And Plum Juice Consumption on Risk Factors Associated with Kidney Stone Formation

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European Journal of Clinical Nutrition (2002) 56, 1020–1023 ß 2002 Nature Publishing Group All rights reserved 0954–3007/02 $25.00 www.nature.com/ejcn ORIGINAL COMMUNICATION Effect of blackcurrant-, cranberry- and plum juice consumption on risk factors associated with kidney stone formation

T Keßler1*, B Jansen1 and A Hesse1

1Division of Experimental Urology, Department of Urology, University of Bonn, Bonn, Germany

Objective: To evaluate the influence of plum-, cranberry- and blackcurrant juice on urinary stone risk factors. Design: Investigations were carried out in 12 healthy male subjects aged 18 – 38 y. All subjects received a standardized diet formulated according to the dietary recommendations of the German Society of Nutrition. The subjects provided 24 h urine collections in a control, three loading phases. In each loading phase a neutral mineral water was substituted for 330 ml of the particular juice. Results: Cranberry juice decreased the urinary pH, whereas the excretion of oxalic acid and the relative supersaturation for uric acid were increased. Blackcurrant juice increased the urinary pH and the excretion of citric acid. The excretion of oxalic acid was increased too. All changes were statistically significant. The plum juice had no significant effect on the urinary composition. Conclusion: It is concluded that blackcurrant juice could support the treatment and metaphylaxis of uric acid stone disease because of its alkalizing effect. Since cranberry juice acidifies urine it could be useful in the treatment of brushite and struvite stones as well as urinary tract infection. Sponsorship: Funded by our own Division respectively the University. European Journal of Clinical Nutrition (2002) 56, 1020 – 1023. doi:10.1038/sj.ejcn.1601442

Keywords: blackcurrant-, cranberry-, plum juice; urolithiasis; kidney stone; ﬂuid intake

Introduction position. The risk for recurrent stone formation is greatly Although urolithiasis is a multifactorial disease, nutrition reduced when the urinary volume exceeds 2.0 l=day. To and especially fluid intake is one of the most important reduce urine concentration consistently it is recommended factors involved. A high fluid intake is therefore the first that the fluid intake should be distributed more or less general advice for prevention of stone recurrences in stone- evenly over 24 h (Hesse & Siener, 1997). Diluting urine has forming patients, irrespective of the stone composition (Pak two major consequences. First, by increasing urine output, et al, 1980; Borghi et al, 1996). An epidemiological study by the concentration of constituent ions and the saturation of Curhan et al (1996) has confirmed that increased fluid intake stone-forming salts are lowered. Second, fluid composition is associated with a reduced risk for kidney stone formation. has a direct influence on urine composition and crystal Owing the dilutional effect, a large fluid intake in the formation (Hesse et al, 1993). Depending on the stone treatment of stone diseases is irrespective of the stone com- composition, several fluids have been found to be suitable, eg mineral water (Hesse et al, 1993; Borghi et al, 1996; Rodgers, 1997), orange juice (Hesse et al, 1993; Wabner & Pak, 1993), apple juice, fruit and herbal teas (Vahlensieck, *Correspondence: T Keßler, Division of Experimental Urology, 1986). Care should be taken to avoid fluids containing Department of Urology, University of Bonn, Sigmund-Freud-Str. 25, lithogenic agents which may increase the risk of stone 53105 Bonn, Germany. formation, such as coffee, black tea, alcohol (Vahlensieck, E-mail: [email protected] 1986) and cola (Weiss et al, 1992; Rodgers, 1999). Guarantor: T Keßler. Contributors: All authors contributed to the design and the Little is known about the influence of plum-, cranberry-, performance of the study and to the writing of the paper. and blackcurrant juice on risk factors for kidney stone Different fruit juices and risk factors associated with kidney stones TKeßler et al 1021 formation. A protective effect in the therapy of urinary tract Table 1 Standardized daily diet infection was attributed to cranberry juice (Bodel et al, 1959; Breakfast 100 g bread rolls Avron et al, 1994). Bodel et al (1959) and Kahn et al (1967) 10 g margarine (semi-fat) observed an acidifying of the urine after ingestion of large 25 g jam amounts of cranberry juice and Howell et al (1988) identified 30 g sausage proanthocyanidins as the compounds in cranberries that are Snack 25 g wholemeal biscuit bar 150 g banana responsible for the inhibition of the adherence of Escherichia Lunch 110 g chicken leg (roasted) with 100 g gravy coli to uroepithelial cells. Klingeberg (1972) found a slight 120 g beans, french decrease in urinary pH immediately after supply of 100 ml of 100 g salad of carrots blackcurrant juice. Blatherwick and Long (1923) showed an Snack 150 g fruit yoghurt (3.5% fat content) 150 g apple acidifying effect in human urine after consumption of Dinner 50 g rye and wheat bread prunes. However these studies had some shortcomings. The 10 g margarine (semi-fat) studies of Kahn et al (1967) and Bodel et al (1959) were 30 g salami limited to only four, respectively five, subjects and they 17 g fresh cheese (60% fat content in dry matter) 50 g tomato ingested an unphysiologically high dosage of 1200 – 150 g apple 4000 ml per day. Blatherwick and Long (1923) studied only Snack 50 g rye and wheat bread two persons. Finally Klingeberg (1972) estimated the pH 5 g margarine (semi-fat) 17 g fresh cheese (60% fat content in dry matter) values using indicator strips with a systematic error greater 50 g tomato then the observed change in the mean pH value. Beverages 400 ml coffee The present study was undertaken to overcome these 100 ml milk (3.5% fat content) shortcomings by evaluating the influence of plum-, cran- 1000 ml fruit tea 750 ml mineral water (on loading days substituted for berry- and blackcurrant juice on the urinary composition 330 ml juice diluted with the mineral water up to 750 ml) and therefore on multiple risk factors of kidney stone for- Composition Energy 9555 kJ (2284 kcal) mation. The study was carried out under standardized con- Protein 83 g dition in a relatively larger group of subjects and with a Fat 89 g Carbohydrate 284 g physiological ingestion of 330 ml of each juice daily. Calcium 780 mg Magnesium 270 mg Oxalic acid 54 mg Methods Ascorbic acid 85 mg All investigations were carried out using 12 healthy male subjects with no previous history of urolithiasis or other renal disorders. The mean age was 29.3 (range 18 – 38) y, Table 2 Composition of the fruit juices their mean body mass index was 24.1 (range 20.1 – 26.3). Plum Cranberry Blackcurrant In a pre-phase each subject was required to provide two 24 h juice juice juice urine collections under normal dietary conditions (urinalysis = see below). Subjects with values out of the reference range pH value (mmol l) 3.75 2.61 2.82 Na (mmol=l) 4.0 2.0 5.0 were excluded from the study. K (mmol=l) 65.6 17.0 55.3 The test series were divided into four consecutive phases Ca (mmol=l) 13.0 2.1 7.2 of 5 days each. The phases were equal but on the loading Mg (mmol=l) 6.26 1.7 5.3 Oxalic acid (mmol=l) 297 167 204 phases a neutral mineral water with no influence on the b b b Citric acid (g=100 g) 0.04 1.10 2.88 urinary composition (unpublished own results) was substi- Vitamin C (mg=100 g) 4.0b 12.0b 177.0a tuted for plum-, cranberry- and blackcurrant juice. Urine Energy content (kJ=l) 2400 1470 1550 a a a samples (24 h) were collected each day. All subjects received (560 kcal=l) (350 kcal=l) (370 kcal=l) a standardized diet (Table 1) formulated according to the (Own analysis, except amanufacture’s information; bunprocessed fruit, data dietary recommendations of the German Society of Nutri- from Souci et al.19) tion (Deutsche Gesellschaft fu¨r Erna¨hrung, 1996). The diet consisted of normal food items to ensure consistency of the investigation results. The subjects were required to eat all of blackcurrant juice (for composition see Table 2). The study the food offered, and the same type and amount of food was protocol is summarized in Table 3. consumed every day. Sport and other extreme exercise were The urine was collected in polyethylene containers and not permitted during the experimental phase. A 4 day mixed with 5 ml=l urine of a 5% solution of thymol in adaptation period on the standardized nutrition preceded isopropanol to preserve the urine. During the collection each investigation day. On days 1 – 4 creatinine was mea- period, the containers and their contents were maintained sured to examine the compliance of participated subjects. at 5C. Each morning after completion of urine collec- Day 5 of each phase was chosen as control (neutral mineral tion the urine samples were brought to our laboratory by water), respectively loading day with plum-, cranberry- and the study subjects. Immediately volume, specific gravity

European Journal of Clinical Nutrition Different fruit juices and risk factors associated with kidney stones TKeßler et al 1022 Table 3 Study protocol Results Prephase Several urinary parameters were altered following the con- 2Â24 h urine; blood sample; anamnesis sumption of each juice. The main results are reported in Control Table 4. The urinary volume in the control and the three Day 1 Day 2 Day 3 Day 4 Day 5 loading phases were nearly equal, which represents the Standardized diet; 24 h urine; neutral mineral water standardization of the investigated subjects. Adaptation Control In the dosage of 330 ml blackcurrant juice alkalized Load (three times) whereas cranberry juice acidified the 24 h urine statistically Day 1 Day 2 Day 3 Day 4 Day 5 significantly. The citric acid excretion was increased statisti- Standardized diet; 24 h urine; plum-, cranberry-, blackcurrant juice Adaptation Load cally significantly after consumption of blackcurrant juice, but it was just slightly and not significantly decreased by cranberry juice. The oxalic acid excretion were increased statistically significantly after the exposure to both juices. (urinometer) and pH (potentiometer) were recorded. Urine The excretions of calcium, magnesium and uric acid were samples were tested for the presence of blood and infection. not significantly changed. The relative supersaturation for Nitrite-positive and haematuria samples were discarded. The calcium oxalate, uric acid, brushite and struvite were not methods used in the analysis of urine samples, with the significantly affected by blackcurrant juice, however cran- relative CV for each method were as follows: Na, K and Ca berry juice increased the relative supersaturation for uric acid by flame photometry, 1.3; Mg by xylidyl-blue reaction, 0.3; significantly, and decreased, but statistically not significantly þ NH4 by ion-selective electrode, 1.5; chloride by coulomb the relative supersaturation for struvite and brushite. metric titration, 2.0; inorganic phosphate by phosphate Plum juice had no observed effect of any of the urinary molybdate reaction, < 5; inorganic sulphate by nephelome- biochemical or physicochemical parameters in a statistically try, < 5; creatinine by Jaffe´ reaction, 2.0; uric acid by uricase significant way. method, < 5; citric acid by citrate lyase method, 1.6; oxalic acid by HPLC enzyme reactor method (Ho¨now et al, 1997), 0.5 (Hesse & Bach, 1982; Hesse et al, 1997). Discussion The relative supersaturations (RS) values for calcium oxa- The significant increase of the urinary pH value and the late, uric acid, brushite and struvite were calculated using increased citric acid excretion after ingestion of blackcurrant EQUIL 2 (Finlayson, 1977; Werness et al, 1985). The Wil- juice did not decrease the relative supersaturation for cal- coxon matched-pairs signed-rank test, as a non-parametric cium oxalate and uric acid, as might have been expected test of significance, was used testing two matched samples regarding the favourable changes in urinary composition for (control and loading day). The significance level was at these stone compounds. On the other hand the oxalic acid 5%, and the P-values (two tailed) were *0.05 P > 0.01; excretion increased significantly as well which in our **0.01 P > 0.001; ***P 0.001. opinion is responsible for the lack of change in relative

Table 4 Mean (s.e.m.) urinary biochemical and physicochemical parameters in 24 h urine before and after consumption of plum-, cranberry- and blackcurrant juice

Control Cranberry juice Blackcurrant juice Plum juice

Volume (l) 2.21 (0.17) 2.17 (0.18) 2.26 (0.18) 2.12 (0.14) pH 6.35 (0.08) 6.18 (0.09)* 6.56 (0.07)** 6.27 (0.10) Citric acid (mmol=day) 3.109 (0.37) 2.780 (0.30) 3.889 (0.41)** 3.175 (0.35) Oxalic acid (mmol=day) 0.344 (0.02) 0.392 (0.02)* 0.420 (0.03)* 0.400 (0.03) Ca (mmol=day) 4.63 (0.29) 4.47 (0.39) 4.21 (0.22) 4.72 (0.30) Mg (mmol=day) 6.35 (0.45) 6.31 (0.63) 5.81 (0.47) 6.40 (0.47) Uric acid (mmol=day) 3.44 (0.17) 3.45 (0.21) 3.64 (0.12) 3.51 (0.27) RS CaOx 3.53 (0.44) 4.15 (0.51) 3.82 (0.62) 4.39 (0.67) RS uric acid 0.67 (0.13) 0.99 (0.21)* 0.47 (0.11) 0.88 (0.24) RS brushite 0.90 (0.06) 0.73 (0.08) 0.89 (0.09) 0.86 (0.09) RS struvite 0.105 (0.03) 0.075 (0.02) 0.114 (0.02) 0.157 (0.07) Na (mmol=day) 178 (9.47) 167 (9.56) 176 (10.18) 168 (12.32) K (mmol=day) 76 (4.55) 67 (3.5) 83 (4.62) 81 (3.78)

NH4 (mmol=day) 29.7 (1.76) 32.4 (2.81) 23.4 (2.33) 38.8 (5.01) Cl (mmol=day) 172 (8.44) 163 (9.03) 165 (9.39) 160 (10.91)

PO4 (mmol=day) 31.6 (2.11) 28.9 (1.82) 28.6 (2.28) 30.2 (2.17) SO4 (mmol=day) 20.3 (0.97) 18.1 (0.97) 17.71 (1.08) 17.4 (1.01) Creatinine (mmol=day) 15.80 (0.62) 15.13 (0.70) 13.96 (0.66) 15.13 (0.76)

(Signiﬁcance level: *0.05 P > 0.01; **0.01 P > 0.001; ***P 0.001.)

European Journal of Clinical Nutrition Different fruit juices and risk factors associated with kidney stones TKeßler et al 1023 supersaturation. The increased oxalic acid excretion was Bodel PT, Cortran R & Kass EH (1959): Cranberry juice and the antibacterial action of hippuric acid. J. Lab. Clin. Med. 54, 881 – caused be the oxalic acid content in blackcurrant juice 888. (204 mmol=l) and especially the high content of ascorbic Borghi L, Meschi T, Amato F, Briganti A & Giannini A (1996): Urinary acid (177 mg=100 g), which is intermediately metabolized volume, water and recurrences in idiopathic calcium nephrolithia- to oxalic acid and excreted in the urine. These findings sis: a 5-year randomized prospective study. J. Urol. 155,839– 843. 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Hesse A & Bach D (1982): Harnsteine: Pathobiochemie und klinisch- chemische Diagnostik. (Urinary stones: Pathobiochemical and Clinical The acidifying effect of cranberry juice was expected, but Chemical Diagnostics.) Stuttgart: Thieme. it is not known which compound in the cranberries is Hesse A & Siener R (1997): Current aspects of epidemiology and responsible for the decrease in urinary pH value. The sig- nutrtion in urinary stone disease. World J. Urol. 15, 165 – 171. nificant increase in risk of uric acid stone formation is a Hesse A, Siener R, Heynck H & Jahnen A (1993): The influence of dietary factors on the risk of urinary stone formation. Scanning consequence of the decreased pH value, however the relative Microsc. 7, 1119 – 1128. supersaturation for struvite and brushite were slightly Hesse A, Tiselius HG & Jahnen A (1997): Urinary Stones. Diagnosis, decreased. Probably the effect of cranberry juice on urinary Treatment, and Prevention of Recurrence. Basel: Karger. composition would be bigger after ingesting a higher Ho¨now H, Bongartz D & Hesse A (1997): An improved HPLC- enzyme-reactor method for the determination of oxalic acid in amount of juice, but because of the energy content of fruit complex matrices. Clin. Chim. Acta 261, 131 – 139. juices the intake should not exceed 500 ml per day, and we Howell AB, Vorsa N, Marderosian AD & Foo LY (1998): Inhibition of also wanted to maintain physiological conditions. The the adherence of P-fimbriated Escherichia coli to uroepithelial-cell explanation of the increased oxalic acid excretion is the surfaces by proanthocyanidin extracts from cranberries. New Engl. J. Med. 339, 1085 – 1086. same as that given for blackcurrant juice. Hughes C, Dutton S & Rruswell AS (1981): High intakes of ascorbic In contrast to Blatherwick and Long (1923) the ingestion acid and urinary oxalate. J. Human Nutr. 35, 274 – 280. of plum juice did not change the urinary pH-value. 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