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Urolithiasis ISSN 2194-7228 UrolithiasisDOI 10.1007/s00240-020-01182-x

Nutrients, vitamins, probiotics andherbal products: an update of their role inurolithogenesis

Renato Nardi Pedro, Asad Ullah Aslam,Jibril Oyekunle Bello, Kamran HassanBhatti, Joseph Philipraj, Idrissa Sissoko,et al.

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Vol.:(0123456789)1 3

Urolithiasis https://doi.org/10.1007/s00240-020-01182-x

INVITED REVIEW

Nutrients, vitamins, probiotics and herbal products: an update of their role in urolithogenesis

Renato Nardi Pedro1,2 · Asad Ullah Aslam1,3 · Jibril Oyekunle Bello1,4 · Kamran Hassan Bhatti1,5 · Joseph Philipraj1,6 · Idrissa Sissoko1,7 · Giovanna Souza Vasconcellos2 · Alberto Trinchieri1 · Noor Buchholz1,8

Received: 16 December 2019 / Accepted: 15 February 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020

AbstractNutrients, vitamins, probiotics, and herbal products may be risk factors, or alternately, protect against the formation of uri-nary stones. The purpose of this review was to update knowledge of the role of nutraceuticals in renal stone formation. A systematic search of the relevant literature published in PubMed in the last ten years was conducted and a narrative review of the data from the included studies was done. Search screened 513 studies that were reduced to 34 after evaluation by title and abstract; other 38 studies were retrieved by references of the selected studies. Beverages high fluid intake confirmed protec-tive effect; orange juice protective effect; apple or grapefruit juice not confirmed as risk factors; sugar-sweetened soda and punch increased risk of stone formation. Energy intake: very high energy intake increased risk factor for women (especially after menopause); dietary acid load increased risk at equal levels of energy intake. Macronutrients confirmed increased risk of high protein intake. Calcium and Oxalate: calcium intake protective effect; oxalate intake only modest increase of risk in men and older women. Metal cations zinc and iron intake no clear impact on the risk of stone formation, dietary copper increased risk; manganese intake reduced risk of stone formation. Fruits and Vegetables decreased risk. Vitamins B6 intake not associated to risk of stone formation; vitamin C intake increased risk in men; vitamin D or supplemental vitamin D intake not associated to increased risk in men and younger women, suggestion of a higher risk in older women; Probiotics Gut colonization with Oxalobacter formigenes associated to lower risk of stone formation, effect of oxalate-degraders pro-biotics on urinary oxalate equivocal. Herbal products efficacy of some herbal products demonstrated in some trials, more investigations needed to confirm their efficacy and safety.

Keywords Urolithiasis · Urinary calculi · Diet · Nutrition · Nutrients · Micronutrients · Metabolic syndrome · Vitamins · Supplements · Probiotics · Antioxidants

Introduction

Urolithiasis is a complex phenomenon with an interplay of various and multiple factors. Ultimately, an imbalance between urinary stone promoters and inhibitors is necessary

to lead to a supersaturation of urine culminating in crys-tallization, crystal aggregation, and adhesion. Recently, an emphasis of nutritional medicine has taken hold in many fields of medicine, and evidence is emerging that many dis-eases are heavily influenced by dietary intake.

* Noor Buchholz noor.buchholz@gmail.com

1 U-Merge Ltd. (Urology for Emerging Countries), London, UK

2 Division of Urology, Faculdade de Medicina São Leopoldo Mandic de Campinas, Sao Paulo, Brazil

3 Department of Urology, Letterkenny University Hospital, Saolta Healthcare Group, Donegal, Ireland

4 Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria

5 Urology Department, Hamad Medical Corporation, Doha, Qatar

6 Department of Urology, Kasturba Medical College, Manipal, Karnataka, India

7 Urology, Faculty of Medicine and Odontostomatology, University of Sciences, Techniques and Technologies, Bamako, Mali

8 Sobeh’s Vascular and Medical Center, U-Merge Ltd, Building 73, 3rd floor, Dubai Health Care City, Dubai, United Arab Emirates

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Since the 1990s there has been an increasing interest in the study of the diet of renal stone formers (RSFs), which resulted in a new knowledge in this area that was dissemi-nated by numerous review papers and guidelines defining the main dietary risks for the formation of urinary stones [1, 2].

In recent years, epidemiological and clinical research on dietary risk factors for stone formation has continued although focusing on new and more specific topics.

The purpose of this review was to update knowledge of the new evidences that has been presented over the last 10 years.

Materials and methods

A systematic search of the relevant literature published in PubMed from October 2009 to September 2019 was conducted.

The search used a combination of terms as both, Medical Subject Headings (MeSH) and keywords.

Urinary stone-related keywords (“urinary calculi” OR “urolithiasis” OR “incident kidney stones”) were used in combination with keywords relating to nutrients (“nutrient” OR “food” OR “diet” OR “vitamin” OR “probiotic” OR “antioxidant” OR “herbal product”).

We included observational and interventional studies aiming to urinary calculi formation as primary outcome. Large series evaluating prospectively the risk of incident kidney stone formation were primarily considered, although some large case–control series were also included, when evidences from prospective studies were lacking. Similarly, randomized controlled trials (RCTs) were mostly selected, but some large non controlled trials were included when more robust evidence was lacking. Results of metanalyses were also included. Experimental studies and clinical stud-ies aiming to evaluate the effect of foods and nutrients on urinary risk factors, narrative reviews and case reports were excluded. We included only full-text articles written in Eng-lish. Literature was evaluated using the Newcastle–Ottawa-Scale or following PRISMA checklist when applicable. A narrative review of the data from the included studies was done.

Results

The search screened 513 studies that were reduced to 34 after evaluation by title and abstract; other 32 studies were retrieved by references of the selected studies (Table 1); information extracted from each study was charted includ-ing: first author’s last name; year of publication; number of subjects; food or nutrients or dietary pattern studied.

Background information related to state of the art before 2009 was obtained by previous reviews [1, 2].

Discussion

Fluid intake

The major role of fluid intake on the risk of urinary stone was well documented by epidemiological studies [3–5] and by an interventional study [6]. Fluid intake was inversely related to the risk of kidney stones with a relative risk of 0.71 in men and of 0.61–0.68 in women in the highest quin-tile of intake compared with those in the lowest quintile [3–5]. An interventional study showed that a large intake of water is effective to reduce the risk of stone recurrences [6].

Other observational studies demonstrated that the risk of formation of kidney stones can be decreased by the con-sumption of different types of fluids including alcoholic bev-erages, coffee, and tea [7, 8].

A positive effect of citrus fruit consumption was not demonstrated although on a theoretical and biochemical basis citrus juices should have a protective effect against the formation of kidney stones by their citrate content that should increase urinary citrate. A 40% higher risk of stone formation was associated with grapefruit juice intake [7, 8], explained as consequence of its effects on intestinal enzymes. Similarly, an increased risk of stone formation was associated to apple juice consumption (240 ml/daily) [7]. Soda consumption seemed to be not associated with the risk of stone formation when the results were adjusted for other dietary components. This result contrasted to the find-ing of an interventional study that had shown a reduction in the recurrence rate of kidney stones following avoidance of soft drinks [9]. No association of milk intake with kidney stone formation was observed.

Up to date

A recent study [10] updated previous reports from ongoing cohorts confirming that consumption of beer, wine, coffee, and tea is associated with a lower risk of stone formation. However, in comparison to the previous assessments per-formed on the same cohorts, some results have changed probably in relation to the greater number of cases and per-son-time available. The finding of a significantly higher risk of kidney stones in subjects consuming apple or grapefruit juice was not confirmed and it was demonstrated that orange juice has a protective effect on the risk of incident renal stone formation [10].

This observation confirms the results of previous inter-vention studies that had demonstrated the effectiveness of orange juice administration in reducing urinary saturation

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Table 1 Studies included in the review

Author References Journal (Year) Subject Design

Ferraro et al. [10] Clin J Am Soc Nephrol (2013) Soda and other beverages Prospective observationalShu et al. [13] Int J Urol (2019) Green tea intake Prospective observationalChen et al. [14] World J Urol (2019) Tea Prospective observationalJeong et al. [18] Am J Kidney Dis (2011) Metabolic syndrome Observational

Cross sectionalRendina et al. [19] J Nephrol (2014) Metabolic syndrome Systematic review and metanalysisAune et al. [21] Eur J Epidemiol (2018) Body weight Systematic review and metanalysisSorensen et al. [22] J Am Soc Nephrol (2014) Body weight

Energy intakeProspective observational

Shu et al. [23] J Endourol (2017) Body weight Prospective observationalOda et al. [24] Int J Urol (2014) Body weight Prospective observationalYoshimura et al. [25] J Epidemiol (2016) Body weight Prospective observationalFerraro et al. [26] J Urol (2015) Body weight

Energy intakeProspective observational

Trinchieri et al. [27] Eur J Clin Nutr (2013) Acid load Case–controlobservational

Vezzoli et al. [28] Nutr Metab Cardiovasc Dis (2015) Acid load ObservationalFerraro et al. [29] Clin J Am Soc Nephrol (2016) Acid load

PotassiumProtein

Prospective observational

Leone et al. [31] Am J Kidney Dis (2017) Mediterraneandiet

Prospective observational

Ferraro et al. [35] J Urol (2017) Prospective observationalTurney et al. [36] Eur J Epidemiol (2014) Meat Prospective observationalTaylor et al. [39] J Urol (2013) Calcium Prospective observationalTang [41] Am J Nephrol (2012) Zinc ObservationalThomas et al. [42] Environ Int (2013) Cadmium Prospective observationalFerraro et al. [43] Cadmium ObservationalFerraro et al. [44] J Urol (2018) Trace metals Prospective observationalSorensen et al. [47] J Urol (2014) Fruit and Vegetables Prospective observationalFerraro et al. [48] Am J Kidney Dis (2019) Antibiotics Prospective observationalFerraro et al. [54] Urolithiasis. (2018) Vitamin B6 Prospective observationalFerraro et al. [55] Am J Kidney Dis (2016) Vitamin C Prospective observationalLappe et al. [56] JAMA (2017) Vitamin D Interventional RCT Wallace et al. [57] Am J Clin Nutr (2011) Vitamin D Interventional RCT Prentice et al. [58] Osteoporos Int (2013) Vitamin D Interventional RCT Malihi et al. [59] Am J Clin Nutr (2019) Vitamin D Interventional RCT Avenell et al. [60] Cochrane Database Syst Rev (2014) Vitamin D MetanalysisBjelakovic et al. [61] Cochrane Database Syst Rev (2014) Vitamin D MetanalysisKahwati et al. [62] JAMA (2018) Vitamin D Systematic review and metanalysisMalihi et al. [63] Am J Clin Nutr (2016) Vitamin D Systematic review and metanalysisFerraro et al. [64] J Urol (2017) Vitamin D ObservationalWei et al. [65] Nephrol Dial Transplant (2018) Vitamin K ObservationalStern et al. [69] Urolithiasis (2016) Dysbiosis ObservationalTicinesi et al. [71] Gut (2018) Dysbiosis ObservationalSiener et al. [77] Kidney Int (2013) Oxalobacter ObservationalJairath et al. [82] Scand J Urol (2015) Oxalobacter Interventional RCT Millner et al. [83] Urolithiasis (2018) Oxalobacter Interventional RCT Hoppe et al. [84] Pediatr Nephrol (2017) Oxalobacter Interventional RCT Lieske et al. [87] Kidney Int (2010) Lactic bacteria Interventional

RCT

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levels with respect to both calcium oxalate and uric acid [11, 12].

The consumption of sugar-sweetened soda and punch was shown to be associated with a higher risk of stone formation [10].

In two large prospective cohorts in China [13], the asso-ciation between green tea intake and incident stones was studied demonstrating that tea drinkers (both male and female) and specifically green tea drinkers had a lower risk of incident stones. This result was confirmed by the study of another large cohort in Taiwan [14] showing that daily consumption of two cups of tea was associated with a lower risk of renal stone formation.

Energy intake

The role of dietary energy intake as a risk for urinary stone formation has been evaluated because obesity and metabolic syndrome were frequently associated to urinary stone forma-tion. Curhan et al. [15], according to the prospective study of two large cohorts that included a total of about 140.000 subjects, showed a 1.38 age-adjusted prevalence odds ratio for men with body mass index of 32 kg/m2 or greater com-pared to those with 21–22.9 kg/m2 and a 1.76 odds ratio for the same comparison in women. Other studies emphasized the association between urinary stone formation and meta-bolic syndrome, which includes in its traits the presence of

Table 1 (continued)

Author References Journal (Year) Subject Design

Suryavanshi et al. [89] Sci Rep (2018) Dysbiosis ObservationalMiller et al. [90] Kidney Int (2019) Dysbiosis ObservationalZampini et al. [91] Sci Rep (2019) Dysbiosis ObservationalCealan et al. [97] Med Pharm Rep (2019) Phyllanthus n. Interventional non controlledSingh et al. [99] J Assoc Physicians India (2010) Dolichos b. Interventional controlledSingh et al. [100] Urol Ann (2011) Crataeva n. Interventional controlledSingh et al. [101] J Altern Complement Med (2012) Celosia a. Interventional controlledBrardi et al. [102] Arch Ital Urol Androl (2012) Agropyrum r. Interventional controlledMonti et al. [103] Arch Ital Urol Androl (2016) Herbal treatment Systematic review and metanalysisMohanty et al. [105] Am J Pharmacol Toxicol (2010) Cystone Interventional

Controlled studyShekar Kumaran et al. [106] Eur J Integr Med (2011) Cystone Interventional

Controlled studyUpadhyay et al. [107] Int J Green Pharm (2011) Boerhavia d .+ Tribulus t. Interventional

Controlled studyCeban et al. [108] Z Phytother (2012) Centaurii herba, Levis-

tici radix and Rosmarini folium i.

InterventionalControlled study

Faridi et al. [109] J Ethnopharmacol (2014) Lapis judaicus InterventionalControlled study

Rathod et al. [110] Int J Res Ajurveda Pharm (2015) Musa s. InterventionalControlled study

Ardakani Movaghati et al. [111] Phytother Res (2019) Nigella s. InterventionalControlled study

Erickson et al. [112] Phytomedicine (2011) Cystone InterventionalControlled study

Erickson et al. [113] Urol Res (2011) Cystone InterventionalControlled study

Peng et al. [115] Zhong Xi Yi Jie He Xue Bao (2010) Quantong InterventionalControlled study

Kobayashi et al. [116] Int J Urol (2008) Choreito Interventional controlledXiang et al. [118] Zhonghua Wai Ke Za Zhi (2018) Ningmitai Interventional

Controlled studyTrinchieri et al. [119] Urolithiasis (2019) Uric acid stone Observational

Case–controlChae et al. [120] Urolithiasis (2013) Uric acid stone InterventionalFink et al. [121] Ann Intern Med (2013) Dietary treatment Systematic review

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central or abdominal obesity defined by waist circumference at least 89 cm for women and 102 cm for men [16–19]. For this reason, it has been suggested that renal stone formers should “modulate their intake of calories as needed to main-tain a healthy weight” [2]. Obesity depends on the balance of dietary energy intake and energy expenditure related to physical activity and resting metabolic rate.

A Canadian study [20] on a large series of 500 renal stone formers compared to the same number of controls disclosed higher intake of energy in female cases than their matched controls although no difference was observed in subjects with a BMI < 20. A higher caloric intake was therefore pre-sent only in overweight or obese female stone formers and no significant association of dietary energy intake and risk of stone formation was shown by stepwise logistic regression.

Up to date

Studies published over the past decade confirmed the link between obesity and the risk of urinary stone formation. In a recent meta-analysis [21] of 5 studies [22–26] including more than 450,000 participants from eight cohort studies the relative risk for urinary stone formation associated to a BMI increment of 5 units was 1.21. The metanalysis was not able to demonstrate any association of energy expenditure by physical activity and risk of renal stone formation [21], but it did not assess the presence of differences in dietary energy intake in renal stone formers with respect to controls.

In the study of Shu et al. [24], including about 75,000 women and more than 61,000 men, no difference of daily dietary energy intake was observed in both female and male renal stone formers compared to female and male controls. Sorensen et al. [23] in their cohort of about 85,000 post-menopausal women showed no difference of raw energy intake and calibrated energy intake (by use of biomarkers) in renal stone forming women compared to controls. When the population was divided by groups based on levels of energy intake, the risk of kidney stones forming was shown to be higher of 42% for women who had a dietary intake greater > 2500 kcal/day, although no protective effect was shown in the women with the lowest dietary intake levels (< 1800 kcal/day). Finally, Ferraro et al. [26] found no asso-ciation of total energy intake with risk of kidney stones in any of the three cohorts evaluated.

The effect of a high energy intake on the risk of stone for-mation could be modulated by the dietary pattern. A dietary pattern involving high intake of foods that increase the acid load of diet can be associated to a higher risk of stone forma-tion at equal levels of energy intake. Two Italian studies [27, 28] have shown that the acid load of the diet of RSFs is higher than that of related controls by age and gender. Another study confirmed this trend by using a surrogate index of the dietary acid load [29]. Furthermore, it has been shown that the risk of

urinary stone formation was decreased in patients who stick to the DASH diet (a diet suggested for the control of hyper-tension), which implies a reduction in the dietary acid load as it provides for a reduction in the consumption of animal proteins and fats in favor of increased consumption of fruits and vegetables [30]. Similarly, Mediterranean dietary pattern with higher intake of dairy products and vegetables and higher monounsaturated fatty acid to saturated fatty acid ratio, seems to be able to reduce the risk of stone formation. In fact, in the large population of Seguimiento Universidad de Navarra (SUN) follow up project [31], risk of incident was lower in subjects with high adherence to the Mediterranean dietary pat-tern with an almost 40% relative risk reduction.

Macronutrients

The contribution of different macronutrients in the patho-genesis of renal stones has been the aim of numerous clinical trials and epidemiological studies. The effect of a diet rich in animal protein was the most studied because it involves the production of an acid load due to the metabolism of sulfur-containing amino acids that can increase urinary cal-cium and reduce urinary citrate. In addition, dietary animal proteins could also have marginal effects on the excretion of oxalate and uric acid. The role of simple carbohydrate consumption has also been studied, because ingestion of a carbohydrate load has been associated with an increase of urinary calcium that could be at least partially mediated by insulin.

The epidemiological evidence was contradictory in that a positive correlation had been shown between animal pro-tein consumption and new kidney stone formation in men but not women whereas sucrose intake was associated with new kidney stone formation in women but not in men [3–5].

Limited information is available for the role of total lipid intake on the risk of stone formation, although some infor-mation on the specific role of fatty acid has been published. The intake of n-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), could decrease the arachidonic acid content of cell membranes promoting hypercalciuria and hyperoxaluria [32]. The administration of eicosapentaenoic acid (EPA) was effective in reducing urinary stone recurrence over the course of 8-year trial [33]. In older women an association between the intake of arachi-donic acid or linoleic acid and the risk for incident kidney stones was detected, although this relation was not observed in men and younger women [34].

Up to date

More recent studies confirmed previous knowledge on the contribution of different macronutrients on the risk of stone formation [35].

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However, the risk of renal stone formation was better dif-ferentiated in relation to the origin of animal proteins [29].

In the study of Ferraro et al. [29] a significant inverse association (HR 0.84) between dairy protein intake and the risk of stone formation was observed in a cohort of younger women (NHS II), although the association was not signifi-cant in men (HPFS) and older women (NHS I).

Conversely, in the same study [29], the intake of nondairy animal proteins was associated with an increased risk of renal stone formation in men and older women.

Increased dairy protein intake was associated with higher calcium and citrate excretion and reduced excretion of oxa-late and uric acid, while an increased intake of nondairy pro-tein was associated with a reduction in urinary citrate, lower urinary pH, and higher excretion of urinary uric acid [29].

The authors concluded that dairy protein intake is associ-ated to a bivalent effect on the risk of urinary stone forma-tion, which is due to high calcium content and acid load of dairy products that implies an increased calcium excretion but also interference in intestinal absorption of oxalate that binds to calcium in the intestinal lumen. On the other hand, nondairy protein intake has a major effect on the risk of for-mation of both calcium and uric acid urinary stones.

Furthermore, in the cohort of more than 50,000 partici-pants in the Oxford arm of the European Prospective Inves-tigation into Cancer and Nutrition (EPIC) the risk of incident stone of moderate/low meat eaters was lower than in high meat eaters (> 100 g/day) [36].

Calcium and oxalate

The role of dietary intake of calcium as a risk factor for the formation of kidney stones was well demonstrated by Curhan et al. [3, 4], which showed an inverse correlation between calcium intake and risk of incident stone formation. An interventional study [37] showed more recurrences in patients on a low calcium diet with respect to those consum-ing a diet with a normal content of calcium.

The protective effect of calcium on the risk of stone for-mation could be explained by the reduction of intestinal absorption of oxalate related to the formation of calcium complexes with oxalate in the intestinal lumen.

On the contrary, the role of dietary oxalate remained ini-tially uncertain due to the unavailability of accurate data on oxalate content in different foods.

A study [38], demonstrated that oxalate intake was asso-ciated with a modest increase in risk of stone formation in men and older women, whereas no association with risk was observed in younger women. The authors [38] concluded that dietary oxalate was not a major risk factor for nephro-lithiasis. They observed that spinach accounted for > 40% of oxalate dietary intake, so it should be enough to advise renal

stone formers to avoid spinach and a few other foods with a very high content of oxalate.

Up to date

It was demonstrated that higher dietary calcium from both non-dairy or dairy sources is associated with a lower kidney stone risk [39].

Metal cations

Some metal cations (sodium, potassium, magnesium) have been considered involved in the pathogenesis of urinary stones. Increased dietary intake of sodium can be a risk factor for the formation of kidney stones as it can induce an increase in urinary calcium by reducing its renal tubu-lar reabsorption. A reduced intake of potassium can induce hypokalemia resulting in increased tubular reabsorption of citrate and hypocitraturia. Finally, a high intake of mag-nesium can increase urinary excretion of magnesium that inhibits calcium oxalate crystallization. The epidemiological studies of Curhan et al. [3–5, 40] have not yielded defini-tive results. A positive association between intake of dietary sodium and risk of kidney stone formation was shown in women but not in men while dietary potassium intake was inversely related to the risk of kidney stone in men and older women but not in younger women. Finally, they observed that dietary intake of magnesium was associated with a reduction in the risk of kidney stones formation in men [40] but not women [4, 5].

Up to date

In recent years, no new evidence has been added regard-ing the effects of dietary intake of sodium, potassium and magnesium, although more information was obtained about trace metals.

Data from a large US population-based cross-sectional study demonstrated that higher dietary intake of zinc was associated with an increased risk of stone formation [41].

Similarly, in participants in the Oxford arm of EPIC study a high intake of zinc was associated with a higher risk of stones [36].

In two large prospectively studied Swedish cohorts of men and women, dietary cadmium exposure (at levels seen in general population) was not associated with increased kidney stone incidence [42].

A cross-sectional study of a sample of the United States population demonstrated in women but not in men a higher prevalence of renal stones in subjects with urinary cadmium levels > 1 μg/g compared to those with ≤ 1 μg/g [43].

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Finally, a prospective analysis of a large population was not able to show any association of dietary zinc and iron intake with the risk of stone formation. On the contrary, die-tary copper was marginally associated with a higher risk of stone formation and manganese intake was associated with a lower risk of stones, although no association of dietary intake of manganese and copper with urinary saturation was found in a subset of participants with 24-h urine collections [44].

Fruits and vegetables

The role of dietary intake of fruits and vegetables in reduc-ing the risk of kidney stones being formed has been empha-sized only in recent years, although Curhan et al. [3] had previously demonstrated an important inverse correlation between dietary intake of potassium, which is a very effi-cient indicator of vegetable consumption, and risk of new stone formation.

Fruits and vegetables of the diet provide a load of alkali that counteracts the acid load of the protein-based diet atten-uating its effect of increased urinary calcium and reduced urinary citrate. In addition, some fruits, such as citrus fruits, have, by themselves, a high content of citrates that contrib-utes to the increase of urinary citrates. Finally, fruits and vegetables have a high content of magnesium that increases urinary magnesium which has an inhibitory effect of uri-nary crystallization. However, fruits and vegetables could also potentially increase the risk of stone formation due to their oxalate and fructose content. For this reason, the con-sumption of many types of fruits and vegetables due to their oxalate content has traditionally been discouraged. Recently, the role of dietary fructose has also been emphasized as a risk factor for kidney stones formation [45] because it may increase the urinary excretion of calcium, oxalate, uric acid, and other factors associated with kidney stone risk. Main sources of fructose are sugar-sweetened soft drinks, fruit juice and punch, and fruit such as apples, bananas, and raisins.

However, in a clinical experimental study [46], the addi-tion of fruit and vegetables to the diet of renal stone formers increased citrate excretion without affecting oxalate excre-tion and decreasing calcium oxalate and uric acid relative saturation.

Up to date

An epidemiological study showed that compliance to a diet for patients with hypertension, which included the advice of increasing fruit and vegetable consumption, was associ-ated with a lower risk of kidney stones formation [30]. In postmenopausal women from the Women’s Health Initiative

observational study, greater fruit and vegetable intake and higher total dietary fiber intake, decreased risk of incident kidney stone formation [47]. Similarly, in participants in the Oxford arm of EPIC studies high intakes of fresh fruit, fiber from wholegrain cereals and magnesium were associated with a lower risk of kidney stone formation [36].

Finally, absorption of oxalate from vegetables can be severely limited by the presence of calcium in the intesti-nal lumen or by the action of oxalate-degrading bacteria. In fact, the prolonged use of antibiotics is associated with an increased risk of kidney stones formation, presumably by the effect on the intestinal flora that reduces bacterial activity of oxalate degradation [48].

Vitamins

Most studies on the possible role of vitamins as a risk factor for kidney stones formation have been directed to the study of the effects of vitamin C and vitamin B6. Both these vita-mins are implicated in oxalate metabolism. Vitamin C can be metabolized to oxalate, while vitamin B6 is a cofactor of oxalate metabolism.

Observational studies showed that consuming high amounts of vitamin C could be a risk factor for kidney stones, although this correlation was only evident after an adjustment for dietary potassium intake [49]. Vitamin B6 intake with the diet was not correlated with the risk of kid-ney stone formation in males while high doses of vitamin B6 appeared to have a protective factor in women [50]. A possible role of vitamin D in the pathogenesis of kidney stones has been hypothesized because the active form of vitamin D, calcitriol (1.25-dihydroxyvitamin D), is able to increase urinary calcium by increasing intestinal absorption of calcium and suppressing parathormone [51]. In 2006, a randomized controlled trial of Women’s Health Initiative (WHI) demonstrated an increased risk of renal calculi (HR 1.17) in postmenopausal women assigned to receive calcium and vitamin D3 supplementation for prevention of fractures [52]. On the contrary, a large epidemiological study of the risk of incident symptomatic kidney stones showed that dietary vitamin D was not independently associated with risk of stone formation [53].

Up to date

A recent study showed the absence of association between levels of vitamin B6 intake and risk of kidney stones form-ing in both men and women [54]. On the contrary, die-tary and supplemental vitamin C intake was significantly associated with higher risk for incident kidney stones in men, but not in women [55]. Recent interventional stud-ies of vitamin D administration have shown contradictory

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results. A randomized clinical trial of vitamin D3 plus calcium administration in older women to reduce the risk of cancer among older women showed an increased risk of urinary calculi [56]. Similarly, two further reports of Women’s Health Initiative (WHI) randomized clinical trial confirmed increased risk of renal stone formation after cal-cium and vitamin D supplementation in postmenopausal women [57, 58]. On the contrary, in a large, population-based randomized clinical trial, monthly supplementa-tion with high-dose vitamin D3 administered over several years for prevention of cardiovascular events, respiratory infections, and falls/fractures, did not affect the incidence rate of kidney stone events, or hypercalcemia [59]. Two Cochrane meta-analyses [60, 61] concluded that vitamin D administration can be associated with increased risk of urinary calculus. In the first meta-analysis, were considered subjects taking vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures, whereas in the second meta-analysis, the effects of vitamin D supplementation were assessed for primary and second-ary prophylaxis of mortality. In both meta-analyses, about 80% of the participants were female, mostly older than 70 years. Another metanalysis of three RCTs confirmed that supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones [62]. On the contrary, a recent meta-analysis did not con-firm this association showing a tendency for less reporting stones in the subjects taking vitamin D [62, 63]. Finally, an epidemiological study showed no statistically signifi-cant association between vitamin D intake or supplemental vitamin D intake and risk of stones in a male population and in a population of younger women although there was a suggestion of a higher risk in older women [64].

Vitamin K—dependent enzymes activate matrix Gla pro-tein (MGP) to a potent locally acting inhibitor of calcifica-tion. In a large population of Flemish subjects the risk of having prevalent nephrolithiasis was increased by the asso-ciation with higher levels of inactive MGP (desphospho-uncarboxylated MGP) [65].

Data on the intake of vitamin E in renal stone formers or interventional studies of the administration of vitamin E for renal stone prevention are lacking, although vitamin E has shown in experimental studies a potential activity to prevent renal stone formation as a result of its antioxidant activity [66].

Probiotics

The role of the gut microbiota in human metabolism and the pathogenesis of various diseases has become increas-ingly important in recent years. The microbiota could have a role in the pathogenesis of allergies, coronary vascular

disease, obesity, and metabolic syndrome. The action of the microbiota was also considered in the pathogenesis of urinary calculi. At first, the presence of Oxalobacter formigenes in the gut and its activity on oxalate has been studied for many years [67]. More recently, it has been hypothesized that the activity of bacteria in the gut may promote the production of organic acids that may be the cause of the increased acid excretion observed in uric acid stone formers [68]. In general, the entire gut microbiota could be involved in the handling of oxalate and other risk factors for urinary stone formation [69]. The study of the microbiota of renal stone formers is still at an early stage and has so far produced results that are not easily interpret-able [70, 71]. In parallel with the study of the microbiota, the use of live bacteria, as probiotics to achieve favorable effects in the treatment of some diseases, including renal stone disease, is increasing. Oxalobacter formigenes and the lactic acid bacteria group are well-known gut oxalate-degraders and have received great research interest over the last decade due to their suspected roles in urolithiasis via an influence on oxalate metabolism. O. formigenes is an obligate anaerobic bacterium which colonizes the gut of almost all humans at early childhood though later in adult-hood, up to one-third of the population convert to nega-tive colonization status attributed to the use and misuse of antibiotics. Unlike O. formigenes which utilizes oxalate as a sole energy source, the lactic acid bacteria group of gut oxalate-degraders (Lactobacillus acidophilus, Bifido-bacterium infantis, etc.) are known to have other sources of energy and can survive with limited oxalate [72]. The intraluminal degradation of oxalate by these bacteria is thought to reduce dietary oxalate absorption and poten-tially reduce urinary oxalate levels. Based on the above, it was believed that probiotics made from gut flora oxalate- degraders could be useful in decreasing urinary oxalate excretion and calcium oxalate stone prevention.

Up to date

New studies evaluated the impact of gut colonization of O. formigenes on the risk of renal stone formation. Colo-nization of the gut with O. formigenes was confirmed to be lower in RSFs than in control subjects and much lower in recurrent RSFs (Table 2) [73–78]. The significance of these findings is affected by possible role of antibiotic therapy on the intestinal colonization of O. formigenes as renal stone formers that do not undergo antibiotic treatment tend to have colonization rates similar those observed in the general population [79]. Trials to evaluate the effect of the administration of oxalate-degraders probiotics on recurrence of stone formation are lacking. However, some trials evaluated the effect of the administration of oxa-late-degraders probiotics on urinary oxalate. The current

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evidence is equivocal with regards to their ability to reduce hyperoxaluria (Tables 3, 4) [80–88] because the results are difficult to assess due to the confounding effects of spontaneous fluctuations in oxalate excretion as a result of diet and changes in endogenous synthesis. Furthermore, modality of administration to achieve and optimal dietary oxalate level required to maintain colonization are debated. More trials are needed to provide answers to several ques-tions about the utility of these preparations in reducing urinary oxalate.

Recent studies addressed the role in urinary stone forma-tion of the whole intestinal microbiome beyond O. formi-genes and other oxalate-degrading bacteria.

In renal stone formers increase of Firmicutes and decrease of Bacteroidetes was observed and at genus level dominance of Collinsella and reduction of Bacteroides, Deinococcus, and Sutterella [89].

Microbial dysbiosis in renal stone formers was found not limited to eubacteria but involved archaea, eukaryotes and fungi.

A comparison of renal stone formers with healthy sub-jects confirmed that oxalate homeostasis in the gut may not be limited to the activity of O. formigenes but may involve numerous bacterial species including Ruminococcus and Oscillospira [90].

Table 2 Association of O. formigenes and renal stone disease

Author Population O. formigenes colonization Urinary oxalate

Kumar [73] 63 CaOx RSFs and 40 controls from North India 65% controls30% RSFs5.6% recurrent RSFs (> 3 episodes)

Lower in OF colonized

Mittal [74] 80 CaOx RSFs and 70 controls from North India 62.2% controls33.3% first-time RSF28% recurrent RSF7% > 4 episodes

Troxel [76] 35 CaOx RSFs and 10 controls from US 60% controls26% first-RSFs

Lower in OF colonized

Kwak [75] 103 CaOx RSFs from Korea 45.6% RSFs Lower in OF colonizedSiener [77] 37 CaOx RSFs from Germany 11/37

67% first RSFs33% 2–4 episodes16% > 4 episodes

Lower in OF colonized on controlled diet

Kaufmann [78] 247 CaOx RSFs259 controls matched by age, gender and region

38% controls17% RSFsOR 0.3

Table 3 Results of trial of administration of O. formigenes preparations

Duncan [80] 4 volunteers O. formigenes strain HC-1 (108 viable cells/mg) oral prepara-tions

Ox degrading activity and gut colonization of up to 9 months

Decreased urinary oxalate over a 6 h test period (3.0 ± 0.6 to 1.9 ± 0.1 mg/h)

Hoppe [81] 16 pts primary hyperoxaluria (3 renal failure, 2 liver-kidney transplant)

O. formigenes preparations4-week treatment

7/11 responders with significant reduction urinary oxalate of 22–92%

Transient gastrointestinal-tract colonizationJairath [82] 80 CaOx RSFs mainly hyperoxaluric rand-

omizedO. formigenes preparation vspotassium magnesium citrate

Hyperoxaluria rateCitrate 77.5% vs 37.5%, p = 0.0006)O. formigenes 82.5% vs 15%, p < 0.0001Decreased urinary oxalate at 1 month 65 vs

40%Citrate mild side effects in 3 pts

Milliner [83] 36 pts primary hyperoxaluria randomised, placebo-controlled, double-blind study

(Oxabact™ OC3) for 24 weeks Not significant decrease in Uox/UcrNo difference, Pox concentration, stone eventswell tolarated

Hoppe [84] 28 pts primary hyperoxaluria randomised, placebo-controlled, double-blind study

(Oxabact™ OC5) for 8 weeks No significant difference urinary oxalate

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Another study showed that urinary microbiome modi-fications induced by antibiotic treatment may have a more significant effect on the risk of urinary stone formation than microbiome gut modifications. Patients with urinary stones appear to have an antibiotic-driven shift in the microbiome urinary that could promote the appearance of the disease. Particularly, in the urinary microbiome, lattobacilli may have a protective role in contrast to the pathogenic role of Enterobacteriaceae [91].

A promising alternative for stone prevention could be the administration of enzymes that metabolize oxalate, instead of live bacteria [92]. Furthermore, evidence is needed of the efficacy of probiotics on the prevention of stone formation beyond their effect on urinary oxalate.

Antioxidants and herbal products

Many recent studies have highlighted the potential effi-cacy of several medicinal herbs or natural compounds for the treatment of nephrolithiasis. Phytotherapeutic agents have been proposed as useful alternative or complementary therapies for the management of urolithiasis, mainly due to their anti-oxidative effects. Crystals which form in the renal tubules are toxic and injurious to renal tubular cells resulting in renal tubular injury by oxidative stress due to Reactive Oxygen Species (ROS) production. Oxidative stress and inflammation cause release of various proteins and sloughing of tubular cell. Injured tubule is a suitable site for crystal attachment and retention of crystals which grow over this nidus and finally become a stone. The role of ROS in the pathogenesis of kidney stone has been experimentally proved [93] and oxidative stress and inflammation have been shown to mediate lithogenic process [94, 95]. Herbal prod-ucts contain macromolecules that can have a potential posi-tive effect in the treatment and prevention of urinary stones for their antioxidant and anti-inflammatory activity, but also by reducing urinary saturation and by inhibitory effect on crystallization, nucleation, and aggregation of crystals and for their antimicrobial, litholytic, antispasmodic, and diuretic effect.

Anti-lithogenic activity of a large number of herbal prod-ucts has been demonstrated by numerous in vitro and experi-mental studies in the animal [96].

Up to date

New studies demonstrated the efficacy of some herbal prod-ucts to reduce the risk of stone formation. An epidemiologi-cal study in a population of about 14,000 subjects demon-strated that the risk of stone formation is decreased in those consuming more than two cups of tea by day (OR = 0.84) or ≥ 20 cup-year (OR = 0.79) [14]. This observation confirms Ta

ble

4 R

esul

ts o

f tria

l of a

dmin

istra

tion

of o

ther

pro

biot

ics

Aut

hor

Subj

ects

Trea

tmen

tRe

sults

Lies

ke [8

5]10

CaO

x R

SFs w

ith e

nter

ic h

yper

oxal

uria

(> 45

 mg/

24 h

)La

ctic

aci

d ba

cter

ia (L

. aci

doph

ilus,

L. b

revi

s, S.

ther

mo-

philu

s, B.

infa

ntis

) (O

xadr

op) f

or 3

 mon

ths a

t dec

reas

-in

g do

sage

+ lo

w o

xala

te d

iet a

nd c

alci

um b

inde

rs

Not

sign

ifica

nt d

ecre

ase

of 1

9%, 2

4% a

nd 2

% o

f urin

ary

oxal

ate

afte

r 1, 2

, 3 m

onth

sFu

rther

dec

reas

e of

20%

at o

ne-m

onth

pos

t stu

dy w

asho

ut

perio

dG

oldf

arb

[86]

20 C

aOx

RSF

s with

idio

path

ic h

yper

oxal

uria

(> 40

 mg/

day)

, dou

ble-

blin

d, ra

ndom

ized

plac

ebo-

cont

rolle

d tri

alLa

ctic

aci

d ba

cter

ia (O

xadr

op) 3

.6 g

dai

ly v

s pla

cebo

for

28 d

ays 1

–2 h

afte

r din

ner o

r the

maj

or m

eal,

diet

not

co

ntro

lled

but d

iet k

ept u

nifo

rm (d

iet d

iary

), 4 

wee

ks,

post-

study

afte

r 4 w

eeks

was

hout

No

decr

ease

of u

rinar

y ox

alat

eO

xadr

op: 5

6.2

vs 5

2.6 

mg/

day

64.1

 mg/

day

(afte

r was

h-ou

t)Pl

aceb

o: 5

7.6

vs 6

2 m

g/da

y 56

.8 m

g/da

y (a

fter w

asho

ut)

No

adve

rse

even

tLi

eske

[87]

40 C

aOx

RSF

s with

mild

hyp

erox

alur

ia, d

oubl

e-bl

ind,

ra

ndom

ized

pla

cebo

-con

trolle

d tri

alC

ontro

lled

diet

(100

0 m

g ca

lciu

m, 8

0–10

0 m

g ox

alat

e,

norm

al p

rote

in, r

educ

ed fa

t) fo

r 1 w

eek

Lact

ic a

cid

bact

eria

(Oxa

drop

) 4 g

dai

ly v

s AK

SB A

gri-

Kin

g Sy

nbio

tic (F

ruct

oolig

osac

char

ide,

Sac

char

omyc

es

cere

visi

ae sp

p, E

. fae

cium

) vs p

lace

bo fo

r 3 w

eeks

Sign

ifica

nt d

ecre

ase

of u

rinar

y ox

alat

e on

con

trolle

d di

et

0.45

± 0.

12 to

0.2

9 ± 0.

09 m

mol

/l/da

y, p

< 0.

0001

, no

furth

er d

ecre

ase

with

use

of p

robi

otic

s, a

dver

se e

vent

: on

e pa

tient

dia

rrhe

a on

(Oxa

drop

)

Cam

pier

i [88

]6

idio

path

ic C

aOx

RSF

s with

hyp

erox

alur

ia

(> 40

 mg/

24 h

)Fr

eeze

-drie

d la

ctic

aci

d ba

cter

ia (L

. aci

doph

ilus,

L. p

lan-

taru

m, L

. bre

vis,

S. th

erm

ophi

lus,

B. in

fant

is),

4 g/

day

for 4

wee

ks b

efor

e m

eals

+ lo

w o

xala

te d

iet

40%

dec

reas

e ur

inar

y ox

alat

e55

.5 ±

19.6

vs 3

3.5 ±

15.9

 mg/

24 h

28.3

± 14

.6 m

g/24

 h o

ne-m

onth

afte

r end

of t

he st

udy

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the finding of Ferraro et al. [10] that in a study of three large ongoing cohort studies including more than 190,000 participants observed a 11% lower risk for stone formation in tea-consumers. A non-controlled study of the efficacy of Phyllanthus niruri plus magnesium and B6 vitamin showed disappearance or size reduction in more than 60% of sub-jects with stones after a 3-month course of treatment [97]. More evidence can be derived from the analysis of recently published randomized controlled trials. Some randomized controlled studies compared the effectiveness of phyto-therapy with that of potassium citrate in reducing the num-ber and size of kidney stones (Table 5) [98–102]. Herbal products were able to increase stone passage/dissolution and to decrease the mean size of stones. However, a recent meta-analysis suggested that citrate can be more effective in decreasing both the size of urinary tract stones and the urinary excretion rate of urate, compared to some herbal remedies [103].

Other studies compared the effect of herbal products with placebo (Table 6) [104–111]. We included in Table 5 an inorganic powder (Lapis judaicus or hajrul yahood), derived by fossil spines of echinoids, that is used in tra-ditional medicine alone or in combination with herbal ingredients. In general, herbal products were superior in promoting stone elimination or reduction of stone size

in most studies. The pooled analysis was not possible because designs of the studies were not comparable. How-ever, a pooled analysis of two randomized controlled trials demonstrated the superiority of an Ayurvedic formulation (Cystone) over placebo in obtaining the clearance of the stones or reducing their size after a 3-month treatment. This finding contrasts with the results of a randomized controlled trial that did not show significant differences on urine composition after Cystone treatment [112, 113]. Furthermore, in the open label extension of the study, the administration of the herbal formulation did not reduce TC-assessed stone burden. On the other hand, the lack of favorable effects on urinary saturation does not rule out that Cystone may have a favorable effect thanks to the activity of macromolecules that can promote stone dissolu-tion and to favorable anti-inflammatory, antimicrobial and antispasmodic effects.

Other studies have assessed the effect of herbal prod-ucts on the passage of stone fragments after lithotripsy (Table 7). Herbal products and compounds were used to increase stone free rate after lithotripsy and to reduce expulsion time of stone fragments. Micali et al. [114] dem-onstrated that clearance of stone fragments in the lower pole can be increased by administration of Phyllanthus niruri. Other Authors, using compounds from traditional

Table 5 Randomized controlled studies evaluating the effect of herbal products in comparison to citrate

Author Treatment Control Endpoint Results

Premgamone et al. [98] Orthosiphon grandiflorus (24 pts)

NaK-Cit 5–10 g (24 pts) No. and size at 18 months ROSRPY (%) = 52 × 100 × (size at week 0-size at week N)/N × size at week 0)

Treated vs controls 28.6 vs 33.8% (NS different)

Singh et al. [99] Dolichos biflorus (kulattha) (24 pts)

K-Cit (23 pts) Stone size at 6 months Treated 5.42 ± 1.55 vs 4.26 ± 1.2 mm (p < 0.05) Controls

6.46 ± 3.08 vs 4.64 ± 1.40 mm.(NS)

Singh et al. [100] Crataeva nurvala (lupeol) Calcury TM) 30 pts

K-Cit 30 pts No. and size at 3 months Treated 38/60 (63%) to 18/60 (30%) renal units with stones 5.52 vs 1.97 mm (p < 0.01)

Controls 37/60 (62%) to 21/60 (35%) renal units with stones 6.22 vs 2.29 mm (p < 0.01)

Singh et al. [101] Celosia argentea 21 pts K-Cit 23 pts Stone size at 6 months Treated 6.47 vs 3.9 mm (p < 0.05)

Controls 6.46 vs 4.04 mm (p > 0.05)

Between groups p > 0.05Brardi et al. [102] Agropyrum repens + K-Cit

25 ptsK-Cit 25 pts No. and size at 5 months Treatment vs K-Cit

Difference no. (− 1.0 ± 0.2 vs. 0.0 ± 0.2 stones)

Difference size (− 3.6 ± 0.9 mm vs. 0.0 ± 0.8 mm)

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Table 6 Randomized controlled studies evaluating the effect of herbal products in comparison to placebo

Herbmed® = varuna (Crataeva nurvala) and banana stem (Musa paradisiaca) (lupeol); Unex® = Boerhavia diffusa and Tribulus terrestris; Canephron® = Herba centauri 18  mg, Radix levistici 18  mg, and Folia rosmarini 18  mg; Gokshuradi Yog. (polyherbal ayurvedic formula-tion) = churna + honey + curd); Cystone®: Shilapuspha (Didymocarpus pedicellata) 130 mg, Pasanabheda (Saxifaga lgulata Syn. Bergenia lig-ulata/ciliata) 98 mg, Manjishtha (Rubia cordifolia) 32 mg, Nagarmusta (Cyperus scariosus) 32 mg, Apamarga (Achyranthes aspera) 32 mg, Gohija (Onosma bracteatum) 32 mg, Sahadevi (Vernonia cinerea) 32 mg, Shilajeet (Purified) 26 mg, and Hajrul yahood bhasma 32 mg

Author Treatment Control Endpoint Results

Patankar et al. [104] Herbmed® (lupeol) 47 pts Placebo 14 pts Size at 3 months US + KUB

Treated vs placeboExpulsion + decrease (%)Group A 5–10 mm69.5% vs 37.5%Group B > 10 mm58.3% vs 16.6%

Mohanty et al. [105] Cystone® 26 pts Placebo 26 pts No. and size at 6 monthsStone 5–10 mmUS + KUB

Treated vs placeboExpulsion 50% vs 8%Size10.56 ± 3.28 to

4.51 ± 6.30 mmp < 0.000110.22 ± 4.1 to a

11.28 ± 6.1 mmShekar Kumaran and Patki

[106]Cystone® 30 pts Placebo 30 pts No. and size at 12 week

Stones 5–12 mmTreated vs placeboExpulsion 66.7% vs 10%Size8.30 + /2.58 to

5.60 ± 1.95 mmp < 0.0018.82 ± 2.92 to

8.89 ± 3.66 mmTime for expulsion12.3 days vs 17.9 days

Upadhyay et al. [107] Unex® 32 pts Placebo 32 pts Stone size at 6 monthsUS + KUB

Treated vs placeboExpulsion/dissolution50% vs 9%Size9.88 ± 3.288 to 3.23 ± 6.541

Ceban et al. [108] Canephron® 137 pts Standard treatment 102 pts Spontaneous passage of < 7 mm ureteral stone at 1 weeks

72.7% versus 33.3%

Faridi et al. [109] Lapis judaicus (mineral) 30 pts

Placebo 30 pts No. and sizeat 10 weeks

TreatedStone size reduction

(p < 0.001)Stone dissolution in 9

patientsRathod and Amilkanthwar

[110]Musa sapientum (kadali)

30 ptsGokshuradi Yog 30 pts No. at 4 weeks Treated vs controls

Dissolved/passed/reduced98% vs 80%Difference size− 4,309 ± 2.655− 3,311 ± 2.444

Ardakani Movaghati et al. [111]

Nigella sativa 30 pts Placebo 30 pts No. at 10 weeks Treated vs placeboDisappeared + decreased96.2% vs 26.8%(p < 0.05)

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Japanese and Chinese medicine obtained favorable results on expulsion time and free stone rates [115–118].

Other stone types

Most of the information on the role of diet in the formation of kidney stones is related to calcium oxalate stones. Informa-tion about the role of diet in other stone types is very limited.

Background

Recommendations on the role of diet in the prevention and treatment of other stone types were mostly expert opinions based on pathophysiological knowledge.

Dietary changes were recommended for uric acid stone formers to reduce urinary uric acid and increase urinary pH values to increase the solubility of uric acid. Reduc-tion in the consumption of meat, chicken, and seafood was suggested to lower purine intake and excretion of uric acid. Reducing animal protein and increasing fruit and vegeta-bles was suggested to raise urinary pH.

Information about the possible role of diet in cystine stone formation was also very limited. A sodium restric-tion was suggested to reduce cystine excretion and con-sumption of fruits and vegetables to increase urinary pH to increase cystine solubility in urine. The effectiveness of restriction of proteins with high cystine content is contro-versial, although the restriction of animal proteins may be useful in increasing urinary pH values.

The possible diet for prevention of calcium phosphate and struvite stones was undefined.

Up date

A small case–control study confirmed that a high intake of animal protein and alcohol is associated with the formation of uric acid stones [119].

Limitations of the review

A limitation of this review is that vast majority of studies taken into account assessed large populations of renal stone formers without making a distinction based on the chemical

Table 7 Effect of herbal products on the passage of stone fragments after lithotripsy

Quantong recipe = traditional Chinese medicine; Choreito = Chorei (Polyporus) 3  g, Takusha (Alismatis Rhizoma) 3  g, Bukuryo (Sclerotium Poriae Cocos) 3  g, Kasseki (Talcum Crystallinum) 3  g, Akyo Asini (Corii Colla) 3  g; Ningmitai* (traditional Chinese medicine) = 450  mg Touhualiao (Herba Polygoni Capitati), 263 mg Baimaogen (Rhizoma Imperatae), 224 mg Dafengteng (Radix Cocculi Trilobi), 169 mg Sankez-hen (Berberidis radix), 169 mg Xianhecao (Herba Agrimoniae), 18 mg Furongye (Folium Hibisci Mutabilis) and 226 mg Lianqiao (Fructus Forsythiae suspensae)

Author Treatment Control Endpoint Results

Micali et al. [116] Phyllanthus niruri 78 pts No treatment 72 pts Stone free rate (SFR) after SWL at 6-month (US + KUB)

Treated vs controlsSFR93.5% vs 83.3% (p = 0.48)SFR in lower calix93.7% vs 70.8% (p = 0.01)Re-treatment rate39.7% vs 43.3% (p = 0.2)

Peng et al. [115] Quantong recipe 32 pts No treatment 32 pts SFR after URS at 1-week Treated vs controls93.8% vs 71.9% (p < 0.05)

Kobayashi et al. [116] Choreito 30 pts Tamsulosin 0.2 mg/day 38 pts Placebo 34 pts

SFR after SWLExpulsion time

Treated vs tamsulosin vs placeboSFR90% vs 84.21% vs 88.24% (NS)Expulsion time27.74 ± 25.36 days15.66 ± 6.14 days35.47 ± 53.70 daysp = 0.011

Takada et al. [117] Choreito 74 pts No treatment 75 pts Expulsion time after SWL Treated vs controls16.0 days21.5 days (p < 0.001)

Xiang et al. [118] Ningmitai + standard treatment (203 pts)

Standard treatment (66 pts) SFR at 1 month after minimally-invasive treatment

Expulsion time

Treated vs ControlsSFR91.6% vs. 68.2% (p = 0.000)Expulsion time4.5 ± 0.4 vs 7.5 ± 1.3 days, p = 0.004

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composition of the stone. For this reason, the conclusions of the review should be limited to only calcium oxalate stone formers that make up majority of kidney stones.

On the other hand, information on the impact of diet on the formation of other stone types is very limited in the literature and concerns small case series [119, 120]. The dietary treatment of other stone types is mainly based on expert opinions or the results of intervention studies that aimed not at assessing the effect of diet on the formation of the stone but rather the modification of specific urinary risk factors for different types of non-calcium stones.

Another limitation of this review is that much of the information presented examined the composition of the diet in terms of content in individual nutrients rather than dietary patterns.

Information on dietary patterns was limited to those stud-ies that assessed the association of the risk of stone forma-tion and the adherence of certain dietary patterns, such as the DASH diet [30] and the Mediterranean Diet [31].

On the other hand, controlled studies with specific die-tary regimens for the prevention of kidney stones are few, although there are numerous short-term intervention studies to assess the effect of food intake or dietary regimens on specific urinary risk factors.

The systematic review of Fink et al. [121] considered only eight studies that had all been published over 10 years ago. Some of these studies have been cited as background stud-ies in the present review [6, 9, 35], while unfortunately no new studies have been identified to update this information.

As a result, the present review was mainly based on large-scale epidemiological studies that assessed dietary intake by food frequency questionnaires (FFQs) whose results like those of other memory-based methods are controversial.

It should therefore be emphasized the need to integrate our information with studies aimed at assessing the dietary patterns of renal stone former population and especially with intervention studies to assess the impact of dietary regimes on the formation of different types of urinary stones rather than the modification of urinary risk factors for stone formation.

Author contributions AUA, JOB, KHB, JP and IS searched the litera-ture and wrote individual chapters of this manuscript. RNP, GSV and AT combined the chapters, streamlined and edited the first version of the manuscript. NB developed the concept, supervised and coordinated the project, edited and amended the final version.

Compliance with ethical standards

Conflict of interest All authors declare that they have no conflict of interest in this publication.

References

1. Curhan GC, Curhan SG (1994) Dietary factors and kidney stone formation. Compr Ther 20:485–489

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