‌ای پیدا کرده‌اند. ویتامین C یک ترکیب دارای خواص آنتی‌اکسیدانی و نسبتاً بی خطر برای موجود زنده است. علاوه بر خواص بیولوژیک متعدد، این ویتامین به عنوان اسیدی کننده‌ی ضعیف ادرار نیز شناخته می‌شود. از آنجایی که کریستال‌های استروویت در pH اسیدی محلول هستند، انتظار می‌رود استفاده از ویتامین C، علاوه بر کمک به انحلال و دفع کریستال‌ها از عوارض بعدی آن‌ها جلوگیری کند.
هدف: تعیین سرعت اثر تزریق ویتامین C در کاهش میزان و شدت کریستال‌های استروویت در مقایسه با پروسه‌های درمانی طولانی مدت معمول ( تغییر رژیم غذایی، استفاده از اسیدی کننده های ادراری خوراکی و داروهای مدر) در موارد کریستالوری استروویتی در گربه‌های خانگی انجام شد.
روش کار: 10 گربه‌ با علائم بیماری دستگاه ادراری تحتانی مانند دیس‌اوری انتخاب شدند. پس از تأیید حضور کریستال‌ها در ادرار با کمک سونوگرافی و انجام آزمایش‌های ادراری، گربه‌ها به دو گروه اصلی و کنترل (هر یک شامل 5 گربه) تقسیم‌بندی شدند. هر دو گروه به مدت دو هفته با روش‌های معمول درمانی شامل استفاده از داروهای مدر، تغییر رژیم غذایی و در صورت لزوم استفاده از آنتی‌بیوتیک‌ها درمان شدند با این تفاوت که در هفته ی اول گروه اصلی ویتامین Cی تزریقی (mg/kg100، زیرجلدی) و گروه کنترل دی ال متیونین خوراکی (mg/cat200 هر هشت ساعت) در کنار درمان قراردادی دریافت کردند. از گربه‌ها در روزهای صفر، هفت و 14 مطالعه نمونه‌گیری انجام شد و pH ادرار، وزن مخصوص، نوع و تعداد کریستال‌های استروویت محاسبه شد. حضور کانون‌های شناور اکوژن در سونوگرافی مثانه نیز بررسی گردیدند.
نتایج: کاهش قابل توجه کریستالوری استروویتی در هر دو گروه تحت درمان، مشاهده شد. ولی در گروه تحت درمان با ویتامین C،کاهش pH و به طبع آن کاهش کریستالوری در مدت زمان کوتاه‌تر و مؤثرتری روی داد. به علاوه در موارد انسداد مجاری ادراری درمان با ویتامین C تأثیر بهتری نشان داد. نتیجه گیری نهایی : بر اساس نتایج این مطالعه، استفاده از ویتامین Cی تزریقی در موارد انسداد مجاری ادراری که نیاز به پاسخ سریع برای جلوگیری از عوارض بعدی انسداد است توصیه می‌شود. هم‌چنین از قرص‌های متیونین می‌توان به منظور پیشگیری در بیماران با علائم نه چندان حاد با pH نسبتاً بالای ادرار و کریستالوری استروویتی خفیف و یا ادامه-ی درمان به منظور جلوگیری از عود مجدد استفاده کرد.
نتیجه گیری نهایی: بر اساس نتایج این مطالعه، استفاده از ویتامین سی تزریقی در موارد انسداد مجاری ادراری که نیاز به پاسخ سریع برای جلوگیری از عوارض بعدی انسداد است توصیه می‌شود. هم‌چنین از قرص‌های متیونین می‌توان به منظور پیشگیری در بیماران با علائم نه چندان حاد با pH نسبتاً بالای ادرار و کریستالوری استروویتی خفیف و یا ادامه-ی درمان به منظور جلوگیری از عود مجدد استفاده کرد.

Keywords [Persian]

  • ویتامین سی
  • استروویت
  • کریستالوری
  • سندرم دستگاه ادراری تحتانی
  • گربه

Introduction

The classic term of FUS  (feline  urologi- cal syndrome) and the most recent FLUTD (feline lower urinary tract disease) are broad terms that are used to describe a number of conditions associated with micturition, which include hematuria, pollakiuria and Periuria. The terms of obstructive uropathy and non-ob- structive uropathy are also used to classify cases of FLUTD depending  on the presence or absence of urethral  obstruction.

Feline lower urinary tract disease (FLUTD), formerly known as ‘Feline urologic syn- drome, FUS, is now more commonly called ‘Feline Idiopathic Cystitis (FIC’). Idiopathic cystitis in cats is a serious disease which may cause obstruction in male urethra and can be life-threatening.

Major causes of FLUTD that have been identified include urolithiasis and the forma- tion of urethral plugs. In many cases, however, no specific cause of disease may be  evident.

Struvite is the most common crystal now- adays and is a material that is comprised of magnesium, ammonium and phosphate. In- creasing ionic concentrations of urinary min- erals is the driving force underlying crystal formation. As the mineral concentration in- creases, urine becomes thermodynamically unstable and struggles to keep its contents in solution. Finally, concentration reaches to a level at which minerals can no longer remain dissolved and are forced out of solution as a solid phase (crystal formation)(Osborne et al., 1996).

Urethral plugs are composed of varying combinations of a protein colloid matrix and crystalline matrix (Osborne et al., 1992, 1996). When the urine becomes saturated with a sol- ute or solutes, crystals may form, aggregate, and grow. Other substances (e.g., cell debris, bacteria, and foreign bodies) must be   present


 

to act as a nidus for crystal precipitation to oc- cur (Kavanagh, 2006). Many factors contrib- ute to the saturation of the urine with a given solute or solutes, including urine volume, pH, concentrations of the solute, and urolith pro- moters and inhibitors

Alkaline urine by affecting hydrogen phos- phate (H3PO4) makes hydrogen ions out of the compound and increases the amount of phosphate ion (PO4-) in urine.  Crystalluria is used as a urine solubility detector and a risk factor for urinary stones and plugs for- mation. (Lulich et al, 2010).

Lower urinary tract signs (LUTS)  are  a set of clinical conditions with similar symp- toms related to inappropriate urine elimina- tion including anuria, pollakiuria, stranguria, dysuria, hematuria and periuria. A majority (i.e., 55 to 69%) of cats with LUTS have feline idiopathic cystitis  (FIC;  Kruger  et  al., 1991; Gerber et al., 2005). Some other causes are urolithiasis (13 to 28%), urethral obstruction (10 to 21%), and urinary tract in- fections (UTI; 1 to 8%).

Urethral obstruction usually occurs  in male cats and is most often caused by the for- mation of urethral plugs, passage of uroliths from the urinary bladder into the urethra or inflammation and swelling associated with feline idiopathic cystitis and likely urethritis. Rising incidence of urinary crystalluria in recent years and the role of these compounds in plug formation followed by complications such as idiopathic cystitis, search for treat- ment with lowest invasion that can relieve the symptoms  in a short  time,  have  gained

considerable attention.

Vitamin C is an essential nutrient for hu- mans and certain other animal species. This vitamin has multiple functions in the body. Based on studies, vitamin C is a urinary acid-

 

 

 

ifier (Carlsson, Wiklund, Engstrand, Weitz- berg, & Lundberg, 2001).

Since struvite crystals are relatively solu- ble in acidic urine, it is expected that with the injection of vitamin C in cats, crystals could be dissolved in a short period of time. In ad- dition, vitamin C is an antioxidant and can stimulate immune system. This drug(medi- cation) can prevent lower urinary tract infec- tions and other diseases.

As there have been no previous studies regarding the therapeutic effects of Vit C in dissolving struvite crystals, this research was designed to evaluate its role in rapid treat- ment of FLUTD and struvite crystalluria compared with conventional medications (diet modifications or urinary oral acidifi- ers).

Immediate treatment of severe FLUTD cases, especially simultaneously with ure- thral obstruction in male cats is very im- portant and is considered as an emergency. Conventional treatment of FLUTD includes urethral catheterization along with bladder flushing, using diuretic drugs, antibiotic therapy (if needed), dietary modification and urinary acidifiers.

As there is currently no treatment protocol for resolving urinary stones and plugs and most therapeutic approaches are just sup- portive and symptomatic, using parenteral compounds that can dissolve these deposits faster was suggested. Using oral acidifiers such as Dl-methionine is associated with problems such as palatability and also time limitation as compared with more rapid sub- cutaneous drug absorption and entering into the blood flow and bladder.

This study was designed to compare the effects of parenteral urinary acidifier like Vi- tamin C with oral urinary acidifiers on rapid urinary crystals dissolution.


Materials and Methods

Ten male cats with lower urinary tract symptoms such as dysuria, anuria, polyuria, pollakiuria, periuria, cystitis and hematuria that were referred to the Small Animal Hos- pital of Tehran University were  selected

The cats were randomly divided into two groups: experimental group (5 cats) and con- trol group (5 cats). History of each group, in- cluding age, breed, weight and type of food were recorded.

Presence of crystals and identifying their type was confirmed by microscopic analyses of urine sediments. Urine pH was checked  by pH meter and urine specific gravity (USG) was measured with refractometer. Crystal precipitation in urinary bladder was also confirmed by ultrasonography. After confirming the FLUTD by the presence of related clinical signs and U/A including the microscopic observation of struvite crystals, alkaline pH and increased SG and the precip- itation of crystals in ultrasonography of the bladder, the cats were randomly divided into two groups as mentioned before to evaluate two different therapies: group1 (5 cats) and group 2 (5 cats)

Group 1 (conventional): This group was treated with oral conventional urine acidifi-  er D/L methionine (170 mg/Kg TID for one week), oral and intravenous diuretic (furose- mide 2mg/kg BID for 7 days) and catheter- ization (in the case of cystitis and obstruc- tion) and diet modification.

Group 2 (Vit C): This group received vita- min C (100 mg/Kg, SC) SID for 7 days and the same conventional therapies including oral and intravenous diuretic (furosemide 2mg/kg BID for 7 days), catheterization (in the case of cystitis and obstruction), v and diet modification.

Urinary    analysis,    ultrasonography   and

 

 

 

clinical examinations for both groups were performed on days 0, 7, 14.

Sterile urine samples through catheteriza- tion or cystocentesis on days 0, 7 and 14 of the study were collected and sent to the labo- ratory for measuring pH, USG and identify- ing crystals types.

The crystals were counted using low magnitude lens (×100LPF) and their type was evaluated with high magnitude lens (×400HPF). The severity  of  Crystalluria was directly observed by light microscopy. Based on the number of struvite crystals in each LPF, a 1-3 plus numerical value was as- signed to each sample.

On days 0, 7 and 14 of the study, to eval- uate accumulation of crystals or debris in urinary bladder (floating echogenic foci) and changes in the wall thickness, abdominal ul- trasonography was performed. 2mm thick- ness was considered normal and any changes beyond this measure were regarded as abnor- mal.

Data Analysis

To investigate the effects of vitamin C  onW urinary parameters and ultra-sono- graphic findings such as bladder wall thick- ness in both groups, the independent sample t-test was selected. Paired sample t-test was used for evaluating the effects of each treat- ment on the factors examined on days 0,7,14. Presence of echogenic foci in urinary blad- der was analyzed by McNemar test. All data were analysed by SPSS 17 (SPSS Inc. Chica- go, Ill, USA).

Results

The cats were either Persians or DSH. The mean age of cats was 29±7.36 months and mean weight was3.0±8.33 Kg. All cats, ex- cept one, had been fed dry food. Three of 10 cats were neutered. Five cats had   hematuria


and complete obstruction.

Results showed that the group treated with Vitamin C had a significant decrease in urine pH at days 7 and 14 (P<0.05). While this re- duction in group treated with oral methionine was not significant at days 7 and 14.

Although struvite Crystalluria in both treated groups were  significantly  decreased at days 7 and 14 (P<0.05), no struvite crys- tals were observed in the urine sediment of four cats of the group  treated  with  Vitamin C (elimination of crystalluria: 80 %); in the group treated with oral methionine average urine struvite crystals  remained  1+ on days 7, 14.

Comparison between crystalluria  severity in experimental and control groups demon- strated that Vitamin C significantly reduced crystalluria in comparison with oral methi- onine at days 7 and 14 (Figs. 1 and 2).

Bladder wall thickness was evaluated on days 0, 7 and 14 and data analysis did not show any influence on cats of both groups (P>0.05) (Fig.3).

Based on bladder ultrasonography, al- though urinary echogenic foci on days 7 and 14 were reduced in both groups, statistical analyses with McNemar test did not show significant differences between two groups (P>0.05).

USG analyses showed that the urine spe- cific gravity on day 7 in both groups had decreased but it was not significant. Mean USG measurements on days 0,7,14 of this study did not show any statistical differences (P>0/05) (Table 1).

 

Figure 1.

 
 

Figure 2.

 
 
 
 

Figure 3.

 
 
 
 

Table 1. Mean USG measurements

 

Factor

group

Day0

Day7

Day14

pH

1

7.04±0.26

5.44±0.17

5.92±0.04

2

6.7±0.09

6.5±0.14

6.44±0.12

Crystal

1

2.4±0.24

0.2±0.2

0.2±0.2

2

2.4±0.24

1±032

1.2±0.2

USG

1

1.031±0.007

1.028±0.005

1.031±0.007

2

1.041±0.003

1.032±0.008

1.038±0.007

 

 

Discussion

The lower urinary tract feline diseases are receiving more attention as the number  of cats with an indoor lifestyle increases as well as multi-cat households.

Although struvite crystalluria in cats is normal, when coupled with clinical symp- toms it can be a indication of struvite stones, idiopathic cystitis and urinary tract infec- tions. Lower urinary tract disease in cats is fairly common and urethra obstruction  can be life-threatening. (Buffington, 2011; Et- tinger & Feldman, 2010). In this study, 90% of the referred cats were fed dry foods. Role of food humidity in formation of calcium oxalate stones has been reported in different studies. Food moisture reduces crystalloid substrates and urine mineral concentration (Lekcharoensuk et al., 2001).

Vitamin C is an essential vitamin with many known properties. This vitamin can acidify urine (Traxer, Huet,  Poindexter, Pak, & Pearle, 2003). As struvite  crystals are relatively soluble in acidic pH, in this study we evaluated the effects of parenteral (SC) vitamin C for a week on urinary fac- tors such as pH and crystalluria compared with classic treatment with a urinary acidi- fier (oral methionine).

Ammonium chloride has also been shown to be an effective urinary acidifier in the cat (Taton  and  others  1984a),  and  largely pre-


vented urinary tract obstruction and urolith formation in a group of cats fed a diet con- taining 0.37 per cent magnesium (dry mat- ter). In the present study, injection of vitamin C significantly reduced urine pH on day sev- en which remained constant up to day 14.

A key factor in control of struvite uroliths on both theoretical and experimental grounds is urine pH (Taton and others 1984a, Tarttelin 1987, Buffington 1988).

In this study, in group treated with vitamin C injections, pH reduction was greater and faster than usual treatment with oral methi- onine (P>0.05).

Average urine pH on day 7 was decreased from 7 to 5.5 in group1 that represents rapid influence on urine pH, whereas oral methi- onine did not show significant decrease in urinary pH (P>0.05).

USG was measured on days 0, 7 and 14 and no significant changes were seen, neither in group 1 nor in group 2.

Buckley showed that increasing diet hu- midity can reduce USG and consequently incidence of calcium oxalate will decrease, however, the effect of USG on struvite was less clear, with no significant difference between treatment groups (Buckley, Haw- thorne, Colyer, & Stevenson, 2011). It seems urine specific gravity is not the determining factor in the severity of struvite crystalluria, however, more studies are needed for    accu-

 

 

 

rate understanding of this issue.

Struvite crystalluria can be seen in normal cats (Schaer, 2009) so crystalluria has no clin- ical importance, but along with other symp- toms of lower urinary tract infections it seems serious and should be treated.

In this study, a significant reduction in stru- vite crystalluria was detected in both treatment groups on days 7 and 14. This reduction in the group treated with vitamin C was found to be faster and more effective and on day 7 crystal- luria reached to zero in all treated cases except one cat. But in group 2 crystalluria remained positive (1+) till day 14. These results reflect the impacts of vitamin C injections  in cases  of severe crystalluria, obstruction and urinary struvite stones compared with methionine. Methionine can be efficient in cases with mild crystalluria or in those that the urine must be kept acidic.

In addition, reducing pH can be effective in treatment and prevention of urinary bacterial infections, which is a risk factor for the forma- tion of struvite stones (Carlsson, et al., 2001). On day 14 no significant changes in cryst- alluria compared with day 7 were seen in both groups. However, in group treated with vita- min C, crystalluria remained at similar rate on days 7 and 14. On the other hand, in group treated with methionine a slight increase in average crystalluria was observed on day 14 compared to day 7 which may show the need

for long term therapy with this  medication.

In this study, two other factors including bladder wall thickness (mm2 <) and floating echogenic foci in bladder ultrasound were investigated in the treatment groups on days 0, 7 and 14. In present study cystitis most-  ly remained unchanged in cats. Cases  that had thickened urinary wall bladder did not change till day 14, which can indicate the need  of  other  treatments  to  reduce bladder

 

inflammation. Therefore, in order to better understand the effects of vitamin C on the bladder wall thickness further studies under controlled conditions are  warranted.

Conclusions

Floating echogenic foci in the bladder can be due to the presence of blood, fat droplets or crystals (Nyland& Mattoon, 2002). Ultra- sonography cannot distinguish these parti- cles (Chew & Buffington, 2014). The pres- ence of these particles in bladder could lead to struvite stone formation risk (Dvorska & Saganuwan, 2015).

In the present study, although echogenic foci were reduced in both treated groups on days 7 and 14, statistically they were not sig- nificant. The results showed that vitamin C and methionine both had similar effects on reducing echogenic foci, however, further studies in the same and controlled condi- tions for more accurate evaluations of these   2 compounds are needed.

Acknowledgments

We would like to gratitude Dr. Shabnam Babazadeh, and Mr. Alireza Ghovati for their patience and support during our  research.

Conflicts of Interest

The authors declared no conflict of  interest.

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