ENDOUROLOGY AND STONE DISEASE The Tolerability of Potassium Citrate Tablet in Patients With Intolerance to Potassium Citrate Powder Abbas Basiri1, Fatemeh Taheri2 , Maryam Taheri1* Purpose: To assess the tolerability of Potassium Citrate (KCit) tablets in patients with kidney stones that were not able to use the powder form of this drug due to unfavorable salty taste and /or gastrointestinal complications. Materials and Methods: Twenty-three stone formers, with intolerance to potassium citrate powder form, which had referred to Labbafinejad stone preventive clinic in 2015, were included in this study. All of the patients took two potassium citrate tablets (10 meq), three times a day for two weeks. Spot urine samples and the 24-hour urine collections were performed before and after KCit therapy. In addition, a visual analog taste scale was completed to gauge the taste and palatability of the KCit tablets in comparison with the powder form. Results: All of the patients claimed that they consumed the tablets as prescribed. The urine pH (5.7 ± 0.6 to 6.1 ± 0.8, p = 0.006), 24-hour citrate (235.8 ± 190.2 to 482.5 ± 323.2, p = 0.0002) and potassium (45.25 ± 22.5 to 75.27 ± 37, p = 0.002) were significantly higher after the treatment. In addition, the mean visual analog scale score was significantly improved in KCit therapy with tablet form versus to powder form of the drug (good vs. terrible score). Conclusion: Oral tolerance of KCit therapy is improved with the use of Potassium Citrate tablet, with beneficial effects on 24-hour urine citrate, potassium, and pH. Keywords: potassium citrate; tolerance; taste; gastrointestinal side-effects. INTRODUCTION Kidney stones remain a public health problem around the world and have a high rate of recur- rence even with treatment(1). The urine profile is one of the deciding indicators of urine stone formation as well as recurrence(2). Consequently, clinical efforts should be focused on correcting the underlying abnormalities. One of these correctable abnormalities is hypocitraturia that is described as an isolated abnormality in up to 10% of calcium stone formers. Furthermore, it is also asso- ciated with additional abnormalities in 20% to 60% of stone formers(3-5). The alkali citrate treatment has two major effects. At first, it increases urinary citrate levels in patients with calcium nephrolithiasis. Moreover, it provides an over- all alkalization which is advantageous for patients with uric acid(6) and cystine stones(7). The numerous benefits of the alkali citrate treatment, promotes its usage in a wide range of urinary system stones treatments. In 1985, the Food and Drug Administration (FDA) ap- proved potassium citrate (KCit) for the treatment of a wide variety of disorders that cause stone formation (8). KCit is available in three forms in global pharma- ceutical market: extended- release tablets, powder for dilution, and oral solution. Between these three forms, however the gastrointestinal (GI) side effects of the liquid preparations have been shown to be more than tablets (33% vs 9.3%)(9), but its effectiveness is better in patients with short intestinal transit such as chronic 1Urology and Nephrology Research Center, Department of Urology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2School of Nutritional sciences and Dietetics, Tehran university of medical sciences, Tehran, Iran. *Correspondence: Urology Nephrology Research Center, No. 103, 9th Boostan Street, Pasdaran Avenue, Tehran, Iran. Tel: 0098 21 22567222. Fax: 0098 21 22567282. Email: taheri233@yahoo.com. Received December 2017 & Accepted January 2018 diarrheal syndromes(10). Despite its widespread use, compliance to long term treatment with KCit is low, mainly due to its inappro- priate salty taste suspected side effects(11) and inconven- ience of bid (two times a day) or tid (three times a day) dosing specially with powder form that is necessary to be prepared. Considering the inconvenient use of the powder formulation and improvement of its tablet taste as declared by the manufacturer, we decided to evaluate the palatability and efficacy of simple form of KCit tab- let (Urocitra) in groups of kidney stone forming patients with intolerance to powder form of this drug due to the unfavorable taste and upper GI side effects. MATERIALS AND METHODS This study was conducted as a quasi-controlled trial in stone formers referred to Labbafinejad stone clinic in 2015. Enrollment criteria included recurrent calcium stone formers whom only urinary metabolic risk fac- tor was hypocitraturia (24-hour urinary citrate less than 320 mg/24 h) and were treated with potassium citrate powder, and were unable to tolerate this drug due to unfavorable salty taste and gastrointestinal complica- tions. The patients were included only after at least one month of therapeutic interventions. Participants were excluded if they had renal failure (creatinine clearance < 60 mL/min), were taking on treatment that altering potassium metabolism (angiotensin-converting enzyme inhibitors, beta-blockers, potassium-sparing diuretics), Endourology and Stone Diseases 16 or consumed any kinds of citrate supplement within the last four weeks. Women were also excluded if they were in pregnancy or lactation. The institutional review board of the Urology and Nephrology Research Center (UNRC) approved the study protocols. Twenty-three patients who met the mentioned criteria were enrolled in the study. Informed consent was taken from patients before participating in the study. Demo- graphic information and initial questionnaires for all individuals were filled. Serum sample, fast urine and 24-hour urine were collected at baseline. To assess the drug influence on kidney function, serum potassium and creatinine were checked. Twenty-four hour urine was measured for volume, potassium, citrate and cre- atinine. Urinary pH was immediately determined on post-voiding spot urine sample using a pH electrode. Then, patients underwent treatment with potassium cit- rate tablets with the dosage of 6 tablets per day (2 tablets every 8 hours, each tablet contains 5 mili-equivalent cit- rate) for two weeks. At the end of the study, the analy- sis of serum metabolites, spot urine sample and 24-hour urine metabolites were repeated. The visual analog taste scale (VATS) (Figure 1) was used to assess patients' satisfaction. Furthermore, the amount of remained KCit tablet and measurement of 24-h urinary potassium were used as another criteria to evaluate patients' compliance (12). It is noteworthy that all of our patients in this study have been advised to general dietary recommendation of preventive stone clinic protocol, at least three months before treatment with potassium citrate tablet. Method of analyzing serum and urine parameters: Serum creatinine were measured using a Jaffe kinetic method with BS-480 chemistry fully automated ana- lyzer. Urine creatinine were measured using a Jaffe kinetic method with BT-4000 full-automated chemis- try analyzer. Urinary citrate was determined by an en- zymatic procedure using reagents from Darman Faraz Kave using Eppendorf Biophotometer. Serum and urine potassium were measured with the Eppendorf flame photometer and EasyLyte electrolyte analyzer, respec- tively. Urinary pH was measured with a pH electrode in urine samples immediately post-voiding using Bante 220 Portable pH Meter. Statistical analysis was performed by SPSS 19. The normal distribution of the data was investigated through the Kolmogrov-smirnov test. As all variables were nor- mally distributed, changes in patients’ urinary metabol- ic profile and serum parameters before and after treat- ment with KCit tablet were identified by the paired t test. Significant changes were defined as p value < .05. RESULTS All the patients completed the study and their average age was 51.14 ± 9.89 (16 males and 7 females). The urinary metabolic profile and serum parameters of the studied population before and after KCit therapy were compared and the results are shown in Table 1. The pa- tients’ urinary pH increased significantly from 5.7 ± 0.6 to 6.1 ± 0.8 after treatment with KCit tablets (P = .006). Urinary citrate also showed a significant increase from 235.8 ± 190.2 to 482.5 ± 323.2 (P = .0002). In addition, mean urinary potassium showed significant increase (P = .002) as expected which indicates patients’ compli- ance. No remarkable changes were observed in serum creatinine and potassium (Table 2). All the individuals claimed that they consumed the tab- lets as prescribed. Only two patients, who had the his- tory of gastrointestinal problems following food intake and most medications, experienced a little heartburn after consumption of KCit tablets, though it was tolera- ble for them with meals and they finished the delivered tablets. The VATS score at baseline to assess the patients’ sat- isfaction about KCit powder, was 8.35 ± 0.77 which represents “terrible” and after treatment changed to 2 ± 0.14, which accounts for “good” in this scale (P = .0001). As it is obvious from the results, patients’ sat- isfaction significantly increased after intake of KCit tablets. DISCUSSION Kidney stone removal has been significantly facilitat- ed by using the recently emerging non-invasive treat- ments(5). Although these therapies- namely percuta- neous nephrolithotomy and extracorporal shockwave lithotripsy- provide satisfactory results with associated acceptable rate of complications, they do not alter the underlying metabolic abnormality. Furthermore, stone recurrence is typically found post-treatment, even in Figure 1. Visual Analogue Taste Scale for assessment the patient’s satisfaction(30). Tolerability of potassium citrate tablets-Basiri et al. Mean ± SD1 Number (percent)2 Age (years) 51.14 ± 9.89 Sex Male 16 (70%) Female 7 (30) Duration of initiation of stone disease (Years) 12.71 ± 9.74 History of stone intervention ESWL (yes) 8 (42%) Surgery (Yes) 14 (74%) Duration of KCit powder consumption before 3.77 ± 4.43 the study (months) Causes of intolerance to KCit powder Inappropriate salty taste 8 (35%) Epigastric pain 7 (30%) Nausea 6 (26%) Heartburn 2 (9%) 1. SD: Standard Deviation. 2. Number for quantitative variables and percent for qualitative variables. 3. The collection of the dis- persed time of consuming the powder form of Potassium citrate. Table 1. Demographic data of the patients and the prevalence of gastro-intestinal complications with powder form of potassium citrate (KCit). Vol 15 No 01 January-February 2017 17 those with a stone-free post-therapy status. In addition, following those therapies, the retained stone particles may aggregate or constitute a nucleus for new stone formation, thereby causing an elevated rate of stone growth. Based on the stone recursion frequency, the development of a medical prophylactic program to pre- vent recurrences is of utmost importance(5). In addition, patient’s compliance to medical recommendations of kidney stone clinic is another important factor, which affects the treatment outcomes. Our study revealed that the compliance of our patients to the tablet form of po- tassium citrate was satisfactory. Potassium citrate has been used as a medical therapy of urolithiasis for more than two decades. Its effectiveness in treatment of urinary system stones has been report- ed in several studies(1,12). Citrate is a known inhibitor of stone formation. In renal tubules citrate complexes with calcium, reduces the availability of ionic calcium to interact with oxalate or phosphate(13,14). Moreover, citrate helps the inhibitory effects of macromolecular modulators of calcium oxalate crystallization process- es, partly by interaction with Tamm-Horsfall protein(15). In addition, citrate prevents crystal agglomeration and growth through its ability to bind to the crystal’s sur- face, and it may prevent adhesion of calcium oxalate to renal epithelial cells(16). Low urinary potassium is related to hypocitraturia(17), therefore one of the advan- tages of potassium preparations is either prevention or correction of hypokalemia. Also simultaneous admin- istration of citrate with thiazide agents can be more ef- fective in lowering urinary calcium excretion(18). Lastly, potassium citrate is a meaningful treatment for uric acid and cystine nephrolithiasis, as it provides an alkali load which increases urinary pH, one of the principal deter- minants of uric acid and cystine solubility(5). Also with considering the effect of KCit in delaying of the ure- ase-induced crystallization, it may be useful in urinary infection stones(19). Several authors supported the benefit of alkaline cit- rates in patients with renal calculi. A meta-analysis con- ducted by Phillip et al.(1), including seven randomized controlled trials with a total of 477 participants in pre- venting stone recurrence through the long-term admin- istration of citrate preparations (at least six months), have been shown that KCit not only reduced the stone size, but also reduced new stone formation significant- ly, and increased citrate levels. In another review, Mat- tle et al.(20) on a short-term therapy (between 1 to 12 weeks) with alkali citrate(21-28) showed that after taking potassium citrate, urine pH increased by 1- 14% com- paring to pretreatment values. The same was true for urinary citrate, which increased by between 27%- 94%. Despite the significant therapeutic effects of alkali cit- rate, the main limitation of its widespread usage is the relatively low GI tolerability of available alkali citrate preparations. In one study, only 62% of patients con- sumed low doses of potassium citrate in long term (11). In a review by Mattle et al., overall, 17% of subjects on placebo and 33% of treated patients with alkali citrate, in order to prevent stone recurrence, prematurely left the randomized trials due to drug side effects. Adverse effects that reduce treatment compliance included up- per gastrointestinal disturbances (epigastric pain, heart- burn, and nausea), loose stools and rash(1). The problems with compliance are poorly reported in the literature, but some reasons cited are high cost, bad taste, and the inconvenience of bid or tid dosing (29,30). Thus, the de- velopment of more tolerable alkali citrate preparations remains an important issue in the treatment of urinary stones. In this study, comparing the price of these two forms of potassium citrate shows that the cost of taking the tablet form is about 30% higher than powder (1.09 $ vs. 0.83 $); however, considering the better tolerability of tablet form and reported unused powder form of this drug, it is obvious that this amount of higher cost of tablet form is acceptable. Whereas in middle Europe there is a preference for po- tassium sodium citrate, in North America (US, Cana- da) KCit is the favored preparation. The result of the criticism levelled against potassium sodium citrate by US authors, is that sodium moiety causes increased calciuria. More specifically, sodium may abolish the decrease in calciuria, one of the beneficial effects pos- sibly exhibited by potassium citrate(29). In our country, currently the only available preparation of KCit is the powder form, which some patients cannot tolerate it, es- pecially due to its unappealing salty taste. The results of this study showed that the transformation of powder for- mulation into KCit tablets, improves the taste of KCit, facilitates taking the drug, and reduces gastrointestinal complications. There is no other study for comparison, the results of this study illustrate that the compliance for KCit tablets was satisfactory with regard to the subjects who took the tablet forms, and completed the study(30). In some countries, there are also other forms of the medication such as the slow-release preparation, which is better tolerated. Other researchers have added an ar- tificial sweetener (Splenda) to the powder form to en- hance the taste property and compliance(30). Our study confirms that changing the powder form to KCit tablet results in more tolerability, however, the question that whether this effect is truly durable in long term has re- mained unanswered, since if these changes sustain over time, there will be a significant reduction in kidney stone recurrence rate. The small sample size and short follow-up time could be considered as shortcomings and limitations of the study. Therefore, a long-term study using higher doses of this easily tolerable medication is suggested to test and challenge our study results. ACKNOWLEDGMENT The authors would like to thanks Mr. Ali Aghaei for his good cooperation in preparation the drug. we thank Saba Jalali and Navid Mokhtari for their kind assis- tance in clarifying the patient’s data and writing the manuscript, respectively. In addition, we would like to thanks Dr. Seyedehleila Tabatabaeefar for her very Tolerability of potassium citrate tablets-Basiri et al. Endourology and Stone Diseases 18 Before KCit After KCit p value Total volume (ml) 1690 ± 473* 2050 ± 760 0.03 pH 5.7±0.6 6.1 ± 0.8 0.006 urine Potassium (mg/day) 45.25 ± 22.5 75.27±37 0.002 Citrate (mg/day) 235.8 ± 190.2 482.5±323.2 0.0002 Creatinine (mg/day) 1.2 ± 0.5 1.1 ± 0.4 0.23 Serum Potassium (mEq/L) 4.19 ± 0.4 4.15±0.4 0.81 Creatinine (mg/dL) 1.18 ± 0.17 1.16±0.15 0.55 Table 2. The results of serum and urine analysis. mEq: milliequivalent. ml: mili-litre. mg: mili-gram. KCit: Potas- sium Citrate. careful correction of the last edition of this manuscript. CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Phillips R, Hanchanale VS, Myatt A, Somani B, Nabi G, Biyani CS. Citrate salts for preventing and treating calcium containing kidney stones in adults. Cochrane Database Syst Rev. 2015CD010057. 2. Rahman F, Birowo P, Widyahening IS, Rasyid N. Effect of citrus-based products on urine profile: A systematic review and meta- analysis. 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