Review

1.

Introduction

2.

Agents used for the prevention of calcium stones formation

3.

Agents used for the prevention of uric acid and calcium stones

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formation 4.

Agents used for the prevention of infection stones formation

5.

Agents used against cystine stones

6.

Potential preventive agents

7.

Conclusion

8.

Expert opinion

Prevention of renal stone disease recurrence. A systematic review of contemporary pharmaceutical options Stavros Sfoungaristos†, Ofer N Gofrit, Vladimir Yutkin, Dov Pode & Mordechai Duvdevani †

The Hebrew University, Hadassah University Hospital, Jerusalem, Israel

Introduction: Renal stone disease has a high recurrence rate. Prompt metabolic evaluation followed by appropriate medical management is of paramount importance for preventing disease recurrence. Areas covered: A PubMed/Medline search was performed to identify randomized controlled studies evaluating medical treatments against renal stone recurrence. Due to the limited number of published randomized studies, non-randomized studies of significant importance were included and reported. Expert opinion: Thiazides are widely used for lowering calcium levels in urine and thus preventing calcium stone formation. Citrate supplements may increase the urine citrate level and increase pH. Allopurinol has shown significant efficacy for preventing formation of calcium stones in hyperuricosuric patients. Prevention of recurrence of infection stones and cystine stones has not been widely studied. Several agents that are used today have shown efficacy outside randomized controlled studies. However, they may produce severe adverse events, which are minimizing their use. Keywords: allopurinol, citrate, prevention, recurrence, renal stone, thiazides Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Nephrolithiasis represents a common disease. It has been reported that the prevalence is ~ 11% for adult men and 7% for women with a tendency to increase due to changes in diet and climate [1,2]. It is expected that other medical conditions with rising prevalence, such as diabetes and obesity, will further increase nephrolithiasis prevalence [3]. Prevention of nephrolithiasis can have a significant cost savings for healthcare systems and the financial benefits are even higher if we consider the association of urolithiasis with other chronic conditions such as renal insufficiency and hypertension [4-6]. The annual cost of stone disease in 2000 was estimated in US $2.81 billion compared to US$3.79 billion in 2007 and this is expected to increase by US$780 million in 2030 due to population growth in United States of America [3]. Renal stone disease has a great tendency to recur if left untreated with a reported 28 -- 52% recurrence rate following 10 years after the first stone formation [7,8]. Prevention of the disease is of paramount importance. Depending on the stone composition, a thorough evaluation should be undertaken to reveal underlying diseases or metabolic abnormalities. Based on the findings, there are several pharmacological options for disease prevention. For this review, we tried to evaluate the available preventive treatment options for renal stone recurrence by conducting a PubMed/Medline search to identify eligible studies. We focused on randomized, controlled studies (Table 1). Due to the limited 10.1517/14656566.2015.1037740 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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S. Sfoungaristos et al.

Article highlights. . . . .

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Thiazides can decrease urine calcium levels and prevent stone formation. Allopurinol is the primary treatment for hyperuricosuria. Potassium citrate can effectively increase urine citrate level and increase pH. Acetohydroxamic acid has shown efficacy for preventing infection stones recurrence; however the high rate of adverse events has minimized its use. L-Methionine is an efficient and safe preventive agent against infection stones and deserves further evaluation. Preventive management of cystine stones recurrence has serious adverse effects. Studies evaluating captopril efficacy against cystine stones have shown conflicting results.

This box summarizes key points contained in the article.

number of published randomized studies, we have also reported results by non-randomized, non-controlled studies that evaluated pharmacological agents, which are commonly used in the clinical practice. 2. Agents used for the prevention of calcium stones formation

Calcium containing stones are consisting 80% of all renal stones [9,10]. Of them, calcium oxalate (CaOx) calculi represent the great majority followed by calcium phosphate (CaP) stones. Several systemic diseases are implicated in the pathogenesis of calcium stones. Primary hyperparathyroidism and sarcoidosis are significant causes of urine calcium supersaturation and stone formation. In addition, previous intestinal or gastric surgery can affect the serum and urine concentrations of oxalate leading to CaOx stone formation [11,12]. Renal tubular acidosis type I, a syndrome characterized by hypokalemia, hyperchloremic metabolic acidosis and inability to lower urine pH below 5.5, can also lead to CaP formation by significantly decreasing urine citrate concentration as well as by hypercalciuria due to systemic acidosis and by the increased urinary supersaturation with respect to CaP that is due to the elevated urine pH. All of the above pathological conditions are well-known causes of renal stone disease and the actual preventive measurement for stone recurrence prevention is the treatment of the primary disease. However, calcium stones are mainly observed in otherwise healthy patients with no underlying pathology. Several abnormal findings can be observed in 24 h urine collection that may promote crystallization and stone formation. These are hypercalciuria affecting 30 -- 60% of stone formers, hyperoxaluria found in 26 -- 67% of the patients, hyperuricosuria in 15 -- 46%, hypomagnesuria in 7 -- 23% and hypocitraturia in 5 -- 29% of stone formers [13]. An acidic urine pH, meaning pH < 6, can be the solitary pathological finding. In the above cases that there is no specific disease to treat, preventive 2

treatment options consist of diet modifications, increase urine output and pharmacotherapy. The latter is actually targeting the pathological findings of 24 h urine analysis. There are several treatments available which are analyzed below. Thiazides Thiazide-type diuretics represent the most commonly used drug group in prevention of renal stone recurrence. Their role is to decrease urine calcium concentration and therefore they are actually used to treat hypercalciuria. Although the actual molecular mechanism affecting calcium transportation is not clear, thiazides use leads to increase of renal sodium excretion and decrease of calcium excretion [14]. Actually, increase of urine sodium excretion has an immediate onset following treatment with thiazides and lasts for 1 or 2 days. Thereafter, urine sodium excretion again matches intake, but at a slightly lower total intravascular volume. This leads to increased proximal tubule sodium and calcium re-absorption. 2.1

Hydrochlorothiazide Laerum and Larsen [15] included 50 patients with multiple calcium stone episodes in a double-blind randomized study. Hypercalciuria was the dominant finding in 26% of the patients, hyperuricosuria in 24% whereas mixed metabolic pathologies observed in the rest of the patients. Participants were randomized to receive hydrochlorothiazide 25 mg twice/day (25 patients) or placebo (25 patients) plus diet recommendations including increase fluids intake and restriction of salt, oxalate and purine-rich foods. Recurrence rates, defined as the presence of a new stone in radiographical examination, after 3 years of median follow-up was significantly lower in the hydrochlorothiazide group (21.7%) compared to the placebo group (48%). Even in cases that thiazides did not manage to prevent a new stone formation, the stone-free time interval was significantly higher in the hydrochlorothiazide group. Regarding metabolic changes in 24 h urine analysis after 10 months of treatment, urine calcium levels were significantly lower in patients receiving thiazide than in patients given placebo [16]. There was also a significant increase in urine magnesium levels in the thiazide group. On the other hand, there were no significant changes in urine levels of uric acid. Interestingly, the thiazide effect found to be independent of pre-treatment urinary calcium levels but it was less beneficial in patients with hyperuricosuria. The effects of thiazides on the prophylaxis of recurrent calcium stone formation were the main objective of a doubleblind, randomized and controlled study initiated by Scholz et al. [17]. The researchers randomized 51 patients with multiple stone episodes in the past to receive hydrochlorothiazide 25 mg twice/day (25 patients) or placebo (26 patients) for 1 year. Hyperoxaluria was the major metabolic abnormality in all studied patients whereas hypercalciuria was found in 12% of them. A significant decrease in urinary calcium excretion was found in patients of thiazide group. On the other 2.1.1

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Prevention of renal stone disease recurrence

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Table 1. Randomized controlled trials for prevention of renal stone recurrence. Study [ref]

No. of patients/ withdrawals

Stone type

Arms

Follow-up (months)

Stone recurrence

Laerum and Larsen (1984) [15]*

50/2

Calcium

40

21.7 versus 48%

Scholz et al. (1982) [17]z

51/3

Calcium

12

24 versus 23.1%

Fernandez-Rodriguez et al. (2006) [18]*

150/0

Calcium

36

32 versus 30 versus 56%

Ala-Opas et al. [19]*

73/0

Calcium

24

21.4 versus 26.7%

Ettinger et al. (1988) [20]*

124/32

Calcium

36

15.8 versus 13 versus 26.7 versus 33.3 versus 45.2%

Borghi et al. (1993) [21]*

75/11

Calcium

36

15.8 versus 12.5 versus 42.8%

Barcelo et al. (1993) [24]*

57/19

Calcium

36

27.8 versus 80%

Soygur et al. [25]* Ettinger et al. (1997) [26]*

110/20 64/23

Calcium Calcium

12 37

0 versus 28.6% 12.9 versus 63.6%

Hofbauer et al. (1994) [27]§

50/12

Calcium

36

68.8 versus 72.7%

Lojanapiwat et al. (2011) [28]*

76/4

Calcium

12

8 versus 42%

Smith (1997) [29]*

132/40

Calcium

60

42.9 versus 69.8%

Ettinger et al. (1986) [30]*

72/12

Calcium

HCT 25 mg twice/day versus Placebo HCT 25 mg twice/day versus Placebo HCT 50 mg/day versus HCT 50 mg/day + K-Cit 20 mEq/day versus Control HCT 50 mg twice/day versus Control CT 25 mg/day versus CT 50 mg/day versus MH 650 mg/day versus MH 1300 mg/day versus Placebo Indapamide 2.5 mg/day versus Indapamide 2.5 mg/day + Allopurinol 300 mg/day versus Control K-Cit 30-60mEq/day versus Placebo K-Cit 60mEq/day versus Control K-Mg-Cit 126mEq/day versus Placebo K-Na-Cit 30 g/day versus Control K-Na-Cit 81mEq/d versus Control Allopurinol 300 mg/day for 1 week and then 100 mg/day versus Placebo Allopurinol 300 mg/day versus Placebo

24

17.2 versus 35.5%

*Stone recurrence was defined radiological (a new stone found in abdominal X-ray) and clinical (spontaneous passage of a new stone). z Stone recurrence was defined clinical (spontaneous passage of a new stone). § Stone recurrence was defined radiological (a new stone found in abdominal X-ray + abdominal ultrasound). AHA: Acetohydroxamic acid; CT: Chlorthalidone; HCT: Hydrochlorothiazide; K-Cit: Potassium citrate, K-Mg-Cit: Potassium-magnesium citrate, K-Na-Cit: Potassiumsodium citrate, MH: Magnesium hydroxide.

hand, changes in total serum calcium levels, ionized calcium and urine levels of oxalate were identical in both groups. In addition, treatment did not alter the natural history of the disease as 24% of thiazide group and 23.1% of the placebo group present with a new stone during the study period, revealing no difference in recurrence-free rates. A recent prospective study by Fernandez-Rodriguez et al. [18] evaluated the prolonged efficacy of thiazides in the prevention of recurrences in patients with CaOx stones. Inclusion criteria were the presence of > 1 episode of calcium stone in the past 36 months resolved spontaneously or after definitive treatment. The metabolic disorders at the baseline was hypercalciuria in 35% of the patients, hypocitraturia in 15%, hyperuricosuria in 4%, hyperoxaluria in 2% and mixed findings in 16%. One hundred and fifty patients randomized in three groups. Group A consisted of 50 patients who received no prophylactic treatment. Groups B and C included

50 patients each who received 50 mg of hydrochlorothiazide once/day or 50 mg of hydrochlorothiazide once/day and 20 mEq of potassium citrate/day. Stone recurrence was defined as any newly radiological detected stone found in the plain abdominal X-ray. Recurrence rates were significantly higher in group A (56%) patients compared to that of group B (32%) and C (30%). Ala-Opas et al. [19] studied 73 patients with recurrent calcium stones episodes. Hypercalciuria was the pathological finding in 44% of the patients. Twenty-eight patients received hydrochlorothiazide 50 mg twice/day whereas the rest 45 patients received no treatment. All patients were on a low-calcium and lowoxalate diet and took 40 g bran daily. No significant differences were found regarding stone recurrence between the thiazide group (21.4%) and the control group (26.7%) after 24 months of follow-up. However, both groups had significant decrease in the stone recurrence rate compared to that before treatment

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onset. This decrease was not significant in the hypercalciuric patients who received hydrochlorothiazide.

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2.1.2

Indapamide Borghi et al. [21] studied indapamide as a potential preventer of calcium stone recurrences. The researchers randomized 75 patients with recurrent episodes of CaOx stone disease and hypercalciuria to either indapamide 2.5 mg/day (n = 25) or indapamide 2.5 mg/day plus allopurinol 300 mg/day (n = 25) or dietary changes (n = 25). Stone recurrence rates improved in all groups compared to pre-treatment ones. This rate in the indapamide group was 15.8% significantly lower compared to only diet group (42.8%). Three patients (12.5%) in the combine treatment group developed a new stone within the 36 months of follow-up. This rate was significantly lower compared to control but not different compared to the indapamide group. Urine calcium concentrations greatly decreased in all groups. Relative supersaturation of CaOx and CaP decreased ~ 50% compared to pre-treatment levels in both indapamide and indapamide + allopurinol groups. 2.1.3

Bendroflumethiazide Two double-blinded, randomized, placebo-controlled trials were identified evaluating the effects of another Thiazidic diuretic, bendroflumethiazide, on prevention of recurrent stone formation. In the first one, Wolf et al. [22] studied 62 patients with idiopathic recurrent CaOx stone disease. The patients were allocated either to treatment with bendroflumethiazide 2.5 mg three times/day or placebo. The results after a median follow-up of 36 months regarding new stones formation rate were not different between the groups leading to the conclusion that thiazides may not be suitable for lifelong prophylaxis in patients with a moderate rate of stone formation. In contrast to the above results, Mortensen et al. [23] randomized 22 male patients to receive either bendroflumethiazide 2.5 mg plus 573 mg potassium chloride three times/day or placebo. Authors observed a significant decrease in the 4

Agents used for the prevention of uric acid and calcium stones formation

3.

Chlorthalidone

One randomized control trial found to examine the efficacy of chlorthalidone in the prevention of renal stone recurrence. Ettinger et al. [20] randomized 124 patients with recurrent CaOx stones to receive chlorthalidone 25 mg/day (n = 19) or chlorthalidone 50 mg/day (n = 23) or magnesium hydroxide 650 mg/day (n = 30) or magnesium hydroxide 1300 mg/day (n = 21) or placebo (n = 31). Urine calcium concentration was significantly decreased in both groups received thiazide. Stone recurrence after 36 months of follow-up was 15.8% in the chlorthalidone 25 mg/day group and 13% in the chlorthalidone 50 mg/day group significantly lower compared to placebo (45.2%) but not to magnesium hydroxide groups (26.7 and 33.3%).

2.1.4

stone formation rate and calcium excretion in patients of thiazide group.

Citrate Citrate supplements represent a major therapeutic option to prevent renal stone recurrence. Their use is extended to all stone compositions apart of infection stones. Actually, in cases with recurrent uric acid stones, citrate may be the only treatment needed to prevent recurrence. Citrate is an important inhibitor of calcium salts crystallization leading to stone formation. Hypocitraturia is a frequently encountered pathology in patients with calcium stones and therefore its management is of paramount importance in order to prevent recurrent stone formation. Several systemic pathologies can influence citrate levels within urine. These conditions should be identified and treated. Such conditions include renal tubular acidosis type I, urinary infection and chronic diarrheas. On the other hand, hypocitraturia is often not correlated with an underlying disease. In these cases, citrate can be administered in order to increase urinary levels. There are several forms of citrate supplements, including potassium citrate (K-Cit), potassium--magnesium citrate (K-Mg-Cit) and potassium-sodium citrate (K-Na-Cit). Although K-Mg-Cit is not actually commercially available, we quote eligible studies evaluating the above agent. 3.1

Potassium citrate Barcelo et al. [24] evaluated the efficacy of K-Cit in preventing stone formation in 57 patients with recurrent episodes of CaOx and CaP stone in the past and hypocitraturia. Patients were randomly allocated to receive either K-Cit 30 -- 60 mEq per day (n = 28) or placebo (n = 29). In 18 patients receiving K-Cit for the whole study period, urine citrate levels increased significantly. Additionally, mean urine pH increased from 5.5 to 6.4 (p < 0.01). Stone recurrence was observed in 27.8% in the K-Cit group significantly lower than the 80% of patients in the placebo group who developed a new stone. Actually, the recurrence rate per year after 3 years of followup was 0.1 stones in the K-Cit group compared to 1.1 stones in the placebo group (p < 0.001). Soygur et al. [25] enrolled 110 patients with low caliceal CaOx stone who underwent shockwave treatment. The stone-free status was documented in 62% of the patients whereas the rest of them had residual stone fragments < 5 mm. Urine analysis revealed hypercalciuria, hypocitraturia and hyperuricosuria in 20, 38 and 18% of the patients respectively. Patients were randomized to dietary changes plus K-Cit 60 mEq per day (n = 46) or just dietary changes (n = 44). Dietary suggestions included increase of fluids intake to achieve at least 2.1 L of urine output, decrease of oxalaterich foods and salt and increase of fiber consumption. The 28 patients who were stone-free after shockwave therapy and 3.1.1

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Prevention of renal stone disease recurrence

received preventive K-Cit treatment did not develop a new stone after 12 months of follow-up. In contrast, 8 out of the 28 patients with residual stones in the control group developed recurrent stone disease. Of the 34 patients with residual stones after shockwave therapy, 44.5% of the patients who received K-Cit spontaneously expulsed the fragments compared to 12.5% of the patients in the control group. As we reported in Section 2.1.1, Fernandez-Rodriguez et al. [18] studied the combined efficacy of thiazides and K-Cit in preventing calcium stone recurrence. The researchers randomized 150 patients by 1:1:1 to receive 50 mg of hydrochlorothiazide once/day or 50 mg of hydrochlorothiazide once/day and 20 mEq of K-Cit or no prophylactic treatment. Recurrence rates were significantly lower in the thiazide groups compared to placebo. However, the addition of citrate did not contribute in stone recurrence prevention. Potassium magnesium citrate There is a single randomized, placebo-controlled trial evaluating K-Mg-Cit as a potential preventing agent for recurrent stone formation conducted by Ettinger et al. [26]. The authors randomized 64 patients with a history of CaOx stones to receive 126 mEq of K-Mg-Cit per day (n = 31) or placebo (n = 33) for 37 months. Four patients (12.9%) of K-Mg-Cit group and 21 patients (63.6%) of the placebo group developed new calcium stones. The relative risk of treatment failure for the K-Mg-Cit group was 0.16 compared to placebo and this remained statistically significant even after adjustment for age, pretreatment stone events rate and urinary biochemical abnormalities. 3.1.2

Potassium sodium citrate We identified two randomized controlled trials studying K-Na-Cit in prevention of renal stone formation. The first was conducted by Hofbauer et al. [27]. They enrolled 50 patients with multiple episodes of CaOx stones in the past suffering by hypercalciuria (44%) and/or hypocitraturia (69%). Patients randomized 1:1 to receive either no additional treatment apart of dietary modifications or K-Na-Cit 30 g per day. Citrate dosage was adjusted afterwards to keep urine pH within 7.0 -- 7.2 levels. Twelve patients withdraw the study. Urine hypercalciuria prevalence was decreased from 48 to 25% in the K-Na-Cit group and increased from 40 to 45% in the control group. Additionally, hypocitraturia was decreased from 72 to 25% and from 65 to 55% in the citrate and control groups respectively. Despite the beneficial effects of citrate in urine biochemical parameters, recurrence rates were found to be very high in both groups after 3 years of follow-up. Five patients (31.2%) in the citrate group and six patients (27.3%) of control group were stone-free at the end of the study period. The stone recurrence rate per year was not also significantly different between the groups (0.7 vs 0.9 stones/year). An interesting finding of this study was that nine patients (56%) of citrate group reported a 3.1.3

painless spontaneous elimination of stone fragments whereas only one patient (4%) of control group reported the same. A recent study by Lojanapiwat et al. [28] evaluated the effects of K-Na-Cit on prevention of calcium stone recurrence and stone growth after shockwave lithotripsy or percutaneous nephrolithotripsy. They studied 76 patients who were stone free (n = 39) or with residual fragments < 4 mm (n = 37) following 8 weeks after treatment. Urine analysis revealed hypercalciuria, hypocitraturia, hyperuricosuria and hyperoxaluria in 14, 46, 1 and 18% of the patients respectively. Patients were randomized in two groups. Group 1 received 81 mEq of K-Na-Cit per day (n = 39) and group 2 received no treatment (n = 37). Hypercalciuria, hyperoxaluria and hyperuricosuria rates were not significantly affected by citrate treatment after 12 months of follow-up. On the other hand, the hypocitraturia rate decreased in group 1 patients from 51.3 to 7.69% whereas urine pH increased from 5.8 to 6.6. Stone recurrence rates within patients who were stone-free were 8% (1 out of 13 patients) in the citrate group and 42% (11 out of 26 patients) in the control group. Allopurinol Allopurinol use is extended to prevent stone recurrence in both calcium-stone and uric acid-stone formers. The main goal of allopurinol treatment is to reverse hyperuricosuria. It is well established that increased levels of urine uric acids may lead to either CaOx stones or uric acid stones formation depending on the acidity of the urine. CaOx stones are forming in urine with pH > 5.5, even though lowering urine pH does not preclude CaOx stone formation. In 1977, Smith [29] studied 132 patients with multiple episodes of CaOx stones and increased levels of serum uric acids. No information regarding urine biochemical parameters were provided. The study cohort was randomized in two groups. The first group included 65 patients who received allopurinol 300 mg per day for 1 week followed by a decrease in allopurinol dosage to 100 mg per day. Therapy was including sodium bicarbonate as needed to keep urine pH > 6.5. The second group was consisting by 67 patients who received placebo plus sodium bicarbonate as described above. Stone recurrence was observed in 69.8 and 42.9% of the patients of placebo and allopurinol groups respectively, providing a significant difference. Ettinger et al. [30] conducted a double-blinded, randomized, placebo-controlled study to evaluate the efficacy of allopurinol in the prevention of recurrent CaOx renal stones. The authors included 72 patients with increased levels of urine uric acid and normal levels of urine calcium and they were assigned 1:1 to receive either 100 mg of allopurinol three times per day or placebo. There were no significant changes in the urine levels of calcium before and after the treatment in both groups. In contrary, urine uric acid was significantly decreased in the allopurinol group from a mean value of 1017 mg/dl before treatment to 660 mg/dl. The mean rate of a stone event was 0.26 per patient per year in the placebo 3.2

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group and 0.12 in the allopurinol group whereas patients in the allopurinol group faced a significantly longer time period before recurrence (33.3 months) compared to patients who received placebo (27.4 months). Furthermore, 22.6% of placebo group patients faced an increase in stone size compared to 13.8% in the allopurinol group. Stone recurrence was the main objective of the study. As recurrence was defined any passage of new stone within the 2 years of follow-up or any growth of a pre-existing calculus or any new stone identified in the annual X-ray film. There was a significantly higher stone recurrence in the placebo group (35.5%) compared to the allopurinol group (17.2%). Borghi et al. [21] conducted the latest study evaluating allopurinol in prevention of CaOx stones. The authors actually compared the efficacy of allopurinol 300 mg per day plus indapamide 2.5 mg per day versus indapamide 2.5 mg per day vs. dietary changes. Study details are described in Section 2.3. The authors reported that stone recurrence was higher in the diet group; however no differences were observed between the other groups. 4. Agents used for the prevention of infection stones formation

Infection stones or struvite stones are composed of magnesium, ammonium and phosphate. Struvite stones are associated with urea-splitting organisms, such as Proteus, Pseudomonas and Klebsiella. These organisms are producing high amounts of ammonium leading to alkanine pH (> 7.2). Struvite stones are usually occurred as stanghorn stones and they have the tendency to recur rapidly. Although complete removal of the stone represents the mainstay of the treatment, prevention is of paramount importance. Several agents have been used in preventing infection stones formation, including acetohydroxamic acid, hemiacidirin and Suby’s G solution, actually as irrigating solutions; however the increase rate of adverse events and the complexity of administration (need for at least to nephrostomy tubes) have eliminating their use in the clinical practice. L-Methionine L-Methionine (LM) is an amino-acid that it is used for the acidification of urine in order to deterrence crystals precipitation. Given the fact that infection stones are crystallized in alkaline urine, LM may be used for the prevention of stone formation. LM is included in the most recent guidelines of European Association of Urology as a preventive measure for recurrent CaP and struvite stones in a dosage of 200 -- 500 mg three times per day [13]. The main goal is to achieve a urine pH level between 5.8 and 6.2. We have to state that there are no randomized studies to support the above recommendations and additionally there are potential consequences of this clinical practice. Jarrar et al. [31] presented the results of a 10 year preventive management of 19 struvite stone formers with LM in a dose 4.1

6

of 1500 -- 3000 mg/day. During the treatment period, the mean urine pH significantly decreased from 7.5 to 5.5. Only two patients (10%) developed a new stone. No significant adverse events were observed. Similar results were observed by Jacobs et al. [32]. After the in vitro study evaluating the optimal conditions for struvite stones dissolution, they reported that LM in a dose of 1500 -- 3000 mg/day may lead to sufficient urine acidification for dissolution. Despite the promising results of LM for preventing infection stones formation, its use has not been studied in randomized, controlled studies. 5.

Agents used against cystine stones

Cystinuria is an autosomal recessive disorder leading in most of the cases to the formation of renal stones. Cystine stones account ~ 1 -- 2% of all urinary stones whereas this rate is higher in children [33,34]. These patients represent a challenging group as cystine stones are sometimes resistant to treatment with shockwaves whereas they have the tendency to recur [35,36]. Cessation of cystine crystals formation is demanding. The solubility of cystine is pH dependent. Apart from stone removal, prevention is a cornerstone for disease management and prevention of renal function [37]. Primary management includes high fluid intake in order to achieve a urinary output > 3 L/day, and urine alkalinization in order to achieve pH > 7.5. However, the primary goal which is to achieve urine cystine levels < 250 mg/L is frequently not achieved by conservative treatment either because of the genetic background of the disease or due to decreased compliance [38]. There are several available medical options, which are reported below. D-Penicillamine D-Penicillamine is bounding to cystine and forming a 50 times more soluble disulfide that it can be easily excreted [39]. It has been showed that the addition of d-penicillamine may result to dissolution and prevention of recurrent cystine stones [40]. Adverse events are dose-dependent and they can be very severe [41]. This is the reason for its limited use. 5.1

Tiopronin Tiopronin or a-mercaptopropionylglycine is a thiol compound, which compounds to cystine to form a more soluble disulfide. It is available in tablets of 100 mg and the recommended dose is 300 -- 1200 mg per day. Pediatric dosage is 15 mg/kg/day. Tiopronin has actually substituted the use of d-penicillamine and nowadays it is considered the first choice for medical treatment of cystinuria. It has been used for both dissolution and prevention [42-44]. It has achieved > 60% remission in stone formation of patients with cystinuria [45]. Although it can lead to adverse events in > 75% of the patients, it has a better safety profile compared to d-penicillamine. 5.2

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Prevention of renal stone disease recurrence

5.3

Captopril

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Captopril is an angiotensin-converting enzyme inhibitor that has been used for the prevention of cystine stones formation. There is a controversy regarding the real benefit of its use [46,47]. Several studies have shown that captopril may result to a significant decline in cystine excretion, reaching a decrease of 18 -- 89%, and it can prevent from recurrent lithiasis [48-51]. However, captopril does not appear to be as effective as d-penicillamine or tiopronin [52]. In addition, there is no evidence that captopril can work in doses that could be used in a living patient to affect urinary cystine solubility. 6.

Potential preventive agents

Febuxostat Febuxostat is a xanthine oxidase inhibitor administered orally. It has shown high efficiency in reducing serum urate levels [53]. In a recent Cochrane Database systematic review, it was found that febuxostat in doses of 80 -- 120 mg is more likely to achieve lower serum uric acid level compared to allopurinol 300 mg [54]. The potential benefit of febuxostat in lowering uric acid excretion in urine was studied by Goldfarb et al. [55]. The authors randomized 99 patients with radiographically evidence of stone disease and hyperuricosuria to receive febuxostat 80 mg per day or allopurinol 300 mg per day or placebo. Febuxostat led to a significant reduction of 24 h urinary uric acid excretion without providing any benefits in lowering stone size. Febuxostat role in preventing stone formation in patients with hyperuricosuria is pending to be evaluated as no studies have demonstrates efficacy in stone prevention yet. 6.1

7.

Conclusion

Renal stone disease represents a common disease. Identifying potential underlying diseases or metabolic pathologies may assist the onset of the appropriate preventive treatment. There are many options depending on the nature of the abnormality. Although there is a great progress in stone disease prevention, there is still a long way to go for obtaining the optimal treatment strategies. 8.

Expert opinion

Apart of the medical or surgical management of urolithiasis, prevention has an equal role in the overall management of the disease. Several metabolic disorders may be implicated in the pathogenesis of nephrolithiasis and our efforts are to identify and treat them. Stone analysis, serum biochemical analysis and 24 h urine analysis represent the cornerstones for the identification of underlined disorders and modifiable risk factors. The above exams will actually guide further management. An interesting study by Milose et al. raised significant

concerns regarding the quality of medical care evaluating if the medical community has really perceived the importance of secondary prevention [56]. The authors identified 28,836 high-risk patients for stone recurrence using medical claims from 2002 to 2006. They found that the overall prevalence of 24 h urine testing was extremely low reaching 7.4%, even though it increased from 7% in 2003 to 7.9% in 2006. Interestingly, the odds of metabolic evaluation were threefold higher if the patient was treated by a nephrologist or urologist. This express the need for clearly defined ‘when’, ‘who’ and ‘by whom’ renal stone patients should be managed. Although it is well known and expressed in this review that medical prevention of renal stone disease may reduce the risk of stone recurrence, there is still a controversy regarding the cost effectiveness of medical prophylaxis [57]. The ideal model for a financially viable health system should combine a low stone recurrence rate and low cost. It seems that we are still far from this model and consequently the need for further research to identify agents that can accurately and efficiently prevent the disease is of paramount importance, at least from the financial point of view. Two recent reviews by Fink et al. [58,59] were the basis for publication of two important guidelines. The American Urological Association guidelines published on 2014 suggest, with grade B recommendation, the systematic use of medical therapy (thiazides, citrate and allopurinol) in high-risk stone formers with specific metabolic disorder after metabolic evaluation [60]. The American College of Physicians published a summary of guidelines on dietary and pharmacological preventive management of recurrent stone disease [61]. The college raised significant concerns regarding the value of routine stone analysis and preventive medical treatment as there is not enough evidence to support this. They suggest that medical therapy should be recommended in specific patients with active disease in which conservative measures (increased fluid intake) failed to reduce stone formation. The scientific panel also supported that the current evidence from randomized trials is insufficient to evaluate the benefits of knowing stone composition and blood and urine biochemistry. Moreover, they supported that our knowledge on how medical therapy is altering the biochemical status should be deepened in order to balance between benefits and harms. In our practice, we encourage complete metabolic evaluation in all high-risk stone formers consisting of stone analysis, 24 h urine analysis and serum biochemistry, including parathyroid hormone and serum uric acid. We suggest a low calorie, fat and sodium intake diet plus high fluid intake in all patients even though low calorie diet has not been justified. Idiopathic hypercalciuria is managed by indapamide 2.5 mg per day plus K-Cit 20 mEq twice to three times a day with weekly follow-up for establishing a urinary pH between 5.8 and 6.2. We manage hypocitraturia by K-Cit and hyperoxaluria either with directed low-oxalate diet or with calcium supplementation with meals if diet fails. In all uric acid stone formers, similar to the American Urological Association

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S. Sfoungaristos et al.

guidelines, we do not routinely recommend allopurinol intake. In contrast, we suggest urine alkalinization with K-Cit to obtain a pH between 6 and 6.5. If urinary or serum uric acid is found high, we recommend allopurinol intake in doses of 100 and 300 mg respectively. Captopril 25 mg once per day is our preference for prevention of cystine stones recurrence due to the good safety profile. Despite the latest increase interest in renal stones, there is no evidence-based conclusion regarding the optimal management of stone recurrence. The absence of universal and well-established medical guidelines have lead to significant deviations on the way that medical community is really managing urolithiasis prevention. The main objective of an interesting recent paper was if medical practitioners, implicated in urolithiasis management, are using thiazides in a really evidence-based fashion [62]. It was reported that only 35% of the patients who were treated with hydrochlorothiazide are receiving a dose of 50 mg per day. The rest are receiving a decreased dose. Given the fact that the available randomized studies have shown hydrochlorothiazide efficacy in a 50 mg dose, it is obvious that most of the patients are receiving a non-evidence treatment at least regarding appropriate dosage. Is this a result due to lack of knowledge or it is just the result Bibliography

of each independent physician experience? No matter which is the reason, it is clear that new studies would assist evidence-based medical management of renal stone disease. There is a complete gap of randomized controlled studies evaluating the appropriate dose of the most commonly used agents (potassium citrate, allopurinol, hydrochlorothiazide, indapamide). Furthermore, there are no studies comparing these agents (chlorthalidone, hydrochlorothiazide, indapamide). We strongly believe that we should increase its sensitivity and research interest on this field. We are still at the beginning of understanding the molecular pathways involved in recurrent stone formation. Knowing better the pathological background, we will be closer to the optimal management.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.

7.

Uribarri J, Oh MS, Carroll HJ. The first kidney stone. Ann Intern Med 1989;111:1006-9

1.

Scales CD Jr, Smith AC, Hanley JM, Saigal CS. Prevalence of kidney stones in the United States. Eur Urol 2012;62:160-5

8.

Trinchieri A, Ostini F, Nespoli R, et al. A prospective study of recurrence rate and risk factors for recurrence after a first renal stone. J Urol 1999;162:27-30

Goldfarb DS. Increasing prevalence of kidney stones in the United States. Kidney Int 2003;63:1951-2

9.

Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med 1992;327:1141-52

Antonelli JA, Maalouf NM, Pearle MS, Lotan Y. Use of the National Health and Nutrition Examination Survey to calculate the impact of obesity and diabetes on cost and prevalence of urolithiasis in 2030. Eur Urol 2014;66(4):724-9

10.

Johnson CM, Wilson DM, O’Fallon WM, et al. Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int 1979;16:624-31

2.

3.

4.

5.

6.

8

Lotan Y, Buendia Jimenez I, Lenoir-Wijnkoop I, et al. Primary prevention of nephrolithiasis is costeffective for a national healthcare system. BJU Int 2012;110:E1060-7 Shoag J, Halpern J, Goldfarb DS, Eisner BH. Risk of chronic and end stage kidney disease in patients with nephrolithiasis. J Urol 2014;192:1440-5 Cupisti A, D’Alessandro C, Samoni S, et al. Nephrolithiasis and hypertension: possible links and clinical implications. J Nephrol 2014;27:477-82

11.

12.

13.

..

Evan AP, Lingeman JE, Worcester EM, et al. Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease. Kidney Int 2010;78:310-17 Matlaga BR, Shore AD, Magnuson T, et al. Effect of gastric bypass surgery on kidney stone disease. J Urol 2009;181:2573-7 Skolarikos A, Straub M, Knoll T, et al. Metabolic evaluation and recurrence prevention for urinary stone patients: EAU guidelines. Eur Urol 2015;67(4):750-63 The European Association of Urology guidelines.

Expert Opin. Pharmacother. (2015) 16(8)

14.

Nijenhuis T, Hoenderop JG, Loffing J, et al. Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney. Kidney Int 2003;64:555-64

15.

Laerum E, Larsen S. Thiazide prophylaxis of urolithiasis. A doubleblind study in general practice. Acta Med Scand 1984;215:383-9

16.

Laerum E. Metabolic effects of thiazide versus placebo in patients under longterm treatment for recurrent urolithiasis. Scand J Urol Nephrol 1984;18:143-9

17.

Scholz D, Schwille PO, Sigel A. Double-blind study with thiazide in recurrent calcium lithiasis. J Urol 1982;128:903-7

18.

Ferna´ndez-Rodrı´guez A, Arrabal-Martı´n M, Garcı´a-Ruiz MJ, et al. The role of thiazides in the prophylaxis of recurrent calcium lithiasis. Actas Urol Esp 2006;30:305-9

19.

Ala-Opas M, Elomaa I, Porkka L, Alfthan O. Unprocessed bran and intermittent thiazide therapy in prevention of recurrent urinary calcium stones. Scand J Urol Nephrol 1987;21:311-14

20.

Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calcium oxalate calculous recurrence but

Prevention of renal stone disease recurrence

acidification of artificial urine--an in vitro study. Scand J Urol Nephrol 2001;35:345-9

magnesium hydroxide does not. J Urol 1988;139:679-84 21.

22.

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 04/17/15 For personal use only.

23.

24.

25.

Borghi L, Meschi T, Guerra A, Novarini A. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol 1993;22:S78-86 Wolf H, Brocks P, Dahl C. Do thiazides prevent recurrent idiopathic renal calcium oxalate stones? Proc Eur Dial Transplant Assoc 1983;20:477-80 Mortensen JT, Schultz A, Ostergaard AH. Thiazides in the prophylactic treatment of recurrent idiopathic kidney stones. Int Urol Nephrol 1986;18:265-9 Barcelo P, Wuhl O, Servitge E, et al. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993;150:1761-4 Soygu¨r T, Akbay A, Ku¨peli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol 2002;16:149-52

26.

Ettinger B, Pak CY, Citron JT, et al. Potassium-magnesium citrate is an effective prophylaxis against recurrent calcium oxalate nephrolithiasis. J Urol 1997;158:2069-73

27.

Hofbauer J, H€obarth K, Szabo N, Marberger M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate urolithiasis--a prospective randomized study. Br J Urol 1994;73:362-5

28.

Lojanapiwat B, Tanthanuch M, Pripathanont C, et al. Alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy. Int Braz J Urol 2011;37:611-16

29.

Smith MJ. Placebo versus allopurinol for renal calculi. J Urol 1977;117:690-2

30.

Ettinger B, Tang A, Citron JT, et al. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986;315:1386-9

31.

32.

Jarrar K, Boedeker RH, Weidner W. Struvite stones: long term follow up under metaphylaxis. Ann Urol(Paris) 1996;30:112-17 Jacobs D, Heimbach D, Hesse A. Chemolysis of struvite stones by

33.

Leusmann DB, Blaschke R, Schmandt W. Results of 5,035 stone analyses: a contribution to epidemiology of urinary stone disease. Scand J Urol Nephrol 1990;24:205-10

46.

Coulthard M, Richardson J, Fleetwood A. Captopril is not clinically useful in reducing the cystine load in cystinuria or cystinosis. Pediatr Nephrol 1991;5:98

47.

Michelakakis H, Delis D, Anastasiadou V, Bartsocas C. Ineffectiveness of captopril in reducing cystine excretion in cystinuric children. J Inherit Metab Dis 1993;16:1042-3

34.

Milliner DS, Murphy ME. Urolithiasis in pediatric patients. Mayo Clin Proc 1993;68:241-8

48.

35.

Katz G, Lencovsky Z, Pode D, et al. Place of extracorporeal shock-wave lithotripsy (ESWL) in management of cystine calculi. Urology 1990;36:124-8

Cohen TD, Streem SB, Hall P. Clinical effect of captopril on the formation and growth of cystine calculi. J Urol 1995;154:164-6

49.

36.

Bhatta KM, Prien EL Jr, Dretler SP. Cystine calculi--rough and smooth: a new clinical distinction. J Urol 1989;142:937-40

Perazella MA, Buller GK. Successful treatment of cystinuria with captopril. Am J Kidney Dis 1993;21:504-7

50.

Sloand JA, Izzo JL Jr. Captopril reduces urinary cystine excretion in cystinuria. Arch Intern Med 1987;147:1409-12

51.

Streem SB, Hall P. Effect of captopril on urinary cystine excretion in homozygous cystinuria. J Urol 1989;142:1522-4

52.

Chow GK, Streem SB. Medical treatment of cystinuria: results of contemporary clinical practice. J Urol 1996;156:1576-8

53.

Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63

37.

38.

39.

Assimos DG, Leslie SW, Ng C, et al. The impact of cystinuria on renal function. J Urol 2002;168:27-30 Pareek G, Steele TH, Nakada SY. Urological intervention in patients with cystinuria is decreased with medical compliance. J Urol 2005;174:2250-2 Lotz M, Bartter FC. Stone dissolution with D-penicillamine in cystinuria. Br Med J 1965;2:1408-9

40.

Dahlberg PJ, van den Berg Kurtz SB, et al. Clinical features and management of cystinuria. Mayo Clin Proc 1977;52:533-42

41.

Halperin EC, Thier SO, Rosenberg LE. The use of D-penicillamine in cystinuria: efficacy and untoward reactions. Yale J Biol Med 1981;54:439-46

54.

Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME. Febuxostat for treating chronic gout. Cochrane Database Syst Rev 2012;11:CD008653

42.

Hayase Y, Fukatsu H, Segawa A. Dissolution of cystine stones by irrigated tiopronin solution. J Urol 1980;124:775-8

55.

43.

Koide T, Kinoshita K, Takemoto M, et al. Conservative treatment of cystine calculi: effect of oral alphamercaptopropionylglycine on cystine stone dissolution and on prevention of stone recurrence. J Urol 1982;128:513-16

Goldfarb DS, MacDonald PA, Gunawardhana L, et al. Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones. Clin J Am Soc Nephrol 2013;8:1960-7

56.

Milose JC, Kaufman SR, Hollenbeck BK, et al. Prevalence of 24-hour urine collection in high risk stone formers. J Urol 2014;191:376-80 An interesting study evaluating how physicians are managing renal stone formers in the everyday practice.

44.

45.

Barbey F, Joly D, Rieu P, et al. Medical treatment of cystinuria: critical reappraisal of long-term results. J Urol 2000;163:1419-23 Pak CY, Fuller C, Sakhaee K, et al. Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine. J Urol 1986;136:1003-8

Expert Opin. Pharmacother. (2015) 16(8)

.

57.

Lotan Y, Cadeddu JA, Pearle MS. International comparison of cost effectiveness of medical management strategies for nephrolithiasis. Urol Res 2005;33:223-30

9

S. Sfoungaristos et al.

58.

59.

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Kainan University on 04/17/15 For personal use only.

..

60.

10

Fink HA, Wilt TJ, Eidman KE, et al. Medical management to prevent recurrent nephrolithiasis in adults: a systematic review for an American College of Physicians Clinical Guideline. Ann Intern Med 2013;158:535-43 Fink HA, Wilt TJ, Eidman KE, et al. Recurrent nephrolithiasis in adults: comparative effectiveness of preventive medical strategies [Internet]. Agency for Healthcare Research and Quality (US); Rockville (MD): 2012; Report No.: 12-EHC049-EF An important and thorough paper stand as the cornerstone for the American guidelines.

..

61.

..

62.

stones: AUA guideline. J Urol 2014;192:316-24 The American Urological Association guidelines Qaseem A, Dallas P, Forciea MA, et al. Dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2014;161:659-67 The American College of Physicians. Vigen R, Weideman RA, Reilly RF. Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion? Int Urol Nephrol 2011;43:813-19

Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney

Expert Opin. Pharmacother. (2015) 16(8)

Affiliation

Stavros Sfoungaristos†1, Ofer N Gofrit2, Vladimir Yutkin3, Dov Pode2 & Mordechai Duvdevani3 † Author for correspondence 1 Fellow of Endourology and Laparoscopic/ Robotic Surgery, The Hebrew University, Hadassah University Hospital, Jerusalem 92120, Israel Tel: +972508946695; E-mail: [email protected] 2 Professor of Urology, The Hebrew University, Hadassah University Hospital, Jerusalem, Israel 3 Urologist, The Hebrew University, Hadassah University Hospital, Jerusalem, Israel

Prevention of renal stone disease recurrence. A systematic review of contemporary pharmaceutical options.

Renal stone disease has a high recurrence rate. Prompt metabolic evaluation followed by appropriate medical management is of paramount importance for ...
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